Treatment with alirocumab reduced cardiovascular outcomes and all-cause deaths by 15 percent in patients with acute coronary syndrome (ACS) and higher-than-ideal atherogenic lipoprotein levels despite intensive or maximally tolerated statin therapy, according to results of the ODYSSEY Outcomes trial. The results were presented by Philippe Gabriel Steg, MD, FACC, on Saturday, March 10 in the first Late-Breaking Clinical Trial session at ACC.18 in Orlando, FL. A 24 percent reduction in the primary outcome was found in patients starting with an LDL-C ≥100 mg/dL.

ODYSSEY Outcomes included 18,924 patients at 1,315 sites in 57 countries who had an ACS within the previous 12 months. Patients had residual LDL-C levels ≥70 mg/dL, non–HDL-C ≥100 mg/dL or apolipoprotein B ≥80 mg/dL after two to 16 weeks of intensive or maximally tolerated statin therapy (atorvastatin or rosuvastatin). Most patients (92.5 percent) qualified due to LDL-C ≥70 mg/dL.

Patients were randomized to either subcutaneous injections of alirocumab 75 mg every two weeks (n=9,462) or placebo (n=9,462). The target LDL-C level was 25 to 50 mg/dL. To maximize the number of patients in the target range, alirocumab was uptitrated to 150 mg every two weeks in patients with LDL-C ≥50 mg/dL. Patients who had LCL-C levels consistently below 15 mg/dL were switched to placebo.

After a median follow-up of 2.8 years, LDL-C levels were 53.3 mg/dL in the alirocumab group compared with 101.4 mg/dL in the placebo group, for an absolute reduction of 54.7 percent. The primary endpoint of major adverse cardiovascular events (MACE) – the time to first occurrence of coronary heart disease (CHD) death, nonfatal myocardial infarction (MI), unstable angina requiring hospitalization or ischemic stroke – was significantly lower in the alirocumab group versus the placebo group (9.5 vs. 11.1 percent).

Looking at the individual components, researchers found nonfatal MI was reduced by 14 percent, stroke by 27 percent and unstable angina by 39 percent (all significant) with alirocumab compared with placebo. While the rate of all-cause death was significantly lower by 15 percent with alirocumab versus placebo (3.5 vs. 4.1 percent), there was no significant difference between the groups for CHD death (2.2 vs. 2.3 percent) and cardiovascular death (2.5 vs. 2.9 percent). In terms of safety, treatment-emergent adverse events occurred in 75.8 percent and 77.1 percent of the alirocumab and placebo groups, respectively. Minor local site reactions at the injection site were the only significant difference between the two groups, occurring in 3.1 percent of those receiving alirocumab and 2.1 percent of those receiving placebo. In the prespecified post hoc analysis by LDL-C level at baseline, patients with an LDL-C ≥100 mg/dL experienced reductions in all endpoints. The 24 percent reduction in MACE translated to an absolute risk reduction (ARR) of 3.4 percent.  CHD death was reduced by 28 percent (ARR 0.9 percent), CV death by 31 percent (ARR 1.3 percent) and all-cause death by 28 percent (ARR 1.7 percent).

"We were really pleased to see the treatment was effective and associated with a reduction in mortality. It is remarkable that such a potent intervention is also so safe," said Steg. "Because the treatment effect was so much more marked in the patients with the highest LDL cholesterol, we believe that these patients are the optimal candidates for therapy."

ODYSSEY Outcomes is the second outcomes trial with a PCSK9 inhibitor to show a reduction in LDL-C and cardiovascular endpoints. At ACC.17, the FOURIER trial with evolocumab reported a 15 percent reduction in the risk of death, MI, stroke, hospitalization for angina or revascularization. Compared with FOURIER, the ODYSSEY Outcomes trial enrolled a higher-risk group of patients, had a longer duration of follow-up (ranging from two to five years), involved a different dosing strategy and had a slightly different primary endpoint.

"Now that we have two trials that consistently show benefits from PCSK9 inhibitors, and given the mortality benefit that we are reporting here for the first time, I think these results may change the equation for these drugs," Steg said. "We're not just talking about preventing nonfatal events such as heart attacks but actually preserving life."

Keywords: ACC18, ACC Annual Scientific Session, Angina, Stable, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Acute Coronary Syndrome, Maximum Tolerated Dose, Brain Ischemia, Stroke, Antibodies, Monoclonal, Apolipoproteins B, Myocardial Infarction, Coronary Disease, Treatment Outcome, Hospitalization, Subtilisins, ACC Scientific Session Newspaper

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