WASHINGTON – The PCSK9 inhibitor evolocumab reduced the incidence of the composite endpoint of cardiovascular death, MI, or stroke by an additional 20% in patients with established cardiovascular disease who were already on background maximum-tolerated statin therapy in the landmark FOURIER trial, Marc S. Sabatine, MD, reported at the annual meeting of the American College of Cardiology.
FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was eagerly anticipated as the first dedicated cardiovascular outcomes trial to report results for a proprotein convertase subtilisin/kexin type 9 inhibitor, the novel drug class that achieves previously unattainable LDL lowering.
FOURIER randomized 27,564 patients with preexisting high-risk cardiovascular disease in 49 countries to double-blind therapy with subcutaneous evolocumab (Repatha) at either 140 mg every 2 weeks or 420 mg once monthly or to placebo injections. Participants had a baseline LDL-cholesterol level of 70 mg/dL or above while on statin therapy, which continued throughout the study. Sixty-nine percent of subjects were on high-intensity statin therapy, and the rest were on a moderate-intensity statin.
The median LDL level plunged from 92 mg/dL at baseline to 30 mg/dL in the evolocumab group, a 59% reduction. Moreover, one-quarter of patients on evolocumab achieved an LDL below 20 mg/dL. And this effect remained durable over the median 26 months of study follow-up.
“The LDL reduction achieved with evolocumab was rock steady over time,” observed Dr. Sabatine, professor of medicine at Harvard Medical School, Boston, and chair of the Thrombolysis in Myocardial Infarction Study Group.
The primary study endpoint – a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization – occurred in 11.3% of controls and 9.8% of the evolocumab group, for a significant 15% relative risk reduction. But Dr. Sabatine drew attention to the prespecified and fully powered secondary endpoint of cardiovascular death, MI, or stroke, which he considers more clinically relevant: 7.4% in controls, compared with 5.9% in the evolocumab group, for a 20% reduction in risk.
The cardiovascular benefits of greater lipid lowering grew over time. The evolocumab group’s relative risk reduction in the secondary composite endpoint was 16% in the first 12 months of follow-up and 25% beyond 12 months.
Even more impressively, the relative risk reduction in the stripped-down secondary endpoint of fatal or nonfatal MI or stroke was 19% in the first 12 months and 33%, compared with placebo, beyond 12 months.
The benefit in terms of cardiovascular risk reduction was consistent across baseline LDL subgroups, including those in the lowest baseline quartile, whose average baseline LDL was 74 mg/dL. Thus, the former LDL goal of a target below 70 mg/dL as representing maximum benefit has flown out the window.
“Even lower LDL appears to be even better, now down in this trial to 22 mg/dL,” the cardiologist declared.
There was no significant difference between the two study arms in the cardiovascular mortality rate, although Dr. Sabatine didn’t consider that surprising.
“Over the past decade, none of the trials of more intensive LDL lowering when compared with patients on moderate-intensity LDL-lowering therapy showed a significant reduction in cardiovascular mortality, which thankfully is now less common after acute MI and acute stroke than it had been in the past,” he said.
The number needed to treat (NNT) in order to prevent one additional cardiovascular death, MI, or stroke, based upon the current 3-year follow-up data, is roughly 50, according to Dr. Sabatine. Projecting out to 5 years, based upon the close fit between FOURIER and the data from the Cholesterol Treatment Trialists Collaboration, the NNT at 5 years for evolocumab is about 30, although the true NNT may actually prove to be smaller than that, given the steadily increasing benefit seen through 3 years. The projected 5-year NNT for the composite of coronary revascularization, cardiovascular death, MI, or stroke drops to about 20, he added.
The treatment was safe and well tolerated. The rate of study discontinuation attributable to treatment-related adverse events was low, at about 1.5% in both treatment arms. The rates of neurocognitive adverse events, new-onset diabetes, cataracts, and muscle-related complaints didn’t differ between the evolocumab and placebo groups, either. Of note, no one developed neutralizing antibodies to evolocumab. Long-term follow-up will continue in roughly 6,000 FOURIER participants.
Discussant Pamela B. Morris, MD, said FOURIER contains an important secondary message that mustn’t get lost in the enthusiasm for a safe and effective new drug.
“I’m very struck by the high event rate in this population, even with LDL levels down to 30 mg/dL. I think what that says is that although LDL cholesterol is etiologic and incredibly important, there were multiple other risk factors in this population, and given a 4.2% event rate per year despite achieving a very low LDL, we can’t take our foot off the gas in terms of other risk factors,” said Dr. Morris of the Medical University of South Carolina, Charleston.
Discussant Sidney C. Smith Jr., MD, a member of the 2013 ACC/AHA cholesterol treatment guidelines committee, which did away with LDL lowering to a target level in favor of a risk-based approach which embraced percent reduction in LDL as a therapeutic goal, asked Dr. Sabatine if it’s time for the committee to revisit and perhaps restore the concept of shooting for an LDL target range.
“We labored with that in the 2013 guidelines, as to whether there’s some optimal range for LDL or one can look at percent reduction as an indicator,” noted Dr. Smith, professor of medicine at the University of North Carolina in Chapel Hill.
Dr. Sabatine replied, “Dr. [Eugene] Braunwald has made the analogy that if this was smoking, we wouldn’t want people to just reduce their amount of smoking by 50%, we’d want them to reduce it to zero cigarettes.”
The investigator added, “My own feeling is that the benefit is more closely related to the absolute reduction than the percent reduction in LDL, and like any other risk factor, you want to get it down as low as you can go.”
In a later video interview, Dr. Smith said that the FOURIER data make a strong case – at least in these first years of what will be much-longer-term drug therapy – that a target LDL in the range of 25-35 mg/dL may be optimal in a very-high-risk patient population.
Dr. Sabatine reported receiving grant support and consultant fees from Amgen, which funded the FOURIER trial.
Simultaneous with his presentation at the ACC meeting, the FOURIER results were published online at NEJM.org (doi: 10.1056/NEJMoa1615664).