Pravastatin Reduces Strokes

Source: Plehn JF, et al. Circulation 1999;99:216-223.

The relationship between cholesterol levels and stroke is controversial. The Cholesterol and Recurrent Events (CARE) trial is the first secondary prevention trial of "statins" after myocardial infarction (MI) that included stroke as a secondary end point. The 4159 patients in this study had average cholesterol levels (mean 209 mg/dL) and LDL levels (139 mg/dL). The primary end point of reduction in cardiac events was reduced 24% in the pravastatin vs. placebo patients. Also, strokes were reduced 32%. The patients were well matched and antiplatelet drug use was 85% in each group. Pravastatin lowered cholesterol 20%, LDL 32%, and triglycerides 14%; HDL was raised 5%. Strokes or TIAs occurred in 92 patients on pravastatin and 124 on placebo—a 27% reduction. There was no increase in intracerebral hemorrhage on pravastatin and no difference in fatal strokes (6 total). Subgroup analysis showed equally beneficial effects for groups based on age, sex, hypertension, smoking, left ventricular ejection fraction, and baseline lipid levels. Plehn and colleagues conclude that pravastatin reduced strokes/TIAs in postmyocardial infarction patients with average cholesterol levels despite concomitant use of antiplatelet agents by most of the patients.

Comment by Michael H. Crawford, MD

Stroke following MI is mainly cardioembolic in the early recovery phase (< 3 months) but is more ischemic later due to the relationship between coronary and cerebrovascular disease. The CARE patients were randomized from three to 20 months (mean 10) postinfarction and only 15% of the strokes were considered embolic. However, the benefit was observed in all types of strokes. The reduction in stroke/TIA rates paralleled the reduction in coronary events, but the point where the event curves separated between the groups was different: 3.5 years for stroke and about 1.5 years for coronary events. Similar results were seen with the 4S secondary prevention study, with a 30% stroke reduction starting after three years. Although the percent reduction is impressive, the P value was not robust at 0.02, but considering that 85% of patients were on antiplatelet drugs, the results are noteworthy.

The mechanism of pravastatin’s benefit is unknown, but a relationship was noted with serum LDL levels; the higher the level, the more the benefit. Stroke reduction was a nonsignificant 14%, with LDL less than 125 mg/dL and 54% with LDL more than 150 mg/dL (P < 0.001). However, in the West of Scotland primary prevention trial of patients with similar lipid levels, but no prior MI, stroke reduction was an insignificant 11% despite similar reductions in cholesterol on pravastatin treatment. Thus, the mechanism of stroke reduction may involve effects of the statins beyond lipid lowering. Also, the West of Scotland study suggests that the results of this trial in postmyocardial infarction patients may not be transferable to patients with less disease. Whatever the mechanism, it appears that stroke reduction should be another expected benefit of lowering LDL cholesterol in postmyocardial infarction patients with LDL more than 130 mg/dL.