Adding alirocumab to high-intensity statin therapy reduced high-risk plaques: PACMAN-AMI
WASHINGTON — In a new study, subcutaneous biweekly alirocumab, added to high-intensity statin therapy, resulted in greater coronary plaque regression in non-infarct-related arteries after 1 year in patients with acute MI.
The PACMAN-AMI study used serial, two-vessel, multimodality intracoronary imaging to assess the effects of the PCSK9 inhibitor alirocumab (Praluent, Sanofi/Regeneron) on coronary atherosclerosis in patients with acute MI.
Among 300 patients undergoing PCI for acute MI, mean change in percent atheroma volume assessed via IVUS in non-infarct-related arteries after 52 weeks was greater for those assigned biweekly alirocumab in addition to rosuvastatin 20 mg compared with those assigned placebo and rosuvastatin (–2.13% vs. –0.92%; difference, –1.21%; 95% CI, –1.78 to –0.65; P < .001).
Adding alirocumab to statin therapy also yielded in favorable changes in secondary endpoints, including a greater reduction in mean change in maximum lipid core burden index within 4 mm assessed by near-infrared spectroscopy (–79.42 vs. –37.6; difference, –41.24; 95% CI, –70.71 to –11.77; P = .006) and greater increase in mean change in minimal fibrous cap thickness assessed by optical coherence tomography (62.67 µm vs. 33.19 µm; difference, 29.65; 95% CI, 11.75-47.55; P = .001) from baseline to week 52.
“These findings indicate incremental coronary plaque regression, lipid core reduction and plaque stabilization with alirocumab and provide a mechanistic rationale in favor of early initiation of very intensive LDL cholesterol lowering in acute MI patients,” Lorenz Räber, MD, PhD, professor of cardiology and director of the catheterization laboratory at Bern University Hospital, Switzerland, said during a late-breaking clinical trial presentation at the American College of Cardiology Scientific Session.
The results were simultaneously published in JAMA.
In other findings, LDL was reduced by 85% in the alirocumab-statin group and by 50% in the placebo-statin group at 52 weeks (P <. 001). Patients who received alirocumab also had significantly greater reductions in triglycerides, lipoprotein(a) and apolipoprotein B, the researchers wrote in JAMA.
Adverse events were similar, at 70.7% in the alirocumab-statin group and 72.8% in the placebo group. Räber said there were no differences in rates of all-cause death and MI or adverse events of special interest, except for general allergic reaction, which was reported in 3.4% patients in the alirocumab group. He noted a significant reduction in need for repeat stenting procedures of about 50%.
The randomized, double-blind PACMAN-AMI trial was conducted at nine centers in Austria, Denmark, Switzerland and the Netherlands, with enrollment from 2017 through 2020. The mean age was 58 years, 81% were men and 53% presented with STEMI. At enrollment, 12% of patients were receiving a regular statin and 7% a high-intensity statin.
All patients received rosuvastatin 20 mg and then underwent random assignment to alirocumab or placebo every 2 weeks, initiated within 24 hours of urgent PCI of the culprit lesion. Within 24 hours of PCI, patients underwent IVUS, NISRS and OCT, with repeat tests at 52 weeks to analyze differences in images before and after treatment.
During a discussion following the presentation, Michael J. Blaha, MD, MPH, said PACMAN-AMI is a “well-done study on a different patient population, with a very thorough deep phenotyping of plaque.”
Blaha said it is important to understand the mechanisms by which alirocumab produces its effects and how that influences outcomes as well as the biology of lipid-lowering therapy. Further, moving lipid-lowering therapy earlier in the treatment course in the hospital after acute MI is also important, according to Blaha. PACMAN-AMI builds on several studies indicating safety in this population, he said.
“All of those things make this study extremely relevant in 2022,” Blaha said.
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With intensive cholesterol-lowering therapy, particularly intensive lowering of LDL in the acute MI setting, over the succeeding year, we can see plaque reduction in other coronary arteries that could have potential for future MIs.
The findings amplify that starting intensive anti-lipid therapy at the earliest possible time following an acute MI is beneficial. The researchers observed incremental plaque reduction with a PCSK9 inhibitor, but dramatic reduction in LDL. What we don’t know is whether the PCSK9 inhibitor is additionally beneficial in plaque reduction over a high-intensity statin.
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This study is like a rung in ladder. The PCSK9 inhibitor manufacturers have slowly been sponsoring a series of trials since those agents were released. They have started to look at the potential role of giving PCSK9 inhibitors, in this case alirocumab, in the immediate setting of the hospital after ACS. By contrast, the ODYSSEY OUTCOMES pivotal trial of alirocumab was for patients with ACS who were out of the hospital, and the FOURIER pivotal trial of evolocumab (Repatha, Amgen) was for patients with stable CHD at least 1 year removed from their event.
The issue in the present study was whether these patients had any measurable changes in atheroma. And there was a reduction in atheroma volume. If you are thinking about using more aggressive lipid lowering beyond high-intensity statins in the immediate post-event time period, while the patient is still in the hospital, where they typically get put on high-intensity statins, this is certainly hypothesis-generating. The study shows beneficial changes in atheroma volume, but we will need to establish impact on outcomes before we can use PCSK9 inhibitors in the hospital setting supported by evidence-based data. It certainly encourages us to pursue that type of data. The just-announced EVOLVE-MI study will be doing that with evolocumab.
PACMAN-AMI adds to the body of data. We have IVUS data showing that plaque reduction takes place with PCSK9 inhibitors. We now have data on atheroma volume with multimodality intracoronary imaging in the immediate post-MI setting. We are starting to put together an interesting story on changes in plaque configuration that support the hypothesis that early intervention by adding these medications on to statins might be beneficial.
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Räber L, et al. Joint American College of Cardiology/Journal of the American Medicine Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; April 2-4, 2022; Washington, D.C. (hybrid meeting).
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