New Studies Do Not Challenge the American College of Cardiology/American Heart Association Lipid Guidelines

The 2013 lipid guidelines from the American College of Cardiology and the American Heart Association broke from earlier guidelines by focusing on cardiovascular risk rather than low-density lipoprotein (LDL) cholesterol levels or targets to guide lipid treatment. However, many have called for a return to LDL cholesterol targets, citing recent evidence that nonstatin lipid-lowering medications can also reduce cardiovascular outcomes (1, 2). This evidence includes IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which found that adding ezetimibe to statin therapy decreased cardiovascular events by 6% to 7% in patients with acute coronary syndrome (3). In addition, clinical trials examining a new class of lipid-lowering agents (proprotein convertase subtilisin/kexin type 9 antibodies [PCSK9-abs]) found a relative reduction of up to 50% in cardiovascular events (4). Should this new evidence lead us to abandon risk-based approaches and return to the LDL-based, treat-to-target approach? No. In fact, this new clinical evidence, which is not based on treatment to LDL cholesterol targets, reinforces the importance of cardiovascular risk and the secondary importance of LDL cholesterol levels. The controversy surrounding this new evidence provides an opportunity to review important principles in applying clinical trial results to real-world clinical care and shows why guidelines should move away from treatment targets based on a single measure of risksuch as blood pressure or hemoglobin A1c leveland toward more global, benefit-based tailored treatment (BTT) (58). Why Is BTT More Effective Than Treatment to Targets? Benefit-based tailored treatment approaches are more effective because focusing on a single patient factor ignores the other patient and treatment factors that determine a patient's chances of benefiting from the proposed treatment. Clinical trials provide evidence about the effect of an intervention (often a medication) on the relative risk reduction (RRRRx) for a target outcome, such as cardiovascular events. Treatment, however, should be based on the best estimate of the absolute risk reduction for a particular patient (6). The BTT approach combines the trial's estimate of the RRRRx with the best available estimate of a patient's baseline risk without treatment (RiskUnRx). The product of these 2 factors provides an estimate of a patient's personalized absolute risk reduction, which can then be weighed against potential treatment harms. RiskUnRx is generally the most important factor in prioritizing patients for treatment. This baseline risk almost always varies tremendously between patients, even in seemingly homogeneous study populations (6). In addition, experience has taught us that major variation in RRRRx for the target disease is uncommon. Of note, no clinical trial has yet found that a patient's baseline LDL cholesterol level substantially affects RRRRx for any lipid treatment (9). Finally, LDL cholesterol level is a relatively minor predictor of overall cardiovascular risk (RiskUnRx), explaining only about 7% of the variance in the risk for cardiovascular events and less than 3% for cardiovascular mortality (5). Therefore, prioritizing LDL cholesterol levels as treatment goals would focus treatment using a factor that only modestly predicts the RiskUnRx and has no proven effect on the RRRRx while largely ignoring the most important factors that influence a patient's treatment benefit: their overall RiskUnRx and the RRRRx (the relative effect of the specific medication and dose on cardiovascular events) (9). The Evidence Against LDL Cholesterol Targets Comes Down to Arithmetic Although evidence that LDL cholesterol reduction is in the causal pathway of statin treatment might seem to support a return to LDL cholesterol targets, this is a misconception. Causal factors are important in guiding treatment only to the degree that they help determine the RiskUnRx, the RRRRx, or treatment harms. Low-density lipoprotein cholesterol level has little or no demonstrated effect on any of these. In fact, the research that first suggested that using overall cardiovascular risk was better than using LDL cholesterol targets assumed that LDL cholesterol reduction is the sole mechanism of action of statins (10). Nonetheless, a BTT strategy of targeting patients with a 10-year cardiovascular risk greater than 10% for treatment was shown to be both more efficient and more effective than any treat-to-target approach, saving about 100000 more quality-adjusted life-years each year in the United States (10). Ezetimibe Trials Further Support Elimination of LDL Cholesterol Targets Benefit-based tailored treatment predicts that patients with very high cardiovascular risk are the most likely to benefit from further reductions in LDL cholesterol level and that the degree of LDL cholesterol elevation has little importance (5). That is exactly what the new ezetimibe trials foundthe benefit was shown for the very-high-risk patients with acute coronary syndrome despite their LDL cholesterol levels already being low at baseline (3). These trials provide more evidence that overall cardiovascular risk is a better predictor of benefit than the degree of LDL cholesterol elevation. What Would Make LDL Cholesterol Levels Important Again? A patient's LDL cholesterol level could become more relevant if future research shows that the relative effect of the lipid medication (RRRRx) on cardiovascular outcomes varies substantively by pretreatment LDL cholesterol level, and more attention to this issue seems warranted (9). If such evidence arises, the effect of LDL cholesterol level on the RRRRx could become an important secondary factor to consider when estimating net treatment benefit. How Could BTT Influence Medical Care? The advantage of the BTT approach goes beyond lipid treatment, making it particularly important to provide a counterargument to persons lobbying for a return to LDL treatment goals. Other clinical decisions for which BTT has proved to be useful include aneurysm repair; chemotherapeutic regimens; carotid endarterectomy; diabetes control; fibrinolytic therapy; and, more recently, blood pressure treatment (58, 10). The concept is simple: Focus on using individual-level estimates of baseline risk for the outcome (RiskUnRx) along with trial-guided measures of the RRRRx to estimate a patient's expected absolute benefit. This can then be weighed against the safety, adverse effects, and burden of the treatment, with consideration of individual-patient circumstances and preferences (58, 10)tradeoffs that, for the new cholesterol drugs, are not as well-understood. Conclusion The evidence that reducing LDL cholesterol is a shared effect of statins, ezetimibe, and PCSK9-abs is compelling evidence that LDL cholesterol lowering itself reduces cardiovascular events. However, this new evidence in no way supports the argument that we should return to LDL cholesterol targets. The American College of Cardiology's response to such arguments is exactly as it should be: These new medications are most appropriate for patients at very high cardiovascular risk.