When Clinical Trials Fail to Reduce Heart Disease

The top-line news that the HORIZON trial failed to show that lowering lipoprotein(a) [Lp(a)] reduces cardiovascular events, including heart attacks and strokes, got me thinking about the many clinical trials over the past several decades that have surprisingly failed to produce the results we anticipated. Importantly, clinical trialists embrace the concept of equipoise: genuine uncertainty about whether a treatment will ultimately help or harm patients. In that sense, an “unsuccessful” or negative trial is not necessarily a failure of science—it is the scientific process working as intended. Consider CAST (Cardiac Arrhythmia Suppression Trial), in which drugs that successfully suppressed premature ventricular contractions after a heart attack unexpectedly increased mortality, apparently because of their proarrhythmic effects. As the famous pharmacologic aphorism goes, “Drugs are poisons with occasional beneficial side effects.” We saw similar surprises more recently. AIM-HIGH failed to show that raising HDL cholesterol with niacin reduced cardiovascular events, despite substantially increasing HDL levels. PROMINENT demonstrated that substantially lowering triglycerides with pemafibrate did not reduce cardiovascular events. STRENGTH found that a high-dose combination of EPA and DHA failed to reduce major cardiovascular events. And most recently, ZEUS found that ziltivekimab successfully inhibited the IL-6 inflammatory pathway and lowered hsCRP, but this biological effect did not translate into a reduction in heart attack, stroke, or cardiovascular death.

These unexpected results are a sobering reminder of why randomized clinical trials are indispensable. Epidemiologic and observational studies help us identify associations and generate important hypotheses; randomized clinical trials test whether modifying those factors actually changes clinical outcomes. The distinction is critical: an association does not necessarily establish causation, and changing a biomarker does not necessarily improve a patient’s prognosis. HORIZON therefore represents an important test of the Lp(a) hypothesis, even though its top-line result was disappointing. We will need to see the full data before drawing final conclusions about how deeply Lp(a) must be lowered, for how long, and in which patients. Fortunately, cardiovascular medicine also provides numerous examples where the biology has been repeatedly validated in randomized trials. In the cholesterol arena, statins, ezetimibe, and PCSK9 inhibitors have consistently demonstrated that lowering LDL cholesterol reduces cardiovascular events in high risk individuals. And in appropriately selected patients with elevated triglycerides and residual cardiovascular risk, purified EPA (icosapent ethyl) has demonstrated cardiovascular benefit. The lesson is not that negative trials are failures—they keep us honest, challenge attractive hypotheses, and ultimately make cardiovascular medicine better. The best clinical trials don’t simply confirm what we believe, they tell us when we are wrong.

Michael Miller, MD, MASPC, FACC, FAHA, FNLA, is a cardiologist and Professor of Medicine at the Hospital of the University of Pennsylvania and Chief of Medicine at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia. He is President of the American Board of Clinical Lipidology and Deputy Editor of the Journal of Clinical Lipidology, the flagship publication of the National Lipid Association. A nationally recognized expert in preventive cardiology and lipidology, Dr. Miller has spent his career examining what really works and what doesn’t in the prevention of cardiovascular disease.

Learn more at www.drmichaelmiller.net