Aromatase Inhibitors and the Risk of Cardiovascular Outcomes in Women With Breast Cancer

Abstract

Background: The association between aromatase inhibitors and cardiovascular outcomes among women with breast cancer is controversial. Given the discrepant findings from randomized controlled trials and observational studies, additional studies are needed to address this safety concern. Methods: We conducted a population-based cohort study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study population consisted of women newly diagnosed with breast cancer initiating hormonal therapy with aromatase inhibitors or tamoxifen between April 1, 1998, and February 29, 2016. We usedCox proportional hazards models with inverse probability of treatment and censoring weighting to estimate hazard ratios (HRs) with 95% CIs comparing new users of aromatase inhibitors with new users of tamoxifen for each of the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality). Results: The study population consisted of 23 525 patients newly diagnosed with breast cancer, of whom 17 922 initiated treatment with either an aromatase inhibitor or tamoxifen (8139 and 9783, respectively). The use of aromatase inhibitors was associated with a significantly increased risk of heart failure (incidence rate, 5.4 versus 1.8 per 1000 person-years; HR, 1.86 [95% CI, 1.14–3.03]) and cardiovascular mortality (incidence rate, 9.5 versus 4.7 per 1000 person-years; HR, 1.50 [95% CI, 1.11–2.04]) compared with the use of tamoxifen. Aromatase inhibitors were associated with elevated HRs, but with CIs including the null value, for myocardial infarction (incidence rate, 3.9 versus 1.8 per 1000 person-years; HR, 1.37 [95% CI, 0.88–2.13]) and ischemic stroke (incidence rate, 5.6 versus 3.2 per 1000 person-years; HR, 1.19 [95% CI, 0.82–1.72]). Conclusions: In this population-based study, aromatase inhibitors were associated with increased risks of heart failure and cardiovascular mortality compared with tamoxifen. There were also trends toward increased risks, although nonsignificant, of myocardial infarction and ischemic stroke. The increased risk of cardiovascular events associated with aromatase inhibitors should be balanced with their favorable clinical benefits compared with tamoxifen.

Endocrine therapy use and cardiovascular risk in postmenopausal breast cancer survivors

“…5 16 Comparison with other studies A recent meta-analysis of trials reported an increased risk of CVD, excluding VTE, in tamoxifen compared with AI users (RR: 1.18, 95% CI 1.05 to 1.33), 17 with results suggestive of a cardioprotective effect of tamoxifen, consistent with the results of this study. 10 Most (5/6) previous studies directly comparing the risk of MI in AI and tamoxifen users have reported a higher risk in AI users, similar to our results (RRs ranged from 0.99 to 2.02). 10 18-22 Two previous trials and five observational studies have compared MI risk in tamoxifen users with non-use/placebo, with 4/7 studies finding a reduced risk in tamoxifen users (RRs ranged from 0.20 to 0.83) [23][24][25][26][27][28][29] ; two analogous studies of AI use versus placebo or non-use found no association.…”

“…A recent analysis of UK data observed higher risks of heart failure (HF) and possible higher risks of myocardial infarction (MI) and stroke in AI compared with tamoxifen users; it was suggested that the higher risks of cardiovascular events associated with AIs may therefore need to be taken account in treatment decisions. 10 However, this study directly compared AIs and tamoxifen, and other evidence, summarised by a recent systematic review, has suggested that tamoxifen may have an underlying protective association with some CVD outcomes, making interpretation of the findings unclear. 4 Using data on women with postmenopausal breast cancer from two large electronic medical record datasets, we therefore aimed to: (i) examine the consistency of estimated associations between endocrine therapy drug class (AI/tamoxifen) and CVD risk between UK and US cohorts and (2) compare CVD risks between users of both drug classes and ER/PR+ breast cancer patients unexposed to endocrine therapy to investigate the key question of whether differences between the two drug classes were driven by underlying harmful or protective associations.…”

Increased P450 aromatase levels in post-menopausal women after acute ischemic stroke

“…The role of aromatase in cardiovascular disease has also been highlighted by studies in breast cancer patients who were administered aromatase inhibitors (17). A recent study demonstrated increased risks of heart failure and cardiovascular mortality in the patients taking aromatase inhibitors as compared with patients taking tamoxifen (18). Administration of the speci c aromatase inhibitor, fadrozole, in male rats enhanced the neurodegenerative effects of kainic acid and this was reversed by administration of estradiol, con rming that neuroprotective effects of aromatase are mediated by estradiol (19).…”

<p>Analyses of DNA Methylation Involved in the Activation of Nuclear Karyopherin Alpha 2 Leading to Identify the Progression and Prognostic Significance Across Human Breast Cancer</p>

“…1 Although the progression of modern medical technology has advanced the therapeutic effect of breast cancer, it remains the main cancer-related cause of female deaths. [2][3][4][5] Therefore, the progress in molecular diagnostic and recognition of prognostic value biomarkers in patients are desired in the medical field.…”