Alirocumab was well tolerated. Injection site reactions (6.1% vs. 3.3%) and general allergic reactions (3.4% vs. 0%) were more common on alirocumab, but there were no significant differences between the arms of this study for serious adverse events. There were slightly more neurocognitive events (2.0 vs. 0%) and abnormal alanine transferase levels (0.7% vs. 0%) in the alirocumab group.
The data are generally consistent with two previously published trials with another PCSK9 inhibitor, according to Dr. Räber. In the randomized GLAGOV trial published more than 5 years ago, evolocumab also produced about a 1% absolute reduction (P < .001) in plaque volume at the end of 78 weeks of follow-up relative to placebo.
However, that trial was limited to patients with coronary artery disease without a recent cardiovascular event. The more recent HUYGENS trial, which was presented virtually at the 2021 annual meeting of the European Society of Cardiology meeting and has not yet been published, looked at one of the endpoints also evaluated in PACMAN-AMI. In that study of 161 randomized NSTEMI patients, there was also about a doubling of fibrous cap thickness (42.7 vs. 21.5 mcm) for the PCSK9 inhibitor relative to placebo.
Clinical endpoints were not compared in either the PACMAN-AMI or HUYGENS trial.
PACMAN-AMI confirms plaque stabilization
Nevertheless, the message of plaque stabilization is important, according to Anthony N. DeMaria, MD, Founding Director of the Sulpizio Cardiovascular Center at the University of San Diego. Although he acknowledged that a 1% absolute reduction in mean plaque volume might “make you want to yawn,” he argued that this is a misreading of important changes observed in plaque physiology.
“What we have now is evidence that very low lipid levels result in plaque remodeling. The plaques might not get a whole lot smaller, but the changes are important,” he said, noting, for example, that a thicker fibrous cap and increased plaque stability “clearly plays a role in reducing risk of subsequent events.”
“You cannot help but be impressed by the relationship of lipid lowering and the favorable effect on remodeling,” he added.
The data associating PCSK9 inhibitors with protection from cardiovascular events is already extensive, according to Michael J. Blaha, MD, Director of Clinical Research for Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins University, Baltimore, but he called PACMAN-ACS “an extremely relevant study.”
Dr. Michael Blaha
“This provides more evidence of the mechanism of benefit, which I think is extremely important when talking to patients about the goals of therapy,” he said.
PACMAN-AMI provided a very simple take home message for Pamela B. Morris, MD, Director of Preventive Cardiology, Medical University of South Carolina, Charleston.
“This study shows that if you get LCL-C under 50 mg/dL regardless of treatment, there is a favorable remodeling effect,” Dr. Morris said. In AMI patients, the data confirm “go early and go low,” she added. “You should do whatever is necessary [go get to these lower targets].”
Dr. Räber has financial relationships with Abbott, Amgen, AstraZeneca, Boston Scientific, Biotronik, Canon, Heartflow, Medtronic, Occlutech, Regeneron, Sanofi, and Vifor. Dr. Blaha reports financial relationships with Akcea, Amgen, Bayer, Inozyme, Kaleido, Kowa, Medimmune, Novartis, Novo Nordisk, Regeneron, Roche, Sanofi, Siemens, and 89Bio. Dr. DeMaria reports no potential conflicts of interest. Dr. Morris reports a financial relationship with Amgen. The investigator-initiated trial received research grants from Infraredx, Regeneron, and Sanofi.