ACCP Cardiology PRN Journal Club. Twelve or 30 Months of Dual Antiplatelet Therapy After Drug-...

ACCP Cardiology PRN Journal Club

Twelve or 30 Months of Dual Antiplatelet Therapy After Drug-

Eluting StentsNicole Gasbarro, PharmD

PGY-2 Cardiology ResidentUniversity of Illinois Hospital and Health Sciences System

Chicago, Illinois1/28/15

Mauri L, et al. N Eng J Med. 2014; 371 (23): 2155-66

Disclosures• I have nothing to disclose concerning possible financial or

personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation.

Background• Dual Antiplatelet Therapy (DAPT) post coronary stenting

– P2Y12 inhibitor + aspirin– Prevents thrombotic complications– Duration of therapy depends on stent type

Levine G, et al. Circulation. 2011; 124(23): e574-e651Windecker S, et al. Eur Heart J. 2014; 35:2541-619Excellence NlfHaC. NICE technology appraisal guidance. 2008; p. 152

Guideline Minimum Duration of DAPT for Drug-Eluting Stent (DES)

Minimum Duration of DAPT for Bare Metal Stent (BMS)

ACCF/AHA/SCAI (2011)

12 months • 1 month in clinically stable patients

• 12 months for ACS indication

ESC (2014) • 6 months in clinically stable patients


• 1 month in clinically stable patients


NICE (2008) 12 months No comment

Background• Risks Beyond 12 Months with DES

– Stent thrombosis• Concern originated from first generation DES studies• Conflicting evidence from the literature• Several studies show new-generation stents may not carry the same risk

Mauri L, et al. N Eng J Med. 2014; 371 (23): 2155-66Mauri L, et al. N Eng J Med. 2007 Mar 8;356(10):1020-9

Study Patients ResultsStefanini G, et al. Eur Heart J. 2012;33(10):1214-22

4062 4 years follow up: biodegradable polymer DES vs. durable polymer DES (1.3% vs 2.8% HR 0.56, 95% CI 0.35-0.90, p = 0.015)

Palmerini T, et al. Lancet. 2012;379(9824):1393-1402

50,844 1 year follow up: everolimus-eluting stents vs. paclitaxel-eluting stents (OR 0.28, 95% CI 0.16-0.48), permanent polymer-based sirolimus-eluting stents (OR 0.41, 95% CI 0.24-0.70)2 years follow-up: everolimus-eluting stents vs. BMS (OR 0.35, 95% CI 0.17-0.69)

Dangas G, et al. JACC Cardiovasc Interv. 2013;6(9):914-922

4989 3 years follow up: everolimus-eluting stents vs. paclitaxel-eluting stents (0.7% vs. 1.7%;HR 0.45; 95% CI 0.26-0.78; p = 0.003)

Background• Risks Beyond 12 Months with DES

– Ischemic events unrelated to the treated coronary lesion• Cutlip D, et al. (2004)

– Hazard rate 1.7% for target-lesion events and 6.3% for nontarget-lesion events

• Extended DAPT Beyond 12 Months with DES– Reduced risk of myocardial infarction (MI)

• Eisenstein E, et al. (2007)– Increased risk of bleeding without reduction in MI

• ARCTIC-Interruption (2014), OPTIMIZE (2013), Valgimigli M, et al. (2012), Park S, et al. (2010)

– No difference between bleeding rates and thrombotic events• ITALIC (2014)

Cutlip D, et al. Circulation. 2004;110: 1226-1230Park S, et al. N Eng J Med. 2010; 362(15):1374-82Valgimigli, et al. Circulation. 2012; 125 (16):2015-26

BackgroundExtended DAPT Beyond 12 Months with DES

Vs.


Potential benefits:↓ Risk for stent thrombosis

↓ ischemic events

Potential risks:↑ bleeding

Purpose:To determine the

benefits and risks of continuing DAPT

beyond 12 months after DES

Objectives• Efficacy– To determine whether DAPT beyond 12 months

is associated with reduction in stent thrombosis or major adverse cardiovascular and cerebrovascular events

• Safety– To determine the impact of DAPT beyond 12

months on moderate or severe bleeding


Study Design• Multicenter, international, randomized, double-blind, placebo-

controlled trial of 9961 patients

• Collaboration– FDA– Eight stent and pharmaceutical manufacturers– Harvard Clinical Research Institute (HCRI)

• Funding– Eight stent and pharmaceutical manufacturers

• Abbott Vascular, Boston Scientific Corporation, Cordis Corporation, Medtronic, Inc., Bristol-Myers Squibb Company/Sanofi Pharmaceuticals Partnership, Eli Lilly and Company, Daiichi Sankyo Company Limited

– Grant from the US Department of Health and Human Services

Mauri L, et al. N Eng J Med. 2014; 371 (23): 2155-66Mauri L, et al. N Eng J Med. 2014; 371 Suppl: 18

Study Design• Enrollment

Mauri L, et al. N Eng J Med. 2014; 371 (23): 2155-66Mauri L, et al. N Eng J Med. 2014; 371 Suppl: 18

Sponsor Study DES Type Drug Type DES #

HCRI DAPT Study Cypher, Endeavor, TAXUS (Liberté, Express, or Element), Xience (V or PRIME)/PROMUS

Clopidogrel, prasugrel

5276

Abbott Xience V USA DAPT Xience V (everolimus-eluting stent)


868

Boston Scientific

TAXUS Liberté Post Approval Study TAXUS Liberté (paclitaxel-eluting stent)

Prasugrel 2202

Cordis CYPRESS – CYPHER for Evaluating Sustained Safety

Cypher (sirolimus-eluting stent)


804

Medtronic EDUCATE – The MEDTRONIC Endeavor Drug Eluting Stenting: Understanding Care, Antiplatelet Agents and Thrombotic Events

Endeavor (zotarolimus-eluting stent)


811

Methods• Intervention


• Enrollment within 72 hours after stent placement

• Assigned to thienopyridine + aspirin

12 months 30 months

• If eligible, randomly assigned to receive thienopyridine or placebo + aspirin

• Treatment period ended

• Aspirin only

Follow-up ended at 33 months

0

Mauri L, et al. N Eng J Med. 2014; 371 Suppl: 23-24

Inclusion Criteria

Randomization at 12 months• “12 month clear”

Enrollment• > 18 years of age• PCI with stent deployment (or had within 3 days)• No contraindication to DAPT for at least 30

months after enrollment and stent implantation

Exclusion Criteria

Enrollment• Stent diameter <2.25 mm or > 4.0 mm• Pregnant women• Planned surgery necessitating discontinuation of DAPT

(> 14 days) within 30 months following enrollment• Concurrent medical condition with life expectancy < 3

years• Concurrent enrollment in another device or drug study• Long-term warfarin (or similar anticoagulant) therapy• Hypersensitivity or allergies to one of the study drugs• Treated with both DES and BMS during the index

procedure

Randomization at 12 months• Pregnant women• Subject switched thienopyridine type or dose within 6

months prior to randomization• PCI or cardiac surgery between 6 weeks post index

procedure and randomization• Planned surgery necessitating discontinuation of

antiplatelet therapy (> 14 days) within the 21 months following randomization

• Concurrent medical condition with a life expectancy of < 3 years

• Long-term warfarin (or similar anticoagulant) therapy

Methods• Primary Endpoints – Efficacy• Definite or probable stent thrombosis• Major adverse cardiovascular and cerebrovascular

events (MACCE)

– Safety• Incidence of moderate or severe bleeding

– Primary analysis period: months 12 to 30


Statistics• Primary Efficacy Analysis = Superiority Analysis

– Log-rank test stratification– Two-sided alpha level of 0.05– Hazard ratios: 0.45 for stent thrombosis, 0.75 for MACCE– Annual loss to follow-up of no more than 3%– Sample of 9800 patients yields ~ 85% power

• Primary Safety Analysis = Noninferiority Analysis– Annualized rate for moderate or severe bleeding of 1.9%– Absolute noninferiority margin of 0.8%– One-sided alpha level of 0.025 – Sample of 9960 patients yields ~ 80% power


Study Demographics


Characteristic Continued Thienopyridine (n = 5020)

Placebo (n = 4941)

Indication for PCI – no. (%) STEMI NSTEMI Unstable angina Stable angina Other

534 (10.6)776 (15.5)838 (16.7)1882 (37.5)990 (19.7)

531 (10.3)767 (15.5)825 (16.7)1870 (37.8)968 (19.6)

Any risk factor for stent thrombosis – no./total no. (%)*

2410/4751 (50.7) 2389/4685 (51.0)

Thienopyridine at start of open-label period – no. (%) Clopidogrel Prasugrel

3275 (65.2)1745 (34.8)

3230 (65.4)1711 (34.6)

Type of DES at index procedure – no. (%) Everolimus-eluting Paclitaxel-eluting Zotarolimus-eluting Sirolimus-eluting > 1 type

2345 (46.7)1350 (26.9)642 (12.8)577 (11.5)106 (2.1)

2358 (47.7)1316 (26.6)622 (12.6)541 (10.9)104 (2.1)

* Risk factors for stent thrombosis: enzyme positive ACS, renal insufficiency/ failure, LVEF < 30%, > 2 vessels, > 2 lesions/vessel, lesion length ≥ 30 mm, bifurcation lesion with sidebranch ≥ 2.5 mm, in-stent restenosis of a DES, vein bypass graft stented, thrombus-containing lesion, prior brachytherapy

Results• Primary Efficacy Endpoints


Thienopyridine Placebo

Benefit suggested across all stent and drug types

Results• Primary Efficacy Endpoints


Outcome Continued Thienopyridine (N = 5020) (%)

Placebo (N = 4941)

(%)

Hazard Ratio, Thienopyridine vs. Placebo (95% CI)

P value

Stent thrombosis Definite Probable

19 (0.4)15 (0.3)5 (0.1)

65 (1.4)58 (1.2)7 (0.1)

0.29 (0.17-0.48)0.26 (0.14-0.45)0.71 (0.22-2.23)

<0.001<0.0010.55

MACCE Death Cardiac Vascular Noncardiovascular Myocardial infarction Stroke Ischemic Hemorrhagic Type uncertain

211 (4.3)98 (2.0)45 (0.9)5 (0.1)48 (1.0)99 (2.1)37 (0.8)24 (0.5)13 (0.3)0

285 (5.9)74 (1.5)47 (1.0)5 (0.1)22 (0.5)198 (4.1)43 (0.9)34 (0.7)9 (0.2)1 (<0.1)

0.71 (0.59-0.85)1.36 (1.00-1.85)1.00 (0.66-1.52)0.98 (0.28-3.39)2.23 (1.32-3.78)0.47 (0.37-0.61)0.80 (0.51-1.25)0.68 (0.40-1.17)1.20 (0.50-2.91)--

<0.0010.050.980.980.002<0.0010.320.160.680.32

Results• Non-Cardiovascular Deaths – 12 to 33 Months

• Blinded Adjudication

Mauri L, et al. N Eng J Med. 2014; 371 Suppl: 18

Relatedness for Deaths* ThienopyridineN=5020

PlaceboN=4941

P value

Bleeding-Related Death 11 (0.22%) 3 (0.06%) 0.057

Trauma-Related Death 9 (0.18%) 2 (0.04%) 0.07

Cancer-Related Death 31 (0.62%) 14 (0.28%) 0.02

* Overlapping categories/not mutually exclusive

ThienopyridineN=5012

PlaceboN=4940

P value

Cancer-Related Death 25 (0.50%) 14 (0.28%) 0.11

Non-Cardiovascular Death 45 (0.90%) 28 (0.57%) 0.06

All-Cause Mortality 105 (2.09%) 83 (1.68%) 0.14

Results• Primary Safety Endpoint


Bleeding Complications

Continued Thienopyridine (N = 4710) (%)

Placebo (N = 4649)

(%)

Difference % points (95%

CI)

Two-Sided P value for Difference

GUSTO severe or moderate* Severe Moderate

119 (2.5)

38 (0.8)81 (1.7)

73 (1.6)

26 (0.6)48 (1.0)

1.0 (0.4 to 1.5)

0.2 (-0.1 to 0.6)0.7 (0.2 to 1.2)

0.001

0.150.004

BARC type 2, 3, or 5 Type 2 Type 3 Type 4

263 (5.6)145 (3.1)122 (2.6)7 (0.1)

137 (2.9)72 (1.5)68 (1.5)4 (0.1)

2.6 (1.8 to 3.5)1.5 (0.9 to 2.1)1.1 (0.6 to 1.7)0.1 (-0.1 to 0.2)

<0.001<0.001<0.0010.38

* One-sided P = 0.70 for noninferiority

Discussion

• Thienopyridine + aspirin > 1 year was associated with a reduced risk of stent thrombosis and MACCE compared to aspirin alone

• A longer duration of thienopyridine treatment was associated with a greater risk of bleeding– Severe or fatal bleeding uncommon

• Unexpected finding – all cause mortality higher in the thienopyridine group– Difference driven by an increase in the number of deaths from

noncardiovascular causes

Author’s Conclusion

• DAPT beyond 1 year after placement of a DES, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and MACCE but was associated with an increase risk of bleeding


Critique

Strengths Weaknesses

• Study DesignNumber of subjectsMulticenter

• Multiple stent types used

• Primary efficacy and safety endpoints appropriately powered

• Patients not randomly assigned to specific stent type or thienopyridine

• Downplay of potential risks of bleeding and mortality

• Lack of applicability to patients with ischemic events/high risk of bleeding

Clinical Implications

• Reinforces the importance of DAPT• Increase in bleeding is concerning• Other trials suggesting shorter durations of

DAPT for some patients cannot be ignored• From an interventionalist perspective,

extending DAPT may be considered in some patients

Acknowledgements

• Journal Club Mentors– Wes Zemrak, PharmD, BCPS

• Maine Medical Center, Portland, ME

• Program Director– Robert DiDomenico, PharmD, FCCP

• University of Illinois at Chicago College of Pharmacy, Chicago, IL

• ACC PRN Journal Club Coordinator– Craig Beavers; PharmD, BCPS (AQ-Cardiology)

• TriStar Centennial Medical Center, Nashville, TN

References• Mauri L, Kereiakes D, Yeh R, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Eng J Med. 2014; 371 (23): 2155-66

• Levine G, Bates E, Blankenship J, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011; 124:e574-e651

• Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J. 2014 Oct 1;35(37):2541-619

• Excellence NlfHaC. Drug-eluting stents for the treatment of coronary artery disease. NICE technology appraisal guidance 2008; p. 152

• Luscher T, Steffel J, Eberli F, et al. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation. 2007;115:1051-1058

• Cutlip D, Chhabra A, Baim D, et al. Beyond restenosis: five-year clinical outcomes from second-generation coronary stent trials. Circulation. 2004;110: 1226-1230

• Eisenstein E, Anstrom K, Kong D, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297:159-68

• Collet JP, Silvain J, Barthélémy O, et al. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomized trial. Lancet. 2014 July 15 (Epub ahead of print)

• Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA. 2013;310:2510-22

• Park S-J, Park D-W, Kim Y-H, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med. 2010;362:1374-82.

• Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation. 2012;125:2015-26.

• Gilard M, Barragan P, Noryani A, et al. Six-month versus 24-month dual antiplatelet therapy after implantation of drug eluting stents in patients non-resistant to aspirin: ITALIC, a randomized multicenter trial. J Am Coll Cardiol. 2014 Nov 16. doi: 10.1016/j.jacc.2014.11.008

• Doboesh P, Stacy Z, Ansara A, et al. Drug-eluting stents: a mechanical and pharmacologic approach to coronary artery disease. Pharmacotherapy. 2004; 24(11):1554-1577

Twelve or 30 Months of Dual Antiplatelet Therapy After Drug-

Eluting StentsNicole Gasbarro, PharmD

PGY-2 Cardiology ResidentUniversity of Illinois Hospital and Health Sciences System

Chicago, Illinois1/28/15


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