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Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial

BMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e6409 (Published 09 October 2012) Cite this as: BMJ 2012;345:e6409

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Re: Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial

To the Editor,

Timing Hypothesis: Is it years since menopause or age at baseline?

Schierbeck et al 1 reported that initiation of hormone replacement therapy (HRT) early after menopause significantly reduced risk of mortality, heart failure (HF) , or myocardial infarction (MI) without any apparent increase in risk of cancer , venous thromboembolism, or stroke when compared to no treatment. The results of this study require caution in the interpretation.

The Danish study relies on a "Timing Hypothesis" suggesting beneficial effects of HRT if initiated early after menopause. However, we believe that timing of HRT initiation has more relevance to the age of participants at baseline than to their years since menopause. Increased age is a well established cardiovascular risk factor.

Analysis of HRT arm of WHI for cardiovascular events by age at baseline 2 supports this "Age Hypothesis". Total number of CHD events in age groups 50-59 year, 60 - 69 year, and 70-79 year receiving HRT in WHI were 59, 174, and 163 respectively. The hazard ratio (HR) for age groups 50-59 year, 60 - 69 year, and 70-79 year was 0.93 , 0.98 , and 1.26, respectively, reflecting an increased trend for CHD events with older age. Similar findings were presented in the Danish Study. Incidence rate for composite of death, hospitalization due to HF, and MI at 16 years was higher than at 10 years in the HRT group ( n = 33 vs. 16 , HR= 0.61 vs. 0.41). At 10 years, HR for the primary endpoint was higher in age group >/=50 years compared to age group < 50 years ( HR: 0.63 vs. 0.35).

It has to be noted that mean age in WHI was considerably higher than the Danish study (63 years vs. 50 years). If the age of initiation of HRT in the present study had been similar to that of WHI, similar outcomes may have been observed. The relatively younger age of participants in this study and the absence of risk factors, other than smoking in about half of participants, explain their low event rate and support the need for further follow up.

Finally, the present study, not designed to evaluate cardiovascular outcomes a priori, did not include an electrocardiogram follow up protocol to identify silent myocardial infarction. WHI mentioned total 22 cases of silent MI. 3, 4

Pavankumar B. Patel, MD, MPH
Fellow
Division of Endocrinology and Metabolism
University of Texas Medical Branch at Galveston, Texas , USA

L. Maria Belalcazar, MD
Assistant Professor
Division of Endocrinology and Metabolism
University of Texas Medical Branch at Galveston, Texas , USA
lmbelalc@utmb.edu

1. Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, Køber L, Jensen JE. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012; 345: e6409.

2. Rossouw J et al Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease
by Age and Years Since Menopause JAMA, April 4, 2007—Vol 297, No. 13

3. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291(14):1701-12.

4. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33.

Competing interests: No competing interests

30 October 2012
Pavankumar B. Patel
Endocrinology Fellow
L. Maria Belalcazar , MD , Assistant Professor, lmbelalc@utmb.edu
University of Texas Medical Branch at Galveston
301 University Blvd, Galveston, TX, USA 77555