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COMMENTARIES |
The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York.
Address correspondence to Ira S. Nash, MD, The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, Box 1030, 1 Gustave L. Levy Place, New York, NY 10029. E-mail: ira.nash{at}msnyuhealth.org
In this issue of the Journal of Gerontology: Medical Sciences, Aronow asks if the 1999 National Cholesterol Education Project Adult Treatment Panel III (NCEP-ATP III) guidelines for cholesterol management (1) should be changed for "elderly and younger persons at high risk for cardiovascular disease" (2) and then answers in the affirmative. His assessment is based principally on the review of recent, large-scale clinical trials that have demonstrated benefits with lipid-lowering among patients whose pretreatment low density lipoprotein (LDL) cholesterol levels were at or near current treatment targets.
Ratcheting down lipid treatment targets for specific populations rests on fulfilling three criteria: 1) demonstrating that lower levels of blood lipids lead to better cardiovascular outcomes; 2) demonstrating that the lower targets are achievable and not associated with negative noncardiovascular effects; and 3) demonstrating that these findings pertain to the particular population of interest—in this case, elderly people and those persons at high risk.
The clinical trial data cited by Aronow are compelling. The Heart Protection Study (3), PROVE IT–TIMI 22 (4), and ASCOT–LLA (5) all demonstrated incremental reductions in coronary heart disease endpoints with lowering LDL cholesterol below the NCEP-ATP III targets. The findings of PROVE IT were particularly striking. Over 4000 patients were randomized to receive either 80 mg of atorvastatin or 40 mg of pravastatin after an acute coronary event. The pravastatin group achieved a median LDL cholesterol of 95 mg/dl, which was below the NCEP ATP III target of 100 mg/dl, but still had a statistically significantly higher incidence of CHD endpoints than the atorvastatin group, in which the median LDL cholesterol was only 62 mg/dl.
These trials, and others with intermediate endpoints such as plaque volume (6) or intima-medial thickness (7), have demonstrated that high-dose statin treatment can routinely achieve LDL cholesterol levels that, until recently, would have been considered strikingly low. Other studies have achieved similar lipid levels with combination pharmacotherapy (8). Despite the fact that LDL cholesterol levels below 70 mg/dl are rare in the industrialized West, accumulating evidence suggests that they may approximate the true human "normal" (9,10). Such levels are consistently associated with lower cardiovascular risk, and there are no data to suggest that cholesterol levels this low predispose to other, nonvascular pathology (11,12). While "there must be lower limits to ... physiologic variables ... these lower limits are ... beyond Western values and not reached by current dietary or drug interventions" (10).
Do these findings pertain to elderly persons and high-risk younger individuals? Several lines of evidence suggest strongly that they do. First, clinical trials have shown consistent benefit across subgroups that vary by age and baseline risk. Second, statins, the principal class of lipid-lowering agents, are generally quite safe, even in elderly persons (13). Finally, perhaps the most convincing support comes from a provocative analysis of risk factors for coronary and other diseases by Law and Wald (10). They analyzed the "dose response" between cholesterol levels and ischemic heart disease and concluded that the data best fit a straight line when the logarithm of mortality was plotted on the vertical axis and absolute value of serum cholesterol was plotted on a linear horizontal axis. A relationship of this sort implies that risk can be reduced by a constant percentage by a given reduction in cholesterol, regardless of the absolute value of the starting (pretreatment) cholesterol level. The logical conclusions of this observation are profound: Patients at high risk have a higher absolute benefit from treatment, and treatment should be based on patient risk, not on the pretreatment levels of any particular risk factor. Since advanced age is itself an extremely important risk factor for the development of coronary disease (14), it follows that elderly people, or those at high risk on the basis of nonlipid characteristics, are particularly likely to benefit from aggressive lipid-lowering strategies, even if their pretreatment levels are acceptable by current guidelines.
When the risk is high, aim low.
References
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