Greater long-term benefit of PCSK9i in multivessel disease

In a combined analysis of the FOURIER and FOURIER-OLE trials, initial treatment with evolocumab versus placebo reduced the risk of MACE in patients with and with no multivessel disease (MVD). The risk reduction did occur earlier and was larger in patients with MVD.

This summary is based on the publication of McClintick DJ, O’Donoghue ML, De Ferrari GM, et al. - Long-Term Efficacy of Evolocumab in Patients With or Without Multivessel Coronary Disease. J Am Coll Cardiol. 2024 Feb 13;83(6):652-664. doi: 10.1016/j.jacc.2023.11.029

Introduction and methods

Background

A prespecified analysis of the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial showed the relative and absolute risk reductions of MACE with evolocumab versus placebo were greater in patients with multivessel disease (MVD) compared with those with no MVD [1]. Interestingly, during the median follow-up time of 2.2 years (Q1–Q3: 1.8–2.6), the cumulative incidence curves of the treatment arms diverged rapidly in patients with MVD, while they only started to deviate near the end in patients with no MVD. Additional follow-up data were collected in the FOURIER Open-Label Extension (FOURIER-OLE) trial.

Aim of the study

The authors assessed the long-term benefit of evolocumab in patients with and with no MVD.

Methods

In the FOURIER trial, 27,564 patients with ASCVD who had LDL-c ≥70 mg/dL or non–HDL-c ≥100 mg/dL while on optimized statin therapy were randomized to subcutaneous evolocumab (either 140 mg every 2 weeks or 420 mg monthly, per patient preference) or placebo [2].

Of them, 6635 entered the FOURIER-OLE trial to receive evolocumab during an additional mean follow-up time of 5.0 years (Q1–Q3: 4.6–5.1). Of the 23,656 patients with coronary artery disease in the FOURIER trial, 6007 (25.4%) had residual MVD (≥40% stenosis in ≥2 large coronary arteries), of whom 5887 continued in the FOURIER-OLE trial.

Outcomes

The prespecified primary endpoint was a composite outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The prespecified key secondary endpoint was a composite outcome of CV death, MI, or stroke.

Main results

• In the group initially allocated to placebo, the incidence rate of the primary endpoint across the combined follow-up of the FOURIER and FOURIER-OLE trials was higher in patients with MVD compared with those with no MVD (adjusted HR: 1.40; 95%CI: 1.26–1.54; P<0.0001), as was the incidence rate of the key secondary endpoint (adjusted HR: 1.32; 95%CI: 1.17–1.50; P<0.0001). This indicated a higher baseline risk in the first subgroup.
• Over the entire FOURIER and FOURIER-OLE follow-up period, initial allocation to evolocumab reduced the risk of MACE compared with initial allocation to placebo both in patients with and with no MVD, although the magnitude of effect tended to be twice as large in patients with MVD.
• For the primary endpoint, the relative risk reduction was 23% (HR: 0.77; 95%CI: 0.68–0.87; P<0.0001) in patients with MVD and 11% (HR: 0.89; 95%CI: 0.82–0.96; P=0.0033) in patients with no MVD (P for interaction=0.062). The corresponding absolute risk reductions at 8 years were 5.9% and 2.8%, respectively.
• For the key secondary endpoint, the relative risk reduction was 31% (HR: 0.69; 95%CI: 0.59–0.81; P<0.0001) in patients with MVD and 15% (HR: 0.85; 95%CI: 0.77–0.94; P=0.0014) in patients with no MVD (P for interaction=0.031), with absolute risk reductions at 8 years of 6.0% and 2.1%, respectively.
• The cumulative incidence curves showed earlier divergence between the initial allocation to evolocumab and initial allocation to placebo arms in patients with MVD compared with those with no MVD. In the first year of the FOURIER trial, the relative risk reductions for the primary and key secondary endpoints were 18% to 29%, respectively, in patients with MVD, whereas they were both <10% in patients with no MVD. After the first year until the end of the parent FOURIER trial, the relative risk reductions were 29% and 35%, respectively, in patients with MVD and 15% and 19%, respectively, in patients with no MVD.
• During the first 3 years of the FOURIER-OLE trial, initial allocation to evolocumab versus placebo resulted in relative risk reductions of 37% (primary endpoint) and 38% (key secondary endpoint) in patients with MVD and risk reductions of 23% to 28%, respectively, in patients with no MVD. Thereafter (year 4 through end of OLE), there were no significant differences in risk reduction between the evolocumab and placebo arms in patients with and with no MVD.
• With regard to CV death, the cumulative incidence curves of the initial allocation to evolocumab and placebo arms in patients with MVD remained largely superimposed for the first 3 years, after which they started to diverge (relative risk reduction beyond first year: 31%). In contrast, there was no treatment benefit of evolocumab in patients with no MVD.

Conclusion

In this combined analysis of the FOURIER and FOURIER-OLE trials, initial treatment with evolocumab versus placebo reduced the risk of MACE in patients with and with no MVD. Although the magnitude of benefit increased over time in both subgroups, the risk reduction tended to occur earlier and was more pronounced in patients with MVD. Evolocumab treatment was also associated with a late risk reduction in CV death in patients with MVD but not in those with no MVD. The authors conclude their findings “support early initiation of intensive LDL-c lowering and prolonged treatment both in patients with and without MVD.”

Find this article online at J Am Coll Cardiol.

References

1. Sabatine MS, De Ferrari GM, Giugliano RP, et al. Clinical benefit of evolocumab by severity and extent of coronary artery disease: analysis from FOURIER. Circulation. 2018;138:756–766.
2. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–1722.