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The ACCOAST trial

Acute Coronary Syndromes (ACS)


Is time to reconsider pretreatment with P2Y12 receptor inhibitors in NSTE-ACS?

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.

Is upstream DAPT in NSTEACS dead or alive?

Dr Leonardo Bolognese, MD, FESC (IT)

Although many clinicians have adopted a practice of pretreatment with dual antiplatelet therapy (DAPT) in patients with non–ST-segment-elevation acute coronary syndromes (NSTEMI ACS) and European and American guidelines (1,2) recommend giving P2Y12inhibitors as soon as possible, the optimal timing of DAPT is a subject of continuing debate.
Much of this controversy stems from the fact that previous clinical trials have not been explicitly designed to inform clinical practice. Instead, contemporary management strategies are a patchwork of individualized interpretation of the evidence, which is far from robust.
Two studies, one post-hoc observational study of a larger trial involving patients with NSTEMI ACS (3) and one randomized involving patients undergoing elective percutaneous coronary intervention (PCI) (4), suggested that pretreatment with clopidogrel could reduce the rate of ischemic events at the cost of an increase in the rate of major bleeding.

PCI-CURE was a nonrandomized, post hoc observational study of a larger trial (CURE) designed to compare clopidogrel with placebo in patients with NSTEMI ACS with planned conservative treatment. Sites routinely practicing an early invasive strategy were excluded from the trial; patients receiving GP IIb/IIIa inhibitors within 3 days were excluded. PCI was performed on the basis of clinical indications, such as refractory ischemia. Patients randomized to clopidogrel were considered pretreated, whereas those who received placebo were not. The median period of pretreatment was 6 days. Thus, the study design is very far from current clinical practice.
In order to focus on the question of benefit of clopidogrel pre-treatment and reduction of PCI-related procedural complications, it is necessary to evaluate short-term treatment effects.
In the PCI-CURE 30-day trial data, the pre-treatment benefit with clopidogrel was limited to reduction of frequency of MI, with a trend toward benefit in need for urgent revascularization but no effect at all on cardiovascular death (3).

CREDO is the only randomized trial to date that provides partially relevant information on the pretreatment questions. Patients with symptomatic coronary artery disease and evidence of ischemia who were referred for PCI or were thought to be at a high likelihood for requiring PCI were randomized to receive clopidogrel (300 mg) or matching placebo 3 to 24 hours before PCI.
Thus, CREDO is really a comparison of administering a loading dose before PCI versus not administering a loading dose; however, there is no direct comparison of giving a loading dose before PCI versus at the time of PCI.
Nevertheless, there were no significant differences in outcome at 30 days. A prespecified subgroup analysis did, however, show a trend toward benefit in the patients who received the study drug 6 hours before PCI.
A subsequent post hoc analysis suggested that clopidogrel had to be ingested at least 15 hours before PCI to decrease 30-day clinical events.
Subsequent randomized studies did not confirm the benefit of clopidogrel pretreatment with respect to ischemic events among patients in stable condition who were undergoing elective PCI, (5-7) and a recent metanalysis did not show a survival benefit of clopidogrel pretreatment among more than 37,000 patients undergoing PCI, while there was an excess of major bleeding and little impact on ischemic outcomes (8).
The ACCOAST study is the first randomized trial that specifically addressed the issue of pretreatment with P2Y12 inhibitors in NSTEMI. The results offer new insights and give rise up new questions:
  1. For which patients groups does ACCOAST apply? The risk profile of ACCOAST population was similar to that in contemporary randomized clinical trials of patients with ACS who were undergoing PCI, but lower than that of the main registries on NSTEMI ACS. Furthermore, timing for coronary angiography was relatively short when compared to every-day clinical practice. Thus, ACCOAST findings are certainly applicable to most intermediate risk patients presenting with NSTE-ACS addressed to an early invasive strategy.
  2. Do we need preloading in NSTEMI anymore? Times to PCI are now shrinking and the risk of an ischemic complication before coronary angiography is extremely low. Thus, the practical difference between upstream and downstream therapy is diminishing. In addition, a relevant percentage of NSTE-ACS population does not need pretreatment as they undergo to CABG or are medically managed. Finally, the rapid onset of action of the new oral P2Y12 inhibitors associated with the short delays to catheterization, suggest that a pretreatment strategy may be avoided in most patients as demonstrated in the ACCOAST trial.
  3. Can the ACCOAST results be applied to other P2Y12inhibitors, such as clopidogrel and ticagrelor? For clopidogrel, as previously mentioned, the oldest studies suggest a potential benefit for pretreatment when there is a very long delay between randomization and PCI (3,4). More recent studies have not confirmed the benefit of pretreatment with shorter delays and higher doses of clopidogrel (5-8). For ticagrelor, in the PLATO trial (9), all patients were pretreated with clopidogrel, ticagrelor or both before PCI; thus, the question of pretreatment has not been addressed for ticagrelor. One may speculate that similar result would be achieved when ticagrelor would be used within the same study design instead of prasugrel.

Conclusion The new insights provided by the ACCOAST trials have important every-day practical implications: in patients with an intermediate risk and a short delay (< 24) from admission to angiography, pretreatment should be avoided; in high-risk patients with a delay from admission to angiography of > 24 hours, pretreatment with either clopidogrel (on the basis of old data) or ticagrelor (without data) may be considered.

References

 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;358:527-33
4. 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;158:585-91
8. 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.