Design of the randomized, placebo‐controlled evolocumab for early reduction of LDL‐cholesterol levels in patients with acute coronary syndromes (EVOPACS) trial

Abstract

Statins lower low‐density lipoprotein cholesterol (LDL‐C) and improve clinical outcomes in patients with atherosclerotic cardiovascular disease (CVD). Patients with acute coronary syndromes (ACS) often do not achieve LDL‐C targets despite potent statin treatment, and have a particularly high risk of early recurrent events. Evolocumab, a proprotein convertase subtilisin/kexin type (PCSK9)‐inhibitor resulting in rapid, marked LDL‐C reduction, has been studied in hypercholesterolemic subjects without CVD and stabilized patients with CVD; the feasibility, safety, and efficacy of this treatment initiated in the acute phase of ACS remain unknown. We report the design of evolocumab for early reduction of LDL‐cholesterol levels in patients with ACS (EVOPACS), a phase‐3, multicenter, randomized, double‐blind, placebo‐controlled trial to assess the feasibility, safety, and LDL‐C‐lowering efficacy of evolocumab on top of atorvastatin 40 mg in patients with ACS. The primary endpoint is percent change in LDL‐C from baseline to 8 weeks. Secondary endpoints are adverse events and serious adverse events. Against a background of beneficial cardiovascular effects of statins beyond LDL‐C lowering and in view of preclinical evidence of similar effects of PCSK9 inhibition, the study will also address a variety of exploratory endpoints including the change in C‐reactive protein and other inflammatory biomarkers; platelet reactivity; and occurrence of contrast‐induced acute kidney injury and myocardial injury in patients undergoing cardiac catheterization. An intracoronary imaging sub‐study will investigate the change from baseline in the lipid core burden index in non‐culprit lesions, as assessed by serial near‐infrared spectroscopy. Recruitment began in January 2018 and enrollment of 308 patients is planned.

PCSK9 inhibition and inflammation: A narrative review

“…Again on a pharmacological clinical approach, in spite of the general suggestion that PCSK9 inhibitors should be recommended only after an initial 2-3 month run-up treatment adaptation with maximally tolerated statin doses, an earlier initiation of PSCK9 mAb treatment may be justified by the evidence that in the acute phase of ACS PCSK9 may raise coronary plaque vulnerability, inflammation and platelet aggregation [130]. Findings from the EVOPACS [EVOlocumab for Early Reduction of LDL-cholesterol Levels in Patients With Acute Coronary Syndromes (NCT03287609)] trial will certainly shed light on this matter [134].…”

Targeting Early Atherosclerosis: A Focus on Oxidative Stress and Inflammation

“…Clinical studies demonstrated that PCSK9 inhibitors reduce the incidence of major cardiovascular events in patients with CVD but not cardiovascular mortality [239]. Ongoing studies will assess the effectiveness of these drugs on patients with acute cardiovascular events such as acute coronary syndrome, exploring not only the degree of LDL lowering but also their effect on inflammatory markers, platelet function, or plaque composition [240].…”

A short review of proprotein convertase subtilisin/kexin type 9 inhibitors

“…Many phase III clinical trials for the PCSK9 inhibitors have been completed, and one is ongoing at the time of conducting this review. Four of the five clinical trials reviewed investigate PCSK9 antibody inhibition in patients with a history of clinically evident CVD: the FOURIER trial for evolocumab, the ODYSSEY OUT-COMES trial for alirocumab, the SPIRE-1 and SPIRE-2 trials for bococizumab, and the EVOPACS trial for evolocumab (Sabatine et al, 2017;Bays et al, 2015;Ridker et al, 2016;Koskinas et al, 2018). The fifth clinical trial, BERSON, investigates evolocumab in patients with diabetes mellitus and dyslipidemia (Lorenzatti et al, 2019).…”

“…The EVOPACS trial for evolocumab (fully human monoclonal antibody) commenced enrolment in January 2018. It is a randomized, double-blind, placebo-controlled multicenter study (Koskinas et al, 2018). The 308 patients included so far in this study have ACS, with a corresponding recent hospitalization.…”