FOURIER Trial Data Questions: Are PCSK9 Inhibitors The Right Choice?
Questions surround the use of expensive PCSK9 inhibitors as long-term therapy for atherosclerotic CVD.
Editor's Note: The original version of this article was updated to clarify that the study's primary or secondary endpoint was not cardiovascular mortality. Because cardiovascular mortality was not an endpoint, the study did not "fail." It was successful in showing a risk reduction in composite endpoints. The original article emphasized the lack of mortality data, but ignored the improvement in composite endpoints. The article was updated on April 17, 2017, to reflect this.
In 2005, a loss-of-function mutation was found, supporting the concept that inhibitors of the enzyme could help lower LDL cholesterol and consequently reduce atherosclerotic cardio-vascular events.
Monoclonal antibodies to PCSK9 are now available to treat patients at high atherosclerotic risk — either due to familial hypercholesterolemia with intact LDL receptors who would have otherwise needed plasmapheresis, or because of having LDL levels far above guideline limits despite maximal therapy with moderate- or high-intensity statins. However, data supporting clinical outcomes with PCSK9-inhibitor use is lacking.
Prior studies have shown that patients with angiographically established CAD who were already on chronic statin therapy and were randomized to receive treatment with PCSK9 inhibitors had significant plaque regression compared to the placebo group.1 However, translating those findings into clinical benefits on hard endpoints — such as cardiovascular death — has been difficult.
Results of the FOURIER trial were recently published in The New England Journal of Medicine, and the findings were presented at the American College of Cardiology 66th Annual Session & Expo (ACC.17) with mixed reviews.2
The goal of the trial was to provide some of the much-needed evidence regarding the risk reduction of cardiovascular events attributable to the addition of PCSK9 inhibitors to guideline-directed antilipid therapies, and to evaluate for potential side effects of very low LDL levels.
The study was funded by Amgen. A total of 27,564 individuals from 49 countries who had established atherosclerotic cardiovascular disease and LDL levels greater than or equal to 70 mg/dl, and who were already on statin therapy, were randomized to receive either evolocumab or a placebo.
Participants were monitored for a median follow-up period of only 2.2 years, despite original plans for 4 years of follow-up due to higher than expected event rates in the primary and secondary end-points.
The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The secondary endpoint was also a composite — cardiovascular death, myocardial infarction, or stroke.2
Greater than 80% of the patients enrolled had a prior myocardial infarction, and there were no significant differences between the placebo and evolocumab groups for the demographic characteristics reported. Further, 69% of the patients enrolled were already on high-intensity statin therapy and another 30% were on moderate-intensity statin therapy.
There was clearly a significant drop in the mean LDL from 92 mg/dL at baseline to 30 mg/dL in the evolocumab group. The authors also report significant decreases in both the primary and secondary composite endpoints from 11.3% and 7.4% in the placebo groups to 9.8% and 5.9% in the evolocumab groups respectively.2