As it turns out the PCSK9 inhibitor saga ends not with a bang but a whimper. The results of the highly anticipated FOURIER trial show that the drugs work, though not as powerfully as many had hoped and expected. The question now will be whether the modest efficacy of the drugs is worth their immodest cost, at least for the vast majority of patients who are not at extreme high risk for cardiovascular disease.
Now the FOURIER trial will allow much more precise calculations of the drugs’ benefits. In the trial, which was presented today at the American College of Cardiology meeting in Washington, DC and published simultaneously in the New England Journal of Medicine, 27,564 patients with CV disease and LDL levels above 70 mg/dl already receiving statins were randomized to evolocumab or placebo. At 48 weeks LDL fell by 59%, from 92 mg/dl at baseline to 30 mg/dl
The primary end point, which was the composite of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization, was reduced by 15%, from 11.3% (1,563 patients) to 9.8% (1,344 patients) (hazard ratio 0.85, CI 0.79-0.92, p <0.001).
The key secondary endpoint, the more rigorous composite of CV death, MI, or stroke, was reduced by 20%, from 7.4% (1,013 patients) to 5.9% (816 patients) (HR 0.80, CI 0.73-0.88, p<0.001). The investigators reported that the findings were consistent across subgroups, including those with very low LDL levels at baseline. There were no significant differences in adverse events, including new onset of diabetes and neurocognitive events, though there were more injection site reactions in the active treatment group.
The investigators also reported an improvement over time. The risk reduction in the primary endpoint increased from 12% in the first year to 19% afterwards and for the secondary endpoint from 16% to 25%. Referring to this observation, the panel chair at the presentation in Washington, Valentin Fuster (Mt. Sinai) said that “the future is brighter than the present.”
There was no significant difference in cardiovascular death or all-cause mortality. The difference in the primary endpoint was achieved through the absolute reductions of 1.5% in coronary revascularization (reduced from 7% to 5.5%), 1.2% in MI (from 4.6% to 3.4%), and .4% in stroke (from 1.9% to 1.5%).
The authors calculated that 74 patients would need to be treated for 2 years to prevent a CV death, MI, or stroke. At the ACC Marc Sabatine, the PI of FOURIER, said that the NNT at 3 years was 50.
What does it mean?
Experts with whom I spoke agreed the trial successfully demonstrated clinical benefit with the drug, but they were less certain about the general importance of this benefit. And they were concerned by the modest size of the risk reduction and the lack of any signal of a mortality benefit. But all agreed that that trial represents a remarkable and positive example of the rapid translation of genetic research to clinical therapeutics.
Sek Kathiresan (Broad Institute) said that his take-home message was that “treating with a PCSK9 inhibitor to get LDL to ultra-low levels will prevent a recurrent heart attack or stroke. But,” he asked, “at what cost?”
James Stein (University of Wisconsin) said that he sees the result as “an extra base hit in the late innings of a tight baseball game.” The results validate the LDL hypothesis and the reduction in MI and strokes in particular represents welcome news to his patients, but, he acknowledged, “the bigger question is going to be the economics of it because these drugs are so darn expensive.”