Narrative Review: Lack of Evidence for Recommended Low-Density Lipoprotein Treatment Targets: A Solvable Problem

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, 8). 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, 8). 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 (711). 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, 1217). 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. Appendix Table 1. Known Lipid-Independent Effects of Statins* 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 (2123). 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) (1517), 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 (2426). 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. Methods Implicit in recommendations to pursue a specific treatment goal (such as LDL cholesterol level <1.81 mmol/L [<70 mg/dL]) is the assumption that reaching the goal is a strong predictor of the degree of patient benefit independent of all known confounders, including the treatment or treatments. Otherwise, we would simply give people the treatments used in studies. Therefore, we sought to identify studies that examined whether reaching low LDL cholesterol targets or a more substantial percentage reduction of LDL cholesterol (the 2 goals put forth in the NCEP guidelines) is a strong independent predictor of cardiovascular risk reduction. We sought to examine all controlled trials, cohort studies (see Glossary), and casecontrol studies that examined the independent association between LDL cholesterol levels and major cardiovascular outcomes in patients with LDL cholesterol levels less than 3.36 mmol/L (<130 mg/dL). We began by reviewing all of the literature cited in the 2004 NCEP expert panel report (1) that proposed the new treatment goal of less than 1.81 mmol/L (<70 mg/dL). The NCEP expert report does not note whether a formal MEDLINE review was conducted, so we also reviewed all citations from the American College of Physicians lipid guidelines (3, 4), a recent meta-analysis (2), and the Cochrane database (27). In addition, we conducted an updated MEDLINE review (1 April 2004 to 20 May 2006) using the following search: ((low density lipoprotein cholesterol OR ldl cholesterol) AND (cohort study OR casecontrol study OR case control study OR randomized, controlled study OR clinical trial) [limited to human and adults]. All abstracts of the 1214 articles produced in this search were screened by trained masters-level research associates, and all identified controlled trials, cohort studies, and casecontrol studies that reported any morbidity or mortality outcomes underwent full independent review by 2 of the authors. Finally, we contacted members of the NCEP expert panel, prominent cardiovascular clinical trialists, and experts in lipid therapy and asked whether they could identify any additional studies that met our inclusion criteria (Appendix). We began our review by examining the literature and arguments cited by the NCEP in support of its recommendation (1). Next, we reviewed all identified experimental evidence and all valid observational evidence (controlled longitudinal studies [cohort and casecontrol studies] that used a multivariable regression technique to control for all known major confounders) that met our inclusion criteria (that is, assessed the independent association between LDL cholesterol level and major cardiovascular outcomes in patients with LDL cholesterol levels <3.36 mmol/L [<130 mg/dL]). Criteria for quality ratings of eligible articles were planned by protocol but were rendered unnecessary because no studies met our minimum inclusion criteria. Therefore, we examined methodologic limitations in the studies found in our literature review. Most major problems found in the experimental literature could be classified as not considering the alter