Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction - The PACMAN-AMI Trial

Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction - The PACMAN-AMI Trial
Laurie Grund, PharmD, Geritom Medical, Inc.

Background: The risk of recurrent atherothrombotic events remains particularly high in patients with acute myocardial infarction, which is largely attributed to frequent coexistence of multiple non-obstructive lesions in the non-infarct-related arteries. Previous trials have demonstrated the benefits of statin therapy and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors on reduction in low-density lipoprotein cholesterol (LDL-C) levels and a reduction of ischemic cardiovascular events. Currently, there is limited evidence concerning the effect of PCSK9 inhibition on coronary plaque burden, composition, and phenotype. This trial utilized three different intracoronary imaging modalities to assess plaque composition, plaque lipid content, and fibrous cap thickness within non-infarct-related arteries to study the effectiveness of early initiation (within 24-hours after randomization) of alirocumab on coronary atherosclerosis in patients with acute myocardial infarction at baseline and after 52-weeks of therapy. 

Objective: The objective of this trial was to determine the effects of alirocumab on coronary atherosclerosis using three different modes of intracoronary imaging in patients with acute myocardial infarction, both ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI), in addition to high-intensity statin therapy.

Study Design: A total of 300 patients were randomized between May 2017 to October 2020, to receive treatment with alirocumab (n=148) or placebo (n=152) in addition to high-intensity statin. The trial was designed as an investigator-initiated, multicenter, randomized, double-blind clinical trial. Patients 18 years or older who underwent percutaneous coronary intervention of the culprit lesion for urgent STEMI or NSTEMI were eligible if they were considered suitable for intracoronary imaging with evidence of coronary atherosclerosis, but without significant obstructive disease (greater than 20% blockage but less than 50% by visual estimate) in the proximal portion of two non-infarct-related arteries. For enrollment, patients were also required to have an LDL-C level of at least 125 mg/dL if they had not been receiving a stable statin dose for at least four weeks or an LDL-C level of at least 70 mg/dL if they had been receiving a stable statin dose for at least four weeks prior to acute coronary infarction and randomization. Patients were excluded from enrollment if they had left main or three-vessel coronary artery disease, history of coronary artery bypass grafting, severe kidney dysfunction, liver disease, or known statin intolerance. Once enrolled, patients were randomly allocated in a 1:1 fashion to receive either 150 mg alirocumab or placebo, administered biweekly via subcutaneous injection for 52-weeks, in addition to rosuvastatin 20 mg once daily. Lab values and intracoronary imaging with three different modalities were used at baseline and at 52-weeks to assess disease state progression or regression in non-infarct-related arteries.

Results: For the primary endpoint, change in mean percent atheroma volume (PAV) from baseline with intravascular ultrasound, showed significantly greater reduction in the alirocumab group compared with placebo (-2.13% [95% CI -2.53% to -1.73%] vs -0.92% [95% CI -1.28% to -0.56%]; and a between group difference of -1.21% [95% CI -1.78% to -0.65%]; P<0.001). For secondary clinical outcomes, the number of centrally adjudicated clinical events in the alirocumab vs the placebo group were found to be 2 (1.4%) vs 1 (0.7%) for all cause mortality, 2 (1.4%) vs 0 for cardiac death, 2 (1.4%) vs 3 (2.0%) for myocardial infarction, and 12 (8.2%) vs 28 (18.5%) for ischemia-driven coronary revascularization. Additionally, the biochemical analysis showed a significant reduction in LDL-C from baseline and 52-weeks between the two as-treated groups. Upon enrollment, the mean (SD) LDL-C level was 152.8 (33.8) mg/dL (n=258). After 52-weeks, the mean (SD) LDL-C level was 74.4 (30.5) mg/dL in the placebo group (n=132) and 23.6 (23.8) mg/dL in the alirocumab group (n=126) (P<0.001), which represents a 76.5 (95% CI -83.2 to -69.8) mg/dL reduction in the placebo group and a 131.2 (95% CI -137.0 to -125.4) mg/dL reduction in the alirocumab group (providing a between group difference of -54.7 mg/dL [95% CI -63.5 to -45.9]; P<0.001). Of note, patients assigned to the alirocumab treatment group also demonstrated significantly greater reductions in triglycerides, lipoprotein(a), and apolipoprotein B.  

Conclusion: Trial results indicated that among patients with acute myocardial infarction, the addition of alirocumab, compared with placebo, to high-intensity statin therapy, resulted in greater coronary plaque regression in non-infarct-related arteries after 52-weeks. Limitations to consider with this trial compared to previous intravascular ultrasound based studies include lower enrollment and patient retention. Strengths include investigating two non-infarct related arteries per patient to achieve power for the primary and secondary endpoints. Authors also noted that additional research is needed to understand if alirocumab improves clinical outcomes in patients with acute myocardial infarction.

Key Point: The early initiation of alirocumab, in addition to high-intensity statin therapy, may result in greater coronary plaque regression in non-infarct-related arteries after 52-weeks among patients with acute myocardial infarction, both STEMI and NSTEMI. Alirocumab, in addition to high-intensity statin, may be a viable treatment option for secondary prevention of acute coronary syndrome and to further reduce the risk of disease state progression. 

Reference:

  1. Räber L, Ueki Y, Otsuka T, et al. Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial. JAMA. 2022;327(18):1771-1781. doi:10.1001/jama.2022.5218.