FOURIER: Is evolocumab worth the cost?
ACC.17 Late breaking clinical trial: Primary results of the further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER) trial
Reported from the American College of Cardiology 2017 Scientific Sessions in Washington.
While the initial idea of this short report series from ACC was to focus on interventional trials, it is impossible not to start with FOURIER, which actually deals with secondary prevention. Reasons for the opportunity to do so are manifold. First, FOURIER has been announced in the previous weeks as a positive study but with no mention of the treatment effect of the investigational drug, a PCSK9 inhibitor. Second, with its >27,000 patients, the study is what we can reasonably call a “mega-trial”. Some may argue that such number of patients tends to over-power the comparison for the primary endpoint - thus providing statistically significant differences for small absolute risk effects.
Is it the case for FOURIER? The devil is in the details.
FOURIER randomized patients with cardiovascular disease (more than 80% with a previous myocardial infarction) and LDL cholesterol ≥70 mg/dL to evolocumab or placebo. About 70% of patients was on a high-intensity treatment with statins, the remainder being on a moderate-intensity statin regimen. At a median follow-up of 26 months, the number needed to treat with evolocumab to avoid a primary endpoint (cardiovascular death, MI, stroke, hospitalisation for unstable angina, or coronary revascularisation) was 67 (9.8% vs 11.3%; P<0.001, corresponding to a 15% reduction). The secondary endpoint (cardiovascular death, MI, or stroke) was also significantly reduced (5.9% vs 7.4%; P<0.001, corresponding to a 20% reduction) with evolocumab compared with placebo. There was no difference in cardiovascular mortality, but this endpoint was generally low in both groups, which makes difficult to find a difference. Also, the Kaplan-Meier curves suggest accrual of the treatment effect over time, which could theoretically makes mortality significantly reduced, and combined endpoint associated with an even lower number needed to treat at a later follow-up. Importantly, no significant safety issues were observed at the study follow-up.
What are the implications of FOURIER?
First, the LDL hypothesis (the lower the better) is alive. Second, is a therapy that does not save lives but reduces nonfatal events justified in view of its considerable costs? Cost-effectiveness analyses are underway to corroborate such hypothesis. Third and foremost, even in the evolocumab arm, the rate of the primary endpoint in patients with cardiovascular disease, at a relatively short follow up, was as high as about 10%: this reminds us that there is still ample room for improving the outcomes of secondary prevention.