Large absolute benefit with PCSK9 inhibitor in ACS patients with polyvascular disease
Patients with Recent Acute Coronary Syndrome and Polyvascular Disease Derive Large Absolute Benefit from Alirocumab: ODYSSEY OUTCOMES Trial
Introduction and methods
Patients with peripheral artery disease (PAD) or cerebrovascular disease (CeVD) have an increased risk of MACE and death compared to those without, regardless of history of coronary artery disease (CAD) [1-3]. When PAD or CeVD concur with acute coronary syndrome, risk of MACE and death are even more elated [4,5]. Intensive therapy is needed to prevent secondary events in these patients. The PCSK9 inhibitor alirocumab reduced MACE and death in patients with recent ACS and elevated lipids compared to placebo, as demonstrated in the ODYSSEY OUTCOMES trial (for MACE: absolute risk reduction, ARR 1.6%, 95%CI:0.7-2.4%, P=0.0003, for death: ARR 0.6%, 95%CI:0.2-0.6%) .
ODYSSEY OUTCOMES was a multicenter, double-blind, placebo-controlled trial in 18924 ACS patients (MI or unstable angina) with elevated lipids and who were on statin therapy. Patients were assigned in a 1:1 ratio to receive alirocumab or placebo.
This pre-specified analysis of the ODYSSEY OUTCOMES trial examined whether reduction of MACE and death by alirocumab was influenced by the presence of polyvascular disease (PAD, CeVD or both) to identify preferred patients for this therapy. For this purpose, 3 subgroups were defined: monovascular disease (CAD without PAD or CeVD), polyvascular disease in 2 vascular beds (CAD and either PAD or CeVD) and polyvascular disease in 3 vascular beds (CAD, PAD and CeVD).
The primary endpoint was MACE, a composite of coronary heart disease death, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalizations. Secondary endpoint was all-cause death. Median follow-up was 2.8 years.
- At baseline, 17370 patients (91.8%) had monovascular disease, 1405 (7.4%) had polyvascular disease in 2 beds, 149 (0.8%) had polyvascular disease in 3 beds.
- In the placebo group, incidence of MACE was 10.0%, 22.2% and 39.7% in those with one, two or three diseased vascular beds, respectively. Corresponding ARRs with alirocumab were 1.4% (0.6-2.3%, quartile 1 to quartile 3), 1.9% (-2.4% to 6.2%) and 13.0% (-2.0% to 28.0%) (Pinteraction=0.0006).
- In the placebo group, incidence of death was 3.5%, 10.0% and 21.8% in those with one, two or three diseased vascular beds, respectively. Corresponding ARRs with alirocumab were 0.4% (-0.1% to 1.0%), 1.3% (-1.8% to 4.3%) and 16.2% (5.5% to 26.8%) (Pinteraction=0.002).
- There were no differences in incidence of adverse events between alirocumab and placebo groups, with the exception of local injection-site reactions (more in the alirocumab group). There were no differences in adverse events between the subgroups.
This subanalysis of the ODYSSEY OUTCOMES trial showed that patients with a recent ACS and concurrent polyvascular disease have a high risk of MACE and death. Treatment with alirocumab on top of statin therapy resulted in a large absolute risk reduction in patients with polyvascular disease, thereby identifying these patients as a subgroup that could greatly benefit of treatment with alirocumab.