The use of aromatase inhibitors is associated with a statistically significant, 26% increased risk of cardiovascular disease, compared with tamoxifen, according to a meta-analysis of seven randomized controlled trials involving nearly 30,000 postmenopausal women with early-stage breast cancer.
However, as reported here at the CTRC-AACR San Antonio Breast Cancer Symposium by principal investigator Eitan Amir, MD, Senior Fellow in the Division of Medical Oncology and Hematology at Princess Margaret Hospital in Toronto, the absolute risk of cardiovascular events with either drug was shown to be low—4.2% with aromatase inhibitors and 3.4% with tamoxifen.
Dr. Amir noted that in December 2008, the Food and Drug Administration added a warning label to anastrozole cautioning about a potential increased rvisk for ischemic cardiovascular events in women with preexisting ischemic disease, a warning based on results of the landmark ATAC—Anastrozole (Arimidex), Tamoxifen Alone or in Combination—trial.
“Based on ATAC, an increased risk of cardiovascular disease remains after completion of aromatase inhibitor therapy, but how long that [increased risk] remains has been unclear.”
Number to Harm Low
So Dr. Amir and colleagues undertook a systematic review of published trials assessing primary adjuvant endocrine therapy in postmenopausal women. The analysis showed that 132 patients must be treated with an aromatase inhibitor before one cardiovascular event—myocardial infarction, angina, or heart failure—occurs.
“The number needed to harm is relatively high. It's not a common toxicity, but is a potentially serious one,” Dr. Amir said. But the risk is “more substantial” in women who have risk factors for cardiovascular disease.
The potential for cardiovascular disease needs to be weighed against other risks and benefits when prescribing aromatase inhibitors, he noted.
The cardiovascular risk associated with aromatase inhibitors is of similar magnitude to the risk for endometrial cancer and venous thrombosis with five years of tamoxifen therapy, he said.
In the meta-analysis, any duration of aromatase inhibitor use was associated with a 66% decreased risk of endometrial carcinoma and a 45% decreased risk of venous thrombosis, compared with tamoxifen.
In addition to the increased risk of cardiovascular disease, aromatase inhibitors were associated with a 47% increased risk of bone fractures. The risks for cerebrovascular events, secondary cancers other than endometrial, and death without recurrence were similar for both agents.
For a secondary analysis, the researchers looked at whether switching from tamoxifen to aromatase inhibitors had any effect on serious adverse effects, including death.
“There was a trend toward increased harm with upfront strategies. Starting with one agent and then switching to another may be the best way to manage side effects and reduce the risk of dying from causes other than breast cancer,” Dr. Amir said. But this is strictly hypothesis-generating at this point.
An investigator from the ATAC trial, however, disagreed: “After 10 years, there is no statistical difference in the risk of myocardial infarction, angina, or any other major cardiovascular event between the arms,” said Aman U. Buzdar, MD, Professor of Medicine in the Department of Breast Medical Oncology of the University of Texas MD Anderson Cancer Center. In ATAC, women were given anastrozole, tamoxifen, or both.
Although some open label studies have suggested “a hint of increased cardiovascular events” with use of aromatase inhibitors, when all the studies and all the adverse events are weighed, “there is no question the safety profile of aromatase inhibitors is better [than that of tamoxifen],” Dr. Buzdar said.
“Aromatase inhibitors are better at keeping women alive and free of disease. And their side effects are predictable and preventable.”
An observational study of aromatase inhibitors presented at the meeting found that neither aromatase inhibitors nor tamoxifen increased the risk for myocardial infarction.
The study, which included 44,463 breast cancer patients and 88,101 controls, also showed that patients treated with tamoxifen had a lower risk of fracture and stroke than those treated with aromatase inhibitors.
“These data provide reassurance regarding use of AIs in community-based populations, but do not supplant the data from clinical trials,” said study author Jennifer A. Ligibel, MD, a medical oncologist at Dana-Farber Cancer Institute and Assistant Professor of Medicine at Harvard Medical School.
As to why aromatase inhibitors might raise the risk of cardiovascular disease, Dr. Amir raised several possibilities, including a direct effect on the endothelium and a protective effect from tamoxifen.
In the question-and-answer period after the presentation, Harold J. Burstein, MD, PhD, also a medical oncologist at Dana-Farber, also noted that there is an increased incidence of hypercholesterolemia and hypertension in patients on aromatase inhibitors.
“The rate of actual events is extraordinarily low, however,” said Dr. Burstein, who is also Associate Professor of Medicine at Harvard Medical School and a member of the ASCO panel reviewing the risks and benefits of the agents.
But for patients at risk for osteoporosis and fractures, Paul E. Goss, MD, PhD, Director of Breast Cancer Research at Massachusetts General Hospital Cancer Center and Professor of Medicine at Harvard Medical School, commented, “I think there is no doubt that tamoxifen has a more favorable impact on the bone.”