Data for a new drug that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) show that it is associated with a near 60% reduction in low-density lipoprotein (LDL) cholesterol and a significant reduction in cardiovascular events—making evolocumab (Repatha, Amgen) the first PCSK9 inhibitor to be associated with a reduction in hard cardiovascular outcomes. However, the drug was not associated with a reduction in cardiovascular mortality.
Writing in The New England Journal of Medicine, Marc S Sabatine (Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medicine School, Boston, USA) and others report that PCSK9 inhibitors have “emerged as a new class of drugs that effectivey lower LDL cholesterol levels” but add that data for the effect of these drugs on cardiovascular outcomes are limited. The FOURIER (Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk), therefore, was a dedicated cardiovascular outcomes trial that, Sabatine et al report, “tested the clinical efficacy and safety of evolocumab when added to high-intensity statin therapy in patients with clinically evident atherosclerotic cardiovascular disease”.
In the study, 27,564 patients were randomised to receive usual treatment (statin therapy) plus evolocumab (13,784) or usual treatment plus placebo (13,780). Overall, the mean age of the patients was 63 years, 24.6% were women, and 81.1% had a history of myocardial infarction. The primary endpoint was major cardiovascular events, defined as cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina, or coronary revascularisation.
At 48 weeks, evolocumab plus usual care was associated with a significant reduction in the risk of the primary outcome: 9.8% vs. 11.3% for usual care plus placebo (p<0.001). There was also a significant reduction in risk of the key secondary composite endpoint—cardiovascular death, myocardial infarction, and stroke—with evolocumab plus usual care (5.9% vs. 7.4%, respectively; p<0.001). The authors report: “The magnitude of the risk reduction with regard to the primary endpoint tended to increase over time from 12% in the first year to 19% beyond the first year. Likewise, for the key secondary endpoint, the risk reduction increased from 16% in the first year to 25% beyond the first year”.
However, when the individual components of the primary endpoint were assessed, the PCSK9 inhibitor was not associated with a significant reduction in cardiovascular mortality: 1.8% vs. 1.7% (p=0.62). According to Sabatine et al, the lack of benefit on cardiovascular mortality means that the p valves for the other components “should be considered exploratory”. There were no significant differences between groups in the rate of all-cause death, but usual care plus evolocumab was associated with a significant reduction in myocardial infarction (3.4% vs. 4.6%, respectively; p<0.001) and coronary revascularisation (5.5% vs. 7%, respectively; p<0.001) compared with usual care and placebo.
As in previous studies of evolocumab, the drug was associated with a near 60% (59%) reduction in LDL cholesterol compared with placebo (p<0.001 for the difference). “At 48 weeks in the evolocumab group, the LDL cholesterol level was reduced to 70mg per deciliter (1.8mmol per liter) or lower in 87% of patients,” the authors report. They add that these data “provide insight into the benefit of decreasing LDL cholesterol to median levels lower than those in previous trials”. “These findings show that patients with atherosclerotic cardiovascular disease benefit from the lowering of LDL cholesterol below current targets,” the authors conclude.
Sabatine presented the results of FOURIER during a late-breaking trial session of the 2017 scientific sessions of the American College of Cardiology (17–19 March, Washington, DC, USA).