Lack of outcome benefit and clopidogrel “resistance”

Summary

Impaired response to clopidogrel, or “resistance” is a cornerstone concept for justification of more aggressive antiplatelet regimens, and development of new more potent drugs. There are over 1,000 citations (although predominantly reviews, or case reports) in MEDLINE related to clopidogrel “resistance”, while about 100 of them attempted to link low response to adverse clinical outcomes. However, most of these studies are woefully small, and not randomised. The TRITON trial assessed head-to-head novel antiplatelet agent prasugrel versus clopidogrel in patients with acute coronary syndromes. This study was the first in a decade to challenge clopidogrel monopoly, and to indirectly test the “resistance” hypothesis. The primary endpoint was the rate of cardiovascular death, non-fatal myocardial infarction, or stroke, and occurred in 12.1% of patients treated with clopidogrel, and 9.9% of patients randomised to prasugrel, suggesting impressive vascular outcome benefit of prasugrel over clopidogrel. However, the Food and Drug Administration (FDA) presented more balanced, and realistic outlook on TRITON. While very early periprocedural benefit exists, long-term prasugrel therapy yielded identical to clopidogrel vascular outcomes among 13,608 TRITON patients challenging the postulate that clopidogrel “resistance” phenomenon is clinically relevant. Despite the fact that prasugrel 10 mg/daily cause 2.5 times more potent platelet inhibition than conventional clopidogrel 75 mg/daily, with fewer patients exhibiting broad response variability, and/or antiplatelet “resistance”, the vascular benefit beyond acute phase was identical. Keeping in mind growing over time bleeding, cancer, and mortality risks associated with chronic prasugrel use, small observational studies should be judged with skepticism as hypothesis-generating, pending confirmation in randomised trials.

Keywords

Clopidogrel - prasugrel - drug resistance - clinical outcomes

• References

• 1 CAPRIE Steering Committee.. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events. Lancet 1996; 348: 1329-1339.
• 2 CURE Trial Investigators.. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Eng J Med 2001; 345: 494-502.
• 3 Chen ZM, Jiang LX, Chen YP. et al. COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group.. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607-1621.
• 4 Lev EI, Patel RT, Maresh KJ. et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006; 47: 27-33.
• 5 Serebruany VL, Steinhubl SR, Berger PB. et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246-251.
• 6 Duffy B, Bhatt DL. Antiplatelet agents in patients undergoing percutaneous coronary intervention: how many and how much?. Am J Cardiovasc Drugs 2005; 5: 307-318.
• 7 von Heymann C, Redlich U, Moritz M. et al. Aspirin and clopidogrel taken until 2 days prior to coronary artery bypass graft surgery is associated with increased postoperative drainage loss. Thorac Cardiovasc Surg 2005; 53: 341-345.
• 8 Best-selling cardiovascular drugs of 2008. Med Ad News 2009; 28: 10.
• 9 Pena A, Collet JP, Hulot JS. et al. Can we override clopidogrel resistance?. Circulation 2009; 119: 2854-2857.
• 10 Siller-Matula J, Schrör K, Wojta J. et al. Thienopyridines in cardiovascular disease: focus on clopidogrel resistance. Thromb Haemost 2007; 97: 385-393.
• 11 Gurbel PA, Tantry US. Aspirin and clopidogrel resistance: consideration and management. J Interv Cardiol 2006; 19: 439-448.
• 12 Prasugrel Secondary Review. Available for download at http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009–4412b1–00-FDA.htm.
• 13 Wiviott SD, Braunwald E, McCabe CH. et al. the TRITON-TIMI 38 Investigators.. Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2007; 357: 2001-2015.
• 14 Serebruany VL. The FDA Prasugrel Review: Adjudication of Myocardial Infarction Controversy. Cardiology 2009; 114: 126-129.
• 15 Serebruany V, Shalito I, Kopyleva O. Prasugrel development – claims and achievements. Thromb Haemost 2009; 101: 14-22.
• 16 Floyd J, Wolfe S. Prasugrel STEMI subgroup analysis. Lancet 2009; 373: 1845-1846.
• 17 King SB, 3rd Smith Jr SC, Hirshfeld Jr. JW. 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: 2007. Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee. Circulation 2008; 117: 261-295.
• 18 von Beckerath N, Taubert D, Pogatsa-Murray G. et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 2005; 112: 2946-2950.
• 19 Aleil B, Jacquemin L, De Poli F. et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study. JACC Cardiovasc Interv 2008; 1: 631-638.
• 20 Jernberg T, Payne CD, Winters KJ. et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 2006; 27: 1166-1173.
• 21 Jakubowski JA, Matsushima N, Asai F. et al. A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y₁₂ inhibitor, compared with clopidogrel in healthy humans. Br J Clin Pharmacol 2007; 63: 421-430.
• 22 Serebruany VL, Midei MG, Meilman H. et al. Platelet inhibition with prasugrel (CS-747) compared with clopidogrel in patients undergoing coronary stenting: the subset from the JUMBO study. Postgrad Med J 2006; 82: 404-410.
• 23 Saw J, Densem C, Walsh S. et al. The effects of aspirin and clopidogrel response on myonecrosis after percutaneous coronary intervention: a BRIEF-PCI (Brief Infusion of Intravenous Eptifibatide Following Successful Percutaneous Coronary Intervention) trial substudy. JACC Cardiovasc Interv 2008; 1: 654-659.
• 24 Wallentin L, Becker RC, Budaj A. et al the PLATO Investigators.. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2009; 361: 1045-1057.
• 25 Serebruany VL, Atar D. The PLATO trial: Do you believe in magic?. Eur Heart J. 2009 in press.
• 26 Price MJ, Berger PB, Angiolillo DJ. et al. Evaluation of individualized clopidogrel therapy after drug-eluting stent implantation in patients with high residual platelet reactivity: design and rationale of the GRAVITAS trial. Am Heart J 2009; 157: 818-824.
• 27 Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel (TRIGGER-PCI). NCT00910299. Available at: http://clinicaltrials.gov/ct2/show/NCT00910299.