Starting alirocumab in the hospital dropped lipids to levels not seen in sham-treated patients, paving the way for larger trials.
BOSTON, MA—Early initiation of a PCSK9 inhibitor in STEMI patients prior to their primary PCI procedures leads to swift drops in LDL cholesterol levels, even on a background of a high-intensity statin, results of the small, randomized EPIC-STEMI study show .
With just 68 patients, the trial offers no insights on the clinical impact of aggressive lowering, however, and alirocumab (Praluent; Sanofi/Regeneron) initiation did not have an impact on STEMI infarct size.
Still, say the authors, the findings carve out a role for a PCSK9 inhibitor, even in patients not already taking lipid-lowering therapies prior to their MIs.
“Routine, early administration of a PCSK9 inhibitor has the potential to substantially reduce morbidity and mortality globally after high-risk ACS by further reducing LDL beyond statins in a much greater number of high-risk patients than is currently treated with these agents,” said Shamir R. Mehta, MD (McMaster University/Population Health Research Institute, Hamilton, Canada), who presented the EPIC-STEMI results earlier this week during a late-breaking clinical science session at TCT 2022.
The findings were published simultaneously in EuroIntervention.
In the landmark trials, PCSK9 inhibitors, given as twice-monthly injections, were typically started months to years after the original ACS event, and only in patients already being treated by high-dose statins. Other recent trials, including EVOPACS and EVACS, tested an earlier start of PCSK9 inhibitors and showed similar, quick reductions in LDL cholesterol, while PACMAN-AMI demonstrated that alirocumab started early after ACS led to greater coronary plaque regression and stabilization as compared with placebo.
“EPIC-STEMI adds to the results of these trials as it evaluates initiation of PCSK9 inhibitor routinely to patients with STEMI before primary PCI regardless of baseline LDL cholesterol levels or prior statin use,” Mehta et al write.
EPIC-STEMI randomized 68 STEMI patients to subcutaneous alirocumab 150 mg or a sham injection (using an active alirocumab pen but without an internal needle) upon arrival at the cath lab, regardless of baseline LDL cholesterol levels, with follow-up doses at 2 and 4 weeks. High-intensity statins were also initiated in both groups; just 16 patients had been taking a statin prior to their ACS event.
At a median of 45 days, LDL cholesterol levels were reduced by 72.9% in the alirocumab group as compared with 48.1% in the sham-treated patients (P < 0.001). More than 92% of patients in the active treatment arm had met or surpassed the European Society of Cardiology/European Atherosclerosis Society dyslipidemia guideline target—LDL cholesterol ≤ 1.4 mmol/L (< 55 mg/L)—as compared with 56.7% in the sham arm (P < 0.001).
We wanted to give patients the best drugs that we have available when they are coming in with a major life-threatening event. Shamir R. Mehta
A hoped-for benefit of the swift initiation of alirocumab was a reduction in infarct size, as measured by CKMB area under the curve, but no differences were seen between groups, “suggesting that the very early initiation of alirocumab may not modify the size or severity of the index STEMI event,” investigators say.
To TCTMD, Mehta speculated that it likely takes some time after PCSK9 is inhibited for LDL receptors to be upregulated enough to bring down circulating LDL levels. “While we did see a slightly more rapid fall in LDL within the first 24 hours with alirocumab, the difference was not significant until about 2 weeks,” he said. “We know that in this setting early high-intensity statin therapy is effective, [but] adding a PCSK9 inhibitor takes this concept to a different level.”
There were no differences in NT-proBNP or C-reactive protein levels between groups.
Where to Go From Here
Discussing the trial with the press prior to his late-breaking presentation, Mehta stressed that the point of the trial was to try to reach a broader population of patients for PCSK9 inhibition, noting that just 1% of patients who’ve had a prior ACS are currently taking these medications.
“There’s a variety of [reasons] for that, but one of the reasons is that we are missing the high-risk patients because we are not treating them acutely,” he said. “So in this particular case we wanted to give patients the best drugs that we have available when they are coming in with a major life-threatening event.”
Notably, he continued, “if you look at history, this is the way that statins were initially introduced. They were introduced very selectively—initially only lipidologists gave statins—and then it migrated to the cardiology population. And then they were only given to a selected number of patients who had had an acute coronary syndrome, until we reached the point where patients get [them] within hours of having a STEMI.”
Routinely giving statins at the time of hospital admission for ACS, regardless of LDL cholesterol levels, has become standard practice worldwide, he noted. “We believe the same may be true with PCSK9 inhibitors, it just has not yet been evaluated.”
In the case of these particular injectable medications, there have been major barriers to uptake, most notably cost, but also issues related to access and ease of use. “But in terms of the science and in terms of reducing cardiovascular events, this is a strategy that has to be tested.”
Commenting on the study to the press, Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai, New York, NY), noted that the first 30 days to 6 months are especially critical for STEMI patients who face an elevated risk of recurrent MI during this vulnerable phase. The potential for a PCSK9 inhibitor to help with plaque stabilization or reducing inflammation during this period is a strategy that “absolutely warrants” evaluation.
One study trial, EVOLVE-MI, is already underway, she noted.
Also commenting in the press conference, Eric A. Cohen, MD (Sunnybrook Health Sciences Centre, Toronto, Canada), pointed to the fact that an ACS is typically a turning point for many patients. “Keep in mind that STEMI patients typically come to the hospital on zero medications and leave 2 days later on five medications,” he said. That raises the possibility, he said, that having a subcutaneous injection of a PCSK9 inhibitor every 2 weeks could have an impact on pill burden or adherence to therapy. “I think it’s worth studying.”