A decade of continuous hormone-replacement therapy (HRT) reduced the risk of heart failure and myocardial infarction (MI) by half without increasing the risk of cancer or thromboembolic events, Danish researchers reported.
During follow-up for as long as 16 years, twice as many women (33 versus 16) died or had an MI or heart failure without HRT as compared with women randomized to receive hormone therapy, according to Louise Lind Schierbeck, MD, of Hvidore Hospital, in Hvidore, Denmark, and co-authors.
Among the women who received continuous HRT, investigators found no increased risk of cancer, breast cancer, thrombosis, or stroke, they reported online in BMJ.
"In this randomized trial including 1,006 women we found a significantly decreased risk of the composite endpoint ... when hormone replacement therapy was started early in postmenopause," they wrote in conclusion.
"The beneficial effect occurred in the 10-year randomization phase and was maintained for an additional 6 years of nonrandomized follow-up. The trend for all components of the endpoint was in the same direction."
For about 50 years controversy has surrounded the use of HRT in postmenopausal women. Most evidence has pointed to beneficial effects related to cardiovascular health, osteoporosis, and colon cancer risk. However, new concern was fueled by a 2002 report from the Women's Health Initiative (WHI), showing no cardiovascular benefits in women taking HRT.
Disparate results from observational and randomized studies could reflect the latter studies' initiation of HRT in women who were well into menopause, the authors noted in their introduction. Meta-analyses adjusted for age have shown that younger women on HRT have a reduced risk of coronary disease and mortality.
Schierbeck and colleagues sought to examine the effects of HRT initiated early after onset of menopause. They analyzed data from a long-term observational cohort study. Of the 2,016 women enrolled in the study, 1,006 were randomized to HRT or no HRT. Patients in the HRT arm were encouraged to stop HRT after 10 years, largely as a result of concern prompted by the WHI results.
The study was supported by a combination of public and private funding, including contributions by Novo Nordisk, Novartis, and LEO Pharma, all of which market HRT products and provided study drug free of charge. The authors noted that none of the funding sources participated in the design of the study, interpretation of the data, or the decision to publish the results.
Patient accrual occurred during 1990 to 1993, and follow-up continued until June 2008, although randomized treatment stopped after 10 years. The primary endpoint of the randomized study was the composite of death, MI, and heart failure. Investigators relied on several Danish health registries and government statistics to ascertain clinical events and deaths.
Analysis of the composite endpoint showed that women randomized to HRT had a 52% reduction in risk versus the control group (HR 0.48, P=0.015), a difference that remained significant after age adjustment (HR 0.49, P=0.019).
Analysis of the endpoint components showed 15 deaths in the HRT group and 26 in the control group (HR 0.57, P=0.084), one case of new-onset heart failure in the HRT arm versus seven in the control group (P=0.07), and one MI with HRT versus four without (P=0.21).
The data also showed no difference between groups with respect to the adverse events of interest:
- Cancer -- 36 cases with HRT versus 39 without
- Breast cancer -- 10 versus 17
- Stroke -- 11 versus 14
- Venous thromboembolism -- Two in each group
In the follow-up period from 10 to 16 years, the two groups did not differ significantly with respect to any adverse outcomes.
Two studies essentially "blew up" long-held beliefs about the benefits of HRT: The Hormone Estrogen Replacement Study (HERS) and WHI. Houston ob/gyn Ronald Young, MD, was an investigator in both studies. After years of examining HERS and WHI in an effort to explain why they differed so dramatically from the studies before them, the answer is that both studies were flawed.
"Both of the studies looked mainly at older women in a clinical setting that just was not an everyday clinical setting," Young, of Baylor College of Medicine, told MedPage Today. "The average age of women in the WHI was 64. You just don't start giving estrogen that frequently at those doses [used in WHI] to women that age or older."
The Danish study essentially confirmed later analyses of HERS and WHI, which showed that younger women, in the 50-to-60 range, did better than the overall population.
"It shows that if estrogen or estrogen and progestin are used properly in women who are fresh into menopause, that there is no real risk of heart disease or breast cancer or any other kind of cancer and that there is a reduced risk of heart disease and mortality," said Young.
The study was supported by the University of Aarhus, Karen Elise Jensen's Foundation, Novo Nordisk, Novartis, and LEO Pharma. Novo Nordisk, Novartis and LEO Pharma provided study drug free of charge.
Schierbeck had no relevant disclosures. Co-authors disclosed relationships with Nycomed, Novartis, Amgen, Novartis, Eli Lilly, GlaxoSmithKline, and Merck.
From the American Heart Association:
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