Ingelheim, Germany - The design of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) studythe largest ever head-to-head study of competing therapies in secondary stroke preventionhas been changed following the results of the MATCH trial, which were reported recently at the 13th European Stroke Conference.

PRoFESS began in September 2003. So far, approximately 2000 of a planned 15000 recent stroke patients have been randomized to twice-daily aspirin 25 mg/extended-release dipyridamole 200 mg (Aggrenox^®, Boehringer Ingelheim) or clopidogrel 75 mg plus aspirin 75 mg once a day. The primary end point is time to the first recurrent stroke.

But MATCHwhich is due to be published in the Lancet shortlyshowed no overall benefit of the combination of clopidogrel plus aspirin over clopidogrel alone for secondary prevention in 7500 high-risk stroke patients. Although there was a slight nonsignificant reduction in the primary end point with the combination, this was offset by an increase in life-threatening bleeds.

A Boehringer Ingelheim spokesperson told heartwirethat the patients already taking aspirin plus clopidogrel in PRoFESS will discontinue the aspirin part of the protocol and all new patients in the future will take clopidogrel alone. The second part of the studyrandomizing patients to the angiotensin II blocker telmisartan (Micardis^®) or placebowill remain unchanged.

"Unethical" to make any other decision

One of the three cochairs of the PRoFESS steering committee, Dr Ralph Sacco (Columbia University and Mailman School of Public Health, New York, NY) told heartwire: "When PRoFESS was designed, we presumed the standard of care would become clopidogrel plus aspirin, based on studies such as CURE. We did not anticipate some of the safety issues that turned up in MATCH."

We presumed the standard of care would become clopidogrel plus aspirin.

As a result, there was a consensus of opinion between the steering committee and the data safety monitoring board that it would "be almost unethical to continue the clopidogrel plus aspirin arm of PRoFESS because of the increased bleeding seen in MATCH," he said.

None of the various secondary stroke prevention guidelines recommended the combination of clopidogrel and aspirin. Some advise aspirin as first choice or "gold standard" but others, including the AHA guidelines, say all three optionsaspirin alone, Aggrenox, or clopidogrel aloneare equally justified, says Sacco, who is chair of the AHA's Stroke Section.

And while debate will continue about whether aspirin should have been the comparator arm in MATCH and whether the cost of using clopidogrel alone can be justified, there is still a need for a direct comparison between the other two antiplatelet regimens, he believes.

"We've always been accused of indirect comparisons before. We feel this is a scientifically important question to answer."