Intravenous infusions of CSL112, human plasma-derived apolipoprotein A-I (apoA-I), were associated with numerically lower rates of cardiovascular death and myocardial infarction (MI), according to the AEGIS-II study presented during a Late-Breaking Clinical Trial session at ACC.24 in Atlanta and simultaneously published in the New England Journal of Medicine.

In the international, double-blind AEGIS-II study, C. Michael Gibson, MD, FACC, et al., enrolled 18,219 high-risk adult patients (mean age, 65.5 years, 74.1% men) diagnosed with type 1 MI who had multivessel coronary artery disease and evidence of additional cardiovascular risk. They were randomized 1:1 to either placebo (n=9,107) or four weekly 6 g infusions of CSL112 (n=9,112), with the first infusion administered within five days of first medical contact for MI and entire course completed within 30 days of randomization. Follow-up assessments were conducted at screening, at each infusion visit; on days 29, 60 and 90; and every 90 days until day 365.

The primary efficacy outcome of time to first occurrence of the composite of MI, stroke or cardiovascular death randomization through 90 days, assessed in a time-to-first event analysis, was not statistically significantly reduced with CSL112 vs. placebo at 4.8% vs. 5.2% (hazard ratio [HR], 0.93; 95% CI, 0.81-1.05; p=0.24). Furthermore, the numbers were lower in the CSL112 group vs. placebo group at 180 days (622 patients [6.9%] vs. 683 patients [7.6%]; HR, 0.91; 95% CI, 0.81 to 1.01) and at 365 days (885 patients [9.8%] vs. 944 patients [10.5%]; HR, 0.93; 95% CI, 0.85 to 1.02). The results were similar across multiple subgroups.

For the components of the primary endpoint at 90 days, the HRs for CSL112 vs. placebo were 0.83 for death from cardiovascular death, 0.91 for MI and 1.15 for stroke.

Results also showed that the incidence of cardiovascular death or any type of MI was numerically lower in the CSL112 group throughout follow-up: HR, 0.91 at 90 days; HR, 0.89 at 180 days, and HR, 0.92 at 365 days. For the composite of cardiovascular death and non-type 2 MI, which the authors noted may not be affected by plaque stabilization, HRs were 0.91, 0.87 and 0.91 at days 90, 180 and 365, respectively.

Regarding safety, the rate of adverse events was similar on both groups.

"Testing the HDL hypothesis in the context of successful implementation of low-density lipoprotein-lowering therapies is increasingly challenging," wrote Gibson, et al. "The patients in this trial showed excellent adherence to evidence-based and guideline-directed therapies that also included dual antiplatelet therapy. If apolipoprotein A1 infusions have a benefit in reducing myocardial infarction beyond that of modern pharmacotherapies and device-based therapies, the benefit appears to be modest."

In an accompanying editorial comment, Christie M. Ballantyne, MD, FACC, and Vijay Nambi, MD, PhD, FACC, note modulation of HDL and LDL cholesterol has been among the most frustrating aspects of efforts to prevent cardiovascular disease. "Before declaring that the AEGIS-II trial is the final curtain call and retiring therapies aimed at the 'Highly Disappointing Lipoprotein," perhaps a reconceptualization is needed that focuses on developing better assays for characterizing HDL functions … and the correct population in which to test therapies to improve cholesterol efflux and functionality of HDL."