Search

Background:Lowering of atherogenic lipoproteins, including LDL-C, reduces the risk of ischemic stroke. However, concerns have been raised about intense lipid-lowering and a potential increased risk of hemorrhagic stroke. The ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab (ALI) with placebo in 18,924 patients (pts) with recent acute coronary syndrome (ACS) and elevated atherogenic lipoproteins, including LDL-C?70 mg/dL, despite intensive statin therapy, targeting LDL-C levels of 25?50 mg/dL and avoiding sustained LDL-C <15 mg/dL. This prespecified analysis determined the effect of ALI on ischemic and hemorrhagic stroke. We hypothesized that for pts treated with ALI there would be a reduction in risk of ischemic stroke without increasing hemorrhagic stroke, irrespective of history of cerebrovascular disease (CeVD) and of baseline LDL-C.Methods:Pts were randomized to ALI or placebo 1?12 months after ACS. The risk of nonfatal or fatal ischemic or hemorrhagic stroke, stratified by history of CeVD and baseline LDL-C level, was evaluated.Results:Median follow-up was 2.8 years. The figure shows HRs (95% CI) for stroke by history of CeVD and baseline LDL-C category. ALI reduced the risk of any stroke (HR 0.72, 0.57?0.91) and ischemic stroke (HR 0.73, 0.57?0.93) without increasing hemorrhagic stroke (HR 0.83, 0.42?1.65). Among 944 pts (5.0%) with a history of CeVD, treatment effect of ALI on stroke was similar to that in pts without a history of CeVD (Pinteraction=0.37). In total, 7,166 (37.9%), 6,128 (32.4%), and 5,629 (29.7%) pts had a baseline LDL-C of <80, 80?100, >100 mg/dL, respectively. Treatment effect appeared numerically greater for pts with higher baseline LDL-C, but the linear trend was not significant (Pinteraction=0.31).Conclusion:In pts with recent ACS and dyslipidemia despite intensive statin therapy, ALI decreased the risk of ischemic stroke without increasing hemorrhagic stroke, irrespective of history of CeVD and of baseline LDL-C.

Background:Statins reduce ischemic cardiovascular risk irrespective of age, but the evidence is less strong for older patients. The ODYSSEY OUTCOMES trial compared alirocumab (ALI) with placebo, added to high-intensity or maximum-tolerated statin treatment, after ACS in 18,924 patients. ALI reduced the primary composite endpoint (MACE) of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke or unstable angina requiring hospitalization.Methods:In this prespecified analysis comparing the effect of ALI vs placebo on outcomes, we evaluated the impact of age at randomization on the occurrence of ischemic events and the relative impact of ALI vs placebo on these events. Patients were stratified according to age at enrollment (< vs ? 65 years). In addition, age was treated as a continuous variable in regression models.Results:Patients >65 years of age represented 27% of the population (Figure). For the primary outcome, there was no difference in the relative risk reductions between patients ?65 vs <65 years for MACE (HR 0.78, 95% CI 0.68-0.91 vs HR 0.89, 0.798-0.997; Pinteraction=0.19) or for all-cause death (HR 0.77, 0.62-0.95 vs HR 0.94, 0.77-1.15; Pinteraction=0.46). When considering age as a continuous variable, advancing age increased the risk of MACE, with a sharp increase of the slope >65 years (Figure). Age did not affect the relative risk reductions with ALI. However, absolute risk reduction increased with advancing age, with number-needed-to-treat for MACE at 3 years of 43 (25-186) for a 45-year-old patient vs 26 (15-97) or 12 (6-81) for patients at age 75 or 85. Although adverse events were observed more frequently in older patients, there were no differences between ALI and placebo.Conclusion:In patients with recent ACS, ALI improves outcomes irrespective of age. Increasing treatment benefit but not harm with advancing age suggests that marked LDL-C lowering is an important secondary preventive intervention for older patients.

Introduction:Statins reduce CV risk in ACS patients (pts) with non-dialysis chronic kidney disease, but we do not know if the benefit of PCSK9 inhibition after ACS is affected by renal dysfunction.Hypothesis:PCSK9 inhibition with alirocumab decreases the incidence of major adverse CV events (MACE) after ACS independent of glomerular filtration rate (GFR).Methods:In the ODYSSEY OUTCOMES trial, 18,924 pts with recent ACS and raised atherogenic lipoproteins despite intensive/maximum-tolerated statins were randomized to alirocumab 75mg or placebo (PBO) every 2 weeks. GFR was estimated with the MDRD formula. Protocol excluded pts with GFR<30mL/min/1.73 m2; 41 pts with GFR<30 were nonetheless randomized and included in the analysis. Heterogeneity in the alirocumab effect on the primary MACE endpoint (death due to coronary heart disease, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization) was determined by interaction with continuous baseline GFR, and smoothed MACE incidence curves were fit by within treatment group baseline GFR decile. Analyses were done on an intention-to-treat basis.Results:Median follow-up was 2.8 years. At baseline, mean GFR was 80?19mL/min/1.73 m2and LDL-C was 92?31mg/dL in both groups. At 4 months, on average alirocumab decreased LDL-C by 61.9% vs PBO. Overall, alirocumab reduced incident MACE (9.5% vs 11.1%; HR 0.85, 95%CI 0.78?0.93) and was associated with fewer deaths (3.5% vs 4.1%; HR 0.85, 95%CI 0.73?0.98). Risk of MACE increased with decreasing baseline GFR; a consistent effect of alirocumab was observed across the range of GFR (Fig left; P for interaction of treatment and GFR=0.21). Findings were similar for death (Fig right). Adverse events were similar and mean GFR at 36 months did not differ between alirocumab (80?20) and PBO (80?19) groups.Conclusion:In pts with recent ACS, alirocumab is associated with lower incidence of MACE across all GFR ranges. Alirocumab did not affect GFR.