It has been demonstrated that there is a continuous association between cholesterol levels and the risk of myocardial infarction or death from coronary heart disease. Studies have documented that for middle-aged persons, each 0.6 mmol per L drop in total cholesterol confers about 30 percent less risk of coronary heart disease across a wide range of cholesterol levels. Cholesterol lowering has also been shown to reduce the risk of initial and recurrent coronary heart disease in patients with elevated cholesterol levels. MacMahon and associates of the LIPID Trial Research Group conducted a randomized, double-blind trial to evaluate the effects of cholesterol lowering on carotid atherosclerosis among patients with a history of myocardial infarction or unstable angina and average or below average levels of total cholesterol (from 154 to 270 mg per dL [4 to 7 mmol per L]).
A total of 522 patients were randomized to treatment with a low-fat diet plus pravastatin (40 mg daily) or with a low-fat diet plus placebo. The mean age of participants at the time of enrollment was 61 years. Before randomization and again after two and four years, ultrasound scans of the right common carotid artery were performed. The choice of this vessel as the primary end point in the trial was based on studies demonstrating the histologic validity of such ultrasound measurements. Total cholesterol was measured at the initial visit and at annual visits thereafter. Additional lipid studies were also performed three years after randomization. The primary study outcome was the change from baseline in carotid wall thickness after two and four years of follow-up. Follow-up data were available from 88 percent of study participants after two years and from 77 percent after four years.
Over the four-year study period, total cholesterol was reduced by an average of 38.6 mg per dL (1.0 mmol per L) in the pravastatin group compared with the placebo group. In addition, during the first three years of follow-up, low-density-lipoprotein (LDL) cholesterol, apolipoprotein B and total triglyceride levels were reduced by an average of 34.7 mg per dL (0.9 mmol per L), 1.93 mg per dL (0.05 mmol per L) and 11.2 mg per dL (0.29 mmol per L), respectively, in the pravastatin group compared with the placebo group. Over the same interval, apolipoprotein A1 and high-density-lipoprotein (HDL) cholesterol levels increased by 2.31 mg per dL (0.06 mmol per L) in the group receiving pravastatin and by 1.93 mg per dL (0.05 mmol per L) in the group receiving placebo.
After two years of follow-up, the mean carotid wall thickness increased by 0.039 mm in the placebo group and was essentially unchanged in the pravastatin group. After four years of follow-up, the mean carotid wall thickness had increased by a total of 0.048 mm in the placebo group and declined by 0.014 mm in the pravastatin group. Overall, after two years, there was a 0.049-mm difference in carotid wall thickness between the groups and after four years, a 0.062-mm difference between the groups. The ratio of lumen-to-wall thickness increased by 5 percent after two years and by 8 percent after four years in patients receiving pravastatin compared with those receiving placebo.
The results of this study demonstrate that treatment with the HMG CoA reductase inhibitor pravastatin reduced the development of carotid atherosclerosis among patients with a history of coronary heart disease and average to below-average cholesterol levels. Treatment with pravastatin reduced total cholesterol levels by 19 percent, LDL cholesterol levels by 27 percent, apolipoprotein B levels by 19 percent and total triglyceride levels by 13 percent. Conversely, apolipoprotein A1 and HDL cholesterol levels both increased by about 5 percent. There was no detectable carotid wall thickening over four years of follow-up among patients receiving pravastatin.
The authors conclude that cholesterol-lowering agents can reduce the risk of clinical sequelae of atherosclerotic disease in not only a large proportion of the at-risk population but also those patients with average or below-average cholesterol levels. These findings combined with results from previous trials suggest that such treatment might also be expected to reduce the risk of ischemic stroke.