Effect of alirocumab on major adverse cardiovascular events according to renal function in patients with a recent acute coronary syndrome: prespecified analysis from the ODYSSEY OUTCOMES randomized clinical trial
José Tuñón, Philippe Gabriel Steg, Deepak L Bhatt, Vera A Bittner, Rafael Díaz, Shaun G Goodman, J Wouter Jukema, Yong-Un Kim, Qian H Li, Christian Mueller, Alexander Parkhomenko, Robert Pordy, Piyamitr Sritara, Michael Szarek, Harvey D White, Andreas M Zeiher, Gregory G Schwartz, for the ODYSSEY OUTCOMES Investigators
This prespecified analysis of the ODYSSEY OUTCOMES trial examined whether the reduction of Major adverse cardiovascular events (MACE) with alirocumab, added to intensive or maximum-tolerated statin therapy after Acute coronary syndrome (ACS), depends upon the level of estimated glomerular filtration rate (eGFR).
The trial was a randomized, double-blind, placebo-controlled comparison of alirocumab or placebo in 18,918 patients with an ACS (myocardial infarction or unstable angina) 1–12months before randomization. Qualifying patients had persistent dyslipidemia [LDL-C≥ 70mg/dL (1.81mmol/L), nonhigh-density lipoprotein cholesterol (non-HDL-C) ≥ 100mg/dL (2.59mmol/L), or apolipoprotein B≥ 80mg/dL (0.0016mmol/L)] despite treatment with atorvastatin 40–80 mg daily, rosuvastatin 20–40mg daily, or the maximum-tolerated dose of one of these statins (including no statin in case of documented intolerance).
Participants were randomly assigned (1:1) to receive alirocumab 75mg or matching placebo subcutaneously every 2weeks. A treat-totarget design aimed to achieve an LDL-C level of 25–50mg/dL among alirocumab treated patients. Alirocumab 75mg was blindly up-titrated to 150mg if the LDL-C level was >50mg/dL. If LDL-C was <15mg/dL on two consecutive measurements on the 75mg dose of alirocumab, placebo was blindly substituted for the rest of the trial.
The primary outcome was a composite of MACE, including death due to coronary heart disease, non-fatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. Death from any cause was a secondary outcome. All outcomes were blindly adjudicated.
This prespecified analysis also investigated whether the effect of alirocumab on MACE and death varied across the range of baseline renal function, analyzed the incidence of adverse effects as a function of eGFR, and looked for potential effects of alirocumab on eGFR.
A total of 18 924 patients underwent randomization; Of these, 9462 were assigned to alirocumab and 9462 to placebo.
Alirocumab decreased LDL-C by 62.2% and 48.5% vs. placebo at 4 and 36 months, respectively. Overall, alirocumab reduced risk of the primary outcome (coronary heart disease death, non-fatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization) with fewer deaths. There was no interaction between continuous eGFR and treatment on the primary outcome or death (P = 0.14 and 0.59, respectively). Alirocumab reduced primary outcomes in patients with eGFR ≥90mL/min/1.73 m2 (n = 7470; hazard ratio 0.784, 95% confidence interval 0.670–0.919; P = 0.003) and 60 to <90 (n = 9326; 0.833, 0.731–0.949; P= 0.006), but not in those with eGFR< 60 (n = 2122; 0.974, 0.805–1.178; P = 0.784). Adverse events other than local injection-site reactions were similar in both groups across all categories of eGFR.
In patients with recent ACS, alirocumab was associated with fewer cardiovascular events and deaths across the range of renal function studied, with larger relative risk reductions in those with eGFR > 60 mL/min/1.73 m2.
- Tuñón, J., Steg, P.G., Bhatt, D.L., Bittner, V.A., Díaz, R., Goodman, S.G., Jukema, J.W., Kim, Y.U., Li, Q.H., Mueller, C. and Parkhomenko, A., 2020. Effect of alirocumab on major adverse cardiovascular events according to renal function in patients with a recent acute coronary syndrome: prespecified analysis from the ODYSSEY OUTCOMES randomized clinical trial. European heart journal, 41(42), pp.4114-4123.