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

Abstract

Importance: Coronary plaques that are prone to rupture and cause adverse cardiac events are characterized by large plaque burden, large lipid content, and thin fibrous caps. Statins can halt the progression of coronary atherosclerosis; however, the effect of the proprotein convertase subtilisin kexin type 9 inhibitor alirocumab added to statin therapy on plaque burden and composition remains largely unknown.

Objective: To determine the effects of alirocumab on coronary atherosclerosis using serial multimodality intracoronary imaging in patients with acute myocardial infarction.

Design, setting, and participants: The PACMAN-AMI double-blind, placebo-controlled, randomized clinical trial (enrollment: May 9, 2017, through October 7, 2020; final follow-up: October 13, 2021) enrolled 300 patients undergoing percutaneous coronary intervention for acute myocardial infarction at 9 academic European hospitals.

Interventions: Patients were randomized to receive biweekly subcutaneous alirocumab (150 mg; n = 148) or placebo (n = 152), initiated less than 24 hours after urgent percutaneous coronary intervention of the culprit lesion, for 52 weeks in addition to high-intensity statin therapy (rosuvastatin, 20 mg).

Main outcomes and measures: Intravascular ultrasonography (IVUS), near-infrared spectroscopy, and optical coherence tomography were serially performed in the 2 non-infarct-related coronary arteries at baseline and after 52 weeks. The primary efficacy end point was the change in IVUS-derived percent atheroma volume from baseline to week 52. Two powered secondary end points were changes in near-infrared spectroscopy-derived maximum lipid core burden index within 4 mm (higher values indicating greater lipid content) and optical coherence tomography-derived minimal fibrous cap thickness (smaller values indicating thin-capped, vulnerable plaques) from baseline to week 52.

Results: Among 300 randomized patients (mean [SD] age, 58.5 [9.7] years; 56 [18.7%] women; mean [SD] low-density lipoprotein cholesterol level, 152.4 [33.8] mg/dL), 265 (88.3%) underwent serial IVUS imaging in 537 arteries. At 52 weeks, mean change in percent atheroma volume was -2.13% with alirocumab vs -0.92% with placebo (difference, -1.21% [95% CI, -1.78% to -0.65%], P < .001). Mean change in maximum lipid core burden index within 4 mm was -79.42 with alirocumab vs -37.60 with placebo (difference, -41.24 [95% CI, -70.71 to -11.77]; P = .006). Mean change in minimal fibrous cap thickness was 62.67 μm with alirocumab vs 33.19 μm with placebo (difference, 29.65 μm [95% CI, 11.75-47.55]; P = .001). Adverse events occurred in 70.7% of patients treated with alirocumab vs 72.8% of patients receiving placebo.

Conclusions and relevance: Among patients with acute myocardial infarction, the addition of subcutaneous biweekly alirocumab, compared with placebo, to high-intensity statin therapy resulted in significantly greater coronary plaque regression in non-infarct-related arteries after 52 weeks. Further research is needed to understand whether alirocumab improves clinical outcomes in this population.

Trial registration: ClinicalTrials.gov Identifier: NCT03067844.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Räber reported receiving grants from Sanofi, Regeneron, and Infraredx to Inselspital and speaker fees from Sanofi during the conduct of the study and grants from Abbott, Heartflow, Boston Scientific, and Biotronik to Inselspital and grants from Abbott, Amgen, AstraZeneca, Occlutech, Sanofi, Canon, and Medtronic for speaker and consultation fees outside the submitted work. Dr Losdat reported affiliation with CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees; however, CTU Bern is involved in design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organizations, in particular, pharmaceutical and medical device companies provide direct funding to some of these studies (for an up-to-date list of CTU Bern's conflicts of interest see http://www.ctu.unibe.ch/research/declaration_of_interest/index_eng.html). Dr Iglesias reported receiving grants to his institution from Biotronik, AstraZeneca, Abbott Vascular, Philips Volcano, Terumo Corp, Biosensors, and Medtronic and personal fees from Biotronik, AstraZeneca, Philips Volcano, Terumo Corp, Bristol Myers Squibb/Pfizer, Cardinal Health, Medtronic, and Novartis outside the submitted work. Dr van Geuns reported receiving grants from Amgen, InfraRedx, AstraZeneca, and Sanofi and personal fees from Abbott outside the submitted work. Dr Radu Juul Jensen reported having taken up a full-time position at the pharmaceutical company Novo Nordisk after completion of the trial and initial analysis; the new work is unrelated to the work in the current article. Dr Stortecky reported receiving grants to the institution from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott and personal fees from Boston Scientific, Teleflex, and BTG outside the submitted work. Dr Spirk reported receiving personal fees from Sanofi-Aventis (Suisse) outside the submitted work. Dr Siontis reported receiving personal fees from Abbott Vascular outside the submitted work. Dr Matter reported receiving personal fees from Amgen as a consultant and speaker during the conduct of the study and grants to the institution from EliLilly, AstraZeneca, Novartis, MSD, Swiss National Science Foundation, and Swiss Heart Foundation; personal fees from Novartis to the institution; and nonfinancial support from Roche Diagnostics outside the submitted work. Dr Daemen reported receiving institutional grant/research support from AstraZeneca, Abbott Vascular, Boston Scientific, ACIST Medical, Medtronic, Microport, Pie Medical, and ReCor Medical. Dr Heg reported the following: https://www.ctu.unibe.ch/research/declaration_of_interest/index_eng.html. Dr Windecker reported receiving research and educational grants to the institution from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohme, Miracor Medical, Novartis, NovoNordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi-Aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave outside the submitted work and serving as an unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave and Xeltis, but has not received personal payments by pharmaceutical companies or device manufacturers, and is a member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. Dr Engstrøm reported receiving personal fees from Abbott for speaker fees and serving on an advisory board outside the submitted work. Dr Lang reported receiving grants and personal fees from Janssen, and AOPOrphan, personal fees from MSD, and grants from Neutrolis outside the submitted work. Dr Koskinas reported receiving grants from Sanofi, Regeneron, and Infraredx during the conduct of the study and personal fees from Amgen and Daiichi Sankyo outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flow of Patients in the PACMAN-AMI Randomized Clinical Trial

LDL-C indicates low-density lipoprotein cholesterol. aSpecific reasons for other exclusions were not documented at the site of evaluation. See eTable 1 in Supplement 4 for additional inclusion and exclusion criteria. bExcluded by investigator and did not receive study drug.

Figure 2.. Changes in Percent Atheroma Volume via Intravascular Ultrasonography in Patients Treated With Alirocumab vs Placebo Added to High-Intensity Statin Therapy

The parallel line plot contains 1 vertical line for each imaged vessel, which extends from the baseline value to the value at 52 weeks. Descending lines indicate a reduction (ie, regression) in percent atheroma volume over time, whereas ascending lines indicate an increase (ie, progression) in percent atheroma volume. Baseline values are placed in ascending order for the alirocumab group and descending order for the placebo group. The ends of the boxes in the boxplots are located at the first and third quartiles, with the black line indicating the median and the dashed white line indicating the mean. Whiskers extend to the upper and lower adjacent values, the location of the furthest point within a distance of 1.5 IQRs from the first and third quartiles. Dots indicate more extreme values.

Figure 3.. Example of Plaque Regression, Lipid Regression, and Fibrous Cap Thickening in a Trial Patient

All images were obtained from the same lesion in the same patient and matched for the 2 time points of intracoronary imaging investigation. For intravascular ultrasonography (IVUS), external elastic lamina borders (green line) and lumen borders (red line) are superimposed and a reduction in percent atheroma volume from 62% to 50% is indicated. Note the calcification (solid white linear structure) extending between 3 and 5 hours in this matched IVUS cross section in panels A and D. For near-infrared spectroscopy, a reduction in maximum lipid core burden index (4 mm) was measured; the dotted lines in panels B and E indicate the 4-mm region with greatest lipid accumulation. For optical coherence tomography, an increase in minimal fibrous cap thickness (noted by white arrows in panels C and F) from 56 μm to 158 μm was measured.