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Thursday, January 19, 2012

There Is No Scientific Basis to Support Treating to LDL Targets

 
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There Is No Scientific Basis to Support Treating to LDL Targets

First, no major randomized clinical trial (RCT) has tested the benefits of treating patients according to LDL targets.5 The clinical trials tested fixed doses of drugs that lower lipid levels in specific patient populations. In some of these trials, drugs were shown to reduce risk (eg, statins), but in others, this reduction in risk was not demonstrated (eg, clofibrate and torcetrapib). Other drugs, such as ezetimibe, remain to be tested. The trials do not demonstrate that all drugs that reduce lipid levels reduce patient risk. Thus, the dogma that treating to target is based on clinical trial evidence belies the fact that no clinical trial has yet tested this strategy.
                       
As noted above, trials show that not all drugs that improve lipid profiles reduce patient risk. In fact, almost all the trial evidence for patient benefit is for a single medication class—statins—that is known to have multiple biological activities that are often referred to as “pleiotropic” effects. Standard doses of the first generation of statins, such as simvastatin, dramatically reduce cardiovascular events and mortality. High-potency statins, such as atorvastatin, reduce nonfatal events by an additional 15–20%. Thus, the trial evidence indicates that the use of statins, and not treatment to target, can reduce risk. Although the mechanism(s) by which statins exert their benefit is controversial, one does not need to impugn the cholesterol hypothesis to recognize that different lipid-lowering drugs could possibly have deleterious effects that offset their potential benefit. Further, it is quite possible that a surrogate measure, such as LDL, may appear to be a single entity even though clinically important subcomponents (such as heterogeneity in particle size) or interactions (such as total cholesterol/high-density lipoprotein [HDL] ratio) may exist. Thus, we cannot assume that lowering LDL, by any means, will improve patient outcomes.

A closer look at the evidence demonstrates further reasons against basing treatment decisions on LDL levels. In considering recommendations, it is useful to recognize that there are only 2 factors that determine the benefit of a treatment for an individual patient: (1) the risks of morbidity or mortality in the absence of treatment and (2) the degree to which the treatment reduces or increases these risks.6 LDL levels are not useful in either of these areas. The LDL level contributes little to estimating cardiovascular risk overall and especially compared with non-HDL9 or total cholesterol/HDL ratio.1012 Moreover, clinical trials demonstrate that the relative effects of statin therapy are not substantially related to a patient's pretreatment LDL.13,14 It should be noted that although C-reactive protein has been demonstrated to be an independent predictor of cardiovascular risk, it is not strongly related to the relative risk reduction of statins, although the evidence is not entirely consistent.13,15,16 Thus, there is strong scientific evidence that LDL is not a very useful factor in determining who is at risk for cardiovascular disease or how much that risk will be reduced by a statin.

The conclusion that the evidence does not support a target-based approach may seem counterintuitive to those whose work has been focused on the biology of cardiovascular disease mechanisms, but the science of clinical decision-making requires a different approach. The critical component of good clinical decision-making is not the scientific evidence regarding disease pathogenesis or treatment mechanisms but rather the best empirical predictors of patient risk and factors that reduce risk, the 2 elements that help determine the risks and benefits of a treatment in individual patients.6,7 As has been demonstrated conclusively, it does not matter whether LDL is the sole biological mechanism mediating the treatment benefits of statins. What matters is that LDL does not appreciably help predict a patient's cardiovascular risk or a statin's relative risk reduction and therefore provides a poor premise on which to base treatment recommendations. Beyond statins, we must extend our concern to the question of whether treatments might be harmful and not just whether they may or may not be effective.                       
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