Long-term use of evolocumab leads to further reductions in cardiovascular events, including cardiovascular death, in patients with atherosclerotic cardiovascular disease who were already on statin therapy, according to new study results. Michelle L. O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston, presented these findings from the FOURIER-OLE study Monday at the European Society of Cardiology (ESC) Congress 2022 in Barcelona, Spain. The original FOURIER trial showed that the use of evolocumab, a PCSK9 inhibitor, lowered low-density lipoprotein (LDL) cholesterol levels to from a median of 2.4 mmol/L to a median of 0.78 mmol/L and reduced the risk of cardiovascular events – but not cardiovascular death – compared to placebo over a median follow-up of 2.2 years. The drug was safe and well-tolerated. The FOURIER-OLE (open-label-extension) study was conducted at select sites in Europe and the U.S. that participated in the original trial. The OLE study enrolled 6,635 patients from FOURIER. All patients in the OLE study self-injected open-label evolocumab, choosing between 140 mg every 2 weeks or 420 mg monthly. The median follow-up in the extension study was 5 years, and the maximum exposure to evolocumab in FOURIER and FOURIER-OLE was 8.4 years. Longer-term use of the drug continued to show that it was safe and well-tolerated. The primary endpoint of FOURIER-OLE was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction (MI), stroke, unstable angina or coronary revascularization. The MACE rate was lower for patients originally randomized to evolocumab during very long-term follow-up on open-label evolocumab (15.4%) compared to those switched from placebo to evolocumab at the inception of the extension study (17.5%; hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.75-0.96; p=0.008). The same was true for the key secondary endpoint, a composite of cardiovascular death, MI or stroke (evolocumab-evolocumab 9.7% vs. placebo-evolocumab 11.9%; HR: 0.80; 95% CI: 0.68-0.93; p=0.003). Importantly, O’Donoghue said, cardiovascular death itself was also lower for patients originally randomized to evolocumab during very long-term follow-up on open-label evolocumab (3.32%) compared to patients originally on placebo (4.45%; HR: 0.77; 95% CI: 0.60-0.99; p=0.04). The Kaplan-Meier estimate curves of cardiovascular death were virtually imposed through the entire FOURIER trial for evolocumab vs. placebo and stayed that way until after 3 years until they diverged in favor of patients randomized to evolocumab in the original trial. At 48 weeks in the original FOURIER trial, the placebo patients had a median LDL cholesterol level of 2.22 mmol/L, which continued through 3.2 years. Placebo patients entering the FOURIER-OLE study saw their median LDL-C quickly fall to about the same level as that of OLE patients who were originally randomized to evolocumab, and this parity continued through 260 weeks. The median LDL-C of all FOURIER-OLE patients was 0.75 mmol/L at week 260 (interquartile range: 0.44-1.29). Also, the rates of injection site reactions, muscle-related events and new-onset diabetes were no higher among patients in the OLE compared to those in the placebo arm of the original trial. O’Donoghue concluded that the long-term use of evolocumab with median follow-up of more than 7 years led to durable reductions in LDL-C and was both safe and well-tolerated and that earlier initiation of the drug is associated with continued accrual of cardiovascular benefit, including cardiovascular mortality, over the next several years. “FOURIER-OLE included patients with the longest study exposure to a PCSK9 inhibitor so far,” she said in an ESC press release announcing the OLE study results. “Long-term LDL cholesterol lowering with evolocumab was safe and well-tolerated for more than 8 years and led to further reductions in cardiovascular events compared with delayed treatment initiation. These data provide further support to guidelines recommending lipid-lowering therapy with PCSK9 inhibitors and targeting very low levels of LDL cholesterol.” The FOURIER trial was funded by Amgen.