Starting alirocumab in the hospital lowered lipids to levels not observed in sham-treated patients, paving the way for larger studies.
BOSTON, MA – Early initiation of a PCSK9 inhibitor in STEMI patients prior to their primary PCI procedure results in a rapid decrease in LDL-C levels, even in the context of high-intensity statin use, according to the results of the small, randomized EPIC-STEMI study show .
However, with only 68 patients, the study provides no insight into the clinical implications of aggressive reduction, and initiation with alirocumab (Praluent; Sanofi/Regeneron) had no impact on STEMI infarct size.
Still, the authors say, the results suggest a role for a PCSK9 inhibitor, even in patients who were naïve to lipid-lowering therapies prior to their heart attack.
“Routine, early administration of a PCSK9 inhibitor has the potential to significantly reduce morbidity and mortality from high-risk ACS worldwide by further lowering LDL beyond statins in a much larger number of high-risk patients than are 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 results were published simultaneously in EuroIntervention.
In the landmark studies, PCSK9 inhibitors injected twice monthly were started typically months to years after the initial ACS event and only in patients already treated with high-dose statins. Other recent studies including EVOPACS and EVACS, tested earlier initiation of PCSK9 inhibitors and showed similar, rapid reductions in LDL-C, while PACMAN-AMI showed that alirocumab resulted in greater regression and stabilization of coronary artery plaque early after ACS compared to placebo.
“EPIC-STEMI contributes to the results of these studies because it evaluates the routine use of PCSK9 inhibitors in patients with STEMI prior to primary PCI, regardless of baseline LDL-C levels or prior statin use,” write Mehta et al.
Sham controlled design
EPIC-STEMI randomized 68 STEMI patients to subcutaneous alirocumab 150 mg or sham (using an active alirocumab pen but no internal needle) upon arrival at the cath lab, regardless of baseline LDL-C levels, with follow-up doses at 2 and 4 weeks. Both groups were also started on high-intensity statins; only 16 patients had taken a statin prior to their ACS event.
After a median of 45 days, LDL-C levels were reduced by 72.9% in the alirocumab group compared to 48.1% in the sham-treated patients (P < 0.001). More than 92% of patients in the active treatment arm had met or exceeded the European Society of Cardiology/European Atherosclerosis Society dyslipidemia guideline target LDL-C ≤ 1.4 mmol/L (< 55 mg/L) compared to 56.7% in arm false arm (P < 0.001).
We wanted to give patients the best medicines we have when they come in with a serious life-threatening event. Shamir R Mehta
A hoped-for benefit of rapid initiation of alirocumab was a reduction in infarct size, as measured by CKMB area under the curve, but no differences were found between groups, “suggesting that very early initiation of alirocumab may not have reduced the size.” altered or index STEMI event severity,” the investigators say.
Speaking to TCTMD, Mehta speculated that once PCSK9 is inhibited, it will likely take some time for LDL receptors to be sufficiently upregulated to lower circulating LDL levels. “While we saw a slightly faster drop in LDL with alirocumab within the first 24 hours, the difference was only significant after about 2 weeks,” he said. “We know that early high-intensity statin therapy is effective in this situation, [but] Adding a PCSK9 inhibitor takes this concept to another level.”
There were no differences in NT-proBNP or C-reactive protein levels between groups.
Where to from here
Discussing the study with the press prior to his landmark presentation, Mehta emphasized that the purpose of the study is to reach a broader patient population for PCSK9 inhibition, noting that only 1% of patients were already taking ACS currently these medications.
“There are a variety of [reasons] for that, but one of the reasons is that we miss the high-risk patients because we don’t treat them acutely,” he said. “So in this particular case, we wanted to give patients the best medication that we have available when they arrive with a serious life-threatening event.”
In particular, he continued, “If you look at history, this is how statins were originally introduced. They were introduced very selectively – at first only lipidologists gave statins – and then migrated into the cardiology population. And then they were only given to a select number of patients who had acute coronary syndrome until we got to the point where patients are coming [them] within hours of a STEMI.”
Routine statin administration at the time of hospital admission for ACS, regardless of LDL cholesterol levels, has become standard practice worldwide, he noted. “We think this might also apply to PCSK9 inhibitors, it just hasn’t been evaluated yet.”
In the case of these particular injectable drugs, there have been major barriers to uptake, primarily cost, but also issues related to access and ease of use. “But from a scientific perspective and in terms of reducing cardiovascular events, this is a strategy that needs to be tested.”
Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai, New York, NY) commented on the study to the press, noting that the first 30 days to 6 months are particularly critical for STEMI patients who are at increased risk of developing a exposed to recurrent MI during this vulnerable phase. The potential of a PCSK9 inhibitor to help stabilize plaque or reduce inflammation during this time is a strategy that “fully warrants” evaluation.
A study, EVOLVE-MI, is already underway, she noted.
Eric A. Cohen, MD (Sunnybrook Health Sciences Centre, Toronto, Canada) also commented on the press conference, noting that ACS is typically a turning point for many patients. “Keep in mind that STEMI patients typically come into the hospital with no medication and walk out two days later on five drugs,” he said. This raises the possibility, he said, that a subcutaneous injection of a PCSK9 inhibitor every 2 weeks could impact pill burden or adherence to therapy. “I think it’s worth studying.”