PARIS — Adding the PCSK9 inhibitor evolocumab (Repatha, Amgen) to high-intensity statin therapy in the very high-risk setting of acute coronary syndrome (ACS) safely lowers low-density lipoprotein cholesterol (LDL-C), according to the EVOPACS trial.
The primary endpoint of percentage change in LDL-C from baseline to 8 weeks was 77.1% (mean, 139 mg/dL to 31 mg/dL) among patients receiving evolocumab and 35.4% (mean, 132 mg/dL to 80 mg/dL) in those receiving placebo (95% CI, –45.2% to –36.2%; P < .001).
Overall, 95.7% of patients in the evolocumab group and 37.6% in the placebo group reached an LDL-C target of less than 70 mg/dL at 8 weeks.
An LDL-C of less than 55 mg/dL — a new target in the updated European Society of Cardiology (ESC) lipid guidelines released today — was achieved by 90.1% and 10.7% of patients, respectively, Konstantinos Koskinas, MD, MSc, Bern University Hospital, Switzerland, reported simultaneously here at the European Society of Cardiology (ESC) Congress 2019 and published online August 31 in the Journal of the American College of Cardiology.
“This was a needed first study to show that evolocumab can be administered acutely in ACS patients,” he told theheart.org | Medscape Cardiology. “It doesn’t raise safety concerns, it lowers LDL cholesterol adequately, and now the next step would be the clinical translation of this early achievement of LDL targets” into a dedicated cardiovascular (CV) outcomes trial.
Commenting further, he said, “We believe that in patients who would be eligible for this treatment because of their elevated LDL, it is a reasonable approach to start earlier rather than to wait for several months. We cannot say, at this stage that this will actually improve clinical outcomes, but we have reasons to believe this will increase adherence because we know that starting an acute treatment is more effective in the long term for patients achieving their targets. Also, this is an approach endorsed in the new guidelines.”
Although previous proprotein convertase subtilisin/kexin type 9 (PSCK9)-inhibitor trials in patients without atherosclerotic CV disease (CVD) or with stable coronary artery disease have included patients with an ACS, the time between the index event and enrollment ranged, for example, from 2.6 months in ODYSSEY Outcomes to 3.4 years in FOURIER.
Evolocumab for Early Reduction of LDL-cholesterol levels in patients with acute coronary syndrome (EVOPACS) enrolled 308 patients within 24 hours of an ST-segment myocardial infarction (STEMI) or within 72 hours of a non-ST-elevation (NSTE)-ACS and randomly assigned them to evolocumab injection, 420 mg every 4 weeks, or placebo, both with atorvastatin, 40 mg/day.
Most patients (78.2%) were statin-naive at baseline, with the remainder on low- to moderate-intensity (11.4%) or high-intensity (10.4%) statins. All had LDL-C levels at screening that were higher than guideline-recommended target levels despite high-intensity statin therapy or not projected to reach these targets with high-intensity statins.
Their mean age was 60 years, 37% presented with STEMI, and 63% presented with NSTE-ACS. Treatment of the index ACS event was percutaneous coronary intervention (PCI) in 84%, medical therapy in 9%, and coronary bypass surgery in 7%.
Evolocumab compared with placebo resulted in reductions of 26.5% in total cholesterol, 34.2% in apolipoprotein B, 34.6% in non-high-density lipoprotein cholesterol (P < .001 for all), and 20% in triglycerides (P = .024). Evolocumab raised high-density lipoprotein cholesterol by 4.8% (P = .03), without significant differences in changes in apolipoprotein A1, according to the paper.
Subgroup analyses of the primary endpoint showed a greater LDL-C reduction with evolocumab vs placebo among patients who had been on statin therapy at baseline (mean, –55.8%) compared with those not on statins (mean, –36.5%; P for interaction < .001). LDL-C reductions were consistent regardless of ACS type, patient sex, or age.
As for safety, patients in the evolocumab and placebo groups had similar rates of adverse events (50.3% vs 50.7%), serious adverse events (7.7% vs 7.2%), and adverse events leading to treatment discontinuation (1.3% vs 2%). Two deaths judged unrelated to the study drug occurred in the evolocumab group, Koskinas said.
Adjudicated cardiovascular events also did not differ in the evolocumab and placebo groups, including CV death (2 vs 0), myocardial infarction (4 vs 1), revascularization (33 vs 39), and hospitalization for recurrent ACS (0 vs 1).
Exploratory analyses showed evolocumab did not result in differences at 8 weeks in inflammatory biomarkers, such as high-sensitivity C-reactive protein (CRP), interleukin (IL)-1β, and IL-6 levels, nor in platelet reactivity, acute renal injury, or post-PCI myocardial injury.
Although previous PCSK9 studies have shown that these medications do not suppress inflammation, the investigators had hypothesized that they might be able to see a difference because CRP is known to be more elevated in the acute ACS setting, and with statins, there has been a greater reduction in ACS, Koskinas explained in an interview.
“We did not see confirmation of that hypothesis, but we don’t think this is the definitive answer,” he said. “It might be related to the time points we chose to measure these endpoints and also requires further investigation to confirm.”
Limitations of the trial include the following, Koskinas said: It was not powered to assess clinical outcomes, the primary endpoint was available in 90% of patients, and events prior to the 4-week assessment were not captured. A prespecified imaging substudy planned in 50 patients was completed in only 10 patients, with results still ongoing.
Commenting for theheart.org | Medscape Cardiology, session co-chair Alaide Chieffo, San Raffaele Scientific, Milan, Italy, said, “This study was very well conducted, very interesting, very good results, but this is a pilot study.
“It is just demonstrating that the drug is safe, it reduces LDL, but it is not demonstrating any impact on clinical outcomes. So before inserting these [drugs] in our clinical therapy, we should really see if it is going to impact on clinical outcomes.”
The study was supported by Amgen. Koskinas reports having received consulting fees from Amgen and Sanofi. Coauthor disclosure information is listed in the paper.
European Society of Cardiology (ESC) Congress 2019. Presentation 82. Presented August 31, 2019.
J Am Coll Cardiol. Published online August 31, 2019. Article