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.

FOURIER（高风险受试者中 PCSK9 抑制的进一步心血管结果研究）试验旨在研究 evolocumab 治疗的心血管结果。该试验在中位随访 2.2 年（而非计划的 3.6 年）后终止。我们质疑这个决定。据调查人员称，事件发生率比预期高出 50%。然而，关键次要事件的累计数量（1829 件）仅比目标数量（1630 件）高出 12%。此外，大约三分之一的事件包括非动脉粥样硬化性心肌梗塞、出血性中风以及与心肌梗塞或中风无关的心血管死亡。此外，在试验进行到一半时，样本量从 22,500 变为 27,500，尽管目标事件数量的增长已步入正轨。最后，经过两年的随访，全因死亡率开始出现向安慰剂倾斜的趋势。在 > 2.5 年随访的参与者中，evolocumab 为 4.8%，安慰剂为 4.3%。长期随访将产生更多事件，从而更有能力评估 evolocumab 对全因死亡率的影响。我们的结论是，适应性设计具有假阳性疗效结果的公认风险，但假阴性安全结果的风险却被低估。