REPLY
Cholesterol Reduction, Heart Disease, and Mortality
J. Michael Gaziano, MD;
Patricia R. Hebert, PhD; and
Charles H. Hennekens, MD
15 April 1997 | Volume 126 Issue 8 | Page 661
IN RESPONSE:
Few preventive measures have been so well studied as the lowering of cholesterol levels for the primary and secondary prevention of coronary heart disease. The strength and consistency of the abundant data from in vitro, animal, and observational studies and randomized trials would make any explanation other than cause and effect extremely unlikely. Our article focused on the decision to treat hypercholesterolemic patients while weighing the certainty of benefit of treatment in reducing the risk for heart disease against the uncertainty about any increased risk for nonvascular death.
Recent trial data show reductions not only in nonfatal events but also in total mortality rates among high-risk patients with known coronary disease [1] and intermediate-risk patients with risk factors but without previous coronary disease [2]. Stehbens [3] argued that the findings of the 4S trial were the result of a failure of randomization, citing the maldistribution of a few baseline characteristics. The even distribution of almost all baseline characteristics, however, argues for a successful randomization. The findings are also completely consistent with those of previous observational studies, meta-analyses of previous randomized trials, and two recent large-scale trials: the WOSCOP (West of Scotland) study [2] and the CARE (Cholesterol and Recurrent Events) trial [4].
Regarding the small number of lives saved in the 4S trial, the absolute number depends on the baseline risk of the patients who were enrolled. Event rates in randomized trials tend to be lower than expected because of the healthy-volunteer effect and possibly because of additional medical attention that may be provided as a result of the trial. This can reduce the power of a study to detect the most-plausible, small, clinically important benefits. However, when the observed 30% reduction in mortality rate is extrapolated to clinical practice, lowering levels of cholesterol could save several thousand lives at a cost similar to that of many other commonly used interventions.
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Author and Article Information
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Brigham and Women's Hospital, Boston, MA 02215-1204
1. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease. The Scandinavian Simvastatin Survival Study (4S). Scandinavian Simvastatin Survival Study Group. Lancet. 1994; 344:1383-9.
2. Shepard J, Cobbe S, Ford I, Isles C, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995; 333:1301-7.
3. Stehbens WE. Validity of the 4S simvastatin trial [Letter]. Lancet. 1995; 345:264.
4. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996; 335:1001-9.
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