Although statins remain the gold standard for primary prevention of cardiovascular disease, the number needed to treat (NNT) is huge: 500 to prevent one additional death at five years for those with a 10 percent 10-year risk of atherosclerotic cardiovascular disease (ASCVD). Moreover, intolerance mostly due to myopathies makes statin discontinuation fairly common. Bempedoic acid is a new statin-like lipid lowering agent which avoids activation in muscle tissue and is speculated to cause fewer muscle-related adverse effects. Bempedoic acid statin alternative seems to reduce LDL in previous trials, but it’s unclear if this translates to reduced cardiovascular events.

The CLEAR Outcomes trial just published in NEJM evaluated the effects of bempedoic acid on cardiovascular outcomes in 13,970 statin-intolerant adults at high risk for cardiovascular disease who were randomized to either bempedoic acid 180 mg daily or placebo. Participants were allowed to take other lipid lowering drugs. After at least three years of follow up, the primary composite endpoint of death, stroke, myocardial infarction (MI), or revascularization occurred in fewer patients getting bempedoic acid than placebo (hazard ratio 0.87). When these outcomes were analyzed independently, there was a significant reduction in fatal and nonfatal MI and coronary revascularization but not in fatal or nonfatal stroke, cardiovascular mortality, or all-cause mortality between the groups. Myalgias were similar between groups but participants in the bempedoic acid group experienced more frequent gout, cholelithiasis, and elevations in serum creatinine, uric acid, and/or liver enzymes.

Trials of cardiovascular interventions often use composite outcomes to increase the power by combining data from multiple endpoints. This way, the trial can be shorter and smaller. However, while all the individual outcomes contribute the same weight to the composite, not all outcomes matter to the same degree clinically — for example death and nonfatal MI. Speaking of nonfatal MIs, let us remember the recent study summarized in the EBM Focus “Death of a Surrogate” that showed nonfatal MI was not nearly an inadequate surrogate for cardiovascular heart disease, which suggests it should not be part of composite outcomes representing cardiovascular death. Here, although the composite was reduced with bempedoic acid, the individual outcome of mortality was unaffected when analyzed independently.

This trial contains other major threats to validity. First, the protocol was changed six times. Changes to the primary and secondary outcomes after review of interim data bias results in favor of the intervention. In addition, prior to randomization, eligible participants completed a one-week run-in period of daily single-blind placebo and were excluded from the trial if adherence was less than 80 percent, subjecting the results to adherence bias, which also favors the intervention and limits generalizability to a real-world population. The study was also funded by the drug developer, which is hard to avoid these days but nonetheless introduces more bias in favor of the intervention. Taken together, the “composite” impact of all of these potential sources of bias is a likely overestimation of magnitude of benefit, making it difficult to trust the study outcomes and authors’ conclusions. A change in practice involving bempedoic acid as a statin alternative is not justified based on this trial alone.


Practice Point: Bempedoic acid, a new statin alternative, reduces LDL but its true effects on cardiovascular outcomes remain uncertain.

EBM Pearl: Protocol amendments introduce bias, especially when based on interim analysis of trial data.

Reference: N Engl J Med. 2023 Mar 4

For more information, see the topic Hypercholesterolemia in DynaMed.