Principal Findings:

A total of 20,332 patients from 695 sites in 35 countries were randomized. A 2 × 2 factorial design, as described above, was employed. The median time to randomization from index event was about 15 days. About 51% of patients had no symptoms or no significant disability from the index event. Patients were at high risk for cardiovascular events, with 74% having hypertension, 28.3% with diabetes, 6.7% with prior myocardial infarction, and 24.6% with either prior stroke or transient ischemic attack (before index event). Approximately 52% of the patients with stroke had evidence of small-vessel ischemic disease. Follow-up averaged about 2.5 years.

Aspirin + dipyridamole vs. clopidogrel: The incidence of the primary endpoint of any recurrent stroke was similar between the aspirin + dipyridamole arm (9.0%) and the clopidogrel arm (8.8%) (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.92-1.11). This failed to meet the predefined noninferiority criteria for aspirin + dipyridamole compared with clopidogrel. The incidence of the main secondary outcome of stroke, myocardial infarction, or vascular death was similar between the two arms as well (13.1% vs. 13.1%, HR 0.99, 95% CI 0.92-1.07, p = 0.83). New or worsening heart failure, a tertiary outcome, was significantly better in the aspirin + dipyridamole arm (HR 0.78, 95% CI 0.62-0.96).

The investigators also noted a significantly higher risk of intracranial hemorrhage with aspirin + dipyridamole compared with clopidogrel (1.4% vs. 1.0%, HR 1.42 95% CI 1.11-1.83, p=0.006); the incidence of ischemic strokes was similar (7.7% vs. 7.9%). Major hemorrhagic events were observed more frequently in the aspirin + dipyridamole arm (4.1%) compared with the clopidogrel arm (3.6%) as well (HR 1.15, 95% CI 1.00-1.32, p = 0.06). Dropouts due to headache were also more common in the aspirin + dipyridamole arm.

Telmisartan vs. placebo: At the end of 1 year, the mean blood pressure difference between telmisartan and placebo was 3.8/2.2 mm Hg. The incidence of the primary endpoint of any recurrent stroke was similar between the telmisartan (8.7%) and placebo (9.2%) arms (HR 0.95, 95% CI 0.86-1.04, p = 0.23). The incidence of major vascular events (cardiovascular death, myocardial infarction, stroke, and new or worsening heart failure) was also similar between the two arms (13.5% vs. 14.4%, HR 0.94, 95% CI 0.87-1.01, p = 0.11). Rates of new-onset diabetes mellitus, also a prespecified secondary endpoint, were similar between the two arms (1.2% vs. 1.5%, HR 0.82, 95% CI 0.65-1.04, p = 0.10).

Further exploratory analysis indicated that there may be a benefit with telmisartan compared with placebo beyond 6 months in reducing the incidence of recurrent stroke (5.3% vs. 6.0%, HR 0.88, 95% CI 0.78-0.99). Adverse events, including hypotension, syncope, diarrhea, nausea, and atrial fibrillation, were more common with telmisartan compared with placebo. Moreover, although the incidence of hyperkalemia was similar between the two arms (0.1% vs. 0.1%, p = 0.07), the proportion of patients with severe hyperkalemia (potassium >5.5 mmol/L) was greater with telmisartan compared with placebo (1.6% vs. 0.8%, p < 0.001).