Women Should Not Use Hormone Replacement for Heart-Disease Prevention

Women Should Not Use Hormone Replacement for Heart-Disease Prevention

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Sep- Oct 02	Rank Last Period Jul- Aug 02
1	B.J. Druker, et al., "Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia," New Engl. J. Med., 344(14): 1031-7, 5 April 2001. [Oregon Hlth. Sci. U., Portland; U. Texas, M.D. Anderson Canc. Ctr., Houston; Nova Pharmaceut. Corp., E. Hanover, NJ; U. Calif., Los Angeles] *417XH	53	4
2	C. Bombardier, et al., "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis," New Engl. J. Med., 343(21): 1520-8, 23 November 2000. [14 institutions worldwide] *375PR 49	49	†
3	J.E. Rossouw, et al. (Women’s Health Initiat. Invest.), "Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial," JAMA-J. Amer. Med. Assoc., 288(3): 321-3, 17 July 2002. [8 U.S. institutions] *573AK 46	46	†
4	B.J. Druker, et al., "Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome," New Engl. J. Med., 344(14): 1038-42, 5 April 2001. [Oregon Hlth. Sci. U., Portland; U. Calif., Los Angeles; U. Texas, M.D. Anderson Canc. Ctr., Houston; Nova Pharmaceut. Corp., E. Hanover, NJ] *417XH 45	45	5
5	B.M. Brenner, et al., "Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy," New Engl. J. Med., 345(12): 861-9, 20 September 2001. [8 institutions worldwide] *473JW 43	43	8
6	E.J. Lewis, et al., "Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes," New Engl. J. Med., 345(12):851-60, 20 September 2001. [9 institutions worldwide] *473JW	38	†
7	E. Lagasse, et al., *"Purified hematopoietic stem cells can differentiate into hepatocytes in vivo, "* Nature Medicine, 6(11): 1229-34, November 2000. [StemCells, Sunnyvale, CA; Oregon Health Sci. U., Portland; Baylor Coll. Med., Houston, TX; Stanford U. Sch. Med., CA] *370GH	37	6
8	W.C. Knowler, et al. (Diabetes Prevention Prog. Res. Group), "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin," New Engl. J. Med., 346(6): 393-403, 7 February 2002. [35 U.S. institutions] 37	37	†
9	J. Tuomilehto, et al., "Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance," New Engl. J. Med., 344(18): 1343-50, 3 May 2001. [9 Finnish institutions]	36	†
10	G.R. Bernard, et al., "Efficacy and safety of recombinant human activated protein C for severe sepsis," New Engl. J. Med., 344(10): 699-709, 8 March 2001. [9 institutions worldwide] *408AX	35	†

SOURCE: ISI's Hot Papers Database. Read the full legend.

cientists and journal editors (though not Science Watch) tend to dislike declamatory titles, but the stark heading to the column this time reflects a worry that had been emerging before, and will have been cemented by, the results of the Women’s Health Initiative (WHI) trial, published in July, 2002 (paper #3). The trial had been scheduled to end in 2005 but it was stopped on May 31st last year, when safety monitors decided that more harm than good was likely to result from continuation.

It may surprise Science Watch readers that in the mid-1990s it was even possible to recruit more than 16,000 women over 50 who were willing to be randomized to a placebo or to hormone-replacement therapy (HRT, which in this trial was an oral combination of conjugated equine estrogens and the progestin medroxyprogesterone acetate). Are not the benefits of HRT now so widely accepted that this therapy is a standard option for women who have passed the menopause? True, the benefits, including avoidance of hot flashes, improved well-being, and reduction of the risk of osteoporosis and the fractures that can accompany that bone disease, are not really in dispute, and more than one-third of postmenopausal women in the U.S. had been taking HRT, a proportion similar to that for other countries. However, many other claims have been made, including prevention of Alzheimer’s disease, a benefit in terms of colorectal cancer, and a possible halving in cardiovascular disease risk, while safety concerns have focused on breast cancer. There was plenty for the WHI trials to address.

The results are expressed in two ways. First, a statistically conventional hazard ratio, where a value greater than 1.00 is not good news and is very likely to be bad news if the 95% confidence interval does not span 1.00. Second, in terms of absolute risk or benefit, which is easier for patients to understand. Paper #3 tells us that for every 10,000 women-years of exposure to this type of HRT, there were 7 more coronary heart disease events than expected, 8 more strokes, 8 more cases of pulmonary embolism, and 8 extra invasive breast cancers—risks which taken together outweigh the 6 fewer colorectal cancers and 5 fewer hip fractures.

Two weeks before WHI appeared JAMA provided the follow-up of a smaller but similar (except that the women had a history of coronary heart disease) study. A reduction in cardiovascular disease outcomes was not sustained, another blow for HRT for this purpose (S. Hulley, et al., JAMA, 288: 58-66, 2002). That journal struck again, so to speak, in November of last year with yet more evidence of lack of cardiovascular benefit and "a potential for harm" in another placebo-controlled trial involving combined HRT (D.D. Waters, et al., JAMA, 288:2432, 2002).

These and other studies have initiated a serious debate in medical journals about how HRT should now be used, which is a question of immense public-health importance. Also interesting is what went wrong. Some professional bodies had pronounced in favor of having heart-disease prevention as an indication for HRT, and did so on the basis of non-randomized (observational) evidence, which now looks to have been misleading. Yet similar evidence seems to have got it right for the risk of venous thromboembolic disease and perhaps for the benefit of HRT in colorectal cancer. This paradox intrigues Prof. Jan Vandenbroucke, a clinical epidemiologist from Leiden, Netherlands. Science Watch caught up with him in Oxford, U.K., where he has been spending a few months exploring this challenge. He says: "Observational epidemiologic studies have always been perfect for picking up unexpected or unpredictable side-effects such as drinking water and cholera and intrauterine radiation and leukemia." With HRT, those diseases that were unpredictable at the time the hormones were prescribed (e.g., colon cancer) showed the same trends in both observational and randomized studies. However, when women in observational studies were taking HRT physicians were risk-averse and did not prescribe HRT for those at risk of heart disease, and the women themselves sought cardiovascular health benefits by, for example, lifestyle changes. "As many an epidemiologist had warned, and as is now clear for all to see," Professor Vandenbroucke adds, "a run-of-the-mill observational study fails when investigating these same cardiac effects."

Mr. David W. Sharp, M.A. (Cambridge), is a contributing editor to The Lancet, London, U.K.

Science Watch^®, March/April 2003, Vol. 14, No. 2
Citing URL: http://www.sciencewatch.com/march-april2003/sw_march-april2003_page5.htm