ABC | Volume 112, Nº4, April 2019

Review Article Ferrari et al PCSK9 Inhibitors in Clinical Practice Arq Bras Cardiol. 2019; 112(4):453-460 some reports that warned of a possible increase in the risk of neurocognitive events with the use of PCSK9i. Indeed, there is some biological plausibility to support the argument that a very sharp reduction in lipids can negatively impact cognitive function, regardless of the ability of the drug to cross the blood-brain barrier. 46,47 To date, the leading assessment of the risk of cognitive deficits with the use of a PCSK9i (evolocumab) plus statin as compared to placebo plus statin is the EBBINGHAUS trial, 48 which randomized 1,974 patients. The subjects had a mean age of 63 years and were followed up for approximately 19 months. All completed the Cambridge Neuropsychological Test Automated Battery at 6, 12, and 24 months. No difference was observed between the groups in terms of cognitive function, scores on the cognitive function battery, or in subjective self-assessment of daily cognitive ability. 48 In a pre-specified secondary analysis of the FOURIER study, Giugliano et al. 49 analyzed approximately 26,000 patients, with special attention to the relationship between the LDL concentration reached at 4 weeks and subsequent CV outcomes. There was no reduction in safety with very low LDL concentrations over an average of 2 years. In the MENDEL-2 50 study, a large trial of evolocumab monotherapy, there was a rapid and marked decrease in levels of LDL and apolipoprotein B over 12 weeks in comparison with the placebo or ezetimibe group. LDL reductions in excess of 50% were reported in 72% of patients who received evolocumab. Severe adverse effects occurred at comparable rates across groups. In addition, injection-site reactions were infrequent with evolocumab and did not differ between groups. Biweekly and monthly evolocumab administration yielded comparable reductions in LDL levels, with good tolerability and safety. 50 The LAPLACE-2 51 study compared evolocumab versus ezetimibe versus placebo in patients with hypercholesterolemia who were receiving stable doses of statins. Adverse events were similar in the three groups (36% of patients treated with statin plus evolocumab, 40% of those who received statin plus ezetimibe, and 39% of those who received statin plus placebo); musculoskeletal symptoms and headache were the most common. Intolerable adverse events that resulted in discontinuation of treatment occurred in only 1.9%, 1.8%, and 2.2% of participants in the evolocumab, ezetimibe, and placebo groups, respectively. Severe adverse events were reported in 2.1% of the patients treated with evolocumab, 0.9% of those treated with ezetimibe, and 2.3% of those in the control group. Neurocognitive events were reported in only 1 patient treated with evolocumab, compared with 3 patients treated with ezetimibe and no patients in the control groups. It bears stressing that the study was conducted for a short period (3 months) and, despite some adverse events, the benefits seemed to outweigh the risk of PCSK9i therapy. 51 The GAUSS-2 52 study evaluated evolocumab versus ezetimibe in statin-intolerant dyslipidemic patients over 3 months. The rate of adverse events leading to treatment discontinuation was 8% in the evolocumab group – lower than in the ezetimibe arm (13%). Muscle pain occurred in only 8% of patients treated with evolocumab, versus 18% of those treated with ezetimibe. Discontinuation due to musculoskeletal side effects occurred in 5% of patients the evolocumab group, again a rate numerically lower than in the ezetimibe group (6%). 52 In the GAUSS-3 study, 53 patients who were intolerant to statins were treated with evolocumab 420 mg (with placebo ezetimibe) or ezetimibe 10 mg per day (with placebo evolocumab). Myalgia was reported by approximately 29% of patients treated with ezetimibe and 21% of those treated with evolocumab. However, muscular symptoms leading to discontinuation were very infrequent in the evolocumab group, occurring in only 1 out of 145 treated patients. 53 This seems very relevant, as it suggests that PCSK9i therapy can be used successfully in people with statin intolerance. Interestingly, subjects with null mutation of the PCSK9 gene have been described. A U.S. woman inherited a mutation from her father and another from her mother which effectively eliminated PCSK9 function. 54 Her lifetime average LDL levels were only 14 mg/dL and, more importantly, she seems to lead a healthy life. In other words, even in a setting of marked reduction of LDL to extraordinarily low levels due to a genetic mutation, there is no evidence of any relevant harm to the overall health of the individual. Another factor that is worthy of note is measurement of vitamin E levels. It is known that lipoproteins are involved in vitamin E transport, 55 and are necessary for steroidogenesis. Therefore, when levels of LDL are extremely low, vitamin E measurement – and, possibly, supplementation – seems necessary. 56 In fact, data from the DESCARTES 57 study showed that the substantial reduction in LDL in patients treated with evolocumab also reduced their levels of vitamin E. Nevertheless, there was no alteration in tissue levels of vitamin E, and the reduction was not clinically significant. Furthermore, there is no evidence of compromised synthesis of steroid, adrenal, or gonadal hormones, even in patients with extremely low LDL. 57 Overall, these data support that even very low concentrations of LDL by inhibition of PCSK9 do not translate into increased risk. In addition to these results, preliminary data from an analysis of nearly 3,000 patients enrolled in the DESCARTES and OSLER-1 studies showed no increase in adverse events and no cases of hemorrhagic stroke among patients with LDL levels below 40 or 25 mg/dL. 50 Two open-label extensions of the FOURIER study, designed to evaluate the long-term safety of evolocumab in approximately 6,600 patients, are underway. 49 These results will certainly provide clearer evidence on the safety profile of PCSK9i. Cost-effectiveness Despite current evidence supporting the superiority of PCSK9i in the reduction of LDL concentrations in comparison to statins and ezetimibe, the cost-effectiveness ratio cannot be ignored. Estimates suggest that use of these agents is associated with significant expenditures for patients in different scenarios: a) € 78,485.00 for those with a family history of hypercholesterolemia alone; b) € 176,735.00 for those with 457