Rush to PCSK9 Inhibitor Pretreatment Disappoints in Acute MI Trial

Heart attack patients gained faster control of LDL cholesterol starting PCSK9 inhibitor therapy immediately in the cath lab, the AMUNDSEN trial showed, while a clinical benefit could not be proven.

High-risk patients with acute myocardial infarction (MI) who had a first injection of evolocumab (Repatha) right before percutaneous coronary intervention (PCI) were significantly more likely to achieve cholesterol targets 1 year into the study, reported Gilles Montalescot, MD, PhD, of Pitié-Salpêtrière Hospital in Paris.

The proportion of patients reaching LDL cholesterol <55 mg/dL and at least 50% reduction from baseline to 12 months came out to 82% among those given upfront evolocumab versus 40% of peers randomized to standard care (adjusted OR 5.54, 95% CI 4.50-6.82).

Meanwhile, the evolocumab and control groups shared similar rates of all-cause death or unplanned cardiovascular hospitalization at 12 months (14.6% vs 15.4%, adjusted OR 0.94, 95% CI 0.73-1.19) in this study of over 2,100 participants, Montalescot reported at the European Society of Cardiology Congress in Munich, Germany. The study was simultaneously published in JAMA.

This would suggest no clinically meaningful acute pleiotropic effects of PCSK9 inhibitors, beyond LDL cholesterol-mediated effects, in adjunct to standard care, the AMUNDSEN trialists suggested.

“This study, to the authors’ knowledge, is the first adequately sized randomized trial evaluating systematic PCSK9 inhibition in patients with acute MI at the time of mechanical reperfusion in the catheterization laboratory, added to standard care with high-intensity lipid-lowering therapy, compared with a control standard care group in whom lipid-lowering therapy can be adjusted and intensified — including with PCSK9 inhibition during follow-up — as currently recommended by guidelines,” Montalescot’s group noted.

Lipid lowering is of great interest for heart attack patients, as acute coronary syndrome patients with elevated LDL cholesterol are at high risk for long-term recurrent cardiovascular events.

Some would argue that PCSK9 inhibitors — powerful lipid-lowering agents indicated for primary and secondary prevention of cardiovascular disease — are well positioned for a larger role in acute MI. One trial had shown another PCSK9 inhibitor, alirocumab (Praluent), to boost LDL cholesterol lowering as an early adjunct to standard high-intensity statins in acute MI, the idea being that lower LDL cholesterol is better for secondary prevention.

AMUNDSEN now pumps the brakes on rapid lipid-lowering starting in the cath lab.

“This is a study that, in some ways, challenges the currently popular ‘strike early and strike strong’ concept, although one could argue that starting treatment early during hospitalization is intended to improve adherence, rather than to achieve true pleiotropic effects or improve cardiovascular outcomes compared with a more delayed initiation,” commented Davide Capodanno, MD, PhD, of University of Catania, in Catania, Italy.

Capodanno highlighted the very low 3.8% of standard-care patients in the trial who subsequently received a PCSK9 inhibitor as permitted during follow-up. “It almost seems as though hospitalization represents the last — and perhaps only — opportunity for many patients to gain access to this therapy,” he told MedPage Today.

It was ultimately no surprise that AMUNDSEN was unable to prove a clinical benefit to immediate PCSK9 inhibition, others experts said.

“There was a hypothesis of a rapid treatment effect emerging and kudos to the investigators for testing that. But the reality is that most LDL-lowering trials, whether they were with statins or with PCSK9 inhibitors, showed an initial lag phase before a clinical benefit emerged. The relative risk reduction in the first year is usually smaller than in subsequent years,” Shamir Mehta, MD, MSc, of McMaster University and Hamilton Health Sciences in Ontario, Canada, told MedPage Today.

“That, coupled with the modest sample size and the fact that almost all patients in both placebo and treatment groups received high-intensity statin therapy really limits the ability of this trial to show meaningful differences in clinical outcomes. A pragmatic trial with a larger sample size and longer term follow-up is needed for that,” said Mehta, who was not involved with AMUNDSEN.

Sunil Rao, MD, of NYU Langone Health in New York City, agreed that the study does not change practice given these limitations.

“I think studies like this are very important and I would like to see more randomized trials of lipid-lowering therapies in patients with acute coronary syndrome,” he commented.

Indeed, the concept of very early PCSK9 inhibitor administration in acute MI has another chance to advance with the EVOLVE-MI trial. That trial has already exceeded 6,000 participants and boasts a longer expected follow-up of 3.5-4 years.

AMUNDSEN was conducted in six countries and enrolled adults with high-risk ST-elevation MI (STEMI; age >55) or non-ST-elevation MI (NSTEMI) with one or more additional high-risk characteristics.

Montalescot’s group had 2,161 patients randomized 1:1 to receive evolocumab 140 mg subcutaneously every 2 weeks for 1 year (first injection before PCI) or standard care alone. Standard care included high-intensity oral lipid-lowering therapy with the option of PCSK9 inhibitor use per guideline indication.

Across these patients, mean age was 67, 79% were men, and the split between STEMI and NSTEMI was 58% and 42%, respectively.

Mean LDL cholesterol at admission was 116 mg/dL. At 6 weeks, this fell to 16 mg/dL with upfront evolocumab and 56 mg/dL with standard care.