The trial showed alirocumab reduced MACE by 24% with an ARR of 3.4% and all-cause death by 29% with an ARR of 1.7% in patients with ACS and baseline LDL-C ≥100 mg/dL.
P. Gabriel Steg, MD
Alirocumab (Praulent, Sanofi) has been shown to reduce major adverse cardiovascular events (MACE), as well as reduce all-cause mortality when compared to placebo in patients with acute coronary syndrome (ACS) with elevated levels of atherogenic lipoproteins despite intensive or maximum-tolerated statin therapy, according to the much-anticipated results of the ODYSSEY OUTCOMES trial.
Presented by P. Gabriel Steg, MD, at the 67th American College of Cardiology’s Scientific Sessions in Orlando, Florida, the trial showed an absolute risk reduction (ARR) of 1.6% (hazard ratio [HR], 0.85; 95% CI, 0.78—0.93; P = .0003) in MACE—a composite including coronary heart disease (CHD), non-fatal myocardial infarction (MI), ischemic stroke, or unstable angina requiring hospitalization—over the course of the 4-year study period.
“Among patients with ACS and baseline [low-density lipoprotein cholesterol (LDL-C)] 100 mg/dL or greater—the patients that may benefit the most from this treatment—alirocumab reduced MACE by 24% with an ARR of 3.4%,” Steg, a professor of cardiology at Université Paris-Diderot, as well as faculty with the National Heart and Lung Institute, said. “All-cause death was reduced by 29% with an ARR of 1.7% compared with placebo.”
MACE occurred in the intervention arm in 9.5% (n = 903) of patients compared with 11.1% (n = 1052) in the placebo arm. The composite factors of coronary heart disease death (alirocumab, 2.2%, n = 205; placebo, 2.3%, n = 222; HR, 0.92; 95% CI, 0.76—1.11; P = .38), non-fatal MI (alirocumab, 6.6%, n = 626; placebo, 7.6%, n = 722; HR 0.86,; 95% CI, 0.77—0.96; P = .006), ischemic stroke (alirocumab, 1.2%, n = 111; placebo, 1.6%, n = 152; HR, 0.73; 95% CI, 0.57—0.93; P = .01.), and unstable angina (alirocumab, 0.4%, n = 37; placebo, 0.6%, n = 60; HR, 0.61; 95% CI, 0.41—0.92; P = .02.) were also lower across the board for patients receiving alircoumab.
The trial randomized 18,924 patients to receive either the intervention (n = 9462) or placebo (n = 9462). Patient retention post-randomization was excellent, with only 14 patients in the alirocumab arm and 9 in the placebo arm lost to follow-up, although 14.2% (n = 1343) and 15.8% (n = 1496) in the intervention arm and placebo arm, respectively, discontinued treatment prematurely.
“We looked at the primary efficacy in the main pre-specified subgroups and found on interaction, and in fact, a consistent benefit regardless of age, sex, the region of the world, and time between index and randomization,” Steg said. “Given that this was all in pre-specified subgroups, we wanted to further explore, with a post-hoc analysis, the mortality in these 3 subgroups.”
In addition to showing a reduction in MACE and all-cause death in patients with baseline LDL-C 100 mg/dL or greater, incidence of CHD death and cardiovascular death resulted in an ARR of 1.0 (HR, 0.72; 95% CI, 0.53—0.98) and 1.3 (HR, 0.69; 95% CI, 0.52–0.92), respectively.
Alirocumab, a fully monoclonal PCSK9 inhibitor, has been shown to provide substantial reductions in LDL-C and has shown to be safe and well-tolerated in previous studies, but this marks the first time a reduction in all-cause mortality was observed.
At baseline, the alirocumab arm and placebo arms were similar in LDL-C, both with mean levels of 87 mg/dL (range, 73—104 mg/dL) each. Other measurements of lipids, such as non-high-density lipoproteins (HDL), apolipoprotein B, HDL-C, triglycerides, and lipoprotein(a), were all nearly identical in both groups.
The therapy was also well-tolerated in the ODYSSEY trial, with the only distinctive and clinically significant difference between the intervention and the control arms being a local injection site reaction, occurring in 3.8% (n = 360) patients receiving alirocumab compared to 2.1% (n = 203) in the placebo arm.
“There was no difference between adverse events or serious adverse events between the 2 groups,” Steg said. “There was no increase in the frequency of worsening or complications of diabetes, no difference in new-onset diabetes in patients without diabetes at baseline, and no difference in general allergic reactions, hepatic disorders, neurocognitive disorders, cataracts, or incidence of hemorrhagic stroke.”
In comparison to the FOURIER trial, a landmark trial which was the first to show reductions in MACE with a PCSK9 inhibitor, Steg noted it was important to recognize the differences between the 2 in order to realize the clinical significance. There were a few notable differences, including patient population—the ODYSSEY trial tested patients with ACS conditions, while the FOURIER trial tested stabilized patients with atherosclerotic cardiovascular disease, Steg noted.
“Two other important features are the intensity of the background statin therapy, which I believe is pretty maximal in ODYSSEY, and the length of follow-up, which can be the key differentiator,” Steg said. “It was slightly longer in ODYSSEY, with 44% of the patients reaching more than 3 years follow-up and being followed for 7 to 8 months longer than in FOURIER.”
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