The much-anticipated results of the FOURIER study at last have provided a look at hard outcomes with a PCSK9 inhibitor. Evolocumab added to statin therapy in patients with clinically evident atherosclerotic cardiovascular disease produced a significant 15 percent reduction in the primary endpoint – a composite of myocardial infarction (MI), stroke, hospitalization for angina, revascularization or cardiovascular death (11.3 percent with placebo, 9.8 percent with evolocumab). For the secondary endpoint of cardiovascular death, MI or stroke, there was a 25 percent reduction after the first year.
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Cardiovascular mortality was not reduced, but statistically significant reductions were seen for MI (27 percent) and stroke (21 percent). The reductions in the primary and key secondary endpoints were consistent across all the key subgroups, including dosing regimen of evolocumab and baseline LDL-C levels, including those with the lowest quartile of LDL-C – starting at 74 mg/dL – in whom evolocumab reduced LDL-C down to 22 mg/dL.
FOURIER included 27,564 patients on a moderate- to high-intensity statin regimen followed at 1,272 sites in 49 countries. Most patients (81 percent) had a history of MI, 19 percent had suffered an ischemic stroke and 13 percent had symptomatic peripheral artery disease. The median baseline LDL-C was 92 mg/dL. To be included, patients had an LDL-C ≥70 mg/dL or a non–high density lipoprotein cholesterol ≥100 mg/dL and were on optimized statin therapy. Exclusions included an acute MI or stroke within the previous four weeks, advanced heart failure, uncontrolled heart rhythm disorders, planned cardiac surgery and end-stage kidney disease.
Patients were randomly assigned (1:1) to receive subcutaneous injections of evolocumab (either 140 mg every two weeks or 420 mg every month based on patient preference) or matching placebo. LDL-C was reduced by 59 percent with evolocumab, from a median of 92 to 30 mg/dL, which remained steady throughout the duration of the study.
The rate of adverse events, including allergic reactions, neurocognition, new-onset diabetes and muscle-related problems, were the same in both study arms. Rates of injection site reactions were slightly more common with evolocumab (2.1 vs. 1.6 percent), but most were mild and the overall rates of stopping the study drug due to suspected treatment-related adverse events were low and similar in both groups (1.6 and 1.5 percent). Only 0.3 percent of patients developed antibodies that could bind evolocumab and none interfered with the drug.
Yet, the relatively short follow-up (mean 2.2 years) is a limitation of the study, and PCSK9 inhibitors remain to be studied in other high-risk populations, acknowledged Marc S. Sabatine, MD, FACC, who presented the study.
"Given this was a relatively short trial, I fully expect larger benefits to accrue over the long-term. FOURIER provides high-quality evidence that evolocumab works, and I felt fortunate after ACC.17 to bring this information back to my patients in lipid clinic as we work together to optimize their preventive therapy." — Seth Martin, MD, FACC
“FOURIER was an exciting way to kick off ACC.17,” says Seth Martin, MD, FACC. “Given this was a relatively short trial, I fully expect larger benefits to accrue over the long-term. FOURIER provides high-quality evidence that evolocumab works, and I felt fortunate after ACC.17 to bring this information back to my patients in lipid clinic as we work together to optimize their preventive therapy,” he adds.
Results from EBBINGHAUS, the prospectively planned cognitive sub-study of FOURIER – aptly named for the German psychologist and father of the study of human memory, Hermann Ebbinghaus – “alleviate concerns that very low cholesterol levels, such as those achieved with the combination of a PCSK9 inhibitor and statin, would negatively impact cognitive function,” says Sandra Lewis, MD, FACC.
The neurocognitive function of 1,974 patients (average age 63 years, 28 percent women) was evaluated using the Cambridge Neuropsychological Test Automated Battery, completed by patients at study entry and at 24, 48 and 96 weeks and at the end of the study to assess executive function, working memory, memory function and reaction time. They also completed a questionnaire assessing their everyday cognition before, during and at the end of the study.
“Patients who reached very low LDL values – less than 25 mg/dL – had cognitive function that was similar with those with higher LDL values,” says Robert P. Giugliano, MD, SM, FACC, who presented the study.
The mean change in the primary endpoint of executive function as measured by the Spatial Working Memory strategy index was minus 0.29 with placebo and minus 0.21 with evolocumab (p for non-inferiority < 0.0001). The outcomes for all secondary endpoints were similar for placebo and evolocumab. Also similar were the patient self-reports via the questionnaire and the investigator-reported cognitive adverse events for both placebo and evolocumab.
“Physicians and patients can be comfortable that the improvement in cardiovascular risk seen in the overall FOURIER study did not come with decline in cognitive function throughout the study period. Long-term term follow-up data are needed to add further support,” says Lewis.
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