Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of Alirocumab

Abstract

Background: Apolipoprotein B (apoB) provides an integrated measure of atherogenic risk. Whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndrome beyond that provided by low-density lipoprotein cholesterol is uncertain.

Methods: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy. Primary outcome was major adverse cardiovascular events (MACE; coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, hospitalization for unstable angina). Associations between baseline apoB or apoB at 4 months and MACE were assessed in adjusted Cox proportional hazards and propensity score-matched models.

Results: Median follow-up was 2.8 years. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata (3.2 [95% CI, 2.9-3.6], 4.0 [95% CI, 3.6-4.5], and 5.5 [95% CI, 5.0-6.1] events per 100 patient-years in strata <75, 75-<90, ≥90 mg/dL, respectively; P_trend<0.0001) and after adjustment for low-density lipoprotein cholesterol (P_trend=0.035). Higher baseline apoB stratum was associated with greater relative (P_trend<0.0001) and absolute reduction in MACE with alirocumab versus placebo. In the alirocumab group, the incidence of MACE after month 4 decreased monotonically across decreasing achieved apoB strata (4.26 [95% CI, 3.78-4.79], 3.09 [95% CI, 2.69-3.54], and 2.41 [95% CI, 2.11-2.76] events per 100 patient-years in strata ≥50, >35-<50, and ≤35 mg/dL, respectively). Compared with propensity score-matched patients from the placebo group, treatment hazard ratios for alirocumab also decreased monotonically across achieved apoB strata. Achieved apoB was predictive of MACE after adjustment for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol but not vice versa.

Conclusions: In patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, MACE increased across baseline apoB strata. Alirocumab reduced MACE across all strata of baseline apoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved apoB was associated with lower risk of MACE, even after accounting for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol, indicating that apoB provides incremental information. Achievement of apoB levels as low as ≤35 mg/dL may reduce lipoprotein-attributable residual risk after acute coronary syndrome.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT01663402.

Keywords: PCSK9 inhibitors; acute coronary syndrome; apolipoproteins B; cholesterol, LDL; heart disease risk factors.

Figure 1.

Spline analysis of continuous baseline apoB and incident MACE in the placebo group. A, Hazard ratio set to 1.00 at the overall baseline median (79 mg/dL) concentration of apoB. Score test P<0.0001 for spline effect. This reflects spline of degree 2 (piecewise quadratic curve) with 3 knots, located at the 25th (69 mg/dL), 50th (79 mg/dL), and 75th (93 mg/dL) percentiles and spanning the approximate 1st (50 mg/dL) to 99th (150 mg/dL) percentiles overall. Dotted lines indicate the lower and upper bounds of the 95% CI. B, Histogram of baseline apoB in the placebo group. ApoB indicates apolipoprotein B; and MACE‚ major adverse cardiovascular events.

Figure 2.

Relative and absolute treatment effects on the incidence rate for MACE, overall and by stratum of baseline apoB. Relative and absolute treatment effects on the incidence rate of MACE, overall and by stratum of baseline apoB. Forest plots depict relative and absolute risk reduction (ARR) with alirocumab compared with placebo. For relative risk reduction, there was a significant linear trend in the log hazard ratio (HR) across baseline strata, with point estimates progressively further <1.00 for higher strata. ApoB indicates apolipoprotein B; and MACE‚ major adverse cardiovascular events.

Figure 3.

Unadjusted cumulative incidence of the primary composite outcome across baseline apoB strata. ApoB indicates apolipoprotein B; HR‚ hazard ratio; and MACE, major adverse cardiovascular events.

Figure 4.

Incidence rate for first major adverse cardiovascular events after month 4 according to achieved apoB stratum at month 4 in the alirocumab group and in propensity score–matched patients from the placebo group. ApoB indicates apolipoprotein B; ARR, absolute risk reduction; and HR, hazard ratio.

Figure 5.

Spline analyses of continuous achieved apoB adjusted for achieved low-density lipoprotein cholesterol, and incidence of MACE in patients treated with alirocumab. A, Hazard ratio set to 1.00 at the median concentration of apoB (39 mg/dL) achieved within the alirocumab group at month 4. Score test P=0.0009 for apoB spline effect. This reflects spline of degree 2 (piecewise quadratic curve) with 3 knots, located at the 25th percentile (35 mg/dL), median (39 mg/dL), and 75th percentile (53 mg/dL) and spanning the minimum (35 mg/dL) to ≈99th (125 mg/dL) percentiles within the alirocumab group. Dotted lines indicate the lower and upper bounds of the 95% CI. B, Histogram of month 4 apoB levels within the alirocumab group. The lower limit of detection for apoB was 35 mg/dL. ApoB indicates apolipoprotein B; and MACE‚ major adverse cardiovascular events.