European Heart Journal Advance Access originally published online on February 22, 2007
European Heart Journal 2007 28(5):640-641; doi:10.1093/eurheartj/ehl521
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Acute coronary syndromes, response to clopidogrel, and worsened cardiovascular outcomes: the hen and the egg dilemma
Department of Medicine Johns Hopkins University 9101 East Stayman Drive Ellicott City Towson MD 21204 USA
E-mail address: heartdrug{at}aol.com
I enjoyed reading the quality paper by Geisler et al.1 that tried to link low response to clopidogrel with the incidence of major cardiovascular events and death in a broad spectrum of post-stent patients. The team should be acknowledged for the effort, clean data, and the realistic assessment of the frequency of low response (5.8%) after loading with 600 mg clopidogrel. The major home-take message the authors try to deliver to the readership is that at 3 months after stenting the incidence of death and AMI was higher in the low clopidogrel responders. However, such conclusions are not fully supported by the presented evidence, and deserve at least some clarification, and/or adjustment.
The major limitation of the index analysis is the fact that almost all of the low responders (81.8%, or 18 out of 22 patients) underwent emergency revascularization, whereas only the minority (43.1%, or 147 out of 341 average responders) experienced acute coronary event (Table 1). In contrast, the majority of patients from the control group was subjected to the elective angioplasty and stenting, and did not suffer an acute event at the time of intervention. In short, low response cohort was not stable, experienced more myocardial damage, and probably worsened outcomes even before clopidogrel therapy. How fair and balanced is to declare low response to clopidogrel as a major risk factor to such harmful association remains to be seen, especially when patients were already at higher risk, and platelet glycoprotein IIb/IIIa inhibitors were not allowed. Although ISAR-REACT 2 trial revealed that addition of abciximab to 600 mg loading with clopidogrel improves cardiovascular outcomes in the troponin-elevated ACS patients,2 the index patients were deliberately denied the benefit, substantially limiting the practical value of the study. Obviously, the thrombotic burden in some patients with ACS exceeds the ability of even high dose loading with clopidogrel to prevent secondary events. However, it is not reasonable to generalize such clinical scenario, and blame clopidogrel's low response for recurrent events, especially acknowledging that no-load 75 mg clopidogrel saved 119 lives and provided an absolute mortality benefit after AMI in the COMMIT trial.3
Another critical baseline difference in the index study is the 14.6% less use of statins in the low responders group with highly significant (P = 0.001) hyperlipidaemia when compared with the average responders. Recent meta-analysis of 13 trials with almost 18 000 patients strongly suggests that statins reduce death and cardiovascular events after 4 months of treatment in ACS patients.4
There are also certain shortcomings of the study design that limit our ability to adequately interpret the platelet data. Although the definition of low response, and lack of baseline platelet function assessment are questionable, but still acceptable, random non-pre-specified sample collection times cannot be advocated. Indeed, the single platelet test was performed after at least 6 h after clopidogrel loading, but with the broad mean of 34.8 ± 25.9 h after stenting. In common terms, it means that some patients were already treated with the maintenance clopidogrel dose for 1 or 2 days, and the data analysis should be adjusted accordingly. This is especially important because platelet activity after acute thrombotic events is not consistent, nor unchanged, but rather undergoing phasic changes,5 which in turn are dependent on the success of reperfusion.6 Therefore, single platelet aggregation test done randomly, not at the pre-specified time point after coronary intervention, may be used as a reliable screening laboratory tool, but falls way too short to provide clinically meaningful conclusions.
In fact, the index study is timely to provide some important insight that ACS patients exhibit worse cardiovascular outcomes after stenting, reinforce the protective role of statins (directly), and platelet glycoprotein IIb/IIIa inhibitors (indirectly). However, multiple unadjusted variables with regard to group composition, baseline characteristics, and lack of strictly pre-specified time point for the platelet assessment limit the clinical utility of the study.
References
- Geisler T, Langer H, Wydymus M, Gohring K, Zurn C, Bigalke B, Stellos K, May AE, Gawaz M. (2006) Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 27:2420–2425.
[Abstract/Free Full Text] - Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H, Graf I, Ibrahim M, Pache J, Seyfarth M, Schuhlen H, Dirschinger J, Berger PB, Schomig A. (2006) Intracoronary Stenting and Antithrombotic: Regimen Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 295:1531–1538.
[Abstract/Free Full Text] - Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS. (2005) 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 366:1607–1621.[CrossRef][ISI][Medline]
- Hulten E, Jackson JL, Douglas K, George S, Villines TC. (2006) The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Arch Intern Med 166:1814–1821.
[Abstract/Free Full Text] - Serebruany VL, Midei MG, Malinin AI, Oshrine BR, Lowry DR, Sane D, Tanguay JF, Steinhubl SR, Berger PB, O'Connor CM, Hennekens CH. (2004) Absence of interaction between atorvastatin and clopidogrel in prospective data: the interaction of atorvastatin and clopidogrel (INTERACTION Study). Arch Intern Med 164:2051–2057.
[Abstract/Free Full Text] - Gurbel PA, Serebruany VL, Shustov AR, Dalesandro M, Gumbs SI, Grabletz BS, Bahr RD, Ohman EM, Topol EJ. (1998) Increased baseline platelet P-selectin, and PECAM-1 as predictors of unsuccessful thrombolysis in patients with acute myocardial infarction. Coron Artery Dis 9:451–456.[ISI][Medline]
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