Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome

Abstract

BACKGROUNDPatients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODSWe conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non−highdensity lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTSThe median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group). CONCLUSIONSAmong patients who had a previous acute coronary syndrome and who were receiving highintensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY OUTCOMES ClinicalTrials.gov number, NCT01663402.

The Potential of Probiotics in the Prevention and Treatment of Atherosclerosis

“…Monoclonal antibodies targeting PCSK9, namely alirocumab and evolocumab, have shown success in lowering LDL‐C and are currently approved for use in hypercholesterolemic patients who otherwise fail to respond to statin therapy . Thus, in the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) clinical trial of 18 924 participants, the risk of recurring cardiovascular events was reduced in patients with previous acute coronary syndrome who were on high intensity statin therapy when they received alirocumab compared to the placebo control . In the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial involving 27 564 participants with CVD and LDL‐C of 70 mg dL –1 (1.8 mmol L –1 ), evolocumab reduced both LDL‐C and the risk of cardiovascular events compared to those receiving placebo .…”

Real‐world study: Escalating targeted lipid‐lowering treatment with PCSK9‐inhibitors and lipoprotein apheresis

“…Sustained exposure to highly elevated LDL‐C levels accelerates cholesterol deposition and vascular inflammation with subsequent development of ASCVD progression and premature cardiovascular events . The evidence clearly indicates that reducing LDL‐C by statins, ezetimibe, or monoclonal antibodies for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition can prevent ASCVD‐associated events . LDL‐C has both a causal and a cumulative effect on the risk of ASCVD.…”

Trials in “True” Dyslipidemic Patients Are Urged to Reconsider Comprehensive Lipid Management as a Means to Reduce Residual Cardiovascular Risk

“…Evolocumab and alirocumab, the two compounds that reached the market, were tested in full programs of phase III studies (PROFICIO and ODYSSEY, respectively) focusing on changes in the lipid profile and tolerability in candidates suitable for this type of medicine (i.e., high‐risk statin‐intolerant patients with primary hypercholesterolemia and patients with heterozygous FH inadequately controlled by standard therapy) ( Table 1 ). However, the two main cardiovascular outcome trials using anti–PCSK‐9 antibodies (FOURIER and ODYSSEY OUTCOMES, respectively) did not target these “challenging” patients but rather broad categories of high‐risk patients with LDL‐C levels perhaps not “optimal” but acceptably controlled through statins (baseline LDL‐C 92 mg/dL in FOURIER and 87 mg/dL in ODYSSEY OUTCOMES). These values are substantially lower than those of most studies with surrogate outcomes that provided backing to regulatory filing ( Table 1 ).…”

“…The meta‐regression scatter plot was constructed using the same data on statin trials published by Silverman et al . in 2016 (eFigure in the Supplemental Material of the quoted paper) with the addition of seven more recent studies with ezetimibe and PCSK‐9 inhibitors . Data of individual trials included in the analysis are shown in Table .…”