http://www.annals.org/content/145/7/520.full
Abstract
Recent national recommendations have proposed that physicians should titrate lipid therapy to achieve low-density lipoprotein (LDL) cholesterol levels less than 1.81 mmol/L (<70 mg/dL) for patients at very high cardiovascular risk and less than 2.59 mmol/L (<100 mg/dL) for patients at high cardiovascular risk. To examine the clinical evidence for these recommendations, the authors sought to review all controlled trials, cohort studies, and case–control studies that examined the independent relationship between LDL cholesterol and major cardiovascular outcomes in patients with LDL cholesterol levels less than 3.36 mmol/L (<130 mg/dL).
For those with LDL cholesterol levels less than 3.36 mmol/L (<130 mg/dL), the authors found no clinical trial subgroup analyses or valid cohort or case–control analyses suggesting that the degree to which LDL cholesterol responds to a statin independently predicts the degree of cardiovascular risk reduction. Published studies had avoidable limitations, such as a reliance on ecological (aggregate) analyses, use of analyses that ignore statins' other proposed mechanisms of action, and failure to account for known confounders (especially healthy volunteer effects). Clear, compelling evidence supports near-universal empirical statin therapy in patients at high cardiovascular risk (regardless of their natural LDL cholesterol values), but current clinical evidence does not demonstrate that titrating lipid therapy to achieve proposed low LDL cholesterol levels is beneficial or safe.
Key Summary Points
No high-quality evidence could be found that suggests that titrating lipid therapy to recommended low-density lipoprotein (LDL) cholesterol targets is superior to empirically prescribing doses of statins used in clinical trials for all patients at high cardiovascular risk.
Studies addressing benefits of achieving LDL cholesterol goals have had avoidable problems, such as reliance on ecological (aggregate) analyses, ignoring statins' other proposed mechanisms of action, and not accounting for known confounders (especially healthy volunteer effects).
Much more reliable evidence on currently proposed LDL cholesterol goals could be expeditiously produced by conducting cohort analyses of past statin trials that control for statin dose and pill adherence.
Dichotomous comparisons (such as comparing those who reach goal vs. those who do not) can mistakenly suggest that not achieving the treatment goal results in moderate risk when in fact almost all of the risk is caused by large deviations from the ideal goal.
Proposals for treatment goals should also consider the risks, patient burden, and societal costs of the treatments that may be needed to reach those goals.
In 2004, a National Cholesterol Education Program (NCEP) expert panel recommended that physicians titrate lipid therapy to reach a low-density lipoprotein (LDL) cholesterol level less than 1.81 mmol/L (<70 mg/dL) in patients at very high risk for cardiovascular events (1, 2). The panel stated that consistent and compelling evidence showed a strong relationship between LDL cholesterol level and cardiovascular outcomes down to this level (1, 2). However, others have reviewed the same literature and have concluded that there is no valid evidence from clinical trials (see Glossary) supporting this conclusion (3, 4). Since the early 1900s, we have known that familial hyperlipidemia syndromes result in premature cardiovascular disease, and in the United States and northern Europe, cohort studies have usually found that LDL cholesterol is a major independent cardiovascular risk factor at levels above 3.75 mmol/L (>145 mg/dL) (5, 6). However, these studies had limited ability to assess whether this relationship continued at lower LDL cholesterol levels, and some suggested that this association was less marked as LDL cholesterol level approached 3.36 mmol/L (130 mg/dL), especially when high-density lipoprotein cholesterol levels were normal (7,
. Furthermore, studies in southern Europe, where LDL cholesterol levels tend to be lower in general, have often found a less strong association than those conducted in northern Europe, even in the moderate LDL cholesterol range (3.36 to 4.14 mmol/L [130 to 160 mg/dL]) (7, . In addition, studies in Asia and in elderly persons have often found no decrease or even an increase in cardiovascular risk when LDL cholesterol level drops below 3.36 mmol/L (130 mg/dL) (9). These results raised questions about whether the strong association found at higher levels of LDL cholesterol could be extended to lower LDL cholesterol levels; they also raised concerns that total LDL cholesterol is an unreliable marker of benefit and may be confounded by dietary factors or LDL subparticles that are the true causal factors (7–11).These concerns seemed to be allayed when multiple clinical trials showed that statin therapy dramatically decreased cardiovascular events in almost all groups at high risk and that this benefit extended to those with pretreatment LDL cholesterol levels of 2.33 to 2.59 mmol/L (90 to 100 mg/dL) (1, 2, 12–17). Several recent trials have also shown greater benefits for high-dose statin therapy compared with low to moderate doses for those with acute coronary syndromes (14, 17) and known coronary artery disease (15, 16) (although the results in the IDEAL [Incremental Decrease in Endpoints Through Aggressive Lipid Lowering] study [16], in which participants had stable coronary artery disease, did not reach statistical significance). However, these studies generally used fixed doses of statins (placebo vs. statin or low-dose vs. high-dose statin) and therefore cannot directly shed light on whether clinicians should prescribe the doses used in the studies or titrate lipid therapy to achieve recommended LDL cholesterol goals.
This is particularly relevant because statins do much more than decrease LDL cholesterol levels. Although strong mechanistic evidence supports the LDL hypothesis, strong basic science evidence (18) also suggests that the effects of statins on inflammation, thrombosis, and oxidation are plausible mechanisms for mediating the benefits of statin therapy (often referred to as “pleiotropic effects”) (Appendix Table 1). Indeed, some statin trials seem to run counter to the LDL hypothesis. For example, trials have found that statins substantially reduce the risk for stroke, which is more consistent with their hypothesized antithrombotic effects than with their LDL-lowering effects (high LDL levels are not a major independent risk factor for stroke) (19). In addition, a recent large statin trial conducted in patients receiving dialysis found no substantial benefit despite reductions of 42% in LDL cholesterol levels (20), suggesting that even dramatic reductions are not always associated with clinically significant lowering of cardiovascular risk.
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Appendix Table 1. Known Lipid-Independent Effects of Statins*Graphic
For clinicians and patients, this issue is much more than an academic debate. Compared with empirically treating patients at high cardiovascular risk with statin doses similar to those used in clinical trials, titrating lipid therapy to recommended LDL cholesterol goals entails considerably greater clinical complexity, frequent use of multidrug therapy, and greater societal and patient out-of-pocket costs; these, in turn, can result in increased patient burden and lower adherence to all treatments (21–23). Fewer than half of those receiving high doses of statins in clinical trials have achieved LDL cholesterol levels less than 1.81 mmol/L (<70 mg/dL) (15–17), and it is unclear whether achieving this goal is truly feasible even if multidrug therapy is used. Most important, if reducing total LDL cholesterol to very low levels is not truly the dominant beneficial mechanism of statin therapy, pursuit of such values using multidrug therapy could result in net harm to patients (22). This concern may be heightened by recent clinical trials suggesting that some treatments that “improve” lipid profiles, such as hormone replacement therapy and muraglitazar, actually increase cardiovascular risk (24–26).
In this paper, we examine the clinical evidence for and against recommended treatment goals for LDL cholesterol levels and outline an approach by which the benefits of these and other proposed treatment goals may be better assessed in the future.
