Total CV events lowered by PCSK9i-induced Lp(a) reduction in ACS patients

Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial

Literature - Szarek M, Bittner VA, Aylward, P, et al. - Eur Heart J. 2020;ehaa649. doi: 10.1093/eurheartj/ehaa649.

Introduction and methods

Elevated baseline levels of lipoprotein(a) [Lp(a)] have been associated with first CV outcome in epidemiological studies and Mendelian randomization analyses [1-3]. Recently, it has been shown in patients treated with a PCSK9 inhibitor, that reduction in Lp(a) can predict reduction in risk of a first CV event, independent of LDL-c levels [4]. Similar results have been reported for first PAD or VTE events [5]. However, the risk reduction on total CV burden has not been analyzed yet.

This post-hoc analysis of the ODYSSEY OUTCOMES trial in patients with acute coronary syndrome (ACS) receiving intensive statin therapy, evaluated whether baseline Lp(a) levels and reduction in Lp(a) and LDL-c corrected for Lp(a) cholesterol (LDL-c[corr]) by alirocumab treatment could independently predict total CV events.

Patients (n=18924, ≥40 years) who were 1-12 months before randomization hospitalized with ACS (MI or unstable angina) were included in the trial. Participants had to have an LDL-c of ≥70 mg/dL (1.81 mmol/L), or a non-HDL-c of ≥100 mg/dL (2.59 mmol/L), or apolipoprotein B of ≥80 mg/dL, measured during stable treatment with atorvastatin 40-80 mg daily, or rosuvastatin 20-40 mg daily, or the maximum tolerated dose of either statin. Patients were randomized in a 1:1 ratio to 75 mg of alirocumab or matching placebo given every 2 weeks by subcutaneous injection. The median follow-up was 2.8 years (2.3-3.4 years).

For the present analysis, all CV outcomes collected in the trial including, CV death, hemorrhagic stroke, hospitalization for HF, ischemia-driven coronary revascularization, major PAD event (critical limb ischemia, lower extremity revascularization, and amputation due to ischemia), and VTE (deep vein thrombosis and pulmonary embolism) were examined.

Main results

  • In the placebo group, the estimated number of total CV events per 100 patients from baseline to 4 years time was 53.7 among patients in the highest Lp(a) quartile (≥59.6 mg/dL), compared to 37.5 among those in the lowest quartile (<6.7 mg/dL). This corresponds to an adjusted 60% higher CV risk in individuals with high baseline Lp(a) levels (P<0.001).
  • Alirocumab reduced first CV events compared to placebo, with a corresponding HR of 0.88 (95% CI: 0.82-0.94, P=0.0002). The HR for reduction of total CV events with alirocumab was 0.85 (95% CI:0.78-0.93, P=0.0004).
  • Individuals with a high Lp(a) (≥59.6 mg/dL) baseline concentration had a greater reduction in total CV events when treated with alirocumab compared to the ones with a low Lp(a) (<6.7 mg/dL) baseline concentration (HR 0.75, 95% CI: 0.64-0.88 vs. HR 0.95, 95% CI: 0.79-1.14, respectively, Ptrend=0.045).
  • The absolute median change in Lp(a) concentration after 4 month of treatment with alirocumab was -5.0 (-13.6 to 0) mg/dL. Patients grouped in the high baseline Lp(a) (≥59.6 mg/dL) quartile showed the highest median change compared to patients in the low Lp(a) (<6.7 mg/dL) quartile (-20.1 [-34.0 to -8.0] mg/dL vs. 0 [-1.4 to 0] mg/dL, respectively).
  • The absolute median change in LDL-c[corr] with alirocumab therapy was -51.3 (-67.1 to -34.0) mg/dL. There was no difference in LDL-c[corr] change between the high and low Lp(a) quartiles (-47.2 [-63.5 to -31.4] mg/dL vs. -53.3 [-68.8 to -35.5] mg/dL, respectively).
  • A risk model adjusted for baseline Lp(a) and LDL-c[corr] concentration and 4 month change in LDL-c[corr] levels, predicted a relative risk reduction of 2.5% in total CV events for each 5 mg/dL reduction in Lp(a) (HR 0.975, 95% CI: 0.953-0.997, P=0.029). Each reduction of 51.3 mg/dL LDL-c[corr] predicted a relative reduction of 15.8% in CV events (HR 0.842, 95% CI: 0.755-0.944, P=0.002).
  • In patients with high baseline Lp(a) levels, the reduction in Lp(a) attributed for 39% to the joint predicted risk reduction of total CV events, while in patients with low baseline Lp(a) levels this attribution in joint risk prediction was 0%.


This study showed that LDL-c[corr] and Lp(a) reductions by alirocumab in patients with ACS, were independently associated with fewer total CV events. Although most risk reduction was attributed to a lowered LDL-c[corr], the contribution of reduced Lp(a) levels to reduce the risk of CV events was most evident in individuals with high Lp(a) baseline levels.


1. Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res 2016;57: 1953–75.

2. Burgess S, Ference BA, Staley JR, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol 2018;3:619–27.

3. Lamina C, Kronenberg F, Lp GC. Estimation of the required lipoprotein(a)-lowering therapeutic effect size for reduction in coronary heart disease outcomes: a Mendelian randomization analysis. JAMA Cardiol 2019;4:575–79.

4. Bittner VA, Szarek M, Aylward PE, et al. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol 2020; 75:133–44.

5. Schwartz GG, Steg PG, Szarek M, et al. Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of a randomized clinical trial. Circulation 2020;141:1608–17.

Find this article online at Eur Heart J.

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