Antiplatelet Therapy in Acute Coronary Syndromes

use, recently failed in clinical trials. However, the two oral drugs

prasugrel (Effient®) and ticagrelor (Brilinta™) have succeeded in large phase III clinical trials.

Prasugrel is a thienopyridine-like clopidogrel, but instead of 85% of the prodrug being converted to an inactive metabolite, esterases convert the prodrug into an intermediate metabolite, which is then converted to active metabolite by one single CYP step. This results in a much higher and consistent level of active metabolite in the bloodstream, with a stronger and more rapid inhibition of ADP- induced platelet aggregation.16

In the Assess Improvement in

Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel – Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) study, including both STEMI and NSTE-ACS patients, prasugrel markedly reduced myocardial infarction and stent thrombosis compared with clopidogrel. The most important finding was the potent effect in patients with diabetes, a group known to be resistant to both aspirin and clopidogrel. Thus, for the first time there is an oral platelet inhibitor with a clear clinical effect on patients with diabetes.23

Not surprisingly, prasugrel was markedly better than clopidogrel for patients with genetic polymorphisms for low enzymatic activity in

CYP2C19.16

and here a reduction in mortality could also be seen.24

The STEMI patients also benefited markedly with prasugrel, Interestingly,

although the entire prasugrel-treated population suffered from increased bleeding complications, neither patients with diabetes nor STEMI patients suffered from this. Prasugrel does not seem to have any poor responders and seems to solve the problem of clopidogrel resistance.

Furthermore, prasugrel reduces platelet–monocyte

complex formation and annexin exposure on the platelet surface (a prerequisite for coagulation activation).25

Otherwise, bleeding complications were the major limitation for prasugrel in TRITON. They were clearly increased in the whole population, and patients with a previous transient ischaemic attack (TIA)/stroke suffered from significantly increased intracranial and fatal bleedings. Older patients (>75 years of age) and those with low weight had increased bleeding complications, resulting in a net neutral effect on the combined end-point of cardiovascular events and bleeding complications.

1. Michelson AD, J Thromb Thrombolysis, 2003;16(1–2):7–12.

2. Wallentin LC, J Am Coll Cardiol, 1991;18(7):1587–93.

3. ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group, Lancet, 1988;2(8607):349–60.

4. Baigent C, Blackwell L, Collins R, et al., Lancet, 2009;373(9678):1849–60.

5. CAPRIE Steering Committee, Lancet, 1996;348(9038):1329–39. 6. Yusuf S, Zhao F, Mehta SR, et al., N Engl J Med, 2001;345(7):494–502.

7. Steinhubl SR, Berger PB, Mann JT III, et al., JAMA, 2002;288(19):2411–20.

8. Sabatine MS, Hamdalla HN, Mehta SR, et al., Am Heart J, 2008;155(5):910–17.

9. Chen ZM, Jiang LX, Chen YP, et al., Lancet, 2005;366(9497):1607–21.

10. Sabatine MS, Cannon CP, Gibson CM, et al., N Engl J Med, 2005;352(12):1179–89.

Ticagrelor is not a prodrug like clopidogrel and prasugrel, and thus does not require conversion in the liver for activation. Furthermore, it is a classic competitive antagonist without irreversible binding, a property that can be important for patients in need of urgent surgery or with bleeding complications, as the effects of the drug are lost much more rapidly compared with the five to seven days needed to restore platelet function for other thienopyridines.

In the phase III trial A Study of Platelet Inhibition and Patient Outcomes (PLATO), ticagrelor significantly reduced cardiovascular events compared with clopidogrel, surprisingly without significantly increasing bleeding complications.26

This is probably the reason

ticagrelor also resulted in a significant reduction in total mortality, a very rare finding in antiplatelet studies.

Conclusions

Antiplatelet therapy for ACS is changing. We are moving from late blocking of platelet activation to the possibility of inhibiting platelet activation early in the cascade, thereby reducing degranulation of alpha and dense granulae and the release of growth factors, vasocontractile agents and adhesive, pro-thrombotic and inflammatory proteins. Oral platelet inhibitors are becoming more efficient with less individual variability, solving problems of clopidogrel resistance.

There is increasing awareness of the negative effects of bleeding on long-term risk and mortality. In fact, the antithrombotic drugs that have succeeded in improving the most important end-point – mortality – have achieved this not by reducing cardiovascular events, but by reducing bleeding complications. This pattern has been seen for fondaparinux in OASIS-5, for bivalirudin in HORIZONS and recently for ticagrelor in PLATO.22,26,27

At the same time, in the aforementioned studies new drugs have been tested against old therapies. When new drugs are combined, there is a lack of evidence for added benefit, especially when new drugs emerge on both the antiplatelet and anticoagulant side. The cost of novel treatments will also be a challenge. As generic antiplatelet drugs appear, such as clopidogrel, in the near future platelet-function tests will allow us to discriminate which patient groups will benefit from newer therapies and which patients will do well on old therapies, thus saving costs. n

11. Bhatt DL, Fox KA, Hacke W, et al., N Engl J Med, 2006;354(16): 1706–17.

12. Hillarp A, Lethagen S, Mattiasson I, J Thromb Haemost, 2003;1(1):196–7.

13. Eikelboom JW, Hankey GJ, Thom J, et al., Circulation, 2008;118(17):1705–12.

14. Jolly SS, Pogue J, Haladyn K, et al., Eur Heart J, 2009;30(8):900–907.

15. Wallentin L, Varenhorst C, James S, et al., Eur Heart J, 2008;29(1):21–30.

16. Mega JL, Close SL, Wiviott SD, et al., N Engl J Med, 2009;360(4):354–62.

17. Gurbel PA, Becker RC, Mann KG, et al., J Am Coll Cardiol, 2007;50(19):1822–34.

18. Erlinge D, Varenhorst C, Braun OO, et al., J Am Coll Cardiol, 2008;52(24): 1968–77.

19. Kastrati A, Mehilli J, Neumann FJ, et al., JAMA, 2006;295(13):1531–8.

20. Giugliano RP, White JA, Bode C, et al., N Engl J Med, 2009;360(21):2176–90.

21. Stone GW, Grines CL, Cox DA, et al., N Engl J Med, 2002;346(13): 957–66.

22. Stone GW, Witzenbichler B, Guagliumi G, et al.,

N Engl J Med, 2008;358(21):2218–30.

23. Wiviott SD, Braunwald E, Angiolillo DJ, et al., Circulation, 2008;118(16): 1626–36.

24. Montalescot G, Wiviott SD, Braunwald E, et al., Lancet, 2009;373(9665): 723–31.

25. Braun OO, Johnell M, Varenhorst C, et al., Thromb Haemost, 2008;100(4):626–33.

26. Wallentin L, Becker RC, Budaj A, et al., N Engl J Med, 2009;361(11):1045–57.

27. Jolly SS, Faxon DP, Fox KA, et al., J Am Coll Cardiol, 2009;54(5):468–76.

EUROPEAN CARDIOLOGY

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