Clinical Efficacy and Safety of Alirocumab After Acute Coronary Syndrome According to Achieved Level of Low-Density Lipoprotein Cholesterol: A Propensity Score-Matched Analysis of the ODYSSEY OUTCOMES Trial

Abstract

Background: Recent international guidelines have lowered recommended target levels of low-density lipoprotein cholesterol (LDL-C) for patients at very high risk for major adverse cardiovascular events (MACE). However, uncertainty persists whether additional benefit results from achieved LDL-C levels below the conventional targets. Inferences from previous analyses are limited because patients who achieve lower versus higher LDL-C on lipid-lowering therapy differ in other characteristics prognostic for MACE and because few achieved very low LDL-C levels. To overcome these limitations, we performed a propensity score-matching analysis of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) which compared alirocumab with placebo in 18 924 patients with recent acute coronary syndrome receiving intensive or maximum-tolerated statin treatment.

Methods: Patients on alirocumab were classified in prespecified strata of LDL-C achieved at 4 months of treatment: <25 (n=3357), 25 to 50 (n=3692), or >50 mg/dL (n=2197). For each stratum, MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) after month 4 was compared in patients receiving placebo with similar baseline characteristics and adherence by using 1:1 propensity score matching.

Results: Across achieved LDL-C strata of the alirocumab group, patients differed by baseline LDL-C, lipoprotein(a), use of intensive statin therapy, study medication adherence, and other demographic, medical history, biometric, and laboratory criteria. After propensity score matching, characteristics were similar in corresponding patients of the alirocumab and placebo groups. Treatment hazard ratio, 95% CI, and absolute risk reduction (number per 100 patient-years) for MACE were similar in those with achieved LDL-C <25 mg/dL (hazard ratio, 0.74 [95% CI, 0.62-0.89]; absolute risk reduction, 0.92) or 25 to 50 mg/dL (hazard ratio, 0.74 [95% CI, 0.64-0.87]; absolute risk reduction, 1.05). Patients with achieved LDL-C >50 mg/dL had poorer adherence and derived less benefit (hazard ratio, 0.87 [95% CI, 0.73-1.04]; absolute risk reduction, 0.62). No safety concerns were associated with a limited period of LDL-C levels <15 mg/dL.

Conclusions: After accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-C levels <25 mg/dL had a reduction in the risk of MACE that was similar to that of patients who achieved LDL-C levels of 25 to 50 mg/dL. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Keywords: PCSK9 protein, human; acute coronary syndrome; hydroxymethylglutaryl-CoA reductase inhibitors; lipoprotein(a); lipoproteins, LDL.

Figure 1.

Waterfall plots of percent change in LDL-C from baseline to month 4. LDL-C indicates low-density lipoprotein cholesterol.

Figure 2.

Incidence rates for major adverse cardiovascular events after month 4 according to ranges of low-density lipoprotein cholesterol achieved at month 4 in the alirocumab group and in propensity score–matched patients from the placebo group. ALI indicates alirocumab; ARR, absolute risk reduction; PBO, placebo; and PSM, propensity score-matched.

Figure 3.

Incidence rates for major adverse cardiovascular events after month 4 according to ranges of low-density lipoprotein cholesterol achieved at month 4 in the alirocumab group and in propensity score–matched patients from the placebo group, excluding patients in the alirocumab group with any protocol-defined dose adjustment at or after month 4. ALI indicates alirocumab; ARR, absolute risk reduction; PBO, placebo; and PSM, propensity score-matched.

Figure 4.

Spline analyses of continuous TWMA LDL-C in the alirocumab group. Hazard ratio (dashed lines represent upper and lower bounds of 95% CI) is relative to 50 mg/dL. Degree = 3, 3 knots located at LDL-C quartiles (62.5, 42.8, 31.8). P<0.0001 for spline effects. The risk of MACE decreased with decreasing TWMA LDL-C to a nadir at ≈23 mg/dL, without evidence of a further decrease in risk of MACE below that LDL-C level. Note that this analysis is limited to the alirocumab group and is unadjusted, and patients with lower achieved LDL-C were at lower risk for MACE for reasons in addition to their achieved LDL-C. Therefore, a nadir of MACE at ≈23 mg/dL should be interpreted cautiously and does not necessarily imply the optimal achieved LDL-C level in all patients. LDL-C indicates low-density lipoprotein cholesterol; MACE, major adverse cardiovascular events; and TWMA, time-weighted moving average.