SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) · PMA P060008/8046 FDA Summary of Safety and...
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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Drug-Eluting Coronary Stent System (NIQ) Device Trade Name: TAXUS® Libert6d Paclitaxel-Eluting Coronary Stent System (Monorail and Over-the-Wire) Applicant's Name and Address: Boston Scientific Corporation One Boston Scientific Place Natick, MA 01760-1537 Date of Panel Recommendation: None Premarket Approval Application (PMA) Number: P060008/SO46 Date of FDA Notice of Approval: February 22, 2012 Expedited: Not applicable The original PMA (P060008) was approved on October 10, 2008 and is indicated for improving luminal diameter for the treatment of de novo lesions < 28 mm in length in native coronary arteries 2.50 to 4.00 mm in diameter. The SSED to support the indication is available on the CDRH website and is incorporated by reference here: http://www.accessdata.fda.-ov/cdrh docs/pdf6/P060008bepdf PMA supplement S008 was approved on May 21, 2009 to revise the indications of the product, specifically, for improving luminal diameter for the treatment of de novo lesions in native coronary arteries 2.25 to <4.00 mm in diameter in lesions <28mm in length. The SSED to support the indication is available on the CDRH website and is incorporated by reference here: http://www.accessdata.fda.ov/cdrh docs/pdf6/P060008S008b.pdf PMA supplement S011 was approved on July 13, 2009 to revise the indications of the product, specifically, for improving luminal diameter for the treatment of de novo lesions in native coronary arteries 2 2.75 to <4.00 mm in diameter in lesions <34 mm in length. The SSED to support the indication is available on the CDRH website and is incorporated by reference here: http://www.accessdata.fda.,zov/cdrh docs/pdf6/P060008S011b.pdf PMA P060008/SO46 FDA Summary of Safety and Effectiveness Data page 1
Transcript of SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) · PMA P060008/8046 FDA Summary of Safety and...
SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)
I GENERAL INFORMATION
Device Generic Name Drug-Eluting Coronary Stent System (NIQ)
Device Trade Name TAXUSreg Libert6d Paclitaxel-Eluting Coronary Stent System (Monorail and Over-the-Wire)
Applicants Name and Address Boston Scientific Corporation One Boston Scientific Place Natick MA 01760-1537
Date of Panel Recommendation None
Premarket Approval Application (PMA) Number P060008SO46
Date of FDA Notice of Approval February 22 2012
Expedited Not applicable
The original PMA (P060008) was approved on October 10 2008 and is indicated for improving luminal diameter for the treatment of de novo lesions lt 28 mm in length in native coronary arteries 250 to 400 mm in diameter The SSED to support the indication is available on the CDRH website and is incorporated by reference here httpwwwaccessdatafda-ovcdrh docspdf6P060008bepdf
PMA supplement S008 was approved on May 21 2009 to revise the indications of the product specifically for improving luminal diameter for the treatment of de novo lesions in native coronary arteries 225 to lt400 mm in diameter in lesions lt28mm in length The SSED to support the indication is available on the CDRH website and is incorporated by reference here httpwwwaccessdatafdaovcdrh docspdf6P060008S008bpdf
PMA supplement S011 was approved on July 13 2009 to revise the indications of the product specifically for improving luminal diameter for the treatment of de novo lesions in native coronary arteries 2 275 to lt400 mm in diameter in lesions lt34 mm in length The SSED to support the indication is available on the CDRH website and is incorporated by reference here httpwwwaccessdatafdazovcdrh docspdf6P060008S011bpdf
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This supplement approval revises the indications statement to include patients undergoing primary angioplasty to treat acute ST-segment elevation myocardial infarction true posterior myocardial infarction or presumed new left bundle branch block with symptoms of acute myocardial infarction lasting gt 20 minutes and lt 12 hours in duration
II INDICATIONS FOR USE
The TAXUSreg Libert6 Paclitaxel-Eluting Coronary Stent System (Monorail and Over-the-Wire Systems) is indicated for improving luminal diameter
for the treatment of de novo lesions in native coronary arteries 275 mm to 400 mm in diameter in lesions 34 mm in length
for the treatment of de novo lesions in native coronary arteries 225 mm to 250 mm in diameter in lesions lt 28 mm in length or
in patients undergoing primary angioplasty to treat acute ST-segment elevation myocardial infarction true posterior myocardial infarction or presumed new left bundle branch block with symptoms of acute myocardial infarction lasting gt 20 minutes and lt 12 hours in duration
III CONTRAINDICATIONS
Use of the TAXUS Libert6 Paclitaxel-Eluting Coronary Stent System is contraindicated in
patients with Known hypersensitivity to 3t6L stainless steel Known hypersensitivity to paclitaxel or structurally-related compounds
Known hypersensitivity to the polymer or its individual components
Coronary Artery Stenting is contraindicated for use in Patients who can not receive recommended anti-platelet andor anticoagulant therapy
Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the stent or delivery device
IV WARNING AND PRECAUTIONS
The warnings and precautions can be found in the TAXUS Libert6 Paclitaxel-Eluting Coronary Stent System Directions for Use (DFU)
V DEVICE DESCRIPTION
The TAXUS Libert6 Paclitaxel-Eluting Coronary Stent System is a device drug combination
product comprised of two regulated components a device (Libert6 Coronary Stent System) and a
drug product (a formulation of paclitaxel contained in a polymer coating) Please refer to the
device description provided in the original SSED and subsequent SSEDs for additional details
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VI ALTERNATIVE PRACTICES OR PROCEDURES
There are several other treatment alternatives for coronary artery disease exercise diet drug therapy percutaneous coronary interventions (such as angioplasty and placement of bare metal stents coated stents and other drug eluting stents) and coronary artery bypass surgery (CABG) A patient should fully discuss these alternatives with hisher physician to select the method that best meets expectations and lifestyle
VII MARKETING HISTORY
The TAXUS Liberte Paclitaxel-Eluting Coronary Stent System is commercially available in the United States and in the following countries The device has not been withdrawn from marketing for any reason related to its safety or effectiveness
Albania Dominican Rep Kuwait Qatar Algeria Dutch Antilles Latvia Romania AntiguaBarbuda Ecuador Lebanon Russia Argentina Egypt Libya Saudi Arabia Armenia El Salvador Liechtenstein Scotland Aruba Estonia Lithuania SerbiaMontenegro Australia Finland Luxembourg - Singapore Austria France Macau Slovakia Bahamas Georgia Macedonia Slovenia Bahrain Germany Malaysia South Africa Bangladesh Great Britain Malta Spain Barbados Greece Martinique Sri Lanka Belarus Guatemala Mauritania Sudan Belgium Guyana Mauritius Suriname Belize Haiti Mexico Sweden Bermuda Honduras Moldavia Switzerland Bolivia Hong Kong Morocco Syria Bosnia Hungary Myanmar Taiwan Brazil Iceland Nepal Thailand Brunei India Netherlands TrinidadTobago Bulgaria Indonesia New Zealand Tunisia Canada Iran Nicaragua Turkey Chile Iraq Norway United Arab Emirates China Ireland Oman Ukraine
Colombia Israel Pakistan Uruguay Costa Rica Italy Panama Venezuela
Croatia Jamaica Paraguay Vietnam
Cyprus Japan x Peru West Bank Gaza Strip Czech Republic Jordan Philippines a Yemen
Denmark Kenya Poland
Djibouti Korea a Portugal
VIII POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH
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Below is a list of the potential adverse effects (eg complications) in alphabetical order which may be associated with the use of a coronary stent in coronary arteries
Abrupt stent closure Acute myocardial infarction o Allergic reaction to anticoagulants or antithrombotic therapy or contrast medium or stent
materials Angina Arrhythmias including ventricular fibrillation (VF) and ventricular tachycardia (VT) Arteriovenous fistula Cardiac tamponade Cardiogenic shock pulmonary edema Death Dissection Emboli distal (air tissue or thrombotic material or material from device(s) used in the
procedure) Heart failure Hematoma Hemorrhage requiring transfusion Hypotensionhypertension Infection local andor systemic o Ischemia myocardial Pain at the access site o Perforation or rupture of coronary artery o Pericardial effusion Pseudoaneurysm feioral Renal failure Respiratory failure Restenosis of stented segment Shock Stent embolization Stent migration Stent thrombosisocclusion Strokecerebrovascular accidentTIA Total occlusion of coronary artery Vessel spasm Vessel trauma requiring surgical repair or reintervention
Potential adverse events not captured above that may be unique to the paclitaxel drug coating
Allergicimmunologic reaction to drug (paclitaxel or structurally-related compounds) or the polymer stent coating (or its individual components)
Alopecia Anemia Blood product transfusion Gastrointestinal symptoms
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Hematologic dyscrasia (including leukopenia neutropenia thrombocytopenia) Hepatic enzyme changes Histologic changes in vessel wall including inflammation cellular damage or necrosis Myalgia arthralgia Peripheral neuropathy
For the specific adverse events that occurred in the HORIZONS AMI clinical study please see Section X below
IX SUMMARY OF PRECLINICAL STUDIES
A series of non-clinical laboratory studies were performed to support the original approval and subsequent indication expansions - those related to the stent and the stent delivery system [ie the stent on either the Monorail (MR) or Over-The-Wire (OTW) stent delivery system (SDS)]the polymer substance [ie poly(styrene-b-isobutylene-b-styrene) (SIBS)] the drug substance (ie paclitaxel) and the finished combination product (ie TAXUS Libert6 Paclitaxel-Eluting Coronary Stent) No new nonclinical studies were needed to support the approval of this supplement
X SUMMARY OF CLINICAL STUDIES
A series of clinical studies (TAXUS ATLAS Workhorse ATLAS Small Vessel and ATLAS Long Lesion) were performed to support the original approval and subsequent indication expansions Please refer to previous SSEDs for details The HORIZONS AMI trial was performed to establish a reasonable assurance of safety and effectiveness for TAXUS Express 2
Paclitaxel-Eluting Coronary Stent System for the proposed expanded indication under IDE G040188 Data from this clinical study were the basis for the PMA approval decision The TAXUS Liberte stent uses the same drug-polymer coating formulation as the TAXUS Express 2
stent In addition nonclinical studies of design attributes and the ATLAS clinical studies in stable patients with coronary artery disease have established that the performance of the TAXUS Libert6 is similar Given these supportive data outcomes in patients with AMI would also be expected to be similar between these two stents and therefore the safety and effectiveness data from the HORIZONS AMI trial were considered applicable for the TAXUS Libert6 Paclitaxel-Eluting Coronary Stent System as well A summary of the clinical study is presented below
A HORIZONS AMI Clinical Trial
Objectives The trial had two primary objectives and was designed and powered to address both the primary and sub-study objectives
Primary objective for the pharmacology randomization To evaluate the use of bivalirudin in patients with ST segment elevation acute myocardial infarction (STEMI) undergoing a primary angioplasty strategy compared to unfractionated heparin plus routine use of GP lIbIlla inhibitors
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Primary objective for the stent randomization To establish the safety and effectiveness of the paclitaxel-eluting TAXUS Express stent in STEMI patients by showing that compared to an otherwise identical Express BMS the TAXUS Express results in (1) reduced rates of ischemia-driven target lesion revascularization at 1 year (2) a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year and (3) a lower rate of analysis segment binary angiographic restenosis at 13 months
Design
The HORIZONS AMI trial was a prospective dual-arm single-blind randomized multi-center trial that enrolled STEMI patients defined by clinical symptoms consistent with acute MI lasting greater than 20 minutes but less than 12 hours and specific ECG criteria consisting of ST-segment elevation of gt 1mm in gt 2 contiguous leads presumed new LBBB or true posterior MI with ST depression of gt Imm in gt 2 contiguous anterior leads A total of 3602 patients were randomized (primary randomization) in a 11 fashion in the emergency room to anticoagulation with unfractionated heparin plus routine GP Ilblila inhibition or bivalirudin and bail-out GP IlbIla inhibition
Emergent coronary angiography with left ventriculography was performed after the primary randomization followed by triage to either percutaneous coronary intervention (PCI) coronary artery bypass graft (CABG) surgery or medical management at physician discretion
After coronary angiography a total of 3006 patients were triaged to PCI and randomized (secondary randomization) in a 31 fashion to either a TAXUS Express stent or an Express stent In order to be eligible for the second randomization patients had to have at least one acute infarct-related artery with an expectation that study stents could be delivered to all culprit lesions Exclusion criteria included true bifurcation lesions definitely requiring stenting of the side branch vessel lesions requiring greater than 100 mum of stent length unprotected left main culprit lesions and stent thrombosis lesions The secondary randomization was stratified by the following four factors the result from the primary randomization (to ensure equal distribution of the two arms from the primary randomization in the secondary randomization) the presence or absence of medically treated diabetes whether any of the lesions were greater than 26 mm in length such that overlapping stents would be used and whether the clinical study site was within or outside of the US
Table 1 HORIZONS AMI CLINICAL TRIAL OVERVIEW
HORIZONS AMI (Indication Expansion)
Study Type Prospective multicenter randomized single-blind
Total 3006 Number of Patients (ITT) TAXUS 2257
Control 749
Dose Release Formulation Slow Release (SR) (1 g mm2)
gt 25 mm to Lesion Criteria Vessel Diameter (by visual estimate) lt 40 mm
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HORIZONS AMI (Indication Expansion)
Lesion Criteria Lesion Length (by visual estimate) lt 100 mm
Product Used TAXUS Express Paclitaxel-Eluting Coronary Stent System
Antiplatelet Therapy Aspirin indefinitely and clopidogrel or ticlopidine for 6 months (I year or longer recommended)
30 days clinical 6 months clinical
Follow-Up 12 month clinical 13 month angiographicIVUS
2 3 years clinical
Abbreviations ITT=intent-to-treat IVUS=intravascular ultrasound
1 Clinical Inclusion and Exclusion Criteria
Primary Randomization - Inclusion Criteria
1 The patient must be at least 18 years of age (there is no upper age limit) 2 Must have clinical symptoms consistent with AMI (eg angina or anginal equivalent) lasting
gt20 minutes but lt12 hours in duration If the symptom duration at the time of evaluation is lt1 hour to rule out unstable angina the symptoms must be unresponsive to nitroglycerin (ie ongoing) prior to signing the informed consent Patients with symptom onset within 12 hours in whom the symptoms lasted gt1 hour but subsequently resolved may still be enrolled if the ECG at the time of the evaluation shows definite ongoing ST segment elevation
3 ECG criteria ST-segment elevation of gt 1 mm in gt 2 contiguous leads or (presumably new) left bundle branch block or true posterior MI with ST depression of gt 1 mm in gt 2 contiguous anterior leads
4 The patient or guardian agrees to the study protocol and the schedule of clinical and angiographic follow-up and provides informed written consent as approved by the appropriate Institutional Review BoardEthical Committee of the respective clinical site
Primary Randomization - Exclusion Criteria
1 The patient has a known hypersensitivity or contraindication to any of the following medications
Heparin pork or pork products Both abciximab and eptifibatide Aspirin Both Clopidogrel and Ticlopidine Bivalirudin Paclitaxel or Taxol
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o The polymer components of the TAXUS Express DES stent (SIBS) Stainless steel andor o Contrast media (patients with documented sensitivity to contrast which can be
effectively pre-medicated with steroids and diphenhydramine (eg rash) may be
enrolled Patients with true anaphylaxis to prior contrast media however should not be enrolled)
2 Prior administration of thrombolytic therapy bivalirudin GP IlbIlla inhibitors low molecular weight heparin or fondaparinux for this admission Patients receiving prior unfractionated heparin may be enrolled and treated per randomization
3 Current use of coumadin 4 Systemic (intravenous) Paclitaxel or Taxol use within 12 months 5 Female of childbearing potential unless a recent pregnancy test is negative who possibly
plans to become pregnant any time after enrollment into this study 6 History of bleeding diathesis or known coagulopathy (including heparin-induced
thrombocytopenia) or will refuse blood transfusions 7 History of intra-cerebral mass aneurysm arteriovenous malformation or hemorrhagic
stroke 8 Stroke or transient ischemic attack within the past 6 months or any permanent residual
neurologic defect 9 Gastrointestinal or genitourinary bleeding within the last 2 months or major surgery within
six weeks 10 Recent history or known current platelet count lt100000 cellsmm3 or Hgb lt10 gdL (note
baseline labs did not have to be available prior to enrollment) 11 Extensive peripheral vascular disease such that emergent angiography and intervention in
the opinion of the investigator is likely to be difficult or complicated 12 An elective surgical procedure is planned that would necessitate interruption of
thienopyridines during the first six months post enrollment 13 Non-cardiac co-morbid conditions are present with life expectancy lt1 year or that may result
in protocol non-compliance 14 Patients who are actively participating in another drug or device investigational study which
have not completed the primary endpoint follow-up period 15 Previous enrollment in this trial 16 Patients who underwent coronary stent implantation within the past 30 days
Secondary Randomization - Angiographic Inclusion Criteria
1 At least one acute infarct artery target vessel is present in which a ALL hemodynamically significant lesions can be stented with study stents and
b ALL such lesions have a visually estimated reference diameter gt225 mm and lt 40
nun 2 Expected ability to deliver the stent(s) to all culprit lesions (absence of excessive proximal
tortuosity or severe calcification) 3 Expected ability to fully expand the stent(s) at all culprit lesions (absence of marked
calcification)
Secondary Randomization - Angiographic Exclusion Criteria
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1 One or more hemodynamically significant lesion(s) is present in the infarct vessel (or side branches) which can only undergo balloon angioplasty or cannot be stented with a study stent (ie do not meet the angiographic inclusion criteria for a study stent)
Note The only exception to this exclusion criterionis bifurcationlesions with main branch andostial side branch involvement which may be enrolledas long as the main branch is eligible to be treatedwith a study stent The ostialside branch lesion should then be treated with balloon angioplastywith bail-outstenting performed onlyfor a sub-optimalresult in the side branch(diameterstenosis gt50 or dissection NHLBI type C refractoryto prolonged(gt2 minute) balloon inflations) Bifurcation lesions are otherwise excluded if the plannedstrategy definitely requires2 stents (eg planned T-stenting V-stenting culotte stenting or crush)
2 The presence of a bifurcation lesion in the infarct vessel which will definitely require the implantation of two stents for treatment
Note A true bifurcationlesion qualifiesfor randomizationif the operatorbelieves heshe will be likely able to successfully approachthe lesion with provisionalstenting (ie the side branch ostial lesion is dilatedfirst and stented onlybr a sub-optimal result as defined above after prolonged(gt2 minute) ballooninflations)
3 Anticipated need for greater than 100mm of study stent length 4 The infarct related artery is an unprotected left main segment 5 Patients with significant multi-vessel disease or anatomical features otherwise unfavorable
for angioplasty such that the patient will have a high likelihood of requiring bypass surgery prior to 30 days
6 The culprit vessel or lesion cannot be identified 7 Patient presenting with possibleprobable stent thrombosis 8 Any patient in whom angiography demonstrates the infarct lesion to be at the site of a
previously implanted stent (bare metal or drug-eluting)
2 Follow-up Schedule
Clinical follow-up was performed at 30 days (plusmn 1 week) 6 months (plusmn 2 weeks) 1 year (+ 2 weeks) 2 years (plusmn I month) and 3 years (plusmn 1month) Angiographic follow-up was performed at 13 months (-2 weeks + 52 weeks) for a subset of patients (approximately the first 1500 randomized patients) Certain sites also participated in the HORIZONS IVUS substudy where intravascular ultrasound was performed at baseline (post-procedure) and at 13 month follow-up (approximately the first 400 patients)
3 Clinical Endpoints
Primary Efficacy Endpoint Ischemic target lesion revascularization Primary Safety Endpoint The composite rate of death reinfarction stent thrombosis
or stroke (MACE)
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Major Secondary Endpoint Analysis segment binary restenosis in the 13 month angiographic subset
All primary and major secondary endpoints were analyzed both on an intent-to-treat (ITT) basis
(all patients analyzed as part of their assigned treatment group) and on a per protocol basis
(patients analyzed as part of their assigned treatment group only if they actually received their
assigned treatment) The principal analyses were by intention-to-treat
The primary and major secondary endpoints were analyzed using risk differences and compared to the pre-specified non-inferiority margin Kaplan-Meier curves and survival analyses were also constructed Secondary efficacy and safety data were analyzed using descriptive statistics
For principle statistical analyses all endpoints were analyzed on a per patient basis
B Accountability of PMA Cohort
Refer to Table 3 for primary endpoint patient disposition
Table 2 Patient Disposition
TAXUS DES EXPRESS BMS Combined Patient Disposition N=2257 N=749 N=3006
Patients Enrolled (ITT Population) 1000 (22572257) 1000 (749749) 1000 (30063006)
Completed I year follow-up 969 (21862257) 955 (715749) 965 (29013006) Reason not completed
Lost to Follow-up 30 (682257) 40 (30749) 33 (983006)
PatientPhysician withdrawal 09 (202257) 11 (8749) 09 (283006)
Death 34 (762257) 35 (26749) 34 (1023006)
Patients qualified for PP analysis 951 (21462257) 960 (719749) 953 (28653006)
Stented Patients 992 (22382257) 993 (744749) 992 (29823006)
Includes patients with 30 day 6 month or 1 year follow-up or any follow-up visit post the follow-up window or
any MACE event
C Study Population Demographics and Baseline Parameters
The baseline demographics and medical history are reported in Table 4
Table 3 HORIZONS AMI Patient Demogra hics and Medical Histor ITT Po ulation) TAXUS Express Bare Metal Expressshy
(N=2257) (749)
Age (median (IQR) yrs) 599 (524 694) 593 (518 692) Male 770 (17382257) _ 760 (569749) Diabetes rnellitus 161 (3642256) 152 (114749)
- Insulin requiring 43 (982256) 41 (31749) Hypertension 512 (1152256) 519 (389749) Hyperlipidemia 422 (95312256) 411 (3081749) Current smoker 463 (10412246) 519 (388748) Prior myocardial infarction 91 (2062256) 109 (821749) Prior percutaneous coronary intervention 95 (2142255) 77 (58749)
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Prior coronary artery bypass graft 22 (502256) 19 (14749) Anemia 110 (2352130) 76 (54715) Killip class 2-4 88 (1992254) 80 (60748) Renal insufficiency2 156 (3282102) 154 (107696) LVEF 3lt40 143 (2791948) 140 (91652) IQR = interquartile range Defined using the World Health Organization (WHO) criteria as a hematocrit value at initial presentation of lt39 for men and lt36 for women 2Baseline calculated creatinine clearance using the Cockcroft-Gault equation lt60 mLmin
Left ventricular ejection fraction visual assessment from the baseline contrast left ventriculogram
D Safety and Effectiveness Results
The primary and secondary endpoints of the trial were met and are reported in Table 5 and Table 6 Theclinical results of the trial are reported in Table 7 In Figure 1 the rates of ischemic TLR are illustrated for all patients and those patients who were not in the protocol required angiographic subset Figures 2-6 provide results of major clinical outcomes to 3 years Angiographic and IVUS results are reported in Table 8
Table 4 HORIZONS AMI Primary Endpoints UTAXUSExpress Bare Metal Difference HazardRatih - P-vaie
Isehemic TLR (N=2257) Express (95 C)(95tl) (N=749) -
I Year 45 (98) 75 (54) -30 (-51 -09) 059 (043 083) 00018
Safety MACE TAXL Exptes BareMetal 7 Difference HazardRatio YP-valuie
(N=2257) Express (9CI J95CI) - (N=749) lt _____
I Year 81 (181) 80 (59) 01 (-21 24) 102 (076 136) 00075 P-value for the test of superiority
Safety MACE includes death reinfarction stroke or stent thrombosis
3 P-value for the test of non-inferiority
Table 5 HORIZONS AMI Secondary Endpoint
Binary TAXUS I re Metali Difference - Hazard Ratio P-value Res Express - 5 CI) (95 C)-Express
er Leion) N 2257 (N-749) _ 1
13 Month 100 (1081081) 229 (76322) -129 (-180 - 044 (033 lt00001 78) 057)
P-value superiority
Adverse effects that occurred in the PMA clinical study
Observed adverse event experience comes from the HORIZONS AMI trial Major clinical
events for this study are shown in Table 6
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 1 2 and 3 Years (ITT Population)
Expressi Bare Metal Express- -TAXUS
30 Day Clinical Endpoints Net Adverse Clinical Events 103 (232) 90 (67) MACE 12 48 (109) 45 (34)
43 (32)MACE 2 (Safety MACE)3 45 (102)
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Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
Death - Cardiac -Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischemic TVR Ischemic TLR Stroke Major bleeding (non-CABG) Target Lesion stent thrombosis
1 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE)3
Death - Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction schemic TVR schemic TLR
Stroke
Major bleeding (non-CABG) Target Lesion stent thrombosis
2 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE) Death
- Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischernic TVR Ischemic TLR StrokeP Major bleeding (non-CABG) Target Lesion stent thrombosis
3 Year Clinical Endpoints I4et Adverse ClinicalEventsl
SMACE 14
Du A P060008SO4
TAXUS Exprcs (N-2257-7 21 (47) 20 (44) 01(3) 17 (37) 12 (28) 04(10)
36(80) 23 (51) 21 (46) 05 (11) 71(159) 23 (50)
158 (355) 106 (237) 81 (181) 35(7 8 ) 24(54) 11(24)
37(81) 20(45) 18(39)
68(152) 59 (129) 46 (101)
10(23)
77 (172) 31 (69)
215 (480) 168 (373) 110 (245)
43 (96) 27 (60) 17 (36)
57 (123) 31 (67) 10 (64) 94 (210) 109 (236) 83 (180) 14(30)
80 (178) 42 (91)
245 (544) 200k441)240(75
FTDA Sulmmary of Safety and Effectiveness Data
Bare MctalExpr
19(14) 17(13) 01(1) 22(16) 16(12) 05(4)
35 (26) 26 (19) 26 (19) 05 (4) 56 (42) 27 (20)
163(121) 124 (92) 80 (59) 35 (26) 27 (20) 08(6)
45 (33) 19(14) 26(19) 70 (52) 88 (64) 74 (54) 07(5)
66 (49) 34 (25)
260 (191) 222 (162) 112 (82) 53 (39) 33 (24) 21 (15) 60 (43) 28 (20) 32 (23) 98 (72)
167(119) 142 (101)
11(8) 70 (52) 41 (30)
280 (205)
page 12
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
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18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
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Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
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6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
This supplement approval revises the indications statement to include patients undergoing primary angioplasty to treat acute ST-segment elevation myocardial infarction true posterior myocardial infarction or presumed new left bundle branch block with symptoms of acute myocardial infarction lasting gt 20 minutes and lt 12 hours in duration
II INDICATIONS FOR USE
The TAXUSreg Libert6 Paclitaxel-Eluting Coronary Stent System (Monorail and Over-the-Wire Systems) is indicated for improving luminal diameter
for the treatment of de novo lesions in native coronary arteries 275 mm to 400 mm in diameter in lesions 34 mm in length
for the treatment of de novo lesions in native coronary arteries 225 mm to 250 mm in diameter in lesions lt 28 mm in length or
in patients undergoing primary angioplasty to treat acute ST-segment elevation myocardial infarction true posterior myocardial infarction or presumed new left bundle branch block with symptoms of acute myocardial infarction lasting gt 20 minutes and lt 12 hours in duration
III CONTRAINDICATIONS
Use of the TAXUS Libert6 Paclitaxel-Eluting Coronary Stent System is contraindicated in
patients with Known hypersensitivity to 3t6L stainless steel Known hypersensitivity to paclitaxel or structurally-related compounds
Known hypersensitivity to the polymer or its individual components
Coronary Artery Stenting is contraindicated for use in Patients who can not receive recommended anti-platelet andor anticoagulant therapy
Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the stent or delivery device
IV WARNING AND PRECAUTIONS
The warnings and precautions can be found in the TAXUS Libert6 Paclitaxel-Eluting Coronary Stent System Directions for Use (DFU)
V DEVICE DESCRIPTION
The TAXUS Libert6 Paclitaxel-Eluting Coronary Stent System is a device drug combination
product comprised of two regulated components a device (Libert6 Coronary Stent System) and a
drug product (a formulation of paclitaxel contained in a polymer coating) Please refer to the
device description provided in the original SSED and subsequent SSEDs for additional details
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 2
VI ALTERNATIVE PRACTICES OR PROCEDURES
There are several other treatment alternatives for coronary artery disease exercise diet drug therapy percutaneous coronary interventions (such as angioplasty and placement of bare metal stents coated stents and other drug eluting stents) and coronary artery bypass surgery (CABG) A patient should fully discuss these alternatives with hisher physician to select the method that best meets expectations and lifestyle
VII MARKETING HISTORY
The TAXUS Liberte Paclitaxel-Eluting Coronary Stent System is commercially available in the United States and in the following countries The device has not been withdrawn from marketing for any reason related to its safety or effectiveness
Albania Dominican Rep Kuwait Qatar Algeria Dutch Antilles Latvia Romania AntiguaBarbuda Ecuador Lebanon Russia Argentina Egypt Libya Saudi Arabia Armenia El Salvador Liechtenstein Scotland Aruba Estonia Lithuania SerbiaMontenegro Australia Finland Luxembourg - Singapore Austria France Macau Slovakia Bahamas Georgia Macedonia Slovenia Bahrain Germany Malaysia South Africa Bangladesh Great Britain Malta Spain Barbados Greece Martinique Sri Lanka Belarus Guatemala Mauritania Sudan Belgium Guyana Mauritius Suriname Belize Haiti Mexico Sweden Bermuda Honduras Moldavia Switzerland Bolivia Hong Kong Morocco Syria Bosnia Hungary Myanmar Taiwan Brazil Iceland Nepal Thailand Brunei India Netherlands TrinidadTobago Bulgaria Indonesia New Zealand Tunisia Canada Iran Nicaragua Turkey Chile Iraq Norway United Arab Emirates China Ireland Oman Ukraine
Colombia Israel Pakistan Uruguay Costa Rica Italy Panama Venezuela
Croatia Jamaica Paraguay Vietnam
Cyprus Japan x Peru West Bank Gaza Strip Czech Republic Jordan Philippines a Yemen
Denmark Kenya Poland
Djibouti Korea a Portugal
VIII POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH
PMA P0600088046 FDA Summary of Safety and Effectiveness Data page 3
Below is a list of the potential adverse effects (eg complications) in alphabetical order which may be associated with the use of a coronary stent in coronary arteries
Abrupt stent closure Acute myocardial infarction o Allergic reaction to anticoagulants or antithrombotic therapy or contrast medium or stent
materials Angina Arrhythmias including ventricular fibrillation (VF) and ventricular tachycardia (VT) Arteriovenous fistula Cardiac tamponade Cardiogenic shock pulmonary edema Death Dissection Emboli distal (air tissue or thrombotic material or material from device(s) used in the
procedure) Heart failure Hematoma Hemorrhage requiring transfusion Hypotensionhypertension Infection local andor systemic o Ischemia myocardial Pain at the access site o Perforation or rupture of coronary artery o Pericardial effusion Pseudoaneurysm feioral Renal failure Respiratory failure Restenosis of stented segment Shock Stent embolization Stent migration Stent thrombosisocclusion Strokecerebrovascular accidentTIA Total occlusion of coronary artery Vessel spasm Vessel trauma requiring surgical repair or reintervention
Potential adverse events not captured above that may be unique to the paclitaxel drug coating
Allergicimmunologic reaction to drug (paclitaxel or structurally-related compounds) or the polymer stent coating (or its individual components)
Alopecia Anemia Blood product transfusion Gastrointestinal symptoms
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 4
Hematologic dyscrasia (including leukopenia neutropenia thrombocytopenia) Hepatic enzyme changes Histologic changes in vessel wall including inflammation cellular damage or necrosis Myalgia arthralgia Peripheral neuropathy
For the specific adverse events that occurred in the HORIZONS AMI clinical study please see Section X below
IX SUMMARY OF PRECLINICAL STUDIES
A series of non-clinical laboratory studies were performed to support the original approval and subsequent indication expansions - those related to the stent and the stent delivery system [ie the stent on either the Monorail (MR) or Over-The-Wire (OTW) stent delivery system (SDS)]the polymer substance [ie poly(styrene-b-isobutylene-b-styrene) (SIBS)] the drug substance (ie paclitaxel) and the finished combination product (ie TAXUS Libert6 Paclitaxel-Eluting Coronary Stent) No new nonclinical studies were needed to support the approval of this supplement
X SUMMARY OF CLINICAL STUDIES
A series of clinical studies (TAXUS ATLAS Workhorse ATLAS Small Vessel and ATLAS Long Lesion) were performed to support the original approval and subsequent indication expansions Please refer to previous SSEDs for details The HORIZONS AMI trial was performed to establish a reasonable assurance of safety and effectiveness for TAXUS Express 2
Paclitaxel-Eluting Coronary Stent System for the proposed expanded indication under IDE G040188 Data from this clinical study were the basis for the PMA approval decision The TAXUS Liberte stent uses the same drug-polymer coating formulation as the TAXUS Express 2
stent In addition nonclinical studies of design attributes and the ATLAS clinical studies in stable patients with coronary artery disease have established that the performance of the TAXUS Libert6 is similar Given these supportive data outcomes in patients with AMI would also be expected to be similar between these two stents and therefore the safety and effectiveness data from the HORIZONS AMI trial were considered applicable for the TAXUS Libert6 Paclitaxel-Eluting Coronary Stent System as well A summary of the clinical study is presented below
A HORIZONS AMI Clinical Trial
Objectives The trial had two primary objectives and was designed and powered to address both the primary and sub-study objectives
Primary objective for the pharmacology randomization To evaluate the use of bivalirudin in patients with ST segment elevation acute myocardial infarction (STEMI) undergoing a primary angioplasty strategy compared to unfractionated heparin plus routine use of GP lIbIlla inhibitors
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 5
Primary objective for the stent randomization To establish the safety and effectiveness of the paclitaxel-eluting TAXUS Express stent in STEMI patients by showing that compared to an otherwise identical Express BMS the TAXUS Express results in (1) reduced rates of ischemia-driven target lesion revascularization at 1 year (2) a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year and (3) a lower rate of analysis segment binary angiographic restenosis at 13 months
Design
The HORIZONS AMI trial was a prospective dual-arm single-blind randomized multi-center trial that enrolled STEMI patients defined by clinical symptoms consistent with acute MI lasting greater than 20 minutes but less than 12 hours and specific ECG criteria consisting of ST-segment elevation of gt 1mm in gt 2 contiguous leads presumed new LBBB or true posterior MI with ST depression of gt Imm in gt 2 contiguous anterior leads A total of 3602 patients were randomized (primary randomization) in a 11 fashion in the emergency room to anticoagulation with unfractionated heparin plus routine GP Ilblila inhibition or bivalirudin and bail-out GP IlbIla inhibition
Emergent coronary angiography with left ventriculography was performed after the primary randomization followed by triage to either percutaneous coronary intervention (PCI) coronary artery bypass graft (CABG) surgery or medical management at physician discretion
After coronary angiography a total of 3006 patients were triaged to PCI and randomized (secondary randomization) in a 31 fashion to either a TAXUS Express stent or an Express stent In order to be eligible for the second randomization patients had to have at least one acute infarct-related artery with an expectation that study stents could be delivered to all culprit lesions Exclusion criteria included true bifurcation lesions definitely requiring stenting of the side branch vessel lesions requiring greater than 100 mum of stent length unprotected left main culprit lesions and stent thrombosis lesions The secondary randomization was stratified by the following four factors the result from the primary randomization (to ensure equal distribution of the two arms from the primary randomization in the secondary randomization) the presence or absence of medically treated diabetes whether any of the lesions were greater than 26 mm in length such that overlapping stents would be used and whether the clinical study site was within or outside of the US
Table 1 HORIZONS AMI CLINICAL TRIAL OVERVIEW
HORIZONS AMI (Indication Expansion)
Study Type Prospective multicenter randomized single-blind
Total 3006 Number of Patients (ITT) TAXUS 2257
Control 749
Dose Release Formulation Slow Release (SR) (1 g mm2)
gt 25 mm to Lesion Criteria Vessel Diameter (by visual estimate) lt 40 mm
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 6
HORIZONS AMI (Indication Expansion)
Lesion Criteria Lesion Length (by visual estimate) lt 100 mm
Product Used TAXUS Express Paclitaxel-Eluting Coronary Stent System
Antiplatelet Therapy Aspirin indefinitely and clopidogrel or ticlopidine for 6 months (I year or longer recommended)
30 days clinical 6 months clinical
Follow-Up 12 month clinical 13 month angiographicIVUS
2 3 years clinical
Abbreviations ITT=intent-to-treat IVUS=intravascular ultrasound
1 Clinical Inclusion and Exclusion Criteria
Primary Randomization - Inclusion Criteria
1 The patient must be at least 18 years of age (there is no upper age limit) 2 Must have clinical symptoms consistent with AMI (eg angina or anginal equivalent) lasting
gt20 minutes but lt12 hours in duration If the symptom duration at the time of evaluation is lt1 hour to rule out unstable angina the symptoms must be unresponsive to nitroglycerin (ie ongoing) prior to signing the informed consent Patients with symptom onset within 12 hours in whom the symptoms lasted gt1 hour but subsequently resolved may still be enrolled if the ECG at the time of the evaluation shows definite ongoing ST segment elevation
3 ECG criteria ST-segment elevation of gt 1 mm in gt 2 contiguous leads or (presumably new) left bundle branch block or true posterior MI with ST depression of gt 1 mm in gt 2 contiguous anterior leads
4 The patient or guardian agrees to the study protocol and the schedule of clinical and angiographic follow-up and provides informed written consent as approved by the appropriate Institutional Review BoardEthical Committee of the respective clinical site
Primary Randomization - Exclusion Criteria
1 The patient has a known hypersensitivity or contraindication to any of the following medications
Heparin pork or pork products Both abciximab and eptifibatide Aspirin Both Clopidogrel and Ticlopidine Bivalirudin Paclitaxel or Taxol
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 7
o The polymer components of the TAXUS Express DES stent (SIBS) Stainless steel andor o Contrast media (patients with documented sensitivity to contrast which can be
effectively pre-medicated with steroids and diphenhydramine (eg rash) may be
enrolled Patients with true anaphylaxis to prior contrast media however should not be enrolled)
2 Prior administration of thrombolytic therapy bivalirudin GP IlbIlla inhibitors low molecular weight heparin or fondaparinux for this admission Patients receiving prior unfractionated heparin may be enrolled and treated per randomization
3 Current use of coumadin 4 Systemic (intravenous) Paclitaxel or Taxol use within 12 months 5 Female of childbearing potential unless a recent pregnancy test is negative who possibly
plans to become pregnant any time after enrollment into this study 6 History of bleeding diathesis or known coagulopathy (including heparin-induced
thrombocytopenia) or will refuse blood transfusions 7 History of intra-cerebral mass aneurysm arteriovenous malformation or hemorrhagic
stroke 8 Stroke or transient ischemic attack within the past 6 months or any permanent residual
neurologic defect 9 Gastrointestinal or genitourinary bleeding within the last 2 months or major surgery within
six weeks 10 Recent history or known current platelet count lt100000 cellsmm3 or Hgb lt10 gdL (note
baseline labs did not have to be available prior to enrollment) 11 Extensive peripheral vascular disease such that emergent angiography and intervention in
the opinion of the investigator is likely to be difficult or complicated 12 An elective surgical procedure is planned that would necessitate interruption of
thienopyridines during the first six months post enrollment 13 Non-cardiac co-morbid conditions are present with life expectancy lt1 year or that may result
in protocol non-compliance 14 Patients who are actively participating in another drug or device investigational study which
have not completed the primary endpoint follow-up period 15 Previous enrollment in this trial 16 Patients who underwent coronary stent implantation within the past 30 days
Secondary Randomization - Angiographic Inclusion Criteria
1 At least one acute infarct artery target vessel is present in which a ALL hemodynamically significant lesions can be stented with study stents and
b ALL such lesions have a visually estimated reference diameter gt225 mm and lt 40
nun 2 Expected ability to deliver the stent(s) to all culprit lesions (absence of excessive proximal
tortuosity or severe calcification) 3 Expected ability to fully expand the stent(s) at all culprit lesions (absence of marked
calcification)
Secondary Randomization - Angiographic Exclusion Criteria
PMA P0600080o46 FDA Summary of Safety and Effectiveness Data page 8
1 One or more hemodynamically significant lesion(s) is present in the infarct vessel (or side branches) which can only undergo balloon angioplasty or cannot be stented with a study stent (ie do not meet the angiographic inclusion criteria for a study stent)
Note The only exception to this exclusion criterionis bifurcationlesions with main branch andostial side branch involvement which may be enrolledas long as the main branch is eligible to be treatedwith a study stent The ostialside branch lesion should then be treated with balloon angioplastywith bail-outstenting performed onlyfor a sub-optimalresult in the side branch(diameterstenosis gt50 or dissection NHLBI type C refractoryto prolonged(gt2 minute) balloon inflations) Bifurcation lesions are otherwise excluded if the plannedstrategy definitely requires2 stents (eg planned T-stenting V-stenting culotte stenting or crush)
2 The presence of a bifurcation lesion in the infarct vessel which will definitely require the implantation of two stents for treatment
Note A true bifurcationlesion qualifiesfor randomizationif the operatorbelieves heshe will be likely able to successfully approachthe lesion with provisionalstenting (ie the side branch ostial lesion is dilatedfirst and stented onlybr a sub-optimal result as defined above after prolonged(gt2 minute) ballooninflations)
3 Anticipated need for greater than 100mm of study stent length 4 The infarct related artery is an unprotected left main segment 5 Patients with significant multi-vessel disease or anatomical features otherwise unfavorable
for angioplasty such that the patient will have a high likelihood of requiring bypass surgery prior to 30 days
6 The culprit vessel or lesion cannot be identified 7 Patient presenting with possibleprobable stent thrombosis 8 Any patient in whom angiography demonstrates the infarct lesion to be at the site of a
previously implanted stent (bare metal or drug-eluting)
2 Follow-up Schedule
Clinical follow-up was performed at 30 days (plusmn 1 week) 6 months (plusmn 2 weeks) 1 year (+ 2 weeks) 2 years (plusmn I month) and 3 years (plusmn 1month) Angiographic follow-up was performed at 13 months (-2 weeks + 52 weeks) for a subset of patients (approximately the first 1500 randomized patients) Certain sites also participated in the HORIZONS IVUS substudy where intravascular ultrasound was performed at baseline (post-procedure) and at 13 month follow-up (approximately the first 400 patients)
3 Clinical Endpoints
Primary Efficacy Endpoint Ischemic target lesion revascularization Primary Safety Endpoint The composite rate of death reinfarction stent thrombosis
or stroke (MACE)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 9
Major Secondary Endpoint Analysis segment binary restenosis in the 13 month angiographic subset
All primary and major secondary endpoints were analyzed both on an intent-to-treat (ITT) basis
(all patients analyzed as part of their assigned treatment group) and on a per protocol basis
(patients analyzed as part of their assigned treatment group only if they actually received their
assigned treatment) The principal analyses were by intention-to-treat
The primary and major secondary endpoints were analyzed using risk differences and compared to the pre-specified non-inferiority margin Kaplan-Meier curves and survival analyses were also constructed Secondary efficacy and safety data were analyzed using descriptive statistics
For principle statistical analyses all endpoints were analyzed on a per patient basis
B Accountability of PMA Cohort
Refer to Table 3 for primary endpoint patient disposition
Table 2 Patient Disposition
TAXUS DES EXPRESS BMS Combined Patient Disposition N=2257 N=749 N=3006
Patients Enrolled (ITT Population) 1000 (22572257) 1000 (749749) 1000 (30063006)
Completed I year follow-up 969 (21862257) 955 (715749) 965 (29013006) Reason not completed
Lost to Follow-up 30 (682257) 40 (30749) 33 (983006)
PatientPhysician withdrawal 09 (202257) 11 (8749) 09 (283006)
Death 34 (762257) 35 (26749) 34 (1023006)
Patients qualified for PP analysis 951 (21462257) 960 (719749) 953 (28653006)
Stented Patients 992 (22382257) 993 (744749) 992 (29823006)
Includes patients with 30 day 6 month or 1 year follow-up or any follow-up visit post the follow-up window or
any MACE event
C Study Population Demographics and Baseline Parameters
The baseline demographics and medical history are reported in Table 4
Table 3 HORIZONS AMI Patient Demogra hics and Medical Histor ITT Po ulation) TAXUS Express Bare Metal Expressshy
(N=2257) (749)
Age (median (IQR) yrs) 599 (524 694) 593 (518 692) Male 770 (17382257) _ 760 (569749) Diabetes rnellitus 161 (3642256) 152 (114749)
- Insulin requiring 43 (982256) 41 (31749) Hypertension 512 (1152256) 519 (389749) Hyperlipidemia 422 (95312256) 411 (3081749) Current smoker 463 (10412246) 519 (388748) Prior myocardial infarction 91 (2062256) 109 (821749) Prior percutaneous coronary intervention 95 (2142255) 77 (58749)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 10 IS
Prior coronary artery bypass graft 22 (502256) 19 (14749) Anemia 110 (2352130) 76 (54715) Killip class 2-4 88 (1992254) 80 (60748) Renal insufficiency2 156 (3282102) 154 (107696) LVEF 3lt40 143 (2791948) 140 (91652) IQR = interquartile range Defined using the World Health Organization (WHO) criteria as a hematocrit value at initial presentation of lt39 for men and lt36 for women 2Baseline calculated creatinine clearance using the Cockcroft-Gault equation lt60 mLmin
Left ventricular ejection fraction visual assessment from the baseline contrast left ventriculogram
D Safety and Effectiveness Results
The primary and secondary endpoints of the trial were met and are reported in Table 5 and Table 6 Theclinical results of the trial are reported in Table 7 In Figure 1 the rates of ischemic TLR are illustrated for all patients and those patients who were not in the protocol required angiographic subset Figures 2-6 provide results of major clinical outcomes to 3 years Angiographic and IVUS results are reported in Table 8
Table 4 HORIZONS AMI Primary Endpoints UTAXUSExpress Bare Metal Difference HazardRatih - P-vaie
Isehemic TLR (N=2257) Express (95 C)(95tl) (N=749) -
I Year 45 (98) 75 (54) -30 (-51 -09) 059 (043 083) 00018
Safety MACE TAXL Exptes BareMetal 7 Difference HazardRatio YP-valuie
(N=2257) Express (9CI J95CI) - (N=749) lt _____
I Year 81 (181) 80 (59) 01 (-21 24) 102 (076 136) 00075 P-value for the test of superiority
Safety MACE includes death reinfarction stroke or stent thrombosis
3 P-value for the test of non-inferiority
Table 5 HORIZONS AMI Secondary Endpoint
Binary TAXUS I re Metali Difference - Hazard Ratio P-value Res Express - 5 CI) (95 C)-Express
er Leion) N 2257 (N-749) _ 1
13 Month 100 (1081081) 229 (76322) -129 (-180 - 044 (033 lt00001 78) 057)
P-value superiority
Adverse effects that occurred in the PMA clinical study
Observed adverse event experience comes from the HORIZONS AMI trial Major clinical
events for this study are shown in Table 6
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 1 2 and 3 Years (ITT Population)
Expressi Bare Metal Express- -TAXUS
30 Day Clinical Endpoints Net Adverse Clinical Events 103 (232) 90 (67) MACE 12 48 (109) 45 (34)
43 (32)MACE 2 (Safety MACE)3 45 (102)
PMA P0600085046 FDA Summary of Safety and Effectiveness Data page 11
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
Death - Cardiac -Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischemic TVR Ischemic TLR Stroke Major bleeding (non-CABG) Target Lesion stent thrombosis
1 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE)3
Death - Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction schemic TVR schemic TLR
Stroke
Major bleeding (non-CABG) Target Lesion stent thrombosis
2 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE) Death
- Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischernic TVR Ischemic TLR StrokeP Major bleeding (non-CABG) Target Lesion stent thrombosis
3 Year Clinical Endpoints I4et Adverse ClinicalEventsl
SMACE 14
Du A P060008SO4
TAXUS Exprcs (N-2257-7 21 (47) 20 (44) 01(3) 17 (37) 12 (28) 04(10)
36(80) 23 (51) 21 (46) 05 (11) 71(159) 23 (50)
158 (355) 106 (237) 81 (181) 35(7 8 ) 24(54) 11(24)
37(81) 20(45) 18(39)
68(152) 59 (129) 46 (101)
10(23)
77 (172) 31 (69)
215 (480) 168 (373) 110 (245)
43 (96) 27 (60) 17 (36)
57 (123) 31 (67) 10 (64) 94 (210) 109 (236) 83 (180) 14(30)
80 (178) 42 (91)
245 (544) 200k441)240(75
FTDA Sulmmary of Safety and Effectiveness Data
Bare MctalExpr
19(14) 17(13) 01(1) 22(16) 16(12) 05(4)
35 (26) 26 (19) 26 (19) 05 (4) 56 (42) 27 (20)
163(121) 124 (92) 80 (59) 35 (26) 27 (20) 08(6)
45 (33) 19(14) 26(19) 70 (52) 88 (64) 74 (54) 07(5)
66 (49) 34 (25)
260 (191) 222 (162) 112 (82) 53 (39) 33 (24) 21 (15) 60 (43) 28 (20) 32 (23) 98 (72)
167(119) 142 (101)
11(8) 70 (52) 41 (30)
280 (205)
page 12
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 13
18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 14
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
VI ALTERNATIVE PRACTICES OR PROCEDURES
There are several other treatment alternatives for coronary artery disease exercise diet drug therapy percutaneous coronary interventions (such as angioplasty and placement of bare metal stents coated stents and other drug eluting stents) and coronary artery bypass surgery (CABG) A patient should fully discuss these alternatives with hisher physician to select the method that best meets expectations and lifestyle
VII MARKETING HISTORY
The TAXUS Liberte Paclitaxel-Eluting Coronary Stent System is commercially available in the United States and in the following countries The device has not been withdrawn from marketing for any reason related to its safety or effectiveness
Albania Dominican Rep Kuwait Qatar Algeria Dutch Antilles Latvia Romania AntiguaBarbuda Ecuador Lebanon Russia Argentina Egypt Libya Saudi Arabia Armenia El Salvador Liechtenstein Scotland Aruba Estonia Lithuania SerbiaMontenegro Australia Finland Luxembourg - Singapore Austria France Macau Slovakia Bahamas Georgia Macedonia Slovenia Bahrain Germany Malaysia South Africa Bangladesh Great Britain Malta Spain Barbados Greece Martinique Sri Lanka Belarus Guatemala Mauritania Sudan Belgium Guyana Mauritius Suriname Belize Haiti Mexico Sweden Bermuda Honduras Moldavia Switzerland Bolivia Hong Kong Morocco Syria Bosnia Hungary Myanmar Taiwan Brazil Iceland Nepal Thailand Brunei India Netherlands TrinidadTobago Bulgaria Indonesia New Zealand Tunisia Canada Iran Nicaragua Turkey Chile Iraq Norway United Arab Emirates China Ireland Oman Ukraine
Colombia Israel Pakistan Uruguay Costa Rica Italy Panama Venezuela
Croatia Jamaica Paraguay Vietnam
Cyprus Japan x Peru West Bank Gaza Strip Czech Republic Jordan Philippines a Yemen
Denmark Kenya Poland
Djibouti Korea a Portugal
VIII POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH
PMA P0600088046 FDA Summary of Safety and Effectiveness Data page 3
Below is a list of the potential adverse effects (eg complications) in alphabetical order which may be associated with the use of a coronary stent in coronary arteries
Abrupt stent closure Acute myocardial infarction o Allergic reaction to anticoagulants or antithrombotic therapy or contrast medium or stent
materials Angina Arrhythmias including ventricular fibrillation (VF) and ventricular tachycardia (VT) Arteriovenous fistula Cardiac tamponade Cardiogenic shock pulmonary edema Death Dissection Emboli distal (air tissue or thrombotic material or material from device(s) used in the
procedure) Heart failure Hematoma Hemorrhage requiring transfusion Hypotensionhypertension Infection local andor systemic o Ischemia myocardial Pain at the access site o Perforation or rupture of coronary artery o Pericardial effusion Pseudoaneurysm feioral Renal failure Respiratory failure Restenosis of stented segment Shock Stent embolization Stent migration Stent thrombosisocclusion Strokecerebrovascular accidentTIA Total occlusion of coronary artery Vessel spasm Vessel trauma requiring surgical repair or reintervention
Potential adverse events not captured above that may be unique to the paclitaxel drug coating
Allergicimmunologic reaction to drug (paclitaxel or structurally-related compounds) or the polymer stent coating (or its individual components)
Alopecia Anemia Blood product transfusion Gastrointestinal symptoms
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 4
Hematologic dyscrasia (including leukopenia neutropenia thrombocytopenia) Hepatic enzyme changes Histologic changes in vessel wall including inflammation cellular damage or necrosis Myalgia arthralgia Peripheral neuropathy
For the specific adverse events that occurred in the HORIZONS AMI clinical study please see Section X below
IX SUMMARY OF PRECLINICAL STUDIES
A series of non-clinical laboratory studies were performed to support the original approval and subsequent indication expansions - those related to the stent and the stent delivery system [ie the stent on either the Monorail (MR) or Over-The-Wire (OTW) stent delivery system (SDS)]the polymer substance [ie poly(styrene-b-isobutylene-b-styrene) (SIBS)] the drug substance (ie paclitaxel) and the finished combination product (ie TAXUS Libert6 Paclitaxel-Eluting Coronary Stent) No new nonclinical studies were needed to support the approval of this supplement
X SUMMARY OF CLINICAL STUDIES
A series of clinical studies (TAXUS ATLAS Workhorse ATLAS Small Vessel and ATLAS Long Lesion) were performed to support the original approval and subsequent indication expansions Please refer to previous SSEDs for details The HORIZONS AMI trial was performed to establish a reasonable assurance of safety and effectiveness for TAXUS Express 2
Paclitaxel-Eluting Coronary Stent System for the proposed expanded indication under IDE G040188 Data from this clinical study were the basis for the PMA approval decision The TAXUS Liberte stent uses the same drug-polymer coating formulation as the TAXUS Express 2
stent In addition nonclinical studies of design attributes and the ATLAS clinical studies in stable patients with coronary artery disease have established that the performance of the TAXUS Libert6 is similar Given these supportive data outcomes in patients with AMI would also be expected to be similar between these two stents and therefore the safety and effectiveness data from the HORIZONS AMI trial were considered applicable for the TAXUS Libert6 Paclitaxel-Eluting Coronary Stent System as well A summary of the clinical study is presented below
A HORIZONS AMI Clinical Trial
Objectives The trial had two primary objectives and was designed and powered to address both the primary and sub-study objectives
Primary objective for the pharmacology randomization To evaluate the use of bivalirudin in patients with ST segment elevation acute myocardial infarction (STEMI) undergoing a primary angioplasty strategy compared to unfractionated heparin plus routine use of GP lIbIlla inhibitors
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Primary objective for the stent randomization To establish the safety and effectiveness of the paclitaxel-eluting TAXUS Express stent in STEMI patients by showing that compared to an otherwise identical Express BMS the TAXUS Express results in (1) reduced rates of ischemia-driven target lesion revascularization at 1 year (2) a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year and (3) a lower rate of analysis segment binary angiographic restenosis at 13 months
Design
The HORIZONS AMI trial was a prospective dual-arm single-blind randomized multi-center trial that enrolled STEMI patients defined by clinical symptoms consistent with acute MI lasting greater than 20 minutes but less than 12 hours and specific ECG criteria consisting of ST-segment elevation of gt 1mm in gt 2 contiguous leads presumed new LBBB or true posterior MI with ST depression of gt Imm in gt 2 contiguous anterior leads A total of 3602 patients were randomized (primary randomization) in a 11 fashion in the emergency room to anticoagulation with unfractionated heparin plus routine GP Ilblila inhibition or bivalirudin and bail-out GP IlbIla inhibition
Emergent coronary angiography with left ventriculography was performed after the primary randomization followed by triage to either percutaneous coronary intervention (PCI) coronary artery bypass graft (CABG) surgery or medical management at physician discretion
After coronary angiography a total of 3006 patients were triaged to PCI and randomized (secondary randomization) in a 31 fashion to either a TAXUS Express stent or an Express stent In order to be eligible for the second randomization patients had to have at least one acute infarct-related artery with an expectation that study stents could be delivered to all culprit lesions Exclusion criteria included true bifurcation lesions definitely requiring stenting of the side branch vessel lesions requiring greater than 100 mum of stent length unprotected left main culprit lesions and stent thrombosis lesions The secondary randomization was stratified by the following four factors the result from the primary randomization (to ensure equal distribution of the two arms from the primary randomization in the secondary randomization) the presence or absence of medically treated diabetes whether any of the lesions were greater than 26 mm in length such that overlapping stents would be used and whether the clinical study site was within or outside of the US
Table 1 HORIZONS AMI CLINICAL TRIAL OVERVIEW
HORIZONS AMI (Indication Expansion)
Study Type Prospective multicenter randomized single-blind
Total 3006 Number of Patients (ITT) TAXUS 2257
Control 749
Dose Release Formulation Slow Release (SR) (1 g mm2)
gt 25 mm to Lesion Criteria Vessel Diameter (by visual estimate) lt 40 mm
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HORIZONS AMI (Indication Expansion)
Lesion Criteria Lesion Length (by visual estimate) lt 100 mm
Product Used TAXUS Express Paclitaxel-Eluting Coronary Stent System
Antiplatelet Therapy Aspirin indefinitely and clopidogrel or ticlopidine for 6 months (I year or longer recommended)
30 days clinical 6 months clinical
Follow-Up 12 month clinical 13 month angiographicIVUS
2 3 years clinical
Abbreviations ITT=intent-to-treat IVUS=intravascular ultrasound
1 Clinical Inclusion and Exclusion Criteria
Primary Randomization - Inclusion Criteria
1 The patient must be at least 18 years of age (there is no upper age limit) 2 Must have clinical symptoms consistent with AMI (eg angina or anginal equivalent) lasting
gt20 minutes but lt12 hours in duration If the symptom duration at the time of evaluation is lt1 hour to rule out unstable angina the symptoms must be unresponsive to nitroglycerin (ie ongoing) prior to signing the informed consent Patients with symptom onset within 12 hours in whom the symptoms lasted gt1 hour but subsequently resolved may still be enrolled if the ECG at the time of the evaluation shows definite ongoing ST segment elevation
3 ECG criteria ST-segment elevation of gt 1 mm in gt 2 contiguous leads or (presumably new) left bundle branch block or true posterior MI with ST depression of gt 1 mm in gt 2 contiguous anterior leads
4 The patient or guardian agrees to the study protocol and the schedule of clinical and angiographic follow-up and provides informed written consent as approved by the appropriate Institutional Review BoardEthical Committee of the respective clinical site
Primary Randomization - Exclusion Criteria
1 The patient has a known hypersensitivity or contraindication to any of the following medications
Heparin pork or pork products Both abciximab and eptifibatide Aspirin Both Clopidogrel and Ticlopidine Bivalirudin Paclitaxel or Taxol
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o The polymer components of the TAXUS Express DES stent (SIBS) Stainless steel andor o Contrast media (patients with documented sensitivity to contrast which can be
effectively pre-medicated with steroids and diphenhydramine (eg rash) may be
enrolled Patients with true anaphylaxis to prior contrast media however should not be enrolled)
2 Prior administration of thrombolytic therapy bivalirudin GP IlbIlla inhibitors low molecular weight heparin or fondaparinux for this admission Patients receiving prior unfractionated heparin may be enrolled and treated per randomization
3 Current use of coumadin 4 Systemic (intravenous) Paclitaxel or Taxol use within 12 months 5 Female of childbearing potential unless a recent pregnancy test is negative who possibly
plans to become pregnant any time after enrollment into this study 6 History of bleeding diathesis or known coagulopathy (including heparin-induced
thrombocytopenia) or will refuse blood transfusions 7 History of intra-cerebral mass aneurysm arteriovenous malformation or hemorrhagic
stroke 8 Stroke or transient ischemic attack within the past 6 months or any permanent residual
neurologic defect 9 Gastrointestinal or genitourinary bleeding within the last 2 months or major surgery within
six weeks 10 Recent history or known current platelet count lt100000 cellsmm3 or Hgb lt10 gdL (note
baseline labs did not have to be available prior to enrollment) 11 Extensive peripheral vascular disease such that emergent angiography and intervention in
the opinion of the investigator is likely to be difficult or complicated 12 An elective surgical procedure is planned that would necessitate interruption of
thienopyridines during the first six months post enrollment 13 Non-cardiac co-morbid conditions are present with life expectancy lt1 year or that may result
in protocol non-compliance 14 Patients who are actively participating in another drug or device investigational study which
have not completed the primary endpoint follow-up period 15 Previous enrollment in this trial 16 Patients who underwent coronary stent implantation within the past 30 days
Secondary Randomization - Angiographic Inclusion Criteria
1 At least one acute infarct artery target vessel is present in which a ALL hemodynamically significant lesions can be stented with study stents and
b ALL such lesions have a visually estimated reference diameter gt225 mm and lt 40
nun 2 Expected ability to deliver the stent(s) to all culprit lesions (absence of excessive proximal
tortuosity or severe calcification) 3 Expected ability to fully expand the stent(s) at all culprit lesions (absence of marked
calcification)
Secondary Randomization - Angiographic Exclusion Criteria
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1 One or more hemodynamically significant lesion(s) is present in the infarct vessel (or side branches) which can only undergo balloon angioplasty or cannot be stented with a study stent (ie do not meet the angiographic inclusion criteria for a study stent)
Note The only exception to this exclusion criterionis bifurcationlesions with main branch andostial side branch involvement which may be enrolledas long as the main branch is eligible to be treatedwith a study stent The ostialside branch lesion should then be treated with balloon angioplastywith bail-outstenting performed onlyfor a sub-optimalresult in the side branch(diameterstenosis gt50 or dissection NHLBI type C refractoryto prolonged(gt2 minute) balloon inflations) Bifurcation lesions are otherwise excluded if the plannedstrategy definitely requires2 stents (eg planned T-stenting V-stenting culotte stenting or crush)
2 The presence of a bifurcation lesion in the infarct vessel which will definitely require the implantation of two stents for treatment
Note A true bifurcationlesion qualifiesfor randomizationif the operatorbelieves heshe will be likely able to successfully approachthe lesion with provisionalstenting (ie the side branch ostial lesion is dilatedfirst and stented onlybr a sub-optimal result as defined above after prolonged(gt2 minute) ballooninflations)
3 Anticipated need for greater than 100mm of study stent length 4 The infarct related artery is an unprotected left main segment 5 Patients with significant multi-vessel disease or anatomical features otherwise unfavorable
for angioplasty such that the patient will have a high likelihood of requiring bypass surgery prior to 30 days
6 The culprit vessel or lesion cannot be identified 7 Patient presenting with possibleprobable stent thrombosis 8 Any patient in whom angiography demonstrates the infarct lesion to be at the site of a
previously implanted stent (bare metal or drug-eluting)
2 Follow-up Schedule
Clinical follow-up was performed at 30 days (plusmn 1 week) 6 months (plusmn 2 weeks) 1 year (+ 2 weeks) 2 years (plusmn I month) and 3 years (plusmn 1month) Angiographic follow-up was performed at 13 months (-2 weeks + 52 weeks) for a subset of patients (approximately the first 1500 randomized patients) Certain sites also participated in the HORIZONS IVUS substudy where intravascular ultrasound was performed at baseline (post-procedure) and at 13 month follow-up (approximately the first 400 patients)
3 Clinical Endpoints
Primary Efficacy Endpoint Ischemic target lesion revascularization Primary Safety Endpoint The composite rate of death reinfarction stent thrombosis
or stroke (MACE)
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Major Secondary Endpoint Analysis segment binary restenosis in the 13 month angiographic subset
All primary and major secondary endpoints were analyzed both on an intent-to-treat (ITT) basis
(all patients analyzed as part of their assigned treatment group) and on a per protocol basis
(patients analyzed as part of their assigned treatment group only if they actually received their
assigned treatment) The principal analyses were by intention-to-treat
The primary and major secondary endpoints were analyzed using risk differences and compared to the pre-specified non-inferiority margin Kaplan-Meier curves and survival analyses were also constructed Secondary efficacy and safety data were analyzed using descriptive statistics
For principle statistical analyses all endpoints were analyzed on a per patient basis
B Accountability of PMA Cohort
Refer to Table 3 for primary endpoint patient disposition
Table 2 Patient Disposition
TAXUS DES EXPRESS BMS Combined Patient Disposition N=2257 N=749 N=3006
Patients Enrolled (ITT Population) 1000 (22572257) 1000 (749749) 1000 (30063006)
Completed I year follow-up 969 (21862257) 955 (715749) 965 (29013006) Reason not completed
Lost to Follow-up 30 (682257) 40 (30749) 33 (983006)
PatientPhysician withdrawal 09 (202257) 11 (8749) 09 (283006)
Death 34 (762257) 35 (26749) 34 (1023006)
Patients qualified for PP analysis 951 (21462257) 960 (719749) 953 (28653006)
Stented Patients 992 (22382257) 993 (744749) 992 (29823006)
Includes patients with 30 day 6 month or 1 year follow-up or any follow-up visit post the follow-up window or
any MACE event
C Study Population Demographics and Baseline Parameters
The baseline demographics and medical history are reported in Table 4
Table 3 HORIZONS AMI Patient Demogra hics and Medical Histor ITT Po ulation) TAXUS Express Bare Metal Expressshy
(N=2257) (749)
Age (median (IQR) yrs) 599 (524 694) 593 (518 692) Male 770 (17382257) _ 760 (569749) Diabetes rnellitus 161 (3642256) 152 (114749)
- Insulin requiring 43 (982256) 41 (31749) Hypertension 512 (1152256) 519 (389749) Hyperlipidemia 422 (95312256) 411 (3081749) Current smoker 463 (10412246) 519 (388748) Prior myocardial infarction 91 (2062256) 109 (821749) Prior percutaneous coronary intervention 95 (2142255) 77 (58749)
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Prior coronary artery bypass graft 22 (502256) 19 (14749) Anemia 110 (2352130) 76 (54715) Killip class 2-4 88 (1992254) 80 (60748) Renal insufficiency2 156 (3282102) 154 (107696) LVEF 3lt40 143 (2791948) 140 (91652) IQR = interquartile range Defined using the World Health Organization (WHO) criteria as a hematocrit value at initial presentation of lt39 for men and lt36 for women 2Baseline calculated creatinine clearance using the Cockcroft-Gault equation lt60 mLmin
Left ventricular ejection fraction visual assessment from the baseline contrast left ventriculogram
D Safety and Effectiveness Results
The primary and secondary endpoints of the trial were met and are reported in Table 5 and Table 6 Theclinical results of the trial are reported in Table 7 In Figure 1 the rates of ischemic TLR are illustrated for all patients and those patients who were not in the protocol required angiographic subset Figures 2-6 provide results of major clinical outcomes to 3 years Angiographic and IVUS results are reported in Table 8
Table 4 HORIZONS AMI Primary Endpoints UTAXUSExpress Bare Metal Difference HazardRatih - P-vaie
Isehemic TLR (N=2257) Express (95 C)(95tl) (N=749) -
I Year 45 (98) 75 (54) -30 (-51 -09) 059 (043 083) 00018
Safety MACE TAXL Exptes BareMetal 7 Difference HazardRatio YP-valuie
(N=2257) Express (9CI J95CI) - (N=749) lt _____
I Year 81 (181) 80 (59) 01 (-21 24) 102 (076 136) 00075 P-value for the test of superiority
Safety MACE includes death reinfarction stroke or stent thrombosis
3 P-value for the test of non-inferiority
Table 5 HORIZONS AMI Secondary Endpoint
Binary TAXUS I re Metali Difference - Hazard Ratio P-value Res Express - 5 CI) (95 C)-Express
er Leion) N 2257 (N-749) _ 1
13 Month 100 (1081081) 229 (76322) -129 (-180 - 044 (033 lt00001 78) 057)
P-value superiority
Adverse effects that occurred in the PMA clinical study
Observed adverse event experience comes from the HORIZONS AMI trial Major clinical
events for this study are shown in Table 6
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 1 2 and 3 Years (ITT Population)
Expressi Bare Metal Express- -TAXUS
30 Day Clinical Endpoints Net Adverse Clinical Events 103 (232) 90 (67) MACE 12 48 (109) 45 (34)
43 (32)MACE 2 (Safety MACE)3 45 (102)
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Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
Death - Cardiac -Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischemic TVR Ischemic TLR Stroke Major bleeding (non-CABG) Target Lesion stent thrombosis
1 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE)3
Death - Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction schemic TVR schemic TLR
Stroke
Major bleeding (non-CABG) Target Lesion stent thrombosis
2 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE) Death
- Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischernic TVR Ischemic TLR StrokeP Major bleeding (non-CABG) Target Lesion stent thrombosis
3 Year Clinical Endpoints I4et Adverse ClinicalEventsl
SMACE 14
Du A P060008SO4
TAXUS Exprcs (N-2257-7 21 (47) 20 (44) 01(3) 17 (37) 12 (28) 04(10)
36(80) 23 (51) 21 (46) 05 (11) 71(159) 23 (50)
158 (355) 106 (237) 81 (181) 35(7 8 ) 24(54) 11(24)
37(81) 20(45) 18(39)
68(152) 59 (129) 46 (101)
10(23)
77 (172) 31 (69)
215 (480) 168 (373) 110 (245)
43 (96) 27 (60) 17 (36)
57 (123) 31 (67) 10 (64) 94 (210) 109 (236) 83 (180) 14(30)
80 (178) 42 (91)
245 (544) 200k441)240(75
FTDA Sulmmary of Safety and Effectiveness Data
Bare MctalExpr
19(14) 17(13) 01(1) 22(16) 16(12) 05(4)
35 (26) 26 (19) 26 (19) 05 (4) 56 (42) 27 (20)
163(121) 124 (92) 80 (59) 35 (26) 27 (20) 08(6)
45 (33) 19(14) 26(19) 70 (52) 88 (64) 74 (54) 07(5)
66 (49) 34 (25)
260 (191) 222 (162) 112 (82) 53 (39) 33 (24) 21 (15) 60 (43) 28 (20) 32 (23) 98 (72)
167(119) 142 (101)
11(8) 70 (52) 41 (30)
280 (205)
page 12
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
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18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
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Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
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6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
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Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
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Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
Below is a list of the potential adverse effects (eg complications) in alphabetical order which may be associated with the use of a coronary stent in coronary arteries
Abrupt stent closure Acute myocardial infarction o Allergic reaction to anticoagulants or antithrombotic therapy or contrast medium or stent
materials Angina Arrhythmias including ventricular fibrillation (VF) and ventricular tachycardia (VT) Arteriovenous fistula Cardiac tamponade Cardiogenic shock pulmonary edema Death Dissection Emboli distal (air tissue or thrombotic material or material from device(s) used in the
procedure) Heart failure Hematoma Hemorrhage requiring transfusion Hypotensionhypertension Infection local andor systemic o Ischemia myocardial Pain at the access site o Perforation or rupture of coronary artery o Pericardial effusion Pseudoaneurysm feioral Renal failure Respiratory failure Restenosis of stented segment Shock Stent embolization Stent migration Stent thrombosisocclusion Strokecerebrovascular accidentTIA Total occlusion of coronary artery Vessel spasm Vessel trauma requiring surgical repair or reintervention
Potential adverse events not captured above that may be unique to the paclitaxel drug coating
Allergicimmunologic reaction to drug (paclitaxel or structurally-related compounds) or the polymer stent coating (or its individual components)
Alopecia Anemia Blood product transfusion Gastrointestinal symptoms
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 4
Hematologic dyscrasia (including leukopenia neutropenia thrombocytopenia) Hepatic enzyme changes Histologic changes in vessel wall including inflammation cellular damage or necrosis Myalgia arthralgia Peripheral neuropathy
For the specific adverse events that occurred in the HORIZONS AMI clinical study please see Section X below
IX SUMMARY OF PRECLINICAL STUDIES
A series of non-clinical laboratory studies were performed to support the original approval and subsequent indication expansions - those related to the stent and the stent delivery system [ie the stent on either the Monorail (MR) or Over-The-Wire (OTW) stent delivery system (SDS)]the polymer substance [ie poly(styrene-b-isobutylene-b-styrene) (SIBS)] the drug substance (ie paclitaxel) and the finished combination product (ie TAXUS Libert6 Paclitaxel-Eluting Coronary Stent) No new nonclinical studies were needed to support the approval of this supplement
X SUMMARY OF CLINICAL STUDIES
A series of clinical studies (TAXUS ATLAS Workhorse ATLAS Small Vessel and ATLAS Long Lesion) were performed to support the original approval and subsequent indication expansions Please refer to previous SSEDs for details The HORIZONS AMI trial was performed to establish a reasonable assurance of safety and effectiveness for TAXUS Express 2
Paclitaxel-Eluting Coronary Stent System for the proposed expanded indication under IDE G040188 Data from this clinical study were the basis for the PMA approval decision The TAXUS Liberte stent uses the same drug-polymer coating formulation as the TAXUS Express 2
stent In addition nonclinical studies of design attributes and the ATLAS clinical studies in stable patients with coronary artery disease have established that the performance of the TAXUS Libert6 is similar Given these supportive data outcomes in patients with AMI would also be expected to be similar between these two stents and therefore the safety and effectiveness data from the HORIZONS AMI trial were considered applicable for the TAXUS Libert6 Paclitaxel-Eluting Coronary Stent System as well A summary of the clinical study is presented below
A HORIZONS AMI Clinical Trial
Objectives The trial had two primary objectives and was designed and powered to address both the primary and sub-study objectives
Primary objective for the pharmacology randomization To evaluate the use of bivalirudin in patients with ST segment elevation acute myocardial infarction (STEMI) undergoing a primary angioplasty strategy compared to unfractionated heparin plus routine use of GP lIbIlla inhibitors
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 5
Primary objective for the stent randomization To establish the safety and effectiveness of the paclitaxel-eluting TAXUS Express stent in STEMI patients by showing that compared to an otherwise identical Express BMS the TAXUS Express results in (1) reduced rates of ischemia-driven target lesion revascularization at 1 year (2) a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year and (3) a lower rate of analysis segment binary angiographic restenosis at 13 months
Design
The HORIZONS AMI trial was a prospective dual-arm single-blind randomized multi-center trial that enrolled STEMI patients defined by clinical symptoms consistent with acute MI lasting greater than 20 minutes but less than 12 hours and specific ECG criteria consisting of ST-segment elevation of gt 1mm in gt 2 contiguous leads presumed new LBBB or true posterior MI with ST depression of gt Imm in gt 2 contiguous anterior leads A total of 3602 patients were randomized (primary randomization) in a 11 fashion in the emergency room to anticoagulation with unfractionated heparin plus routine GP Ilblila inhibition or bivalirudin and bail-out GP IlbIla inhibition
Emergent coronary angiography with left ventriculography was performed after the primary randomization followed by triage to either percutaneous coronary intervention (PCI) coronary artery bypass graft (CABG) surgery or medical management at physician discretion
After coronary angiography a total of 3006 patients were triaged to PCI and randomized (secondary randomization) in a 31 fashion to either a TAXUS Express stent or an Express stent In order to be eligible for the second randomization patients had to have at least one acute infarct-related artery with an expectation that study stents could be delivered to all culprit lesions Exclusion criteria included true bifurcation lesions definitely requiring stenting of the side branch vessel lesions requiring greater than 100 mum of stent length unprotected left main culprit lesions and stent thrombosis lesions The secondary randomization was stratified by the following four factors the result from the primary randomization (to ensure equal distribution of the two arms from the primary randomization in the secondary randomization) the presence or absence of medically treated diabetes whether any of the lesions were greater than 26 mm in length such that overlapping stents would be used and whether the clinical study site was within or outside of the US
Table 1 HORIZONS AMI CLINICAL TRIAL OVERVIEW
HORIZONS AMI (Indication Expansion)
Study Type Prospective multicenter randomized single-blind
Total 3006 Number of Patients (ITT) TAXUS 2257
Control 749
Dose Release Formulation Slow Release (SR) (1 g mm2)
gt 25 mm to Lesion Criteria Vessel Diameter (by visual estimate) lt 40 mm
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 6
HORIZONS AMI (Indication Expansion)
Lesion Criteria Lesion Length (by visual estimate) lt 100 mm
Product Used TAXUS Express Paclitaxel-Eluting Coronary Stent System
Antiplatelet Therapy Aspirin indefinitely and clopidogrel or ticlopidine for 6 months (I year or longer recommended)
30 days clinical 6 months clinical
Follow-Up 12 month clinical 13 month angiographicIVUS
2 3 years clinical
Abbreviations ITT=intent-to-treat IVUS=intravascular ultrasound
1 Clinical Inclusion and Exclusion Criteria
Primary Randomization - Inclusion Criteria
1 The patient must be at least 18 years of age (there is no upper age limit) 2 Must have clinical symptoms consistent with AMI (eg angina or anginal equivalent) lasting
gt20 minutes but lt12 hours in duration If the symptom duration at the time of evaluation is lt1 hour to rule out unstable angina the symptoms must be unresponsive to nitroglycerin (ie ongoing) prior to signing the informed consent Patients with symptom onset within 12 hours in whom the symptoms lasted gt1 hour but subsequently resolved may still be enrolled if the ECG at the time of the evaluation shows definite ongoing ST segment elevation
3 ECG criteria ST-segment elevation of gt 1 mm in gt 2 contiguous leads or (presumably new) left bundle branch block or true posterior MI with ST depression of gt 1 mm in gt 2 contiguous anterior leads
4 The patient or guardian agrees to the study protocol and the schedule of clinical and angiographic follow-up and provides informed written consent as approved by the appropriate Institutional Review BoardEthical Committee of the respective clinical site
Primary Randomization - Exclusion Criteria
1 The patient has a known hypersensitivity or contraindication to any of the following medications
Heparin pork or pork products Both abciximab and eptifibatide Aspirin Both Clopidogrel and Ticlopidine Bivalirudin Paclitaxel or Taxol
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 7
o The polymer components of the TAXUS Express DES stent (SIBS) Stainless steel andor o Contrast media (patients with documented sensitivity to contrast which can be
effectively pre-medicated with steroids and diphenhydramine (eg rash) may be
enrolled Patients with true anaphylaxis to prior contrast media however should not be enrolled)
2 Prior administration of thrombolytic therapy bivalirudin GP IlbIlla inhibitors low molecular weight heparin or fondaparinux for this admission Patients receiving prior unfractionated heparin may be enrolled and treated per randomization
3 Current use of coumadin 4 Systemic (intravenous) Paclitaxel or Taxol use within 12 months 5 Female of childbearing potential unless a recent pregnancy test is negative who possibly
plans to become pregnant any time after enrollment into this study 6 History of bleeding diathesis or known coagulopathy (including heparin-induced
thrombocytopenia) or will refuse blood transfusions 7 History of intra-cerebral mass aneurysm arteriovenous malformation or hemorrhagic
stroke 8 Stroke or transient ischemic attack within the past 6 months or any permanent residual
neurologic defect 9 Gastrointestinal or genitourinary bleeding within the last 2 months or major surgery within
six weeks 10 Recent history or known current platelet count lt100000 cellsmm3 or Hgb lt10 gdL (note
baseline labs did not have to be available prior to enrollment) 11 Extensive peripheral vascular disease such that emergent angiography and intervention in
the opinion of the investigator is likely to be difficult or complicated 12 An elective surgical procedure is planned that would necessitate interruption of
thienopyridines during the first six months post enrollment 13 Non-cardiac co-morbid conditions are present with life expectancy lt1 year or that may result
in protocol non-compliance 14 Patients who are actively participating in another drug or device investigational study which
have not completed the primary endpoint follow-up period 15 Previous enrollment in this trial 16 Patients who underwent coronary stent implantation within the past 30 days
Secondary Randomization - Angiographic Inclusion Criteria
1 At least one acute infarct artery target vessel is present in which a ALL hemodynamically significant lesions can be stented with study stents and
b ALL such lesions have a visually estimated reference diameter gt225 mm and lt 40
nun 2 Expected ability to deliver the stent(s) to all culprit lesions (absence of excessive proximal
tortuosity or severe calcification) 3 Expected ability to fully expand the stent(s) at all culprit lesions (absence of marked
calcification)
Secondary Randomization - Angiographic Exclusion Criteria
PMA P0600080o46 FDA Summary of Safety and Effectiveness Data page 8
1 One or more hemodynamically significant lesion(s) is present in the infarct vessel (or side branches) which can only undergo balloon angioplasty or cannot be stented with a study stent (ie do not meet the angiographic inclusion criteria for a study stent)
Note The only exception to this exclusion criterionis bifurcationlesions with main branch andostial side branch involvement which may be enrolledas long as the main branch is eligible to be treatedwith a study stent The ostialside branch lesion should then be treated with balloon angioplastywith bail-outstenting performed onlyfor a sub-optimalresult in the side branch(diameterstenosis gt50 or dissection NHLBI type C refractoryto prolonged(gt2 minute) balloon inflations) Bifurcation lesions are otherwise excluded if the plannedstrategy definitely requires2 stents (eg planned T-stenting V-stenting culotte stenting or crush)
2 The presence of a bifurcation lesion in the infarct vessel which will definitely require the implantation of two stents for treatment
Note A true bifurcationlesion qualifiesfor randomizationif the operatorbelieves heshe will be likely able to successfully approachthe lesion with provisionalstenting (ie the side branch ostial lesion is dilatedfirst and stented onlybr a sub-optimal result as defined above after prolonged(gt2 minute) ballooninflations)
3 Anticipated need for greater than 100mm of study stent length 4 The infarct related artery is an unprotected left main segment 5 Patients with significant multi-vessel disease or anatomical features otherwise unfavorable
for angioplasty such that the patient will have a high likelihood of requiring bypass surgery prior to 30 days
6 The culprit vessel or lesion cannot be identified 7 Patient presenting with possibleprobable stent thrombosis 8 Any patient in whom angiography demonstrates the infarct lesion to be at the site of a
previously implanted stent (bare metal or drug-eluting)
2 Follow-up Schedule
Clinical follow-up was performed at 30 days (plusmn 1 week) 6 months (plusmn 2 weeks) 1 year (+ 2 weeks) 2 years (plusmn I month) and 3 years (plusmn 1month) Angiographic follow-up was performed at 13 months (-2 weeks + 52 weeks) for a subset of patients (approximately the first 1500 randomized patients) Certain sites also participated in the HORIZONS IVUS substudy where intravascular ultrasound was performed at baseline (post-procedure) and at 13 month follow-up (approximately the first 400 patients)
3 Clinical Endpoints
Primary Efficacy Endpoint Ischemic target lesion revascularization Primary Safety Endpoint The composite rate of death reinfarction stent thrombosis
or stroke (MACE)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 9
Major Secondary Endpoint Analysis segment binary restenosis in the 13 month angiographic subset
All primary and major secondary endpoints were analyzed both on an intent-to-treat (ITT) basis
(all patients analyzed as part of their assigned treatment group) and on a per protocol basis
(patients analyzed as part of their assigned treatment group only if they actually received their
assigned treatment) The principal analyses were by intention-to-treat
The primary and major secondary endpoints were analyzed using risk differences and compared to the pre-specified non-inferiority margin Kaplan-Meier curves and survival analyses were also constructed Secondary efficacy and safety data were analyzed using descriptive statistics
For principle statistical analyses all endpoints were analyzed on a per patient basis
B Accountability of PMA Cohort
Refer to Table 3 for primary endpoint patient disposition
Table 2 Patient Disposition
TAXUS DES EXPRESS BMS Combined Patient Disposition N=2257 N=749 N=3006
Patients Enrolled (ITT Population) 1000 (22572257) 1000 (749749) 1000 (30063006)
Completed I year follow-up 969 (21862257) 955 (715749) 965 (29013006) Reason not completed
Lost to Follow-up 30 (682257) 40 (30749) 33 (983006)
PatientPhysician withdrawal 09 (202257) 11 (8749) 09 (283006)
Death 34 (762257) 35 (26749) 34 (1023006)
Patients qualified for PP analysis 951 (21462257) 960 (719749) 953 (28653006)
Stented Patients 992 (22382257) 993 (744749) 992 (29823006)
Includes patients with 30 day 6 month or 1 year follow-up or any follow-up visit post the follow-up window or
any MACE event
C Study Population Demographics and Baseline Parameters
The baseline demographics and medical history are reported in Table 4
Table 3 HORIZONS AMI Patient Demogra hics and Medical Histor ITT Po ulation) TAXUS Express Bare Metal Expressshy
(N=2257) (749)
Age (median (IQR) yrs) 599 (524 694) 593 (518 692) Male 770 (17382257) _ 760 (569749) Diabetes rnellitus 161 (3642256) 152 (114749)
- Insulin requiring 43 (982256) 41 (31749) Hypertension 512 (1152256) 519 (389749) Hyperlipidemia 422 (95312256) 411 (3081749) Current smoker 463 (10412246) 519 (388748) Prior myocardial infarction 91 (2062256) 109 (821749) Prior percutaneous coronary intervention 95 (2142255) 77 (58749)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 10 IS
Prior coronary artery bypass graft 22 (502256) 19 (14749) Anemia 110 (2352130) 76 (54715) Killip class 2-4 88 (1992254) 80 (60748) Renal insufficiency2 156 (3282102) 154 (107696) LVEF 3lt40 143 (2791948) 140 (91652) IQR = interquartile range Defined using the World Health Organization (WHO) criteria as a hematocrit value at initial presentation of lt39 for men and lt36 for women 2Baseline calculated creatinine clearance using the Cockcroft-Gault equation lt60 mLmin
Left ventricular ejection fraction visual assessment from the baseline contrast left ventriculogram
D Safety and Effectiveness Results
The primary and secondary endpoints of the trial were met and are reported in Table 5 and Table 6 Theclinical results of the trial are reported in Table 7 In Figure 1 the rates of ischemic TLR are illustrated for all patients and those patients who were not in the protocol required angiographic subset Figures 2-6 provide results of major clinical outcomes to 3 years Angiographic and IVUS results are reported in Table 8
Table 4 HORIZONS AMI Primary Endpoints UTAXUSExpress Bare Metal Difference HazardRatih - P-vaie
Isehemic TLR (N=2257) Express (95 C)(95tl) (N=749) -
I Year 45 (98) 75 (54) -30 (-51 -09) 059 (043 083) 00018
Safety MACE TAXL Exptes BareMetal 7 Difference HazardRatio YP-valuie
(N=2257) Express (9CI J95CI) - (N=749) lt _____
I Year 81 (181) 80 (59) 01 (-21 24) 102 (076 136) 00075 P-value for the test of superiority
Safety MACE includes death reinfarction stroke or stent thrombosis
3 P-value for the test of non-inferiority
Table 5 HORIZONS AMI Secondary Endpoint
Binary TAXUS I re Metali Difference - Hazard Ratio P-value Res Express - 5 CI) (95 C)-Express
er Leion) N 2257 (N-749) _ 1
13 Month 100 (1081081) 229 (76322) -129 (-180 - 044 (033 lt00001 78) 057)
P-value superiority
Adverse effects that occurred in the PMA clinical study
Observed adverse event experience comes from the HORIZONS AMI trial Major clinical
events for this study are shown in Table 6
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 1 2 and 3 Years (ITT Population)
Expressi Bare Metal Express- -TAXUS
30 Day Clinical Endpoints Net Adverse Clinical Events 103 (232) 90 (67) MACE 12 48 (109) 45 (34)
43 (32)MACE 2 (Safety MACE)3 45 (102)
PMA P0600085046 FDA Summary of Safety and Effectiveness Data page 11
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
Death - Cardiac -Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischemic TVR Ischemic TLR Stroke Major bleeding (non-CABG) Target Lesion stent thrombosis
1 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE)3
Death - Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction schemic TVR schemic TLR
Stroke
Major bleeding (non-CABG) Target Lesion stent thrombosis
2 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE) Death
- Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischernic TVR Ischemic TLR StrokeP Major bleeding (non-CABG) Target Lesion stent thrombosis
3 Year Clinical Endpoints I4et Adverse ClinicalEventsl
SMACE 14
Du A P060008SO4
TAXUS Exprcs (N-2257-7 21 (47) 20 (44) 01(3) 17 (37) 12 (28) 04(10)
36(80) 23 (51) 21 (46) 05 (11) 71(159) 23 (50)
158 (355) 106 (237) 81 (181) 35(7 8 ) 24(54) 11(24)
37(81) 20(45) 18(39)
68(152) 59 (129) 46 (101)
10(23)
77 (172) 31 (69)
215 (480) 168 (373) 110 (245)
43 (96) 27 (60) 17 (36)
57 (123) 31 (67) 10 (64) 94 (210) 109 (236) 83 (180) 14(30)
80 (178) 42 (91)
245 (544) 200k441)240(75
FTDA Sulmmary of Safety and Effectiveness Data
Bare MctalExpr
19(14) 17(13) 01(1) 22(16) 16(12) 05(4)
35 (26) 26 (19) 26 (19) 05 (4) 56 (42) 27 (20)
163(121) 124 (92) 80 (59) 35 (26) 27 (20) 08(6)
45 (33) 19(14) 26(19) 70 (52) 88 (64) 74 (54) 07(5)
66 (49) 34 (25)
260 (191) 222 (162) 112 (82) 53 (39) 33 (24) 21 (15) 60 (43) 28 (20) 32 (23) 98 (72)
167(119) 142 (101)
11(8) 70 (52) 41 (30)
280 (205)
page 12
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 13
18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 14
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
Hematologic dyscrasia (including leukopenia neutropenia thrombocytopenia) Hepatic enzyme changes Histologic changes in vessel wall including inflammation cellular damage or necrosis Myalgia arthralgia Peripheral neuropathy
For the specific adverse events that occurred in the HORIZONS AMI clinical study please see Section X below
IX SUMMARY OF PRECLINICAL STUDIES
A series of non-clinical laboratory studies were performed to support the original approval and subsequent indication expansions - those related to the stent and the stent delivery system [ie the stent on either the Monorail (MR) or Over-The-Wire (OTW) stent delivery system (SDS)]the polymer substance [ie poly(styrene-b-isobutylene-b-styrene) (SIBS)] the drug substance (ie paclitaxel) and the finished combination product (ie TAXUS Libert6 Paclitaxel-Eluting Coronary Stent) No new nonclinical studies were needed to support the approval of this supplement
X SUMMARY OF CLINICAL STUDIES
A series of clinical studies (TAXUS ATLAS Workhorse ATLAS Small Vessel and ATLAS Long Lesion) were performed to support the original approval and subsequent indication expansions Please refer to previous SSEDs for details The HORIZONS AMI trial was performed to establish a reasonable assurance of safety and effectiveness for TAXUS Express 2
Paclitaxel-Eluting Coronary Stent System for the proposed expanded indication under IDE G040188 Data from this clinical study were the basis for the PMA approval decision The TAXUS Liberte stent uses the same drug-polymer coating formulation as the TAXUS Express 2
stent In addition nonclinical studies of design attributes and the ATLAS clinical studies in stable patients with coronary artery disease have established that the performance of the TAXUS Libert6 is similar Given these supportive data outcomes in patients with AMI would also be expected to be similar between these two stents and therefore the safety and effectiveness data from the HORIZONS AMI trial were considered applicable for the TAXUS Libert6 Paclitaxel-Eluting Coronary Stent System as well A summary of the clinical study is presented below
A HORIZONS AMI Clinical Trial
Objectives The trial had two primary objectives and was designed and powered to address both the primary and sub-study objectives
Primary objective for the pharmacology randomization To evaluate the use of bivalirudin in patients with ST segment elevation acute myocardial infarction (STEMI) undergoing a primary angioplasty strategy compared to unfractionated heparin plus routine use of GP lIbIlla inhibitors
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 5
Primary objective for the stent randomization To establish the safety and effectiveness of the paclitaxel-eluting TAXUS Express stent in STEMI patients by showing that compared to an otherwise identical Express BMS the TAXUS Express results in (1) reduced rates of ischemia-driven target lesion revascularization at 1 year (2) a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year and (3) a lower rate of analysis segment binary angiographic restenosis at 13 months
Design
The HORIZONS AMI trial was a prospective dual-arm single-blind randomized multi-center trial that enrolled STEMI patients defined by clinical symptoms consistent with acute MI lasting greater than 20 minutes but less than 12 hours and specific ECG criteria consisting of ST-segment elevation of gt 1mm in gt 2 contiguous leads presumed new LBBB or true posterior MI with ST depression of gt Imm in gt 2 contiguous anterior leads A total of 3602 patients were randomized (primary randomization) in a 11 fashion in the emergency room to anticoagulation with unfractionated heparin plus routine GP Ilblila inhibition or bivalirudin and bail-out GP IlbIla inhibition
Emergent coronary angiography with left ventriculography was performed after the primary randomization followed by triage to either percutaneous coronary intervention (PCI) coronary artery bypass graft (CABG) surgery or medical management at physician discretion
After coronary angiography a total of 3006 patients were triaged to PCI and randomized (secondary randomization) in a 31 fashion to either a TAXUS Express stent or an Express stent In order to be eligible for the second randomization patients had to have at least one acute infarct-related artery with an expectation that study stents could be delivered to all culprit lesions Exclusion criteria included true bifurcation lesions definitely requiring stenting of the side branch vessel lesions requiring greater than 100 mum of stent length unprotected left main culprit lesions and stent thrombosis lesions The secondary randomization was stratified by the following four factors the result from the primary randomization (to ensure equal distribution of the two arms from the primary randomization in the secondary randomization) the presence or absence of medically treated diabetes whether any of the lesions were greater than 26 mm in length such that overlapping stents would be used and whether the clinical study site was within or outside of the US
Table 1 HORIZONS AMI CLINICAL TRIAL OVERVIEW
HORIZONS AMI (Indication Expansion)
Study Type Prospective multicenter randomized single-blind
Total 3006 Number of Patients (ITT) TAXUS 2257
Control 749
Dose Release Formulation Slow Release (SR) (1 g mm2)
gt 25 mm to Lesion Criteria Vessel Diameter (by visual estimate) lt 40 mm
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 6
HORIZONS AMI (Indication Expansion)
Lesion Criteria Lesion Length (by visual estimate) lt 100 mm
Product Used TAXUS Express Paclitaxel-Eluting Coronary Stent System
Antiplatelet Therapy Aspirin indefinitely and clopidogrel or ticlopidine for 6 months (I year or longer recommended)
30 days clinical 6 months clinical
Follow-Up 12 month clinical 13 month angiographicIVUS
2 3 years clinical
Abbreviations ITT=intent-to-treat IVUS=intravascular ultrasound
1 Clinical Inclusion and Exclusion Criteria
Primary Randomization - Inclusion Criteria
1 The patient must be at least 18 years of age (there is no upper age limit) 2 Must have clinical symptoms consistent with AMI (eg angina or anginal equivalent) lasting
gt20 minutes but lt12 hours in duration If the symptom duration at the time of evaluation is lt1 hour to rule out unstable angina the symptoms must be unresponsive to nitroglycerin (ie ongoing) prior to signing the informed consent Patients with symptom onset within 12 hours in whom the symptoms lasted gt1 hour but subsequently resolved may still be enrolled if the ECG at the time of the evaluation shows definite ongoing ST segment elevation
3 ECG criteria ST-segment elevation of gt 1 mm in gt 2 contiguous leads or (presumably new) left bundle branch block or true posterior MI with ST depression of gt 1 mm in gt 2 contiguous anterior leads
4 The patient or guardian agrees to the study protocol and the schedule of clinical and angiographic follow-up and provides informed written consent as approved by the appropriate Institutional Review BoardEthical Committee of the respective clinical site
Primary Randomization - Exclusion Criteria
1 The patient has a known hypersensitivity or contraindication to any of the following medications
Heparin pork or pork products Both abciximab and eptifibatide Aspirin Both Clopidogrel and Ticlopidine Bivalirudin Paclitaxel or Taxol
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 7
o The polymer components of the TAXUS Express DES stent (SIBS) Stainless steel andor o Contrast media (patients with documented sensitivity to contrast which can be
effectively pre-medicated with steroids and diphenhydramine (eg rash) may be
enrolled Patients with true anaphylaxis to prior contrast media however should not be enrolled)
2 Prior administration of thrombolytic therapy bivalirudin GP IlbIlla inhibitors low molecular weight heparin or fondaparinux for this admission Patients receiving prior unfractionated heparin may be enrolled and treated per randomization
3 Current use of coumadin 4 Systemic (intravenous) Paclitaxel or Taxol use within 12 months 5 Female of childbearing potential unless a recent pregnancy test is negative who possibly
plans to become pregnant any time after enrollment into this study 6 History of bleeding diathesis or known coagulopathy (including heparin-induced
thrombocytopenia) or will refuse blood transfusions 7 History of intra-cerebral mass aneurysm arteriovenous malformation or hemorrhagic
stroke 8 Stroke or transient ischemic attack within the past 6 months or any permanent residual
neurologic defect 9 Gastrointestinal or genitourinary bleeding within the last 2 months or major surgery within
six weeks 10 Recent history or known current platelet count lt100000 cellsmm3 or Hgb lt10 gdL (note
baseline labs did not have to be available prior to enrollment) 11 Extensive peripheral vascular disease such that emergent angiography and intervention in
the opinion of the investigator is likely to be difficult or complicated 12 An elective surgical procedure is planned that would necessitate interruption of
thienopyridines during the first six months post enrollment 13 Non-cardiac co-morbid conditions are present with life expectancy lt1 year or that may result
in protocol non-compliance 14 Patients who are actively participating in another drug or device investigational study which
have not completed the primary endpoint follow-up period 15 Previous enrollment in this trial 16 Patients who underwent coronary stent implantation within the past 30 days
Secondary Randomization - Angiographic Inclusion Criteria
1 At least one acute infarct artery target vessel is present in which a ALL hemodynamically significant lesions can be stented with study stents and
b ALL such lesions have a visually estimated reference diameter gt225 mm and lt 40
nun 2 Expected ability to deliver the stent(s) to all culprit lesions (absence of excessive proximal
tortuosity or severe calcification) 3 Expected ability to fully expand the stent(s) at all culprit lesions (absence of marked
calcification)
Secondary Randomization - Angiographic Exclusion Criteria
PMA P0600080o46 FDA Summary of Safety and Effectiveness Data page 8
1 One or more hemodynamically significant lesion(s) is present in the infarct vessel (or side branches) which can only undergo balloon angioplasty or cannot be stented with a study stent (ie do not meet the angiographic inclusion criteria for a study stent)
Note The only exception to this exclusion criterionis bifurcationlesions with main branch andostial side branch involvement which may be enrolledas long as the main branch is eligible to be treatedwith a study stent The ostialside branch lesion should then be treated with balloon angioplastywith bail-outstenting performed onlyfor a sub-optimalresult in the side branch(diameterstenosis gt50 or dissection NHLBI type C refractoryto prolonged(gt2 minute) balloon inflations) Bifurcation lesions are otherwise excluded if the plannedstrategy definitely requires2 stents (eg planned T-stenting V-stenting culotte stenting or crush)
2 The presence of a bifurcation lesion in the infarct vessel which will definitely require the implantation of two stents for treatment
Note A true bifurcationlesion qualifiesfor randomizationif the operatorbelieves heshe will be likely able to successfully approachthe lesion with provisionalstenting (ie the side branch ostial lesion is dilatedfirst and stented onlybr a sub-optimal result as defined above after prolonged(gt2 minute) ballooninflations)
3 Anticipated need for greater than 100mm of study stent length 4 The infarct related artery is an unprotected left main segment 5 Patients with significant multi-vessel disease or anatomical features otherwise unfavorable
for angioplasty such that the patient will have a high likelihood of requiring bypass surgery prior to 30 days
6 The culprit vessel or lesion cannot be identified 7 Patient presenting with possibleprobable stent thrombosis 8 Any patient in whom angiography demonstrates the infarct lesion to be at the site of a
previously implanted stent (bare metal or drug-eluting)
2 Follow-up Schedule
Clinical follow-up was performed at 30 days (plusmn 1 week) 6 months (plusmn 2 weeks) 1 year (+ 2 weeks) 2 years (plusmn I month) and 3 years (plusmn 1month) Angiographic follow-up was performed at 13 months (-2 weeks + 52 weeks) for a subset of patients (approximately the first 1500 randomized patients) Certain sites also participated in the HORIZONS IVUS substudy where intravascular ultrasound was performed at baseline (post-procedure) and at 13 month follow-up (approximately the first 400 patients)
3 Clinical Endpoints
Primary Efficacy Endpoint Ischemic target lesion revascularization Primary Safety Endpoint The composite rate of death reinfarction stent thrombosis
or stroke (MACE)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 9
Major Secondary Endpoint Analysis segment binary restenosis in the 13 month angiographic subset
All primary and major secondary endpoints were analyzed both on an intent-to-treat (ITT) basis
(all patients analyzed as part of their assigned treatment group) and on a per protocol basis
(patients analyzed as part of their assigned treatment group only if they actually received their
assigned treatment) The principal analyses were by intention-to-treat
The primary and major secondary endpoints were analyzed using risk differences and compared to the pre-specified non-inferiority margin Kaplan-Meier curves and survival analyses were also constructed Secondary efficacy and safety data were analyzed using descriptive statistics
For principle statistical analyses all endpoints were analyzed on a per patient basis
B Accountability of PMA Cohort
Refer to Table 3 for primary endpoint patient disposition
Table 2 Patient Disposition
TAXUS DES EXPRESS BMS Combined Patient Disposition N=2257 N=749 N=3006
Patients Enrolled (ITT Population) 1000 (22572257) 1000 (749749) 1000 (30063006)
Completed I year follow-up 969 (21862257) 955 (715749) 965 (29013006) Reason not completed
Lost to Follow-up 30 (682257) 40 (30749) 33 (983006)
PatientPhysician withdrawal 09 (202257) 11 (8749) 09 (283006)
Death 34 (762257) 35 (26749) 34 (1023006)
Patients qualified for PP analysis 951 (21462257) 960 (719749) 953 (28653006)
Stented Patients 992 (22382257) 993 (744749) 992 (29823006)
Includes patients with 30 day 6 month or 1 year follow-up or any follow-up visit post the follow-up window or
any MACE event
C Study Population Demographics and Baseline Parameters
The baseline demographics and medical history are reported in Table 4
Table 3 HORIZONS AMI Patient Demogra hics and Medical Histor ITT Po ulation) TAXUS Express Bare Metal Expressshy
(N=2257) (749)
Age (median (IQR) yrs) 599 (524 694) 593 (518 692) Male 770 (17382257) _ 760 (569749) Diabetes rnellitus 161 (3642256) 152 (114749)
- Insulin requiring 43 (982256) 41 (31749) Hypertension 512 (1152256) 519 (389749) Hyperlipidemia 422 (95312256) 411 (3081749) Current smoker 463 (10412246) 519 (388748) Prior myocardial infarction 91 (2062256) 109 (821749) Prior percutaneous coronary intervention 95 (2142255) 77 (58749)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 10 IS
Prior coronary artery bypass graft 22 (502256) 19 (14749) Anemia 110 (2352130) 76 (54715) Killip class 2-4 88 (1992254) 80 (60748) Renal insufficiency2 156 (3282102) 154 (107696) LVEF 3lt40 143 (2791948) 140 (91652) IQR = interquartile range Defined using the World Health Organization (WHO) criteria as a hematocrit value at initial presentation of lt39 for men and lt36 for women 2Baseline calculated creatinine clearance using the Cockcroft-Gault equation lt60 mLmin
Left ventricular ejection fraction visual assessment from the baseline contrast left ventriculogram
D Safety and Effectiveness Results
The primary and secondary endpoints of the trial were met and are reported in Table 5 and Table 6 Theclinical results of the trial are reported in Table 7 In Figure 1 the rates of ischemic TLR are illustrated for all patients and those patients who were not in the protocol required angiographic subset Figures 2-6 provide results of major clinical outcomes to 3 years Angiographic and IVUS results are reported in Table 8
Table 4 HORIZONS AMI Primary Endpoints UTAXUSExpress Bare Metal Difference HazardRatih - P-vaie
Isehemic TLR (N=2257) Express (95 C)(95tl) (N=749) -
I Year 45 (98) 75 (54) -30 (-51 -09) 059 (043 083) 00018
Safety MACE TAXL Exptes BareMetal 7 Difference HazardRatio YP-valuie
(N=2257) Express (9CI J95CI) - (N=749) lt _____
I Year 81 (181) 80 (59) 01 (-21 24) 102 (076 136) 00075 P-value for the test of superiority
Safety MACE includes death reinfarction stroke or stent thrombosis
3 P-value for the test of non-inferiority
Table 5 HORIZONS AMI Secondary Endpoint
Binary TAXUS I re Metali Difference - Hazard Ratio P-value Res Express - 5 CI) (95 C)-Express
er Leion) N 2257 (N-749) _ 1
13 Month 100 (1081081) 229 (76322) -129 (-180 - 044 (033 lt00001 78) 057)
P-value superiority
Adverse effects that occurred in the PMA clinical study
Observed adverse event experience comes from the HORIZONS AMI trial Major clinical
events for this study are shown in Table 6
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 1 2 and 3 Years (ITT Population)
Expressi Bare Metal Express- -TAXUS
30 Day Clinical Endpoints Net Adverse Clinical Events 103 (232) 90 (67) MACE 12 48 (109) 45 (34)
43 (32)MACE 2 (Safety MACE)3 45 (102)
PMA P0600085046 FDA Summary of Safety and Effectiveness Data page 11
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
Death - Cardiac -Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischemic TVR Ischemic TLR Stroke Major bleeding (non-CABG) Target Lesion stent thrombosis
1 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE)3
Death - Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction schemic TVR schemic TLR
Stroke
Major bleeding (non-CABG) Target Lesion stent thrombosis
2 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE) Death
- Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischernic TVR Ischemic TLR StrokeP Major bleeding (non-CABG) Target Lesion stent thrombosis
3 Year Clinical Endpoints I4et Adverse ClinicalEventsl
SMACE 14
Du A P060008SO4
TAXUS Exprcs (N-2257-7 21 (47) 20 (44) 01(3) 17 (37) 12 (28) 04(10)
36(80) 23 (51) 21 (46) 05 (11) 71(159) 23 (50)
158 (355) 106 (237) 81 (181) 35(7 8 ) 24(54) 11(24)
37(81) 20(45) 18(39)
68(152) 59 (129) 46 (101)
10(23)
77 (172) 31 (69)
215 (480) 168 (373) 110 (245)
43 (96) 27 (60) 17 (36)
57 (123) 31 (67) 10 (64) 94 (210) 109 (236) 83 (180) 14(30)
80 (178) 42 (91)
245 (544) 200k441)240(75
FTDA Sulmmary of Safety and Effectiveness Data
Bare MctalExpr
19(14) 17(13) 01(1) 22(16) 16(12) 05(4)
35 (26) 26 (19) 26 (19) 05 (4) 56 (42) 27 (20)
163(121) 124 (92) 80 (59) 35 (26) 27 (20) 08(6)
45 (33) 19(14) 26(19) 70 (52) 88 (64) 74 (54) 07(5)
66 (49) 34 (25)
260 (191) 222 (162) 112 (82) 53 (39) 33 (24) 21 (15) 60 (43) 28 (20) 32 (23) 98 (72)
167(119) 142 (101)
11(8) 70 (52) 41 (30)
280 (205)
page 12
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 13
18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 14
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
Primary objective for the stent randomization To establish the safety and effectiveness of the paclitaxel-eluting TAXUS Express stent in STEMI patients by showing that compared to an otherwise identical Express BMS the TAXUS Express results in (1) reduced rates of ischemia-driven target lesion revascularization at 1 year (2) a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year and (3) a lower rate of analysis segment binary angiographic restenosis at 13 months
Design
The HORIZONS AMI trial was a prospective dual-arm single-blind randomized multi-center trial that enrolled STEMI patients defined by clinical symptoms consistent with acute MI lasting greater than 20 minutes but less than 12 hours and specific ECG criteria consisting of ST-segment elevation of gt 1mm in gt 2 contiguous leads presumed new LBBB or true posterior MI with ST depression of gt Imm in gt 2 contiguous anterior leads A total of 3602 patients were randomized (primary randomization) in a 11 fashion in the emergency room to anticoagulation with unfractionated heparin plus routine GP Ilblila inhibition or bivalirudin and bail-out GP IlbIla inhibition
Emergent coronary angiography with left ventriculography was performed after the primary randomization followed by triage to either percutaneous coronary intervention (PCI) coronary artery bypass graft (CABG) surgery or medical management at physician discretion
After coronary angiography a total of 3006 patients were triaged to PCI and randomized (secondary randomization) in a 31 fashion to either a TAXUS Express stent or an Express stent In order to be eligible for the second randomization patients had to have at least one acute infarct-related artery with an expectation that study stents could be delivered to all culprit lesions Exclusion criteria included true bifurcation lesions definitely requiring stenting of the side branch vessel lesions requiring greater than 100 mum of stent length unprotected left main culprit lesions and stent thrombosis lesions The secondary randomization was stratified by the following four factors the result from the primary randomization (to ensure equal distribution of the two arms from the primary randomization in the secondary randomization) the presence or absence of medically treated diabetes whether any of the lesions were greater than 26 mm in length such that overlapping stents would be used and whether the clinical study site was within or outside of the US
Table 1 HORIZONS AMI CLINICAL TRIAL OVERVIEW
HORIZONS AMI (Indication Expansion)
Study Type Prospective multicenter randomized single-blind
Total 3006 Number of Patients (ITT) TAXUS 2257
Control 749
Dose Release Formulation Slow Release (SR) (1 g mm2)
gt 25 mm to Lesion Criteria Vessel Diameter (by visual estimate) lt 40 mm
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 6
HORIZONS AMI (Indication Expansion)
Lesion Criteria Lesion Length (by visual estimate) lt 100 mm
Product Used TAXUS Express Paclitaxel-Eluting Coronary Stent System
Antiplatelet Therapy Aspirin indefinitely and clopidogrel or ticlopidine for 6 months (I year or longer recommended)
30 days clinical 6 months clinical
Follow-Up 12 month clinical 13 month angiographicIVUS
2 3 years clinical
Abbreviations ITT=intent-to-treat IVUS=intravascular ultrasound
1 Clinical Inclusion and Exclusion Criteria
Primary Randomization - Inclusion Criteria
1 The patient must be at least 18 years of age (there is no upper age limit) 2 Must have clinical symptoms consistent with AMI (eg angina or anginal equivalent) lasting
gt20 minutes but lt12 hours in duration If the symptom duration at the time of evaluation is lt1 hour to rule out unstable angina the symptoms must be unresponsive to nitroglycerin (ie ongoing) prior to signing the informed consent Patients with symptom onset within 12 hours in whom the symptoms lasted gt1 hour but subsequently resolved may still be enrolled if the ECG at the time of the evaluation shows definite ongoing ST segment elevation
3 ECG criteria ST-segment elevation of gt 1 mm in gt 2 contiguous leads or (presumably new) left bundle branch block or true posterior MI with ST depression of gt 1 mm in gt 2 contiguous anterior leads
4 The patient or guardian agrees to the study protocol and the schedule of clinical and angiographic follow-up and provides informed written consent as approved by the appropriate Institutional Review BoardEthical Committee of the respective clinical site
Primary Randomization - Exclusion Criteria
1 The patient has a known hypersensitivity or contraindication to any of the following medications
Heparin pork or pork products Both abciximab and eptifibatide Aspirin Both Clopidogrel and Ticlopidine Bivalirudin Paclitaxel or Taxol
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 7
o The polymer components of the TAXUS Express DES stent (SIBS) Stainless steel andor o Contrast media (patients with documented sensitivity to contrast which can be
effectively pre-medicated with steroids and diphenhydramine (eg rash) may be
enrolled Patients with true anaphylaxis to prior contrast media however should not be enrolled)
2 Prior administration of thrombolytic therapy bivalirudin GP IlbIlla inhibitors low molecular weight heparin or fondaparinux for this admission Patients receiving prior unfractionated heparin may be enrolled and treated per randomization
3 Current use of coumadin 4 Systemic (intravenous) Paclitaxel or Taxol use within 12 months 5 Female of childbearing potential unless a recent pregnancy test is negative who possibly
plans to become pregnant any time after enrollment into this study 6 History of bleeding diathesis or known coagulopathy (including heparin-induced
thrombocytopenia) or will refuse blood transfusions 7 History of intra-cerebral mass aneurysm arteriovenous malformation or hemorrhagic
stroke 8 Stroke or transient ischemic attack within the past 6 months or any permanent residual
neurologic defect 9 Gastrointestinal or genitourinary bleeding within the last 2 months or major surgery within
six weeks 10 Recent history or known current platelet count lt100000 cellsmm3 or Hgb lt10 gdL (note
baseline labs did not have to be available prior to enrollment) 11 Extensive peripheral vascular disease such that emergent angiography and intervention in
the opinion of the investigator is likely to be difficult or complicated 12 An elective surgical procedure is planned that would necessitate interruption of
thienopyridines during the first six months post enrollment 13 Non-cardiac co-morbid conditions are present with life expectancy lt1 year or that may result
in protocol non-compliance 14 Patients who are actively participating in another drug or device investigational study which
have not completed the primary endpoint follow-up period 15 Previous enrollment in this trial 16 Patients who underwent coronary stent implantation within the past 30 days
Secondary Randomization - Angiographic Inclusion Criteria
1 At least one acute infarct artery target vessel is present in which a ALL hemodynamically significant lesions can be stented with study stents and
b ALL such lesions have a visually estimated reference diameter gt225 mm and lt 40
nun 2 Expected ability to deliver the stent(s) to all culprit lesions (absence of excessive proximal
tortuosity or severe calcification) 3 Expected ability to fully expand the stent(s) at all culprit lesions (absence of marked
calcification)
Secondary Randomization - Angiographic Exclusion Criteria
PMA P0600080o46 FDA Summary of Safety and Effectiveness Data page 8
1 One or more hemodynamically significant lesion(s) is present in the infarct vessel (or side branches) which can only undergo balloon angioplasty or cannot be stented with a study stent (ie do not meet the angiographic inclusion criteria for a study stent)
Note The only exception to this exclusion criterionis bifurcationlesions with main branch andostial side branch involvement which may be enrolledas long as the main branch is eligible to be treatedwith a study stent The ostialside branch lesion should then be treated with balloon angioplastywith bail-outstenting performed onlyfor a sub-optimalresult in the side branch(diameterstenosis gt50 or dissection NHLBI type C refractoryto prolonged(gt2 minute) balloon inflations) Bifurcation lesions are otherwise excluded if the plannedstrategy definitely requires2 stents (eg planned T-stenting V-stenting culotte stenting or crush)
2 The presence of a bifurcation lesion in the infarct vessel which will definitely require the implantation of two stents for treatment
Note A true bifurcationlesion qualifiesfor randomizationif the operatorbelieves heshe will be likely able to successfully approachthe lesion with provisionalstenting (ie the side branch ostial lesion is dilatedfirst and stented onlybr a sub-optimal result as defined above after prolonged(gt2 minute) ballooninflations)
3 Anticipated need for greater than 100mm of study stent length 4 The infarct related artery is an unprotected left main segment 5 Patients with significant multi-vessel disease or anatomical features otherwise unfavorable
for angioplasty such that the patient will have a high likelihood of requiring bypass surgery prior to 30 days
6 The culprit vessel or lesion cannot be identified 7 Patient presenting with possibleprobable stent thrombosis 8 Any patient in whom angiography demonstrates the infarct lesion to be at the site of a
previously implanted stent (bare metal or drug-eluting)
2 Follow-up Schedule
Clinical follow-up was performed at 30 days (plusmn 1 week) 6 months (plusmn 2 weeks) 1 year (+ 2 weeks) 2 years (plusmn I month) and 3 years (plusmn 1month) Angiographic follow-up was performed at 13 months (-2 weeks + 52 weeks) for a subset of patients (approximately the first 1500 randomized patients) Certain sites also participated in the HORIZONS IVUS substudy where intravascular ultrasound was performed at baseline (post-procedure) and at 13 month follow-up (approximately the first 400 patients)
3 Clinical Endpoints
Primary Efficacy Endpoint Ischemic target lesion revascularization Primary Safety Endpoint The composite rate of death reinfarction stent thrombosis
or stroke (MACE)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 9
Major Secondary Endpoint Analysis segment binary restenosis in the 13 month angiographic subset
All primary and major secondary endpoints were analyzed both on an intent-to-treat (ITT) basis
(all patients analyzed as part of their assigned treatment group) and on a per protocol basis
(patients analyzed as part of their assigned treatment group only if they actually received their
assigned treatment) The principal analyses were by intention-to-treat
The primary and major secondary endpoints were analyzed using risk differences and compared to the pre-specified non-inferiority margin Kaplan-Meier curves and survival analyses were also constructed Secondary efficacy and safety data were analyzed using descriptive statistics
For principle statistical analyses all endpoints were analyzed on a per patient basis
B Accountability of PMA Cohort
Refer to Table 3 for primary endpoint patient disposition
Table 2 Patient Disposition
TAXUS DES EXPRESS BMS Combined Patient Disposition N=2257 N=749 N=3006
Patients Enrolled (ITT Population) 1000 (22572257) 1000 (749749) 1000 (30063006)
Completed I year follow-up 969 (21862257) 955 (715749) 965 (29013006) Reason not completed
Lost to Follow-up 30 (682257) 40 (30749) 33 (983006)
PatientPhysician withdrawal 09 (202257) 11 (8749) 09 (283006)
Death 34 (762257) 35 (26749) 34 (1023006)
Patients qualified for PP analysis 951 (21462257) 960 (719749) 953 (28653006)
Stented Patients 992 (22382257) 993 (744749) 992 (29823006)
Includes patients with 30 day 6 month or 1 year follow-up or any follow-up visit post the follow-up window or
any MACE event
C Study Population Demographics and Baseline Parameters
The baseline demographics and medical history are reported in Table 4
Table 3 HORIZONS AMI Patient Demogra hics and Medical Histor ITT Po ulation) TAXUS Express Bare Metal Expressshy
(N=2257) (749)
Age (median (IQR) yrs) 599 (524 694) 593 (518 692) Male 770 (17382257) _ 760 (569749) Diabetes rnellitus 161 (3642256) 152 (114749)
- Insulin requiring 43 (982256) 41 (31749) Hypertension 512 (1152256) 519 (389749) Hyperlipidemia 422 (95312256) 411 (3081749) Current smoker 463 (10412246) 519 (388748) Prior myocardial infarction 91 (2062256) 109 (821749) Prior percutaneous coronary intervention 95 (2142255) 77 (58749)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 10 IS
Prior coronary artery bypass graft 22 (502256) 19 (14749) Anemia 110 (2352130) 76 (54715) Killip class 2-4 88 (1992254) 80 (60748) Renal insufficiency2 156 (3282102) 154 (107696) LVEF 3lt40 143 (2791948) 140 (91652) IQR = interquartile range Defined using the World Health Organization (WHO) criteria as a hematocrit value at initial presentation of lt39 for men and lt36 for women 2Baseline calculated creatinine clearance using the Cockcroft-Gault equation lt60 mLmin
Left ventricular ejection fraction visual assessment from the baseline contrast left ventriculogram
D Safety and Effectiveness Results
The primary and secondary endpoints of the trial were met and are reported in Table 5 and Table 6 Theclinical results of the trial are reported in Table 7 In Figure 1 the rates of ischemic TLR are illustrated for all patients and those patients who were not in the protocol required angiographic subset Figures 2-6 provide results of major clinical outcomes to 3 years Angiographic and IVUS results are reported in Table 8
Table 4 HORIZONS AMI Primary Endpoints UTAXUSExpress Bare Metal Difference HazardRatih - P-vaie
Isehemic TLR (N=2257) Express (95 C)(95tl) (N=749) -
I Year 45 (98) 75 (54) -30 (-51 -09) 059 (043 083) 00018
Safety MACE TAXL Exptes BareMetal 7 Difference HazardRatio YP-valuie
(N=2257) Express (9CI J95CI) - (N=749) lt _____
I Year 81 (181) 80 (59) 01 (-21 24) 102 (076 136) 00075 P-value for the test of superiority
Safety MACE includes death reinfarction stroke or stent thrombosis
3 P-value for the test of non-inferiority
Table 5 HORIZONS AMI Secondary Endpoint
Binary TAXUS I re Metali Difference - Hazard Ratio P-value Res Express - 5 CI) (95 C)-Express
er Leion) N 2257 (N-749) _ 1
13 Month 100 (1081081) 229 (76322) -129 (-180 - 044 (033 lt00001 78) 057)
P-value superiority
Adverse effects that occurred in the PMA clinical study
Observed adverse event experience comes from the HORIZONS AMI trial Major clinical
events for this study are shown in Table 6
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 1 2 and 3 Years (ITT Population)
Expressi Bare Metal Express- -TAXUS
30 Day Clinical Endpoints Net Adverse Clinical Events 103 (232) 90 (67) MACE 12 48 (109) 45 (34)
43 (32)MACE 2 (Safety MACE)3 45 (102)
PMA P0600085046 FDA Summary of Safety and Effectiveness Data page 11
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
Death - Cardiac -Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischemic TVR Ischemic TLR Stroke Major bleeding (non-CABG) Target Lesion stent thrombosis
1 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE)3
Death - Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction schemic TVR schemic TLR
Stroke
Major bleeding (non-CABG) Target Lesion stent thrombosis
2 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE) Death
- Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischernic TVR Ischemic TLR StrokeP Major bleeding (non-CABG) Target Lesion stent thrombosis
3 Year Clinical Endpoints I4et Adverse ClinicalEventsl
SMACE 14
Du A P060008SO4
TAXUS Exprcs (N-2257-7 21 (47) 20 (44) 01(3) 17 (37) 12 (28) 04(10)
36(80) 23 (51) 21 (46) 05 (11) 71(159) 23 (50)
158 (355) 106 (237) 81 (181) 35(7 8 ) 24(54) 11(24)
37(81) 20(45) 18(39)
68(152) 59 (129) 46 (101)
10(23)
77 (172) 31 (69)
215 (480) 168 (373) 110 (245)
43 (96) 27 (60) 17 (36)
57 (123) 31 (67) 10 (64) 94 (210) 109 (236) 83 (180) 14(30)
80 (178) 42 (91)
245 (544) 200k441)240(75
FTDA Sulmmary of Safety and Effectiveness Data
Bare MctalExpr
19(14) 17(13) 01(1) 22(16) 16(12) 05(4)
35 (26) 26 (19) 26 (19) 05 (4) 56 (42) 27 (20)
163(121) 124 (92) 80 (59) 35 (26) 27 (20) 08(6)
45 (33) 19(14) 26(19) 70 (52) 88 (64) 74 (54) 07(5)
66 (49) 34 (25)
260 (191) 222 (162) 112 (82) 53 (39) 33 (24) 21 (15) 60 (43) 28 (20) 32 (23) 98 (72)
167(119) 142 (101)
11(8) 70 (52) 41 (30)
280 (205)
page 12
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 13
18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 14
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
HORIZONS AMI (Indication Expansion)
Lesion Criteria Lesion Length (by visual estimate) lt 100 mm
Product Used TAXUS Express Paclitaxel-Eluting Coronary Stent System
Antiplatelet Therapy Aspirin indefinitely and clopidogrel or ticlopidine for 6 months (I year or longer recommended)
30 days clinical 6 months clinical
Follow-Up 12 month clinical 13 month angiographicIVUS
2 3 years clinical
Abbreviations ITT=intent-to-treat IVUS=intravascular ultrasound
1 Clinical Inclusion and Exclusion Criteria
Primary Randomization - Inclusion Criteria
1 The patient must be at least 18 years of age (there is no upper age limit) 2 Must have clinical symptoms consistent with AMI (eg angina or anginal equivalent) lasting
gt20 minutes but lt12 hours in duration If the symptom duration at the time of evaluation is lt1 hour to rule out unstable angina the symptoms must be unresponsive to nitroglycerin (ie ongoing) prior to signing the informed consent Patients with symptom onset within 12 hours in whom the symptoms lasted gt1 hour but subsequently resolved may still be enrolled if the ECG at the time of the evaluation shows definite ongoing ST segment elevation
3 ECG criteria ST-segment elevation of gt 1 mm in gt 2 contiguous leads or (presumably new) left bundle branch block or true posterior MI with ST depression of gt 1 mm in gt 2 contiguous anterior leads
4 The patient or guardian agrees to the study protocol and the schedule of clinical and angiographic follow-up and provides informed written consent as approved by the appropriate Institutional Review BoardEthical Committee of the respective clinical site
Primary Randomization - Exclusion Criteria
1 The patient has a known hypersensitivity or contraindication to any of the following medications
Heparin pork or pork products Both abciximab and eptifibatide Aspirin Both Clopidogrel and Ticlopidine Bivalirudin Paclitaxel or Taxol
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 7
o The polymer components of the TAXUS Express DES stent (SIBS) Stainless steel andor o Contrast media (patients with documented sensitivity to contrast which can be
effectively pre-medicated with steroids and diphenhydramine (eg rash) may be
enrolled Patients with true anaphylaxis to prior contrast media however should not be enrolled)
2 Prior administration of thrombolytic therapy bivalirudin GP IlbIlla inhibitors low molecular weight heparin or fondaparinux for this admission Patients receiving prior unfractionated heparin may be enrolled and treated per randomization
3 Current use of coumadin 4 Systemic (intravenous) Paclitaxel or Taxol use within 12 months 5 Female of childbearing potential unless a recent pregnancy test is negative who possibly
plans to become pregnant any time after enrollment into this study 6 History of bleeding diathesis or known coagulopathy (including heparin-induced
thrombocytopenia) or will refuse blood transfusions 7 History of intra-cerebral mass aneurysm arteriovenous malformation or hemorrhagic
stroke 8 Stroke or transient ischemic attack within the past 6 months or any permanent residual
neurologic defect 9 Gastrointestinal or genitourinary bleeding within the last 2 months or major surgery within
six weeks 10 Recent history or known current platelet count lt100000 cellsmm3 or Hgb lt10 gdL (note
baseline labs did not have to be available prior to enrollment) 11 Extensive peripheral vascular disease such that emergent angiography and intervention in
the opinion of the investigator is likely to be difficult or complicated 12 An elective surgical procedure is planned that would necessitate interruption of
thienopyridines during the first six months post enrollment 13 Non-cardiac co-morbid conditions are present with life expectancy lt1 year or that may result
in protocol non-compliance 14 Patients who are actively participating in another drug or device investigational study which
have not completed the primary endpoint follow-up period 15 Previous enrollment in this trial 16 Patients who underwent coronary stent implantation within the past 30 days
Secondary Randomization - Angiographic Inclusion Criteria
1 At least one acute infarct artery target vessel is present in which a ALL hemodynamically significant lesions can be stented with study stents and
b ALL such lesions have a visually estimated reference diameter gt225 mm and lt 40
nun 2 Expected ability to deliver the stent(s) to all culprit lesions (absence of excessive proximal
tortuosity or severe calcification) 3 Expected ability to fully expand the stent(s) at all culprit lesions (absence of marked
calcification)
Secondary Randomization - Angiographic Exclusion Criteria
PMA P0600080o46 FDA Summary of Safety and Effectiveness Data page 8
1 One or more hemodynamically significant lesion(s) is present in the infarct vessel (or side branches) which can only undergo balloon angioplasty or cannot be stented with a study stent (ie do not meet the angiographic inclusion criteria for a study stent)
Note The only exception to this exclusion criterionis bifurcationlesions with main branch andostial side branch involvement which may be enrolledas long as the main branch is eligible to be treatedwith a study stent The ostialside branch lesion should then be treated with balloon angioplastywith bail-outstenting performed onlyfor a sub-optimalresult in the side branch(diameterstenosis gt50 or dissection NHLBI type C refractoryto prolonged(gt2 minute) balloon inflations) Bifurcation lesions are otherwise excluded if the plannedstrategy definitely requires2 stents (eg planned T-stenting V-stenting culotte stenting or crush)
2 The presence of a bifurcation lesion in the infarct vessel which will definitely require the implantation of two stents for treatment
Note A true bifurcationlesion qualifiesfor randomizationif the operatorbelieves heshe will be likely able to successfully approachthe lesion with provisionalstenting (ie the side branch ostial lesion is dilatedfirst and stented onlybr a sub-optimal result as defined above after prolonged(gt2 minute) ballooninflations)
3 Anticipated need for greater than 100mm of study stent length 4 The infarct related artery is an unprotected left main segment 5 Patients with significant multi-vessel disease or anatomical features otherwise unfavorable
for angioplasty such that the patient will have a high likelihood of requiring bypass surgery prior to 30 days
6 The culprit vessel or lesion cannot be identified 7 Patient presenting with possibleprobable stent thrombosis 8 Any patient in whom angiography demonstrates the infarct lesion to be at the site of a
previously implanted stent (bare metal or drug-eluting)
2 Follow-up Schedule
Clinical follow-up was performed at 30 days (plusmn 1 week) 6 months (plusmn 2 weeks) 1 year (+ 2 weeks) 2 years (plusmn I month) and 3 years (plusmn 1month) Angiographic follow-up was performed at 13 months (-2 weeks + 52 weeks) for a subset of patients (approximately the first 1500 randomized patients) Certain sites also participated in the HORIZONS IVUS substudy where intravascular ultrasound was performed at baseline (post-procedure) and at 13 month follow-up (approximately the first 400 patients)
3 Clinical Endpoints
Primary Efficacy Endpoint Ischemic target lesion revascularization Primary Safety Endpoint The composite rate of death reinfarction stent thrombosis
or stroke (MACE)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 9
Major Secondary Endpoint Analysis segment binary restenosis in the 13 month angiographic subset
All primary and major secondary endpoints were analyzed both on an intent-to-treat (ITT) basis
(all patients analyzed as part of their assigned treatment group) and on a per protocol basis
(patients analyzed as part of their assigned treatment group only if they actually received their
assigned treatment) The principal analyses were by intention-to-treat
The primary and major secondary endpoints were analyzed using risk differences and compared to the pre-specified non-inferiority margin Kaplan-Meier curves and survival analyses were also constructed Secondary efficacy and safety data were analyzed using descriptive statistics
For principle statistical analyses all endpoints were analyzed on a per patient basis
B Accountability of PMA Cohort
Refer to Table 3 for primary endpoint patient disposition
Table 2 Patient Disposition
TAXUS DES EXPRESS BMS Combined Patient Disposition N=2257 N=749 N=3006
Patients Enrolled (ITT Population) 1000 (22572257) 1000 (749749) 1000 (30063006)
Completed I year follow-up 969 (21862257) 955 (715749) 965 (29013006) Reason not completed
Lost to Follow-up 30 (682257) 40 (30749) 33 (983006)
PatientPhysician withdrawal 09 (202257) 11 (8749) 09 (283006)
Death 34 (762257) 35 (26749) 34 (1023006)
Patients qualified for PP analysis 951 (21462257) 960 (719749) 953 (28653006)
Stented Patients 992 (22382257) 993 (744749) 992 (29823006)
Includes patients with 30 day 6 month or 1 year follow-up or any follow-up visit post the follow-up window or
any MACE event
C Study Population Demographics and Baseline Parameters
The baseline demographics and medical history are reported in Table 4
Table 3 HORIZONS AMI Patient Demogra hics and Medical Histor ITT Po ulation) TAXUS Express Bare Metal Expressshy
(N=2257) (749)
Age (median (IQR) yrs) 599 (524 694) 593 (518 692) Male 770 (17382257) _ 760 (569749) Diabetes rnellitus 161 (3642256) 152 (114749)
- Insulin requiring 43 (982256) 41 (31749) Hypertension 512 (1152256) 519 (389749) Hyperlipidemia 422 (95312256) 411 (3081749) Current smoker 463 (10412246) 519 (388748) Prior myocardial infarction 91 (2062256) 109 (821749) Prior percutaneous coronary intervention 95 (2142255) 77 (58749)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 10 IS
Prior coronary artery bypass graft 22 (502256) 19 (14749) Anemia 110 (2352130) 76 (54715) Killip class 2-4 88 (1992254) 80 (60748) Renal insufficiency2 156 (3282102) 154 (107696) LVEF 3lt40 143 (2791948) 140 (91652) IQR = interquartile range Defined using the World Health Organization (WHO) criteria as a hematocrit value at initial presentation of lt39 for men and lt36 for women 2Baseline calculated creatinine clearance using the Cockcroft-Gault equation lt60 mLmin
Left ventricular ejection fraction visual assessment from the baseline contrast left ventriculogram
D Safety and Effectiveness Results
The primary and secondary endpoints of the trial were met and are reported in Table 5 and Table 6 Theclinical results of the trial are reported in Table 7 In Figure 1 the rates of ischemic TLR are illustrated for all patients and those patients who were not in the protocol required angiographic subset Figures 2-6 provide results of major clinical outcomes to 3 years Angiographic and IVUS results are reported in Table 8
Table 4 HORIZONS AMI Primary Endpoints UTAXUSExpress Bare Metal Difference HazardRatih - P-vaie
Isehemic TLR (N=2257) Express (95 C)(95tl) (N=749) -
I Year 45 (98) 75 (54) -30 (-51 -09) 059 (043 083) 00018
Safety MACE TAXL Exptes BareMetal 7 Difference HazardRatio YP-valuie
(N=2257) Express (9CI J95CI) - (N=749) lt _____
I Year 81 (181) 80 (59) 01 (-21 24) 102 (076 136) 00075 P-value for the test of superiority
Safety MACE includes death reinfarction stroke or stent thrombosis
3 P-value for the test of non-inferiority
Table 5 HORIZONS AMI Secondary Endpoint
Binary TAXUS I re Metali Difference - Hazard Ratio P-value Res Express - 5 CI) (95 C)-Express
er Leion) N 2257 (N-749) _ 1
13 Month 100 (1081081) 229 (76322) -129 (-180 - 044 (033 lt00001 78) 057)
P-value superiority
Adverse effects that occurred in the PMA clinical study
Observed adverse event experience comes from the HORIZONS AMI trial Major clinical
events for this study are shown in Table 6
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 1 2 and 3 Years (ITT Population)
Expressi Bare Metal Express- -TAXUS
30 Day Clinical Endpoints Net Adverse Clinical Events 103 (232) 90 (67) MACE 12 48 (109) 45 (34)
43 (32)MACE 2 (Safety MACE)3 45 (102)
PMA P0600085046 FDA Summary of Safety and Effectiveness Data page 11
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
Death - Cardiac -Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischemic TVR Ischemic TLR Stroke Major bleeding (non-CABG) Target Lesion stent thrombosis
1 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE)3
Death - Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction schemic TVR schemic TLR
Stroke
Major bleeding (non-CABG) Target Lesion stent thrombosis
2 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE) Death
- Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischernic TVR Ischemic TLR StrokeP Major bleeding (non-CABG) Target Lesion stent thrombosis
3 Year Clinical Endpoints I4et Adverse ClinicalEventsl
SMACE 14
Du A P060008SO4
TAXUS Exprcs (N-2257-7 21 (47) 20 (44) 01(3) 17 (37) 12 (28) 04(10)
36(80) 23 (51) 21 (46) 05 (11) 71(159) 23 (50)
158 (355) 106 (237) 81 (181) 35(7 8 ) 24(54) 11(24)
37(81) 20(45) 18(39)
68(152) 59 (129) 46 (101)
10(23)
77 (172) 31 (69)
215 (480) 168 (373) 110 (245)
43 (96) 27 (60) 17 (36)
57 (123) 31 (67) 10 (64) 94 (210) 109 (236) 83 (180) 14(30)
80 (178) 42 (91)
245 (544) 200k441)240(75
FTDA Sulmmary of Safety and Effectiveness Data
Bare MctalExpr
19(14) 17(13) 01(1) 22(16) 16(12) 05(4)
35 (26) 26 (19) 26 (19) 05 (4) 56 (42) 27 (20)
163(121) 124 (92) 80 (59) 35 (26) 27 (20) 08(6)
45 (33) 19(14) 26(19) 70 (52) 88 (64) 74 (54) 07(5)
66 (49) 34 (25)
260 (191) 222 (162) 112 (82) 53 (39) 33 (24) 21 (15) 60 (43) 28 (20) 32 (23) 98 (72)
167(119) 142 (101)
11(8) 70 (52) 41 (30)
280 (205)
page 12
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 13
18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 14
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
o The polymer components of the TAXUS Express DES stent (SIBS) Stainless steel andor o Contrast media (patients with documented sensitivity to contrast which can be
effectively pre-medicated with steroids and diphenhydramine (eg rash) may be
enrolled Patients with true anaphylaxis to prior contrast media however should not be enrolled)
2 Prior administration of thrombolytic therapy bivalirudin GP IlbIlla inhibitors low molecular weight heparin or fondaparinux for this admission Patients receiving prior unfractionated heparin may be enrolled and treated per randomization
3 Current use of coumadin 4 Systemic (intravenous) Paclitaxel or Taxol use within 12 months 5 Female of childbearing potential unless a recent pregnancy test is negative who possibly
plans to become pregnant any time after enrollment into this study 6 History of bleeding diathesis or known coagulopathy (including heparin-induced
thrombocytopenia) or will refuse blood transfusions 7 History of intra-cerebral mass aneurysm arteriovenous malformation or hemorrhagic
stroke 8 Stroke or transient ischemic attack within the past 6 months or any permanent residual
neurologic defect 9 Gastrointestinal or genitourinary bleeding within the last 2 months or major surgery within
six weeks 10 Recent history or known current platelet count lt100000 cellsmm3 or Hgb lt10 gdL (note
baseline labs did not have to be available prior to enrollment) 11 Extensive peripheral vascular disease such that emergent angiography and intervention in
the opinion of the investigator is likely to be difficult or complicated 12 An elective surgical procedure is planned that would necessitate interruption of
thienopyridines during the first six months post enrollment 13 Non-cardiac co-morbid conditions are present with life expectancy lt1 year or that may result
in protocol non-compliance 14 Patients who are actively participating in another drug or device investigational study which
have not completed the primary endpoint follow-up period 15 Previous enrollment in this trial 16 Patients who underwent coronary stent implantation within the past 30 days
Secondary Randomization - Angiographic Inclusion Criteria
1 At least one acute infarct artery target vessel is present in which a ALL hemodynamically significant lesions can be stented with study stents and
b ALL such lesions have a visually estimated reference diameter gt225 mm and lt 40
nun 2 Expected ability to deliver the stent(s) to all culprit lesions (absence of excessive proximal
tortuosity or severe calcification) 3 Expected ability to fully expand the stent(s) at all culprit lesions (absence of marked
calcification)
Secondary Randomization - Angiographic Exclusion Criteria
PMA P0600080o46 FDA Summary of Safety and Effectiveness Data page 8
1 One or more hemodynamically significant lesion(s) is present in the infarct vessel (or side branches) which can only undergo balloon angioplasty or cannot be stented with a study stent (ie do not meet the angiographic inclusion criteria for a study stent)
Note The only exception to this exclusion criterionis bifurcationlesions with main branch andostial side branch involvement which may be enrolledas long as the main branch is eligible to be treatedwith a study stent The ostialside branch lesion should then be treated with balloon angioplastywith bail-outstenting performed onlyfor a sub-optimalresult in the side branch(diameterstenosis gt50 or dissection NHLBI type C refractoryto prolonged(gt2 minute) balloon inflations) Bifurcation lesions are otherwise excluded if the plannedstrategy definitely requires2 stents (eg planned T-stenting V-stenting culotte stenting or crush)
2 The presence of a bifurcation lesion in the infarct vessel which will definitely require the implantation of two stents for treatment
Note A true bifurcationlesion qualifiesfor randomizationif the operatorbelieves heshe will be likely able to successfully approachthe lesion with provisionalstenting (ie the side branch ostial lesion is dilatedfirst and stented onlybr a sub-optimal result as defined above after prolonged(gt2 minute) ballooninflations)
3 Anticipated need for greater than 100mm of study stent length 4 The infarct related artery is an unprotected left main segment 5 Patients with significant multi-vessel disease or anatomical features otherwise unfavorable
for angioplasty such that the patient will have a high likelihood of requiring bypass surgery prior to 30 days
6 The culprit vessel or lesion cannot be identified 7 Patient presenting with possibleprobable stent thrombosis 8 Any patient in whom angiography demonstrates the infarct lesion to be at the site of a
previously implanted stent (bare metal or drug-eluting)
2 Follow-up Schedule
Clinical follow-up was performed at 30 days (plusmn 1 week) 6 months (plusmn 2 weeks) 1 year (+ 2 weeks) 2 years (plusmn I month) and 3 years (plusmn 1month) Angiographic follow-up was performed at 13 months (-2 weeks + 52 weeks) for a subset of patients (approximately the first 1500 randomized patients) Certain sites also participated in the HORIZONS IVUS substudy where intravascular ultrasound was performed at baseline (post-procedure) and at 13 month follow-up (approximately the first 400 patients)
3 Clinical Endpoints
Primary Efficacy Endpoint Ischemic target lesion revascularization Primary Safety Endpoint The composite rate of death reinfarction stent thrombosis
or stroke (MACE)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 9
Major Secondary Endpoint Analysis segment binary restenosis in the 13 month angiographic subset
All primary and major secondary endpoints were analyzed both on an intent-to-treat (ITT) basis
(all patients analyzed as part of their assigned treatment group) and on a per protocol basis
(patients analyzed as part of their assigned treatment group only if they actually received their
assigned treatment) The principal analyses were by intention-to-treat
The primary and major secondary endpoints were analyzed using risk differences and compared to the pre-specified non-inferiority margin Kaplan-Meier curves and survival analyses were also constructed Secondary efficacy and safety data were analyzed using descriptive statistics
For principle statistical analyses all endpoints were analyzed on a per patient basis
B Accountability of PMA Cohort
Refer to Table 3 for primary endpoint patient disposition
Table 2 Patient Disposition
TAXUS DES EXPRESS BMS Combined Patient Disposition N=2257 N=749 N=3006
Patients Enrolled (ITT Population) 1000 (22572257) 1000 (749749) 1000 (30063006)
Completed I year follow-up 969 (21862257) 955 (715749) 965 (29013006) Reason not completed
Lost to Follow-up 30 (682257) 40 (30749) 33 (983006)
PatientPhysician withdrawal 09 (202257) 11 (8749) 09 (283006)
Death 34 (762257) 35 (26749) 34 (1023006)
Patients qualified for PP analysis 951 (21462257) 960 (719749) 953 (28653006)
Stented Patients 992 (22382257) 993 (744749) 992 (29823006)
Includes patients with 30 day 6 month or 1 year follow-up or any follow-up visit post the follow-up window or
any MACE event
C Study Population Demographics and Baseline Parameters
The baseline demographics and medical history are reported in Table 4
Table 3 HORIZONS AMI Patient Demogra hics and Medical Histor ITT Po ulation) TAXUS Express Bare Metal Expressshy
(N=2257) (749)
Age (median (IQR) yrs) 599 (524 694) 593 (518 692) Male 770 (17382257) _ 760 (569749) Diabetes rnellitus 161 (3642256) 152 (114749)
- Insulin requiring 43 (982256) 41 (31749) Hypertension 512 (1152256) 519 (389749) Hyperlipidemia 422 (95312256) 411 (3081749) Current smoker 463 (10412246) 519 (388748) Prior myocardial infarction 91 (2062256) 109 (821749) Prior percutaneous coronary intervention 95 (2142255) 77 (58749)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 10 IS
Prior coronary artery bypass graft 22 (502256) 19 (14749) Anemia 110 (2352130) 76 (54715) Killip class 2-4 88 (1992254) 80 (60748) Renal insufficiency2 156 (3282102) 154 (107696) LVEF 3lt40 143 (2791948) 140 (91652) IQR = interquartile range Defined using the World Health Organization (WHO) criteria as a hematocrit value at initial presentation of lt39 for men and lt36 for women 2Baseline calculated creatinine clearance using the Cockcroft-Gault equation lt60 mLmin
Left ventricular ejection fraction visual assessment from the baseline contrast left ventriculogram
D Safety and Effectiveness Results
The primary and secondary endpoints of the trial were met and are reported in Table 5 and Table 6 Theclinical results of the trial are reported in Table 7 In Figure 1 the rates of ischemic TLR are illustrated for all patients and those patients who were not in the protocol required angiographic subset Figures 2-6 provide results of major clinical outcomes to 3 years Angiographic and IVUS results are reported in Table 8
Table 4 HORIZONS AMI Primary Endpoints UTAXUSExpress Bare Metal Difference HazardRatih - P-vaie
Isehemic TLR (N=2257) Express (95 C)(95tl) (N=749) -
I Year 45 (98) 75 (54) -30 (-51 -09) 059 (043 083) 00018
Safety MACE TAXL Exptes BareMetal 7 Difference HazardRatio YP-valuie
(N=2257) Express (9CI J95CI) - (N=749) lt _____
I Year 81 (181) 80 (59) 01 (-21 24) 102 (076 136) 00075 P-value for the test of superiority
Safety MACE includes death reinfarction stroke or stent thrombosis
3 P-value for the test of non-inferiority
Table 5 HORIZONS AMI Secondary Endpoint
Binary TAXUS I re Metali Difference - Hazard Ratio P-value Res Express - 5 CI) (95 C)-Express
er Leion) N 2257 (N-749) _ 1
13 Month 100 (1081081) 229 (76322) -129 (-180 - 044 (033 lt00001 78) 057)
P-value superiority
Adverse effects that occurred in the PMA clinical study
Observed adverse event experience comes from the HORIZONS AMI trial Major clinical
events for this study are shown in Table 6
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 1 2 and 3 Years (ITT Population)
Expressi Bare Metal Express- -TAXUS
30 Day Clinical Endpoints Net Adverse Clinical Events 103 (232) 90 (67) MACE 12 48 (109) 45 (34)
43 (32)MACE 2 (Safety MACE)3 45 (102)
PMA P0600085046 FDA Summary of Safety and Effectiveness Data page 11
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
Death - Cardiac -Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischemic TVR Ischemic TLR Stroke Major bleeding (non-CABG) Target Lesion stent thrombosis
1 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE)3
Death - Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction schemic TVR schemic TLR
Stroke
Major bleeding (non-CABG) Target Lesion stent thrombosis
2 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE) Death
- Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischernic TVR Ischemic TLR StrokeP Major bleeding (non-CABG) Target Lesion stent thrombosis
3 Year Clinical Endpoints I4et Adverse ClinicalEventsl
SMACE 14
Du A P060008SO4
TAXUS Exprcs (N-2257-7 21 (47) 20 (44) 01(3) 17 (37) 12 (28) 04(10)
36(80) 23 (51) 21 (46) 05 (11) 71(159) 23 (50)
158 (355) 106 (237) 81 (181) 35(7 8 ) 24(54) 11(24)
37(81) 20(45) 18(39)
68(152) 59 (129) 46 (101)
10(23)
77 (172) 31 (69)
215 (480) 168 (373) 110 (245)
43 (96) 27 (60) 17 (36)
57 (123) 31 (67) 10 (64) 94 (210) 109 (236) 83 (180) 14(30)
80 (178) 42 (91)
245 (544) 200k441)240(75
FTDA Sulmmary of Safety and Effectiveness Data
Bare MctalExpr
19(14) 17(13) 01(1) 22(16) 16(12) 05(4)
35 (26) 26 (19) 26 (19) 05 (4) 56 (42) 27 (20)
163(121) 124 (92) 80 (59) 35 (26) 27 (20) 08(6)
45 (33) 19(14) 26(19) 70 (52) 88 (64) 74 (54) 07(5)
66 (49) 34 (25)
260 (191) 222 (162) 112 (82) 53 (39) 33 (24) 21 (15) 60 (43) 28 (20) 32 (23) 98 (72)
167(119) 142 (101)
11(8) 70 (52) 41 (30)
280 (205)
page 12
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 13
18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 14
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
1 One or more hemodynamically significant lesion(s) is present in the infarct vessel (or side branches) which can only undergo balloon angioplasty or cannot be stented with a study stent (ie do not meet the angiographic inclusion criteria for a study stent)
Note The only exception to this exclusion criterionis bifurcationlesions with main branch andostial side branch involvement which may be enrolledas long as the main branch is eligible to be treatedwith a study stent The ostialside branch lesion should then be treated with balloon angioplastywith bail-outstenting performed onlyfor a sub-optimalresult in the side branch(diameterstenosis gt50 or dissection NHLBI type C refractoryto prolonged(gt2 minute) balloon inflations) Bifurcation lesions are otherwise excluded if the plannedstrategy definitely requires2 stents (eg planned T-stenting V-stenting culotte stenting or crush)
2 The presence of a bifurcation lesion in the infarct vessel which will definitely require the implantation of two stents for treatment
Note A true bifurcationlesion qualifiesfor randomizationif the operatorbelieves heshe will be likely able to successfully approachthe lesion with provisionalstenting (ie the side branch ostial lesion is dilatedfirst and stented onlybr a sub-optimal result as defined above after prolonged(gt2 minute) ballooninflations)
3 Anticipated need for greater than 100mm of study stent length 4 The infarct related artery is an unprotected left main segment 5 Patients with significant multi-vessel disease or anatomical features otherwise unfavorable
for angioplasty such that the patient will have a high likelihood of requiring bypass surgery prior to 30 days
6 The culprit vessel or lesion cannot be identified 7 Patient presenting with possibleprobable stent thrombosis 8 Any patient in whom angiography demonstrates the infarct lesion to be at the site of a
previously implanted stent (bare metal or drug-eluting)
2 Follow-up Schedule
Clinical follow-up was performed at 30 days (plusmn 1 week) 6 months (plusmn 2 weeks) 1 year (+ 2 weeks) 2 years (plusmn I month) and 3 years (plusmn 1month) Angiographic follow-up was performed at 13 months (-2 weeks + 52 weeks) for a subset of patients (approximately the first 1500 randomized patients) Certain sites also participated in the HORIZONS IVUS substudy where intravascular ultrasound was performed at baseline (post-procedure) and at 13 month follow-up (approximately the first 400 patients)
3 Clinical Endpoints
Primary Efficacy Endpoint Ischemic target lesion revascularization Primary Safety Endpoint The composite rate of death reinfarction stent thrombosis
or stroke (MACE)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 9
Major Secondary Endpoint Analysis segment binary restenosis in the 13 month angiographic subset
All primary and major secondary endpoints were analyzed both on an intent-to-treat (ITT) basis
(all patients analyzed as part of their assigned treatment group) and on a per protocol basis
(patients analyzed as part of their assigned treatment group only if they actually received their
assigned treatment) The principal analyses were by intention-to-treat
The primary and major secondary endpoints were analyzed using risk differences and compared to the pre-specified non-inferiority margin Kaplan-Meier curves and survival analyses were also constructed Secondary efficacy and safety data were analyzed using descriptive statistics
For principle statistical analyses all endpoints were analyzed on a per patient basis
B Accountability of PMA Cohort
Refer to Table 3 for primary endpoint patient disposition
Table 2 Patient Disposition
TAXUS DES EXPRESS BMS Combined Patient Disposition N=2257 N=749 N=3006
Patients Enrolled (ITT Population) 1000 (22572257) 1000 (749749) 1000 (30063006)
Completed I year follow-up 969 (21862257) 955 (715749) 965 (29013006) Reason not completed
Lost to Follow-up 30 (682257) 40 (30749) 33 (983006)
PatientPhysician withdrawal 09 (202257) 11 (8749) 09 (283006)
Death 34 (762257) 35 (26749) 34 (1023006)
Patients qualified for PP analysis 951 (21462257) 960 (719749) 953 (28653006)
Stented Patients 992 (22382257) 993 (744749) 992 (29823006)
Includes patients with 30 day 6 month or 1 year follow-up or any follow-up visit post the follow-up window or
any MACE event
C Study Population Demographics and Baseline Parameters
The baseline demographics and medical history are reported in Table 4
Table 3 HORIZONS AMI Patient Demogra hics and Medical Histor ITT Po ulation) TAXUS Express Bare Metal Expressshy
(N=2257) (749)
Age (median (IQR) yrs) 599 (524 694) 593 (518 692) Male 770 (17382257) _ 760 (569749) Diabetes rnellitus 161 (3642256) 152 (114749)
- Insulin requiring 43 (982256) 41 (31749) Hypertension 512 (1152256) 519 (389749) Hyperlipidemia 422 (95312256) 411 (3081749) Current smoker 463 (10412246) 519 (388748) Prior myocardial infarction 91 (2062256) 109 (821749) Prior percutaneous coronary intervention 95 (2142255) 77 (58749)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 10 IS
Prior coronary artery bypass graft 22 (502256) 19 (14749) Anemia 110 (2352130) 76 (54715) Killip class 2-4 88 (1992254) 80 (60748) Renal insufficiency2 156 (3282102) 154 (107696) LVEF 3lt40 143 (2791948) 140 (91652) IQR = interquartile range Defined using the World Health Organization (WHO) criteria as a hematocrit value at initial presentation of lt39 for men and lt36 for women 2Baseline calculated creatinine clearance using the Cockcroft-Gault equation lt60 mLmin
Left ventricular ejection fraction visual assessment from the baseline contrast left ventriculogram
D Safety and Effectiveness Results
The primary and secondary endpoints of the trial were met and are reported in Table 5 and Table 6 Theclinical results of the trial are reported in Table 7 In Figure 1 the rates of ischemic TLR are illustrated for all patients and those patients who were not in the protocol required angiographic subset Figures 2-6 provide results of major clinical outcomes to 3 years Angiographic and IVUS results are reported in Table 8
Table 4 HORIZONS AMI Primary Endpoints UTAXUSExpress Bare Metal Difference HazardRatih - P-vaie
Isehemic TLR (N=2257) Express (95 C)(95tl) (N=749) -
I Year 45 (98) 75 (54) -30 (-51 -09) 059 (043 083) 00018
Safety MACE TAXL Exptes BareMetal 7 Difference HazardRatio YP-valuie
(N=2257) Express (9CI J95CI) - (N=749) lt _____
I Year 81 (181) 80 (59) 01 (-21 24) 102 (076 136) 00075 P-value for the test of superiority
Safety MACE includes death reinfarction stroke or stent thrombosis
3 P-value for the test of non-inferiority
Table 5 HORIZONS AMI Secondary Endpoint
Binary TAXUS I re Metali Difference - Hazard Ratio P-value Res Express - 5 CI) (95 C)-Express
er Leion) N 2257 (N-749) _ 1
13 Month 100 (1081081) 229 (76322) -129 (-180 - 044 (033 lt00001 78) 057)
P-value superiority
Adverse effects that occurred in the PMA clinical study
Observed adverse event experience comes from the HORIZONS AMI trial Major clinical
events for this study are shown in Table 6
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 1 2 and 3 Years (ITT Population)
Expressi Bare Metal Express- -TAXUS
30 Day Clinical Endpoints Net Adverse Clinical Events 103 (232) 90 (67) MACE 12 48 (109) 45 (34)
43 (32)MACE 2 (Safety MACE)3 45 (102)
PMA P0600085046 FDA Summary of Safety and Effectiveness Data page 11
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
Death - Cardiac -Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischemic TVR Ischemic TLR Stroke Major bleeding (non-CABG) Target Lesion stent thrombosis
1 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE)3
Death - Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction schemic TVR schemic TLR
Stroke
Major bleeding (non-CABG) Target Lesion stent thrombosis
2 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE) Death
- Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischernic TVR Ischemic TLR StrokeP Major bleeding (non-CABG) Target Lesion stent thrombosis
3 Year Clinical Endpoints I4et Adverse ClinicalEventsl
SMACE 14
Du A P060008SO4
TAXUS Exprcs (N-2257-7 21 (47) 20 (44) 01(3) 17 (37) 12 (28) 04(10)
36(80) 23 (51) 21 (46) 05 (11) 71(159) 23 (50)
158 (355) 106 (237) 81 (181) 35(7 8 ) 24(54) 11(24)
37(81) 20(45) 18(39)
68(152) 59 (129) 46 (101)
10(23)
77 (172) 31 (69)
215 (480) 168 (373) 110 (245)
43 (96) 27 (60) 17 (36)
57 (123) 31 (67) 10 (64) 94 (210) 109 (236) 83 (180) 14(30)
80 (178) 42 (91)
245 (544) 200k441)240(75
FTDA Sulmmary of Safety and Effectiveness Data
Bare MctalExpr
19(14) 17(13) 01(1) 22(16) 16(12) 05(4)
35 (26) 26 (19) 26 (19) 05 (4) 56 (42) 27 (20)
163(121) 124 (92) 80 (59) 35 (26) 27 (20) 08(6)
45 (33) 19(14) 26(19) 70 (52) 88 (64) 74 (54) 07(5)
66 (49) 34 (25)
260 (191) 222 (162) 112 (82) 53 (39) 33 (24) 21 (15) 60 (43) 28 (20) 32 (23) 98 (72)
167(119) 142 (101)
11(8) 70 (52) 41 (30)
280 (205)
page 12
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 13
18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 14
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
Major Secondary Endpoint Analysis segment binary restenosis in the 13 month angiographic subset
All primary and major secondary endpoints were analyzed both on an intent-to-treat (ITT) basis
(all patients analyzed as part of their assigned treatment group) and on a per protocol basis
(patients analyzed as part of their assigned treatment group only if they actually received their
assigned treatment) The principal analyses were by intention-to-treat
The primary and major secondary endpoints were analyzed using risk differences and compared to the pre-specified non-inferiority margin Kaplan-Meier curves and survival analyses were also constructed Secondary efficacy and safety data were analyzed using descriptive statistics
For principle statistical analyses all endpoints were analyzed on a per patient basis
B Accountability of PMA Cohort
Refer to Table 3 for primary endpoint patient disposition
Table 2 Patient Disposition
TAXUS DES EXPRESS BMS Combined Patient Disposition N=2257 N=749 N=3006
Patients Enrolled (ITT Population) 1000 (22572257) 1000 (749749) 1000 (30063006)
Completed I year follow-up 969 (21862257) 955 (715749) 965 (29013006) Reason not completed
Lost to Follow-up 30 (682257) 40 (30749) 33 (983006)
PatientPhysician withdrawal 09 (202257) 11 (8749) 09 (283006)
Death 34 (762257) 35 (26749) 34 (1023006)
Patients qualified for PP analysis 951 (21462257) 960 (719749) 953 (28653006)
Stented Patients 992 (22382257) 993 (744749) 992 (29823006)
Includes patients with 30 day 6 month or 1 year follow-up or any follow-up visit post the follow-up window or
any MACE event
C Study Population Demographics and Baseline Parameters
The baseline demographics and medical history are reported in Table 4
Table 3 HORIZONS AMI Patient Demogra hics and Medical Histor ITT Po ulation) TAXUS Express Bare Metal Expressshy
(N=2257) (749)
Age (median (IQR) yrs) 599 (524 694) 593 (518 692) Male 770 (17382257) _ 760 (569749) Diabetes rnellitus 161 (3642256) 152 (114749)
- Insulin requiring 43 (982256) 41 (31749) Hypertension 512 (1152256) 519 (389749) Hyperlipidemia 422 (95312256) 411 (3081749) Current smoker 463 (10412246) 519 (388748) Prior myocardial infarction 91 (2062256) 109 (821749) Prior percutaneous coronary intervention 95 (2142255) 77 (58749)
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 10 IS
Prior coronary artery bypass graft 22 (502256) 19 (14749) Anemia 110 (2352130) 76 (54715) Killip class 2-4 88 (1992254) 80 (60748) Renal insufficiency2 156 (3282102) 154 (107696) LVEF 3lt40 143 (2791948) 140 (91652) IQR = interquartile range Defined using the World Health Organization (WHO) criteria as a hematocrit value at initial presentation of lt39 for men and lt36 for women 2Baseline calculated creatinine clearance using the Cockcroft-Gault equation lt60 mLmin
Left ventricular ejection fraction visual assessment from the baseline contrast left ventriculogram
D Safety and Effectiveness Results
The primary and secondary endpoints of the trial were met and are reported in Table 5 and Table 6 Theclinical results of the trial are reported in Table 7 In Figure 1 the rates of ischemic TLR are illustrated for all patients and those patients who were not in the protocol required angiographic subset Figures 2-6 provide results of major clinical outcomes to 3 years Angiographic and IVUS results are reported in Table 8
Table 4 HORIZONS AMI Primary Endpoints UTAXUSExpress Bare Metal Difference HazardRatih - P-vaie
Isehemic TLR (N=2257) Express (95 C)(95tl) (N=749) -
I Year 45 (98) 75 (54) -30 (-51 -09) 059 (043 083) 00018
Safety MACE TAXL Exptes BareMetal 7 Difference HazardRatio YP-valuie
(N=2257) Express (9CI J95CI) - (N=749) lt _____
I Year 81 (181) 80 (59) 01 (-21 24) 102 (076 136) 00075 P-value for the test of superiority
Safety MACE includes death reinfarction stroke or stent thrombosis
3 P-value for the test of non-inferiority
Table 5 HORIZONS AMI Secondary Endpoint
Binary TAXUS I re Metali Difference - Hazard Ratio P-value Res Express - 5 CI) (95 C)-Express
er Leion) N 2257 (N-749) _ 1
13 Month 100 (1081081) 229 (76322) -129 (-180 - 044 (033 lt00001 78) 057)
P-value superiority
Adverse effects that occurred in the PMA clinical study
Observed adverse event experience comes from the HORIZONS AMI trial Major clinical
events for this study are shown in Table 6
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 1 2 and 3 Years (ITT Population)
Expressi Bare Metal Express- -TAXUS
30 Day Clinical Endpoints Net Adverse Clinical Events 103 (232) 90 (67) MACE 12 48 (109) 45 (34)
43 (32)MACE 2 (Safety MACE)3 45 (102)
PMA P0600085046 FDA Summary of Safety and Effectiveness Data page 11
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
Death - Cardiac -Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischemic TVR Ischemic TLR Stroke Major bleeding (non-CABG) Target Lesion stent thrombosis
1 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE)3
Death - Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction schemic TVR schemic TLR
Stroke
Major bleeding (non-CABG) Target Lesion stent thrombosis
2 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE) Death
- Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischernic TVR Ischemic TLR StrokeP Major bleeding (non-CABG) Target Lesion stent thrombosis
3 Year Clinical Endpoints I4et Adverse ClinicalEventsl
SMACE 14
Du A P060008SO4
TAXUS Exprcs (N-2257-7 21 (47) 20 (44) 01(3) 17 (37) 12 (28) 04(10)
36(80) 23 (51) 21 (46) 05 (11) 71(159) 23 (50)
158 (355) 106 (237) 81 (181) 35(7 8 ) 24(54) 11(24)
37(81) 20(45) 18(39)
68(152) 59 (129) 46 (101)
10(23)
77 (172) 31 (69)
215 (480) 168 (373) 110 (245)
43 (96) 27 (60) 17 (36)
57 (123) 31 (67) 10 (64) 94 (210) 109 (236) 83 (180) 14(30)
80 (178) 42 (91)
245 (544) 200k441)240(75
FTDA Sulmmary of Safety and Effectiveness Data
Bare MctalExpr
19(14) 17(13) 01(1) 22(16) 16(12) 05(4)
35 (26) 26 (19) 26 (19) 05 (4) 56 (42) 27 (20)
163(121) 124 (92) 80 (59) 35 (26) 27 (20) 08(6)
45 (33) 19(14) 26(19) 70 (52) 88 (64) 74 (54) 07(5)
66 (49) 34 (25)
260 (191) 222 (162) 112 (82) 53 (39) 33 (24) 21 (15) 60 (43) 28 (20) 32 (23) 98 (72)
167(119) 142 (101)
11(8) 70 (52) 41 (30)
280 (205)
page 12
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 13
18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 14
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
Prior coronary artery bypass graft 22 (502256) 19 (14749) Anemia 110 (2352130) 76 (54715) Killip class 2-4 88 (1992254) 80 (60748) Renal insufficiency2 156 (3282102) 154 (107696) LVEF 3lt40 143 (2791948) 140 (91652) IQR = interquartile range Defined using the World Health Organization (WHO) criteria as a hematocrit value at initial presentation of lt39 for men and lt36 for women 2Baseline calculated creatinine clearance using the Cockcroft-Gault equation lt60 mLmin
Left ventricular ejection fraction visual assessment from the baseline contrast left ventriculogram
D Safety and Effectiveness Results
The primary and secondary endpoints of the trial were met and are reported in Table 5 and Table 6 Theclinical results of the trial are reported in Table 7 In Figure 1 the rates of ischemic TLR are illustrated for all patients and those patients who were not in the protocol required angiographic subset Figures 2-6 provide results of major clinical outcomes to 3 years Angiographic and IVUS results are reported in Table 8
Table 4 HORIZONS AMI Primary Endpoints UTAXUSExpress Bare Metal Difference HazardRatih - P-vaie
Isehemic TLR (N=2257) Express (95 C)(95tl) (N=749) -
I Year 45 (98) 75 (54) -30 (-51 -09) 059 (043 083) 00018
Safety MACE TAXL Exptes BareMetal 7 Difference HazardRatio YP-valuie
(N=2257) Express (9CI J95CI) - (N=749) lt _____
I Year 81 (181) 80 (59) 01 (-21 24) 102 (076 136) 00075 P-value for the test of superiority
Safety MACE includes death reinfarction stroke or stent thrombosis
3 P-value for the test of non-inferiority
Table 5 HORIZONS AMI Secondary Endpoint
Binary TAXUS I re Metali Difference - Hazard Ratio P-value Res Express - 5 CI) (95 C)-Express
er Leion) N 2257 (N-749) _ 1
13 Month 100 (1081081) 229 (76322) -129 (-180 - 044 (033 lt00001 78) 057)
P-value superiority
Adverse effects that occurred in the PMA clinical study
Observed adverse event experience comes from the HORIZONS AMI trial Major clinical
events for this study are shown in Table 6
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 1 2 and 3 Years (ITT Population)
Expressi Bare Metal Express- -TAXUS
30 Day Clinical Endpoints Net Adverse Clinical Events 103 (232) 90 (67) MACE 12 48 (109) 45 (34)
43 (32)MACE 2 (Safety MACE)3 45 (102)
PMA P0600085046 FDA Summary of Safety and Effectiveness Data page 11
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
Death - Cardiac -Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischemic TVR Ischemic TLR Stroke Major bleeding (non-CABG) Target Lesion stent thrombosis
1 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE)3
Death - Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction schemic TVR schemic TLR
Stroke
Major bleeding (non-CABG) Target Lesion stent thrombosis
2 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE) Death
- Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischernic TVR Ischemic TLR StrokeP Major bleeding (non-CABG) Target Lesion stent thrombosis
3 Year Clinical Endpoints I4et Adverse ClinicalEventsl
SMACE 14
Du A P060008SO4
TAXUS Exprcs (N-2257-7 21 (47) 20 (44) 01(3) 17 (37) 12 (28) 04(10)
36(80) 23 (51) 21 (46) 05 (11) 71(159) 23 (50)
158 (355) 106 (237) 81 (181) 35(7 8 ) 24(54) 11(24)
37(81) 20(45) 18(39)
68(152) 59 (129) 46 (101)
10(23)
77 (172) 31 (69)
215 (480) 168 (373) 110 (245)
43 (96) 27 (60) 17 (36)
57 (123) 31 (67) 10 (64) 94 (210) 109 (236) 83 (180) 14(30)
80 (178) 42 (91)
245 (544) 200k441)240(75
FTDA Sulmmary of Safety and Effectiveness Data
Bare MctalExpr
19(14) 17(13) 01(1) 22(16) 16(12) 05(4)
35 (26) 26 (19) 26 (19) 05 (4) 56 (42) 27 (20)
163(121) 124 (92) 80 (59) 35 (26) 27 (20) 08(6)
45 (33) 19(14) 26(19) 70 (52) 88 (64) 74 (54) 07(5)
66 (49) 34 (25)
260 (191) 222 (162) 112 (82) 53 (39) 33 (24) 21 (15) 60 (43) 28 (20) 32 (23) 98 (72)
167(119) 142 (101)
11(8) 70 (52) 41 (30)
280 (205)
page 12
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 13
18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 14
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
Death - Cardiac -Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischemic TVR Ischemic TLR Stroke Major bleeding (non-CABG) Target Lesion stent thrombosis
1 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE)3
Death - Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction schemic TVR schemic TLR
Stroke
Major bleeding (non-CABG) Target Lesion stent thrombosis
2 Year Clinical Endpoints Net Adverse Clinical Events MACE 12 MACE 2 (Safety MACE) Death
- Cardiac - Noncardiac
Reinfarction - Q wave - Non Q wave
Death or reinfarction Ischernic TVR Ischemic TLR StrokeP Major bleeding (non-CABG) Target Lesion stent thrombosis
3 Year Clinical Endpoints I4et Adverse ClinicalEventsl
SMACE 14
Du A P060008SO4
TAXUS Exprcs (N-2257-7 21 (47) 20 (44) 01(3) 17 (37) 12 (28) 04(10)
36(80) 23 (51) 21 (46) 05 (11) 71(159) 23 (50)
158 (355) 106 (237) 81 (181) 35(7 8 ) 24(54) 11(24)
37(81) 20(45) 18(39)
68(152) 59 (129) 46 (101)
10(23)
77 (172) 31 (69)
215 (480) 168 (373) 110 (245)
43 (96) 27 (60) 17 (36)
57 (123) 31 (67) 10 (64) 94 (210) 109 (236) 83 (180) 14(30)
80 (178) 42 (91)
245 (544) 200k441)240(75
FTDA Sulmmary of Safety and Effectiveness Data
Bare MctalExpr
19(14) 17(13) 01(1) 22(16) 16(12) 05(4)
35 (26) 26 (19) 26 (19) 05 (4) 56 (42) 27 (20)
163(121) 124 (92) 80 (59) 35 (26) 27 (20) 08(6)
45 (33) 19(14) 26(19) 70 (52) 88 (64) 74 (54) 07(5)
66 (49) 34 (25)
260 (191) 222 (162) 112 (82) 53 (39) 33 (24) 21 (15) 60 (43) 28 (20) 32 (23) 98 (72)
167(119) 142 (101)
11(8) 70 (52) 41 (30)
280 (205)
page 12
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 13
18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 14
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
Table 6 HORIZONS AMI Kaplan-Meier Estimates of Clinical Endpoints at 30 Day 12 and 3 Years (ITT Population)
- TAXUS EpresB tBar6MetalzExpresst
2 sect (N=2257) 1 N79
MACE 2 (Safety MACE) 136 (300) 129 (94) Death 56 (123) 66 (48) - Cardiac 32(71) 38(28)
- Noncardiac 24 (52) 29 (20) Reinfarction 70 (150) 66 (47) - Q wave 35(75) 28(20) - Non Q wave 40(84) 38(27) Death or reinfarction 118 (260) 115 (84)
Ischemic TVR 124 (265) 176 (125) Ischenic TLR 94 (202) 151 (107) Stroke 16 (35) 14 (10)
Major bleeding (non-CABG) 84 (188) 73 (54)
Target Lesion stent thrombosis 48 (103) 43 (31) NetAdverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACE1 includes death reinfarction stroke or ischemic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
All Patients Non-Angio Subset
7 -TAXUS DES (n225 ) -TAXUS DES (n=1346)
--- EXPRESS BMS (n=749) --- EXPRESS EMS (n56) 15 ----- 15
12 1 12
E000015
6 4 1 jo 2B 16 12 1111 11 8As 225 2
Time in MonthsN-1-R~oTimeS 7492 0 3 6 Is in 5 16a Months 2427 30 NumberatRisk 24i 27 306 33 1327 61 33 36 05 3 0 12 1
to 3 Years For Figure 1 HORIZONS AMI Cumulative Rates of Ischemic Target Lesion Revascularization All Patients and Patients Not in the Protocol Required Angiographic Subset
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 13
18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 14
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
18 -_ TAXUS DES (n=2257)
EXPRESS BMS (n=749) 15
12
ci)
0)
0
HR [95 G11=
3 105 [084 133]
p=0660
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2094 2037 1971 1928 1875 1289 EXPRESS BMS 749 684 669 648 634 615 412
Figure 2 HORIZONS AMI Cumulative Rates of Safety MACE (Death Reinfarction Stent Thrombosis or Stroke) to 3 Years
8 __ TAXUS DES (n=2257)
7 - -- EXPRESS BMS (n=749)
6
2 [ HR [95 CU=
084 [060117] 1 p= 0311
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2257 2170 2138 2097 2072 2026 1409 EXPRESS BMS 749 713 702 683 674 657 443
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 14
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
Death Figure Cumulative to 3 HORIZONS AlvI Rates of All 3 Years
6 - TAXUS DES (n=2257)
EXPRESS BMS (n=749) 5
Q- 4
HR [95 Cf]= 1 084 [054 130]
p= 0424
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk
DES 2257 2170 2138 2097 2072 2026 1409 TAXUS 702 674 657 443EXPRESS BMS 749 713 683
Figure 4 HORIZONS AMI Cumulative Rates of Cardiac Death to 3 Years
8 084p[0541 0-TAXUJS1 DES (n=2257)
7 --- EXPRESS BMS (n=749)
Time in Months
2170 2138 2097 2072 2902 1409TAXUS DES o 2257 HR 95 C=
4
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
657 443 EXPRESS BMS 749 791 72 68 674
Years Figure HORIZONS AMI Cumulative Rates of Reinfarcetion to 3 5
PMA P060008O46 FDA Summary of Safety and Effectiveness Data page 15
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
6 6_ TAXUS DES (n=2238) --- EXPRESS BMS (n=744)
5
U)
0 4- 3 +
Q HR [95 Cq= 0 1 110 [074165]
lt p= 0629
0 3 6 9 12 15 18 21 24 27 30 33 36
Time in Months Number at Risk TAXUS DES 2238 2108 2066 2013 1980 1932 1341 EXPRESS BMS 744 695 683 664 654 637 425
Figure 6 HORIZONS AMI Cumulative Rates of ARC Definite and Probable Stent Thrombosis to 3 Years
shy
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 16
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
Table 8 HORIZONS AMI 13 Month Angiograpbic and IVUS Results) JTAXUS Express BareMetalExpressQCA
(=910 Patientsi 1081lesiois) (N 293 Patieiits 332 leiions)
Follow-up MLD in-stent (mm) 236 075 (1062) 198 plusmn 082 (328)
Follow-up MLD in-segment (mm) 209 plusmn 068 (1062) 184 076 (328)
Follow-up DS in-stent 187 plusmn 228 (1062) 326 plusmn 249 (328)
Follow-up DS in-segment 288 plusmn 196 (1062) 374 plusmn 220 (328) Late Loss in-stent (mm) 04t plusmn 064 (1062) 082 plusmn 070 (328) Late Loss in-segment (mm) 030 056 (1062) 059 + 064 (328)
Binary restenosis in-stent 82 (871062) 210 (69328) Binary restenosis in-segment 96 (1021062) 232 (76328)
IVUS TAXUS Express Bari MetaUEipress (N 1 96 pt 219 esions) (N62 yts 67 lesiois)
Neointimal Volume (mm) 194 216 (191) 374 + 300 (65) Percent net volume obstruction () 79 +74 (191) 198 + 158 (65)
Incomplete Apposition (late) 583 (95163) 333 (1236) Incomplete Apposition (late- 429 (70163) 194 (736) acquired) QCA - quantitative coronary angiography RVD = reference vessel diameter MLD = minimal lumen diameter DS = percent diameter stenosis
IQR = interquartile range SD = standard deviation Follow-up QCA results on stented lesions only (per lesion)
Subgroup Analyses
The HORIZONS AMI trial data were retrospectively evaluated for possible sex-based
differences in baseline characteristics and clinical outcomes as well as for any interaction
between treatment and sexgender The HORIZONS AMI trial was not designed or powered to
study safety or effectiveness in sex-specific subgroups so these analyses were performed post hoc and are considered hypothesis generating
In the HORIZONS AMI population of patients randomized to TAXUS Express DES 17382257
(77) subjects were male and 5192257 (23) subjects were female The proportions in the
Express BMS group were similar (76 male 24 female) According to the Nationwide
Inpatient Sample (a large database of inpatient admissions from 1988 to 2004) men had almost 2
times the age-adjusted STEMI rate as women (men 624 women 376) The gender proportions enrolled in this trial are similar to other trials in the STEMI population23
In subjects treated with TAXUS Express DES 12-month TLR rates were 68 in females and
39 in males and Safety MACE rates were 101 in females and 75 in males In subjects treated with Express BMS 12-month TLR rates were 121 in females and 60 in males and
Safety MACE rates were 123 in females and 66 in males (Table 9) Primary and secondary endpoint outcomes data stratified by gender are shown in Tables 9 and 10 HORIZONS AMI
clinical results at 30 Days 1 Year 2 Year and 3 Year in male and female patients are reported in
Table 11 Within the female group cardiac death was numerically higher through 30 days in
those treated with TAXUS Express versus bare metal Express but the numerical difference
between groups narrowed over time Other trials of interventional treatment for AMI have shown 4 5 but differencesfemale sex to be associated with higher mortality rates compared to men
appear to be largely explained by baseline risk factors such as BSA and angiographic disease
severity Rates of reinfarction and stent thrombosis in females were numerically lower in
PMA P060008So46 FDA Summary of Safety and Effectiveness Data page 17
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
TAXUS Express DES versus bare metal Express at 30 days and through 3 years Formal interaction testing revealed no difference (at a significance level of p=015) between males and
females in treatment effect at any time point suggesting the conclusions of the overall study can
be generalized for males and females
Fable9 HORIZONSAM irimary Endpoints by Gender
TAXUS Express Bare Metal Express 1 YearIschemic TLR (N=2257) j (N 749)
(N 569)Male (N=2307) (N=1738) Male (N=2307) 39 (66) 60 (33)
(N=519) (N 180)Female (N=699) 68 (34) 121 (21)
TAXUS Express Bare Metal Express Safety MACE _(N-=2257) (N=749)
(N=569)(N=1738)Male (N=2307) 75 (129) 66 (37)
(N=180)(N=519)Female (N699)Female (N=699) 101 (52) _ 123 (22)
Safety MACE includes death reinfarction stroke or stent thromoosis
Table 10 HORIZONS AMI Secondary Endpoint by Gender Binary Restendsis at 13 TAX-U Express 7 Bare Metal Express
mnh(N=2257) - - (N=749)
Lesi6n)-(Per
(N=1738) (N=569) Male (N=2307) 96 (83863) 226 (55243)
(N=519) (NA180) Female (N699) 115 (25218) 236 (2189)
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days I Year 2 Year and 3 Year (Stent ITTPopulation TAXUS Express TAXUS Express KBare Metal Bare Metal
En4p1mnt Male Patients Female Patients ltExpress Male Exprss Female
(N=1738) (N-519) Patients Patients (N=569)-(N80
30 Day Net Adverse Clinical 86 (149) 162 (84) 72 (41) 161 (29) Eventst
MACE 12 41(71) 74 (38) 35 (20) 78 (14)
MACE 2 (Safety 39 (68) 66 (34) 32 (18) 78 (14) MACE) 3
Death 15 (26) 41 (21) 16 (9) 28(5)
Cardiac 14 (24) 39 (20) 16 (9) 22 (4)
-Noncardiac 01 (2) 02(1) 00(0) 06(1)
Reinfarction 16(27) 20(10) 16(9) 39(7)
- Q wave 12 (21) 14 (7) 12 (7) 28 (5)
- Non Q wave 04 (7) 06 (3) 04 (2) 11 (2)
Death or reinfarction 29 (51) 56 (29) 28 (16) 56 (10) Ischemic TVR 20 (35) 35 (18) 21 (12) 39 (7) Ischemic TLR 18(32) 31 (16) 21(12) 39(7)
Stroke 06(10) 02(1) 02(1) - 17(3)
PMA P060008046 FDA Summary of Safety and Effectiveness Data page 18
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30
Days 1 Year 2 Year and 3 Year (Stent ITT Population) TAXUS Express TAXU E r lBxre Metnl Bare Metal
Femle Patieiitsgtlt Express Male ExpressFemaleEndpoint Male Patients Patients Patients(N=1738) shy
(N=569) (N-180)
Major bleeding (non- 61(105) 107(55) 46(26) 106(19)
CABG) Target Lesion stent 20 (35) 28 (14) 21(12) 45(8) thrombosis
I Year
Net Adverse Clinical 133(231) 237(122) 137(77) 245(44) Events I
MACE 12 93 (161) 148 (76) 104 (58) 190 (34)
MACE 2 (Safety 75 (129) 101 (52) 66 (37) 123 (22) MACE) 3
Death 29(50) 54(28) 28(16) 56(10) - Cardiac 18(32) 43(22) I 23(13) 39(7) -Noncardiac 11 (18) 1 12(6) 05 (3) 18 (3)
Reinfarction 36(62) 38(19) 38(21) 68(12)
- Q wave 21(36) | 1 1 28(5)18 (9) l6(9) 22 (11) 22 (12) 40 (7)- Non Q wave 17 (28) |
Death or reinfarction 62 (108) 86 (44) 60 (34) 100 (18)
Ischemic TVR 50(85) 89 (44) 72 (40) 138 (24)
39 (66) 68 (34) 60 (33) 121 (21)1schemic TLR Stroke 09 (16) 14(7) 04(2) 17(3)
Major bleeding (non- 64 (110) 120(61) 50(28) 117(21)
CABG)
Target Lesion stent 31(52) 34(17) 29(16) 51(9) thrombosis
2 Year
Net Adverse Clinical 194 (333) 287 (147) 245 (135) 307 (55)Events 159 (271) 200 (102) 214 (117) 247 (44)MACE 12
MACE 2 (Safety 105 (179) 129 (58) 105 (58) 134 (24)
MACE)3 Death 37(63) 65(33) 51 (28) 62 (11)
-Cardiac 22(38) 43(22) 29(16) 45(8) 18 (3)- Noncardiac 15 (25) 23 (11) 23 (12)
55 (27) 53 (29) 80 (14)Reinfarction 58 (96) 24 (6)- Q wave 33 (55) 24 (12) 26 14) 46(8)- Non Q wave 28 (46) 37 (18) 28 (15)
Death or reinfarction 90 (153) 112 (57) 94 (52) 112 (20)
Ischemic TVR 104 (173) 129 (63) 160 (86) 185 (32)
lschemic TLR 77 (128) 102 (50) 136 (73) 162 (28)
Stroke [3 (22) 16 (8) 10 (5) j 17 (3) 54 (30) 123 (22)Major bleeding (non- 65 (113) 124 (63)
CABG) 36 (20) 57 (10)Target Lesion stent 41 (69) 42 (21)
thrombosis 3 Year
319 (57)Net Adverse Clinical 223 (381) 319 (163) 267 (148)
Events 234 (129) 259 (46)MACE 1 189 (321) 237 (120)
PMA P060008SO46 FDA Surnary of Safety and Effectiveness Data page 19
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
Table 11 HORIZONS AMI Clinical Endpoints All TAXUS Express Male and Female Patients at 30 Days 1Year 2 Year and 3 Year (Stent ITT Population)
Endpoint TAXUSExprt
Male Patients (N-1738)
_____________________(N=569)gt
TAXUS Express Female Patients
(N=51)
Bare Metal Epress Male
Patients-
Bare MetalV E ipress Female
Patients-ItS
MACE 2 (Safety 129 (220) 158 (80) 125 (69) 140 (25) MACE)
3
Death 50 (85) 75 (38) 64 (35) 74 (13) - Cardiac 28 (47) 47 (24) 36 (20) 45 (8) - Noncardiac 23 (38) 29 (14) 28 (15) 30 (5)
Reinfarction 69(115) 72(35) 61 (33) 80(14)
- Q wave 37(62) 26(13) 26 (14) 34(6) - Non Q wave
Death or reinfarction 36 (59)
112 (190) 53 (25) 138 (70)
36 (19) 114 (63) [
46 (8) 118 (21)
Ischemic TVR 117 (194) 146 (71) 171 (92) 192 (33) Ischemic TLR 87 (145) 117 (57) 145 (78) 169 (29) Stroke 16 (26) 19(9) 13(7) 17(3)
Major bleeding (non- 70 (120) 134 (68) 57 (32) 123 (22) CABG) Target Lesion stent 46 (77) 53 (26) 38 (21) 57 (10) thrombosis
Net Adverse Clinical Events includes MACEl and non-CABG related major bleeding 2 MACEl includes death reinfarction stroke or ischenic target vessel revascularization 3 MACE2 includes death reinfarction stent thrombosis or stroke
PMEA P060008S046 FDA Summary of Safety and Effectiveness Data page 20
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
XI PANEL MEETING RECOMMENDATION AND FDAS POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990 this PMA was not referred to the Circulatory System Devices Panel an FDA advisory committee for review and recommendation because the information in the PMA did not require advisory panel input
XII CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA supplement approval as described above The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise identical Express BMS the TAXUS Express results in a similar rate of the composite of death reinfarction stroke or stent thrombosis at 1 year Given the similarities between the TAXUS Liberte Stent and the TAXUS Express 2 stent and available
supportive nonclinical and clinical data (see Section X above) the safety decision based on the HORIZONS AMI trial was considered applicable
B Effectiveness Conclusions
The HORIZONS AMI trial showed that in STEMI patients compared to an otherwise
identical Express BMS the TAXUS Express results in reduced rates of ischemia-driven
target lesion revascularization at 1year and a lower rate of analysis segment binary
angiographic restenosis at 13 months Given the similarities between the TAXUS Liberte Stent and the TAXUS Express2 stent and available supportive nonclinical and
clinical data (see Section X above) the effectiveness decision based on the
HORIZONS AMI trial was considered applicable
C Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use
XIII CDRH DECISION
CDRH issued an approval order on February 22 2012
PMA P060008SO46 FDA Summary of Safety and Effectiveness Data page 21
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
XIV APPROVAL SPECIFICATIONS
Directions for use See device labeling
Hazards to Health from Use of the Device See Indications Contraindications Warnings Precautions and Adverse Events in the device labeling
Post-approval Requirements and Restrictions See approval order
XV REFERENCES
1 Movahed M Ramaraj R Hashemzadeh M et al Rate of Acute ST-Elevation Myocardial Infarction in the United States from 1988 to 2004 (from the Nationwide Inpatient Sample) Am J Cardiol 20091045-8
2 GUSTO Investigators An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N Engl J Med 1993 329 673-82
3 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abciximab for Acute Myocardial Infarction Results of the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
4 Lansky AJ Pietras C Costa RA et al Gender Differences in Outcomes After Primary Angioplasty Versus Primary Stenting With and Without Abeiximab for Acute Myocardial Infarction Results of the Controlled Abeiximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial Circulation 2005 1111611-18
5 Berger JS Elliott L Gallup et al Sex Differences in Mortality Following Acute Coronary Syndrome JAMA 2009302(8)874-882
PMA P060008S046 FDA Summary of Safety and Effectiveness Data page 22
