Effect of Early Versus Delayed Evolocumab Treatment on Complex Coronary Artery Revascularization

Aims In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Patients with Elevated Risk (FOURIER) trial, the PCSK9 inhibitor evolocumab (Evo) significantly reduced the rate of major adverse cardiovascular events and coronary revascularization. The aim was to investigate the effect of initial randomization to Evo on the incidence of complex coronary revascularization during long-term follow-up. Methods and results In FOURIER, patients with atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol (LDL-C) >= 70 mg/dL despite optimized statin therapy were randomized to Evo or placebo. At the end of the trial, patients had the option to be treated with Evo in the open-label extension (OLE) at participating sites. All cases of coronary revascularization were centrally reviewed, and complex revascularization was defined as coronary artery bypass graft surgery (CABG) or complex percutaneous coronary intervention (PCI) using the GLOBAL LEADERS definition. Event rates through 8 years were compared between patients randomized in the parent trial to Evo or placebo. Of 27 564 patients in FOURIER, 6635 patients (median achieved LDL-C 30 mg/dL) continued in OLE (total median follow-up 7.2 years). Patients initially randomized to Evo were treated on average 2.2 years earlier than patients starting treatment during OLE. In patients receiving Evo earlier, the rate for complex coronary revascularization through 8 years was reduced by 24% (HR 0.76 [0.67, 0.87], P < 0.001). This effect was consistent for both CABG (HR 0.77 [0.63, 0.94], P = 0.01) and complex PCI (HR 0.78 [0.65, 0.93], P = 0.006) individually. Early vs. delayed Evo therapy resulted in lower total stent length implanted (22 521 mm vs. 28 946 mm, P < 0.001). Conclusion Compared with delayed treatment initiation, early and sustained treatment with Evo significantly reduced the likelihood of complex revascularization during long-term follow-up. Lay summary Lowering circulating LDL-cholesterol reduces its accumulation in the blood vessels of the heart, legs, and other parts of the body, known as atherosclerosis. Evolocumab is a drug that lowers LDL-cholesterol by similar to 60%. In this study, patients with known atherosclerosis were randomly assigned to receive evolocumab earlier or later. Patients who started evolocumab earlier less frequently needed complex invasive procedures to restore the blood flow to the heart. These results show that early, aggressive lowering of LDL-cholesterol results in fewer coronary bypass surgeries and complex stenting procedures. Trial Registration clinicaltrials.gov, unique identifiers NCT01764633, NCT02867813, and NCT03080935.