Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

Presented as a Midday Symposium at the 45th ASHP Midyear Clinical Meeting and Exhibition

Tuesday, December 7, 2010 Anaheim, California

Planned and conducted by ASHP Advantage and supported by an educational grant from AstraZeneca

Please be advised that this activity is being audio recorded for archival purposes and, in some cases, for repurposing of the content for enduring materials.

2 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

AGENDA 11:30 a.m. – 11:35 a.m. Introductory Remarks Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ-Cardiology)

11:35 a.m. – 12:00 p.m. Update on Oral Antiplatelet Therapy in Acute Coronary Syndrome Toby C. Trujillo, Pharm.D., BCPS (AQ-Cardiology)

12:00 p.m. – 12:40 p.m. Clinical Challenges in Oral Antiplatelet Therapy Julie H. Oestreich, Pharm.D., Ph.D.

12:40 p.m. – 1:15 p.m. Emerging P2Y12 Treatment Strategies Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ-Cardiology)

1:15 p.m. – 1:30 p.m. Faculty Discussion and Audience Questions All Faculty

FACULTY Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology) Activity Chair and Moderator Associate Professor of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center Omaha, Nebraska

Julie H. Oestreich, Pharm.D., Ph.D. Assistant Professor of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center Omaha, Nebraska

Toby C. Trujillo, Pharm.D., BCPS (AQ Cardiology) Associate Professor University of Colorado Denver School of Pharmacy Clinical Specialist – Cardiology/Anticoagulation University of Colorado Hospital Aurora, Colorado

3 Optimizing Oral 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 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.

The faculty and planners report the following relationships:

Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology)

Dr. Dobesh declares that he has served as a consultant to sanofi-aventis and has received research grants from AstraZeneca and Eli Lilly and Company.

Julie H. Oestreich, Pharm.D., Ph.D.

Dr. Oestreich declares that she has no relationships pertinent to this activity.

Toby C. Trujillo, Pharm.D., BCPS (AQ Cardiology)

Dr. Trujillo declares that he has served as a speaker for sanofi-aventis.

Carla J. Brink, M.S., B.S.Pharm.

Ms. Brink declares that she has no relationships pertinent to this activity.

4 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

ACTIVITY OVERVIEW

Despite recent advances in the treatment of acute coronary syndrome (ACS), mortality associated with both ST-segment elevation myocardial infarction (STEMI) and non-ST- segment elevation myocardial infarction (NSTEMI) remains unacceptably high. Patients who experience an acute myocardial infarction are at increased risk for future coronary episodes, and mortality increases with subsequent events.

While the need for dual antiplatelet therapy in patients with ACS is well established, pharmacists are met with many clinical dilemmas as they seek to optimize therapy. In this symposium, the faculty will tackle many of these questions, including duration of oral antiplatelet therapy, clopidogrel nonresponsiveness, drug interactions with proton pump inhibitors, and laboratory testing of platelet reactivity and patient genotypes. In addition, emerging treatment strategies, including triple antiplatelet therapy and pipeline antiplatelet agents, will be addressed.

Using patient case examples and interactive questions, the faculty will engage participants in the clinical decision-making process involved in optimizing oral antiplatelet therapy for patients with ACS.

ACTIVITY OBJECTIVES

At the conclusion of this knowledge-based educational activity, participants should be able to  Identify patient factors to consider when selecting an appropriate oral antiplatelet therapy.  Describe the implications of recent clinical trials evaluating the safety and efficacy of current and emerging oral antiplatelet therapies for patients with acute coronary syndrome.  Define clopidogrel nonresponsiveness and devise a treatment strategy to manage it.  List factors to consider when deciding whether to use laboratory testing of platelet reactivity or patient genotype to guide selection of oral antiplatelet therapy.

LIST OF ABBREVIATIONS

For a list of abbreviations used in this symposium, please see page 76.

5 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

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 2 hours (0.2 CEUs) of continuing pharmacy education credit (ACPE activity #204- 000-10-480-L01P).

Attendees must complete a Continuing Pharmacy Education Request online and may immediately print their official statements of continuing pharmacy education credit at the ASHP Learning Center at http://ce.ashp.org following the activity.

Complete instructions for receiving your statement of continuing pharmacy education online are on the next page. Be sure to record the session code beginning with “A” announced during the activity.

Your educational opportunities related to antiplatelet therapy in patients with ACS reach beyond today’s symposium…

A live webinar on March 2, 2011, where faculty will explore issues raised by participant questions in today’s symposium (1 hour CPE).

Informational podcast interviews with the faculty about their experiences managing patients with ACS.

e-Newsletters featuring tips for incorporating information related to the use of oral antiplatelet therapy in ACS into practice, as well as updates on emerging information.

Web-based activity based on today’s live symposium (2 hours CPE, but please note that individuals who claim CPE credit for the live symposium are ineligible to claim credit for the web-based activity).

For more information and to sign up to receive e-mail updates about this educational series, go to

www.ashpadvantage.com/optimize

6 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

Instructions for Processing CPE online at http://ce.ashp.org

The ASHP Learning Center allows participants to obtain statements of continuing pharmacy education (CPE) conveniently and immediately using any computer with an internet connection. To obtain your CPE statements for ASHP Advantage activities, please visit http://ce.ashp.org

1. Log in to the ASHP Learning Center using your e-mail address and password. If you have not logged in to the new ASHP Learning Center (launched August 2008) and are not a member of ASHP, you will need to set up an account by clicking on “Become a user” and following the instructions. 2. Once logged in to the site, click on “Process Meeting CE.” 3. If you are a registered attendee at the ASHP Midyear Clinical Meeting, click on the start button to the right of ASHP Midyear Clinical Meeting 2010. If you are not registered to attend the ASHP Midyear Clinical Meeting, click on the start link to the right of the activity title. If this activity title does not appear in your meeting list, enter the 5-digit activity code in the box above the list and click submit. The activity code for this activity is 10480. Click register again when prompted. When you receive the “thank you for registering” message, click continue. This step will bring you back to your meeting list. Click on the start link to the right of the activity title. Do not click on “remove" or you will not be able to process CE for this activity. 4. Click on the click here link to view sessions associated with the day of the activity. This activity was held on Tuesday, December 7, 2010. 5. Enter the session code (e.g., A12345 and note that the letter is case sensitive) that was announced during the activity, and select the number of hours equal to your participation in the activity. 6. Click submit to receive the attestation page. 7. Confirm your participation and click submit. 8. New this year, complete the overall Midyear evaluation and click the “finish” button. You will then be able to view and print your transcript. Session Code CPE credit Date of Activity Activity Code (announced during the live hours activity)

Tuesday 10480 2 December 7, 2010

NEED HELP? Contact ASHP Advantage at [email protected].

7 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

8 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

Toby C. Trujillo, Pharm.D., BCPS (AQ Cardiology) Associate Professor University of Colorado Denver School of Pharmacy Clinical Specialist – Cardiology/Anticoagulation University of Colorado Hospital Aurora, Colorado

Toby C. Trujillo, Pharm.D., BCPS (AQ Cardiology), is Associate Professor of Clinical Pharmacy at the University of Colorado Denver School of Pharmacy 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.

Within the American Heart Association, Dr. Trujillo is a member of the Clinical Pharmacology Committee, which resides under the Council on Clinical Cardiology. 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.

9 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

Toby C. Trujillo, Pharm.D., BCPS (AQ Cardiology)

PRESENTATION Update on Oral Antiplatelet Therapy in Acute Coronary Syndrome

OVERVIEW Antiplatelet therapy has been a cornerstone in the treatment of patients with acute coronary syndrome (ACS) since the 1980s. Depending on the ACS subpopulation being studied, the implementation of aspirin (ASA) monotherapy provided significant reductions in morbidity and mortality.

Although the routine use of ASA became the standard of care, a significant number of patients continued to suffer from major ischemic events. The development of ticlopidine and clopidogrel in the 1990s represented another major advance in the treatment of cardiovascular disease. Studies quickly established that at a minimum these agents were equivalent and sometimes superior to ASA monotherapy in the prevention of ischemic events in multiple patient populations with atherosclerotic vascular disease, including ACS. Interest in monotherapy for ACS waned with the publication of the CURE trial, which provided the initial support for dual oral antiplatelet therapy. Along with the dramatic increase in the use of stents in patients undergoing percutaneous coronary intervention (PCI), clinical trials have established the combination of ASA pus clopidogrel as standard of care in patients with ACS over the last decade.

Similar to the earlier situation with ASA monotherapy, however, substantial numbers of patients continue to experience ischemic events on dual antiplatelet therapy. In addition, there has been a growing recognition that variable response to clopidogrel may contribute to the residual clinical burden seen with dual antiplatelet therapy. Prasugrel is a new antiplatelet agent with a mechanism of action similar to clopidogrel that may offer pharmacokinetic and pharmacodynamic advantages. In a head-to-head comparison in patients with ACS, prasugrel was more effective at reducing myocardial infarction than clopidogrel when both were added to ASA therapy. The impact of dual antiplatelet therapy will continue to be modified with the development of new oral antiplatelet agents, such as prasugrel.

10 Update on Oral Antiplatelet Therapy in Acute Coronary Syndrome

Toby C. Trujillo, Pharm.D., BCPS (AQ Cardiology) Associate Professor University of Colorado Denver School of Pharmacy Aurora, Colorado

Understanding Acute Coronary Syndrome (ACS)

Non-ST Elevation ST Elevation (UA/NSTEMI) (STEMI)

PCI +/- Medical Fibrinolysis Therapy Stent

UA = unstable angina, NSTEMI = non-ST-segment elevation myocardial infarction, STEMI = ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention

ACC/AHA Guidelines • NSTE ACSNSTE ACS • STEMI – Early invasive for high risk – Reperfusion therapy –– --blockersblockers • Primary PCI ––NitratesNitrates • Fibrinolytics –– --blockersblockers – ACE inhibitors/ARB ––NitratesNitrates – Aldosterone antagonists –– ACE inhibitors/ARB –– StatinsStatins – Aldosterone antagonists – Anticoagulants – Statins – Antiplatelet therapy • Aspirin (ASA) – Anticoagulants

••P2YP2Y1212 receptor antagonists – Antiplatelet therapy • GP IIb/IIIa inhibitors • Aspirin

••P2YP2Y1212 receptor antagonists • GP IIb/IIIa inhibitors

Anderson JL et al. J Am Coll Cardiol. 2007; 50:e1-e157. King SB 3rd et al. J Am Coll Cardiol. 2008; 51:172-209.

11 Existing and Future Antiplatelet Agents Enlarged slide on page 21

Angiolillo DJ et al. Eur Heart J. 2010; 31:17-28.

Aspirin in Acute Coronary Syndrome

Unstable Acute Myocardial Infarction Angina *p<0.0001 *p=0.003 *p=0.012 *p<0.011

Death or Ml Reocclusion Ml Death 20 30 4 17.1 25 3.3 11.8

15 3 20 10 9.4

10 2 1.9 % of Patients of % 6.5 11 10 5 5 1

0 0 0 0 Placebo ASA Placebo ASA Placebo ASA Placebo ASA

RISC Group. Lancet Roux et al. JACC ISIS-2. Lancet ISIS-2. Lancet 1990; 336:827-30. 1992; 19:671-7. 1988; 2:349-60. 1988; 2:349-60.

CURE Study Primary Endpoint: MI/Stroke/CV Death

0.140.14 Placebo 0.120.12 + ASA+ ASA 20%20% RRRRRR 0.100.10 0.080.08 azard Rate Clopidogrel pp = 0.00009 00009000009 0.060.06 + ASA+ ASA n = 12,562n 12,562 0.040.04 0.020.02 0.000.00

Cumulative H 00 336699 1212 Months of FollowFollow--upup

RRR = relative risk reduction

Yusuf S et al. N Engl J Med. 2001; 345:494-502.

12 CURE: Bleeding Results

Placebo Clopidogrel Endpoint + ASA* + ASA* N = 6303 N = 6259

• Major bleeding 2.7% 3.7%**

Life-threatening bleeding 18%1.8% 22%2.2% †

Non-life-threatening bleeding 0.9% 1.5% ‡

• Minor bleeding 2.4% 5.1% §

* In combination with standard therapy **p = 0.001; †p = NS; ‡p = 0.002; §p < 0.001

Yusuf S et al. N Engl J Med. 2001; 345:494-502.

PCIPCI--CURE:CURE: Results

Composite of MI or cardiovascular death from randomization to end of follow-follow-upup

0.150.15 PlaceboPlacebo 12.6%12.6% + ASA+ ASA 31%31% RRRRRR

ard Rate 00000.100 0 8.8%8.8% z Clopidogrel + ASA+ ASA 0.050.05 pp== 0.0020.002 n = 26582658n

Cumulative Ha 0.00.0 00 100100 200200 300300 400400 Days of FollowFollow--upup

Mehta SR et al. Lancet. 2001; 358; 527-33.

CREDO Early Effects of Pre-treatment with Clopidogrel – 28-Day Results

1010 Death, MI, or UTVR 99 No pre-preNo -treatmenttreatment - PlaceboPlacebo** 88 8.3%8.3% 18.5% 77 RRRRRR point

(%) 6.8%6.8% P=0.23P=0.23 d e 66 PrePre--treatmenttreatment – Clopidogrel* Clopidogrel* 55 44

Occurrenc 33

Combined En 22 11 00 00771414 2121 2828 Days from Randomization *Plus ASA and other standard therapies UTVR = urgent target vessel revascularization Steinhubl SR et al. JAMA. 2002; 288:2411-20.

13 Clopidogrel in ACS • NSTE ACS • STEMI – CURE (n=12,562) – CLARITY (n=3491) • 300/75 mg vs. placebo within 24 hours • Patients age 18-75 yr within 12 of symptom onset hours • Significant reductions in death, MI, – Clopidogrel 300/75 mg and stroke – Placebo – PCI-CURE (n=2658) • Significant reductions in occluded • 31% RRR in CV death or MI vessel, death, MI by angiography and up to 30 days – CREDO (n=2116) – COMMIT (n=45 ,852) • 300/75 mg vs. placebo 3-24 hours before PCI, 75 mg vs. placebo after • Patients within 24 hours of 28 days suspected MI • 27% RRR MI/stroke death 1 year – Clopidogrel 75 mg • 18.5% RRR in death, MI, UTVR – Placebo • Benefit only seen if load > 6 hours • 9% reduction in death/MI/stroke before PCI over treatment period – ACUITY (n=13,819) • Benefit with bivalirudin monotherapy contigent 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 SR et al. JAMA. 2002; 288:2411-20; Stone GW et al. N Engl J Med. 2006; 355:2203-16; Sabatine MS et al. N Engl J Med. 2005; 352:1179-89; Chen ZM et al. Lancet. 2005; 366:1607-21.

Limitations of Dual Antiplatelet Therapy ASA plus Clopidogrel • Increased bleeding • Delayed onset • Modest level of platelet inhibition • Variable response – Pharmacogenomics – Drug interactions • Irreversible mechanism of action • Delayed offset • Residual clinical events

Which of the following statements is true?

a. No clinical benefit is derived with increasing clopidogrel to 150 mg/day b. Prasugrel reduces risk of CV mortality compared with clopidogrel in treatment of ACS c. Higher aspirin dose further reduces mortality compared with aspirin 81 mg daily d. Prasugrel increases risk of bleeding compared with clopidogrel in treatment of ACS

14 CURRENT Trial: Study Design

ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)  Planned early (<24 hours) invasive management with intended PCI  Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

Clopidogrel 600600--mgmg load, N = 25,087N 25,087 Clopidogrel 300300--mgmg load, 150 mg/day x 7 days, then 75 mg/day then 75 mg/day

Aspirin Aspirin Aspirin Aspirin 300-325 mg/day 75-100 mg/day 300-325 mg/day 75-100 mg/day

PCI 17,232 (70%) No PCI 7855 (30%) Efficacy outcomes: CV death, MI, or stroke at day 30 Stent thrombosis at day 30 Safety outcomes: Bleeding Key subgroup: PCI vs. no PCI

CURRENT-OASIS 7 Investigators et al. N Engl J Med. 2010; 363:930-42.

CURRENT Trial Results: Clopidogrel Double vs. Standard Dose Standard Double HR 95% CI P Intn P CV death/MI/stroke PCI (2N = 17,232) 4.5 3.9 0.85 0.74-0.99 0.036 0.016 No PCI (2N = 7855) 4.2 4.9 1.17 0.95-1.44 0.14 Overall (2N = 25,087) 4.4 4.2 0.95 0.84-1.07 0.370 MI PCI (2N = 17,232) 2.6 2.0 0.78 0.64-0.95 0.012 0.025 No PCI (2N = 7855) 1.4 1.7 1.25 0.87-1.79 0.23 Overall (2N = 25,087) 2.2 1.9 0.86 0.73-1.03 0.097 CV Death PCI (2N = 17,232) 1.9 1.9 0.96 0.77-1.19 0.68 1.0 No PCI (2N = 7855) 2.8 2.7 0.96 0.74-1.26 0.77 Overall (2N = 25,087) 2.2 2.1 0.96 0.81-1.14 0.628 Stroke PCI (2N = 17,232) 0.4 0.4 0.88 0.55-1.41 0.59 0.50 No PCI (2N = 7855) 0.8 0.9 1.11 0.68-1.82 0.67 Overall (2N = 25,087) 0.5 0.5 0.99 0.70-1.39 0.950

CURRENT-OASIS 7 Investigators et al. N Engl J Med. 2010; 363:930-42.

CURRENT Trial Results: Enlarged slide on page 21 Clopidogrel Double vs. Standard Dose

CURRENT-OASIS 7 Investigators et al. N Engl J Med. 2010; 363:930-42.

15 CURRENT Trial Results: Enlarged slide on page 22 ASA High Dose vs. Low Dose

CURRENT-OASIS 7 Investigators et al. N Engl J Med. 2010; 363:930-42.

P2Y12 Receptor Inhibitors • Clopidogrel – Prodrug: 2-step cytochrome P-450 conversion • 2C19 patient variation • Drug interactions (PPIs) • Large amount of patient variability in response – Onset delayed – Irreversible inhibition of the P2Y receptor (life of the platelet) 12

• Prasugrel – Prodrug: Single-step cytochrome P-450 conversion • Multiple enzymes capable of conversion • Lacks patient variability compared to clopidogrel • Provides more potent platelet inhibition compared with clopidogrel – Onset in about 30 minutes – Irreversible inhibition of the P2Y12 receptor (life of the platelet) PPIs = proton pump inhibitors

Biotransformation and Mode of Action Enlarged slide on page 22 Clopidogrel, Prasugrel, and Ticagrelor

Schömig A. N Engl J Med. 2009; 361:1108-11.

16 TRITON-TIMI 38

ACS (STEMI or UA/NSTEMI) and planned PCI

CLOPIDOGREL PRASUGREL 300-mg loading dose 60-mg loading dose 75-mg maintenance dose 10-mg maintenance dose N = 13,608

Median duration of therapy—14.5 months

1o endpoint: CV death, MI, stroke 2o endpoints: CV death, MI, stroke, rehospitalization due to recurrent ischemia CV death, MI, UTVR Stent thrombosis (ARC definite/probable) Safety endpoints: TIMI major bleeds, life-threatening bleeds

ARC = Academic Research Consortium Wiviott SD et al. N Engl J Med. 2007; 357:2001-15.

TRITON-TIMI 38 Trial Results 15 138 Events Clopidogrel 12.1 HR 0.81 CV death/MI/Stroke (0.73-0.90) p = 0.0004 10 9.9 NNT = 46 Prasugrel point (%) d En

5 35 TIMI Major and Prasugrel Events Non-CABG Bleeds 2.4 HR 1.32 1.8 (1.03-1.68) Clopidogrel p = 0.03 0 0 30 60 90120 150 180210 240 270 300 330 360 390 420 450 NNH = 167 Days NNT = number needed to treat NNH = number needed to harm Wiviott SD et al. N Engl J Med. 2007; 357:2001-15.

TRITON-TIMI 38 Results Enlarged slide on page 23

Wiviott SD et al. N Engl J Med. 2007; 357:2001-15.

17 TRITONTRITON--TIMITIMI 38 Trial Enlarged slide on page 23 Bleeding Outcomes

NNHNNH

167167

200200

200200

250250

334334

8484 100100 1010 Wiviott SD et al. N Engl J Med. 2007; 357:2001-15.

TRITON-TIMI 38 Trial Bleeding Risk Subgroups

PostPost--hochoc analysis Risk (%)Risk (%) PriorPrior YesYes + 3737+ Stroke / TIA NoNo pp = 0.0060.006= -1616

≥ 75 yr --11 Age < 75 yryr< pp = 0.180.18= --1616

< 60 kgkg< +3+3 WeightWeight ≥ 60 kg pp = 0.360.36= --1414

OVERALLOVERALL --1313

0.5 1 2 Prasugrel Better HRHR Clopidogrel Better

TRITON-TIMI 38 Trial Net Clinical Benefit by Subgroup Prasugrel vs. Clopidogrel by Subgroup

Prior stoke or TIA HR 1.54 (95% CI 1.02–2.32); p=0.04 3.8%

≥ 75 Years of age HR 0.99 (95% CI 0.81–1.21); p=0.92 16% Weight ≤ 60 kg HR 1.03 (95% CI 0.69–1.53); p=0.89

80% of patients in TRITON-TIMI 38 demonstrated a significant reduction in CV death, MI, or stroke without an increase in bleeding

TIA = transient ischemic attack Wiviott SD et al. N Engl J Med. 2007; 357:2001-15.

18 TRITON-TIMI 38 Trial Enlarged slide on page 24 Subgroups

Diabetes STEMI

Montalescot G. Eur Heart J. 2009; 11(suppl G):G18-G24.

2009 ACCF/AHA PCI Guidelines Duration of Thienopyridine Therapy • In patients receiving a stent (BMS or DES) during PCI for ACS (Class I recommendation) – Clopidogrel 75 mg daily for at least 12 months (Class I recommendation) and up to 15 months (Class I recommendation) or – Prasugrel 10 mg daily for at least 12 months (Class I recommendation) or at least 15 months (Class IIb recommendation)

• Continuation of clopidogrel or prasugrel beyond 15 months may be considered in patients undergoing DES placement (Class IIb recommendation)

• If the risk of morbidity because of bleeding outweighs the anticipated benefit afforded by thienopyridine therapy, earlier discontinuation should be considered (Class I recommendation)

Kushner FG et al. Circulation. 2009; 120:2271-306.

2009 ACCF/AHA PCI Guidelines

• Conservative strategy (medical therapy without PCI ± stent)  Clopidogrel loading dose 300 mg, followed by 75 mg daily at least one month and ideally up to 1 year

King SB 3rd et al. J Am Coll Cardiol. 2008; 51:172-209.

19 Evolution of Antiplatelet Therapy in ACS

ASA

108 ASA + Clopidogrel ASA + - 22% Prasugrel Reduction in Ischemic - 20% Events

- 19%

Increase in Major Bleeds

+ 60% + 38% + 32%

0 PlaceboPlacebo ATTCATTC CURECURE TRITON-TIMITRITON-TIMI 38 38 Single Dual Higher Antiplatelet Rx Antiplatelet Rx IPA IPA = Inhibition of platelet aggregation

Conclusion

• Dual antiplatelet therapy represents a significant advance in the treatment of patients with ACS • Despite proven benefits, not all patients benefit equally with ASA plus clopidogrel • Emerging evidence suggests additional benefits may be realized with new agents or altered dosing

20 Existing and Future Antiplatelet Agents

Angiolillo DJ et al. Eur Heart J. 2010; 31:17-28.

CURRENT Trial Results: Clopidogrel Double vs. Standard Dose

CURRENT-OASIS 7 Investigators et al. N Engl J Med. 2010; 363:930-42.

21 CURRENT Trial Results: ASA High Dose vs. Low Dose

CURRENT-OASIS 7 Investigators et al. N Engl J Med. 2010; 363:930-42.

Biotransformation and Mode of Action Clopidogrel, Prasugrel, and Ticagrelor

Schömig A. N Engl J Med. 2009; 361:1108-11.

22 TRITON-TIMI 38 Results

Wiviott SD et al. N Engl J Med. 2007; 357:2001-15.

TRITONTRITON--TIMITIMI 38 Trial Bleeding Outcomes

NNHNNH

167167

200200

200200

250250

334334

8484 100100 1010 Wiviott SD et al. N Engl J Med. 2007; 357:2001-15.

23 TRITON-TIMI 38 Trial Subgroups

Dia bet es STEMI

Montalescot G. Eur Heart J. 2009; 11(suppl G):G18-G24.

24 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

SELECTED REFERENCES 1. Anderson JL, Adams CD, Antman EM et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST- Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007; 50:e1-e157. 2. Angiolillo DJ, Capodanno D, GotoS. Platelet thrombin receptor antagonism and atherothrombosis. Eur Heart J. 2010; 31:17-28. 3. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324:71-86. 4. Chen ZM, Jiang LX, Chen YP et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005; 366:1607-21. 5. CURRENT-OASIS 7 Investigators, Mehta SR, Bassand JP et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010; 363:930-42. 6. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988; 2:349- 60. 7. King SB 3rd, Smith SC Jr, Hirshfeld JW Jr et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2008; 51:172-209. 8. Kushner FG, Hand M, Smith SC Jr et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009; 120:2271-306. 9. Mehta SR, Yusuf S, Peters RJ et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001; 358:527-33. 10. Montalescot G. Benefits for specific subpopulations in TRITON-TIMI 38. Eur Heart J. 2009; 11(suppl G):G18-G24.

25 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

11. RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet. 1990; 336:827-30. 12. Roux S, Christeller S, Lüdin E. Effects of aspirin on coronary reocclusion and recurrent ischemia after thrombolysis: a meta-analysis. J Am Coll Cardiol.1992; 19:671-7. 13. Sabatine MS, Cannon CP, Gibson CM et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005; 352:1179-89. 14. Schömig A. Ticagrelor--is there need for a new player in the antiplatelet-therapy field? N Engl J Med. 2009; 361:1108-11. 15. Steinhubl SR, Berger PB, Mann JT 3rd et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002; 288:2411-20. 16. Stone GW, McLaurin BT, Cox DA et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006; 355:2203-16. 17. Wiviott SD, Braunwald E, McCabe CH et al. for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007; 357:2001-15. 18. Yusuf S, Zhao F, Mehta SR et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345:494-502.

26 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

SELF–ASSESSMENT QUESTIONS 1. Which of the following statements is true regarding the use of aspirin or clopidiogrel or both in the treatment of acute coronary syndrome?

a. The combination of aspirin plus clopidogrel does not increase the risk of bleeding compared with aspirin alone. b. The combination of aspirin plus clopidogrel reduces the risk of recurrent MI compared with aspirin alone. c. In the CURRENT trial, a daily dose of aspirin 300-325 mg led to a reduction in the risk of myocardial infarction (MI) compared with lower daily dose of 75-100 mg. d. In the CURRENT trial, a daily dose of aspirin 300-325 mg led to a reduction in the risk of total mortality compared with lower daily dose of 75-100 mg.

2. All of the following are considered limitations with dual antiplatelet therapy of aspirin plus clopidogrel EXCEPT

a. Increased bleeding compared with aspirin monotherapy. b. Variable antiplatelet response with clopidogrel. c. Quick offset of action with drug discontinuation. d. Irreversible inhibition of platelet function.

3. The Triton-TIMI 38 study comparing clopidogrel and prasugrel in patients with acute coronary syndrome and planned percutaneous coronary intervention showed that

a. Patients with a previous history of stroke had an overall net benefit with prasugrel compared with clopidogrel. b. Patients with a previous history of diabetes had an overall net benefit with prasugrel compared with clopidogrel. c. Patients aged 75 and greater had an overall net benefit with prasugrel compared with clopidogrel. d. Patients weighing less than 60 kg had an overall net benefit with prasugrel compared with clopidogrel.

Answers 1. b 2. c 3. b

27 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

28 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

Julie H. Oestreich, Pharm.D., Ph.D. Assistant Professor of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center Omaha, Nebraska

Julie H. Oestreich, Pharm.D., Ph.D., is Assistant Professor in the Department of Pharmacy Practice in the College of Pharmacy at the University of Nebraska Medical Center (UNMC) in Omaha, Nebraska.

Dr. Oestreich earned her Doctor of Pharmacy degree from Ohio Northern University in Ada, Ohio, and her Doctor of Philosophy in Pharmaceutical Sciences degree from the University of Kentucky College of Pharmacy in Lexington, Kentucky. She was also awarded a Graduate Certificate in Clinical Research Skills. She completed a post- doctoral fellowship at the Saha Cardiovascular Research Center in the College of Medicine at the University of Kentucky. This fellowship was supported by a Ruth L. Kirschstein National Research Service Award Institutional Training Grant (T32).

At the UNMC College of Pharmacy, Dr. Oestreich assists in the cardiology therapeutics module and coordinates an elective in pharmacogenomics. Her research specialty is platelet function testing and evaluating the effectiveness of antiplatelet agents. Her dissertation entitled, “Variability in ADP-mediated Platelet Response,” focused on platelet function in healthy volunteers, and she continues to study the variability of P2Y12 and other platelet receptor pathways in humans and in animal models. Dr. Oestreich has received competitive fellowship support from the American Heart Association, Pharmaceutical Research and Manufacturers of America Foundation, American Foundation for Pharmaceutical Education, and Sigma Xi Scientific Research Society.

Dr. Oestreich is an active member of the American College of Clinical Pharmacy and currently serves as chair of its Pharmacokinetics and Pharmacodynamics Practice and Research Network. She is also an active member of the American Pharmacists Association (APhA) and will serve as chair-elect of the Clinical Sciences Section of the APhA Academy of Pharmaceutical Research and Science starting in 2011. She has authored several articles and national abstracts in the area of platelet function and antiplatelet effectiveness.

29 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

Julie H. Oestreich, Pharm.D., Ph.D.

PRESENTATION Clinical Challenges in Oral Antiplatelet Therapy

OVERVIEW Increasing evidence supports relevant variability in clopidogrel effectiveness as measured by platelet function tests. Several clinical studies in patients treated with aspirin and clopidogrel have associated high platelet reactivity with adverse cardiovascular events. The potential usefulness of platelet function testing is further magnified by the availability of more potent P2Y12 receptor antagonists, including prasugrel and potentially ticagrelor. Thus far, platelet tests have been more successful at identifying patients with lower risk than predicting which patients will experience adverse outcomes and, therefore, have not been widely used.

Other unique challenges of clopidogrel therapy include recent FDA labeling changes regarding the drug interaction with omeprazole and reduced effectiveness of clopidogrel in CYP2C19 loss-of-function allele carriers. The strong FDA labeling change for omeprazole and other potent CYP2C19 inhibitors is based on consistent pharmacokinetic and pharmacodynamic effects, but the clinical relevance of this interaction is still being debated. Similarly, patients who have one or two loss-of-function alleles for the CYP2C19 gene demonstrate decreased active metabolite formation and impaired platelet inhibition with clopidogrel. The impact of CYP2C19 carrier status on cardiovascular events has varied in retrospective analyses of large-scale clinical trials, although the combined evidence suggests a small, yet significant effect. At the present time, routine genetic or platelet function testing is not recommended; nonetheless, high platelet reactivity and CYP2C19 metabolizer status, if known, should be taken into consideration—along with other clinical factors known to influence clopidogrel effectiveness and bleeding risk—when assessing appropriate antiplatelet therapy.

30 Clinical Challenges in Oral Antiplatelet Therapy

Julie H. Oestreich, Pharm.D., Ph.D. Assistant Professor of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center Omaha, Nebraska

Which of the following is TRUE regarding clopidogrel variability? a. Platelet reactivity on clopidogrel is a dichotomous variable allowing for highly sensitive, specific cut-off values for predicting CV events b. Platelet function tests for clopidogrel have low negative predictive values for CV events c. Several prospective clinical trials attributed CV events on clopidogrel to PPI use d. Patients with high platelet reactivity on clopidogrel have increased risk for CV events

Clinical Challenge #1: CLOPIDOGREL VARIABILITY

31 Biotransformation and Mode of Action: Clopidogrel, Prasugrel, and Ticagrelor Enlarged slide on page 22

Schömig Aet al. N Engl J Med. 2009; 361:1108-11.

Distribution of Clopidogrel Response in 544 Volunteers A Normal Distribution: Consistent with a Poly-Genetic and Poly-Environmental Influence 112

96

80

Number of 64 patients 48

32

16

0 <= -20 [-10,0] [11,20] [31,40] [51,60] [71,80] [91,100] Change in Aggregation to 5 μmol/L ADP Serebruany VL et al. J Am Coll Cardiol. 2005; 45:246-51.

Terminology

• Clopidogrel ‘resistance’ • Clopidogrel nonresponsiveness • High on-treatment platelet reactivity Context • Pharmacokinetic formation of active metabolite • Pharmacodynamic platelet inhibition • Cardiovascular events on compliant aspirin and clopidogrel treatment

32 Bleeding time LTALTA VerifyNowVerifyNow TEGTEG

MultiplateMultiplate Flow cytometry VASP phosphorylation analyzeranalyzer

Plateletworks

P-VASP VASP Impedance aggregometry Platelet Activation OthersOthers

Which Assay Is Best?

Assay LTA VASP Multiplate VerifyNow

Small whole Physiologic Advantages Versatile Standardized blood volume environment

Long history- Minimal SititSensitive to UfidlUser friendly correlated sample P2Y effect and fast with outcomes 12 manipulation

Not Less Disadvantages Expensive Expensive standardized experience

Specialized Specialized user user

Oestreich JH et al. Thromb Haemost. 2009; 101:217-9.

Correlation of Clopidogrel Responsiveness with Clinical Outcomes • One of first trials to correlate lower antiplatelet effects of clopidogrel to clinical outcomes – 60 patients with STEMI with PCI + stent – Clopidogrel 300 mg LD, then 75 mg daily – Platelet activity assessed at PCI and daily x 5 days • Patients separated into quartiles based on ADP- induced platelet aggregation • Major adverse cardiac events evaluated at 6 months

Matetzky S et al. Circulation. 2004; 109:3171-5.

33 Correlation of Clopidogrel Responsiveness with Clinical Outcomes 6-Month Recurrent CV Events (%)

40% 40% p=0.007

30%

20%

10% 6.7% 0% 0% 0% 1st 2nd 3rd 4th n=15 n=15 n=15 n=15 Matetzky S et al. Circulation. 2004; 109:3171-5.

High On-treatment Platelet Reactivity: PREPARE POST-STENTING Trial

• Patients undergoing elective PCI + stent (n=192) receiving clopidogrel – 600 mg LD (n=60); 300 mg LD (n=75) – Alreadyygy() on 75 mg daily (n=57) • Platelet tests (pretreatment and ~24 hours post-PCI) – LTA with ADP 20 μmol/L – Thrombelastograph (TEG) • Results at 6 months – 20% of patient with MACE (n=38) – 80% of patients event free (n=154)

Gurbel PA et al. J Am Coll Cardiol. 2005; 46:1820-6.

PREPARE POST-STENTING Trial

Patients with Patients without Ischemic Events Ischemic Events pp--valuevalue

LTA-ADP 20 pre-treatment (%) 71 ± 9 73 ± 12 NS LTA-ADP 20 post-treatment (%) 63 ± 12 56 ± 16 0.02

TEG MA pre-treatment (mm) 72 ± 7 67 ± 8 <0.001 TEG MA post-treatment (mm) 74 ± 5 65 ± 5 <0.001

Lowest LTA post-treatment quartile (<50% platelet aggregation) – MACE 10% Highest LTA post-treatment quartile (>67% platelet aggregation) – MACE 32% p = 0.02

MA = maximal absorption (clot strength) Gurbel PA et al. J Am Coll Cardiol. 2005; 46:1820-6.

34 Other Studies

• At least 28 studies link on-treatment platelet reactivity and clopidogrel responsiveness to clinical endpoints in PCI patients – n = 46–1608 patients – Multippyle assays

• Clinical outcomes – Stent thrombosis – Major adverse cardiac events (death, MI, TVR) – Cardiac death

Bonello L et al. J Am Coll Cardiol. 2010; 56:919-33.

ROC Curve Analyses of Cut-off Values Study Cut-off Endpoint AUC OR

Price et al. > 235 PRU 6-mo post-PCI CVD/MI/ST 0.71

Gurbel et al. ADP 5 > 46% 2-yr post-PCI MACE 0.77 3.9 (2008) ADP 20 > 59% 0.78 3.8

Blindt et al. > 48% PRI 6-mo ST 0.79 1.16

Frere et al. ADP 10 > 70% 1-mo post-PCI MACE + stroke 0.74 > 53% PRI 0.73

Bonello et al. > 50% PRI 6-mo post-PCI MACE 0.55 (2007) Marcucci et al. ≥ 240 PRU 1-yr CV death + MI 0.66 2.38- 2.75 Sibbing et al. > 468 AU/min 30-day ST 0.78 12.0

Cuisset et al. ADP 10 > 67% 1-mo ST 0.69 5.8

Breet et al. Multiple assays 1-yr death, MI, ST, and stroke 0.61-0.63 2.1-2.5

Laboratory Definitions of High On-treatment Platelet Reactivity

• PRI > 50% by VASP phosphorylation • > 235 – 240 PRU (P2Y12 reaction units) by VerifyNow P2Y12 assay • > 46% maximal ADP 5 μmol/L-induced aggregation by light transmission aggregometry • > 468 arbitrary aggregation units/min in response to ADP by the Multiplate analyzer

Bonello L et al. J Am Coll Cardiol. 2010; 56:919-33.

35 Platelet Function Guided Therapy

Non-emergent PCI: ACS and stable angina (n = 1122)

Loading doses (LD): ASA 250 mg, clopidogrel 600 mg VASP ≥ 50%

Randomization (n=429)

CONTROL (n =215) VASP-guided LD (n =214)

Maintenance doses: Up to 3 additional 600-mg LD ASA 160 mg, clopidogrel 75 mg every 24 hours until VASP < 50% before PCI 1° endpoint: Definite stent thrombosis (ARC definition) 2° endpoints: MACE including CV death, MI, and UTVR TIMI major and minor bleeding at 30 days

Bonello L et al. Am J Cardiol. 2009; 103:5-10.

Platelet Function Guided Therapy

VASP after first LD 66 ± 11 67 ± 10 VASP after sensitization  37 ± 12 p < 0.01

17 patients (8%) (%) Platelet reactivity

Bonello L et al. Am J Cardiol. 2009; VASP 1 VASP 2 VASP 3 VASP 4 103:5-10. n = 215 n = 215 n= 83 n = 40

Early Definite Stent Thrombosis and Other MACE during 1 Month Follow-up Control VASP-VASP-guidedguided Group Group Endpoint n,(%) (n=214) (n=215)(n=215) pp--valuevalue

Acute stent thrombosis 2 (0.9) 000.250.25

SubSub--acuteacute stent thrombosis 8 (3.7)1 (0.5)0.02

Early DST 10 (4.7) 1 (0.5)0.01

Cardiovascular death 4 (1.8) 0000.06.06

Myocardial infarction 10 (4.8) 1 (0.5) 0.01

Urgent revascularization 5 (2.3) 0000.06.06

All MACEAll MACE 19 (8.9) 1 (0.5)<0.001

Bonello L et al. Am J Cardiol. 2009; 103:5-10.

36 The Sweet Spot: Is There a Therapeutic Window for

P2Y12 Inhibition? n = 2,533

Incidence of bleeding (%)

Incidence of ST (%)

Platelet inhibition determined by Multiplate analyzer.

Sibbing D et al. J Am Coll Cardiol. 2010; 56:317-8.

Take-home Message: Clopidogrel Nonresponsiveness and On-treatment Platelet Reactivity

• Clopidogrel variability as measured by platelet function tests correlates with clinical outcomes in patients undergggoing PCI – Good negative predictive value – Poor positive predictive value • Using platelet tests for individualized dosing is advancing – VerifyNow is most convenient assay • Platelet function test that best predicts clinical outcomes is not known

Clinical Challenge #2: CLOPIDOGREL-PPI DRUG INTERACTION

37 Biotransformation of Clopidogrel

Bonello L et al. J Am Coll Cardiol. 2010; 56:919-33.

OCLA Study

• Patients undergoing elective PCI with stenting (n=140) – ASA plus clopidogrel 300 mg LD, 75 mg qd – Randomized • Placebo x 7 days • Omeprazole 20 mg qd x 7 days – VASP at baseline • 83.2% vs. 83.9%; p=NS – VASP at day 7 • Placebo 39.8% • Omeprazole 51.4% • p<0.0001

GilardGilard M et al. J Am Coll CardiolCardiol.. 2008;2008; 51:25651:256--6060..

Clopidogrel and Proton Pump Inhibitor Interaction

Clopidogrel: HR 0.94 (0.80 – 1.11) TRITON-TIMI 38 Trial (n=13,608)

33% on PPI Prasugrel: HR 0.99 (0.83 – 1.19) PPI use did not impact - Primary endpoint -MI CV Death, MI, or Stroke - Stent thrombosis

O’Donoghue ML et al. Lancet. 20092009; 374:989; 374:989--9797..

38 Clopidogrel-PPI Meta-analysis Enlarged slide on page 48

Odds ratios for MACE according to PPI use (n = 46,037)

Hulot JS et al. J Am Coll Cardiol. 2010; 56:134-43.

PPIs Associated with CV Risk Enlarged slide on page 48 Independent of Clopidogrel Use Danish cohort study: hazard ratios for MACE according to PPI and clopidogrel use (n = 24,704 on clopidogrel)

Charlot M et al. Ann Intern Med. 2010; 153:378-86.

COGENT Trial Methods

• Phase 3 efficacy and safety study of CGT-2168, a fixed-dose combination of clopidogrel (75 mg) and omeprazole (20 mg) compared with clopidogrel •Composite endpoint of CV death, non-fatal MI, CABG or PCI, or ischemic stroke • Target sample size increased from 3200 to ~5000 patients with an accrual period of 1 year and maximum follow up of 2 years • Study ended at 3761 patients when the sponsor declared bankruptcy

Bhatt DL et al. N Engl J Med. 2010 Oct 6 [Epub ahead of print].

39 COGENT Trial Results Event rates at 180 days were 5.7% in placebo group and 4.9% in omeprazole group, HR = 0.99 (0.68-1.44), p = 0.96

n = 3761

Bhatt DL et al. N Engl J Med. 2010 Oct 6 [Epub ahead of print].

FDA Advisory and Plavix® Labeling Change Reminder: October 27, 2010

• FDA continues to warn against the concomitant use of clopidogrel and omeprazole – Separating the dose of clopidogrel and omeprazole in time will not reduce this drug interaction • Recommendation applies only to omeprazole and not to all PPIs • Pantoprazole may be an alternative PPI for consideration

U.S. Food and Drug Administration. (URL in reference list).

Take-home Message: Clopidogrel Drug Interactions

• PK/PD evidence supports an interaction between clopidogrel and PPIs – However, significant effects with platelet function tests have not always matched clinical outcomes • EidEvidence for cli liinical re levance is con flitiflicting an d no t yet convincing – Retrospective studies limited by general increased cardiovascular risk – COGENT study used novel formulation • Regardless of scientific evidence, FDA label leaves little room for alternative interpretations

40 Clinical Challenge #3: CLOPIDOGREL AND CYP2C19

CYP2C19 Alleles and Associated Phenotypes

CYP2C19 alleles Phenotype

One or two gain-of-function alleles Ultrarapid metabolizer (UM) ((1/17*1/*17 or *17/* 17)

No variant alleles (*1/*1) Extensive metabolizer (EM)

One loss-of-function allele Intermediate metabolizer (IM) (*2, *3, others) Two loss-of-function alleles Poor metabolizer (PM) (*2, *3, others)

Mega JL et al. N Engl J Med. 2009; 360:354-62.

CYP2C19 Genotype Frequency

European African Chinese of Descent Descent Asian Origin (n=1356) (n=966) (n=573)

Extensive metabolism: CYP2C19 *1/*1 74% 66% 38%

Intermediate metabolism: CYP2C19 *1/*2 or *1/*3 26% 29% 50%

Poor metabolism: CYP2C19 *2/*2, *2/*3, or *3/*3 2% 4% 14%

Xie HG et al. Annu Rev Pharmacol Toxicol. 2001; 41:815-50.

41 Clopidogrel and CYP2C19: Pharmacokinetic and Pharmacodynamic Effects Healthy carriers of one or more CYP2C19 reduced-function alleles had 32% relative reduction in active metabolite exposure and a 9% absolute reduction in MPA

Clopidogrel 75 mg Clopidogrel 75 mg 0-t MPA Δ AUC

Clopidogrel active metabolite Antiplatelet response by LTA exposure Mega JL et al. N Engl J Med. 2009; 360:354-62.

Clopidogrel and CYP2C19 Clinical Outcomes: TRITON TIMI-38 n = 1477 15%

p = 0.01 Carriers 12% 12.1% h Event Noncarriers t 9% 8.0%

6% p = 0.02

% Patients wi 3% 2.6% 0.8% 0% D/MI/Stroke Stent Thrombosis

Mega JL et al. N Engl J Med. 2009; 360:354-62.

Clopidogrel and CYP2C19 Clinical Outcomes: Meta-analysis

Odds ratios for MACE according to CYP2C19 (n = 11,959)

Hulot JS et al. J Am Coll Cardiol. 2010; 56:134-43.

42 Clopidogrel and CYP2C19 Clinical Outcomes: Stent Thrombosis Meta-Analysis n = 4905

Hulot JS et al. J Am Coll Cardiol. 2010; 56:134-43.

Clopidogrel and CYP2C19 Clinical Outcomes: PLATO

Analysis from the PLATO trial 15% p=0.46

12% 11.2% 10.0% 9% Carrier Noncarrier 6% n = 9842

3% 2.3% 1.5% 0% CV Death/MI/Stroke Stent Thrombosis

Wallentin L et al. Lancet. 2010; 376:1320-8.

Clopidogrel and CYP2C19 Clinical Outcomes: CURE Trial (n = 5059) 12% Carriers p = NS Noncarriers p = 0.02 10% 10% 9.5%

troke 8% )

S 80%8.0% 7.7% 6%

4% at 1-year at 1-year (% 2% CV Death, MI, or CV Death, MI, 0% LOF (*2,*3) GOF (*17) Paré G et al. N Engl J Med. 2010; 363:1704-14.

43 Usefulness of Genetic Testing for Predicting Cardiac Outcomes

• CYP2C19 is a consistent predictor of clopidogrel PK/PD and is significantly associated with clinical outcomes in some trials • No prospective studies have evaluated genetic testing and the effectiveness of subsequent treatment changes • Positive predictive value is estimated at 12-20%

Changes to the Plavix® (Clopidogrel) Product Label

Plavix prescribing information. 2010 Aug (URL in ref list).

ACCF/AHA: Approaches to the FDA Boxed Warning

• ‘It neither mandates, requires, nor recommends genetic testing, thereby allowing for flexibility in clinical decisions.’

• ‘The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time.’

Holmes DR Jr et al. J Am Coll Cardiol. 2010; 56:321-41. Society for Cardiovascular Angiography and Interventions et al. Circulation. 2010; 122:537-57.

44 Take-home Message: Clopidogrel and CYP2C19

• PK/PD and clinical evidence supports a significant effect of CYP2C19 metabolizer status on clopidogrel effectiveness – However, genetic testing demonstrates low positive predictive value – GWAS attributes 12% of variability to CYP2C19 • Key cardiology groups do not recommend routine genetic testing for clopidogrel at this time – If genetic information is known, it should be considered in context with other risk factors • We still do not know how to best optimize clopidogrel therapy and improve clinical outcomes

Amish Pharmacogenomics of AntiPlatelet Intervention (PAPI) Study Genome-wide association study (n = 429)

Attributes 12% of clopidogrel variability to CYP2C19

Shuldiner AR et al. JAMA. 2009; 302:849-57.

Genome-Wide Association Study: PAPI Study (n = 429)

Shuldiner AR et al. JAMA. 2009; 302:849-57.

45 Genetic factors - Polymorphisms of CYP - Polymorphisms of GPIa - Polymorphisms of P2Y12 - Polymorphisms of GP IIIa

Suboptimal Clopidogrel Response

Clinical factors Cellular factors - Failure to prescribe - Accelerated platelet turnover - Poor compliance - Reduced CYP3A metabolic activity - Under dosing - Increased ADP exposure - Poor absorption - Up-regulation of the P2Y pathway 12 - Drug/drug interactions - Up-regulation of the P2Y pathway 1 - Acute coronary syndrome - Up-regulation of P2Y independent - Diabetes mellitus pathways - Elevated body mass index Angiolillo DJ et al. J Am Coll Cardiol.Cardiol. 20072007; 49:1505; 49:1505--1616..

What information is necessary for appropriate clopidogrel prescribing?

Name: Ima Clotter BMI: 22 Gender: F Age: 62 Platelet reactivity: ____ CYP2C19 metblitabolizer stttatus: ____ Inflammatory index: ____ Coagulation efficiency: ____

Calculated target level of P2Y12 receptor inhibition: ____

P2Y12 antagonist: ____ Predicted dose: ____

Clopidogrel: Current Recommendations

Testing Result Recommendation

No routine platelet function or genetic Indication for clopidogrel testing is recommended Low or normal on-treatment platelet Follow population-based guidelines reactivity

High on-treatment platelet reactivity Consider alternative strategy

CYP2C19*1/*1 Follow population-based guidelines

CYP2C19 loss-of-function Consider alternative agent polymorphism

*Consider other factors, including age, BMI, DM, and bleeding risk

46 TC is a 58-year-old man recently started on clopidogrel 75 mg daily. CYP2C19 genotype is CYP2C19*1/*2. VerifyNow test is slightly elevated (PRU = 245). What is the recommended treatment strategy for TC? a. Continue clopidogrel 75 mg daily b. Increase clopidogrel maintenance dose to 150 mg daily c. Start prasugrel d. Start ticagrelor

47 Clopidogrel-PPI Meta-analysis

Odds ratios for MACE according to PPI use (n = 46,037)

Hulot JS et al. J Am Coll Cardiol. 2010; 56:134-43.

PPIs Associated with CV Risk Independent of Clopidogrel Use Danish cohort study: hazard ratios for MACE according to PPI and cloppgidogrel use (n = 24,704 on cloppg)idogrel)

Charlot M et al. Ann Intern Med. 2010; 153:378-86.

48 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

SELECTED REFERENCES 1. Abraham NS, Hlatky MA, Antman EM et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointstinal risks of antiplatelet therapy and NSAID use. Circulation. 2010 Nov 8 [Epub ahead of print]. 2. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007; 49:1505-16. 3. Bhatt DL, Cryer BL, Contant CF et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010 Oct 6 [Epub ahead of print]. 4. Blindt R, Stellbrink K, de Taeye A et al. The significance of vasodilator-stimulated phosphoprotein for risk stratification of stent thrombosis. Thromb Haemost. 2007; 98:1329-34. 5. Bonello L, Camoin-Jau L, Armero S et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol. 2009; 103:5-10. 6. Bonello L, Paganelli F, Arpin-Bornet M et al. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost. 2007; 5:1630-6. 7. Bonello L, Tantry US, Marcucci R et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 2010; 56:919-33. 8. Breet NJ, Van Werkum JW, Bouman HJ et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA. 2010; 303:754-62. 9. Charlot M, Ahlehoff O, Norgaard ML et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med. 2010; 153:378-86. 10. Cuisset T, Frere C, Quilici J et al. Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogrel-treated patients. Am J Cardiol. 2009; 104:1078-82. 11. Frere C, Cuisset T, Quilici J et al. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome. Thromb Haemost. 2007; 98:838-43. 12. Gilard M, Arnaud B, Cornily JC et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol. 2008; 51:256-60.

49 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

13. Gurbel PA, Antonino MJ, Bliden KP et al. Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target. Platelets. 2008; 19:595-604. 14. Gurbel PA, Bliden KP, Guver K et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol. 2005; 46:1820-6. 15. Gurbel PA, Tantry US, Shuldiner AR et al. Genotyping: one piece of the puzzle to personalize antiplatelet therapy. J Am Coll Cardiol. 2010; 56:112-6. 16. Hochholzer W, Trenk D, Fromm MF et al. Impact of cytochrome P450 2C19 loss-of- function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol. 2010; 55:2427-34. 17. Holmes DR Jr, Dehmer GJ, Kaul S et al. ACCF/AHA clopidogrel clinical alert: approaches to the FDA "boxed warning": a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2010; 56:321-41. 18. Hulot JS, Collet JP, Silvain J et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010; 56:134-43. 19. Jeong YH, Kim IS, Park Y et al. Carriage of cytochrome 2C19 polymorphism is associated with risk of high post-treatment platelet reactivity on high maintenance- dose clopidogrel of 150 mg/day: results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) study. JACC Cardiovasc Interv. 2010; 3:731-41. 20. Marcucci R, Gori AM, Paniccia R et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of- care assay: a 12-month follow-up. Circulation. 2009; 119:237-342. 21. Matetzky S, Shenkman B, Guetta V et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004; 109:3171-5. 22. Mega JL, Close SL, Wiviott SD et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009; 360:354-62. 23. O’Donoghue ML, Braunwald E, Antman EM et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet. 2009; 374:989-97.

50 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

24. Oestreich JH, Smyth SS, Campbell CL. Platelet function analysis: at the edge of meaning. Thromb Haemost. 2009; 101:217-9. 25. Paré G, Mehta SR, Yusuf S et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010; 363:1704-14. 26. Plavix prescribing information. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2010 Aug. http://products.sanofi- aventis.us/PLAVIX/plavix.pdf (accessed 2010 Nov 3). 27. Price MJ, Endemann S, Gollapudi RR et al. Prognostic significance of post- clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J. 2008; 29:992-1000. 28. Schömig A. Ticagrelor--is there need for a new player in the antiplatelet-therapy field? N Engl J Med. 2009; 361:1108-11. 29. Serebruany VL, Steinhubl SR, Berger PB et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol. 2005; 45:246-51. 30. Shuldiner AR, O’Connell JR, Bliden KP et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009; 302:849-57. 31. Sibbing D, Braun S, Morath T et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol. 2009; 53:849-56. 32. Sibbing D, Steinhubl SR, Schulz S et al. Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: initial evidence of a therapeutic window. J Am Coll Cardiol. 2010; 56:317-8. 33. Simon T, Verstuyft C, Mary-Krause M et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009; 360:363-75. 34. Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, Writing Committee Members et al. ACCF/AHA clopidogrel clinical alert: approaches to the FDA "boxed warning": a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association. Circulation. 2010; 122:537-57. 35. U.S. Food and Drug Administration. FDA reminder to avoid concomitant use of Plavix (clopidogrel) and omeprazole. Updated 10/27/10. www.fda.gov/Drugs/DrugSafety/ucm231161.htm (accessed 2010 Nov 9). 36. Wallentin L, James S, Storey RF et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010; 376:1320-8. 37. Xie HG, Kim RB, Wood AJ et al. Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol. 2001; 41:815-50.

51 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

SELF–ASSESSMENT QUESTIONS 1. Which of the following laboratory test results would indicate high on-treatment platelet reactivity or clopidogrel nonresponsiveness?

a. PRI 42% (platelet reactivity index) by vasodilator-stimulated phosphoprotein (VASP) phosphorylation. b. 185 PRU (P2Y12 reaction units) by VerifyNow P2Y12 test. c. 382 arbitrary aggregation units/min in response to adenosine diphosphate (ADP) by the Multiplate analyzer. d. 55% maximal ADP 5 μM-induced aggregation by light transmission aggregometry.

2. Which of the following statements most appropriately describes the interaction between clopidogrel and proton pump inhibitors (PPIs)?

a. Occurs because CYP2C19 is the only enzyme capable of converting clopidogrel to its intermediate and active metabolites. b. Is supported by the results of the prospective COGENT trial of a fixed-dose combination of clopidogrel and omeprazole. c. Is relevant because clopidogrel’s prescribing information clearly states that clopidogrel and omeprazole should not be used together. d. Can be easily evaluated by retrospective studies because PPI use is independent of all other risk factors.

3. According to key cardiology groups, which of the following statements best describes the role of genetic testing or platelet function testing when selecting antiplatelet therapy?

a. Routine testing is recommended, and the results should be considered together with other risk factors. b. Routine testing is recommended, and the results should be the only risk factor considered. c. Routine testing is not recommended, but, if available, the results should be considered together with other risk factors. d. Routine testing is not recommended, and, if available, the results should not be considered.

Answers 1. d 2. c 3. c

52 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology) Activity Chair and Moderator 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 received the UNMC College of Pharmacy Educator of the Year Award for 2010, an award he has received twice within the last four years.

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.

53 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology)

PRESENTATION

Emerging P2Y12 Treatment Strategies

OVERVIEW Dual antiplatelet therapy (clopidogrel and aspirin) has been part of standard-of-care for the management of patients with acute coronary syndrome and patients undergoing percutaneous coronary intervention for about a decade. Issues, such as a large variability of antiplatelet activity, drug-drug interactions, and pharmacogenomic polymorphisms of metabolism, have raised serious questions about the role of standard dosing of clopidogrel for all patients. A number of alternative approaches have been investigated over the last several years.

Increasing the loading and maintenance doses of clopidogrel have been explored with variable success. While this may have some benefit in patients, it is unknown if this strategy will consistently overcome issues of nonresponsiveness. Adding cilostazol has also been investigated, but large phase III trials are still needed to secure this as a solid strategy. The most promise has come in selecting newer P2Y12 antiplatelet agents that do not have the same limitations as clopidogrel. Prasugrel has demonstrated a significant reduction in ischemic endpoints compared with clopidogrel, but at the cost of increased bleeding. Ticagrelor is a different type of P2Y12 inhibitor that does not need to be metabolized to an active metabolite, while it also provides faster reversibility compared with both clopidogrel and prasugrel. Ticagrelor has demonstrated a significant reduction in ischemic endpoints compared with clopidogrel. While there is also an increase in bleeding with ticagrelor, the severity of the bleeding is not as high as with prasugrel. Pharmacists need to understand the pros and cons of these different options as we care for patients with acute coronary syndrome.

54 Emerging P2Y12 Treatment Strategies

Paul P. Dobesh, Pharm.D., FCCP, BCPS (AQ Cardiology) Associate Professor of Pharmacy Practice College of Pharmacy University of Nebraska Medical Center Omaha, Nebraska

Emerging Treatment Strategies

• Increasing dose of clopidogrel

• Switching to different P2Y12 inhibitor – Ticlopidine – Prasugrel – Ticagrelor – Future agents • Triple antiplatelet therapy – Adding cilostazol – PAR-1 inhibitors

PLAVIX® PI: Clinical Pharmacology August 2010 Table 4: Active Metabolite Pharmacokinetics and Antiplatelet Responses* by CYP2C19 Metabolizer Status

Ultrarapid Extensive Intermediate Poor Dose (n=10) (n=10) (n=10) (n=10) Cmax 300 mg (24 h) 24 (10) 32 (21) 23 (11) 11 (4) (ng/mL) 600 mg (24 h) 36 (13) 44 (27) 39 (23) 17 (6) 75 mg (Day 5) 12 (6) 13 (7) 12 (5) 4(1)4 (1) 150 mg (Day 5) 16 (9) 19 (5) 18 (7) 7 (2) IPA (%)* 300 mg (24 h) 40 (21) 39 (28) 37 (21) 24 (26) 600 mg (24 h) 51 (28) 49 (23) 56 (22) 32 (25) 75 mg (Day 5) 56 (13) 58 (19) 60 (18) 37 (23) 150 mg (Day 5) 68 (18) 73 (9) 74 (14) 61 (14) VASP- 300 mg (24 h) 73 (12) 68 (16) 78 (12) 91 (12) PRI (%) 600 mg (24 h) 51 (20) 48 (20) 56 (26) 85 (14) 75 mg (Day 5) 40 (9) 39 (14) 50 (16) 83 (13) 150 mg (Day 5) 20 (10) 24 (10) 29 (11) 61 (18) * Reported as mean (SD)

55 OPTIMUS Study

• Patients with DM type 2 on chronic dual antiplatelet therapy were screened for clopidogrel responsiveness – Platelet aggregation > 50% with 20 µmol/L ADP by LTA defined nonresponsiv eness – Screened 64 patients – 40 (62.5%) nonresponsive • Platelet aggregation 39.9% ± 8% in responders • Platelet aggregation 66.2% ± 8% in nonresponders – Nonresponders then randomized • Clopidogrel 75 mg daily (n=20) • Clopidogrel 150 mg daily (n=20)

Angiolillo DJ et al. Circulation. 2007; 115:708115:708--16.16.

OPTIMUS Study Enlarged slide on page 69

Angiolillo DJ et al. Circulation. 2007; 115:708115:708--16.16.

OPTIMUS Study

50%

Angiolillo DJ et al. Circulation. 2007; 115:708115:708--16.16.

56 Accelerated Platelet Inhibition by Double Dose Clopidogrel According to Gene Polymorphism (ACCEL-DOUBLE) Study • 126 PCI-treated patients • All given clopidogrel 150 mg daily x 1 month • Genotypin g –CYP3A5 – CYP2C19 – ABCB1 • Platelet function testing performed at 1 month – LTA with 5 and 20 μmol/L – VerifyNow P2Y12 test

Jeong YH et al. JACC Cardiovasc Interv. 2010; 3:731-41.

ACCEL-DOUBLE: Results Enlarged slide on page 69

• CYP3A5 and ABCB1 did not influence platelet reactivity • CYP2C19 predictive of high post-treatment platelet reactivity – OR 5.5 (1.33-23.26) p=0.018

Jeong YH et al. JACC CardiovascInterv. Interv. 2010; 3:7313:731--41.41.

Dosing Based on CYP2C19 Status • Patients with high on-treatment platelet reactivity on clopidogrel 75 mg daily – Identified 41 patients • 21 with wildtype (*1/*1) CYP2C19 status • 20 carriers of a 2C19 loss-of-function allele – VerifyNow P2Y12 test • Baseline (75 mg daily): PRU=285 • Clopidogrel 150 mg daily: PRU=220 • PRU “normalized” (<235) with 150 mg daily in 56% of patients • No significant difference in antiplatelet response based on 2C19 status

Barker CM et al. JACC Cardiovasc Interv. 2010; 3:1001-7.

57 GRAVITAS Trial Successful PCI with DES without major complication or GP IIbIIb//IIIaIIIa use

PostPost--PCIPCI VerifyNow P2Y12 assay (PRU) 1212--2424 hours post-post-PCIPCI

n ~ 6600 Yes No PRU ≥ 230?230? Responder

Nonresponder Random selection

ABCn=1109 n=1105 n=586 “Standard therapy” “Standard therapy” “Tailored therapy” clopidogrel 75 mg + clopidogrel 75 mg + clopidogrel 150 mg/day placebo/day placebo/day

Clinical followfollow--upup and VerifyNowassessment at 30 days, 6 months

Primary end point: 6 month CV death, nonfatal MI, ARC def/def/probprob stent thrombosis

Price M et al. Presented at AHA Scientific Sessions 2010. Abstract 21791.

GRAVITAS Trial Results 14% High PR - High Dose p=0.18 12% High PR - Standard Dose 12% 10% Normal PR - Standard Dose 10% 8% atients P 6%

% of p=0.98 p=0.20 4% p=0.10 2% 2.3%2.3% 2.3% 1.4% 1.4% 0% CV Death/MI/ST GUSTO Severe/Mod Any GUSTO Bleeding Bleeding PR = platelet reactivity Price M et al. Presented at AHA Scientific Sessions 2010. Abstract 21791.

Ongoing Clinical Trials All trials assessing platelet reactivity by VerifyNow

Clopidogrel TrialTrial nnPatientsPatients Outcome Therapy

ARCTIC 2500 Elective 12 month MD preference PCI+DESPCI+DES MACE

DANTE442 NSTE ACS 6 & 12 month 75 mg vs. 150 mg qd PCIPCI MACE

TOPAS-1 450 Previous 6 month 600 mg LD, 75 mg qd PCI ± stent ST

TRIGGER-PCI 2150 PCI CV death, MI 600 mg LD, 75 mg qd vs. prasugrel 60 mg LD, 10 mg qd

58 Emerging Treatment Strategies

• Increasing dose of clopidogrel

• Switching to different P2Y12 inhibitor – Ticlopidine – Prasugrel – Ticagrelor – Future agents • Triple antiplatelet therapy – Adding cilostazol – PAR-1 inhibitors

Clopidogrel-to-Ticlopidine Crossover Study n=143

75% Absolute ΔΔ in % Inhibition of Platelet 63% AggAggmaxmax ≤ 10% Aggregation < 20%

50% 44% 34% 33% 21% 25% 19% 11.4% 3.5% 0% Responders NR to NR to NR to Both Responders NR to NR to NR to Both to Both Clopidogrel Ticlopidine to Both Clopidogrel Ticlopidine 83% of NR to clopidogrel 67% of NR to clopidogrel responded to ticlopidine responded to ticlopidine 20% of clopidogrel responders 27% of clopidogrel responders became NR to ticlopidine became NR to ticlopidine

Campo G et al. J Am Coll Cardiol.Cardiol. 2007; 50:113250:1132--7.7.

TRITON TIMI-38 Trial: Results WiviottWiviottSD et al. N EnglJ Med. 2007; 357:2001357:2001--15.15. 1515 138138 eventsevents Clopidogrel 12.112.1 HR 0.810.81HR CV Death / MI / Stroke (0.73(0.73--0.90)0.90) 9.99.9 P=0.0004P=0.0004 1010 NNT = 4646NNT int (%) Prasugre easugel o Endp 55 3535 TIMI Major Prasugrel eventsevents NonNon--CABGCABG Bleeds 2.42.4 HR 1.321.32HR 1.81.8 (1.03(1.03--1.68)1.68) Clopidogrel P=0.03P=0.03 00 003030 60609090 180180 270270 360360 450450 NNH = 167NNH 167 DaysDays

59 Inhibition of Platelet Aggregation (IPA) at 24 Hours

100.0

80.0

60.0 t Aggregation t Aggregation (%) e 40.0

20.0

0.0 Clopidogrel Responder Clopidogrel Nonresponder

Inhibition of Platel --20.0 Response to Response to Prasugrel *Responder =  25% Clopidogrel IPA at 4 and 24 h Brandt JT et al. Am Heart J. 2007; 153:66.e9153:66.e9--16.16.

PLATO Study Design

NSTENSTE--ACSACS (moderate-(moderate-toto--highhigh risk) or STEMI (if primary PCI) ClopidogrelClopidogrel--treatedtreated or --naive;naive; randomized within 24 hours of index event

n=18,624n=18,624

CCClopidogrel Ticagrelor If pre-preIf -treated,treated, no additional loading dose; 180 mg loading dose, then if naive, standard 300 mg loading dose, 90 mg bid maintenance then 75 mg/day maintenance (additional 90 mg prepre--PCI)PCI)

Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding

Wallentin L et al. N EnglJ Med. 2009; 361:1045361:1045--57.57.

PLATO Trial: Results

Clopidogrel 1212 11.711.7 1010 9.89.8 88 Ticagrelor

66 e incidence (%) v 44 p<0.001 HR 0.84 (95% CI 0.77 to 0.92) 22 NNT=53

Cumulati 00 006060 120120180180240240300300360360 Days after randomization

Wallentin L et al. N EnglJ Med. 2009; 361:1045361:1045--57.57.

60 PLATO Trial Individual Endpoints TicagrelorTicagrelor Clopidogrel HR for All patients (n=9,333)(n=9,333) (n=9,291)(n=9,291) (95% CI) p value Primary objective, (%) CV death + MI + stroke9.8 11.7 0.84 (0.770.84 (0.77––0.92)0.92)<0.001

Secondary objectives, (%) Total death + MI + stroke 10.2 12.3 0.84 (0.770.84 (0.77––0.92)0.92)<0.001

CV death + MI + stroke + 14.614.6 16.716.7 0.88 (0.810.88 (0.81––0.95)0.95) <0.001<0.001 ischemia + TIA + arterial thrombotic events

Myocardial infarction 5.85.8 6.96.9 0.84 (0.750.84 (0.75––0.95)0.95) 0.0050.005 CV deathCV death 4.04.0 5.15.1 0.79 (0.690.79 (0.69––0.91)0.91) 0.0010.001 StrokeStroke 1.51.5 1.31.3 1.17 (0.911.17 (0.91––1.52)1.52) 0.220.22

Total death 4.55.9 0.78 (0.690.78 (0.69––0.89)0.89)<0.001

Wallentin L et al. N EnglJ Med. 2009; 361:1045361:1045--57.57.

PLATO Results – Major Bleeding Non-CABG and CABG Related 9% Ticagrelor pp=NS=NS 7.9% Clopidogrel 7.4% p=NSp=NS 5.8% 6% p=0.026p=0.026 5.3% 4.5% 3.8% p=0.025p=0.025 3% 28%2.8% 2.2%

0% Non-CABG Non-CABG CABG CABG PLATO TIMI PLATO TIMI

Total PLATO major bleeding: 11.6% ticagrelor vs. 11.2% clopidogrel; p=0.43 Total TIMI major bleeding: 7.9% ticagrelor vs. 7.7% clopidogrel; p=0.57 Wallentin L et al. N EnglJ Med. 2009; 361:1045361:1045--57.57.

PLATO Trial Other Findings

Ticagrelor Clopidogrel All Patients (n=9,235)(n=9,235) (n=9,186)(n=9,186) pp--valuevalue

DyspneaDyspnea,, % Any 13.813.8 7.87.8 <0.001 With D/C o f s tu dy trea tmen t 09090.90 9 01010.10 1 <0. 001<0001001

Ventricular pauses, % First weekweekFirst ≥ 3 seconds 5.8 3.63.6 0.010.01 ≥ 5 seconds 2.0 1.21.2 0.100.10 At 30 daysdaysAt ≥ 3 seconds 2.1 1.71.7 0.520.52 ≥ 5 seconds 0.8 0.60.6 0.600.60

Wallentin L et al. N EnglJ Med. 2009; 361:1045361:1045--57.57.

61 PLATO Trial Other Findings – Laboratory Parameters

Ticagrelor Clopidogrel All Patients (n=9,325) (n=9,186)(n=9,186) pp--valuevalue

% increase in SCr from baseline At 1 month 101010 ±± 2222 888 ±± 2121 <0. 001<0001001 At 12 months 11 ±±2222 9 ±22± 22 <0.001 FollowFollow--upup visit 10 ±±2222 10 ±±2222 0.590.59

% increase in uric acid from baseline At 1 month 14 ±±46467 ±44± 44 <0.001 At 12 months 15 ±±52527 ±31± 31 <0.001 FollowFollow--upup visit 7 ±±43438 ±±4848 0.56

Wallentin L et al. N EnglJ Med. 2009; 361:1045361:1045--5757..

The ONSET/OFFSET Study

Gurbel PA et al. Circulation.Circulation. 2009; 120:2577120:2577--85.85.

Nonresponders RESPOND Study Enlarged slide on page 70

• Cross-over study • Grouped by response to 300 mg LD of Clopidogrel – ≤ 10% absolute Δ in platelet aggregation to 20 µmol/L ADP by LTA Responders – Nonresponders (n=41) – Responders (n=57) • Clopdiogrel 600 mg LD and 75 mg daily • Ticagrelor 180 mg LD and 90 mg bid Gurbel PA et al. Circulation. 2010; 121:1188-99.

62 What is Next? • Elinogrel – First available i.v. and oral

• Cangrelor ADP-P2Y12 receptor antagonist • ERASE MI Trial – Parenteral ADP-P2Y12 receptor antagonist • INNOVATE PCI Trial • ATP analogue • Plasma ha lf-life o f 5-9 minutes • 20 minutes for return to normal platelet function – CHAMPION Trials • Stopped - no benefit –PHOENIX Trial

New P2Y12 Inhibitors vs. Clopidogrel Enlarged slide on page 70 Meta-Analysis

Results in patients undergoing any PCI

Prasugrel Prasugrel Cangrelor Cangrelor Ticagrelor Elinogrel

Prasugrel Prasugrel Cangrelor Cangrelor Ticagrelor Elinogrel

BellemainBellemain--AppaixAppaixA et al. J Am Coll Cardiol. 2010; 56:154256:1542--51.51.

New P2Y12 Inhibitors vs. Clopidogrel Enlarged slide on page 71 Meta-Analysis Results in patients undergoing PCI for STEMI

Prasugrel Cangrelor Ticagrelor Elinogrel

Prasugrel Ticagrelor Elinogrel

BellemainBellemain--AppaixAppaixA et al. J Am Coll Cardiol. 2010; 56:154256:1542--51.51.

63 Emerging Treatment Strategies

• Increasing dose of clopidogrel

• Switching to different P2Y12 inhibitor – Ticlopidine – Prasugrel – Ticagrelor – Future agents • Triple antiplatelet therapy – Adding cilostazol – PAR-1 inhibitors

Antiplatelet Impact of Cilostazol Enlarged slide on page 71

Angiolillo DJ et al. Eur Heart J. 2008; 29:220229:2202--11.11.

Cilostazol Triple Antiplatelet Therapy •OPTIMUS-2 – 25 patients with DM type 2 and CAD on DAT • Placebo x 14 days with cross-over • Cilostazol 100 mg bid x 14 days with cross-over – VASP assay (36. 3% cilostazol vs . 59 .9% placebo; pp0=0.0002) • DECREASE Registry – Nonrandomized evaluation of DES patients • DAT (n=1656) vs. TAT (n=1443) for 12 months – Death: HR 0.76 (0.40 – 1.45); p=0.41 – MI: HR 0.23 (0.08 – 0.70); p=0.001 – Stent thrombosis: HR 0.14 (0.04 – 0.52); p=0.004 – Major bleeding: HR 0.97 (0.44 – 2.12); p=0.94 Angiolillo DJ et al. Eur Heart J. 2008; 29:2202-11. Lee SW et al. Am Heart J. 2010; 159:284-91.e1.

64 Cilostazol Enlarged slide on page 72 Triple Antiplatelet Therapy • ACCEL-AMI: 90 patients with STEMI after PCI + stenting • Standard group – clopidogrel 75 mg daily • High maintenance dose group – clopidogrel 150 mg daily • Triple group – clopidogrel 75 mg daily + cilostazol 100 mg twice daily – Platelet function testing at baseline and at 1 month

Jeong YH et al. Circ CardiovascInterv. Interv. 2010; 3:172010; 3:17--26.26.

Oral Antiplatelet Therapies

P2Y12 Inhibition: Clopidogrel Ticlodipine ADPADP Prasugrel Ticagrelor Elinogrel ADP P2Y Thrombin 12 ADP

PAR-1 PAR-1 cAMP Inhibition: Collagen PLATELET Activation Vorapaxar TXA2 Atopaxar COX

GP IIb/IIb/IIIaIIIa TXA2 (Fibrinogen receptor) Aspirin

Adapted from Schafer AI. Am J Med. 1996; 101:199101:199--209.209.

Thrombin Receptor Antagonism Vorapaxar program (29,500 patients) NSTE ACSACSNSTE 2º prevention n=10,000n=10,000 n=19,500n=19,500 TRA*CER trial TRA 2°2TRA °PP--TIMITIMI 50 trial (TRA*CER Committees 2009) (Morrow et al. 2009)

Vorapaxar Placebo Vorapaxar Placebo

FollowFollow--upup 1 yr minimumminimum

11oo endpoint: Composite of CV 11oo endpoint: Composite of CV death, MI, stroke, urgent death, MI, stroke, and urgent revascularization and revascularization RI w/ rehospitalization ClinicalTrials.gov ClinicalTrials.gov Identifier: NCT00527943. Identifier: NCT00526474.

65 LANCELOT-ACS Trial Subjects with NSTE ACS nn = 603= 603

Randomization within 72 hours of symptom onset Randomize DoubleDouble--blindblind 1:1:1:11:1:1:1 Atopaxar Atopaxar Atopaxar Placebo 400mg LD, 400mg LD, 400mg LD, daily 50mg/day 100mg/day 200mg/day

12 Weeks Active Treatment, 4 Weeks Follow-up

Primary Endpoint: Major bleeding (CURE) at 12 weeks

O’Donoghue M. Presented at TCT 2010, 2010 Sept 23.

LANCELOT-ACS Trial

14% Incidence of any TIMI Bleeding TIMI minimal TIMI minor 12% TIMI major

10% P trend = 0.63

8% 8.3%

6% 9.4% 7.3% 6.2% 4% 7.2% 1.3%

2% 0.7% 2.6% 1.3% 1.4% 0.7% 0.7% 0% Placebo Active combined 50mg daily 100mg daily 200mg daily atopaxar n=138 n=455 n=153 n=156 n=146 O’Donoghue M. Presented at TCT 2010, 2010 Sept 23.

LANCELOT-ACS Trial 12.0% Incidence of CV death, MI, or stroke

10.0% P trend = 0.28 8.0%

6.0% 5.6% 5.7%

4.0% 3.3%

1.9% 2.0% 2.0%

0.0% Placebo Active combined 50mg daily 100mg daily 200mg daily atopaxar n=142 n=461 n=156 n=157 n=148

O’Donoghue M. Presented at TCT 2010, 2010 Sept 23.

66 PR is a 78-year-old man (72 kg) with a history of smoking and dyslipidemia. • Just admitted to the hospital with unstable angina • Scheduled to go to PCI tomorrow

Which of the following would be the most appropriate option for providing the optimal reduction in CV death, MI, and stroke? a. Clopidogrel 300 mg LD, then 75 mg daily b. Prasugrel 60 mg LD, then 10 mg daily c. Ticagrelor 180 mg LD, then 90 mg twice daily d. Clopidogrel 600 mg LD, then 75 mg daily

TB is a 67-year-old man (80 kg) with history of hypertension, DM type 2, gout, and asthma. • Currently hospitalized with STEMI and going to PCI • Other medical history is non-contributory, except some problems with medication adherence

Which of the following would be the best option for TB? a. Clopidogrel 300 mg LD, then 75 mg daily b. Prasugrel 60 mg LD, then 10 mg daily c. Ticagrelor 180 mg LD, then 90 mg twice daily d. Clopidogrel 300 mg LD, then 75 mg daily and cilostazol 100 mg daily

TC is a 58-year-old man recently started on clopidogrel 75 mg daily. CYP2C19 genotype is CYP2C19*1/*2. VerifyNow test is slightly elevated (PRU = 245). What is the recommended treatment strategy for TC? a. Continue clopidogrel 75 mg daily b. Increase clopidogrel maintenance dose to 150 mg daily c. Start prasugrel d. Start ticagrelor

67 Emerging Treatment Strategies

• Increasing dose of clopidogrel

• Switching to different P2Y12 inhibitor – Ticlopidine – Prasugrel – Ticagrelor – Future agents • Triple antiplatelet therapy – Adding cilostazol – PAR-1 inhibitors

68 OPTIMUS Study

Angiolillo DJ et al. Circulation. 2007; 115:708-115:708-16.16.

ACCEL-DOUBLE: Results

• CYP3A5 and ABCB1 did not influence platelet reactivity • CYP2C19 predictive of high post-treatment platelet reactivity – OR 5 .5 (1 . 33-23. 26) p=0. 018

Jeong YH et al. JACC Cardiovasc Interv. Interv. 2010; 3:731-3:731-41.41.

69 Nonresponders RESPOND Study

• Cross-over study • Grouped by response to 300 mg LD of Clopidogrel – ≤ 10% absolute Δ in platelet aggregation to 20 µmol/L ADP by LTA Responders – Nonresponders (n=41) – Respp()onders (n=57) • Clopdiogrel 600 mg LD and 75 mg daily • Ticagrelor 180 mg LD and 90 mg bid Gurbel PA et al. Circulation. 2010; 121:1188-99.

New P2Y12 Inhibitors vs. Clopidogrel Meta-Analysis

Results in patients undergoing any PCI

Prasugrel Prasugrel Cangrelor Cangrelor Ticagrelor Elinogrel

Prasugrel Prasugrel Cangrelor Cangrelor Ticagrelor Elinogrel

BellemainBellemain--AppaixAppaixA et al. J Am Coll Cardiol. 2010; 56:1542-56:1542-51.51.

70 New P2Y12 Inhibitors vs. Clopidogrel Meta-Analysis Results in patients undergoing PCI for STEMI

Prasugrel Cangrelor Ticagrelor Elinogrel

Prasugrel Ticagrelor Elinogrel

BellemainBellemain--AppaixAppaixA et al. J Am Coll Cardiol. 2010; 56:1542-56:1542-51.51.

Antiplatelet Impact of Cilostazol

Angiolillo DJ et al. Eur Heart J. 2008; 29:220229:2202--11.11.

71 Cilostazol Triple Antiplatelet Therapy • ACCEL-AMI: 90 patients with STEMI after PCI + stenting • Standard group – clopidogrel 75 mg daily • High maintenance dose group – clopidogrel 150 mg daily • Triple group – clopidogrel 75 mg daily + cilostazol 100 mg twice daily – Platelet function testing at baseline and at 1 month

Jeong YH et al. Circ Cardiovasc IntervInterv.. 2010; 3:173:17--26.26.

72 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

SELECTED REFERENCES

1. Angiolillo DJ, Capranzona P, Goto S et al. A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study. Eur Heart J. 2008; 29:2202-11. 2. Angiolillo DJ, Shoemaker SB, Desai B et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation. 2007; 115:708-16. 3. Barker CM, Murray SS, Teirstein PS et al. Pilot study of the antiplatelet effects of increased clopidogrel maintenance dosing and its relationship to CYP2C19 genotype in patients with high on-treatment reactivity. JACC Cardiovasc Interv. 2010; 3:1001-7.

4. Bellemain-Appaix A, Brieger D, Beygui F et al. New P2Y12 inhibitors versus clopidogrel in percutaneous coronary intervention: a meta-analysis. J Am Coll Cardiol. 2010; 56:1542-51. 5. Berger JS, Roe MT, Gibson CM et al. Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: the Early Rapid ReversAl of platelet thromboSis with intravenous Elinogrel before PCI to optimize reperfusion in acute Myocardial Infarction (ERASE MI) pilot trial. Am Heart J. 2009; 158:998-1004.e1. 6. Bhatt DL, Lincoff AM, Gibson CM et al. for the CHAMPION PLATFORM Investigators. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med. 2009; 361:2330-41. 7. Brandt JT, Payne CD, Wiviott SD et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. 2007; 153:66.e9-16. 8. Campo G, Valgimigli M, Gemmati D et al. Poor responsiveness to clopidogrel: drug-specific or class-effect mechanism? Evidence from a clopidogrel-to-ticlopidine crossover study. J Am Coll Cardiol. 2007; 50:1132-7. 9. Gurbel PA, Bliden KP, Butler K et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009; 120:2577-85. 10. Gurbel PA, Bliden KP, Butler K et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation. 2010; 121:1188-99. 11. Harrington RA, Stone GW, McNulty S et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med. 2009; 361:2318-29. 12. Jeong YH, Hwang JY, Kim IS et al. Adding cilostazol to dual antiplatelet therapy achieves greater platelet inhibition than high maintenance dose clopidogrel in patients with acute myocardial infarction: results of the adjunctive cilostazol versus high maintenance dose clopidogrel in patients with AMI (ACCEL-AMI) study. Circ Cardiovasc Interv. 2010; 3:17-26.

73 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

13. Jeong YH, Kim IS, Park Y et al. Carriage of cytochrome 2C19 polymorphism is associated with risk of high post-treatment platelet reactivity on high maintenance-dose clopidogrel of 150 mg/day: results of the ACCEL-DOUBLE (Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene Polymorphism) study. JACC Cardiovasc Interv. 2010; 3:731-41. 14. Lee SW, Park SW, Yen SC et al. Triple antiplatelet therapy reduces ischemic events after drug-eluting stent implantation: Drug-Eluting stenting followed by Cilostazol treatment REduces Adverse Serious cardiac Events (DECREASE registry). Am Heart J. 2010; 159:284-91.e1. 15. Morrow DA, Scirica BM, Fox KA et al. for the TRA 2°P-TIMI 50 Investigators. Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial. Am Heart J. 2009; 158:335-41.e3. 16. O’Donoghue M. LANCELOT ACS: a prospective, randomized, double-blind, placebo- controlled trial of a reversible PAR-1 thrombin receptor antagonist in patients with acute coronary syndromes. Paper presented at TCT 2010, Washington, DC; 2010 Sept 23. 17. Plavix prescribing information. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2010 Aug. http://products.sanofi- aventis.us/PLAVIX/plavix.pdf (accessed 2010 Nov 3). 18. Price M et al. Standard versus high-dose clopidogrel according to platelet function testing after PCI: results of the GRAVITAS trial. Presented at American Heart Association Scientific Sessions 2010, Chicago; 2010 Nov 16. Abstract 21791. 19. Schafer AI. Antiplatelet therapy. Am J Med. 1996; 101:199-209. 20. TRA*CER Executive and Steering Committees. The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA*CER) trial: study design and rationale. Am Heart J. 2009; 158:327-34.e4. 21. Wallentin L, Becker RC, Budaj A et al. for the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009; 361:1045-57. 22. Wiviott SD, Braunwald E, McCabe CH et al. for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007; 357:2001-15.

74 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

SELF–ASSESSMENT QUESTIONS

1. RJ is a 64-year old man who was recently admitted to the hospital with a non-ST- segment elevation myocardial infarction. He also has a history of hypertension, diabetes mellitus, and dyslipidemia. He received a loading dose of clopidogrel 300 mg before percutaneous coronary intervention with stent placement, followed by 75 mg daily. On day three of hospitalization, the cardiologist asks for a VerifyNow test. The results demonstrate a platelet reactive units (PRU) value of 300. How would you describe the meaning of this value to the cardiologist?

a. This patient is most likely to have a cardiovascular event. b. This patient has suboptimal platelet inhibition. c. This patient is at increased risk for major bleeding. d. This patient must undergo genetic testing.

2. Which of the following would be an appropriate management strategy for RJ?

a. Give an additional 300 mg loading dose of clopidogrel. b. Give an additional 600 mg loading dose of clopidogrel. c. Give a maintenance dose of clopidogrel 150 mg daily. d. Give a maintenance dose of clopidogrel 300 mg daily.

3. Which of the following outcomes was demonstrated to be significantly reduced by the use of ticagrelor compared with clopidogrel in the PLATO trial?

a. Stroke. b. Major bleeding. c. Intracranial hemorrhage. d. Cardiovascular death.

4. All of the following provide platelet inhibition via binding to the P2Y12 receptor EXCEPT

a. Vorapaxar. b. Prasugrel. c. Ticagrelor. d. Elinogrel.

Answers 1. b 2. c 3. d 4. a

75 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

LIST OF ABBREVIATIONS

AC adenylyl cyclase ACC American College of Cardiology ACCF American College of Cardiology Foundation ACE angiotensin-converting enzyme ACS acute coronary syndrome

ADP adenosine diphosphate, endogenous activator of the P2Y12 receptor on platelets AHA American Heart Association ARB angiotensin receptor blocker ARC Academic Research Consortium ASA aspirin ATP adenosine triphosphate ATTC Antithrombotic Trialists’ Collaboration AUC area under the curve BMI body mass index BMS bare-metal stent Ca calcium CABG coronary artery bypass grafting CAD coronary artery disease cAMP cyclic adenosine monophosphate CI confidence interval COX cyclooxegenase CV cardiovascular CVD cardiovascular disease CYP cytochrome P DAT dual antiplatelet therapy D/C discontinue DES drug-eluting stent DL DerSimonian and Laird DM diabetes mellitus DST definite stent thrombosis ECG electrocardiogram EM extensive metabolizer 5-HT2A 5-hydroxy tryptamine 2A GOP gain of function GP glycoprotein GUSTO Global Use of Strategies to Open Occluded Coronary Arteries GWAS genome-wide association study HDL-C high-density lipoprotein cholesterol

76 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

HR hazard ratio IM intermediate metabolizer IPA inhibition of platelet aggregation IP3 inositol triphosphate LD loading dose LDL-C low-density lipoprotein cholesterol LOF loss of function LTA light transmission aggregometry MA maximal amplitude (clot strength) MACE major adverse coronary event MD physician MI myocardial infarction MPA maximal platelet aggregation NNH number needed to harm NNT number needed to treat NR nonresponsive NSTE non-ST-segment elevation NSTEMI non-ST-segment elevation myocardial infarction OR odds ratio PAR-1 protease-activated receptor 1 PCI percutaneous coronary intervention

PGE1 prostaglandin E1 PI prescribing information PKA protein kinase PK/PD pharmacokinetics and pharmacodynamics PLC phospholipase C PM poor metabolizer PPI proton pump inhibitor PRI platelet reactivity index (unit of measure for VASP phosphorylation assay that measures effectiveness of P2Y12 receptor antagonists) PRU P2Y12 reaction units (unit of measure for VerifyNow P2Y12 test) RI recurrent ischemia ROC receiver operating curve, a graphical plot of true positive rate (sensitivity) versus false positive rate (1- specificity)* RRR relative risk reduction SNP single nucleotide polymorphism ST stent thrombosis STEMI ST-segment elevation myocardial infarction TEG thrombelastograph TIA transient ischemic attack TIMI Thrombolysis in Myocardial Infarction

77 Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome

TVR target vessel revascularization

TxA2 thromboxane A2 UA unstable angina UM ultrarapid metabolizer UTVR urgent target vessel revascularization VASP vasodilator-stimulated phosphoprotein, a downstream intracellular mediator of P2Y12 receptor activation in platelets VASP-PRI vasodilator-stimulated phosphoprotein platelet reactivity index vWF von Willebrand factor

*ROC area under the curve (AUC) of 1.0 would represent a perfectly accurate test, and an AUC of 0.5 represents the line of no discrimination (test is equal to random guess).

78