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Published: March 1999

Tamoxifen and Venous Thromboembolism

Presriber Update 18: 29-31
March 1999

Medsafe Editorial Team

Evidence now strongly supports the suspicion that tamoxifen increases the risk of venous thromboembolism (VTE). This observation is consistent with the fact that tamoxifen has oestrogenic activity.
One study, based on a sub-population of 10,000 women with breast cancer, identified 25 cases of VTE with an adequately confirmed diagnosis, and calculated a relative risk of VTE with tamoxifen use of 7.1 (95% CI 1.5-33). Another study used data from a Scottish trial of tamoxifen in the treatment of breast cancer in 1312 women. In this study the risk of VTE in users compared with non-users was higher by a factor of 2.50 (95% CI 1.11-5.56). In addition, the American Breast Cancer Prevention Study involving 13,388 women found the rate of pulmonary embolism among the tamoxifen group to be three times that in recipients of placebo (relative risk 3.01; 95% CI 1.15-9.27).
These results do not greatly affect the benefit-risk assessment for tamoxifen in the treatment of breast cancer. However, wellwomen with an elevated risk of breast cancer should not be treated with tamoxifen as a preventive measure (an unapproved indication) without an assessment of the personal risk factors for VTE.

Tamoxifen increases VTE risk

A recent observational study1 conducted using the United Kingdom General Practice Research Database (GPRD) provides strong evidence in favour of the suspected association between tamoxifen and venous thromboembolism (VTE). Although tamoxifen has antioestrogenic activity, it also produces oestrogen-like effects at some receptors. It is presumably this oestrogenic activity that results in an increased risk of VTE.

Risk of VTE more than doubled with tamoxifen

The GPRD study used a base population of 10,000 women with a diagnosis of breast cancer, and within this group identified women who were hospitalised with deep vein thrombosis or pulmonary embolism. The cases were aged ≤ 70 years, and women who had had undergone mastectomy, chemotherapy, radiotherapy, trauma or major surgery in the previous 6 months were excluded. All cases were of first time idiopathic thromboembolic events.

Twenty-five cases met the criteria and had an adequately confirmed diagnosis. These were matched to 172 controls for age and duration of cancer. The calculated relative risk of developing a VTE with current use of tamoxifen was 7.1 (95% CI 1.5-33), adjusted for body mass index, smoking status and hysterectomy status.

A previous study2 used 1312 women who had undergone mastectomy for breast cancer in a Scottish trial where they were randomised to either tamoxifen or no adjuvant treatment. Data about VTE in these women was obtained from hospital records. This study found 25 cases of VTE, of whom 15 were currently using tamoxifen. The relative risk of a thromboembolic event was 2.50 (95% CI 1.11-5.56) for users of tamoxifen versus non-users. However, this result was confounded by the fact that 8 of the cases had undergone inpatient surgery during the previous 6 months and one had metastatic colon cancer. Six of these nine patients were current users of tamoxifen.

In the Scottish study women were excluded after recurrence of breast cancer, but there was no evidence of confirmation of diagnosis of VTE, and data were not obtained on body mass index or blood pressure. It was unclear whether other risk factors were controlled for in the study design or analysis. The study also found that tamoxifen had a small protective effect against myocardial infarction (relative risk 0.29; 95% CI 0.12-0.66) and other ischaemic events (0.58; 0.29-1.15).

The American Breast Cancer Prevention Trial3 (BCPT) involving 13,388 women at elevated risk of breast cancer randomised to receive tamoxifen or placebo also confirmed that tamoxifen increases the risk of VTE. 18 women in the tamoxifen group versus 6 in the placebo group developed pulmonary embolism (RR 3.01; CI 1.15-9.27) and 35 versus 22 developed deep vein thrombosis (1.60; 0.91-2.86). A greater excess of risk was found in women aged > 50 years. A total of 3 women, all in the tamoxifen group, died following pulmonary embolism. The annual rate of deep vein thrombosis in tamoxifen users was 1.34 per 1000 women. No note was taken of the presence of risk factors in those who developed VTE.

In addition, the study found that stroke was more frequent (RR 1.59; CI 0.93-2.77) and transient ischaemic attack less frequent (0.75; 0.40-1.44) in the tamoxifen group compared with the placebo group.

Assess the risk of VTE when prescribing tamoxifen for breast cancer prevention

This evidence that tamoxifen causes VTE does not significantly alter the benefit-risk ratio for tamoxifen when it is used to treat breast cancer. However, prescribers should be aware the risk of VTE is increased if tamoxifen is used with cytotoxic agents. If tamoxifen is contemplated for the prevention of breast cancer (an unapproved indication), the personal risk of VTE in the woman should be assessed, and the expected benefit carefully weighed against the risk. Tamoxifen should be contraindicated in the prevention of breast cancer if the woman has a personal history of VTE and/or hereditary thrombophilia. Any woman taking tamoxifen should be advised of the symptoms of pulmonary embolism and deep vein thrombosis and told to report these promptly, particularly in the presence of risk factors for VTE.

References
  1. Meier CR, Jick H. Tamoxifen and risk of idiopathic venous thromboembolism. Br J Clin Pharmacol 1998;45:608-12.
  2. McDonald CC, Alexander FE, Whyte BW, Forrest Ap, Stewart HJ, for the Scottish Cancer Trials Breast Group.  Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial.  BMJ 1995;311:977-80.
  3. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study J Nat Cancer Institute 1998;90:1371-88.

 

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