Reference: N Engl J Med. 2023 Mar 4 early online
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.
Although statins remain the gold standard for primary prevention of cardiovascular disease, the NNT is 500(!) to prevent one additional death at 5 years for those with a 10% 10-year risk of ASCVD. Moreover, intolerance mostly due to myopathies makes statin discontinuation fairly common. Bempedoic acid (BA) is a new statin-like lipid lowering agent which avoids activation in muscle tissue and is speculated to cause fewer muscle-related adverse effects. BA 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 BA on cardiovascular outcomes in 13,970 statin-intolerant adults at high risk for cardiovascular disease who were randomized to either BA 180 mg daily or placebo. Participants were allowed to take other lipid lowering drugs. After at least 3 years of follow up, the primary composite endpoint of death, stroke, MI, or revascularization occurred in fewer patients getting BA 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 BA 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 BA, 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 1-week run-in period of daily single-blind placebo and were excluded from the trial if adherence was less than 80%, 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 BA as a statin alternative is not justified based on this trial alone.
For more information, see the topic Hypercholesterolemia in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Nicole Jensen, MD, Family Physician at WholeHealth Medical. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, Deputy Editor at DynaMed; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; Elham Razmpoosh, PhD, Postdoctoral fellow at McMaster University; and Sarah Hill, MSc, Associate Editor at DynaMed.