ABC | Volume 111, Nº1, July 2018

Viewpoint Indications of PCSK9 Inhibitors for Patients at High and Very High Cardiovascular Risk Paulo Eduardo Ballvé Behr, 1 Emilio Hideyuki Moriguchi, 2,3 Iran Castro, 4 Luiz Carlos Bodanese, 1 Oscar Pereira Dutra, 4 Paulo Ernesto Leães, 5 Pedro Pimentel Filho 6 Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul, 1 Porto Alegre, RS - Brazil Faculdade de Medicina - Universidade Federal do Rio Grande do Sul, 2 Porto Alegre, RS - Brazil Serviço de Cardiologia - Hospital de Clínicas de Porto Alegre, 3 Porto Alegre - Brazil Instituto de Cardiologia / Fundação Universitária de Cardiologia, 4 Porto Alegre, RS - Brazil Irmandade Santa Casa de Misericórdia de Porto Alegre, 5 Porto Alegre, RS - Brazil Hospital Nossa Senhora da Conceição, 6 Porto Alegre, RS - Brazil Mailing Address: Paulo Eduardo Ballvé Behr • Av. Ipiranga, 6690 sala 300. CEP 9061-000, Jardim Botânico, Porto Alegre, RS – Brazil E-mail: pbehr@cardiol.br , pbehr@terra.com.br Manuscript received November 30, 2017, revised manuscript March 01, 2018, accepted April 25, 2018 Keywords Cardiovascular Diseases/complications; Cardiovascular Diseases/mortality; Coronary Artery Disease; Proprotein Convertase 9; Hyperlipoproteinemia Type II; Ezetimibe, Simvastatin Drug Combination. DOI: 10.5935/abc.20180133 Atherosclerotic cardiovascular disease (CVD) is the major cause of ischemic acute coronary events and a significant proportion of ischemic strokes and peripheral artery ischemia. Such events result in significant mortality, physical and/or mental incapacity and costs for the individual and society. 1 LDL-C as a risk factor The causality of plasma LDL-C levels and reduced LDL-C uptake mediated by the LDL-C receptor in the pathophysiology of CVD has been very consistently established. 2 For patients at very high risk for premature events, such as those with familial hypercholesterolemia (FH), an elevated LDL-C level is an extremely prevalent risk factor. 3 Difficulty of achieving the goals with statins A relevant clinical question is the difficulty of achieving the LDL-C levels recommended by the guidelines for patients at very high cardiovascular (CV) risk. Even using high-potency statins, a substantial proportion of those patients will not achieve the LDL-C target, partially because of the pharmacogenetic effects that determine wide inter-individual variability in the response to statins. This emphasizes the need for an additional reduction in LDL-C levels with new therapeutic options aimed at those atherogenic particles. 4 PCSK9 inhibitors The proprotein convertase subtilisin/kexin type 9 (PCSK9), a member of the serine protease family, plays a central role in the regulation of the liver LDL-C receptor activity. Individuals with mutations in the PCSK9 gene and function loss, and consequent lower LDL-C levels, have a substantially reduced risk of developing coronary artery disease. Inversely, heterozygous individuals for the PCSK9 mutation, with function gain, have a phenotype consistent with FH. Those findings have stimulated the investigation of the use of PCSK9 inhibitors (PCSK9-I) as an innovative therapeutic alternative to improve the control of elevated LDL-C levels. 5,6 Several clinical studies with different monoclonal antibodies against circulating PCSK9, both in isolation and combined with statins, have confirmed significant reductions in LDL-C levels, reaching up to 60%. 7,8 FOURIER, SPIRE and ODYSSEY The FOURIER trial, published in 2017, showed a significant reduction in relevant clinical events, such as acute myocardial infarction (AMI) and atherothrombotic ischemic stroke, in patients with established CVD and plainly treated with moderate- and high-potency statins, associated or not with ezetimibe. The median LDL-C level was 92 mg/dL, and patients receiving evolocumab reached a median LDL-C level of 30 mg/dL. Safety data showed no significant adverse effect, except for injection-site reactions, in the median follow-up of 2.2 years. 9 The recently published EBBINGHAUS trial, assessing patients who received either PCSK9-I or placebo in addition to statin therapy, has shown no significant difference in cognitive function, even in individuals with very-low LDL-C levels. 10 Another study using the monoclonal antibody bococizumab has shown a significant reduction in CV events, which is aligned with the result obtained with evolocumab in the FOURIER trial. However, the SPIRE trial was interrupted because of the development of high rates of antidrug antibodies and consequent reduction in the therapeutic response. 11 The ODYSSEY trial, recently presented as a late-breaking clinical trial at the American College of Cardiology Scientific Session, has assessed patients who had acute coronary syndrome within 1 to 12 months before randomization. All individuals were on moderate- and high-potency statins, associated or not with ezetimibe. The mean follow-up was 2.8 years. 12 The trial has shown a significant reduction in non-fatal AMI, unstable angina and ischemic stroke in patients randomized to receive the PCSK9-I alirocumab. The subgroup of individuals with LDL-C levels greater than 104