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

Ann Oncol. 2017 Mar 1;28(3):487-496. doi: 10.1093/annonc/mdw673.


Background: 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.

Patients and methods: We searched PubMed, Embase (OVID), Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, and from inception to June 2016 for all RCTs comparing cardiovascular and cerebrovascular safety of AIs to tamoxifen, AIs to placebo or no-treatment, or tamoxifen to placebo or no-treatment in the adjuvant or extended adjuvant setting. Relative risks (RRs) were pooled using DerSimonian and Laird random-effects models with analyses stratified by RCT design.

Results: A total of 19 RCTs were included in the meta-analysis (n = 62 345). In the adjuvant setting, AIs were associated with a 19% (RR: 1.19, 95% confidence interval [CI]: 1.07-1.34) increased risk of cardiovascular events compared with tamoxifen. AIs were not associated with an increased risk compared with placebo in the extended-adjuvant setting (RR: 1.01, 95% CI: 0.85-1.20). In the adjuvant setting, tamoxifen was associated with a 33% (RR: 0.67, 95% CI: 0.45-0.98) decreased risk compared with placebo or no-treatment. The results from extended adjuvant RCTs comparing tamoxifen to placebo were inconclusive but suggestive of a small protective effect (RR: 0.91, 95% CI: 0.77-1.07).

Conclusions: The increased risk of cardiovascular events with AIs relative to tamoxifen is likely the result of cardioprotective effects of the latter. This new evidence should be considered when assessing the benefits and risks of AIs in the treatment of breast cancer.

Keywords: anastrozole; aromatase inhibitors; breast cancer; exemestane; letrozole; tamoxifen.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Antineoplastic Agents, Hormonal / adverse effects
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Aromatase Inhibitors / adverse effects*
  • Aromatase Inhibitors / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / pathology
  • Cardiotoxicity / epidemiology*
  • Cardiotoxicity / pathology
  • Female
  • Humans
  • Postmenopause / physiology
  • Randomized Controlled Trials as Topic
  • Risk Factors
  • Tamoxifen / adverse effects*
  • Tamoxifen / therapeutic use


  • Antineoplastic Agents, Hormonal
  • Aromatase Inhibitors
  • Tamoxifen