ABC | Volume 111, Nº1, July 2018

Viewpoint Behr et al PCSK9 in patients at cardiovascular risk Arq Bras Cardiol. 2018; 111(1):104-108 or equal to 100 mg/dL (already treated with statins) and receiving alirocumab had the highest benefit, with a 29% reduction in total mortality as compared to placebo. Cost versus benefit of new therapies Although the advent of precision medicine and the innovative treatments have guided to an individualized approach in prevention and patient’s management, the financial restrictions to the progressive increase in health system costs worldwide often requires balancing the therapeutic benefit and the cost of a certain intervention. Brazilian guideline The recently updated Brazilian Guideline on Dyslipidemias and Atherosclerosis Prevention recommends the use of PCSK9-I (evolocumab and alirocumab) only to patients at high CV risk, receiving optimized treatment with statins at the highest tolerated dose, either associated or not with ezetimibe, and who have not met the recommended LDL-C or non-HDL-C targets. 13 The Brazilian guideline, however, does not indicate which individuals will benefit most from the use of that new class of drugs. Some studies have demonstrated that the quantification of the absolute benefit of an additional therapy is an important factor to support the clinical decision of using or not the new treatment. In addition, financial aspects should be taken into account, but so far cost-effectiveness analyses of the PCSK9-I in Brazil have not been made. 14 Considering that the costs of PCSK9-I are greater than those of the other drugs for the treatment of CVD, it is important to identify among high-risk individuals those whose treatment is associated with greater clinical relevance, which can be estimated by the number needed to treat (NNT) to prevent the first outcome within a certain time. 15 In addition, calculating the NNT can help identify groups of patients who will benefit most from the addition of a non-statin therapy, by combining absolute risk and LDL-C thresholds. In this position statement of the Atherosclerosis Department of the Rio Grande do Sul Society of Cardiology, the selection of patients to use PCSK9-I is more conservative than that of most current guidelines on the use of those drugs. Thus, it is worth emphasizing that the use of antibodies against PCSK9 for individuals who do not meet the criteria presented in this document is not contraindicated, because the therapeutic decision involves clinical judgement and consensus between physicians and patients. Therefore, this position statement was aimed at identifying the individuals who will benefit most from the use of that new class of drugs to treat hypercholesterolemia. This first position statement will not address indications of that new class of drugs for statin-intolerant individuals or those on high-risk primary prevention, such as FH. Considering that evolocumab and alirocumab consistently reduce LDL-C levels by 50% at least, two factors should be observed to quantify the benefit of the treatment: the individuals’ clinical characteristics and the LDL-C levels obtained after maximum treatment with statin/ezetimibe. 1) Clinical characteristics of the patients The clinical characteristics of the patients at CV risk should be identified based on the absolute risk of CV events in 10 years. 16 The greatest benefit derived from the use of PCSK9-I is obtained in individuals at CV risk higher than 20% in 10 years. Thus, patients with previous coronary events or procedures, stroke or aortic aneurysm are classified as “high risk” (20-29% in 10 years). Patients at “very high risk” for CV events (over 30% in 10 years) are those with recurrent acute coronary syndrome, repeated arterial revascularization or repeated strokes within the first year from the initial event. Advanced age, and the association of diabetes or peripheral occlusive arterial disease are aggravating factors. 2) LDL-C cutoff points after maximum treatment with statin/ezetimibe In addition to the patients’ clinical characteristics, the LDL-C cutoff points from which the treatment with PCSK9-I provides the greatest benefits should be indicated. The FOURIER trial has shown that even individuals in the lowest quartile of LDL-C levels had a significant reduction in CV events when receiving evolocumab. However, when assessing that variable, it is worth noting that the reduction in the absolute risk for the same relative reduction in LDL-C level will be smaller when the baseline LDL-C level is lower (Figure 1). In other words, the higher the LDL-C level after treatment with statins/ezetimibe, the greater the benefit deriving from the treatment with PCSK9-I and the smaller the NNT. 17 The relative reduction in CV events resulting from the use of statins, ezetimibe and monoclonal antibodies against PCSK9 has shown consistency with the relationship reported in the Cholesterol Treatment Trialists meta-analysis, in which every 39-mg/dL reduction in LDL-C was associated with a 21% reduction in major CV events. 18 Criteria to support decision-making By associating the two variables presented in an excellent analysis and according to the CV risk and LDL-C levels of patients receiving treatment with statins, Robinson et al. 16 have estimated the NNTs in 5 years to prevent a CV event. 16 (Table 1) Although there is consensus that NNTs up to 50 are acceptable 19 for new interventions, it is worth noting that PCSK9-I are high-cost drugs. On the other hand, NNTs under 20 are rarely obtained for interventions to treat or prevent CVD resulting from the current studies. 20 Assuming that PCSK9-I consistently reduce LDL-C levels by at least 50%, we consider that NNTs under 30 are totally acceptable and identify a subgroup of individuals who will greatly benefit from receiving that new class of drugs. 105