Vorapaxar and amyotrophic lateral sclerosis: Coincidence or adverse association?

Background: Vorapaxar, a novel antiplatelet thrombin PAR-1 inhibitor, is currently approved for post myocardial infarction and peripheral artery disease indications with concomitant use of clopidogrel and/or aspirin. The vorapaxar safety profile was acceptable. However, aside from heightened bleeding risks, excesses of solid cancers and diplopia, there were more amyotrophic lateral sclerosis (ALS) diagnoses after vorapaxar. Study Question: To assess the Food and Drug Administration (FDA) reviews on the potential association of vorapaxar with ALS. Study Design: The review the public FDA records on reported adverse events after vorapaxar. Measures and Outcomes: Incidence of ALS after vorapaxar and placebo. Results: The ALS risk appears very small, about 1 case per 10,000 treated subjects, but quite probable. Indeed, there were overall 2 placebo and 4 vorapaxar ALS incidences in the Phase III clinical trials. Conclusions: Potential adverse association of vorapaxar with ALS risks may be related to off-target neuronal PAR receptor(s) blockade beyond platelet inhibition.