Pharmacological rationale for the very early treatment of acute coronary syndrome with monoclonal antibodies anti-PCSK9

Immediate and aggressive lipid lowering therapies after acute coronary syndromes (ACS) and percutaneous coronary interventions (PCI) are supported by the ESC/EAS dyslipidemia guidelines, recommending the initiation of high-intensity statin therapy within the first 1-4 days of hospitalization. However, whether non statin lipid-lowering agents, added to statin treatment, could produce a further reduction in the risk of major adverse cardiovascular events (MACE) is still unknown. Thus, the efficacy of early treatment post-ACS with monoclonal antibodies (mAbs) anti PCSK9, evolocumab and alirocumab, is under investigation. The rationale to explore the rapid and aggressive pharmacological intervention with PCSK9 mAbs is supported by at least five confirmatory data in ACS: 1) circulating PCSK9 levels are raised during ACS 2) PCSK9 may stimulate platelet reactivity, this last being pivotal in the recurrence of ischemic events; 3) PCSK9 is associated with intraplaque inflammation, macrophage activation and endothelial dysfunction; 4) PCSK9 concentrations are associated with inflammation in the acute phase of ACS; and 5) statins raise PCSK9 levels promptly and, at times, dramatically. In this scenario, appropriate pharmacodynamic characteristics of anti PCSK9 therapies are a prerequisite for an effective response. Monoclonal antibodies act on circulating PCSK9 with a direct and rapid binding by blocking the interaction with the low-density lipoprotein receptor (LDLR). Evolocumab and alirocumab show a very rapid (within 4h) and effective suppression of circulating unbound PCSK9 (-95% ÷ -97%). This inhibition results in a significant reduction of LDL-cholesterol (LDL-C) after 48hours (-35%) post injection with a full effect after 7-10 days (55-75%). The complete and swift inhibitory action by evolocumab and alirocumab could have a potential clinical impact in ACS patients, also considering their potential inhibition of PCSK9 within the atherosclerotic plaque. Thus, administration of evolocumab or alirocumab is effective in lowering LDL-C levels in ACS, although the efficacy to prevent further cardiovascular (CV) events is still undetermined. The answer to this question will be provided by the ongoing clinical trials with evolocumab and alirocumab in ACS. In the present review we will discuss the pharmacological and biological rationale supporting the potential use of PCSK9 mAbs in ACS patients and the emerging evidence of evolocumab and alirocumab treatment in this clinical setting.