Post on 05-Jun-2020
Practical Approaches to Managing Antiplatelet Therapy in
Acute Coronary Syndrome
Presented as a Live Webinar
Wednesday, September 17, 2014 Tuesday, October 7, 2014
1:00 p.m. – 2:00 p.m. ET
www.ashpadvantage.com/acs
Planned and conducted by ASHP Advantage and supported by an educational grant from The Medicines Company.
Practical Approaches to Managing Antiplatelet Therapy in Acute Coronary Syndrome
Activity Overview
In the United States, acute coronary syndrome (ACS) accounts for more than 1.4 million hospital admissions per year. Between 9% and 19% of persons with ACS die in the first six months after diagnosis. Appropriate management of ACS is essential to optimizing patient outcomes. During this activity, faculty will summarize treatment guidelines for ACS, focusing on antiplatelet therapy. Patient cases will be used to illustrate practical approaches to clinical challenges encountered managing ACS patients throughout the continuum of care, especially during the periprocedural period.
Learning Objectives
At the conclusion of this application-based educational activity, participants should be able to • Summarize current published treatment guidelines on the management of patients with acute coronary
syndrome (ACS), focusing on antiplatelet therapy. • Evaluate evolving clinical evidence on the use of antiplatelet therapy in the management of ACS and
potential impact on recommendations from published treatment guidelines. • Discuss practical approaches to managing challenges in antiplatelet therapy for ACS patients at different
points in the continuum of care.
Continuing Education Accreditation
The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.0 hour (0.1 CEU – no partial credit) of continuing pharmacy education credit (ACPE activity #0204-
0000-14-494-L01-P for the live activity and ACPE activity #0204-0000-14-494-H01-P for the on-demand activity).
Participants will process CPE credit online at http://elearning.ashp.org/my-activities, with the option of printing a CE certificate. CPE credit will be reported directly to CPE Monitor. Per ACPE, CPE credit must be claimed no later than 60 days from the date of the live activity or completion of a home study activity.
Webinar Information
Visit http://www.ashpadvantage.com/acs to find: • Webinar registration link• Group viewing information and technical requirements• CPE webinar processing information
Additional Educational Activities in this Initiative This live activity will be archived and offered as web-based on-demand learning at
www.ashpadvantage.com/acs
Practical Approaches to Managing Antiplatelet Therapy in Acute Coronary Syndrome
Activity Faculty
Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology) Associate Professor of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center Omaha, Nebraska Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology), is Associate Professor of Pharmacy Practice at the University of Nebraska Medical Center in Omaha, Nebraska. Dr. Dobesh earned both his Bachelor of Science in pharmacy and Doctor of Pharmacy degrees from South Dakota State University. He completed a specialty residency in internal medicine at the University of Texas at Austin at Brackenridge Hospital, and he is a board-certified pharmacotherapy specialist with added qualifications in cardiology.
Dr. Dobesh’s current responsibilities at the University of Nebraska Medical Center (UNMC) include clinical practice in both internal medicine and cardiology services. He is responsible for teaching pharmacy and medical students, as well as pharmacy and medical residents. His main lecture topics include ischemic heart disease, antithrombotic therapy, and other cardiology and critical care topics. Dr. Dobesh recently received the UNMC College of Pharmacy Distinguished Educator of the Year Award for 2012, an award he has received three times within the last seven years. In 2013, he received the UNMC campus wide Outstanding Educator Award.
Dr. Dobesh has conducted research on antiplatelet and antithrombotic therapy, focusing on the real-world use of these therapies and health-care economics. He has also published book chapters and several manuscripts in this field.
3
Practical Approaches to Managing Antiplatelet Therapy in Acute Coronary Syndrome
Toby C. Trujillo, Pharm.D., FCCP, FAHA, BCPS (AQ Cardiology) Associate Professor University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Clinical Specialist-Anticoagulation/Cardiology University of Colorado Hospital Aurora, Colorado Toby C. Trujillo, Pharm.D., FCCP, FAHA, BCPS (AQ Cardiology), is Associate Professor of Clinical Pharmacy at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences in Aurora, Colorado. He also serves as Clinical Specialist in cardiovascular pharmacotherapy and anticoagulation at University of Colorado Hospital. Dr. Trujillo earned his Bachelor of Science degree in biochemistry from the University of California, Davis and his Doctor of Pharmacy degree from the University of California, San Francisco, where he also completed a residency in pharmacy practice. Dr. Trujillo completed a fellowship in cardiovascular pharmacotherapy at The University of Arizona, and he is a board-certified pharmacotherapy specialist with added qualifications in cardiology. Dr. Trujillo’s current responsibilities at University of Colorado Hospital include providing clinical pharmacy services to cardiology, as well as directing the inpatient anticoagulation program. He also serves as co-chair of the anticoagulation subcommittee of the P&T committee. Dr. Trujillo currently serves as a preceptor to both pharmacy students and residents. His lectures at the School of Pharmacy focus on ischemic heart disease, antithrombotic therapy, and other cardiology and critical care topics. Dr. Trujillo has served in several capacities within the American Heart Association and the Society of Critical Care Medicine. He has also served a number of committees within the American College of Clinical Pharmacy, served as a speaker on numerous occasions on a national level, and authored several articles and book chapters in the area of cardiovascular pharmacotherapy. Dr. Trujillo is a member of the American Society of Health-System Pharmacists, and he helped develop current standards for postgraduate year 2 (PGY2) cardiology residency training programs.
4
Practical Approaches to Managing Antiplatelet Therapy in Acute Coronary Syndrome
Disclosure Statement
In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support and the Accreditation Council for Pharmacy Education’s Guidelines for Standards for Commercial Support, ASHP Advantage requires that all individuals involved in the development of activity content disclose their relevant financial relationships. A commercial interest is any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. A person has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or services may be discussed in the educational activity content over which the individual has control. The existence of these relationships is provided for the information of participants and should not be assumed to have an adverse impact on presentations.
All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage identifies and resolves conflicts of interest prior to an individual’s participation in development of content for an educational activity.
• Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology), declares that he served as a consultant for AstraZeneca; Bristol-Myers Squibb/Pfizer; Daiichi Sankyo, Inc.; Gilead Sciences, Inc.; and Janssen Pharmaceuticals,Inc.; and also received research grants from AstraZeneca and Daiichi Sankyo, Inc. and Eli Lilly and Companyalliance.
• All other faculty and planners report no financial relationships relevant to this activity.
5
Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology)Associate Professor of Pharmacy PracticeCollege of Pharmacy
University of Nebraska Medical Center
Omaha, Nebraska
Toby C. Trujillo, Pharm.D., FCCP, FAHA, BCPS (AQ Cardiology)Associate ProfessorUniversity of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
Clinical Specialist-Anticoagulation/CardiologyUniversity of Colorado Hospital
Aurora, Colorado
Planned and conducted by ASHP Advantage and supported by an educational grant from The Medicines Company.
• Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology), declares that he served as a consultant for Astra Zeneca; Bristol-Myers Squibb/Pfizer; Daiichi Sankyo, Inc.; Gilead Sciences, Inc.; and Janssen Pharmaceuticals, Inc.; and also received research grants from AstraZeneca and Daiichi Sankyo, Inc. and Eli Lilly and Company alliance.
• All other faculty and planners report no financialrelationships relevant to this activity
Disclosures
Learning ObjectivesAt the conclusion of this educational activity, participants should be able to• Summarize current published treatment guidelines on the
management of patients with acute coronary syndrome (ACS), focusing on antiplatelet therapy
• Evaluate evolving clinical evidence on the use of antiplatelet therapy in the management of ACS and potential impact on recommendations from published treatment guidelines
• Discuss practical approaches to managing challenges in antiplatelet therapy for ACS patients at different points in the continuum of care
Platelet Cascade in ACSAdhesion1
Platelets
LipidCore
CollagenGP la/lla Bind
von WillebrandFactor/GP lb Bind
Activation2
Thrombin
ADP
5 HT
TXA2
Aggregation3
FibrinogenActivatedGP llb/llla
Platelet Plug4
Acute Coronary Syndrome
non-ST elevation(UA / NSTEMI)
ST elevation(STEMI)
FibrinolysisPCI +/-Stent
MedicalTherapy
Start and continue indefinitely aspirin 75 to 162 mg/d in all patients unless contraindicated
Aspirin allergic patients with ACS treated medically (without stenting) use clopidogrel or ticagrelor indefinitely
In post-PCI-stented patients, it is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses.
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Smith SC Jr. et al. Circulation. 2011;124:2458-73.
Aspirin Recommendations
6
Antiplatelet Trialists’ Collaboration: Meta-analysis
*Odds reduction in serious vascular events Treatment effect p<0.0001
0 0.5 1.0 1.5 2.0
500-1500 mg 34 19
160-325 mg 19 26
75-150 mg 12 32
<75 mg 3 13
Any aspirin 65 23
Antiplatelet Better Antiplatelet Worse
Aspirin Dose # Trials OR* (%) Odds Ratio
Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86.
Relationship Between Major Bleeding and ASA Dose in ACS Patients
Peters RJG et al. Circulation. 2003; 108:16827.ASA dose (range 75-325 mg)
0
1.0
2.0
3.0
4.0
5.0
Inci
den
ce o
f M
ajo
r B
leed
ing
(%
)
1.9%
3.0% 2.8%
3.4%
3.7%
4.9%
101–199 mg
(N=3109)
≥200 mg
(N=4110)
≤100 mg (N=5320)
PlaceboClopidogrel
(Post-hoc analysis from CURE)
Clopidogrel 75 mg/d for patients allergic or intolerant to aspirin.
P2Y12 inhibitors for post ACS or post PCI with stent placement patients for up to 12 months
Clopidogrel 75 mg dailyPrasugrel 10 mg dailyTicagrelor 90 mg twice daily
Smith SC Jr. et al. Circulation 2011;124:2458-73.
P2Y12 Receptor Inhibitor Recommendations
Used with permission. Schomig A. N Engl J Med. 2009;361:1108-11.
Biotransformation and Mode of ActionClopidogrel, Prasugrel, and Ticagrelor
Clopidogrel 75 mg QD + ASA 75-325 mg QD
(6259 patients)
Placebo + ASA 75-325 mg QD(6303 patients)
Patients withAcute Coronary
Syndrome
(unstable angina or non–ST-segment
elevation MI)
R
Yusuf S et al. N Engl J Med. 2001;345:494-502.
CURE Study Design
3 months double-blind treatment 12 months
Clopidogrel 300 mg loading dose
Primary Endpoint: MI/Stroke/CV Death
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Cu
mu
lati
ve H
azar
d R
ate
Clopidogrel + ASA
3 6 9
Placebo + ASA
Months of Follow-Up
p = 0.00009n = 12,562
0 12
20%RRR
CURE Study
Yusuf S et al. N Engl J Med 2001;345:494-502.
7
Clopidogrel in ACS• STEMI
– CLARITY (n=3,491)• Patients age 18-75 within 12
hours – Clopidogrel 300 mg/75 mg– Placebo
• Significant reductions in occluded vessel, death, MI by angiography and up to 30 days
– COMMIT (n=45,852)• Patients within 24 hours of
suspected MI– Clopidogrel 75 mg– Placebo
• 9% reduction in death/MI/stroke over treatment period
• NSTE ACS– CURE (n=12,562)
• 300/75 vs. placebo within 24 hours of symptom onset
• Significant reductions in death, MI and stroke
– PCI-CURE (n=2,658)• 31% Relative risk
reduction in CV death/MI
– CREDO (n=2,116)• 300/75 vs placebo 3-24 h before
PCI, 75 mg vs placebo after 28 days• 27% RRR MI/ stroke/ death 1 year• 18.5% RRR in Death, MI, UTVR• Benefit only seen if load > 6 hours
prior to PCI
– ACUITY (n=13,819)• Benefit with bivalirudin
monotherapy contingent on clopidogrel loading pre-PCI
Yusuf S et al. N Engl J Med. 2001;345:494-502.Mehta SR et al. Lancet. 2001;358:527-33.
Steinhubl S. JAMA. 2002;288:2411-20.Stone GW et al. N Engl J Med. 2006;355:2203-16.
CLARITY. N Engl J Med. 2005;352:1179-89. COMMIT. Lancet. 2005;366:1607-21.
Clinical Issues with Clopidogrel• Variability of platelet inhibition
– Drug – drug interactions (PPIs)
– Up to 40% of patients are “nonresponsive”
– Role of platelet function testing?
– What to do with the results?
• Genetic polymorphisms in metabolism– Prodrug that must undergo two CYP450
enzyme conversion steps
– CYP 2C19 loss-of-function alleles• Heterozygous vs. homozygous
• Connection with clinical outcomes debated
Biotransformation and Mode of ActionClopidogrel, Prasugrel, and Ticagrelor
Used with permission. Schomig A. N Engl J Med. 2009;361:1108-11.
TRITON TIMI-38ACS (STEMI or UA/NSTEMI) & planned PCI
PRASUGREL60 mg LD/ 10 mg MD
CLOPIDOGREL300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, stroke2o endpoints: CV death, MI, stroke, rehosp-recurr. ischemia
CV death, MI, UTVRStent thrombosis (definite/probable)
Safety endpoints: TIMI major bleeds, life-threatening bleeds
Median duration of therapy - 12 months
Wiviott SD et al. N Engl J Med. 2007;357:2001-15.
n = 13,608
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)P=0.0004
Prasugrel
Clopidogrel
Days
En
dp
oin
t (%
)
12.1
9.9
HR 1.32(1.03-1.68)
P=0.03
Prasugrel
Clopidogrel1.82.4
138events
35events
TRITON TIMI-38 Trial - Results
CV Death / MI / Stroke
TIMI Major Non-CABG Bleeds
NNT = 46
NNH = 167
Wiviott SD et al. N Engl J Med 2007;357:2001-15.
Pri
mar
y E
nd
po
int
(%)
0
2
4
6
8
0 1 2 3 30 6090 180 270 360 450
HR 0.82p=0.01
HR 0.80p=0.003
5.6%
4.7%
6.9%
5.6%
Days
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel
Loading Dose Maintenance DoseWiviott SD et al. N Engl J Med. 2007;357:2001-15.
TRITON – TIMI 38 TrialTiming of Benefit
8
PLATO study design
Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding
ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
Ticagrelor180 mg loading dose, then
90 mg bid maintenance;(additional 90 mg pre-PCI)
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;
randomized within 24 hours of index event
Wallentin L et al. N Engl J Med. 2009;361:1045-57.
n=18,624
PLATO TrialPrimary Endpoint Results
Days after randomization0 60 120 180 240 300 360
12
10
8
6
4
2
0Cu
mu
lati
ve in
cid
ence
(%
)
9.8
11.7Clopidogrel
Ticagrelor
p<0.001HR 0.84 (95% CI 0.77 to 0.92)
NNT=53
Wallentin L et al. N Engl J Med. 2009;361:1045-57.
5.3%
6.6%
0 10 20 30
8
6
4
2
0
Cu
mu
lati
ve i
nci
den
ce (
%)
Clopidogrel
Ticagrelor
4.8%5.4%
HR 0.88 p=0.045
Days after randomization
31 90 150 210 270 330
8
6
4
2
0
Clopidogrel
Ticagrelor
Days after randomization
HR 0.80p<0.001C
um
ula
tive
in
cid
ence
(%
)
*Composite of CV death, MI, or stroke
PLATO TrialTiming of Benefit*
Days 1 - 30 Days 30 – 365
Wallentin L et al. N Engl J Med. 2009;361:1045-57.
PLATO Results – Major BleedingNon-CABG and CABG Related
Total PLATO major bleeding: 11.6% Ticagrelor vs. 11.2% Clopidogrel; p=0.43Total TIMI major bleeding: 7.9% Ticagrelor vs. 7.7% Clopidogrel; p=0.57
p=0.026
p=0.025
p=NS
p=NS
% o
f P
atie
nts
Wallentin L et al. N Engl J Med. 2009;361:1045-57.
Evolving Evidence and Applications for Antiplatelet
Therapy in CV Disease
Case Study 1• PD is a 56 year-old male with a PMhx of HTN, DM,
CAD (s/p MI x 2, PCI x1 with DES placement 2 years ago) presenting to the hospital ED with a 6 hour history of chest squeezing and tightness
• PE: BP 148/92 mm Hg, HR 88 bpm; Ht 72 in, Wt 90 kg, afebrile 3 cm JVD, lungs rales; regular S1, S2, -S3, -S4, no
murmur Abdomen obese, soft, with mild epigastric tenderness;
-FOBT Extremities without edema, pulses 1-2+ throughout
9
Case Study 1
• ECG: 2 mm ST depression, Leads V4-V6 with symmetrical T wave inversion
• CXR: heart failure • Labs:
Hct 45, WBC 8.7, Plts 238K Na 138, K 4.2 BUN 41, SCr 1.82 mg/dL Gluc 142 Est CrCl 58 mL/min (CG) CK-MB 6 (ULN <6) TnT 3.80 (ULN <0.10) LDL 130 mg/dL, HDL 32 mg/dL, TGs 149 mg/dL
Case Study 1
• Medications taken prior to admission
Aspirin 81 mg daily
Clopidogrel 75 mg daily
Metformin 1 g twice daily
Ramipril 10 mg daily
Metoprolol 50 mg twice daily
Amlodipine 10 mg daily
SL NTG 0.4 mg prn chest pain
Case Study 1PD is managed with an invasive strategy for his recurrent MI, recovers quickly, and is discharged home. He returns for follow-up with his cardiologist 2 weeks later. As the clinical pharmacist in the cardiology clinic, you are asked if there are any improvements that can be made in the antithrombotic regimen. You recommend which of the following?
1) Aspirin 81 mg, plus prasugrel 10 mg daily
2) Aspirin 81 mg, plus ticagrelor 90 mg twice daily
3) Aspirin 81 mg, plus clopidogrel 150 mg twice daily
4) Aspirin 81 mg, plus clopidogrel 75 mg, plus vorapaxar 2.5 mg daily
TBX A2
Vorapaxar
Chackalamannil S. J Med Chem. 2006;49:5389-403.
Platelet
PAR-4
TBXA2-R
Thrombin
Anionicphospholipidsurfaces
GP IIb/IIIa
ADP P2Y12
PAR-1
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Aspirin
Vorapaxar• Protease-activated receptor-
1 (PAR-1) antagonist
• Indicated for reduction of CV events in patients with previous MI or PAD
• 1 tablet daily (2.08 mg)
• Boxed warning – do NOT use in history of stroke, TIA, ICH, or active bleeding
• CYP 3A4 metabolism – avoid strong inhibitors, inducers
• No adjustment for renal impairment
• Terminal elimination half-life (t½) = 8 days
TRA 2P – TIMI 50: Trial DesignStable atherosclerosis: History of MI, stroke, or PAD
Receiving standard of care
Vorapaxar 2.5 mg dailyPlacebo
Primary Efficacy Endpoint: CV death, MI, stroke, recurrent ischemia leading to revascularizationPrimary Bleeding Endpoint: GUSTO moderate or severe bleeding
n=26,449
Morrow DA et al. N Engl J Med. 2012;366:1404-13.
Median treatment duration of 30 monthsAt 2 years, study halted in the ischemic stroke group due to in risk of ICH
Key exclusion criteria: planned revascularization, history of bleeding diathesis, recent abnormal bleeding, warfarin, hepatobiliary disease
TRA 2P – TIMI 50: Efficacy ResultsAll Patients
Used with permission. Morrow DA et al. N Engl J Med. 2012;366:1404-13.
Eve
nt
Rat
e (%
)
CV Death, MI, Stroke, or Recurrent Ischemia Leading to Urgent
Coronary Revascularization (UCR)CV Death, MI, or Stroke
HR 0.87 (95% CI, 0.80 – 0.94)
p<0.001
HR 0.88(95% CI, 0.82 – 0.95)
p=0.001
Days Since Randomization Days Since Randomization
10
TRA 2P – TIMI 50: Efficacy ResultsPatients Without a History of Stroke or TIA
Morrow DA et al. N Engl J Med. 2012;366:1404-13.Zontivity Prescribing Information, May 2014.
EndpointsPlacebo
(n=10,090)
Vorapaxar
(n=10,080)
Hazard Ratio
(95% CI)p-
value
1° Endpoint: CV death, MI, stroke, UCR (%)
10.6 8.9 0.83 (0.76 – 0.90) <0.001
CV death, MI, Stroke (%) 8.4 6.8 0.80 (0.73 – 0.89) <0.001
CV death (%) 2.4 2.0 0.86 (0.71 – 1.03)
MI (%) 5.6 4.7 0.82 (0.73 – 0.93)
Stroke (%) 1.4 1.0 0.67 (0.52 – 0.87)
UCR (%) 2.8 2.5 0.88 (0.74 – 1.04)
TRA 2P – TIMI 50: Safety ResultsPatients Without a History of Stroke or TIA
Morrow DA et al. N Engl J Med. 2012;366:1404-13.Zontivity Prescribing Information, May 2014.
GUSTO Bleeding (%)Placebo
(n=10,049)
Vorapaxar
(n=10,059)
Hazard Ratio
(95% CI)
Severe 0.8 1.0 1.24 (0.92 – 1.66)
Moderate or severe 2.0 3.0 1.55 ( 1.30 -1.86)
Any (severe/mod/mild) 17.6 25.0 1.52 (1.43 – 1.61)
Fatal bleeding 0.1 0.2 1.15 (0.56 – 2.36)
Intracranial hemorrhage 0.3 0.4 1.46 (0.92 – 2.31)
Clinically significant bleeding (TIMI)
9.5 13.4 1.47 (1.35 – 1.60)
Gastrointestinal bleeding 3.0 4.0 1.37 (1.18 – 1.59)
Case Study 1PD is managed with an invasive strategy for his recurrent MI, recovers quickly, and is discharged home. He returns for follow-up with his cardiologist 2 weeks later. As the clinical pharmacist in the cardiology clinic, you are asked if there are any improvements that can be made in the antithrombotic regimen. You recommend which of the following?
A.Aspirin 81 mg, plus prasugrel 10 mg daily
B.Aspirin 81 mg, plus ticagrelor 90 mg twice daily
C.Aspirin 81 mg, plus clopidogrel 150 mg twice daily
D.Aspirin 81 mg, plus clopidogrel 75 mg, plus vorapaxar 2.5 mg daily
Case Study 2PD is switched to aspirin plus ticagrelor for dual antiplatelet therapy.
6 months later, he requires surgery for removal of a parotid neoplasm (adenocarcinoma).
The cardiologist following PD comes to you for advice on how his antiplatelet regimen should be managed around the procedure.
Case Study 2Which of the following would you recommend?
A. Stop ASA and ticagrelor 7-10 days pre-op and resume both drugs 1-2 days post-op.
B. Stop ASA and ticagrelor 7-10 days pre-op and administer bridging with SC low-molecular-weight heparin or IV heparin, and resume both drugs 1-2 days post-op.
C. Continue ASA pre-/post-op and stop ticagrelor 7-10 days pre-op, and resume ticagrelor 1-2 days post-op.
D. Continue ASA + ticagrelor pre-/post-op.
E. Stop ASA and ticagrelor 7-10 days pre-op and administer GP IIa/IIIb inhibitor around the time of surgery, and resume both drugs 1-2 days post-op.
Peri-Operative Management of Antiplatelet Therapy
• Perioperative Management of Antithrombotic Therapy (Douketis JD et al. CHEST. 2012; 141(Suppl 2): e326S–e350S.)
• Expert Position Paper on the Management of Antiplatelet Therapy in Patients Undergoing CABG (Sousa-Uva M et al. Eur Heart J. 2014: 35;1510-4.)
• Management of Antiplatelet Therapy in Patients with CAD Requiring Cardiac and Noncardiac Surgery (Capodanno D et al. Circulation. 2013;128:2785-98.)
11
Considerations in Perioperative Management of Antiplatelet Therapy
• Avoid Unnecessary Revascularization and Stent Placement
• Ischemic Risk– Underlying pathophysiology
– Stent placement, type of stent used
• Bleeding Risk– Procedure type
• Consequences of ischemia/bleeding– Stent thrombosis
– Low-risk bleed risk, but severe consequences (pacemaker placement)
Multidisciplinary Discussion Should be Undertaken to Formulate Plan
ACCP Guideline Recommendations
• In patients who are receiving aspirin for the secondary prevention of cardiovascular disease and are having minor dental or dermatologic procedures or cataract surgery, we suggest continuing aspirin around the time of the procedure instead of stopping ASA 7 to 10 days before the procedure (Grade 2C)
• In patients at moderate to high risk for cardiovascular events who are receiving aspirin therapy and require noncardiac surgery, we suggest continuing aspirin around the time of surgery instead of stopping ASA 7 to 10 days before surgery (Grade 2C)
Douketis JD et al. CHEST. 2012;141(Suppl 2):e326S–e350S.
ACCP Guideline Recommendations
• In patients at low risk for cardiovascular events who are receiving aspirin therapy, we suggest stopping aspirin 7 to 10 days before surgery instead of continuation of aspirin (Grade 2C).
• In patients who are receiving aspirin and require CABG surgery, we suggest continuing aspirin around the time of surgery instead of stopping aspirin 7 to 10 days before surgery (Grade 2C).
Douketis JD et al. CHEST. 2012;141(Suppl 2):e326S–e350S.
ACCP Guideline Recommendations
• In patients who are receiving dual antiplatelet drug therapy and require CABG surgery, we suggest continuing aspirin around the time of surgery and stopping clopidogrel/prasugrel 5 days before surgery instead of continuing dual antiplatelet therapy around the time of surgery (Grade 2C).
• In patients with a coronary stent who are receiving dual antiplatelet therapy and require surgery, we recommend deferring surgery for at least 6 weeks after placement of a bare-metal stent and for at least 6 months after placement of a drug-eluting stent instead of undertaking surgery within these time periods (Grade 1C).
Douketis JD et al. CHEST. 2012;141(Suppl 2):e326S–e350S.
ACCP Guideline Recommendations
• In patients who require surgery within 6 weeks of placement of a bare-metal stent or within 6 months of placement of a drug-eluting stent, we suggest continuing dual antiplatelet therapy around the time of surgery instead of stopping dual antiplatelet therapy 7-10 days before surgery (Grade 2C).
Douketis JD et al. CHEST. 2012;141(Suppl 2):e326S–e350S.
Examples of Surgery that May Require Thienopyridine Discontinuation
• Major cardiac or thoracic surgery
• Neurosurgical procedures (may require aspirin discontinuation as well)
• Major orthopedic surgery
• Urologic procedures
• General abdominal surgery
Capodanno D et al. Circulation. 2013;128:2785-98.
12
Role of Bridging Therapy?
• GP IIb/IIIa receptor antagonists– Limited clinical trial information to validate
the efficacy and safety of use for bridging of thienopyridines around surgery
• Small case series all continued aspirin therapy
• Tirofiban or eptifibatide used at standard doses– Thienopyridines stopped 5-7 days pre-op
– GP IIb/IIIa receptor antagonists started Day 3 pre-op and continued up to 4-6 hours prior to surgery
– Restart oral agent post-op when deemed safe
Capodanno D et al. Circulation. 2013;128:2785-98.
Bridging with a GP IIb/IIIa Receptor Antagonist
Used with permission. Capodanno D et al. Circulation. 2013;128:2785-98.
N N
N N
NH
SCF3
OHOH
OO
PO
OPP
OO
OClCl
OO
O
S
4Na+
Future Options for Bridging?Cangrelor
• Intravenous ADP–P2Y12 receptor antagonist – Rapid acting: quick onset, quick offset
– Plasma half-life of 3 – 6 minutes
– 60 minutes for return to normal platelet function
Meadows TA et al. Circ Res. 2007;100:1261-75.Akers W. J Clin Pharmacol. 2010;50:27-35.
Steinhubl S. Thromb Res. 2008;121:527-34.
BRIDGE Trial DesignRandomized, Double-Blind, Placebo-Controlled
Treat per Standard of Care
(CABG rule-in)
0
100
200
300
400
-1 0 1 2 3 4 5-7Elapsed Days
PR
U
CABGCABG
Thru Hospital Discharge
Demonstrate that cangrelor infusion maintains PRU< 240
Cangrelor/Placebo InfusionDose Determined in Stage I :
0.75 µg/kg/min
• Patients with an ACS or treated with a coronary stent (BMS or DES) on a thienopyridine (ticlopidine, clopidogrel or prasugrel) awaiting CABG.
• After thienopyridine discontinuation (<72 hours), patients were administered cangrelor/placebo for at least 48 hours and up to 7 days, which was discontinued 1-6 hours prior to CABG.
• Objective: demonstrate that cangrelor would maintain levels of platelet reactivity <240 P2Y12 Reaction Units (PRU) throughout the pre-operative period as measured by the VerifyNow™ P2Y12 test.
Clopidogrel or prasugrel
Angiolillo DJ et al. JAMA. 2012;307:265-74.
BRIDGE Trial Primary EndpointPercent of patients with PRU<240
for all on-treatment samples:
p<0.0001
OR (95% CI)353 (45.6-2728)
Angiolillo DJ et al. JAMA. 2012;307:265-74.
0
50
100
150
200
250
300
350
400
Baseline Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Last on-infusion
sample
Pre-CABGsample
Time Point
n=80n=70
n=55 n=33n=7
n=1
n=6
n=85
n=84
n=78
Cangrelor Placebo
Ver
ifyN
ow
PR
U
BRIDGE TrialPlatelet Reactivity by Day
n=76n=73
n=57 n=34 n=24
n=14n=86
n=2n=84
n=75
Angiolillo DJ et al. JAMA. 2012;307:265-74.
13
BRIDGE Trial Bleeding EndpointExcessive CABG-related bleeding
(primary safety endpoint)*
*Excessive CABG-related bleeding is defined as the occurrence of one or more of the following 3 components during the CABG procedure or post-operative hospitalization: Surgical re-exploration, 24 hour chest tube output > 1.5 liters, Incidence of PRBC transfusion > 4 units.
p=0.76
Angiolillo DJ et al. JAMA. 2012;307:265-74.
BRIDGE Trial Pre-Operative* Bleeding
Parameter* Cangrelor(n= 106)
Placebo(n= 101)
Odds Ratio(95% CI)
p-value
ACUITY Bleeding (%)
Major 2.8 1.0 2.91 (0.30 – 28.5) 0.358
Minor 17.9 9.9 1.99 (0.88 – 4.51) 0.101
GUSTO Bleeding (%)
Severe/Life threatening 0 0 NA NA
Moderate 1.9 1.0 1.92 (0.17 – 21.5) 0.596
Mild 17.9 9.9 1.99 (0.88 – 4.51) 0.101
TIMI Bleeding (%)
Major 0.9 0 NA NA
Minor 0.9 0 NA NA
Angiolillo DJ et al. JAMA. 2012;307:265-74.* From randomization until surgical incision
BRIDGE Trial Ischemic Events
*Ischemic events not adjudicated; site reported† Ischemia-driven revascularization
Parameter* Cangrelor(N= 106)
Placebo(N= 101)
Incidence of Pre-Procedure Ischemic endpoints (randomization to surgery) (%)
Death/MI/IDR†/Stroke 2.8 4.0
Death 0.9 3.0
MI 1.9 0
IDR† 0.9 0
Stroke 0 0
Incidence of Post-Surgery Ischemic endpoints (through 30 days) (%)
Death/MI/IDR†/Stroke 3.9 4.2
Death 1.0 2.1
MI 2.0 1.0
IDR† 2.5 0
Angiolillo DJ et al. JAMA. 2012;307:265-74.
Potential Bridging Strategy with Cangrelor
Used with permission. Capodanno D et al. Circulation. 2013;128:2785-98.
Case Study 2Which of the following would you recommend?
A. Stop ASA and ticagrelor 7-10 days pre-op and resume both drugs 1-2 days post-op.
B. Stop ASA and ticagrelor 7-10 days pre-op and administer bridging with SC low-molecular-weight heparin or IV heparin, and resume both drugs 1-2 days post-op.
C. Continue ASA pre-/post-op and stop ticagrelor 7-10 days pre-op, and resume ticagrelor 1-2 days post-op.
D. Continue ASA + clopidogrel pre-/post-op.
E. Stop ASA and ticagrelor 7-10 days pre-op and administer GP IIa/IIIb inhibitor around the time of surgery, and resume both drugs 1-2 days post-op.
Learning ObjectivesAt the conclusion of this educational activity, participants should be able to• Summarize current published treatment guidelines on the
management of patients with acute coronary syndrome (ACS), focusing on antiplatelet therapy
• Evaluate evolving clinical evidence on the use of antiplatelet therapy in the management of ACS and potential impact on recommendations from published treatment guidelines
• Discuss practical approaches to managing challenges in antiplatelet therapy for ACS patients at different points in the continuum of care
14
Practical Approaches to Managing Antiplatelet Therapy in Acute Coronary Syndrome
Self‐assessment Questions
The presentation self‐assessment questions are listed here for your convenience. Note the correct answers for future reference. 1. PD is managed with an invasive strategy for his recurrent MI, recovers quickly, and is discharged home. He
returns for follow‐up with his cardiologist 2 weeks later. As the clinical pharmacist in the cardiology clinic, you are asked if there are any improvements that can be made in the antithrombotic regimen. You recommend which of the following?
a. Aspirin 81 mg, plus prasugrel 10 mg daily b. Aspirin 81 mg, plus ticagrelor 90 mg twice daily c. Aspirin 81 mg, plus clopidogrel 150 mg twice daily d. Aspirin 81 mg, plus clopidogrel 75 mg, plus vorapaxar 2.5 mg daily
2. PD is switched to aspirin plus ticagrelor for dual antiplatelet therapy. 6 months later, he requires surgery for removal of a parotid neoplasm (adenocarcinoma). The cardiologist following PD comes to you for advice on how his antiplatelet regimen should be managed around the procedure. Which of the following would you recommend?
a. Stop ASA and ticagrelor 7‐10 days pre‐op and resume both drugs 1‐2 days post‐op. b. Stop ASA and ticagrelor 7‐10 days pre‐op and administer bridging with SC low‐molecular‐weight
heparin or IV heparin, and resume both drugs 1‐2 days post‐op. c. Continue ASA pre‐/post‐op and stop ticagrelor 7‐10 days pre‐op, and resume ticagrelor 1‐2 days
post‐op. d. Continue ASA + ticagrelor pre‐/post‐op. e. Stop ASA and ticagrelor 7‐10 days pre‐op and administer GP IIa/IIIb inhibitor around the time of
surgery, and resume both drugs 1‐2 days post‐op.
Answers
1. No one correct answer. Options a, b, and d are all acceptable 2. Option c is best answer, but option e is acceptable
15