On the Relationship Between Cholesterol Lowering and Coronary Disease Event Rate
To the Editor:
Dr Grundy’s editorial published in the April 21, 1998, issue of this journal1 provides an insightful summary of the reevaluations of the databases from the major statin trials (CARE, 4S, and WOSCOPS). These studies provide apparently divergent interpretations of the relationship between cholesterol lowering and coronary benefits experienced by study subjects. In his review, Dr Grundy elaborates on all 3 possible scenarios on the relationship between cholesterol lowering and clinical benefits: a linear model, a threshold model, and a curvilinear model. Whereas data from 4S2 seem to support the concept of a curvilinear relationship between cholesterol reduction and relative risk reduction, the analyses of the CARE3 and the WOSCOPS4 trials support the notion of a linear relationship up to a threshold level beyond which no further benefits are detected for further reductions in plasma cholesterol.
Advocation of the possibility of a linear relationship between cholesterol reduction and relative risk of coronary heart disease is not based on biologically plausible bases. If the relationship were indeed linear, there would be a degree of plasma cholesterol reduction that would eliminate the risk of coronary heart disease almost completely. This is not expected to be the case with a monofactorial intervention (ie, cholesterol lowering), which, although effective, is bound to have a limited power in situations in which the global coronary risk is contributed by more than just hypercholesterolemia (eg, hypertension, diabetes, smoking, family history, and age). The 2 other models both are biologically plausible, and possibly both are biologically true. Perhaps the apparently divergent results of 4S and WOSCOPS are both valid and can be unified in a single system. We propose that the beneficial effects of cholesterol lowering are a function of baseline event rate of coronary heart disease in the population studied and of the differential between baseline rate and the ideal event rate for the average patient enrolled in the study. For example, in a primary prevention trial like WOSCOPS, in which the event rate in the placebo group was on the order of 8% in 5 years, the outstanding initial effects of cholesterol lowering may rapidly reduce the patient’s risk to a minimum level set by the presence of other modifiable or nonmodifiable risk factors. In the case of WOSCOPS study subjects, this level could be ≈1% per year. Conversely, when the rate of major coronary events is much higher, as was the case in the 4S study (5% per year), the benefits of cholesterol lowering will not be masked by the threshold effect because of the large distance between baseline risk and minimum risk. Thus, the shape of the curve may be determined by the baseline risk in the population being studied.
Although we agree with Dr Grundy that post hoc analyses must be evaluated with caution, it is also true that when these analyses provide us with results that are in line with our expectations, we accept them less critically than when they challenge us with unexpected information. We believe that the subanalyses of major statin trials provide us with an additional point of practical relevance in our dealing with patients: it is possible that a 25% reduction in LDL will produce the maximum benefits in low-risk patients, whereas aggressive reductions in LDL to the levels recommended by the National Cholesterol Education Program Adult Treatment Panel II guidelines,5 or beyond, would be beneficial in high-risk hypercholesterolemic patients.
- Copyright © 1998 by American Heart Association
Grundy SM. Statin trials and goals of cholesterol-lowering therapy. Circulation. 1998;97:1436–1439.
Pedersen TR, Olsson AG, Færgeman O, Kjekshus J, Wedel H, Berg K, Wilhelmsen L, Haghfelt T, Thorgeirsson G, Pyörälä K, Miettinen T, Christophersen B, Tobert JA, Musliner TA, Cook TJ, for the Scandinavian Simvastatin Survival Study Group. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation. 1998;97:1453–1460.
West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 1998;97:1440–1445.
Sacks FM, Moyé LA, Davis BR, Cole TG, Rouleau JL, Nash DT, Pfeffer MA, Braunwald E. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the Cholesterol and Recurrent Events trial. Circulation. 1998;97:1446–1452.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015–3023.
Drs Fazio and Linton raise interesting and important issues about the subgroup analyses of the major statin trials. They speculate that progressive lowering of serum LDL-cholesterol levels must reach a point of diminishing returns in coronary heart disease (CHD) risk reduction, otherwise the complete elimination of LDL from the circulation would drop risk to zero. On the other hand, it is possible that progressive lowering of LDL could produce a continuous lowering of risk such that when LDL levels approach zero, an irreducible baseline of risk is reached. Therefore, the linear model cannot be rejected out of hand. Importantly, logic alone or review of existing literature cannot determine the shape of the relationship between LDL-cholesterol levels and CHD risk reduction, whether linear, curvilinear, or threshold. On the basis of analogy to large epidemiological studies, I speculated that a curvilinear (log-linear) relationship is the most likely, but the final answer must await new clinical trials that are designed to specifically address this issue. It is my view that the accumulated evidence from recent clinical trials, angiographic trials, and epidemiological studies makes a strong case for a target goal for LDL cholesterol in secondary prevention of ≤100 mg/dL. Implementation of therapy to achieve this goal will ensure that most patients with established CHD will receive aggressive cholesterol-lowering therapy; the recent statin trials also make a good case for using statins (or other cholesterol-lowering drugs) in most CHD patients, regardless of baseline LDL-cholesterol levels. Because of the striking risk reduction achieved from statin therapy in patients with established CHD, the major concern at present must be that of inadequate cholesterol management, either from failure to initiate cholesterol-lowering therapy or from insufficient LDL lowering.