AEGIS-II: ApoA-1 did not reduce MACE in patients with myocardial infarction but may provide benefit in patients with high LDL levels

Infusions with human apolipoprotein A-1 (ApoA-1), a cholesterol efflux enhancer, failed to achieve the primary endpoint of a significant reduction in major adverse cardiovascular events (MACE) in patients with myocardial infarction (MI) and additional risk factors at 90 days. This might not be the end of the HDL hypothesis, as an exploratory analysis suggests a benefit for certain subgroups.

The rationale of the AEGIS-II trial was to optimise the function of HDL in the so-called reverse transport of cholesterol from the periphery of the body to the liver, by increasing HDL-mediated cholesterol efflux capacity. This should be accomplished by infusions with ApoA-1, the main component of HDL cholesterol. In the previous AEGIS-I trial, a single infusion of purified human ApoA-1 (CSL112) indeed increased cholesterol efflux in the setting of MI [1].

The phase 3, international AEGIS-II trial (NCT03473223), presented by Prof. Michael Gibson (Harvard Medical School, MA, USA), enrolled 18,219 participants who had been hospitalised for an MI [2,3]. All participants had multivessel disease and additional cardiovascular risk factors. They were randomly assigned to receive infusions of either CSL112 or a placebo for 4 weeks, with the first infusion given within 5 days of hospitalisation. The study’s primary endpoint was the time to the first occurrence of MACE (i.e. MI, stroke, or cardiovascular death) through 90 days.

Participants treated with CSL112 had a 4.8% rate of MACE compared with 5.2% in the placebo group, a difference that was not statistically significant (HR 0.93; 95% CI 0.81–1.05; P=0.24). In an exploratory analysis, the researchers included participants whose LDL cholesterol level was ≥100 mg/dL at baseline despite statin therapy. These participants appeared to have a 30% lower rate of the primary endpoint at 90 days (HR 0.69; 95% CI 0.53–0.90; P=0.007) while those with LDL cholesterol <100 mg/dL had no apparent benefit. “LDL at baseline modulated the treatment effect; the magnitude of treatment effect increased with the LDL concentrations,” Prof. Gibson commented. Overall ApoA-1 appeared to have a reassuring safety profile.

The benefit of ApoA-1 infusions in hyperlipidaemic patients is biologically plausible, but Prof. Gibson emphasised that this observation is hypothesis-generating and requires prospective validation in further studies.

1. 
   
   1. Gibson CM, et al. Circulation 2016;134:1918-1930.
   2. Gibson CM, et al. N Engl J Med 2024;390:1560–1571.
   3. Gibson CM, et al. CSL112 (Apolipoprotein A-I) Infusions And Cardiovascular Outcomes In Patients With Acute Myocardial Infarction (ApoA-I Event Reducing In Ischemic Syndromes II (AEGIS-II) Trial): Primary Trial Results. LB1, Session 402, ACC 2024 Scientific Session, 6–8 April, Atlanta, USA.

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Posted on 16 May 202413 June 2024