NICE, France, May 16 — Dipyridamole plus aspirin (Aggrenox) was not proven non-inferior to clopidogrel (Plavix) in prevention of second strokes, nor was there a difference in that regard between telmisartan (Micardis) and placebo, researchers in the PRoFESS trial found.
Results of the highly promoted PRoFESS (Prevention Regimen for Effectively avoiding Second Strokes) trial were reported in a series of presentations at the European Stroke Conference here.
Among the results:
Dipyridamole plus aspirin failed to establish non-inferiority with clopidogrel in preventing second strokes, even though the study found little difference between the drugs in effectiveness.
Telmisartan was unable to prove that it was better than placebo in preventing second strokes.
Neither strategy proved successful in showing better results in improving functional outcomes or cognitive outcomes.
When asked if the researchers were disappointed in the four-year-long trial outcomes, Ralph Sacco, M.D., of the University of Miami and a member of the PRoFESS study group, was philosophical:
“Disappointment is an emotional term, not a scientific one.” He then paused, and said: “Of course, we are disappointed.”
The trial results, which covered several areas of stroke treatment, represented the work of researchers from 695 centers in 35 countries on six continents. They had enrolled 20,332 patients who had been diagnosed with a non-embolic ischemic stroke into the trial sponsored by Boehringer Ingelheim.
Dr. Sacco reported on outcomes involving 10,181 patients who were randomized to receive the dipyridamole regimen and 10,151 who were randomized to receive clopidogrel.
The primary outcome of the trial was to compare the effectiveness of the dipyridamole arm to clopidogrel with a secondary endpoint of effectiveness in preventing other vascular events.
Statistically the trial was designed to determine if dipyridamole was non-inferior to clopidogrel. In fact, the decision of the trialists to seek a very narrow interpretation of non-inferiority prevented them from achieving that goal.
“The trial showed that there were no significant differences in outcomes among stroke patients on either treatment regimen,” Dr. Sacco said, “but nevertheless we were unable to prove non-inferiority. I think the results still indicate that either of these drugs can be used to prevent second strokes.”
He said clinicians will use their clinical judgment and other factors — such as cost — in deciding which drug is best for individual patients.
In the primary outcome, prevention of a second stroke, 916 dipyridamole patients had strokes (9%) compared with 898 clopidogrel patients (8.8%) (P=0.783).
When analyzing the types of strokes, Dr. Sacco said 25 fewer ischemic strokes occurred with the dipyridamole regimen than with clopidogrel; but 38 more hemorrhagic strokes occurred with the dipyridamole regimen. There were more hemorrhages and intracranial bleeding with the dipyridamole regimen than with clopidogrel (P=0.06).
After about 2.5 years, 7.8% of the dipyridamole patients had died compared with 8.1% of the clopidogrel patients, Dr. Sacco said.
The patients were about 66 years old as a group and two-thirds were men; about 75% had high blood pressure and 28% were diabetic; 46% had high cholesterol.
In the part of the study that judged whether immediate treatment of high blood pressure with the angiotensin receptor blocker telmisartan was beneficial compared with placebo, the results again failed to provide a definitive answer.
“The trial indicates that a modest blood pressure lowering of a mean of only 3.5 mm Hg early after a stroke, with treatment given for about 2.5 years, may be of insufficient intensity and duration to reliably evaluate whether blood pressure lowering is of clinical value in post-stroke patients,” said Salim Yusuf, M.D., of McMaster University in Hamilton, Ontario, another of the trial’s researchers.
The researchers assigned 10,146 of the PRoFESS enrollees to receive telmisartan 80 mg a day and 10,186 to receive placebo.
Overall, 8.7% of the patients receiving telmisartan suffered a second stroke in the 2.5-year time frame of the study, Dr. Yusuf said.
About 9.2% of patients receiving placebo also suffered second strokes in the trial, which translated into a 5% reduction with telmisartan, a difference that failed to reach statistical significance (P=0.23).
In a secondary endpoint, major vascular events — cardiovascular death, myocardial infarction, stroke, or new or worsening heart failure — were experienced by 13.5% of patients on telmisartan and 14.4% of patients on placebo (P=0.11).
Dr. Yusuf said that an ad hoc analysis of the study found that during the first six months following the stroke, 3.4% of telmisartan patients and 3.2% of placebo patients suffered a second cerebrovascular event (P=0.38); but in the following two years, the stroke rate was 5.3% for telmisartan and 6% for placebo patients (P=0.029).
“However, I would not refer to this as significant,” he said, “as this was not a pre-specified endpoint.”
“This analysis suggests little early benefit but potential later benefit with telmisartan which increases over time,” Dr. Yusuf explained.
Hans-Christoph Diener, M.D., of the University of Essen in Germany and another of the PRoFESS researchers, said that none of the treatments in the study appeared to improve outcomes on the Mini Mental State Examination, the Barthel Index, or the Modified Rankin Scale — all measures of cognitive or functional status.
“All randomized trials — and there have been at least 90 of these attempts — investigating neuroprotective substances failed in human ischemic stroke,” he said, in explaining the rationale in comparing the treatments in PRoFESS.
However, at the conclusion of the trial he was forced to conclude that “the neuroprotective effects of aspirin or dipyridamole are unlikely. Telmisartan is unlikely to have neuroprotective property.”
On the Barthel Index, about 43.6% of telmisartan patients achieved a 95-100 score — indicating nearly complete recovery in the ability to perform activities of daily living. About 44.5% of patients on placebo achieved a 95-100 Barthel Index score, Dr. Diener said (P=0.731).
On the Barthel Index, about 42.5% of the dipyridamole patients achieved a 95-100 score — indicated nearly complete recovery in the ability to perform activities of daily living. About 45.6% of patients on clopidogrel achieved a 95-100 Barthel Index score, Dr. Diener said (P=0.206).
On the Modified Rankin Scale, about 49.4% of patients on the dipyridamole regimen achieved a score of 0-2, indicating good functional recovery after stroke, compared with 52% of clopidogrel patients (P=0.376).
The findings were similar between telmisartan and placebo and between patients on extended-release fixed-dose dipyridamole and aspirin and those receiving clopidogrel, with no discernable differences in cognitive outcome as measured on the Mini-Mental State Examination.
Dr. Yusuf has disclosed possible financial conflicts with AstraZeneca, sanofi-aventis, Bristol-Myers Squibb, Merck, Organon, Boehringer Ingelheim and Abbott.
Dr. Diener has disclosed possible financial conflicts with Addex Pharma, Allergan, Almirall, AstraZeneca, Bayer, Berlin Chemie, CoLucid, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Gr??nenthal, Janssen-Cilag, Lilly, 3M Medica, Merck Sharp & Dohme, Novartis, Johnson & Johnson, Pierre Fabre, Pfizer, Roche, Schaper and Br??mmer, sanofi-aventis and Weber & Weber.
Dr. Sacco has disclosed possible financial conflicts with GlaxoSmithKline, Pfizer, Boehringer Ingelheim, sanofi-aventis, Bristol-Myers Squibb, Pfizer, AstraZeneca, GlaxoSmithKline, and Texas Biotechnology.
Primary source: Cerebrovascular Diseases, Vol. 25, Supplement 2, 2008
Diener HJ, et al “Presentation title: Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS) Trial: Cognitive and functional outcomes after stroke”
Sacco R, et al “Presentation title: Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS) Trial: Comparison of a fixed dose combination of extended-release dipyridamole plus asa with clopidogrel”
Yusuf S, et al “Presentation title: Prevention Regimen for Effectively avoiding Second Strokes (PRoFESS) Trial: Telmisartan versus placebo”