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Rates of recurrent stroke were nearly identical with either of two antiplatelet regimens--aspirin plus extended release dipyridamole or clopidogrel alone--in a trial in more than 20,000 patients randomly assigned to one of the two antiplatelet regimens after a recent ischemic stroke.

The study, conducted in 35 countries, "does not show that either aspirin plus extended-release dipyridamole or clopidogrel is superior to the other in the prevention of recurrent stroke," concluded the lead author, Dr. Ralph L. Sacco, of the University of Miami, and his associates in the PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) study group (N. Engl. J. Med. 2008 [doi 10.1056/NEJM0a0805002]).

PRoFESS also investigated whether adding the angiotensin receptor blocker telmisartan (Micardis) to other antihypertensive drugs would provide significant protection against recurrent strokes. The results of this aspect of the study, reported by lead author Dr. Salim Yusuf of McMaster University, Hamilton, Ont., and the PRoFESS study group, showed that telmisartan did not affect recurrent stroke rates, nor did it decrease the risk of major cardiovascular events or new onset diabetes (N. Engl. J. Med. 2008 [doi 10.1056/NEJMoa0804593]).

PRoFESS had a parallel design, in which the 20,332 study patients were randomized to both the antiplatelet and antihypertensive investigational arms, in addition to background medication. The 20,332 patients enrolled were all aged at least 50 years, and had a mean age of 66 years, and 36% were women. All patients had had a stroke within less than 4 months before entering the trial, and were followed for a mean of 2.5 years (range of 1.4-4.4 years).

The 4-year study was supported by Boehringer-Ingelheim, the manufacturer of Aggrenox (200 mg of extended-release dipyridamole and 25 mg of aspirin) and Micardis. Most authors of the study, including Dr. Sacco and Dr. Yusuf, reported receiving consulting fees, honoraria, and/or lecture fees from the company, as well as other pharmaceutical companies; several authors were Boehringer-Ingelheim employees.

Comparing Therapies

The aim of the antiplatelet study was to compare aspirin plus dipyridamole with clopidogrel in patients who had recently had an ischemic stroke, because there are no guidelines for using one of these antiplatelet regimens over the other, according to the authors. Treatment with either 25 mg of aspirin and 200 mg of extended-release dipyridamole (ASA-ERDP) twice a day or 75 mg of clopidogrel once a day was started a median of 15 days after having an ischemic stroke (enrollment was limited to within 90-120 days of the stroke). The most common type of ischemic stroke in the patients, affecting about half, was a small-artery occlusion; nearly 27% had large artery atherosclerosis.

The primary outcome, a recurrent stroke of any type, occurred in 9% of those on ASA-EDRP and in 8.8% of those on clopidogrel. Most of the recurrent strokes were ischemic strokes (87.4%). There were 38 more hemorrhagic strokes among patients on ASA-ERDP, but the number of patients in either group who had strokes that were fatal or disabling were similar (4.1% in the combination group and 3.9% among those on clopidogrel).

A composite of stroke, myocardial infarction, or death from vascular causes, the study's secondary outcome, occurred in 13.1% of those in each group, "suggesting that there is little likelihood for a clinically important difference between the two regimens with regard to these events," the authors wrote.

In most cases, tertiary outcomes (which included MI and death from vascular causes) were similar in the two groups, with the exception of new or worsening congestive heart failure, which was significantly higher (1.8%) among those on clopidogrel than those on the combination (1.4%).

Those on ASA-EDRP experienced more major hemorrhagic events, including intracranial hemorrhage (4.1%), compared with those on clopidogrel (3.6%). The rate of intracranial hemorrhage, which included the hemorrhagic strokes that were included in the primary outcome, was significantly higher among those on ASA-ERDP (1.4% vs. 1%).

The percentage of those permanently stopping treatment because of adverse events was higher for the ASA-EDRP group than for the clopidogrel group (16.4% vs. 10.6%). Headaches were also more common among those on the combination and were a more common reason for permanently stopping the combination treatment, than among those on clopidogrel.

Telmisartan Investigation

As in the antiplatelet arm of PRoFESS, the antihypertensive investigation found no significant differences in the main outcomes.

Previous studies showed that prolonged lowering of blood pressure reduces the risk of recurrent stroke. Other studies indicated that inhibiting the renin-angiotensin system in high-risk patients decreases the rate of subsequent cardiovascular events, including stroke. The investigators reasoned that if an angiotensin receptor blocker (ARB) were added to standard antihypertensive therapy soon after an initial stroke, the combination would result in further reductions of risk.

All 20,332 patients were randomized to receive either 80 mg of telmisartan or placebo once daily. They also received medication for blood pressure control at the discretion of the investigators. Their initial blood pressure was 144/84 mm Hg, and they began the study a median of 15 days following their initial stroke.

In the multivariate analysis, the investigators controlled for age, diabetes status, the use of ACE inhibitors, and the patient's level of disability as quantified by the modified Rankin scale.

The hazard ratio for recurrent stroke in patients taking telmisartan was 0.95. This 5% reduction in risk of the primary outcome was not statistically significant. For the secondary outcome--death from cardiovascular causes, recurrent stroke, mild cardioinfarction, or new or worsening heart failure--the hazard ratio was 0.94, which again was not statistically significant. The hazard ratio for new-onset diabetes was 0.82, which narrowly missed reaching statistical significance.

In a post hoc exploratory analysis, the investigators found that while there were no significant differences in event rates in the first 6 months of following randomization, significant differences did emerge thereafter. This suggests that significant differences in the main outcomes may have emerged with a follow-up period of greater than 30 months.