The Pharmaceutical Journal
Vol 269 No 7206 p43
13 July 2002

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  Risks and benefits of HRT (PDF* 15K)
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HRT trial stopped as risks of long-term use are found to outweigh benefits

A major American trial of the long-term use of hormone replacement therapy in postmenopausal women has been stopped on the orders of its safety committee after an interim analysis showed a small but real increased risk of breast cancer and cardiovascular disease.

The Women's Health Initiative (WHI) trial was studying the use of a combined estrogen and progestogen product in 16,608 postmenopausal women aged 50 to 79 years who started the trial with an intact uterus. The preparation being used in the randomised placebo-controlled trial was Prempro (conjugated equine estrogen 625µg and medroxyprogesterone acetate 2.5mg, the most commonly prescribed HRT product in the United States, supplied by Wyeth. This is not available in the UK but is similar to Premique (Wyeth), which has conjugated equine estrogen 625µg and medroxyprogesterone acetate 5mg.

The trial started in 1997 and was expected to run for eight-and-a-half years. From 1999 onwards, six-monthly interim safety analyses had begun to detect small but consistent adverse effects on cardiovascular outcomes and on an overall measure of harm or benefit. On 31 May 2002, the safety committee found that the risk of developing invasive breast cancer had exceeded the designated acceptable level and ordered that the trial be stopped. The results of the trial were placed on the Journal of the American Medical Association website (jama.ama-assn.org) on 9 July and are to published in the 17 July issue (JAMA 2002;288:321.

After an average of 5.2 years of following up, the estimated hazard ratios seen were 1.29 (95 per cent confidence interval 1.02–1.63) for coronary heart disease with 286 cases; 1.26 (CI 1.00–1.59) for breast cancer with 290 cases; and 1.41 (CI 1.07–1.85) for stroke with 212 cases. Beneficial effects were seen for endometrial cancer, colorectal cancer and hip fracture.

The trial investigators conclude that this HRT preparation "should not be initiated or continued for the primary prevention of CHD".

In an accompanying editorial (ibid, p366), doctors from Harvard Medical School, Boston, say that "the absolute risk of harm to an individual woman is very small" and that in 10,000 women taking the product for a year there would be seven more coronary events and eight more invasive breast cancers.

Dr Brian Curwain, chief pharmacist at New Forest Primary Care Trust, said that he was pointing out to prescribers that the same estrogens were also in Premarin and Prempak-C and that medroxyprogesterone was also in Indivina and Tridestra. "My key message is that it is not advisable to use HRT in order to prevent osteoporosis or cardiovascular problems. We need to be cautious with these preparations."

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