Reviewed by Dr. Anurag Mehta
Sabatine, Marc S., et al. N Engl J Med 2017.376 (2017): 1713-1722

SUMMARY
The FOURIER was a randomized, double-blind, placebo-controlled trial that evaluated the efficacy of evolocumab (a PCSK9 inhibitor) for decreasing future cardiovascular events among 27,564 patients (aged 40 to 85 years) with clinical ASCVD (history of MI, non-hemorrhagic stroke, or symptomatic peripheral artery disease) who were receiving moderate- or high-intensity statins and had LDL-C ≥70 mg/dL. PCSK9 inhibitors are agents that lower serum LDL-C levels by promoting LDL receptor recycling that leads to enhanced LDL-C clearance. The FDA has approved evolocumab as an adjunct to diet and maximally-tolerated statin therapy in adult patients with familial hypercholesterolemia (heterozygous/homozygous) and clinical ASCVD who require additional lowering of LDL cholesterol.

The trial patients were randomized in a 1:1 ratio to receive subcutaneous injections of evolocumab (140 mg every 2 weeks or 420 mg every month) or placebo and were followed for 2.2 years for the development of major cardiovascular events – primary composite outcome of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary outcome of interest was a composite of cardiovascular death, myocardial infarction, or stroke. Evolocumab therapy resulted in a rapid and sustained decrease in LDL-C levels. The baseline median LDL-C in both treatment arms was 92 mg/dL. At 48 weeks, the median LDL-C level in the evolocumab arm was 30 mg/dL and the least-squares mean percentage reduction in LDL-C with evolocumab as compared to placebo was 59% (p<0.001). Treatment with evolocumab significantly reduced the risk of primary outcome as compared to placebo (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio 0.85; 95% CI 0.79 to 0.92, p<0.001). Also, the risk of secondary outcome was significantly lower in the evolocumab arm as compared to placebo (816 patients [5.9%] vs. 1013 patients [7.4%]; hazard ratio 0.80; 95% CI 0.73 to 0.88, p<0.001). The effects of evolocumab were consistent across major subgroups based on sex, age, ASCVD subtype, baseline LDL-C quartiles, intensity of statin therapy, and both evolocumab dosing regimens. Notably, evolocumab had no effect on cardiovascular mortality as compared to placebo. The two treatment arms did not differ in terms of adverse events. EBBINGHAUS, a sub-study of the FOURIER trial revealed that there was no increased risk of memory or other cognitive problems with evolocumab as compared to placebo.

COMMENTARY
The FOURIER trial demonstrated the benefit of using the PCSK9 inhibitor evolocumab in addition to statin therapy for secondary prevention of adverse cardiovascular events in patients with prior ASCVD. The results of this large trial lend credence to the hypothesis that reducing LDL-C to a level lower than what was achieved in prior secondary prevention trials evaluating statins might be more helpful for preventing recurrent cardiovascular events. It is worth noting that the relative risk reduction observed in this trial (15% for the primary endpoint and 20% for the secondary endpoint) was lower than what was anticipated with the degree of LDL-C level lowering achieved. Interestingly, there was a larger relative risk reduction in the second year as compared to the first year, suggesting that had the trial gone longer a larger event reduction would have been seen. At present, the prohibitive cost of evolocumab and no effect on cardiovascular mortality make it a less attractive option as compared to the cheaper alternative of using a high-intensity statin with ezetimibe for secondary prevention. Hopefully, improved insurance coverage in the future will help increase its use among patients at high risk of cardiovascular disease.

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