PCSK9 inhibition as a routine early therapy for ST segment elevation myocardial infarction (STEMI) patients – in addition to statins – should be investigated in a large outcomes trial after a 68-patient randomized trial showed a 22% low-density lipoprotein (LDL) cholesterol reduction versus sham control, an investigator urged on Monday.

Speaking at the Transcatheter Cardiovascular Therapeutics (TCT) 2022 conference in Boston, Shamir R. Mehta, MD, MSc, from McMaster University, Hamilton, Ontario, also said that the trial drug, alirocumab, resulted in a greater proportion of patients achieving more than 50% reduction in LCL cholesterol, or European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) LDL target of ≤1.4 mmol/L (70 mg/dL).

"The big unknown is whether or not achieving this level of LDL reduction will translate into a reduction in clinical events. And so this implies that a randomized trial is needed in order to assess this strategy in a much larger patient population compared with usual care [statins]," he said.

The results for the study – with funding from the drug's manufacturer, Sanofi – were published simultaneously online in EuroIntervention.

Early initiation of high-intensity statin therapy is now standard practice worldwide for STEMI, Mehta said, but stressed: "It didn't start that way, it started with treated only high-risk patients after a delay, and only if their LDL was elevated." He added: "We believe the same situation may be true with PCSK9 inhibitors."

Over the last 15 years, statins have become a routine treatment initiated early for STEMI regardless of LDL levels, with greater reduction of LDL cholesterol levels leading to lower risk with "no apparent lower limit beyond which a benefit is not observed," said Mehta. "Yet, a significant proportion of patients with STEMI never achieve optimal LDL levels with statins."

PCSK9 inhibitors are shown to further reduce LDL and clinical events, but have not been studied when given acutely or as a routine treatment, he said.

The current study, therefore, set out to examine whether a simplified regimen of initiating a PCSK9 inhibitor routinely in the acute STEMI setting on top of standard high-intensity statins could lead to additional benefit by further reducing LDL cholesterol levels.

The randomized, double-blind study assigned 68 STEMI patients about to undergo primary percutaneous coronary intervention (PCI) to receive either early alirocumab 150 mg subcutaneous treatment (n = 38) or matching sham control (n = 30) between May 2019 and April 2021. The first dose was given before primary PCI regardless of baseline LDL cholesterol levels, and again at 2 and 4 weeks post-PCI.

At baseline, there were no significant differences in characteristics between the two groups. The overall mean age was 62 years, 19% were women and approximately 24% were on prior statin therapy. Mean LDL-cholesterol levels were also not significantly different, at 2.97 mmol/L (standard deviation [SD] 1.09) in the alirocumab group and 2.87 mmol/L (SD 0.90) in sham control.

At a median follow-up of 45 days, direct LDL cholesterol reduction – the primary outcome measure – was 72.9% in the alirocumab group (down to 0.75 mmol/L; P<0.001) and 48.1% in sham control (down to 1.30 mmol/L; P<0.001).

A greater proportion of patients in the alirocumab group achieved the ESC/EAS guideline LDL target of ≤1.4 mmol/L (92.1% alirocumab vs 56.7% sham-control; P=0.002) and <50% reduction from baseline (89.5% vs 60%, respectively; P=0.007).

Mehta highlighted the fact that the statin dose given in the trial was "substantially higher" than in prior studies, with the overwhelming majority of patients given either 80 mg of atorvastatin or 40 mg of rosuvastatin daily.

“So this is really treatment on top of state-of-the-art lipid management,” he said.

He added that, at 3 months (12 weeks) – 8 weeks after the last injection of study drug – "any benefit that was achieved while the patient was on active therapy was lost. At 12 weeks, LDL was 1.64 mmol/L in the alirocumab group and 1.41 mmol/L in sham-control group (a between-group difference of 6.2% [95% confidence interval [CI]; -18.0 to -30.3: P = 1).

Study in 'much larger' population needed

Mehta went on to stress that a randomized trial is needed in a "much larger" patient population comparing PCSK9 inhibition with standard of care since it is still unknown whether the levels of LDL cholesterol reduction achieved will translate into a reduction in clinical events.

The approach "would be expected to substantially reduce the number of major cardiovascular events in this high-risk population," however, he stressed.

This would also mean that PCSK9 inhibitors could potentially reach a much broader population, he added, noting that the class of drugs are currently administered in around 1% of the patient population with prior acute coronary syndrome.

"In terms of the patients who really need these drugs, they are not receiving them," said Mehta. "One of the reasons is we are missing the high-risk patients because we are not treating them acutely."

Still, he noted real-world barriers to access for PCSK9 inhibitors including cost, "but in terms of the science, in terms of reducing cardiovascular events, this is a strategy that has to be tested."

Image Credit: Jason Wermers/CRTonline.org