There is a high incidence of early recurrence of cardiovascular (CV) events after acute myocardial infarction (AMI), especially in patients with multivessel coronary artery disease. Apolipoprotein A-I (ApoA-I)-mediated macrophage cholesterol efflux is the first step in retrograde cholesterol transport, and cholesterol from atherosclerotic plaques is transported to the liver for excretion. CSL112 is a plasma-derived intravenous formulation of human ApoA-I that increases cholesterol efflux capacity (CEC).
On April 6, local time, at the first joint session of the latest clinical trial LBCT I-ACC/JACC at the 73rd American College of Cardiology Annual Meeting (ACC.24), C. Dr. Michael Gibson presented the full results of the AEGIS-II trial, which showed that CSL112 did not significantly reduce the risk of CV death, MI, or stroke compared with placebo, but the incidence was statistically low. The study was published simultaneously in the New England Journal of Medicine.
Research Methods:
The AEGIS-II trial is an international, multicenter, randomized, double-blind, placebo-controlled trial that enrolled 18,231 patients with AMI (50.5% STEMI) with coronary multivessel disease and other CV risk factors. Of these, 74 per cent were male, with an average age of 65 years. Patients were randomized to receive either ApoA-I (6g CSL112) infusions or placebo four times a week, with the first infusion administered within 5 days of the first medical contact with AMI. Median low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels at baseline were 84 mg/day and 39 mg/dL, respectively.
The primary efficacy endpoint was the time from randomization to the first occurrence of a composite outcome (CV death, MI, or stroke) within 90 days, analysed on an intention-to-treat basis.
Key secondary efficacy outcomes tested in statistical stratification included the total number of hospitalisations for coronary, cerebral or peripheral ischemia from the start of randomisation to 90 days, and the time to first occurrence of a composite outcome (CV death, MI or stroke) from the start of randomisation to 180 days and 365 days.
Findings:
In terms of primary endpoints, there was no significant difference between study and placebo groups in the primary composite endpoint of risk of MI, stroke, or CV death at 90 days (4.9% vs. 5.2%; P=0.24) (Figure 1). Similarly, at 180 days (6.9% vs. 7.6%; P=0.077) and 365 days (9.8% vs. 10.5%; P=0.137).
Fig.1 Primary endpoint
There was no difference in any of the pre-specified key secondary endpoints except for MI, which was less common in the study arm than placebo at 180 days (5.0% vs. 5.7%) and 365 days (7.2% vs. 7.9%) (Table 1).
Table 1 Other preset key secondary endpoint results
However, in an exploratory analysis published in the Journal of the American College of Cardiology (JACC), patients treated with CSL112 were 14% less likely to develop or die of heart disease within 180 days. In addition, patients treated with CSL112 were 32% less likely to have a heart attack due to stent thrombosis within 90 days and 29% less likely to have 180 days.
In addition, in an exploratory analysis, CSL112 infusion was numerically lower at 90 days (1.4% vs. 1.7%), 180 days (2.2% vs. 2.6%), and 365 days (3.4% vs. 3.9%) compared with placebo infusion (Figure 2). The same was true for patients with type 4b MI at 90 days (0.5 versus 0.8 percent), 180 days (0.6 versus 0.9 percent), and 365 days (0.8 versus 1.0 percent).
Fig.2 Incidence of MI events by MI type
The results of the study were maintained in various subgroups. However, exploratory analyses have found a greater benefit of CSL112 infusion in patients with baseline hyperlipidemia (LDL-C≥100 mg/dL). Compared with placebo, the incidence of the primary composite endpoint at 90 days was significantly lower in the CSL112 group (3.4% vs. 4.9%; P=0.007), 180 days (5.3% vs. 7.3%; P=0.002) and 365 days (7.8% vs. 9.9%; P=0.006) (Figure 3).
Fig.3 The primary endpoint events of patients with baseline hyperlipidemia (LDL-C≥100mg/dL, all on statins).
There was also a significant benefit in the CSL112 group compared with placebo for the outcomes CV death, MI, and CV death/MI (Figure 4). For patients with baseline LDL-C < 100 mg/dL, there was no reduction in risk for the primary endpoint.
Fig.4 CV death and MI events in patients with baseline hyperlipidemia (LDL-C≥100mg/dL, all statins).
In terms of safety, the rates of adverse events and hypersensitivity events were similar between the two groups, but in the CSL112 cohort, there were more immune system disturbance events leading to discontinuation (14 vs. 4; P = 0.02). CSL112 was associated with a good renal safety profile and fewer acute kidney injury events compared with placebo (6.3 versus 7.2 percent; P = 0.02）。
Conclusions of the study
Although CSL112 did not significantly reduce the risk of CV death, any MI, or stroke in the AEGIS-2 trial, exploratory analyses found that CSL112 infusion was numerically associated with a lower incidence of CV death and MI (primarily spontaneous MI and MI due to stent thrombosis) in high-risk patients with AMI. These findings may be consistent with the biological role of ApoA-I and cholesterol efflux enhancement in reducing the risk of plaque destruction. More prospective data are needed to confirm these observations.
Research Reviews
Dr. C. Michael Gibson said that while the study failed to meet the primary endpoint, its data support the hypothesis that HDL-C plays a role in reducing subsequent coronary plaque destruction events such as heart attacks by enhancing cholesterol efflux.
Overall, the results of this trial were consistent with ApoA-I's ability to stabilize cardiac plaques and reduce the risk of plaque rupture, which can lead to heart attacks after 90 days. By administering ApoA-I to remove cholesterol from the body, followed by treatment with cholesterol-lowering drugs to maintain LDL-C levels, a decrease in deaths and heart attacks can be observed over time, which seems plausible. Future research will focus on identifying high-risk patients who may benefit from this approach.
In addition, C. Dr Michael Gibson said the significant reduction in the number of heart attacks due to stent thrombosis could also be explained by the antiplatelet effects of CSL112 or the reduction in intra-arterial cholesterol caused by CSL112 treatment. The reason for the unabated stroke may be that the stroke can be caused by a mechanism other than arterial plaque rupture.
In an accompanying editorial, Dr. Christie M. Ballantyne and Dr. Vijay Nambi from Baylor College of Medicine in Houston, Texas, noted that there are still many unanswered questions in this area that need future research, including the effect of baseline cholesterol efflux capacity values on outcomes, the long-term clinical effects of drugs such as CSL112, and the feasibility of long-term weekly infusions. They say that before declaring the AEGIS-II trial the final curtain and launching therapies targeting "very disappointing lipoproteins," there may be a need to rethink and focus on developing better assays to assess HDL function that can be used in conjunction with genomics, metabolomics, proteomics and transcriptomics to identify new targets and the right populations to test therapies that improve cholesterol efflux and HDL function in these populations.
参考文献1. ACC官网2.Yael L. Maxwell. Full AEGIS-II Results: Raising HDL With Apo A-I No Help After Acute MI. Tctmd. Apr 06, 2024.
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