Aromatase Inhibitors May Increase Risk for CV Disease

Nick Mulcahy

December 09, 2010

December 9, 2010 ( UPDATED December 10, 2010 ) (San Antonio, Texas) — The use of aromatase inhibitors for any length of time by postmenopausal women with breast cancer is associated with a significant 26% increased risk for cardiovascular disease, compared with the use of tamoxifen, according to a meta-analysis of clinical trials by a team of international researchers.

Dr. Eitan Amir

However, the absolute risk for cardiovascular events with either agent in the trials was low — about 4.2% with aromatase inhibitors and 3.4% with tamoxifen — reminded the lead author of the study, Eitan Amir, MD. He is a senior fellow in the division of medical oncology and hematology at the Princess Margaret Hospital, Toronto, Ontario.

Dr. Amir spoke at a press conference here at the 33rd Annual San Antonio Breast Cancer Symposium (SABCS), where the new study is being presented.

"It's not a common toxicity, but [it is] a potentially serious one," said Dr. Amir.

The new meta-analysis used data from 7 clinical trials of tamoxifen and aromatase inhibitors in postmenopausal women with early-stage breast cancer.

The analysis indicated that 132 patients must be treated with an aromatase inhibitor before 1 cardiovascular event occurs. "This number needed to harm is relatively high," said Dr. Amir. The events included myocardial infarction, angina, and heart failure.

The potential for cardiovascular harm with aromatase inhibitors is part of the balance of risks and benefits that must be considered when prescribing them, explained Dr. Amir. Prescribing these agents to women with risk factors for cardiovascular disease is more of a concern than prescribing them to those without such factors because the risk is "probably more substantial in at-risk groups, he added.

The findings are not a complete surprise. In December 2008, the US Food and Drug Administration added a warning label to anastrozole (Arimidex, AstraZeneca) that indicated a potential increased risk for heart disease, Dr. Amir pointed out.

The fact that risk for cardiovascular events has been linked to at least 1 aromatase inhibitor for some time raises questions about why a meta-analysis is only available now.

"Finally we have enough trials and enough follow-up to address the cardiovascular safety of aromatase inhibitors relative to tamoxifen," said Peter Ravdin, MD, about the timing of the meta-analysis. He is codirector of the SABCS and director of the Comprehensive Breast Health Clinic at the Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio.

An observational study of aromatase inhibitors also presented at the meeting found that neither aromatase inhibitors nor tamoxifen were associated with myocardial infarction. However, Dr. Ravdin said he puts more stock in the meta-analysis — with the definitive clinical trials of aromatase inhibitors and tamoxifen — than in a single observational dataset.

The author of the observational study, Jennifer Ligibel, MD, from the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, noted that her data "do not supplant the data from clinical trials."

Similar Magnitude to Tamoxifen

The cardiovascular risk found with aromatase inhibitors is of similar magnitude to the risk for venous thrombosis and endometrial cancer with 5 years of tamoxifen, Dr. Amir and colleagues report.

In the meta-analysis, any duration of aromatase inhibitors was associated with a higher probability of developing cardiovascular disease (odds ratio [OR], 1.26) and bone fractures (OR, 1.48), but a reduced probability of venous thrombosis (OR, 0.55) and endometrial carcinoma (OR, 0.34).

As a secondary analysis, the researchers looked at whether or not switching from treatment with tamoxifen to aromatase inhibitors had any effect on mortality or adverse effects.

"It appears from the data — and this is strictly hypothesis-generating — that if a woman switches from one drug to another, there is a reduction in the risk from death from causes other than breast cancer," Dr. Amir said in a press statement. "This potentially suggests that there may be side effects that build up the longer a woman is on a certain drug, but switching drugs may reduce the side effects."

The meta-analysis findings raise the question of causality. Dr. Amir proposed a number of possible explanations, including the increased rate of hypercholesterolemia associated with aromatase inhibitors. This theory received some support from audience member Harold Burstein, MD, from the Dana-Farber Cancer Institute.

Dr. Burstein, who is a member of the American Society of Clinical Oncology panel looking at aromatase inhibitors, said that patients taking the drugs had increase rates of hypercholesterolemia and hypertension.

The authors have disclosed no relevant financial relationships.

33rd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S2-6. Presented December 9, 2010.


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