Evolocumab's Long-Term Mortality Risk Unclear Due to Shortened Follow-Up of FOURIER

The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 inhibition in Subjects with Elevated Risk) trial was conducted to study cardiovascular outcomes of treatment with evolocumab. The trial was terminated after a median follow-up of 2.2 years instead of the planned 3.6 years. We question this decision. According to the investigators, the event rate was 50% higher than expected. However, the accrued number of key secondary events (1829) was only 12% higher than the targeted number (1630). Also, around one-third of the events consisted of non-atherosclerotic myocardial infarctions, hemorrhagic strokes, and cardiovascular deaths unrelated to myocardial infarction or stroke. Moreover, halfway through the trial, the sample size changed from 22,500 to 27,500, even though the accrual of the targeted number of events was on track. Finally, the rate of all-cause mortality had started to diverge in favor of placebo after 2 years of follow-up. It was 4.8% for evolocumab and 4.3% for placebo in participants with > 2.5 years of follow-up. A long-term follow-up would have yielded more events and thus more power to evaluate the effect of evolocumab on all-cause mortality. We conclude that adaptive designs carry a recognized risk of false-positive efficacy results, but the risk of false-negative safety results is underappreciated.