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

Abstract

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.

Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality

“…Although very low levels of non-HDL cholesterol are related to a reduction in cardiovascular disease events, 24,25 some observations point toward higher all-cause mortality among participants with very low levels, at least in longer-term follow-up. 26 In contrast to what was previously reported, 3 body-mass index and current smoking (at least in some parts of the world) were associated with comparatively modest populationattributable fractions of cardiovascular disease events in the populations participating in the Global Cardiovascular Risk Consortium. These associations may be related to underlying differences in population characteristics, risk-factor definition and prevalence, or methods used to estimate population-attributable fractions.…”

Antithrombotic therapy and bleeding risk in the era of aggressive lipid-lowering: current evidence, clinical implications, and future perspectives

“…Notably, according to data derived from ClinicalTrial.gov, in the FOURIER trial on participants with 3 years of follow-up, the cumulative all-cause mortality rate was 4.75% for the evolocumab group and 4.28% for the placebo group [Figure 1 ]. [ 24 ] Data derived from the ClinicalTrial.gov for a total of 33 lipid-lowering and four outcome trials showed that PCSK9i even did not reduce myocardial infarction nor stroke/transient ischemic attack compared with placebos. [ 25 ]…”

“…Notably, according to data derived from ClinicalTrial.gov, in the FOURIER trial on participants with 3 years of follow-up, the cumulative all-cause mortality rate was 4.75% for the evolocumab group and 4.28% for the placebo group [Figure 1]. [24] Data derived from the ClinicalTrial.gov for a total of 33 lipid-lowering and four outcome trials showed that PCSK9i even did not reduce myocardial infarction nor stroke/transient ischemic attack compared with placebos. [25] Apart from the ODYSSEY OUTCOMES trial on patients who had an ACS 1 to 12 months earlier, there is limited real-world evidence of the impact of PCSK9i therapy on cardiovascular outcomes in patients with a very high risk of ASCVD (as defined by at least two severe ASCVD events or one severe event combined with at least two high-risk factors).…”

“…Note that recent population-based cohort studies from Denmark, [27] Korea, [28] China, [29] and US [30] demonstrated a U-shaped The conception to use data from ClinicalTrials.org to draw this figure was first reported in a commentary article by van Bruggen and Luijendijk. [24] FOURIER: Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; PCSK9: Proprotein convertase subtilisin/kexin type 9.…”

“…The data can be accessed from ClinicalTrials.org (https:// clinicaltrials.gov/ct2/show/results/NCT01764633; in "4. Secondary Outcome" Section).The conception to use data from ClinicalTrials.org to draw this figure was first reported in a commentary article by van Bruggen and Luijendijk [24]. FOURIER: Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; PCSK9: Proprotein convertase subtilisin/kexin type 9.…”