Mannheim, Germany - The combination of aspirin and clopidogrel (Plavix®, Sanofi-Synthelabo/BMS) in high-risk cerebrovascular patients did not show any additional clinical benefit compared with clopidogrel alone, results of the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke (MATCH) trial show. Prof Hans-Christoph Diener (Essen University, Germany) reported the findings here today at the 13th European Stroke Conference.
In addition, patients in the secondary-prevention trial receiving the combination of aspirin and clopidogrel had significantly more life-threatening bleeds compared with those taking clopidogrel alone.
"There are three choices left now for neurologists treating high-risk stroke patients," Diener said. "They can choose to use aspirin alone, clopidogrel alone, or dipyridamole plus aspirin."
But others involved in the trial were more decisive. In a press release, member of the MATCH data and safety monitoring board Dr Donald Easton (Brown Medical School, Providence, RI) said: "Clopidogrel appears to be the appropriate standard therapy for secondary prevention of stroke, MI, and vascular death in stroke patients."
Diener added, however, that MATCH does not solve the issue of how the combination of aspirin plus clopidogrel would have compared with aspirin alone: "We cannot answer this question," he said.
MATCH causes headaches for other large trials
The MATCH results now pose a headache for Boehringer Ingelheim, which has just begun the world's largest head-to-head study in secondary stroke preventionPRoFESScomparing its product Aggrenox® (200-mg extended-release dipyridamole plus 25-mg aspirin) with clopidogrel plus aspirin in 15500 stroke patients. The MATCH results raise issues about the safety of clopidogrel plus aspirin, and Diener said the PRoFESS investigators, including himself, "will be meeting today to discuss the implications of MATCH for this new trial." PRoFESS will also additionally randomize patients to Boehringer Ingelheim's angiotensin II antagonist telmisartan (Micardis®) or placebo.
The MATCH data may also affect the CHARISMA study, which is looking at clopidogrel for patients at high risk of atherothrombosis. It will compare the addition of clopidogrel 75 mg once daily or placebo with a regimen including low-dose aspirin (75-162 mg daily) for preventing the occurrence of major cardiovascular complications (stroke, MI, or cardiovascular death). Diener said he could not comment on the implications for CHARISMA, "because I'm not involved in that study."
Dr Eric Topol (Cleveland Clinic, OH), commented to heartwire : "My view is that is quite difficult to interpret this trial [MATCH], because the design does not represent clinical practicewe start with aspirin and add clopidogrel. The trial tested a hypothesis that is questionable from the standpoint of clinical relevance."
CAPRIE sets stage for MATCH
Diener explained that the rationale for the MATCH study, which included 7500 patients, was derived from the benefit seen in stroke subgroups in the CAPRIE study. CAPRIE compared clopidogrel with aspirin in patients who had suffered an MI, ischemic stroke, or other vascular event. The number of events prevented by the use of clopidogrel rather than aspirin over three years was only 11 in the total population, but in those with a prior ischemic event this rose to 28, and in those with a major ischemic event the number was 34.
The subsequent CURE study showed that adding clopidogrel to aspirin and other standard therapies was beneficial in unstable-angina patients, Diener said, joking, "Cardiologists are usually much quicker than neurologists when it comes to clinical trials."
The population in MATCH consisted of patients who had suffered a transient ischemic event (TIA) or ischemic stroke within the past three months plus at least one of the following events in the past three years: prior ischemic stroke, MI, stable or unstable angina pectoris, diabetes, or symptomatic peripheral arterial disease (PAD). Exclusion criteria included those under 40 years of age, those with severe comorbid conditions, those at increased risk of bleeding, those scheduled for major or vascular surgery, or those who had a contraindication for aspirin or clopidogrel.
Patients were randomized to receive aspirin 75 mg once daily or placebo, with both groups receiving clopidogrel 75 mg once daily as part of standard therapy, for 18 months.
The primary end point of MATCH was a composite of the first occurrence of MI, ischemic stroke, vascular death, or rehospitalization for an acute ischemic event between randomization and the end of the 18-month follow-up period.
Patients randomized early: "Very important" point
Diener stressed that many patients in MATCH were randomized to study therapy early, within one week of their qualifying event. "This is very important, because it has been shown that many subsequent events occur within that first week," he stressed.
The study population was also very high risk, he noted. Almost 80% of patients had high blood pressure, about 70% had diabetes, nearly 60% had hypercholesterolemia, and almost 50% were smokers, he noted, adding that there was also "a large proportion of people with small-vessel disease."
At 18 months, there was no significant difference in the primary end point between those taking aspirin plus clopidogrel and those taking clopidogrel alone. The combination produced a relative risk reduction of only 6.4% (p=0.244). And with regard to safety, almost twice as many patients taking both drugs suffered a life-threatening bleed compared with those taking clopidogrel plus placebo.
Also, there were no differences between the two arms in any of subgroups, Diener said. "There was no subgroup where there would be a benefit of dual therapy over monotherapy," he stressed.
Clopidogrel alone, n=3802, n (%)
Clopidogrel plus aspirin, n=3797, n (%)
Primary end point
|636 (16.7)||596 (15.7)|
|347 (9.1)||339 (8.9)|
|201 (5.3)||201 (5.3)|
|49 (1.3)||96 (2.5)|
A question of duration of therapy?
Diener did say, however, "If you look very carefully at the clopidogrel trials so far, you can see that the bleeding risk increases with time. So it may be that if you are going to use the combination (of clopidogrel plus aspirin) you should use it only for a short time."
To back up this point, he said that in those receiving therapy within the first week of an event compared with those receiving it later and in PAD patients, "there was a trend toward benefit with the combination, but it was not significant."
In conclusion, he reiterated: "Adding aspirin to clopidogrel did not show any additional clinical benefit, and it led to more life-threatening bleeds, particularly intracranial and gastrointestinal bleeds."
Heartwire from Medscape © 2004
Cite this: MATCH trial: No benefit of aspirin added to clopidogrel in high-risk stroke patients - Medscape - May 13, 2004.