Add PCSK9 Inhibitor to High-Intensity Statin at Primary PCI, Proposes Sham-Controlled

September 22, 2022

It's best to have patients on aggressive lipid-lowering therapy before discharge after an acute ST-segment elevation myocardial infarction (STEMI), so why not start it right away — even in the cath lab — using some of the most potent
LDL-lowering agents available?

That was a main idea behind the randomized, sham-controlled EPIC-STEMI trial, in which STEMI patients were started on a PCSK9 inhibitor immediately before direct percutaneous coronary intervention (PCI) and on top of
high-intensity statins.

Those in the trial getting the active agent showed a 22% drop in LDL-cholesterol levels by 6 weeks compared with the control group given a sham injection along with high-intensity statins. They were also more likely to meet LDL goals specified in some guidelines, including reduction by at least 50%. And those outcomes were achieved regardless of baseline LDL levels or prior statin use.  

Adoption of the trial's early, aggressive LDL-reduction strategy in practice "has the potential to substantially reduce morbidity and mortality" in such cases "by further reducing LDL beyond statins in a much greater number of high-risk patients than are currently being treated with these agents," suggested principal investigator Shamir R. Mehta, MD, MSc, when presenting the findings September 19 at Transcatheter Cardiovascular Therapeutics (TCT) 2022 in Boston, Massachusetts.

Adherence to secondary prevention measures in patients with acute coronary syndromes (ACS) is much better if they are started before hospital discharge, explained Mehta, senior scientist with Population Health Research Institute and professor of medicine at McMaster University, Hamilton, Canada. But "as soon as the patient has left the hospital, it is much more difficult to get these therapies on board."

Routine adoption of such aggressive in-hospital, lipid-lowering therapy for the vast population with ACS would likely mean far fewer deaths and cardiovascular events "across a broader patient population."

EPIC-STEMI is among the first studies to explore the strategy. "I think that's the point of the trial that we wanted to make, that we don't yet have data on this. We're treading very carefully with PCSK9 inhibitors, and it's just inching forward in populations. And I think we need a bold trial to see whether or not this changes things."

The PCSK9 inhibitor alirocumab (Praluent) was used in EPIC-STEMI, which was published in EuroIntervention, with Mehta as lead author, the same day as his presentation at TCT. The drug and its sham injection were given on top of either atorvastatin 40-80 mg or rosuvastatin 40 mg.

Early initiation of statins in patients with acute STEMI has become standard, but there's good evidence from intracoronary imaging studies suggesting that the addition of PCSK9 inhibitors might promote further stabilization of plaques that could potentially cause recurrent ischemic events.

Treatment with the injectable drugs plus statins led to significant coronary lesion regression in the GLAGOV trial of patients with stable coronary disease. And initiation of PCSK9 inhibitors with high-intensity statins soon after PCI for ACS improved atheroma shrinkage in non–infarct-related arteries over 1 year in the recent, placebo-controlled PACMAN-AMI trial.

Mehta pointed out that LDL reductions on PCSK9 inhibition, compared with the sham control, weren't necessarily as impressive as might be expected from the major trials of long-term therapy with the drugs.

"You need longer [therapy] in order to see a difference in LDL levels when you use a PCSK9 inhibitor acutely. This is shown also on measures of infarct size." There was no difference between treatment groups in infarct size as measured by levels of the MB fraction of creatine kinase, he reported.

"What this is telling us is that the acute use of a PCSK9 inhibitor did not modify the size or the severity of the baseline STEMI event."

And EPIC-STEMI was too small and never intended to assess clinical outcomes; it was more about feasibility and what degree of LDL-lowering might be expected.

The trial was needed, Mehta said, because the PCSK9 inhibitors haven't been extensively adopted into clinical practice and are not getting to the patients who could most benefit. One of the reasons for that is quite clear to him. "We are missing the high-risk patients because we are not treating them acutely," Mehta told | Medscape Cardiology.

The strategy "has not yet been evaluated, and there have been barriers," he observed. "Cost has been a barrier. Access to the drug has been a barrier. But in terms of the science, in terms of reducing cardiovascular events, this is a strategy that has to be tested."

The aggressive, early LDL reduction strategy should be evaluated for its effect on long-term outcomes, "especially knowing that in the first 30 days to 6 months post-STEMI there's a tremendous uptick in ischemic events, including recurrent myocardial infarction," Roxana Mehran, MD, said at a media briefing on EPIC-STEMI held before Mehta's formal presentation.

The "fantastic reduction acutely" with a PCSK9 inhibitor on top of statins, "hopefully reducing inflammation" similarly to what's been observed in past trials, "absolutely warrants" a STEMI clinical outcomes trial, said Mehran, Icahn School of Medicine at Mount Sinai, New York City, who isn't connected with EPIC-STEMI.

If better post-discharge medication adherence is one of the acute strategy's goals, it will be important to consider the potential influence of prescribing a periodically injected drug, proposed Eric A. Cohen, MD, Sunnybrook Health Sciences Center, Toronto, Canada, at the press conference.

"Keep in mind that STEMI patients typically come to the hospital on zero medications and leave 2 days later on five medications," Cohen observed. "I'm curious whether having one of those as a sub-Q injection every 2 weeks, and reducing the pill burden, will help or deter adherence to therapy. I think it's worth studying."

The trial originally included 97 patients undergoing PCI for STEMI who were randomly assigned to receive the PCSK9 inhibitor or a sham injection on top of high-intensity statins, without regard to LDL levels. Randomization took place after diagnostic angiography but before PCI.

The analysis, however, subsequently excluded 29 patients who could not continue with the study, "mainly because of hospital research clinic closure due to the COVID-19 pandemic," the published report states.

That left 68 patients who had received at least 1 dose of PCSK9 inhibitor, alirocumab 150 mg subcutaneously, or the sham injection, and had at least one blood draw for LDL response which, Mehta said, still left adequate statistical power for the LDL-based primary endpoint.

By 6 weeks, LDL-cholesterol levels had fallen 72.9% in the active-therapy group and by 48.1% in the control group (P < .001). Also, 92.1% and 56.7% of patients, respectively (P = .002), had achieved levels below the 1.4 mmol/L (54 mg/dL) goal in the European guidelines, Mehta reported.

Levels fell more than 50% compared with baseline in 89.5% of alirocumab patients and 60% (P = .007) of controls, respectively.

There was no significant difference in rates of attaining LDL levels below the 70 mg/dL (1.8 mmol/L) threshold specified in US guidelines for very high-risk patients: 94.7% of alirocumab patients and 83.4% of controls (P = .26).

Nor did the groups differ significantly in natriuretic peptide levels, which reflect ventricular remodeling; or in 6-week change in the inflammatory biomarker high-sensitivity C-reactive protein.

An open-label randomized trial scheduled to launch within weeks will explore similarly early initiation of a PCSK9 inhibitor compared with standard lipid management in an estimated 4000 patients hospitalized with STEMI or non-STEMI.

The EVOLVE MI trial is looking at the monoclonal antibody evolocumab (Repatha) for its effect on the primary endpoint of myocardial infarction, ischemic stroke, arterial revascularization, or death from any cause over an expected 3-4 years.

EPIC-STEMI was supported in part by Sanofi. Mehta reports an unrestricted grant from Sanofi to Hamilton Health Sciences for the present study and consulting fees from Amgen, Sanofi, and Novartis. Disclosures for the other authors are in the report.

Cohen discloses receiving grant support from and holding research contracts with Abbott Vascular; and receiving fees for consulting, honoraria, or serving on a speaker's bureau for Abbott Vascular, Medtronic, and Baylis.

Mehran discloses receiving grants or research support from Abbott Vascular, AstraZeneca, Bayer, Bristol-Myers Squibb, CSL Behring, Daiichi-Sankyo/Eli Lilly, Medtronic, OrbusNeich, Abiomed, Boston Scientific, Alleviant, Amgen, AM-Pharma, Applied Therapeutics, Arena, BAIM, Biosensors, Biotronik, CardiaWave, CellAegis, Concept Medical, CeloNova, CERC, Chiesi, Cytosorbents, Duke University, Element Science, Faraday, Humacyte, Idorsia, Insel Gruppe, Philips, RenalPro, Vivasure, and Zoll; receiving consultant fee or honoraria or serving on a speaker's bureau for Novartis, Abbott Vascular, Janssen, Medtronic, Medscape/WebMD, and Cine-Med Research; and holding equity, stock, or stock options with Control Rad, Applied Therapeutics, and Elixir Medical.

Transcatheter Cardiovascular Therapeutics 2022. Late-Breaking Clinical Science in Coronary Artery Disease: Session VI, in Collaboration with Circulation. Presented September 19, 2022.

EuroIntervention. Published online September 19, 2022. Abstract

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