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.

The Lower the ApoB, the Better: Now, How Does ApoB Fit in the Upcoming Era of Targeted Therapeutics?

“…The present study by Hagström et al 11 is a post hoc analysis of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) that compared alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins (LDL-C ≥70, non-HDL-C ≥100, or apoB ≥80 mg/dL) despite high-intensity statin therapy over a median follow-up time of 2.8 years. This study reports several important findings.…”

Eradicating Atherosclerotic Events by Targeting Early Subclinical Disease: It Is Time to Retire the Therapeutic Paradigm of Too Much, Too Late

“…93,94 But similar to the results stratified by CRP concentrations, patients enrolled with end-stage arterial disease who then achieved apoB levels ≤35 mg/dL on PCSK9i still experienced a substantial ASCVD event rate that was over half of the event rate in patients who achieved apoB levels ≥50 mg/dL. 91 Based on key PCSK9i outcome trials, including FOURIER 30 and ODYSSEY OUT-COMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), 31 these agents have been appropriately approved by regulatory agencies to decrease atherosclerotic cardiovascular events. It is genuine progress, but again, the approach remains a long way from eradicating the clinical burden of this scourge.…”

“…87,88 Clinical trials to date of immunomodulatory agents have given the same message: targeting maladaptive sterile inflammation in end-stage atherosclerosis still leaves substantial residual rates of ASCVD events, 44,86,89 even in cohorts specifically selected for what were thought to be proinflammatory conditions. 44,86 Post hoc analyses of PCSK9i trials have implicated residual circulating apoB-lipoproteins in residual ASCVD event risk, 90,91 as would be expected. 14,68,92 With the rise in overnutrition, obesity, the atherometabolic syndrome, and related conditions, C-TRLs (cholesterol-and triglyceriderich apoB-containing lipoproteins) have become increasingly significant contributors to residual apoB-lipoproteins in plasma during LDL-lowering therapies (Figure 1).…”

PCSK9 Inhibitors Reduce PCSK9 and Early Atherogenic Biomarkers in Stimulated Human Coronary Artery Endothelial Cells

“…There are various reports on the efficacy of PCSK9 inhibitors in LDL-C lowering in a variety of comprehensive large-scale clinical trials such as PROFICIO (Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 in Different Populations) [ 17 , 18 , 19 , 20 , 21 , 22 ], FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects with Elevated Risk) [ 23 , 24 , 25 ] and ODYSSEY (Cardiovascular Outcomes After an Acute Coronary Syndrome) [ 26 , 27 , 28 ]. PCSK9 inhibition attenuates atherosclerosis progression and lowers the risk for acute cardiovascular events [ 29 , 30 , 31 ].…”