ABC | Volume 112, Nº4, April 2019

Review Article Ferrari et al PCSK9 Inhibitors in Clinical Practice Arq Bras Cardiol. 2019; 112(4):453-460 Clinical relevance CV risk can be significantly mitigated by aggressive LDL reductions; the higher the risk, the lower the target LDL level. No class of hypolipidemic agents had given rise to such anticipation since the discovery of the statins, 15 as the PCSK9i can promote an additional reduction of up to 60% in LDL levels when compared to statins. 9 The FOURIER study, 8 a randomized clinical trial (RCT) published in 2017, enrolled more than 27,000 patients with atherosclerotic CV disease and LDL levels ≥ 70 mg/dL. Participants, all of whomwere on statin therapy, were randomly allocated to receive add-on evolocumab or placebo for a mean period of 2.2 years. In the evolocumab group, there was a mean reduction in LDL levels of 30 mg/dL from baseline; in absolute terms, when compared to the placebo group, the mean LDL reduction was 56 mg/dL. Most importantly, a 15% reduction was found in the primary endpoint (nonfatal acute myocardial infarction [AMI], stroke, coronary revascularization, hospitalization for unstable angina, and CV mortality), as well as a 20% reduction in the composite secondary hard endpoint of CV death, nonfatal AMI, and nonfatal stroke. At the end of the study, there was an absolute risk reduction of 1.5% for both the primary and secondary endpoints, which translated into a number needed to treat (NNT) of approximately 67. More recently, the ODYSSEY Outcomes 16 study compared alirocumab plus with statin versus statin alone at maximal tolerated dose in approximately 19,000 patients at very high CV risk for 2.8 years. LDL levels were 53.3 mg/dL in the alirocumab + statin group versus 101.4 mg/dL in the statin group, and an absolute reduction of 54.7% was observed. The primary outcome of major adverse CV events was also significantly lower in the combination therapy group. Furthermore, there was a surprising 15% reduction in deaths from any cause in this group (NNT of approximately 63). In the ODYSSEY Outcomes trial, LDL decreased 47 mg/dL after 1 year of follow-up, which, based on the Cholesterol Treatment Trialists (CTT) model, 17 would represent a 24% reduction in the relative risk of major CV events. However, in practice, only a 15% reduction was observed. This divergence can be explained by the difference in follow-up time between ODYSSEY Outcomes (2.5 years) and the CCT analyses (5 years). In fact, CTT data showed a smaller magnitude of benefit regarding LDL reduction in the first year. 17 In an analysis of the FOURIER trial, 18 the clinical benefits of evolocumab differed interestingly depending on the severity and extent of CAD. First, evolocumab reduced LDL levels by 61%. Second, patients with a greater risk profile, i.e., those with more recent AMI (< 2 years), multiple anterior AMIs, and multivessel disease, were those who benefited most from the use of PCSK9i: they experienced relative risk reductions for the primary endpoint of 20%, 18%, and 21%, respectively, versus 5%, 8%, and 7% reductions respectively in low-risk comparators subgroups (i.e., participants without these complications). In the high-risk patient subgroups, the absolute risk reductions in 3 years exceeded 3% (3.4%, 3.7%, and 3.6% respectively), versus approximately 1% in the low-risk groups (0.8%, 1.3%, and 1.2% respectively). Thus, the NNT to avoid the primary outcome over a 3-year period was 27 to 30 in each of the high-risk groups versus 54 in all patients with a history of AMI and 79 to 130 in the low-risk subgroups. 18 That is, in those patients who were more difficult to manage and had a higher risk of events, the reduction of CV risk with evolocumab was more substantial. In this context, it would be reasonable, then, to direct this type of therapy preferentially to those patients with more severe dyslipidemia, considering the more substantial reductions of LDL and, consequently, more encouraging benefits and greater cost-effectiveness. Another aspect to be considered relates to the regression of atheroma volume. Large reductions in LDL levels can promote such an effect, as was suggested by the GLAGOV trial. 19 In this experiment, 968 patients were included in 226 centers across 32 countries. Participants with symptomatic CAD were diagnosed by coronary computed tomography angiography and received monthly evolocumab (420 mg) vs. placebo for 76 weeks, in addition to statins. At the start of the study, the mean LDL level of the participants was 93 mg/dL; by the end, those randomized to evolocumab reached 29 mg/dL, versus 90 mg/dL in controls. In addition, greater regression of atherosclerotic plaque was observed in the evolocumab group (64.3% vs. 47.35%; p < 0.0001), making GLAGOV the first study to demonstrate the benefits of PCSK9i on atherosclerotic plaque. 19 These results appear to hold relevance to clinical practice, as well as external validity. Animal studies play a fundamental role in the development of new drugs. In experiments with mice, administration of alirocumab (3 or 10 mg/kg) for 18 weeks reduced plasma lipid levels, mitigated development of atherosclerosis and improved plaque morphology. When used in combination with atorvastatin (3.6 mg/kg/d), the severity of atherosclerotic lesions was reduced even further, in a dose-dependent manner. 20 However, trials with larger samples – and, preferably, in humans – are lacking. It is estimated that 24 million patients in the U.S. alone could be eligible for PCSK9i therapy. 21 Although there are no such data for the Brazilian population, the efficacy and safety of these agents have been recognized by regulatory agencies in the country, and two PCSK9i have been approved by the National Health Surveillance Agency (ANVISA) and are commercially available: Praluent® (alirocumab) and Repatha™ (evolocumab). 22 Their approved indications for use in Brazil, as well as dosages and the magnitude of LDL reduction achieved, are summarized in table 1. General recommendations for the use of PCSK9i in clinical guidelines Several guidelines, including those cited in subsequent paragraphs, are unanimous in indicating the therapeutic use of PCSK9i only for those patients considered to be at high or very high risk and who were unable to reach LDL targets even after lipid-lowering therapy (such as statins at maximum tolerated dose or statins plus ezetimibe). The UK National Institute for Health and Care Excellence (NICE) does not recommend the use of PCSK9i for patients with primary non-familial hypercholesterolemia or mixed dyslipidemia without evidence of CV disease, regardless of LDL concentration. In patients at high CV risk, the use of 454