Abstract & Commentary
Synopsis: The MATCH data provide quite strong evidence that the clopidogrel-aspirin combination is a less favorable option than previously thought, but its use may not be completely contraindicated.
Source: Diener HC, et al. Aspirin and Clopidogrel Compared with Clopidogrel Alone After Recent Ischaemic Stroke or Transient Ischaemic Attack in High-Risk Patients (MATCH): Randomized, Double-Blind, Placebo-Controlled Trial. Lancet. 2004;364:331-337.
Aspirin is the mainstay of treatment for secondary stroke prevention, but controversy remains regarding its optimal dosing and possible combination with other agents. Recent publicity regarding patients who may be aspirin resistant has further clouded the issue. Clopidogrel (Plavix) is a thienopyridine derivate that works differently than aspirin, inhibiting platelets by blocking the adenosine diphosphate (ADP) receptor. It has come into wide use as a replacement for the agent ticlopidine (Ticlid), which had multiple side effects, including the induction of thrombotic thrombocytopenic purpura (TTP). Clopidogrel has been shown to have an 8.7% relative benefit over aspirin in the prevention of vascular events (CAPRIE study), and has been shown to be beneficial in combination with aspirin in patients with unstable angina (CURE trial). In practice, the CURE data have been extrapolated to stroke/TIA patients, but the safety and efficacy of this regimen has never been systematically studied.
The MATCH trial, reported in Lancet this month, randomized approximately 8000 patients who had suffered a recent stroke/TIA, to either clopidogrel (75 mg) alone, or in combination with aspirin (75 mg). Patients in the study were considered high risk, since each was required to have had a prior stroke, myocardial infarction (MI), diabetes, or symptomatic peripheral arterial disease. The primary endpoint of MI, ischemic stroke or vascular death, occurred in 16.7% of the clopidogrel arm, and in 15.7% who received the combination. This absolute difference of 1%, and relative difference of 6.4%, was not statistically significant. Subgroup analysis comparing patients presenting with stroke vs TIA, or those with risk factors such as diabetes or prior MI, also did not show any significant differences. There was, however, a significant increase in life-threatening bleeding in patients on combination therapy (2.6% compared with 1.3% on clopidogrel alone, P < 0.001). Intracranial hemorrhage was also more common among patients on the combination (P = 0.029). Despite this, there were no reports of hemorrhagic transformations of ischemic stroke, and although bleeding was considered life-threatening, it did not translate into an increased mortality rate.
The MATCH data provide quite strong evidence that the clopidogrel-aspirin combination is a less favorable option than previously thought, but its use may not be completely contraindicated. Recurrent stroke/TIA is known to occur within days after an incident event, and MATCH recruited patients up to 3 months following their qualifying event. Among MATCH patients recruited within 1 week post-stroke, there was actually a 15.6% event rate on combination therapy vs 18.7% on clopidogrel alone, a difference of 3%, which is triple that of the overall cohort. It remains possible that combination therapy, perhaps even including a loading dose of clopidogrel (300 mg was used in the CURE trial), might provide additional benefit post-stroke, if the earliest days to weeks could be properly studied.
Data from other studies will be available in the coming years. The PRoFESS trial will be comparing clopidogrel to a combination of aspirin and extended release dipyridamole (Aggrenox), with or without the angiotensin receptor blocker telmisartan (Micardis). Interestingly, the PRoFESS trial previously included aspirin in the clopidogrel arm, but removed this on the basis of the MATCH results. PRoFESS will provide the head-to-head comparison between Plavix and Aggrenox that we sorely need. Until then, these unfortunately expensive agents can be used interchangeably, and provide limited, but tangible benefit over aspirin alone. — Alan Z. Segal
Dr. Segal, Assistant Professor, Department of Neurology, Weill-Cornell Medical College, Attending Neurologist, New York Presbyterian Hospital, is Assistant Editor of Neurology Alert.