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HAMILTON, Ontario, Aug. 27 -- Two treatment options for preventing recurrent stroke -- one using antiplatelet agents and one an angiotensin-receptor blocker (ARB) -- failed to show a benefit in a multicenter trial.

In a two-by-two factorial trial involving more than 20,000 ischemic stroke patients ages 50 and older, those who received the ARB, telmisartan (Micardis), soon after stroke had similar rates of recurrence as those who received placebo (P=0.23), Salim Yusuf, M.B.B.S., D.Phil., of McMaster University here, and colleagues reported online in the New England Journal of Medicine.

The same patients were also randomized to a combination of aspirin and extended-release dipyridamole (Aggrenox) or clopidogrel (Plavix), and rates of recurrent stroke were similar between the two groups (HR 1.01, 95% CI 0.92 to 1.11).

The results of the trial, the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study, were originally presented in May at the European Stroke Conference in Nice, France. (See: PRoFESS Fails Across the Board in Preventing Second Strokes)

The trial -- which included 20,332 ischemic stroke patients from 695 centers in 35 countries -- randomized patients to 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily (10,181) or to 75 mg of clopidogrel daily (10,151), and to 80 mg of telmisartan daily (10,146) or placebo (10,186).

Patients (mean age 66.1) were followed up for a mean of 2.5 years.

In the comparison of the antiplatelet regimens, recurrent stroke occurred in 9% of the patients who received aspirin plus dipyridamole and 8.8% of those who received clopidogrel (HR 1.01, 95% CI 0.92 to 1.11).

Despite the similar rates of recurrent stroke, the combination treatment failed to meet criteria for noninferiority, which the researchers said was because the study was underpowered.

"There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke," the researchers said.

In addition, the composite endpoint of stroke, myocardial infarction, or death from vascular causes occurred at a rate of 13.1% in each group (HR 0.99, 95% CI 0.92 to 1.07).

The narrow confidence interval suggested "that there is little likelihood for a clinically important difference between the two regimens with regard to these events," the researchers said.

There were more major hemorrhagic events among recipients of the combination treatment (4.1% versus 3.6%; HR 1.15, 95% CI 1.00 to 1.32); however, the risk of recurrent stroke or major hemorrhagic event was similar between the groups (11.7% versus 11.4%; HR 1.03, 95% CI 0.95 to 1.11).

Discontinuation of the study drug occurred more frequently with the combination treatment (29.1% versus 22.6%, P

In the comparison between telmisartan and placebo, recurrent stroke occurred in 8.7% of those taking telmisartan and 9.2% of the placebo group (HR 0.95, 95% CI 0.86 to 1.04, P=0.23).

Mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group through follow-up.

One month after starting treatment, the percentage of patients with a creatinine level of more than 1.5 mg/dL was similar in the two groups (6.2% with telmisartan versus 5.8% with placebo), but the percentage of those with a potassium level of more than 5.5 mmol/L was significantly higher in the telmisartan group (1.6% versus 0.8%, P
Major cardiovascular events occurred in 13.5% of the telmisartan group and 14.4% of the placebo group (HR 0.94, 95% CI 0.87 to 1.01, P=0.11), and there was no significant difference in the occurrence of new-onset diabetes (1.7% with telmisartan versus 2.1% with placebo; HR 0.82, 95% CI 0.65 to 1.04, P=0.10).

However, patients in the telmisartan group were significantly more likely to discontinue the study drug because of adverse events (14.3% versus 11.1%, P
Dr. Yusuf and colleagues said that the trial may have been too short to find a significant benefit for telmisartan. In two other trials that found a gradually increasing benefit in the reduction of stroke, the mean durations were four and 4.5 years.

They also acknowledged some limitations of the study, including a lower adherence to telmisartan compared with placebo and greater use of non-study blood pressure-lowering drugs in the placebo group.

In a separate paper published online two days later in The Lancet Neurology, Dr. Yusuf and colleagues reported that disability following recurrent stroke -- measured with the modified Rankin scale -- did not differ significantly between groups in either the antiplatelet comparison (P=0.38) or the telmisartan and placebo comparison (P=0.61).

In addition, they said, there were no significant between-group differences in cognitive function over time, as measured using the Mini Mental State Examination.

In an editorial accompanying the Lancet Neurology study, Graeme Hankey, M.D., of Royal Perth Hospital in Perth, Australia, and John Eikelboom, M.B.B.S., of McMaster University, wrote that “these results teach us that aspirin and telmisartan are unlikely to have substantial neuroprotective effects.”

They noted, however, that the study was not designed or powered to test whether any of these agents were neuroprotective.

Nor were the measures used direct measures of neuroprotection, but rather surrogate markers, they said.

Finally, they said, the trial may have been too short to detect any potential benefits.