Elevated lipoprotein(a) identifies patients with acute coronary syndrome who derive earlier and greater cardiovascular benefit of alirocumab, particularly for limb events

Abstract Background Lipoprotein(a) Lp(a) is believed to be a causal risk factor for major adverse cardiovascular and limb events (MACE, MALE). Levels ≥50mg/dl are increasingly recognized as a risk enhancing threshold in multiple guidelines. PCSK9 inhibitors have been shown to reduce cardiovascular risk, including traditional MACE and MALE in patients with ASCVD. We assessed whether significantly elevated Lp(a) levels influenced the time to benefit of treatment with the PCSK9 inhibitor alirocumab (ALI) in statin-treated patients with acute coronary syndrome. Methods In post hoc analysis of the ODYSSEY OUTCOMES trial, patients randomized to ALI or placebo were dichotomized by baseline Lp(a) ≥50 (n=5709) or 50 mg/dL (n=13,215). Median follow up was 2.8 yrs. Time-varying treatment hazard ratio (HR) with 95% confidence interval (CI) was determined for MACE (CV death, MI, ischemic stroke, unstable angina, or ischemia-driven coronary revascularization) and MALE (critical limb ischemia, revascularization, or amputation). Results In Lp(a) categories ≥50 vs 50 mg/dL, median baseline Lp(a) was 84 vs 11 mg/dL, median Lp(a) reduction (ALI vs placebo) was 14 vs 3 mg/dL, and median LDL-C reduction was 55 vs 54 mg/dL. There were 2775 MACE and 246 MALE. ALI reduced the composite of MACE+ MALE in both baseline Lp(a) ≥50 and 50 mg/dL categories HR 0.80 (95% CI 0.71, 0.91) and 0.90 (0.83, 0.99), respectively. However, 95% CI for MACE treatment HR was 1 at 1.25 yrs from randomization onwards in patients with Lp(a) ≥50 mg/dL vs 2.45 years onwards with Lp(a) 50 mg/dL (FIGURE, top). Similarly, 95% CI for MALE treatment HR was 1 at 0.24 yrs onwards for patients with Lp(a) ≥50 mg/dL but reached 1 only briefly at 0.6 yrs in those with Lp(a) 50 mg/dL (FIGURE, bottom). Conclusion In this post hoc analysis of the ODYSSEY OUTCOMES trial, we observed that patients with Lp(a) ≥ 50mg/dl derived similar LDL-C lowering, greater absolute Lp(a) lowering and an earlier, as well as greater relative risk reduction for both MACE and MALE compared to those with Lp(a) levels 50mg/dl. Patients with Lp(a) levels ≥ 50mg/dl may represent a particularly higher risk group with early modifiable risk from PCSK9 inhibition with ALI.