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

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e6409 (Published 9 October 2012)
Cite this as: BMJ 2012;345:e6409

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To the editor,

Schierbeck et al(1) reported that, after 10 years of an open randomized study, women receiving hormone replacement therapy (HRT) early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke. In our opinion, this study results warrant caution.

In this trial, the open label design with a “no treatment” group of comparison creates important risks of bias. The awareness of the treated group about the intervention may affect the behavior of patients and staff in favor of the outcome, reduction of cardiac events. The trial largely took place when HRT was widely believed to reduce cardiovascular events prior to the reporting of the Heart and Estrogen∕ Progestin Replacement Study (HERS).(2) Also, the use of composite outcomes in this trial is problematic. Composite outcomes work often as an exaggerated perception of how well interventions work.(3)

Furthermore, the present study was not designed to evaluate cardiovascular outcomes a priori. The cardiovascular outcomes were not standardized, or monitored by the researchers, but based on individual clinicians’ inclusion of data in a national database.

References:
1. Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, Kober L, Jensen JE. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomized trial. BMJ 2012;345:e6409.
2. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.
3. Cordoba G, Schwartz L, Woloshin S, Bae H, Gotzsche PC. Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review. BMJ 2010;341:c3920.

Competing interests: None declared

Anibal P Abelin, Interventional Cardiology

Cristiane M Nunes, Fábio E Camazzola, Rodrigo P Santos

Health Science Post-Graduate Program at Instituto de Cardiologia do Rio Grande do Sul/ Fundação Universitária de Cardiologia, Porto Alegre, RS, Brazil

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I would welcome the authors' observations as to the metabolic profiles of participants in this analysis, noting the reservations by a number of other respondents. In particular HDL levels of 1.7, with glucose of 4.7 and health vitamin D levels seem discordant with values seen in everyday practice (in primary and secondary care, underscoring the suggestion that these are innately healthy women). These may in turn have ameliorated the potentially harmful effects of HRT in those taking it.

Competing interests: None declared

A-K Vania, Hospital Practitioner in Cardiology

Department of Cardiology, Glenfield General Hospital, Groby Rd., Leicester LE3 9QP

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We have read with interest the publication by Schierbeck et al and also the rapid responses. As the authors of the Cochrane review 'Long term hormone therapy for perimenopausal and postmenopausal women'(1) published in 2012 we have considered whether this trial should be included in our review.

However, it does not meet the inclusion criteria for our review as it does not have a placebo control group. We consider that the open label design in the study by Schierbeck et al may have influenced the behaviour of those taking the hormone therapy. Furthermore we have serious concerns about the use of a composite outcome that was not described in the original study protocol in 1990.

The conclusions of our review were "HT is not indicated for primary or secondary prevention of cardiovascular disease..... There are insufficient data to assess the risk of long term HT use in perimenopausal women or postmenopausal women younger than 50 years of age". These conclusions remain unchanged.

(1) Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database of Systematic Reviews 2012, Issue 7. Art. No.: CD004143. DOI: 10.1002/14651858.CD004143.pub4.

Competing interests: None declared

Jane Marjoribanks, Researcher

Cindy Farquhar, Helen Roberts, Anne Lethaby

University of Auckland, Princes St. Auckland 1142

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Schierbeck and colleagues fail to address whether their primary composite outcome was defined in the original protocol. In other words is their analysis exploratory or confirmatory? The main question is whether the results should lead to changes in clinical practice. Schierbeck has advocated for the safety of HRT (1), whereas we believe that the study results should be interpreted with caution and put in the context of previous findings.

 

In their response Schierbeck and colleagues state that “the outcomes in the present study were secondary outcome measures in the original protocol” and “The primary end-point of the present study was defined in the protocol as safety measures for cardiovascular events.”

 

A previous publication of the design of the DOPS study comments on coronary heart disease (defined as angina and myocardial infarction), but nothing is mentioned about the composite outcome (2). In the published trial of fracture outcomes the term “cardiovascular incidents” is used, but it is not described what this means (3). Nothing is stated on clinicaltrials.gov about cardiovascular outcomes. In the protocol, we received from Schierbeck (the version is from 1995, though the study enrolled patients from 1990-1993), it is stated that myocardial infarction would be assessed as a side-effect, but not specified as either a primary or secondary outcome in the data analysis section. In the statistical analysis section it is stated that “incidence of ischemic heart disease” will be evaluated, but not described what this means.

 

We cannot find information about neither the outcome, admission to hospital for heart failure, nor the chosen composite outcome in previous publications or the provided protocol. Would Schierbeck and colleagues please clarify whether the composite outcome of death, admission to hospital for heart failure, and myocardial infarction was defined before the trial started enrolling patients in 1990 or whether it was defined after, as this is still not clear to us.

 

References

1. [Hormones halve risk of cardiovascular disease among women in menopause]. Dagens Medicin; 19th of October 2012.

2. Mosekilde L, Hermann AP, Beck-Nielsen H, Charles P, Nielsen SP, Sorensen OH. The Danish Osteoporosis Prevention Study (DOPS): project design and inclusion of 2000 normal perimenopausal women. Maturitas 1999;31:207-19.

3. Mosekilde L, Beck-Nielsen H, Sorensen OH, Nielsen SP, Charles P, Vestergaard P, et al. Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women—results of the Danish Osteoporosis Prevention Study. Maturitas 2000;36:181-93.

Competing interests: None declared

Jeppe Schroll, PhD Student

Andreas Lundh

The Nordic Cochrane Centre, Tagensvej 22

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Sir, Dr Schierbeck is correct that the methods of her paper made clear that this was a secondary analysis of a trial done to test a different hypothesis.

However whoever wrote the BMJ press release, which includes the following sentence, did not.

“So authors from Denmark carried out a randomised trial over 10 years with additional six years of follow-up to establish whether HRT can reduce cardiovascular risk if it is started early after menopause”.

This is misleading and has encouraged naive journalists to write headlines suggesting that the cardiovascular risks of HRT have somehow been proven to have been false. Even Dr Schierbeck and her colleagues would surely not claim this.

Competing interests: None declared

Jim G Thornton, Professor of obstetrics and gynaecology

University of Nottingham, Hucknall Road. Nottingham

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In response to: http://www.bmj.com/content/345/bmj.e6409

We are thankful for all of the interest in the above publication and hope to have responded to all relevant comments.

As stated in our article, the outcomes in the present study were secondary outcome measures in the original protocol. The primary outcome of the original study should be of no surprise to Dr. Schroll et al. or to others, and it was stated clearly in the manuscript (Methods)[1].

The primary end-point of the present study was defined in the protocol as safety measures for cardiovascular events. These were outcomes defined before data analysis and it was decided to include only hard endpoints that are associated with poor prognosis: all-cause mortality and acute myocardial infarction and heart failure hospital admissions as these are also events validated in the National Danish Registers. There is a risk that clinical silent events are overlooked, but mortality is always captured. Thus, it was decided before data analyses not to include softer endpoints (driven by clinical decisions) that could also be associated with a reduction in mortality (angina, CABG or PCI) as pointed out by Dr Singh et al. For the same reason we did not report on intermediary markers of CVD such as inflammatory measures that are even softer outcome data.

Although randomization is the most critical aspect of any trial, we agree with Dr Schroll et al, Dr Turgeon et al and Dr Roussouw et al that performance and detection bias could be an issue in open-label trials, but the importance of these biases are reduced with endpoints driven by mortality. Further, it is well-understood that no HRT trial—including the WHI—conducted in women with a uterus is completely blinded or placebo-controlled [2;3]. Thus, our results are no less valid than any other randomized HRT trial, especially conducted in women with a uterus. As suggested by Dr Roizen, the benefits seen in DOPS with respect to cardiovascular effects could also have been larger if randomized treatment had continued for more than 10 years. In regards to this latter point, DOPS randomized treatment was stopped because beginning in 2002 it was believed that HRT had negative effects on cardiovascular health and thus, if that was the case, should have resulted in a higher detection rate of CVD in the subsequent post-randomization years of follow-up. However, this was not the case.

Whereas it is well-appreciated that detection bias likely played a role regarding breast cancer detection in the WHI-E+P trial as many women (and their physicians) were un-blinded to HRT treatment, and women were warned of the increased risk of breast cancer related to HRT [2;3], detection bias may have also played a role in breast cancer detection in DOPS. However, despite the likelihood of over-estimating breast cancer in the HRT group due to detection bias, breast cancer risk was in fact reduced by 42% (HR, 0.58; 95% CI, 0.27-1.27) relative to the control group after 10 years of randomized treatment in DOPS. Detection bias in regards to breast cancer is indeed something the Cochrane Center has been concerned about previously. [4;5]Data on actual numbers of cancer events are presented in the results, thus, we are uncertain which data Dr Abrahamson is missing.

As pointed out by several readers (Dr Schroll et al, Dr Abrahamsen, Dr, Turgeon et al, Dr Roussouw et al) and as stated in the limitations of the study, the power of our study is low, but this does not change our findings, as our results does not change the results of any other trial. We completely agree that power is low to detect breast cancer, but power is not a problem in relation to the significant findings driven by all-cause mortality.

We found a decreasing trend in breast cancer risk with HRT (consistent with the WHI-E trial[6]) and we seek to understand our findings in the context of the included women. Thus, the timing hypothesis is a possible explanation.[7]

Although the WHI trials were large, WHI lacks power in a population similar to ours, as acknowledged by Dr Roussouw et al. Unlike WHI, DOPS was a priori designed to “mimic the normal clinical situation” [8] in which perimenopausal and recently postmenopausal women are initiated on HRT. However, in post-hoc analyses from the WHI trials, the HR for CHD and total mortality for women less than 10 years-since-menopause when initiated on HRT was 0.76 (95% CI, 0.50-1.16) and 0.76 (95% CI 0.53-1.09), respectively.[9] These post-hoc analyses are limited in that they were conducted in a sub-group of women from the WHI trials that reflect a much wider span of women relative to DOPS in which the maximum time-since-menopause was only 2 years. Significant reductions in CVD and total mortality have also been reported from meta-analyses of randomized trials of women who were initiated on HRT before age 60 years and within 10 years-since-menopause, 32% [10]and 39%[11]reductions, respectively, relative to placebo.

It is important to realize that DOPS and the WHI trials substantially differ in regards to HRT medications and regimens, age and time-since-menopause when women were randomized; WHI studied women who were on average 64 years old and >10 years-since-menopause when randomized which does not at all replicate clinical practice and therefore, cannot be generalized to the normal practice of initiating HRT at or near the time of menopause. However, DOPS tested the hypothesis that when initiated at or near menopause, HRT reduces CVD and does so safely with no increase in breast cancer or stroke, and importantly with a reduction in the primary endpoint including total mortality. We did in fact analyse the DOPS data separately for estradiol + sequential NETA and estradiol alone (labelled as intact uterus and hysterectomy in Figures 3-6 [1]); these data show that both HRT regimens had similar effects on all outcomes.

The results from DOPS are consistent with the more than 40 observational studies,[12;13]meta-analyses of randomized trials [10;11;14]and post-hoc analyses of the subgroup of young postmenopausal women <60 years of age and/or <10 years-since-menopause when initiated on HRT[9]that all consistently show that HRT reduces CVD and total mortality.[7] Further analyses of the women <2 years-since-menopause in the WHI trials would be more similar to the DOPS cohort and would indeed be very welcome as it may add knowledge to the effect of HRT in recently postmenopausal women.

Naturally, there were few events (including myocardial infarctions) in DOPS due to the relatively young age-group. We are however certain that the diagnoses of outcome events were captured by the Danish registers, and this is in fact a strength of the trial as in DOPS we had almost 100% ascertainment of events over the 10-year randomization period and over the total 16-year follow-up.

We wish to thank Dr McPherson for bringing smaller RCTs to our attention. We did not have the intention to discuss the vast HRT data, but these studies are relevant to our discussions.

In conclusion, DOPS is the only prospective longitudinal randomized trial designed to examine clinical outcomes among women who were specifically a priori randomized to HRT in the perimenopausal/early postmenopausal period. When randomized to DOPS, women were on average 50 years old and 7 months postmenopausal and there is no comparable cohort or outcome data available for comparison from any other randomized trial. Women were randomized for 10 years (~10,000 women-years of randomization), the longest randomized duration than any randomized trial examining clinical outcomes resulting from HRT in women on average 50 years old. Subsequent to randomized treatment, the women were followed for another 6 years for a total follow-up of 16 years (~16,000 women-years of follow-up). DOPS provides long-term longitudinal randomized trial data in a cohort of women, namely, the very women who are normally treated, for which no data previously existed and thus, directly informs women and health-care providers of the long-term effects of HRT after initiation in close proximity to menopause, especially in regards to breast cancer, CVD and total mortality. In addition, unlike other large-scale long-term randomized HRT trials of efficacy and safety, no participants were lost to follow-up (2 women were censored at the time of emigration) in DOPS that had nearly 100% ascertainment of outcome events over 10 years of randomized follow-up and 16 years of total follow-up using the Danish civil registration system and the Danish national hospital discharge register. Finding significant effects in small groups underscores the clinical relevance for efficacy in reducing CVD and total morality and lack of harmful effects on breast cancer and stroke.

Lastly, all relevant conflicts of interests are disclosed properly in the paper as well as in the conflict of interest forms.

Reference List

(1) Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012;345:e6409.
(2) Shapiro S. Risks of estrogen plus progestin therapy: a sensitivity analysis of findings in the Women's Health Initiative randomized controlled trial. Climacteric 2003 Dec;6(4):302-10.
(3) Shapiro S. Recent epidemiological evidence relevant to the clinical management of the menopause. Climacteric 2007 Oct;10 Suppl 2:2-15.
(4) Gotzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database Syst Rev 2011;(1):CD001877.
(5) Jorgensen KJ, Zahl PH, Gotzsche PC. Breast cancer mortality in organised mammography screening in Denmark: comparative study. BMJ 2010;340:c1241.
(6) LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011 Apr 6;305(13):1305-14.
(7) Hodis HN, Mack WJ. A "window of opportunity:" The reduction of coronary heart disease and total mortality with menopausal therapies is age- and time-dependent. Brain Res 2011 Mar 16;1379:244-52.
(8) Mosekilde L, Hermann AP, Beck-Nielsen H, Charles P, Nielsen SP, Sorensen OH. The Danish Osteoporosis Prevention Study (DOPS): project design and inclusion of 2000 normal perimenopausal women. Maturitas 1999 Mar 15;31(3):207-19.
(9) Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007 Apr 4;297(13):1465-77.
(10) Salpeter SR, Walsh JM, Greyber E, Salpeter EE. Brief report: Coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med 2006 Apr;21(4):363-6.
(11) Salpeter SR, Walsh JM, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. J Gen Intern Med 2004 Jul;19(7):791-804.
(12) Grodstein F, Stampfer M. The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Cardiovasc Dis 1995 Nov;38(3):199-210.
(13) Grodstein F, Stampfer MJ. Estrogen for women at varying risk of coronary disease. Maturitas 1998 Sep 20;30(1):19-26.
(14) Salpeter SR, Cheng J, Thabane L, Buckley NS, Salpeter EE. Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women. Am J Med 2009 Nov;122(11):1016-22.

Competing interests: Authors of the discussed research article.

Louise L Schierbeck, Registrar

Lars Køber, Professor, Jens-Erik Beck Jensen, Associate Professor

Department of Endocrinology, Hvidovre Hospital and Department of Cardiology, Rigshospitalet, Denmark

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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: None declared

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

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Schierbeck and colleagues suggest that healthy women treated with hormone replacement therapy (HRT) early after menopause have reduced risk of a composite outcome of mortality, admission to hospital for myocardial infarction, and heart failure (1). In our opinion, the study results should be interpreted with caution.

According to the trial information on clinicaltrials.gov, the primary outcomes were fractures and bone mineral density. Neither the composite outcome nor the individual outcomes are mentioned at all. We contacted Schierbeck and she clarified that the composite outcome had indeed been defined post hoc, before the data analysis, and that no protocol for this analysis had been written. This information has important implications on the interpretation of this study and should have been clearly stated in the published paper. Outcomes defined post-hoc are conventionally considered exploratory and the Schierbeck study should rather be interpreted as an observational study.

Furthermore, the open label design with a “no treatment” group creates important risks of bias. First, awareness of group assignment may affect the behaviour of patients and staff (i.e. performance bias). Second, the outcome ascertainment was not standardised, but is based on coding in the database by individual clinicians. At the time the study was conducted HRT, was thought to have a beneficial effect on cardiovascular disease, which may have influenced choice of diagnostic tests and coding (i.e. detection bias) and differed between treatment arms. Lastly, the trials’ use of envelopes in the randomisation procedure is susceptible to selection bias (2), which could be a reason for the significant imbalance between the groups in regards to age.

The Women’s Health Initiative (WHI) study found that HRT was associated with increased risk of cardiovascular disease and Schierbeck et al. explain their contradictory results with the lower age in their population. This is supported by a subgroup analysis of WHI data that found lower mortality among women less than 60 years old and among women who started HRT less than 10 years after menopause (3). However, another analysis of the same data actually found higher mortality among women initiating estrogen treatment 5 years or less after menopause. (4). The same study also found increased risk of breast cancer among the women initiating combined HRT earlier than 5 years after menopause, a finding that the current study cannot reject due to lack of statistical power. When the benefits and harms of an intervention has to be weighted a study with sufficient power is needed.

Lastly, important conflicts of interest are not disclosed in the paper. According to the Danish Health and Medicines Authority’s public disclosure list at least two additional authors (LS, LK) had undisclosed conflicts with producers of study drugs.

References
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. Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
3. Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-77
4. Prentice RL, Manson JE, Langer RD, Anderson GL, Pettinger M, Jackson RD, et al. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 2009;170:12-23

Competing interests: None declared

Jeppe Bennekou Schroll, PhD student

Andreas Lundh

Nordic Cochrane Centre, Tagensvej 22, 1st floor, 2200 Copenhagen N, Denmark

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Hormone replacement therapy (HRT) in post-menopausal women is the topic of heated debate; central to the controversy is whether the direction of effect of HRT on cardiovascular disease is dependent on time of initiation of therapy relative to age or onset of menopause. The results of the trial by Schierbeck and colleagues initially promise to fuel the discourse, however, the limitations of this trial in the context of existing evidence should temper opinions.

It is important to recognize that few cardiovascular events occurred in this trial despite the 10 years of follow-up, with only 49 participants in total experiencing a primary endpoint event, five of which were myocardial infarctions. For comparison, there were 335 coronary events in the landmark Women’s Health Initiative (WHI) study, including 64 in the subgroup of women 50 to 59 years of age.1 Thus, adding the events of this trial to those of the WHI study is unlikely to have a significantly impact on the existing estimate of effect of HRT in women in this age range.

Even considering this trial in isolation, the results warrant caution. As described in the article, the trial was truncated 10 years prior to the planned follow-up duration, which increases the risk of false positive findings, especially with so few events. Indeed, the relative risk reduction of approximately 50% for the primary outcome is striking and unusual for single interventions in cardiology, and is likely an overestimation, if a benefit does exist. These results could also be influenced by - or be entirely a consequence of - detection bias introduced by the trial’s open-label design, as this trial largely took place when HRT was widely believed to reduce cardiovascular events prior to the reporting of the Heart and Estrogen/Progestin Replacement Study (HERS).2 This explanation is made more likely by the fact that stroke rates were also numerically lower in the HRT group in this trial (hazards ratio 0.77), contrary to the clear increased risk of stroke with HRT independent of age or years since menopause in the double-blind WHI study.3

References
1. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-34.
2. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.
3. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465-77.

Competing interests: None declared

Ricky D Turgeon, Pharmacy Resident

Kelvin Lou

Lower Mainland Pharmacy Services, 899 W 12th Ave Vancouver BC V5Z 1M9

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19 October 2012

It is unfortunate that the absolute risks and cancer event numbers are not clearly stated in this report. While the cardiovascular findings are reassuring, the study does not appear to be powered to exonerate hormone therapy as a risk factor for breast cancer.

My understanding is that the study had 50 breast cancer cases in total; a small number when compared with the 678 invasive breast cancer cases in the WHI(Chlebowski, JAMA 2010; 304: 1684-92).

Competing interests: Authored papers within the DOPS study and papers in collaboration with the WHI investigators. Advisory boards for Nycomed and Amgen. Grant or research support from Novartis, Nycomed, Amgen, and Merck and speaker fees from Nycomed, Merck, Eli Lilly, and Amgen.

Bo Abrahamsen, Professor

Gentofte Hospital, Niels Andersensvej, Copenhagen, Denmark

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