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
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 . Similar results have been reported for first PAD or VTE events . 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.
- 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.