1. New Anti-platelet Agents
Toni L. Ripley, Pharm.D., BCPS, AQ-Card
Associate Professor
Cardiovascular Pharmacy Specialist
American College of Cardiology
Oklahoma Chapter, Annual Meeting
April 10, 2010

2. Disclosures
None

3. Overview Review mechanisms of platelet aggregation
Summarize where current and investigational therapies fit in the physiology of platelet aggregation
Review contemporary controversies of anti-platelet therapy

4. Dorsam and Kunapuli. J Clin Invest 2004;113:340-345.
Gross and Weitz. Clin Pharmacol Ther 2009;86:

5. Eptifibatide Abciximab Tirofiban Clopidogrel Prasugrel
Gross and Weitz. Clin Pharmacol Ther 2009;86:

6. New Anti-platelet Agents: An Overview

7. Prasugrel (Effient®) Oral thienopyridine P2Y12 irreversible inhibitor
Approved for reduction of thrombosis in patients with ACS who are managed with PCI.
TRITON-TIMI 38
Prodrug, requires biotransformation in a two-step process
Wiviott, et all. NEJM 2007;357:

8. Metabolism
(15%)
(85%)
From: J Clin Pharmacol 2008;48:53-59

9. Platelet inhibition: Prasugrel versus clopidogrel
Maximal Platelet Inhibition (Light Transmission Aggregometry)1
P2Y12 Reaction Units (VerifyNow Assay)2
1Wallentin, et al. Eur Heart J 2008;29:21-30; 2Varenhorst, et al. Am Heart J 2009;157:e1-e9.

10. Ticagrelor (Brilinta®)
Oral non-thienopyridine P2Y12 inhibitor
Cyclopentyl-triazolo-pyrimidine (CPTP)
Potent, reversible binding and non-competitive with ADP
No biotransformation
Metabolized to equipotent, active metabolite by CYP3A4
PLATO Wallentin et al. NEJM 2009;361:

11. Platelet inhibition: Ticagrelor versus clopidogrel
Inhibition of platelet aggregation (Light Tranmission Aggregometry)
P2Y12 Reaction Units
(VerifyNow Assay)
Platelet Reactivity Index, VASP-P
Gurbel et al. Circulation 2009;120:

12. Overview of other pipeline agents
Cangrelor1, 2
Vorapaxar3 (SCH )
Elinogrel4 (PRT )
Drug class/chemistry
Non-thienopyridine ATP analogue
PAR-1 receptor blocker
Direct P2Y12 ADP-receptor antagonist
Effect on receptor
Reversible
FDA status
Phase II/III
Phase III
Phase II
Administration
Intravenous
Oral
Intravenous and oral
Clinical data
CHAMPION – PLATFORM and PCI
BRIDGE
TRA●CER
TIMI-50
ERASE MI
INNOVATE-PCI
1NEJM 2009;361: ; 2NEJM 2009;361: ; 3Lancet 2009;373:919-28; 4Am Heart J 2009;158:

13. The Controversies

14. Limitations of current therapies
Cardiovascular event rate1, 2, 3, 4
Aspirin resistance/failure5
Clopidogrel
Variability of response6
Compliance
Genetic polymorphisms
Drug interactions
Bleeding risk
1Yusuf, et al. NEJM 2001;345(7): ;2Mehta, et al. Lancet 2001;358:527-33;3Chen, et al. Lancet 2005;366: ;4Bhatt et al. NEJM 2006;354: ;5Patrono, et al. Chest 2008;133:199S-233S;6Angiolillo. Am J Cardiol 2009;103[suppl];27A-34A.

15. Pharmacogenetics
Plavix (clopidogrel) label. Accessed from on March 29, 2010

16. Polymorphism effects
NEJM 2009;360:354-62; Circulation 2009;119:

17. CYP2C19 Reduced-function Allele Carrier Status and Clinical Outcomes in Clopidogrel-treated Patients
PRESENTATION TIP
This slide presents the clopidogrel clinical outcome data in TRITON-TIMI 38 based on the CYP2C19 genotype in relation to clopidogrel metabolism.
Emphasize that this slide shows the impact of genetic variation, not a comparison between prasugrel and clopidogrel.
KEY POINTS
DNA was collected from 1477 patients with ST-elevation myocardial infarction (MI) and non-ST-elevation ACS treated with prasugrel (60-mg/day loading dose, followed by a 10-mg/day maintenance dose) in the TRITON-TIMI 38 trial.1
395 patients carried at least one CYP2C19 reduced-function allele.1
Patients in this substudy are not reflective of the overall population. Thus, a direct comparison of the prasugrel data cannot be made to the clopidogrel data from this substudy.1
Clopidogrel-treated patients showed an association between CYP2C19 reduced-function allele carrier status and the primary efficacy endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke (carriers, 12.1% vs non- carriers, 8.0%; 95% CI=1.07–2.19; P=0.01).1
Pharmacogenetic analyses were performed on 2943 patients enrolled in a pharmacogenetic substudy of TRITON- TIMI 38. In this genetic substudy, the rate of the primary efficacy endpoint (CV death, nonfatal MI, or nonfatal stroke) in the prasugrel arm (9.4%) was similar to the rate in the overall trial (9.9%); in contrast, the rate in the clopidogrel arm (9.3%) was lower than the rate observed in the overall trial (12.1%). The inconsistency between the observed rates for the pharmacogenetic substudy and those of the overall trial limits interpretation of between drug comparisons.2
BACKGROUND
Of these patients, 71.0% presented with non-ST-elevation acute coronary syndromes, and 29.0% presented with ST-elevation MI.
Patients carrying a CYP2C19 reduced-function allele had a higher rate of each component of the primary efficacy endpoint compared with non-carriers. This included death from cardiovascular causes (2.0% vs 0.4%; HR, 4.79; 95% CI, 1.40–16.37), nonfatal MI (10.1% vs 7.5%; HR, 1.38; 95% CI, 0.94–2.02), and nonfatal stroke (0.88% vs %; HR, 3.93; 95% CI=0.66–23.51).
Rates of the endpoints were expressed as Kaplan-Meier estimates at 15 months, and were compared between carriers and non-carriers of at least 1 reduced-function CYP allele.
REFERENCES
Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:
Data on File: EFF a, DSI/Lilly.

18. CYP2C19 Reduced-function Allele Carrier Status and Clinical Outcomes in Prasugrel-treated Patients
PRESENTATION TIP
This slide presents the prasugrel clinical outcome data in TRITON-TIMI 38 based on the CYP2C19 genotype in relation to prasugrel metabolism.
Emphasize that this slide shows the impact of genetic variation, not a comparison between prasugrel and clopidogrel.
KEY POINTS
DNA was collected from 1466 patients with ST-elevation myocardial infarction and non–ST-elevation ACS treated with prasugrel (60-mg/day loading dose, followed by a 10-mg/day maintenance dose) in the TRITON-TIMI 38 trial.
Four hundred seven patients carried at least 1 CYP2C19 reduced-function allele.1
Patients in this substudy are not reflective of the overall population. Thus, a direct comparison of the prasugrel data cannot be made to the clopidogrel data from this substudy.
Pharmacogenetic analyses were performed on 2943 patients enrolled in a pharmacogenetic substudy of TRITON-TIMI 38. In this genetic substudy, the rate of the primary efficacy endpoint (CV death, nonfatal MI, or nonfatal stroke) in the prasugrel arm (9.4%) was similar to the rate in the overall trial (9.9%); in contrast, the rate in the clopidogrel arm (9.3%) was lower than the rate observed in the overall trial (12.1%). The inconsistency between the observed rates for the pharmacogenetic substudy and those of the overall trial limits interpretation of between drug comparisons.2
Prasugrel-treated patients showed no association between CYP2C19 reduced-function allele carrier status and the primary efficacy endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke (carriers, 8.5% vs non-carriers, 9.8%; 95% CI=0.60–1.31; P=0.27).1
In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving prasugrel, there was no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of the active metabolite of prasugrel or its inhibition of platelet aggregation.3
BACKGROUND
Of these patients, 69.8% presented with non–ST-elevation acute coronary syndromes, and 30.2% presented with ST-elevation myocardial infarction.
No differences in hazard were observed for the individual components of the primary efficacy endpoint for carriers vs non-carriers for CV death (carriers, 0.99% vs non-carriers, 1.58%; HR, 0.80; 95% CI, 0.26–2.47; P=0.70); nonfatal MI (carriers, 6.6% vs non- carriers, 8.1%; HR, 0.82; 95% CI, 0.53–1.27; P=0.37); or nonfatal stroke (1.0% vs 0.82%; HR, 1.30; 95% CI, 0.39–4.31;P=0.67) in prasugrel treated patients.
Rates of the endpoints were expressed as Kaplan-Meier estimates at 15 months, and were compared between carriers and non- carriers of at least 1 reduced-function CYP allele.
No significant associations between any of the other CYP genotypes and the primary efficacy outcome were observed, nor did the rates of non–CABG-related TIMI major or minor bleeding differ significantly across any CYP genotype.
REFERENCES
Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation. 2009;119:
Data on File: EFF a, DSI/Lilly USA, LLC.
Effient Full Prescribing Information. Daiichi Sankyo, Inc. and Lilly USA, LLC.

19. Drug Interactions

20. Drug Interactions – What we know
The mechanism:
Strength of inhibition of PPIs on 2C19:
Omeprazole = esomeprazole > pantoprazole > lansoprazole > rabeprazole
CYP 2C19, 1A2, 2B6
CYP 2C19, 3A4, 2C9, 2B6
J Clinn Pharmacol 2008;48:53-59; Clin Pharmacokinet 2008;47:1-6

21. Death or re-hospitalization for ACS (%)
VA Cohort Study
Death or re-hospitalization for ACS (%)
Adjusted OR 1.25, 95% CI,
Individual PPIs sub-study:
omeprazole 59.7% (3132): OR 1.24, 95% CI ;
rabeprazole 2.9% (151): OR 2.83, 95% CI
Ho et al. JAMA 2009;301:

22. Medco Outcomes Study: Effect of individual PPIs on risk of major CV events
Number at Risk
No PPI
Omeprazole
Esomeprazole
Pantoprazole
Lansoprazole
HR 1.61 ( ), p<0.0001
29.2%
Pantoprazole
HR 1.39 ( ), p=0.0004
24.3%
Lansoprazole
HR 1.57 ( ), p<0.0001
24.9%
Esomeprazole
HR 1.39 ( ), p<0.0001
25.1%
Omeprazole
Ref
17.9%
No PPI

23. Drug Interactions – what we do not know
Other potential mechanisms
Shunting towards inactive pathway
2C19 competition
Transport p-glycoprotein
Clinical impact
Clinical outcomes versus platelet inhibition

24. Drug interactions – new antiplatelets
Effect with new antiplatelets
Prasugrel
Ticagrelor
3A4, 2D6
2C9, 2C19

25. Effect of separate administration of omeprazole with clopidogrel
Bristol Myers Squibb Internal Data
*No statistics
provided
MAI*
*MAI – Maximum platelet aggregation intensity, %
Concomitant administration
12-hour separate administration
BMS unpublished data

26. Drug Interactions - Summary
A clinically relevant drug interaction is a possibility.
It may be a problem with all PPIs
No good strategy to mitigate interaction
Prasugrel
Until this interaction is ruled out:
H2-Blocker
PPIs for patients at higher risk of GIB.
Use PPIs that have the least effect on 2C19 (pantoprazole)

27. Risk of Bleeding

28. Bleeding risks – CURE1
*ACUITY definition, P<0.05 for all; no significant difference when TIMI or GUSTO definitions were applied
1Yusuf et al. NEJM 2001;345:

29. For every 1000 patients treated:
TIMI Prasugrel
6 patients will have a major bleed
5 will have a life-threatening bleed
3 will have a fatal bleed
PLATO2 (similar definition to ACUITY) – Ticagrelor - No increased in overall major bleeding per study or TIMI criteria, but
1 patient will have a fatal intracranial bleed
6-7 patients will have major bleeding unrelated to CABG
1NEJM 2007;357: ; 2NEJM 2009;361:

30. New Antiplatelet Agents
Improved CV event rates
Less risk of drug interactions
Less risk of variation
Increased risk of bleeding

31. Thank you