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.
Biotechnological advances now enable the design of fully human antibodies to target specific antigens in a growing number of diseases. Monoclonal antibodies (mAbs) differ from traditional small chemical molecules in several ways: (1) biological production ‒ they are grown in and extracted from cell cultures; (2) specificity ‒ they demonstrate high target specificity, with a low risk of drug-drug interactions; (3) administration ‒ they are delivered parenterally (intravenously or subcutaneously); (4) dosage interval ‒ their extended half-lives generally allow for spaced dosing (from weekly to monthly). In cardiology, fully human mAbs directed against proprotein convertase subtilisin / kexin type 9 (PCSK9) have shown to be effective in reducing low-density lipoprotein cholesterol (LDL-C) in phase II clinical trials among patients with familial hypercholesterolaemia (FH). PCSK9 inhibitors have just received approval for the treatment of FH and clinical atherosclerotic disease, and patients not at target under maximally tolerated statin therapy or intolerant to statins. Large-scale phase III trials are currently assessing the role of PCSK9 inhibitors in the secondary prevention setting for patients with acute coronary syndromes (ACS) and poorly controlled LDL-C under evidence-based therapies. Another area currently under investigation for fully human mAbs in secondary prevention is their potential ability to inhibit inflammatory pathways. In this context, canakinumab, a specific mAb inhibiting interleukin-1β (IL-1β), has already received approval for the treatment of systemic juvenile idiopathic arthritis. The canakinumab anti-inflammatory thrombosis outcomes trial (CANTOS) is an ongoing trial assessing whether inhibition of IL-1β could reduce the occurrence of cardiovascular adverse events in 17,200 patients with ACS and with defined persisting inflammation.
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