More than 5 million Americans have had a stroke, and more than 500,000 new strokes occur every year. Sixty percent of survivors suffer residual disability. Stroke is the second leading cause of death and disability in developed countries. Although elevated blood pressure is the leading risk factor for stroke, most strokes occur in patients whose blood pressures are below the range at which therapy is used. Studies show that angiotensin-converting enzyme (ACE) inhibitors have multiple effects on blood vessel walls and other components of vascular integrity, suggesting that these drugs could prevent stroke independent of their ability to lower blood pressure. Bosch and colleagues coordinated a large double-blind, randomized, controlled trial in 19 countries of the ACE inhibitor ramipril in patients at high risk of stroke.

The patients were at high risk because of coronary artery disease (7,477 patients), previous stroke or transient ischemic attack (1,013 patients), peripheral artery disease (4,051 patients), diabetes (3,577 patients), or hypertension (4,355 patients). The average age was 66 years, and the average blood pressure was 139/79 mm Hg. Patients were randomly allocated to receive up to 10 mg of ramipril or placebo. The study was double blinded with a run-in phase of 2.5 mg of ramipril daily and a two-week course of placebo. Patients were followed for an average of 4.5 years and monitored for stroke, myocardial infarction, or cardiovascular death.

In the 4,645 patients taking ramipril, 156 strokes were recorded compared with 226 strokes in the 4,652 patients taking placebo. The total incidence of stroke (3.4 percent) and transient ischemic attack (4.1 percent) was significantly lower in patients taking ramipril than in those taking placebo (4.9 percent and 4.9 percent, respectively). Patients treated with ramipril also had significantly lower mortality and functional disability. The trial was terminated early because of the clear benefit from ramipril treatment. The benefits were consistent regardless of blood pressure or subcategory of patient.

The authors conclude that ramipril provided an early and powerful reduction in risk of stroke regardless of type of patient or initial blood pressure. Because another study has shown similar results in patients with existing cerebrovascular disease, the authors call for widespread use of ACE inhibitors in patients at risk of stroke.

editor's note: ACE inhibitors are rapidly becoming the new wonder drugs, with wide applications beyond their original role as antihypertensive agents. In this study, fatal stoke was reduced by an impressive 61 percent, non-fatal stroke by 24 percent, and functional and cognitive outcomes were improved in those patients who did have stroke. The article and an accompanying editorial call for ACE inhibitors to become more widely used, but the editorial highlights some important caveats. First, hypertension remains the principal risk factor for stroke, and it must be controlled. The gains with ramipril were achieved in patients with controlled blood pressure, and those strokes that occurred during the study were most likely to occur in patients with a blood pressure greater than 140/90 mm Hg. Second, not all ACE inhibitors may have the same efficacy and more studies are needed. Concomitant use of aspirin may reduce the effectiveness of ACE inhibitors.

Studies are in progress to provide answers to these questions. For family physicians, the increasingly sophisticated understanding of stroke is welcome—simply plugging a blood vessel with a clot always seemed a crude pathophysiology. Much more important is the prospect of being able to do more than struggle with physical therapy, aspirin, and hope in patients who have had a first event. These patients and their families are often terrified of an impending second stroke. We can now hold out the prospect of at least a 60 percent reduction in future strokes through appropriate and aggressive treatment.—a.d.w.