ABC | Volume 113, Nº4, October 2019

Updated Updated Cardiovascular Prevention Guideline of the Brazilian Society Of Cardiology – 2019 Arq Bras Cardiol. 2019; 113(4):787-891 placebo, with a total of 129,526 individuals followed for 4.8 years, each 40 mg/dL reduced of LDL-c decreased the incidence of CV events by 12% and CAD deaths by 20%. Moreover, the CTT analyses showed that a greater reduction in LDL-c with the use of more potent statins had an additive effect on the prevention of CV events. Findings of 5 RCTs with more than 39,000 individuals combined showed that reducing LDL-c levels in over 20 mg/dL with a more intensive lipid-lowering treatment can decrease the incidence of non-fatal myocardial infarction by 19%, ischemic CVA by 31%, and major CV events by 28%. The use of statins in patients with CAD seems to stabilize atherosclerotic plaques, and can even lead to their volumetric reduction, 95 with an approximately linear relationship between the decrease in LDL-c and the rate of CV events, as well as between LDL-c levels and the progression of the atheroma volume in carotid arteries. In parallel, not only the dose of statin and the reduction in LDL-c decrease CV risk, but the period of statin use also seems to have a central role in reducing the risk for CV death and non-fatal myocardial infarction. In the WOSCOPS study, for instance, the number needed to treat (NNT) with pravastatin after four years of follow-up was 40:1, whereas, after 16 years, NNT decreased to 27:1. 96 Regarding lipid targets for patients in secondary prevention, the scenario was redesigned after the publication of the IMPROVE-IT study 97 (with simvastatin and ezetimibe), whose LDL-c was 50 mg/dL, and the FOURIER study 98 (alirocumab, a PCSK9 inhibitor), which reached mean LDL-c levels as low as 38 mg/dL. Based on the significant and consistent reduction in coronary events in two clinical trials, currently the LDL-c target is < 50 mg/dL; there is no reason, however, in terms of safety, to seek even lower targets, either through diet, statins, ezetimibe, or PCSK9 inhibitors. In a primary prevention scenario, the reduction in vascular events is comparatively lower than in secondary prevention, but it still is robustly cost-effective in diabetic and non-diabetic patients with CV risk > 7.5% in 10 years. 99 As revealed in the CTT meta-analysis, a decrease in LDL-c by 80 mg/dL (with a mean starting LDL-c from 130 to 160 mg/dL) combined with an effective statin regimen for about five years in 10,000 patients in primary prevention typically prevents 500 vascular events (5% of patients). 14 Although the duration of clinical studies with statins is relatively short (3 to 7 years), patients with DM and MS will be subject to a metabolically unfavorable environment for the rest of their lives (10 to 30 years). Assuming that 68% of causes of death in diabetic patients are CV-related, 78 it is reasonable to think that, once the high vascular risk is identified (based on the ORS with or without CACS), more aggressive therapeutic targets should be considered. No RCT has investigated an LDL-c target below 70 mg/ dL (JUPITER) 100 in primary prevention. However, Mendelian randomization studies consistently support that lower LDL-c levels (including the 30-50 mg/dL range) were related to lower CV morbidity and mortality. 101 Furthermore, a subanalysis of the JUPITER study showed that the lower the LDL-c level achieved (< 50 mg/dL), the greater the risk reduction in both diabetic and non-diabetic individuals. 102 3.2.7. Aspirin in Primary Prevention The use of acetylsalicylic acid (ASA) in primary prevention is a controversial issue, but that seems to have recently reached a common denominator. In 2018, three RCT provided an answer to this question: the ASCEND, 103 in diabetic patients; the ARRIVE, 104 in non-diabetic patients at moderate CV risk (median risk of 15% in 10 years); and the ASPREE, 105 in patients aged 70 years or older. All three studies compared low doses of aspirin (100 mg per day) with placebo from 5 (ARRIVE and ASPREE) to 7.5 years (ASCEND), and collectively found: 1) no difference in rates of myocardial infarction and acute myocardial infarction; 2) no difference in CV mortality; 3) no difference in all-cause mortality in ASCEND and ARRIVE, and a small risk increase with aspirin in ASPREE; and 4) greater risk for gastrointestinal malignancy among aspirin users in the ASPREE study (probably due to early diagnosis). These data are consistent with a systematic review by the Antithrombotic Trialists’ Collaboration, 106 which included 95,000 individuals from six RCT. The reduction in risk for vascular events ranged from 0.57 to 0.51% per year (placebo vs. aspirin), while extracranial and major gastrointestinal bleedings increased by 0.03% per year (0.10 to 0.07%). Although observational studies suggest that the use of aspirin benefits primary prevention in patients at high CV risk, 107 this result was not confirmed in subanalyses of ASCEND and ARRIVE. Even in patients at higher estimated risk for CV events, aspirin provided no net benefit since it induced more bleedings in this subpopulation, and the proportional decrease in vascular events was mild compared to that in individuals at lower risk. 103,104 3.2.8. Hypoglycemic Agents in Patients with Diabetes Mellitus Despite the strong effect of glycemic control on microvascular complications among diabetic patients, its benefits for the macrovascular disease were still a paradigm until recently. Medicines such as sulfonylurea and insulin have limitations, despite being very effective in glycemic control, as they induce weight gain and increase the risk for hypoglycemia, two major risk factors for the worsening of symptoms and prognosis in HF and CAD. Several RCT tested these drugs, combined with metformin, by comparing intensive glycemic control and less aggressive targets. In a meta-analysis with 13 RCT and 34,533 diabetic individuals, although the risk for non-fatal myocardial infarction decreased with intensive glycemic control (relative risk – RR 0.85; 95% confidence interval, 0.74–0.96, p < 0.001), there was no significant change in all-cause mortality (RR 1.04; 99% confidence interval, 0.91–1.19) or CV mortality (RR 1.11; 95% confidence interval, 0.86–1.43). 108 809