Evolocumab in Acute ACS Safely Reduces LDL Cholesterol: EVOPACS
This is the first study testing the PCSK9 inhibitor in this setting; a clinical outcomes trial is still needed, one study author says.
PARIS, France—Eight weeks of evolocumab (Repatha; Amgen) added to a regimen of high-intensity statins following an ACS event was safe and vastly reduced LDL cholesterol levels compared with statins and placebo, according to the randomized EVOPACS study.
“The clinical impact of very early LDL cholesterol-lowering with evolocumab initiated in the acute setting of ACS warrants further investigation in a dedicated cardiovascular outcomes trial,” said Konstantinos C. Koskinas, MD (Bern University Hospital, Switzerland), who presented the findings here today at the European Society of Cardiology (ESC) Congress 2019. The trial, he noted, was not powered to assess clinical outcomes.
Both evolocumab and the other available PCSK9 inhibitor alirocumab (Praluent; Sanofi Regeneron) are approved by the US Food and Drug Administration for the prevention of cardiovascular events in adults with established cardiovascular disease, but prior randomized studies of each have only looked at treatment beginning weeks if not months after an ACS event. EVOPACS, which was simultaneously published in the Journal of the American College of Cardiology, provides the first look at how evolocumab performs in this high-risk population immediately following ACS.
This study provides “an incremental knowledge base that we didn't have before,” according to E. Magnus Ohman, MBBS (Duke Clinical Research Institute, Durham, NC), who was not involved in EVOPACS. “A large proportion of the patients were STEMI patients, where it would be awfully hard to administer prior to PCI, but it was at least done within 24 hours,” he told TCTMD. “That is very early, much earlier than any other trials.”
More LDL-Lowering With Evolocumab
For the study, Koskinas and colleagues randomized 308 patients hospitalized for ACS (37% STEMI) to receive high intensity statins plus either placebo or evolocumab 420 mg as soon as possible following the index event, within 24 hours for STEMI and 72 hours for NSTE ACS. Most patients received PCI (84%), with 7% receiving CABG surgery and 9% being prescribed medical therapy.
To be included in the study, patients needed a baseline LDL cholesterol of at least 1.8 mmol/L if they were previously on a high intensity statin, 2.3 mmol/L if they were previously on a low/moderate intensity statin, or at least 3.2 mmol/L if they were not on prior statin therapy. Interestingly, 78.2% of all patients had no statin treatment prior to enrollment in the study.
After 8 weeks, the evolocumab group saw a mean 40.7% greater reduction in LDL cholesterol levels from baseline compared with those randomized to placebo (-77.1% vs -35.4%; P < 0.001). A full 90.1% of the study cohort reached an LDL-level of less than 1.4 mmol/L—as outlined in the latest ESC/European Atherosclerosis Society (EAS) dyslipidemia guidelines announced today—versus only 10.7% of the placebo arm.
Among the patients who had been on statins at baseline, evolocumab had an even greater effect on LDL cholesterol-lowering compared with placebo than in those not on statins (P < 0.001), but there were no differences observed in other key subgroups based on clinical presentation, age, and gender.
Evolocumab significantly affected other lipid measurements compared with placebo, reducing total cholesterol by 26.5%, apolipoprotein B by 34.2%, non-HDL cholesterol by 34.6%, and triglycerides by 20% as well as increasing HDL cholesterol by 4.8%.
There were no differences in safety endpoints between the study groups, with the rate of serious adverse events being 7.7% in the evolocumab arm and 7.2% in the placebo arm (P = 0.84). Two patients in the evolocumab arm died following CABG surgery, but Koskinas said these deaths were ruled unrelated to the study drug.
Also, in exploratory analyses, there were no differences observed between evolocumab and placebo with regard to high-sensitivity C-reactive protein, renal function, platelet reactivity, and post-PCI myocardial injury.
No Clinical Implications, Yet
In discussion following Koskinas’ presentation, session co-chair Pascal Vranckx, MD, PhD (Hartcentrum Hasselt, Belgium), asked how the researchers determined the time points for distributing evolocumab or placebo—within 24 hours for STEMI and 72 hours for NSTE ACS—for this study.
“We wanted our patients to be more or less stabilized and know the effect of the event,” Koskinas replied. “In addition, we wanted to test platelet function, so we wanted the patients first to have received DAPT, which was [with] ticagrelor in most of the patients, and to be at about a steady state at 72 hours. . . . There were reasons to begin as early as possible to really capture the acute phase of the event, but other reasons that we see favor postponing to some point to avoid the confounding effect of acute event.”
Highlighting the fact that almost 80% of the study population had no prior statin therapy, Ohman said that this proportion would probably be even higher in the United States where MI is the first presentation of coronary disease in many patients. It makes sense that this population would see substantial effects of a PCSK9 inhibitor because if “[you] go from nothing to the most potent thing we have, then you'd expect dramatic changes in LDL.”
The main question that remains in this regard is when exactly does the LDL cholesterol drop following drug administration, Ohman noted. “Did it change at 48 hours after administration? 96 hours? That wasn't presented, and so essentially that's still a little bit of an unknown,” he said. “If this type of approach, and I say if because we have no evidence that it does anything to clinical outcomes, . . . turns out to become an important strategy, then you would want to know that.”
These kind of periodic measurements should be built into any future randomized trial looking at this strategy, according to Ohman.
For now, the main take-home message is that “early administration of these types of agents actually lowers the cholesterol quite dramatically and this is consistent with everything else we know from the post-ACS trials,” he said, adding that the clinical implications are not yet defined.
And since most US hospitals don’t yet have PCSK9 inhibitors on formulary, Ohman said, this kind of acute administration is unlikely to happen anytime soon. “An approval process for agents like this goes through a hospital formulary, and they would look at the evidence for therapy that is required in the hospital, and so far we don't have much. This is the only study to date, but it doesn't really answer the clinical question.”
Koskinas KC, Windecker S, Pedrazzini G, et al. Evolocumab for early reduction of LDL-cholesterol levels in patients with acute coronary syndromes (EVOPACS). J Am Coll Cardiol. 2019;Epub ahead of print.
- EVOPACS was supported by Amgen.
- Koskinas reports receiving consulting fees from Amgen and Sanofi.
- Ohman reports no relevant conflicts of interest.