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Prof. Jean-Philippe Collet (FR)Initiation of P2Y12 inhibitors soon after the diagnosis of NSTE-ACS has been recommended for many years and was derived from pivotal clinical studies validating the efficacy of clopidogrel therapy, a pro-drug with a slow onset of action(1,2). The concept of pretreatment has been first revisited by the meta-analysis of Bellemain et al showing no survival benefit for clopidogrel pretreatment in 37,000 patients undergoing PCI but a slight excess of major bleeding and little impact on ischemic outcomes(3). A randomized comparison of pretreatment with prasugrel compared with initiation after diagnostic angiography, but before PCI, has demonstrated no reduction in key ischaemic events at 7 days(4). The question is now whether time has come to change the guidelines and our clinical practice.The ACCOAST study compared pre-treatment with prasugrel 30mg and a further 30mg prior to PCI with a regimen of prasugrel 60mg prior to PCI after diagnostic angiography among 4033 patients with NSTEMI. By 7 days, patients randomized to the pretreatment arm experienced no reduction in the risk of cardiovascular death, recurrent myocardial infarction, stroke, urgent revascularization and bailout use of glycoprotein IIb/IIIa inhibition (hazard ratio 1.02, 95% C.I. 0.84-1.25, p=0.81), with no benefits emerging by 30 days.However, bleeding events using the TIMI major bleeding criteria, were significantly increased among patients randomized to the pretreatment arm by 7 days (pretreatment 2.6% versus no-pretreatment: 1.4%, hazard ratio: 1.90, 95% C.I. 1.19-3.02, p=0.006).In particular, there were significantly more major and life-threatening bleeding complications not related to coronary artery bypass graft (CABG) surgery in the pretreatment group.ACCOAST randomized patients of the real life of whom 20% had a GRACE score of 140 or more and who had angiography within a median time delay from symptom onset of 12 hours. Practical impacts are therefore of importance. First, the use of new P2Y12 inhibitors in NSTE-ACS may be postponed to the time of the decision about PCI, to avoid overtreatment in patients who may need CABG surgery or medical treatment who do not need such high platelet inhibition. Second, can the ACCOAST results be applied to other P2Y12 inhibitors, such as clopidogrel and ticagrelor? The negative study results for prasugrel pretreatment raised a general question on the benefits achieved by pretreatment with new oral platelet inhibitors, even if there is a single and successful study with ticagrelor whereby treatment was given systematically as pretreatment(5). Conclusion: A realistic and pragmatic approach would be to make the decision to initiate P2Y12 receptor inhibitor prior to defining the revascularization strategy according to the intended agent and expected delay to obtaining angiography. In patients with a short delay (< 24—48 hours) from admission to angiography, pretreatment should be avoided; in patients with a delay from admission to angiography of > 48 hours, pretreatment with either clopidogrel (on the basis of old data) or ticagrelor (without data) may be considered.
Dr Leonardo Bolognese, MD, FESC (IT)
1. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA, Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. 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(9281):527–533. 2. Steinhubl SR, Berger S, Mann JT, Fry ETA, DeLago A, Wilmer C, Topol EJ, for the Credo Investigators. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. JAMA. 2002;288:2411–2418. 3. Bellemain-Appaix A, O’Connor SA, Silvain J, Cucherat M, Beygui F, Barthélémy O, Collet J-P, Jacq L, Bernasconi F, Montalescot G. Association of Clopidogrel Pretreatment With Mortality, Cardiovascular Events, and Major Bleeding Among Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-analysis. JAMA J Am Med Assoc. 2012;308:2507–2516. 4. Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay J-F, Ten Berg JM, Miller DL, Costigan TM, Goedicke J, Silvain J, Angioli P, Legutko J, Niethammer M, Motovska Z, Jakubowski JA, Cayla G, Visconti LO, Vicaut E, Widimsky P, the ACCOAST Investigators. Pretreatment with Prasugrel in Non-ST-Segment Elevation Acute Coronary Syndromes. N Engl J Med. 2013; 5. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057
1. Hamm CW, Bassand JP, Agewall S, et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent STsegment elevation: the Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999-3054.2. Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012;60:645-81.3. 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;358:527-334. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-20.5. Widimsky P, Motovsk®¢ Z, Simek S, et al. Clopidogrel pre-treatment in stable angina: for all patients > 6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI? A randomized multicentre trial PRAGUE-8. Eur Heart J 2008;29:1495-503.6. Di Sciascio G, Patti G, Pasceri V, et al. Effectiveness of in-laboratory high-dose clopidogrel loading versus routine pre-load in patients undergoing percutaneous coronary intervention: results of the ARMYDA-5 PRELOAD (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) randomized trial. J Am Coll Cardiol 2010;56:550-7.7. Davlouros PA, Arseniou A, Hahalis G, et al. Timing of clopidogrel loading before percutaneous coronary intervention in clopidogrel-naive patients with stable or unstable angina: a comparison of two strategies. Am Heart J 2009;158:585-918. Bellemain-Appaix A, O’Connor SA, Silvain J, et al. Association of clopidogrel pretreatment with mortality, cardiovascular events, and major bleeding among patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. JAMA 2012;308:2507-16.9. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57.
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