Results of the much anticipated ODYSSEY Outcomes trial were presented today by Professor Phillipe Gabriel Steg, who is the chief of cardiology at Bichat-Claude Bernard Hospital, at the American College of Cardiology (ACC) Scientific Sessions in Orlando. Alirocumab, a monoclonal antibody directed against PCSK9, reduced major adverse cardiovascular events (MACE), myocardial infarction (MI), ischemic stroke and all-cause mortality in patients post-acute coronary syndrome (ACS), who were on high-intensity statin therapy.
Alirocumab has previously been shown to reduce LDL and other atherogenic lipoprotein levels. In this trial, Steg and his colleagues aimed to evaluate the effect of Alirocumab on long term cardiovascular outcomes in ACS patients.
A total of 18,924 patients were randomized at 1315 sites in 57 countries, between Nov 2, 2012 − Nov 11, 2017, with a follow up median period of 2.8 years. Patients who were ≥ 40 years of age, and had a median baseline LDL level of 87 mg/dl were randomized to receive Alirocumab subcutaneously every 2 weeks or a matched placebo. The median time from index ACS to randomization was 2.6 months in both arms. Patients were followed for up to 4 years. The primary outcome of the was a composite of coronary heart disease (CHD) death, non-fatal MI, fatal or non-fatal ischemic stroke and unstable angina requiring hospitalization. Secondary efficacy endpoints include CHD events, cardiovascular (CV) events, CHD death, CV death, and all-cause mortality.
Alirocumab demonstrated a statistically significant 15% reduction in the hazard of major adverse cardiovascular events (MACE) and all-cause mortality, with an absolute risk reduction of 1.6 percent and 0.6 percent, respectively. While Alirocumab did not significantly reduce CHD or CV deaths, it did significantly reduce non-fatal MI, ischemic stroke and unstable angina. After 48 months of therapy, patients on Alirocumab had a median LDL of 53.3mg/dl, whereas those on placebo had a median LDL level of 101.4 mg/dl. Steg reported no adverse events over three years among patients treated with Alirocumab, other than injection site reactions.
“When we look at benefit and risk – here we have all benefit and no risk.” – Prof. Gabriel Steg
In a pre-specified subgroup analysis, Alirocumab showed a statistically significant reduction in the primary endpoint among patients with LDL ≥ 100mg/dl, but not in patients with LDL < 80mg/dl or LDL 80-100mg/dl. The treatment effect of Alirocumab was not statistically significantly modified by baseline LDL levels.
One year ago at the ACC meeting in Washington D.C., the FOURIER trial results were presented and demonstrated a reduction in MACE but no reduction in mortality associated with the use of another PCSK9 inhibitor, Evolocumab. The ODYSSEY Outcomes trial differed from FOURIER in that it enrolled patients with a recent ACS, and not patients with stable CHD. Additionally, the ODYSSEY Outcomes trial had a longer follow-up period.
This trial represents the second PCSK9 monoclonal antibody that has demonstrated a reduction in major adverse cardiovascular events and the first to reduce all-cause mortality.