ABC | Volume 111, Nº2, August 2018

Review Article Leite et al Aspirin and hormonal therapy in breast cancer Arq Bras Cardiol. 2018; 111(2):205-212 Table 1 – Tamoxifen and lipid profile Changes Total cholesterol LDL-c HDL-c Triglycerides Tamoxifen Reduction Reduction Mild alteration Increase LDL-c: low-density lipoprotein cholesterol; HDL-c: high-density lipoprotein cholesterol. A significant reduction in the amount of microvessels in breast cancer was observed after treatment with raloxifene 60 mg/day for 28 days in postmenopausal women without previous endocrine treatment. 15 There is evidence that the benefits of treatment with SERMs were seen not only during the 5 years of active treatment, as well as 5 years after the end of treatment, indicating a long-term effect on the prevention of breast cancer. Adverse effects, notably the thromboembolic events and endometrial cancer, should be considered when assessing the risk-benefit ratio for each patient. 16 Selective estrogen receptor modulators and thromboembolic events A number of studies have demonstrated that the use of tamoxifen is associated with an increased rate of venous thromboembolic events (VTE) and that there is an additional procoagulant effect when tamoxifen is added to chemotherapy. 6,8,9 Raloxifene is also associated with a higher risk of VTE, but with a lower incidence than tamoxifen. The NSABP (National Surgical Adjuvant Breast and Bowel Project) Tamoxifen Prevention Trial 9 allocated 13,388 women at high risk of breast cancer to receive tamoxifen or placebo. The incidence of PE and DVT increased in women who received tamoxifen, especially in patients older than 50 years (RR for PE = 3.0, 95%CI: 1.1-11.2, RR for DVT = 1.6; 95%CI: 0.9‑2.9). The IBIS-1 (International Breast Cancer Intervention Study) 8 allocated 7,154 women at risk for breast cancer to receive tamoxifen or placebo. The use of tamoxifen was associated with an increased risk of developing VTE (Odds Ratio – OR = 2.1, 95%CI: 1.1-4.1). The risk of developing PTE or PE was significantly higher during the 5 years of active treatment with tamoxifen (RR of 2.3; 95%CI 1.4-3.9) but did not persist after its cessation. A meta-analysis of seven trials and 30,023 patients, which compared outcomes in women with breast cancer assigned to treatment with tamoxifen or an aromatase inhibitor, found a higher rate of VTE in those receiving tamoxifen (2.8% vs. 1.6%). 16 An analysis of 13 trials of the NSABP, 17 which evaluated the risk of contralateral breast cancer in 20,878 women who received tamoxifen after primary treatment for this disease, found an increased risk of VTE with tamoxifen. The risks of PE, DVT and superficial phlebitis increased two to three‑fold in patients treated with tamoxifen, and 11 to 15‑fold in patients treated with tamoxifen plus chemotherapy. 18 The STAR (Study of Tamoxifen and Raloxifene) 11 study suggested a lower incidence of DVT and PE in women receiving raloxifene vs. those treated with tamoxifen. This study randomized 19,747 women at risk for breast cancer to raloxifene and tamoxifen use for 5 years. Selective estrogen receptor modulators and cerebrovascular accident In the EBCTCG (Early Breast Cancer Trialists' Collaborative Group) 6 meta-analysis, which compared 21,457 women to receive tamoxifen or placebo, there was an increase in cerebrovascular accident (CVA) rates, but without statistical significance. In a case-control study of 11,045 women with breast cancer, the risk of CVA was not increased by the use of tamoxifen. 19 In a meta-analysis that evaluated the use of tamoxifen in primary or secondary prevention in 39,601 breast cancer patients, the frequency of ischemic CVA was higher in those who received tamoxifen than in the controls. 20 Tamoxifen was associated with an increased risk of CVA, but with a low absolute risk. In the RUTH (Raloxifene Use for The Heart) study, 21 raloxifene was associated with an increased risk of fatal CVA when compared with placebo. The IBIS-1 study 22 did not show statistical significance between the treatment groups (tamoxifen vs. placebo) regarding cerebrovascular or cardiovascular events. A sub-analysis of the MORE 12 study suggested that in women at high risk for arterial events, raloxifene reduced the incidence of coronary events and CVA. However, after 8 years of treatment, the incidence of cardiovascular, coronary, or cerebrovascular events did not significantly differ between the raloxifene and placebo groups. In the STAR study, 11 the risk of CVA was similar in the raloxifene and tamoxifen groups. Selective estrogen receptor modulators and lipid profile There is evidence of changes in the lipid profile with the use of SERMs. The reduction of serum total cholesterol and low‑density lipoprotein cholesterol (LDL-c) levels is a consensus. However, an increase in serum triglyceride levels has also been reported. Sawada and Sato 23 reported that tamoxifen reduced total and LDL cholesterol levels, as well as significantly increased triglycerides. Atalay et al. 24 did not find a significant effect of tamoxifen on total cholesterol or high-density lipoprotein‑cholesterol (HDL-c) but reported a borderline increase in triglycerides. Taken together, these studies suggest that although tamoxifen consistently lowers LDL-c levels, the effects on HDL-c are mild, and tamoxifen use increases serum triglyceride levels. Changes in the lipid profile associated with the use of tamoxifen are summarized in Table 1. Selective estrogen receptor modulators and coronary artery disease Even after consolidation of the clinical use of tamoxifen, there is no definitive evidence of its effect on coronary 207