Cardiovascular Effects of Tamoxifen
Cardiovascular Effects of Tamoxifen
Abstract & Commentary
Synopsis: Data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT) provide the unique opportunity to assess the cardiovascular effects of tamoxifen. One impetus for this investigation was the results of the HERS trial, a large, randomized study of postmenopausal women with cardiac disease that showed an early harmful effect with estrogen/progestin replacement therapy. If such a paradigm applied to tamoxifen, too, then deleterious effects on the heart might compromise the survival benefit from its protective effect in relation to breast cancer. Reis and colleagues published the results of their analysis of the NSABP data and reported a neutral impact on cardiovascular outcomes. They concluded that, when used for breast cancer prevention, tamoxifen is not associated with beneficial or adverse cardiovascular events.
Source: Reis SE, et al. J Natl Cancer Inst. 2001;93:16-21.
During the years 1992 through 1997, the nsabp enrolled 13,388 women at risk for breast cancer into its Breast Cancer Prevention Trial. Included were women older than the age of 60, women 35-59 years old with a greater than 1.33% predicted risk of breast cancer over 5 years, and those women with a history of lobular carcinoma in situ (LCIS). Early results were reported in 1998 and did not reflect an influence by tamoxifen on cardiovascular risk.1 Reis and colleagues recently published updated results of this randomized, placebo-controlled, double-blind study with a median follow-up of 57 months for 13,194 evaluable women.
Based on self-reported histories of myocardial infarctions and/or angina, the study participants were split into those reporting a cardiac history (n = 1048; 8%) and those without a history (n = 12,146; 92%). Women were then randomized to tamoxifen 20 mg q.d. or placebo. Seventy-six percent of the tamoxifen patients were compliant with the study therapy, and analysis was performed on an intent-to-treat basis.
Overall, the rates of cardiovascular events were not significantly different for the placebo and tamoxifen groups. There were 72 events among the 6590 tamoxifen users and 68 among the 6604 placebo patients. This represents a relative risk (RR) of 1.06 for tamoxifen users. Furthermore, there were no differences between groups in types of cardiovascular events (ie, fatal/nonfatal MI, and stable/unstable angina). In the cardiac high-risk participants, there were 44 events, with 25 in the tamoxifen group and 19 in the placebo group (RR = 1.39). In the low-risk cardiac group, there were 96 events, with 47 events in the tamoxifen group and 49 in the placebo group (RR = 0.96).
Reis et al concluded that their study, the largest reported cardiovascular study of a nonsteroid-related compound in women, did not show a cardiac-related treatment effect.
COMMENT BY EDWARD J. KAPLAN, MD
Approximately 1 in 3 women, or nearly 500,000 annually, will die of heart disease. In contrast, 1 in 9 women will develop breast cancer, and 1 in 25 will die of it. Estrogen loss associated with menopause has been associated with an elevated risk of cardiac events. The Heart and Estrogen/Progestin Replacement Study (HERS) Research Group conducted a prospective, placebo-controlled trial of hormone replacement therapy with conjugated estrogens and medroxyprogesterone acetate in women with documented coronary disease that was reported by Hulley et al.2 Despite no statistically significant difference in numbers of myocardial infarctions or cardiac deaths in the treatment and placebo groups, there was a statistically significant time trend noted. There were more cardiac events in the hormone replacement group in the first year but fewer in the fourth and fifth years. This finding raised the issue of the possibility of a similar phenomenon in tamoxifen-treated patients.
Tamoxifen is a nonsteroidal compound that possesses mixed estrogen agonist and antagonist properties. It has known anti-atherosclerotic effects, such as the lowering of low-density lipoprotein (LDL) levels and an increase in high-density lipoprotein (HDL) concentrations. It also has beneficial effects on coronary artery endothelial cells. However, based on the HERS data, it was felt that tamoxifen might exert estrogen antagonist properties on the coronary vasculature that could contribute to myocardial ischemia and thereby induce cardiac events.
The NSABP data as outlined by Reis et al failed to show any influence by tamoxifen on the incidence of cardiac events in either the high- or low-risk cohorts studied. Unlike the HERS trial, no time trend was identified based on cumulative incidence curves, and there was no offsetting of an early adverse effect of tamoxifen by a late beneficial effect.
Two earlier trials randomized breast cancer patients to tamoxifen vs. no adjuvant therapy to evaluate the effect on cardiac health. The Scottish trial enrolled 1070 postmenopausal women who were randomized to tamoxifen 20 mg q.d. ´ 5 years vs. no adjuvant therapy and found a statistically significant reduction in cardiac death rate associated with tamoxifen.3 The end point in that trial excluded nonfatal cardiac events along with cardiac events that may have occurred after any recurrence of breast cancer, and so the usefulness of the results may be somewhat limited. The Stockholm Breast Cancer Study Group trial of 2365 postmenopausal early- stage breast cancer patients randomized participants to tamoxifen 40 mg q.d. vs. no adjuvant therapy and found no significant difference in cardiovascular effects.4
Reis et al described several potential pitfalls in the design of the NSABP study. The major drawback of the study is that the evaluation of cardiac effects was a secondary goal, and the trial was, in fact, not designed to detect differences in incidences of cardiac events. In addition, division of participants into study groups was based on self-reporting, which can be flawed. The 76% compliance rate with tamoxifen assignees may have diluted the ability to detect an effect. Finally, the follow-up period may have to be longer in order to determine the long-term cardiac effects of tamoxifen.
For the reasons cited above, Reis et al stated that they cannot conclude with statistical certainty that there are no cardiac-related treatment effects associated with tamoxifen, but, as mentioned by Jordan in an accompanying editorial,5 tamoxifen for the chemoprevention of breast cancer seems to provide a better safety profile than hormone replacement therapy in women at risk for coronary disease.
References
1. Fisher B, et al. J Natl Cancer Inst. 1998;90:1371-1388.
2. Hulley S, et al. JAMA. 1998;280:605-613.
3. McDonald C, et al. BMJ. 1995;311:977-980.
4. Rutqvist L, et al. J Natl Cancer Inst. 1993;85: 1398-1406.
5. Jordan VC. J Natl Cancer Inst. 2001;93:2-4.
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