Early and long-term PCSK9 inhibitor use associated with continued CV benefit

Long-term evolocumab in patients with established atherosclerotic cardiovascular disease: primary results of the FOURIER-OLE (open-label extension) studies

Presented at the ESC congress 2022 by: Michelle O’Donoghue, MD- Boston, MA, USA

Introduction and methods

In the FOURIER trial, the PCSK9i evolocumab reduced LDL-c levels and the incidence of CV events compared with placebo but not CV death in ASCVD patients with LDL-c ≥70 mg/dL on optimized statin treatment. Over the median follow-up time of 2.2 years, the drug was safe and well-tolerated. At select sites in Europe and the US, an open-label extension (OLE) study was subsequently conducted in 6634 patients who completed the parent FOURIER trial.

All FOURIER-OLE patients self-injected open-label evolocumab (also the patients who were originally allocated to placebo in the parent study), with the choice of 140 mg biweekly or 420 mg monthly (same as in parent study). Median follow-up duration of the FOURIER-OLE study was 5.0 years (maximum exposure to evolocumab in FOURIER plus FOURIER-OLE: 8.4 years).

The primary endpoint was the composite outcome of CV death, MI, stroke, unstable angina, or coronary vascularization. The key secondary endpoint was the composite outcome of CV death, MI, or stroke.

Main results

• In patients switched to evolocumab from placebo, there was a marked reduction in median LDL-c level to 0.75 mmol/L (IQR: 0.44–1.29)/29 mg/dL (IQR: 17–50) at week 260.
• Long-term rates of adverse events (such as injection site reactions, muscle-related events, and new-onset DM) in the evolocumab-treated patients were no higher than those in the placebo-treated patients, regardless of the duration of evolocumab exposure.
• The occurrence of the primary endpoint was 17.5% in patients switched to evolocumab from placebo and 15.4% in patients who had originally been randomized to evolocumab (15% reduction; hazard ratio (HR): 0.85; 95%CI: 0.75–0.96; P=0.008).
• The incidence of the key secondary endpoint was 11.9% in patients switched to evolocumab from placebo and 9.7% in patients who had received evolocumab only (20% reduction; HR: 0.80; 95%CI: 0.68–0.93; P=0.003).
• In the OLE period, the risk of CV death was 4.45% in the placebo–evolocumab group and 3.32% in the evolocumab–evolocumab group (23% reduction; HR: 0.77; 95%CI: 0.60–0.99; P=0.04).
• When looking at CV death risk in the FOURIER and FOURIER-OLE studies together, a divergence between the placebo–evolocumab and evolocumab–evolocumab groups becomes apparent not until 3 years after the start of the FOURIER trial, which highlights both the lag and legacy effects of early sustained reduction of the LDL-c level.

Conclusion

Long-term use of evolocumab (median follow-up duration >7 years) led to durable LDL-c reduction and was both safe and well-tolerated. Early initiation of this treatment was associated with continued accumulation of CV benefit, including CV death, over the next several years. According to Dr. O’Donoghue, “these findings argue for early initiation of a marked and sustained LDL-c reduction to maximize clinical benefit.”

-Our reporting is based on the information provided at the ESC Congress-

The results of this study were simultaneously published in Circulation. Watch a video about the FOURIER-OLE study