MACE safely reduced by another PCSK9 inhibitor in long term outcomes trial in high-risk patients
The ODYSSEY OUTCOMES Trial: Topline Results - Alirocumab in Patients After Acute Coronary Syndrome
Presented at ACC.18 by Ph. Gabriel Steg (Paris, France)Mar. 13, 2018 - news
Introduction and methods
Patients who have experienced a myocardial infarction (MI), show a high cardiovascular event risk in the first year following the event, despite lipid-lowering treatment, as well as in the 3.5 years after that. Thus, additional treatment is needed to lower this residual CV risk.
Alirocumab is a PCSK9 inhibitor that lowers LDL-c, the efficacy and longer term safety of which was evaluated in the ODYSSEY OUTCOMES trial. Participants had experienced an acute coronary syndrome (ACS, MI or unstable angina) 1 to 12 months prior to randomization. Patients were on high-intensity statin therapy (atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily or maximum tolerated dose of one of these agents for ≥2 weeks) and showed inadequate control of lipids despite therapy (LDL-c ≥70 mg/dL (1.8 mmol/L) or non-HDL-c ≥100 mg/dL (2.6 mmol/L) or apolipoprotein B ≥80 mg/dL. 18924 patients were randomized to either alirocumab (75 or 150 mg Q2W) or placebo, and followed for a median of 2.8 years. Treatment target was LDL-c levels between 25 and 50 mg/dL, and allowing levels as low as 15 mg/dL. 1955 Patients experienced a primary endpoint (major adverse cardiovascular events (MACE): coronary heart disease (CHD) death, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization) and 726 patients died.
- Patients on alirocumab showed 62.7% decrease of LDL-c after 4 months, which represents 55.7 mg/dL reduction compared with placebo, and 54.7% at 48 months after randomization (48.1 mg/dL lower than placebo).
- Treatment with alirocumab lowered the primary efficacy endpoint of MACE by 15% over the study period (HR: 0.85, 95%CI: 0.78-0.93, P=0.0003, absolute risk reduction (ARR): 1.7%).
- Of the components of the primary MACE endpoint, CHD death was not significantly reduced (HR: 0.92, 95%CI: 0.76-1.11, P=0.38), but the other components were: non-fatal MI: HR: 0.86 (95%CI: 0.77-0.96, P=0.006), ischemic stroke: HR: 0.73 (95%CI: 0.57-0.93, P=0.01) and unstable angina: HR: 0.61 (95%CI: 0.41-0.92, P=0.02).
- All-cause death was significantly reduced with alirocumab treatment as compared with placebo, but it should be noted that this was not a primary outcome (HR: 0.85, 95%CI: 0.73-0.98, nominal P=0.026, ARR: 0.6%).
- Analysis of the subgroup of patients with baseline LDL-c ≥100 mg/dL showed that these patients benefitted more from treatment with alirocumab than the overall cohort, with MACE showing a 24% reduction (HR: 0.76, 95%CI: 0.65-0.87, ARR: 3.4%, NNT: 29) and all-cause death 29% (HR: 0.71, 95%CI: 0.56-0.90, ARR: 1.7%, NNT: 60).
- Safety events were generally similar between treatment arms (including diabetes worsening or diabetic complications, new onset diabetes, allergic reactions and neurocognitive disorders), without new safety signals. Patients treated with alirocumab did show more local injection site reactions (3.8% vs. 2.1% on placebo).
These results of the ODYSSEY OUTCOMES study show that compared with placebo, in patients with recent ACS, alirocumab 75 or 150 mg Q2W reduced the primary endpoint of MACE. Moreover, a secondary analysis showed that alirocumab treatment was associated with a lower rate of all-cause death. Treatment with this PCSK9 inhibitor was safe and well tolerated over the duration of the trial.
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