Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials.
Topic: Hormone Therapy

Aromatase inhibitors (AIs) have been associated with cardiovascular disease in adjuvant randomized controlled trials (RCTs) comparing these drugs to tamoxifen. However, it is unclear whether this risk is real or due to cardioprotective effects of tamoxifen. To address this question, we conducted a systematic review and meta-analysis of all RCTs of AIs and tamoxifen in adjuvant and extended adjuvant setting.

PICO
Population: Postmenopausal women with breast cancer
Intervention: Aromatase inhibitors and tamoxifen in adjuvant and extended adjuvant setting
Comparison: Comparison between aromatase inhibitors and tamoxifen
Outcomes: Cardiotoxicity as the primary outcome

Included studies:
title: Effects of adjuvant tamoxifen therapy on cardiac disease: results from a randomized trial with long-term follow-up.
abstract: Tamoxifen is associated with a reduced risk of coronary heart disease (CHD). However, there are few reports on long-term effects. Using data from a large Swedish randomized trial of 5 and 2 years of adjuvant tamoxifen in women with early breast cancer, we here present results on morbidity and mortality from cardiac diseases during treatment and long-term after treatment. A total of 4,150 patients were breast cancer recurrence-free after 2 years. Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry were used to define events of disease. Hazard ratios were estimated using Cox regression. Patients assigned to 5 years in comparison with 2 years of postoperative tamoxifen experienced a reduced incidence of CHD [hazard ratio (HR), 0.83; 95 % CI 0.70-1.00], especially apparent during the active treatment period (HR 0.65; 95 % CI 0.43-1.00). The mortality from CHD was significantly reduced (HR 0.72; 95 % CI 0.53-0.97). During the active treatment, the morbidity of other heart diseases was also significantly reduced (HR 0.40; 95 % CI 0.25-0.64) but not after treatment stopped (HR 1.06; 95 % CI 0.87-1.30). Similar results were seen for both heart failure and atrial fibrillation/flutter. As compared to 2 years of therapy, 5 years of postoperative tamoxifen therapy prevents CHD as well as other heart diseases. The risk reduction is most apparent during the active treatment period, and later tends to diminish.
title: Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. The Scottish Cancer Trials Breast Group.
abstract: To determine any cardiac or vascular morbidity associated with long term treatment with tamoxifen given after mastectomy for primary breast cancer.
title: Extending aromatase inhibitor adjuvant therapy to 10 years.
title: A model of the temperature rise in the head due to magnetic resonance imaging procedures.
abstract: A simple model of power deposition in the head is presented in which the temperature increase in the head in general and, in particular, in a small spherical region of unperfused tissue contained within the head is calculated. The result of the calculation provides a limit on the SAR needed to ensure that a 1 degree C temperature rise is not exceeded for unperfused spheres of different sizes, imaging sessions of different lengths of time, and different blood flow rates to the head. The model assumes that the rest of the body during a head imaging session can act as a perfect heat sink at 37 degrees C. The model suggests that current practices in MRI imaging will not cause a temperature rise in the center of small unperfused regions such as the eye of more than 1 degree C.
title: Adjuvant tamoxifen versus placebo in elderly women with node-positive breast cancer: long-term follow-up and causes of death.
abstract: This study analyzes the long-term results and causes of death in elderly women with node-positive breast cancer who participated in a double-blind adjuvant trial that compared tamoxifen with placebo to determine the benefit of 2 years of treatment.
title: Effects of tamoxifen on cardiovascular risk factors in postmenopausal women after 5 years of treatment.
abstract: Adjuvant tamoxifen therapy for breast cancer has been given for a period of several years. Cardiovascular diseases increased in incidence rapidly in women older than 60 years. Favorable changes in cardiovascular risk factors have been seen with 2 years of tamoxifen therapy, and lower rates of myocardial infarction and of hospitalization for heart disease have been observed in tamoxifen-treated women.
title: Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study.
abstract: In postmenopausal women with estrogen receptor-positive early breast cancer, surgery is usually followed by a 5-year course of tamoxifen. This report presents results of a prospective, open-label, randomized study, designed to evaluate the benefits of switching to anastrozole after 2 years of tamoxifen treatment, compared with continuing on tamoxifen for 5 years.
title: The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L).
abstract: The purpose of this study was to evaluate changes in serum lipid parameters {cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein(a) [Lp(a)]}, in postmenopausal women receiving letrozole or placebo after adjuvant tamoxifen for early stage breast cancer (NCIC CTG MA.17L).
title: Effects of physical activity on risk factors for coronary heart disease in previously sedentary women: a five-year longitudinal study.
abstract: Fitness, weight, blood-pressure, and lipids were measured in 290 women joining a fitness programme. Five years later, 110 (38%) had remained active, and the others had become sedentary again. The net effect of being active was to increase fitness by 18% and to reduce weight by 1.9 kg, diastolic blood pressure by 3 mmHg, and triglycerides by 0.15 mmol/L-1. After controlling for age, weight and fitness, physical activity accounted for 1% and 3% of the variance of changes in systolic and diastolic blood pressure respectively, and was not associated with changes in lipids. Change in fitness accounted for only 1% of change in diastolic blood pressure. More 'active' women gave up smoking than 'inactive' (70% versus 10%). Hypertensive women were more sensitive to changes in weight and fitness than normotensive women. It was concluded that physical activity and change in fitness were only weakly related to changes in blood pressure and were unrelated to changes in lipids.
title: Health-related quality of life, psychological distress, and adverse events in postmenopausal women with breast cancer who receive tamoxifen, exemestane, or anastrozole as adjuvant endocrine therapy: National Surgical Adjuvant Study of Breast Cancer 04 (N-SAS BC 04).
abstract: Health-related quality of life (HRQOL), symptoms of depression, and adverse events (AEs) were compared between Japanese postmenopausal patients with hormone-sensitive breast cancer (BC) who received adjuvant tamoxifen, exemestane, or anastrozole in an open-labeled, randomized, multicenter trial designated as the National Surgical Adjuvant Study of Breast Cancer (N-SAS BC) 04 substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. During the first year of treatment, HRQOL and symptoms of depression were analyzed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and its Endocrine Symptom Subscale (ES), and the Center for Epidemiologic Studies Depression Scale (CES-D), respectively. In addition, predefined AEs were analyzed. A total of 166 eligible patients were randomly assigned to receive adjuvant tamoxifen, exemestane, or anastrozole. FACT-B scores increased after treatment began and remained significantly higher in the tamoxifen group than in the exemestane group or anastrozole group during the first year (P = 0.045). FACT-B scores were similar in the exemestane group and anastrozole group. ES scores and CES-D scores were similar in all treatment groups. Arthralgia and fatigue were less frequent, but vaginal discharge was more frequent in the tamoxifen group than in the exemestane group or anastrozole group. HRQOL was better in Japanese postmenopausal women treated with tamoxifen than those treated with exemestane or anastrozole. HRQOL and AEs were similar with exemestane and anastrozole. Given the results of the TEAM trial, upfront use of tamoxifen followed by an aromatase inhibitor (AI) may be an important option for adjuvant endocrine therapy in Japanese postmenopausal women.
title: Phase III randomized adjuvant study of tamoxifen alone versus sequential tamoxifen and anastrozole in Japanese postmenopausal women with hormone-responsive breast cancer: N-SAS BC03 study.
abstract: Clinical trials conducted in Western countries have shown that aromatase inhibitors are associated with better disease-free survival (DFS) than tamoxifen in postmenopausal early breast cancer. Because pharmacogenetic differences in drug-metabolizing genes may cause ethnic differences, assessment of the efficacy and tolerability of aromatase inhibitors in non-white women is warranted. This open-label, randomized clinical trial included 706 postmenopausal Japanese women with hormone-receptor-positive breast cancer, who had received tamoxifen for 1 to 4 years as adjuvant therapy. This study was closed early after entry of approximately 28% of the initially planned patients. They were randomly assigned to either switch to anastrozole or to continue tamoxifen for total treatment duration of 5 years. Primary endpoints were DFS and adverse events. At a median follow-up of 42 months, the unadjusted hazard ratio was 0.69 (95% confidence interval, 0.42-1.14; P = 0.14) for DFS and 0.54 (95% CI, 0.29-1.02; P = 0.06) for relapse-free survival (RFS), both in favor of anastrozole. The incidence of thromboembolic events in the tamoxifen group and bone fractures in the anastrozole group was not excessively high. Switching from tamoxifen to anastrozole was likely to decrease disease recurrence in postmenopausal Japanese breast cancer patients. Ethnic differences in major adverse events may be attributable to a low baseline risk of these events in Japanese.
title: Developmental differences in the analgesia produced by the central cholinergic system.
abstract: In order to study the ontogenesis of cholinergically mediated analgesia in the central nervous system (CNS), 10-day-, 28-day-, and 3-month-old rats were injected with .025, .05, and .10 mg/kg of oxotremorine, a muscarinic receptor agonist. To restrict the effect of oxotremorine to the CNS, methylscopolamine, a peripheral muscarinic antagonist, was injected simultaneously (.19 mg/kg, a dose equimolar to .10 mg/kg of oxotremorine). Following drug injections the tail-flick procedure was used to assess analgesia. Results revealed that oxotremorine was completely ineffective in producing analgesia in the 10-day- and 28-day-old age groups. By 3 months of age oxotremorine produced a dose-dependent analgesia. Since most neurochemical markers of cholinergic receptor function are at mature or near mature levels by 28 days of age, neurochemical indexes of receptor function overestimate the analgesic function of the central cholinergic system.
title: Adjuvant tamoxifen in the management of operable breast cancer: the Scottish Trial. Report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office (MRC), Edinburgh.
abstract: In a trial that began in 1978, 1312 evaluable patients under 80 years of age who either had negative axillary nodes or were postmenopausal with positive axillary nodes were randomised to receive adjuvant tamoxifen 20 mg daily for 5 years, or tamoxifen for the treatment of first relapse. Estimates of oestrogen receptor (ER) content of primary tumour specimens were made in 57%. There has been a highly significant delay in relapse in the adjuvant arm of the trial. This benefit supersedes that from tamoxifen given as treatment for recurrent disease in control-arm patients (93% received this) so that benefit from adjuvant tamoxifen was maintained in the overall survival comparisons. This improvement seems to be independent of nodal and menopausal status. It does not differ significantly with ER level, although the greatest benefit in disease-free survival is in patients with levels of 100 fmol/mg protein or more.
title: Effect of exemestane on the lipidemic profile of post-menopausal operable breast cancer patients following 5-7 years of adjuvant tamoxifen: preliminary results of the ATENA substudy.
abstract: Long-term endocrine therapy for breast cancer may have clinical implications as drugs that potentially alter the lipid profile may increase the risk of developing cardiovascular disease. In this study, a companion subprotocol to the ATENA (Adjuvant post-Tamoxifen Exemestane versus Nothing Applied) trial, we compared the effect of the steroidal aromatase inactivator exemestane on the lipid profile of post-menopausal women with operable breast cancer in the adjuvant setting to that of observation alone following deprivation of 5-7 years primary treatment with tamoxifen. In this open-label, randomized, parallel group study, 340 post-menopausal patients with operable breast cancer who had been treated with tamoxifen for 5-7 years were randomized to either 5 additional years of exemestane (25 mg/day; n=172) or observation alone (n=168). Assessments of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and total serum triglycerides (TRG) were performed at baseline, and at 6 and 12 months. Total TRG levels were significantly reduced compared with baseline for the exemestane and the observational arm. Both total cholesterol and LDL levels were significantly increased above that of baseline values by 6 months, maintained through to 12 months, with no significant difference between the two treatment arms. There was no significant alteration observed for HDL over time or between the two arms. We conclude that sequential adjuvant treatment with exemestane in post-menopausal operable breast cancer patients following cessation of 5-7 years of tamoxifen does not appear to significantly alter the lipidemic profile for at least 12 months compared with an observational arm.
title: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer.
abstract: Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse.
title: Effects of the antiestrogen tamoxifen on low-density lipoprotein concentrations and oxidation in postmenopausal women.
abstract: Our study demonstrates that tamoxifen, when administered to postmenopausal women at a conventional dosage, reduces LDL levels and protects LDL from oxidation. The protective effect of tamoxifen against the development of breast cancer in women considered at risk is being investigated in a placebo-controlled trial sponsored by the National Institutes of Health. Whether tamoxifen also protects against the development of cardiovascular disease in this trial is also of considerable interest.
title: Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial.
abstract: Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2-3 years of tamoxifen to postmenopausal women with hormone-receptor-positive breast cancer. We therefore compared the long-term effects of exemestane monotherapy with sequential treatment (tamoxifen followed by exemestane).
title: Exemestane for breast-cancer prevention in postmenopausal women.
abstract: Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer.
title: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial.
abstract: In the adjuvant setting, tamoxifen is the established treatment for postmenopausal women with hormone-sensitive breast cancer. However, it is associated with several side-effects including endometrial cancer and thromboembolic disorders. We aimed to compare the safety and efficacy outcomes of tamoxifen with those of anastrozole alone and the combination of anastrozole plus tamoxifen for 5 years.
title: Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer.
abstract: The Cancer Research UK "Over 50s" trial compared 5 and 2 years of tamoxifen in women with early breast cancer. Results are reported after median follow-up of 10 years.
title: Effect of tamoxifen at low doses on ultrasensitive C-reactive protein in healthy women.
abstract: The use of tamoxifen as a breast cancer preventive agent may be contraindicated by an increased risk of endometrial cancer and venous thromboembolic events, particularly in postmenopausal women. Since these estrogenic effects may be dose-related, a dose reduction may reduce toxicity. We have recently shown a comparable activity of lower doses of tamoxifen on putative surrogate biomarkers of cardiovascular disease and breast cancer. To provide further insight into the effect of tamoxifen at low doses on the cardiovascular system, we compared the effect of three different doses on circulating levels of C-reactive protein (CRP), an independent risk marker for cardiovascular disease (CVD), which was lowered by tamoxifen at the standard dose of 20 mg day-1 in previous studies. We compared the changes in CRP after 2 months of either placebo (n = 24), or tamoxifen 10 mg alternate daily (n = 26), or 10 mg day-1 (n = 22), or 20 mg day-1 (n = 19) in healthy women aged 35-70 years. The median percent change was -2.2% (95% CI, -23.3 to 42.8) with placebo, -39.1 (95% CI, -59.9 to -28.7) with 10 mg alternate daily, -56.9% (95% CI, -68.6 to -38.4) with 10 mg day-1 and -42.9% (95% CI, -62.6 to 1.6) with 20 mg day-1 (P = 0.291 for the linear dose-response trend). Similar results were obtained when the data were classified according to blood tamoxifen concentrations, with a median reduction of 47% (95% CI, 65.5-36.3) for women with low tamoxifen concentrations (< 30 ng mL-1). We conclude that tamoxifen at low doses is able to lower ultrasensitive CRP and that this might be associated with a beneficial effect on CVD.
title: Tamoxifen and cardiac risk factors in healthy women: Suggestion of an anti-inflammatory effect.
abstract: -Tamoxifen reduces the incidence of breast cancer in women at risk for that disease. Because heart disease is the leading cause of death in women and because tamoxifen is also associated with venous thrombosis, an improved understanding of the association of tamoxifen with cardiovascular disease risk factors is required. In 111 healthy women at a single center, who were participating in a randomized double-blind breast cancer prevention trial, the 6-month effects of oral tamoxifen (20 mg/d) compared with placebo on factors related to inflammation, hemostasis, and lipids were studied. Tamoxifen was associated with reductions of 26% in median C-reactive protein, 22% in median fibrinogen, and 9% in cholesterol (all P:<0.01 compared with placebo). There were no differences in treatment effects on factor VII coagulant activity, fragment 1-2, and triglycerides. In secondary analyses, the effect of tamoxifen on C-reactive protein was larger in postmenopausal women and in women with higher waist-to-hip ratios. The effect on fibrinogen was larger in women with higher baseline cholesterol. Tamoxifen demonstrated effects on inflammatory markers that were consistent with reduced cardiovascular risk. These findings are in contrast to recent reports of increased C-reactive protein associated with postmenopausal estrogen. The potential for beneficial cardiovascular effects of tamoxifen in healthy women is suggested.
title: Preliminary results from the cancer research campaign trial evaluating tamoxifen duration in women aged fifty years or older with breast cancer. Current Trials working Party of the Cancer Research Campaign Breast Cancer Trials Group.
abstract: Although trials of post-surgical tamoxifen therapy for patients with breast cancer have convincingly demonstrated reductions in relapse rates and improvements in survival, the optimal duration of therapy is as yet unclear.
title: [Personal experience with tympanoplasty. II. Reconstruction of the tympanic membrane].
title: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update.
abstract: To update the ASCO clinical practice guideline on adjuvant endocrine therapy on the basis of emerging data on the optimal duration of treatment, particularly adjuvant tamoxifen.
title: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer.
abstract: The aromatase inhibitor letrozole is a more effective treatment for metastatic breast cancer and more effective in the neoadjuvant setting than tamoxifen. We compared letrozole with tamoxifen as adjuvant treatment for steroid-hormone-receptor-positive breast cancer in postmenopausal women.
title: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17.
abstract: Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial.
title: C-reactive protein, fibrinogen, and cardiovascular disease prediction.
abstract: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events.
title: Long term effects of tamoxifen on blood lipid values in breast cancer.
title: Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial.
abstract: The Arimidex (anastrozole), Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole with tamoxifen as adjuvant treatment for postmenopausal women with early-stage breast cancer. After an extended follow-up beyond the 5 years of treatment, we aimed to assess the safety, tolerability, and risk-benefit indices of these compounds.
title: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary results of the Italian Tamoxifen Anastrozole Trial.
abstract: Tamoxifen, which is actually the gold standard adjuvant treatment in estrogen receptor-positive early breast cancer, is associated with an increased risk of endometrial cancer and other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy because of the development of resistance. Therefore new approaches are required.
title: Randomized trial of 2 versus 5 years of adjuvant tamoxifen for women aged 50 years or older with early breast cancer: Italian Interdisciplinary Group Cancer Evaluation Study of Adjuvant Treatment in Breast Cancer 01.
abstract: To compare 2 with 5 years of adjuvant tamoxifen therapy in the treatment of early breast cancer.
title: Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1-98 study.
abstract: Among postmenopausal women with endocrine-responsive breast cancer, the aromatase inhibitor letrozole, when compared with tamoxifen, has been shown to significantly improve disease-free survival (DFS) and time to distant recurrence (TDR). We investigated whether letrozole monotherapy prolonged overall survival (OS) compared with tamoxifen monotherapy.
title: Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years.
abstract: The Scottish Adjuvant Tamoxifen Trial (main trial) was initiated in April 1978 to assess the effect of tamoxifen given to patients with breast cancer immediately after mastectomy (or mastectomy plus radiation therapy) (adjuvant arm) or only after the patients had had a relapse (control arm); 1323 patients were randomly assigned (667 to the adjuvant arm and 656 to the control arm). Results have been reported for the follow-up period from 2.5 through 8 years. In this article, we report updated results after a median follow-up of 15 years. If agreeable and eligible, patients who were disease free at 5 years in the adjuvant arm of the main trial were entered into a duration trial and randomly assigned either to stop taking tamoxifen (169 patients) or to continue taking it indefinitely until relapse or death (173 patients). For this update, we analyzed information on death, recurrence, survival, and other malignancies for all but 21 of the 560 living patients from the original and duration trials to determine the probabilities of total survival, systemic relapse of disease, and death from breast cancer. All statistical tests are two-sided.
title: Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors.
abstract: In 1982, the National Surgical Adjuvant Breast and Bowel Project initiated a randomized, double-blinded, placebo-controlled trial (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement. The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease. However, questions arose about how long the observed benefit would persist, about the duration of therapy necessary to maintain maximum benefit, and about the nature and severity of adverse effects from prolonged treatment.