AEGIS-II: Apo A-I Infusions Did Not Reduce 90-Day MACE but Trended Towards Reduction in CV Death and MI

By Leah Kosyakovsky on

Key Points:

  • Post-MI adverse cardiovascular events remain high despite robust evidence-based antiplatelet, statin, and anticoagulant therapy.
  • Cholesterol efflux is impaired post-MI and has been associated with  short- and long-term MACE. A novel human plasma–derived apolipoprotein A1 (CSL112) was developed to increase cholesterol efflux capacity with the goal of improving cholesterol efflux post-MI.
  • In the AEGIS-II study, intravenous infusions of CSL112 were compared with placebo in patients with type I acute MI. The primary endpoint was 90-day CV death, MI, or stroke.
  • CSL112 did not result in a significant reduction in the primary endpoint; however, patients treated with CSL112 infusions had numerically lower rates of CV death and MI, type-1 MI, and stent thrombosis-related MI compared to placebo. 
  • In an exploratory analysis, CSL112 significantly reduced the primary endpoint in a subgroup of individuals with LDL ≥100 mg/dL.

Adverse outcomes remain substantially high in the acute period after myocardial infarction (MI), despite numerous evidence-based treatments targeting plaque stabilization and progression. One potential contributing pathophysiological mechanism is impaired cholesterol efflux in the acute period post MI, which has been independently associated with short- and long-term MACE post MI. A novel human plasma–derived apolipoprotein A1 (CSL112) has been developed to increase apolipoprotein A1 and cholesterol efflux capacity with the goal of improving cholesterol efflux post-MI. In a breaking presentation at the 2024 ACC conference today, Dr. C. Michael Gibson (BIDMC and Baim Institute, Boston) and his team presented their study: “AEGIS-II – Apolipoprotein A1 Infusions and Cardiovascular Outcomes after Acute Myocardial Infarction.”

The AEGIS-II trial (NCT03473223) was a randomized, double-blind international trial conducted examining the efficacy and safety of CSL112 vs placebo in reducing MACE in patients with acute MI. Participants were required to be hospitalized for type I MI with evidence of multivessel CAD and multiple CV risk factors (including diabetes or two or more of age ≥ 65 years, prior MI, or PAD). Key exclusion criteria were AKI or CKD, ongoing hemodynamic instability, or planned CABG. The primary outcome was time to first occurrence of CV Death, MI or stroke (ascertained over 90 days), and the two key secondary endpoints included 180- and one-year CV death, MI, or stroke. Additional secondary endpoints included individual sub-components of the primary composite as well as 90-day hospitalizations for coronary, cerebral, or peripheral ischemia.

A total of 18,219 patients were 1:1 randomized across 49 countries to either 6g of CSL112 or matching placebo (4.4% albumin), administered over 2 hours within 5 days of presentation and at least a) 12 hours after presentation or b) 12 hours after receiving intravenous contrast for cardiac catheterization (if applicable), whichever came later. Patients then received infusions of CSL112 or placebo weekly for 4 weeks consecutively. Overall, 90% of subjects completed all 4 infusions.

The median age was 66, and 26% were women; 51% of participants had a STEMI (vs 49% NSTEMI), and 88% underwent PCI for index MI. Participants receiving CSL112 had a numerically but not statistically significant reduction in 90-day (4.9% vs 5.2%, HR 0.93 (0.81-1.05); p=0.24), 180-day (6.9% vs 7.6%, HR 0.91 (0.81-1.01); p=0.077), or one-year (9.8% vs 10.5%, HR 0.93 (0.85-1.02); p=0.137) MACE. There were also no differences in 90-day ischemic hospitalizations. 

However, the incidence of the composite of cardiovascular death and type 1 MI was 11-16% lower in the CSL112 group over the study period (HR 0.84, 95% CI (0.7-1.0); p=0.056] on day 90, HR 0.86, (95% CI 0.74-0.99); p=0.048 on day 180, and HR 0.89, 95% CI (0.79-1.0); p=0.07 on day 365). Similarly, the incidence of CV death or any MI was numerically lower in CSL112 treated patients throughout the follow-up period for all three timepoints (HR 0.92, 95% CI (0.8-1.05), 0.89, 95% CI (0.79-0.99), and 0.91, 95% CI (0.82-1.01), respectively). The effect of CSL112 treatment on MI was predominantly observed for type 1 and 4b MI. In exploratory hypothesis-generating analyses, the primary endpoint was significantly reduced specifically in individuals with LDL ≥100 mg/dL, all of whom were already on statin therapy (HR 0.69, 95% CI 0.57-0.88; p=0.007), but not in individuals with LDL <100 mg/dL. CSL112 was well-tolerated, but it was associated with a higher rate of immune system disorder events such as hypersensitivity or anaphylactoid reactions (14 vs 4 events, p=0.02) and lower rate of AKI (570 (6.3%) vs 650 (7.2%) events, p=0.02).

When discussing the clinical implications of the study at the ACC conference, Dr. Gibson stated: “Among AMI patients with multivessel disease and additional cardiovascular risk factors on guideline directed background therapies, 4 weekly infusions of CSL112 compared with placebo did not significantly reduce the primary endpoint of CV death, MI or stroke through 90 days…however, the treatment effect in those patients with an LDL > 100 was statistically significant but not in those with LDL < 100…the benefit on ApoA-1 infusions in hyperlipidemic patients is biologically plausible, but the observation is hypothesis generating and requires prospective validation.”