September 3, 2008 — Results of a randomized trial show no evidence that extended-release dipyridamole (Aggrenox, Boehringer Ingelheim), aspirin, or telmisartan (Micardis, Boehringer Ingelheim) have neuroprotective effects on either disability due to a recurrent stroke or cognitive decline over time.
The results of this third factorial analysis of the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) trial are published online August 29 in Lancet Neurology. Results of the other 2 main analyses, 1 comparing aspirin plus extended-release dipyridamole with clopidogrel for the prevention of recurrent stroke and another comparing telmisartan vs placebo in these same patients, were published online August 27 in the New England Journal of Medicine.
"PROFESS is the largest trial so far to investigate in a prespecified manner whether treatment with antiplatelet drugs or angiotensin II receptor agonists (such as telmisartan) are neuroprotective in patients who have had a recurrent stroke," the researchers, with first author Hans-Christoph Diener, MD, from the University of Duisberg/Essen, in Essen, Germany, conclude. "The degree of functional impairment at 3 months poststroke was similar across treatment arms."
The findings from all 3 analyses were previously presented at the 17th European Stroke Conference in Nice and reported by Medscape Neurology & Neurosurgery at that time.
Neuroprotective Effects?
The PROFESS trial included 20,332 patients from 695 sites in 35 countries. All had had a noncardioembolic ischemic stroke within the previous 120 days. They were randomized in a factorial design to receive aspirin (25 mg) plus extended-release dipyridamole (200 mg) twice daily or clopidogrel (75 mg) (Plavix/Iscover, Bristol-Myers Squibb/ Sanofi-Aventis) once daily. Subjects were then again randomized to receive either 80 mg per day of telmisartan or placebo.
In separate papers, the researcher have previously reported that the combination of aspirin and extended-release dipyridamole did not meet prespecified criteria for noninferiority vs clopidogrel, but rates of recurrent stroke, the primary outcome, were similar between the groups.
The trial also examined the effect of early blood-pressure lowering after a stroke using telmisartan vs placebo and found no benefit of the addition of the angiotensin-receptor blocker (ARB) in prevention of stroke recurrence, major cardiovascular events, or diabetes, at least during the 2.5 years of follow-up in this study.
This third factorial analysis investigated whether or not antiplatelet compounds such as aspirin and dipyridamole or an ARB such as telmisartan might have neuroprotective effects. Previous preclinical data had suggested neuroprotective properties for dipyridamole, aspirin (although only at very high doses), and ARBs in models of cerebral ischemia, the researchers note.
Previous neuroprotection trials have been notoriously negative, but part of the difficulty has been to have putative neuroprotectants on board at the time of stroke. With the PROFESS data, the investigators were able to look for possible neuroprotectant effects of these agents among those patients who went on to have a recurrent stroke during the study. They compared functional outcomes after recurrent strokes while on study treatment using the modified Rankin scale (mRS) and the Barthel Index 3 months after the stroke.
Recurrent strokes occurred in 9% of each treatment group, including those who received aspirin plus dipyridamole or clopidogrel and telmisartan or placebo. There was no significant difference in functional outcomes on either the mRS or the Barthel Index for the comparison of aspirin plus dipyridamole vs clopidogrel (which had not been shown previously to have any putative neuroprotective effect) or for the comparison of telmisartan vs placebo.
In addition, there was no significant difference in the median Mini-Mental State Examination (MMSE) scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE score of 3 points or more between 3 months and the penultimate visit, or the number of patients with dementia among the treatment groups. Further, there was no difference between groups in the proportion of patients with cognitive impairment or dementia.
"There are 2 possible explanations," Dr. Diener told a press conference in Nice when these results were first presented. "The most likely explanation is there is no effect. The other possible explanation is that the observation at 2.5 years is not long enough. Perhaps you have to have treatment and observation times of 10 years or more to see a difference," he speculated.
The researchers note that a planned cognitive substudy of PROFESS using more sophisticated neuropsychological assessments in a subgroup of patients will be reported later.
Burning Clinical Questions
In a Reflection and Reaction commentary accompanying the paper, Graeme J. Hankey, MD, from Royal Perth Hospital, in Western Australia, and John W. Eikelboom, MD, from McMaster University, in Hamilton, Ontario, congratulate the researchers "for completing the largest trial of its kind in the world. The investigators addressed and answered burning clinical questions of the day, and the trial was scientifically rigorous enough to minimize bias and random error and thus ensure the internal validity of the results."
They point out that the PROFESS investigators did not put their trust in indirect comparisons that had suggested superiority of the combination of aspirin and extended-release dipyridamole over clopidogrel but directly compared the 2, finding no evidence in the difference between these interventions in the prevention of major vascular events, including cardiac events in patients with subacute ischemic stroke.
For patients who have had a stroke and are already on 1 of these regimens, they write, "there is no need to change." For patients just going on these medications or those who have had a recurrent stroke while on aspirin, Drs. Hankey and Eikelboom suggest the choice will be determined by several factors.
Clopidogrel would be the choice for those with atherothrombotic vascular disease in other vascular beds, as the combination has not been proven effective in patients with coronary artery disease, they note. Patients predisposed to bleeding or headache, for example, would likely get clopidogrel, since these were both more common with the combination. Clopidogrel costs more, although it only needs to be taken once daily, which may affect compliance, they point out. Patient preference will also play a role.
In terms of the findings of no benefit overall of telmisartan vs placebo in this study, they point out, as the researchers also did, that results of a post hoc analysis suggested some possible benefit for those treated longer than 6 months vs those treated over a shorter period. "Although the results for longer than 6 months are only hypothesis-generating, they are biologically consistent with other trials that show that the longer patients have lower blood pressure (or blood cholesterol), the lower their risk for major vascular events," they write.
These results suggest that trials of interventions that aim to prevent the complications of high blood pressure, such as large artery stenosis, intracranial small-vessel disease, or atrial fibrillation, require follow-up longer than a few years to fully appreciate any potential effect, they conclude.
Finally, with regard to the neuroprotection hypothesis, the trial shows that aspirin and telmisartan are unlikely to have substantial neuroprotective effects, they write. But they alsopoint out that the results may be false-negative, since the trial was not designed or powered primarily to test the neuroprotection hypothesis, and again, may have been too short to see such effects.
"The results of a substudy of PROFESS, which used more sophisticated neuropsychological instruments, will hopefully provide greater insights into this important issue," they conclude.
Question of Efficacy in African Americans Still Open?
Asked for comment on the PROFESS findings, Michael Sloan, MD, from the department of neurology at the University of South Florida, in Tampa, and a spokesperson for the American Heart Association/American Stroke Association said, "This is a very good study, the largest study of secondary stroke prevention and with a very novel strategy. The people who ran the study are outstanding."
With regard to the findings comparing aspirin and extended-release dipyridamole vs clopidogrel, he pointed out that the population in this trial, where about a quarter of patients were Asian or South Asian, is very different from what is seen in the United States, where a much higher proportion are African American. "While the subgroup analysis showed no difference among ethnic groups, the fact that African Americans were underrepresented at only 3% in this trial means no conclusions can be drawn regarding the comparative efficacy of these agents in African Americans."
His practice has been to use both strategies in different patients, he told Medscape Neurology & Neurosurgery. "The choice of therapy is based upon the patient's overall characteristics, response to previous therapy, cost, patient preference, and side-effect profile," he said. For example, a patient with peripheral artery disease, previous coronary artery stenting, transient ischemic attack or stroke symptoms, or those with migraine or other headaches would likely be given clopidogrel, he said. The patient without these features or who has failed aspirin therapy would be given the combination of aspirin and extended-release dipyridamole.
On the telmisartan comparison, Dr. Sloan pointed out that although there was a difference in overall blood pressure between the groups, those in the placebo group were treated with antihypertensive drugs from other classes. "I think in this study, although it's not strictly comparable to PROGRESS or other studies, does suggest that if you have a lower blood pressure by whatever medication, you're going to reduce your stroke risk."
The PROFESS trial was funded by Boehringer Ingelheim. In selected countries, the telmisartan comparison was supported by Bayer Schering Pharma and GlaxoSmithKline. Dr. Diener reports that he has received honoraria and consulting and lecture fees from Abbott, AstraZeneca, Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, D-Pharm, Fresenius, GlaxoSmithKline, Janssen Cilag, Merck, Sharpe & Dohme, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Sankyo, Servier, Solvay, Thrombogenics, Wyeth, and Yamaguchi and grant support from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Janssen Cilag, and Sanofi-Aventis.
Lancet Neurol. 2008; Published online August 29, 2008. Abstract Abstract
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Cite this: Susan Jeffrey. No Neuroprotective Effect of Dipyridamole, Aspirin, or Telmisartan in Recurrent Stroke - Medscape - Sep 03, 2008.
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