Low-density lipoprotein size, pravastatin treatment, and coronary events

Context Small low-density lipoprotein (LDL) particle size has been hypothesized to be a risk factor for coronary heart disease (CHD). Animal models link large LDL to atherosclerosis. However, the strong association between small LDL and other risk factors, particularly triglyceride levels, impedes determining whether LDL size independently predicts CHD in humans. Objective To examine whether LDL size is an independent predictor of recurrent coronary events in patients with known CHD, as opposed to a marker for other lipid abnormalities. Design and Setting Prospective, nested case-control study in the Cholesterol and Recurrent Events (CARE) trial, a randomized placebo-controlled trial of pravastatin conducted in 1989-1996. Participants Survivors of myocardial infarction with typical LDL concentrations (416 cases and 421 controls). Main Outcome Measure Subsequent myocardial infarction or coronary death during the 5-year follow-up, analyzed by quintile of LDL particle size and by treatment group. Results Overall, the mean LDL size was identical in cases and controls (25.6 nm). In patients in the placebo group, large LDL predicted coronary events in models adjusted only for age (relative risk [RR], 1.79; 95% confidence interval [CI], 1.01-3.17) and for age and lipid and nonlipid risk factors (RR, 4.00; 95% CI, 1.81-8.82), comparing those in the highest (mean, 26.6 nm) and lowest (mean, 24.5 nm) quintiles of LDL size. This increased risk was not present in those taking pravastatin (age-adjusted analysis: RR, 0.98; 95% CI, 0.47-2.04; P = .046 for interaction for a difference in the effect of LDL size on coronary events between the placebo and treatment groups; multivariable analysis: RR, 1.33; 95% CI, 0.52-3.38; P = .11 for interaction). Conclusions Large LDL size was an independent predictor of coronary events in a typical population with myocardial infarction, but the adverse effect was not present among patients who were treated with pravastatin. Identifying patients on the basis of LDL size may not be useful clinically, since effective treatment for elevated LDL cholesterol concentrations also effectively treats risk associated with large LDL.