Making The Right Stroke Call

How have the PRoFESS trial results modified your treatment regimen or thought process on stroke care? What factors go into your treatment decision given the results of recent studies (PRoFESS, CHARISMA, ESPRIT, etc.)?
"PRoFESS essentially told us that clopidogrel and aspirin/extended-release dipyridamole have roughly the same efficacy," says Dr. Kasner. However, he notes that clopidogrel has the notable practical advantages of once-daily dosing and better tolerability, compared to ASA/ER-DP needing twice-daily dosing and the pitfall of roughly a 10 percent risk of headache. "Therefore, many of us are now using clopidogrel as first line therapy for secondary stroke—so long as the cost is not a relevant issue—instead of ASA/ER-DP," he says. But for patients who have been on the latter and tolerating it well, it seems reasonable to continue it rather than change course. "We still do not recommend clopidogrel plus aspirin for stroke patients except as a short term intervention after stenting."

Dr. Cohen believes PRoFESS was a well-done study, but the results served to muddy the waters on antiplatelet therapy. "Prior to PRoFESS, CAPRIE had demonstrated that clopidogrel was equal to but not better than ASA for secondary stroke prevention. MATCH and CHARISMA showed that combining ASA and clopidogrel has no additional benefit but had significant increase in risk of bleed. ESPS2 and ESPRIT demonstrated the combination of ASA/ER-DP was significantly better than ASA alone." This begs the questions, Dr. Cohen says, how can it be that non-inferiority cannot be proven for clopidogrel compared to ASA-ERDP?

"One concern that I have is with the large number of patients in the trial who were non-compliant with the study drug. About 30 percent of patients were non-compliant—defined as not taking study drug at least 25 percent of the time. While ASA and clopidogrel are irreversible platelet inhibitors, ER-DP isn't," Dr Cohen says. This means, for the non-compliant patients, the trial was really comparing ASA to clopidogrel. "We know from CAPRIE that there really is no chance of proving non-inferiority in that matchup. I am hoping the PRoFESS investigators will do a post-hoc analysis looking at outcomes in compliant patients. While post-hoc analysis is never definite, it may help explain the surprise outcome of the trial."

That said, PRoFESS has not changed Dr. Cohen's approach to secondary stroke prevention. In almost all cases, non-cardioembolic stroke patients need to be on an antiplatelet drug. The choice of drug needs to be individualized, he says. Those who are ASA allergic get clopidogrel. Those who can't afford expensive prescription antiplatelets get ASA. "Others get the option of choosing ASA/ER-DP or ASA. However, the emphasis continues to be on control of risk factors as the most important part of the plan," he adds.

Dr. Goldstein looks at PRoFESS in a larger context. The study "is important in that it makes a fundamental point about how we interpret isolated research findings. One trial carried out at one point in time may show treatment A is better than treatment B. Another trial carried out at another time might show treatment B is better than treatment C. Therefore, one might conclude treatment A is better than treatment C. What PRoFESS underscores is the hazard of these types of indirect comparisons."

How do you think the results of PRoFESS will modify the next iteration of guidelines (ESO, AHA, ACCP)?
This is, of course, a challenging question. "There is now a bizarre relationship between aspirin, clopidogrel, and ASA/DP that makes guidelines difficult," Dr Kasner says. "It goes like this: ASA/DP beat ASA alone. Clopidogrel only ties ASA alone for stroke patients. Clopidogrel ties ASA/DP for efficacy but wins on practicality and perhaps safety." And, he asks, how can a guideline even recommend clopidogrel over ASA alone since that was a tie? "I think the guidelines will have to say that they are all reasonable options, and the decisions among them may depend on issues unrelated to relative efficacy, namely tolerability, convenience, and cost."

Robert G. Hart, writing for a recent publication,¹ concluded: "Integration of the PRoFESS trial results into recommendations for antiplatelet therapy requires weighing indirect comparisons between trial results. Clopidogrel was only slightly superior to aspirin 325mg per day in the earlier CAPRIE trial and narrowly comparable to extended-release dipyridamole plus low-dose aspirin in PRoFESS. Hence, by one interpretation of indirect comparisons, clopidogrel, dipyridamole plus low-dose aspirin, and aspirin 325mg per day should all be of approximately similar efficacy. More likely, weighing the two trials supporting superiority of extended-release dipyridamole plus low-dose aspirin over low-dose aspirin alone more heavily than the CAPRIE trial results will presumably strengthen the recommendation for clopidogrel over aspirin in future AHA and ACCP guidelines, bringing them into line with the current ESO recommendations."

1. Hart, Robert G. What's new in stroke? The top 10 studies of 2006–2008 Part 1. ARCHIWUM MEDYCYNY WEWN¢TRZNEJ 2008; 118 (11)650-656.