Issues to debate on the Women’s Health Initiative (WHI) study: Hormone replacement therapy and acute coronary outcomes: methodological issues between randomized and observational studies (2022)

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Volume 19 Issue 1

January 2004

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  • Abstract

  • Introduction

  • Methodological issues in the WHI trial

  • Methodological issues in the observational studies

  • Discussion

  • Acknowledgements

  • References

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E. Garbe,

E. Garbe

3To whom correspondence should be addressed. e‐mail: samy.suissa@clinepi.mcgill.ca

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S. Suissa

S. Suissa

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Human Reproduction, Volume 19, Issue 1, January 2004, Pages 8–13, https://doi.org/10.1093/humrep/deh022

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01 January 2004

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    E. Garbe, S. Suissa, Issues to debate on the Women’s Health Initiative (WHI) study: Hormone replacement therapy and acute coronary outcomes: methodological issues between randomized and observational studies, Human Reproduction, Volume 19, Issue 1, January 2004, Pages 8–13, https://doi.org/10.1093/humrep/deh022

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Abstract

A large number of observational studies, supported by animal and basic research studies, have shown a protective effect of hormone replacement therapy (HRT) on acute coronary outcomes. The recent large randomized Women’s Health Initiative (WHI) study reported the opposite result, i.e. a small risk increase of 29% for acute coronary outcomes under estrogen–progestin treatment. Possible methodological reasons for these discrepancies are discussed. Despite randomization, the reported small increase in risk in the WHI study could be spurious because of differential unblinding of HRT users, which could have resulted in higher detection rates of otherwise clinically unrecognized acute myocardial infarction in these women. We show that altering diagnostic patterns because of unblinding could lower the crude rate ratio of 1.28 to 1.02. In the observational studies, the protective effect may have been exaggerated due to a healthy user bias and to the inappropriate choice of the reference group. Using an alternative reference group, the combined rate ratio of 0.67 was increased to 0.82. The diametrical effects of HRT on acute coronary outcomes found between the observational studies and the WHI Study may be a result not only of bias in the observational studies, but also of bias in the WHI Study.

acute myocardial infarction/detection bias/healthy user bias/observational studies/Women’s Health Initiative study

Introduction

The cardiovascular effects of hormone replacement therapy (HRT), used to relieve the symptoms of menopause, have been debated for decades. Since 1981, the time when the first large‐scale observational study reported a lower rate of acute coronary outcomes (fatal) associated with the use of HRT [rate ratio 0.4; 95% confidence interval (CI) 0.2–0.8] (Ross et al., 1981), a large number of studies have been conducted to address this unexpected benefit (Meade and Vickers, 1999). With only a few exceptions, a majority of these observational case–control and cohort studies reproduced this finding of a protective effect. A meta‐analysis of all 25 studies published up until 1997 estimated that the rate ratios of coronary heart disease (CHD) for ever use of HRT relative to never use were 0.70 (95% CI,: 0.65–0.75) for estrogen only and 0.66 (95% CI 0.53–0.84) for estrogen and progestin combinations (Barrett‐Connor and Grady, 1998). In fact, the considerable number of studies and the consistency of the measured protective effects across studies led to clinical practice guidelines that included recommendations to use HRT as preventive therapies (Smith et al., 1995). These and findings of other beneficial effects of HRT have led to their widespread popularity and a rapid increase in their use, particularly during the last decade.

In 2002, the Women’s Health Initiative (WHI) study, a randomized trial of 16000 post‐menopausal women planned for 8year follow‐up, was halted early because of an increase in the risk of breast cancer observed in the group of women treated with HRT (Rossouw et al., 2002). It was also observed that the risk of CHD was increased with the use of HRT with a rate ratio of 1.29 (95% CI 1.02–1.63) relative to placebo. Such an increased risk, albeit small, was not noted in most previous observational studies. This discrepancy between several well‐conducted observational studies and this large randomized trial merits investigation.

Here we describe and discuss particular methodological aspects of the observational and randomized studies that may explain these important and systematic discrepancies.

Methodological issues in the WHI trial

The WHI study was conducted as a large‐scale randomized trial conferring the advantage, in contrast to the observational studies, of the absence of material confounding at baseline. During the course of the study, however, it proved difficult to maintain this advantage due to an unexpected high rate of unblinding of clinic gynaecologists and a high drop‐out rate of study participants from use of the study drug, both active and placebo. Concerns about bias that are usually only raised in epidemiology studies could thus equally relate to the WHI study in its later time course.

Detection bias

Detection bias could be related to unblinding of clinic gynaecologists or unblinding of the women themselves. The blinding was prematurely broken for 3444 (40.5%) HRT users and 548 (6.8%) placebo users, mostly to manage persistent vaginal bleeding. It is uncertain whether the study succeeded in maintaining blinding of other clinical staff. Even if the gynaecologists concealed the unblinded women’s treatment allocation from other clinical staff, the women themselves might have disclosed it when seeking medical advice. It appears only too possible that a woman with new onset of vaginal bleeding after taking the study medication will have guessed that they were on active hormone treatment. These women may have mentioned their bleeding problems or assumptions about treatment allocation to other clinical study staff, thereby creating a potential for detection bias.

Detection bias is of less concern for ‘hard’ clinical outcomes that are easily clinically diagnosed, but it could be of concern for ‘softer’ outcomes that may remain undetected in a substantial number of cases. Several cohort studies have shown that 22–44% of incident myocardial infarctions (MIs) remain clinically unrecognized at the time they occur (Sheifer et al., 2001). There could be potential for detection bias of acute MI even in a randomized trial, if unblinding occurred and electrocardiograms (ECGs) were recorded preferably in HRT users.

In the WHI study, the reported percentage of ‘silent’ MIs of 2.7% is unusually low. (Rossouw et al., 2002). ‘Silent’ MIs, despite their name, are not generally silent. Approximately half of the affected patients experience non‐specific symptoms that at the time may not be recognized to be a consequence of acute MI (Sheifer et al., 2001). The acute MI will then remain clinically undiagnosed. The patient’s state of alertness may affect pain perception, and anxieties about a possibly increased risk of acute MI may increase the request for additional ECG investigations when non‐specific symptoms are experienced. These additional ECG recordings will then increase the number of acute MIs and decrease the number of otherwise ‘silent’ MIs. Detection bias could occur if the request for an additional ECG was related to the known post‐menopausal hormone use from unblinding.

It is likely that ECGs were collected preferably in HRT users as a result of several events that occurred during the time course of the WHI study. In August 1998, results from the Heart and Estrogen/progestin Replacement Study (HERS) were widely publicized. This secondary prevention study, conducted to demonstrate the cardiovascular benefit of HRT treatment, reported the unexpected finding of a small increase in risk of acute MI in HRT‐treated women during the first study year and received widespread media attention (Hulley et al., 1998). In spring 2000 and 2001, all WHI study participants received a warning letter from the investigators that informed them about a slight increase in risk of acute MI and other acute cardiovascular events in hormone users during the first study year. It is conceivable that these publications and letters caused a lot of insecurities among study participants and particularly among those women who knew that they were on HRT treatment due to new onset of vaginal bleeding after study medication. These women may have more frequently requested additional ECGs from their physicians, even in the case of less typical angina pectoris symptoms, and thus have had otherwise clinically unrecognized MIs diagnosed more often.

In the WHI study, ECGs were only collected at baseline and at 3 and 6 years after randomization. ‘Silent’ MIs, that due to increased alertness in HRT users may have been diagnosed more often as acute MI in the hormone‐treated group, may have remained undiagnosed in a substantial number of placebo users, since no ECGs were recorded when the study was halted early. To decrease the potential for detection bias, it would have been necessary to record an ECG in all study participants when the study was stopped. This, to our knowledge, has not been the case. However, even if an ECG had been recorded at this point in time, it would not completely abolish the potential for detection bias, since clinically unrecognized non‐Q‐wave MI would still be missed.

We assessed the potential impact of this detection bias by assuming that the rate of acute MI detection differed according to the blinding status of exposure. TableI shows three hypothetical stratifications for the overall crude rate ratio of 1.28. Taking the figures of 22–44% of unrecognized MI published in the literature, the first calculation assumes that the chance of detecting an acute MI in blinded subjects is only 80% of the chance of detection in unblinded subjects, and hence unblinded subjects are around 1.2 times more likely to be diagnosed than the blinded study subjects. As a result, the rate ratio would be reduced to 1.19. The second one assumes that unblinded subjects are 1.5 times more likely to be diagnosed, resulting in a rate ratio reduced to 1.10. The third stratification assumes that unblinded subjects are 1.8 times more likely to be diagnosed, resulting in a rate ratio of 1.02. Thus, varying degrees of differential detection levels for the diagnosis of an acute MI could reduce the rate ratio to unity.

A further issue affecting detection bias arises from the adjudication of the outcomes. The outcomes that formed the basis of the analysis were adjudicated by clinical centre physicians who were centrally trained and who were expected to be blinded to treatment assignment and patient symptoms, although unblinding did occur. Outcomes were subsequently adjudicated centrally and, despite defined algorithms and central training, agreement rates between local and central adjudication were only 84% for MI, demonstrating leeway for outcome adjudication that may not be independent of treatment assignment. This additional source of misclassification may also accentuate the bias if the adjudication by clinical centre physicians was partly unblinded to the exposure status.

Methodological issues in the observational studies

Healthy user and compliance bias

Several authors raised the possibility that the protective effect of HRT on CHD observed in the epidemiological studies may have been overestimated because of a healthy user bias (Barrett‐Connor and Grady, 1998). Women taking estrogens may have more favourable lifestyles, better levels of several heart disease risk factors, and less diabetes than untreated women. The putative beneficial effects of estrogens on the heart might therefore be spurious and a consequence of healthier lifestyles and less co‐morbidity in HRT‐treated women. Baseline data from the WHI study and some other studies seem to support this notion: women who were ‘current’ hormone users at the time of WHI study enrolment had a lower prevalence of hypertension (34.9% in current hormone users versus 40.5% in never users of hormones), their hypertension was more often treated (65.6% versus 63.2%) and it was more often controlled (38.4% versus 34.3%), respectively (Wassertheil‐Smoller et al., 2000). In the National Health and Nutrition Examination Survey (NHANES I), hormone users had a lower blood pressure, a lower prevalence of diabetes and a lower body mass index at baseline; they were, however, more often smokers (Wolf et al., 1991).

The risk factor profile of HRT‐using women is less consistently beneficial when we consider baseline data from the Nurses Health Study which reported a risk reduction of ∼40% for acute MI in hormone users (Stampfer et al., 1991). In this study, current hormone users were in fact more often suffering from hypertension, appeared to have more familial risk factors of CHD, and they had higher serum cholesterol levels than never users. Current HRT users were, on the other hand, less often smokers, had a lower prevalence of diabetes, and a lower body weight. Yet other studies did not confirm a relevant difference in cardiovascular risk factor profile between HRT users and non‐users (MacLennan et al., 1998).

It has also been suggested that women complying with HRT treatment have a more favourable prognosis with respect to acute coronary outcomes, and the term compliance bias has been used to describe this possibility (Petitti, 1994; Barrett‐Connor and Grady, 1998). Patients who were compliant with placebo treatment in both the Coronary Drug Project (1980) and the Beta‐Blocker Heart Attack Trial (Horwitz et al., 1990) had a risk reduction of acute coronary outcomes of the same magnitude that was observed for HRT treatment in the epidemiological studies (Petitti, 1994). Compliance with HRT treatment could thus be a surrogate parameter for otherwise not easily measurable factors, such as, for example, a healthier lifestyle, a better diet, more physical exercise, less smoking, better compliance with other protective medications and/or better adherence to other protective types of behaviour. Both healthy user bias and compliance bias are therefore interrelated, although adjustment for coronary risk factors did not take away the beneficial effect observed with adherence to medication (Barrett‐Connor and Grady, 1998).

Choice of the reference group

All observational studies compared users of HRT, ever, current or past, with never users. The issue of whether women who never used HRT are comparable with women who do has been the object of much debate. In particular, it has been observed that women who use HRT are generally more health conscious and have lower cardiac risk factors than those who do not (see previous section). Thus, such confounding factors need to be accounted for, and were in some studies. Nevertheless, if this confounding is real, many unmeasured factors would remain unadjusted for and have been proposed as responsible for some residual bias that exaggerates the benefit.

The reference group of never users may in fact be so different that adjustment may be futile, particularly since many unmeasurable risk factors that might modify the risk of cardiovascular disease could not be accounted for in the analysis. An alternative to this approach, geared to the control of confounding, is to question the choice of the reference group. A possible reference group that may be similar to current users of HRT is past users. These women decided to initiate HRT and to stop for some reason. These reasons include either the cessation of menopausal symptoms, concern about safety from published reports or side effects such as bleeding that were deemed undesirable by the patient. However, the fact that these women initiated HRT may in fact be suggestive of greater homogeneity on the cardiovascular risk profile with the corresponding women who initiate and continued to use HRT. Choosing a reference group that on conceptual grounds appears to be similar also avoids the problem of controlling for factors that may be in the causal pathway between exposure and outcome.

We identified all studies that separated HRT exposure into current and past use, focusing on the primary CHD prevention studies. We found nine such studies (Hernandez‐Avila et al., 1990; Rosenberg et al., 1993; Psaty et al., 1994; Heckbert et al., 1997; Sidney et al., 1997; Kaplan et al., 1998; Grodstein et al., 2000; Petitti et al., 2000; Varas‐Lorenzo et al., 2000) and estimated the rate ratio of current HRT use relative to past use. TableII compares this ‘corrected’ rate ratio with the conventional rate ratio of current HRT use relative to never use. The weighted average of the rate ratio relative to never use is 0.67 (0.63–0.73), while the ‘corrected’ rate ratio relative to past use is 0.82 (0.74–0.92). Thus, the use of this reference group of past users decreases the rate reduction from 33 to 18%. We also assessed the combined effect of duration of HRT use from these same nine studies. TableIII shows the rate ratios by duration of HRT use, in comparison with the findings of the WHI study. Relative to past users, current users of HRT for >5 years have similar rate ratios of 0.79 and 0.78, although the CI from the WHI study is wider. For <1 year of use, the rate ratios are 0.99 and 1.78, with wide overlapping CIs.

Discussion

Two recent comparisons of findings from observational studies and randomized controlled trials (RCTs) have shown that the results of both study types mostly agree and that, contrary to often expressed expectations, there is no systematic overestimation of treatment effects in the observational studies (Benson and Hartz, 2000; Concato et al., 2000). The contradictory effect of HRT on acute MI between a large body of epidemiological studies and the WHI randomized trial was therefore rather unexpected. This discrepancy was particularly surprising since the protective effect of HRT on CHD has been supported by animal studies (Adams et al., 1990; Clarkson et al., 1996; Karas, 2002) and basic research studies (Tikkanen, 1993; Guetta and Cannon, 1996; Alvarez et al., 2002; Sanada et al., 2002; Stork et al., 2002), adding biological plausibility to the thesis that estrogens prevent heart disease.

Our methodological considerations suggest that the finding of an increased risk of acute MI for HRT in the WHI study could be due to bias despite the initial randomization. RCTs are usually considered as the gold standard in clinical research where most concerns about bias do not apply. However, with increasing endeavours to reproduce findings from long‐term observational research in randomized studies, we may be facing the limits of randomized research. Indeed, we have to ask ourselves whether the advantage of randomization can be maintained over many years and whether study subjects and physicians can be kept blinded. If this is not the case, opportunities for bias have to be considered in the same way as we require it for observational research. In the WHI study, unblinding of physicians and presumably patients occurred in a substantial proportion of study participants, with an important differential between the HRT and placebo groups. Detection bias could therefore be an alternative explanation for the unexpected small increase in risk of acute MI.

On the other hand, it is possible that the protective effect of HRT on acute MI has been overestimated in previous observational studies. Both healthy user bias and compliance bias would tend to exaggerate the protective effect. It is practically impossible to quantify the impact of these difficult to measure lifestyle factors and risk profiles on the risk estimates in the epidemiology studies. If current HRT users differ systematically in their health habits and risk profiles from non‐users, it may be more appropriate to compare them with past HRT users instead of non‐users, since similar health habits may be assumed in both groups of HRT users. By changing the comparison group in this way in our analyses, the protective effect of HRT use on acute MI became less pronounced. This could indicate that the protective effect of HRT on acute MI may have been overestimated in the observational studies due to a healthy user bias.

The discussion about healthy user and compliance bias becomes more complex when we consider fractures as another outcome: several authors have suggested that the beneficial effects of estrogens on the skeletal system were also exaggerated in the observational studies due to a healthier lifestyle of HRT users (Hochberg, 2000). It is of interest in this respect that the results of the observational studies and the WHI randomized trial were in concordance for fractures: in a meta‐analysis of observational studies (Grady et al., 1992), the risk of hip fractures was summarized as 0.75 for estrogen versus no estrogen use and, in the WHI trial, the risk was 0.66 (95% CI 0.45–0.98) for estrogen–progestin use versus placebo, respectively. The agreement in the effects of HRT on hip fractures between the observational studies and the WHI study could have two interpretations: first that the impact of healthy lifestyles on the risk estimates is less than assumed, which could then equally hold for other end‐points, such as, for example, acute MI; or, alternatively, that other risk factors are of more importance for fractures than the discussed healthy user bias.

Grodstein recently emphasized the remarkable consistency between the WHI trial and the observational studies also for other end‐points, such as, for example, colorectal cancer, breast cancer, stroke and pulmonary embolism, suggesting that there is little confounding in studies of the relationship of hormone therapy to these end‐points (Grodstein et al., 2003). A possible explanation for the similar results for these other end‐points and the discrepancy in the results for the risk of acute coronary events could be related to different risk functions. For acute coronary outcomes, the WHI study shows that the risk increases predominantly on initiation of therapy and decreases with longer hormone therapy, with a rate ratio of 0.78 (NS) for >5 years of hormone use (TableIII). For the other end‐points, the effects are usually observed later in the course of hormone therapy. Early clinical events, as Grodstein pointed out, might not be captured in cohort studies, since these studies do not usually include new users of hormone therapy. However, a protective effect has also been reported in a considerable number of case–control studies where early clinical events will not escape identification. Other factors contributing to the observed discrepancy could be related to clinical differences between the observational studies and the WHI randomized trial. The observational studies mostly included women on unopposed estrogen therapy (due to secular trends in hormone therapy), whereas a combined regimen with medroxyprogesterone acetate (MPA) was administered in the halted arm of the WHI study. Several studies have shown that addition of MPA to estrogen diminishes the elevation in high‐density lipoprotein observed for the use of estrogen alone (Writing Group for the PEPI Trial, 1995). There have been only sparse data on the effect of combined HRT on acute MI. The few data that indicated a protective effect on cardiovascular outcomes also for combined hormone therapy mostly included women on a cyclical combined hormone regimen, i.e. the addition of progestins to estrogens for 10–14 days per month, whereas a continuous combined regimen was used in the WHI study (Grodstein et al., 2003).

Another clinical factor concerns the choice of the estrogen–progestin dose in women of advanced age in the WHI study. Clinicians tend to reduce the dose of estrogen and progestin in elderly women to account for a reduction in hepatic and renal clearance (Genazzani and Gambacciani, 2002). There was no dose reduction undertaken in elderly women in the WHI study. Findings from the Nurses Health Study have suggested that estrogens at a dose of 0.3mg/day exhibit an equally protective effect on acute coronary events as estrogens at a dose of 0.625mg/day (Grodstein et al., 2000). The doses administered in the elderly women in the WHI study may therefore have been too high relative to their dose requirements. As a consequence, we may need more data on the effects of different hormone regimens and lower hormone doses on CHD.

In conclusion, it appears too early to conclude that the opposite effect of post‐menopausal hormones on acute coronary outcomes found between the observational studies and the WHI randomized trial is solely a consequence of bias in the observational studies. We are only just beginning to understand that randomized trials might be equally subject to bias, particularly if they are conducted over many years to study long‐term outcomes that were believed could only be investigated in an observational setting. In the WHI study, detection bias could be an alternative explanation for the small unexpected risk increase.

Acknowledgements

Samy Suissa is a recipient of a Distinguished Investigator award from the Canadian Institutes of Health Research of Canada (CIHR).

Table I.

Illustration of detection bias for the rate ratio of AMI stratified by blinding status of exposure, assuming the unblinded subjects were 1.2, 1.5 and 1.8 times more likely to be diagnosed than the blinded study subjects

Estrogen + progestinPlaceboRate ratio
CasesnRateaCasesnRatea
All subjects164850619.3122810215.11.28
First stratification by exposure blinding (assuming 20% unrecognized MIb)
 Blinded89506217.6112755414.81.19
 Unblinded75344421.81054818.21.19
 Ratio of diagnostic likelihood1.21.2
Second stratification by exposure blinding (assuming 33% unrecognized MIb)
 Blinded81506216.0110755414.61.10
 Unblinded83344424.11254821.91.10
 Ratio of diagnostic likelihood1.51.5
Third stratification by exposure blinding (assuming 44% unrecognized MIa)
 Blinded74506214.6108755414.31.02
 Unblinded90344426.11454825.51.02
 Ratio of diagnostic likelihood1.81.8
Estrogen + progestinPlaceboRate ratio
CasesnRateaCasesnRatea
All subjects164850619.3122810215.11.28
First stratification by exposure blinding (assuming 20% unrecognized MIb)
 Blinded89506217.6112755414.81.19
 Unblinded75344421.81054818.21.19
 Ratio of diagnostic likelihood1.21.2
Second stratification by exposure blinding (assuming 33% unrecognized MIb)
 Blinded81506216.0110755414.61.10
 Unblinded83344424.11254821.91.10
 Ratio of diagnostic likelihood1.51.5
Third stratification by exposure blinding (assuming 44% unrecognized MIa)
 Blinded74506214.6108755414.31.02
 Unblinded90344426.11454825.51.02
 Ratio of diagnostic likelihood1.81.8

aRate as cumulative incidence of acute MI per 1000.

bThe detection rates of 22–44% relate to the proportion of incident MIs that remain clinically unrecognized at the time they occur but can be detected by ECG (Sheifer et al., 2001).

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Table I.

Illustration of detection bias for the rate ratio of AMI stratified by blinding status of exposure, assuming the unblinded subjects were 1.2, 1.5 and 1.8 times more likely to be diagnosed than the blinded study subjects

Estrogen + progestinPlaceboRate ratio
CasesnRateaCasesnRatea
All subjects164850619.3122810215.11.28
First stratification by exposure blinding (assuming 20% unrecognized MIb)
 Blinded89506217.6112755414.81.19
 Unblinded75344421.81054818.21.19
 Ratio of diagnostic likelihood1.21.2
Second stratification by exposure blinding (assuming 33% unrecognized MIb)
 Blinded81506216.0110755414.61.10
 Unblinded83344424.11254821.91.10
 Ratio of diagnostic likelihood1.51.5
Third stratification by exposure blinding (assuming 44% unrecognized MIa)
 Blinded74506214.6108755414.31.02
 Unblinded90344426.11454825.51.02
 Ratio of diagnostic likelihood1.81.8
Estrogen + progestinPlaceboRate ratio
CasesnRateaCasesnRatea
All subjects164850619.3122810215.11.28
First stratification by exposure blinding (assuming 20% unrecognized MIb)
 Blinded89506217.6112755414.81.19
 Unblinded75344421.81054818.21.19
 Ratio of diagnostic likelihood1.21.2
Second stratification by exposure blinding (assuming 33% unrecognized MIb)
 Blinded81506216.0110755414.61.10
 Unblinded83344424.11254821.91.10
 Ratio of diagnostic likelihood1.51.5
Third stratification by exposure blinding (assuming 44% unrecognized MIa)
 Blinded74506214.6108755414.31.02
 Unblinded90344426.11454825.51.02
 Ratio of diagnostic likelihood1.81.8
(Video) New Perspectives on Menopausal Hormones and Heart Disease

aRate as cumulative incidence of acute MI per 1000.

bThe detection rates of 22–44% relate to the proportion of incident MIs that remain clinically unrecognized at the time they occur but can be detected by ECG (Sheifer et al., 2001).

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Table II.

Comparison of rate ratios of acute MI/CHD in all epidemiological studies that reported estimates for past use and current use relative to never use, including estimates of the ‘corrected’ rate ratio using past users as the reference

Epidemiological studyPast use versus never useCurrent use versus never useCurrent use versus past use
Rate ratio95% CIRate ratio95% CIRate ratio95% CI
Hernandez‐Avila (1990)0.600.2–2.10.700.4–1.41.17
Rosenberg et al. (1993)0.900.7–1.30.800.4–1.30.89
Psaty et al. (1994) (estrogen)0.690.44–1.070.660.44–1.000.96
Sidney et al. (1997)1.010.64–1.600.890.52–1.530.88
Heckbert et al. (1997)0.740.57–0.960.700.55–0.890.94
Kaplan et al. (1998)1.220.71–2.090.510.22–1.150.42
Varas‐Lorenzo et al. (2000)0.730.51–1.030.720.59–0.890.99
Petitti et al. (2000) (estrogen)1.000.7–1.40.800.6–1.20.80
Grodstein et al. (2000)0.820.72–0.940.610.52–0.710.74
All studies combined0.670.63–0.730.820.74–0.92
Epidemiological studyPast use versus never useCurrent use versus never useCurrent use versus past use
Rate ratio95% CIRate ratio95% CIRate ratio95% CI
Hernandez‐Avila (1990)0.600.2–2.10.700.4–1.41.17
Rosenberg et al. (1993)0.900.7–1.30.800.4–1.30.89
Psaty et al. (1994) (estrogen)0.690.44–1.070.660.44–1.000.96
Sidney et al. (1997)1.010.64–1.600.890.52–1.530.88
Heckbert et al. (1997)0.740.57–0.960.700.55–0.890.94
Kaplan et al. (1998)1.220.71–2.090.510.22–1.150.42
Varas‐Lorenzo et al. (2000)0.730.51–1.030.720.59–0.890.99
Petitti et al. (2000) (estrogen)1.000.7–1.40.800.6–1.20.80
Grodstein et al. (2000)0.820.72–0.940.610.52–0.710.74
All studies combined0.670.63–0.730.820.74–0.92

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Table II.

Comparison of rate ratios of acute MI/CHD in all epidemiological studies that reported estimates for past use and current use relative to never use, including estimates of the ‘corrected’ rate ratio using past users as the reference

Epidemiological studyPast use versus never useCurrent use versus never useCurrent use versus past use
Rate ratio95% CIRate ratio95% CIRate ratio95% CI
Hernandez‐Avila (1990)0.600.2–2.10.700.4–1.41.17
Rosenberg et al. (1993)0.900.7–1.30.800.4–1.30.89
Psaty et al. (1994) (estrogen)0.690.44–1.070.660.44–1.000.96
Sidney et al. (1997)1.010.64–1.600.890.52–1.530.88
Heckbert et al. (1997)0.740.57–0.960.700.55–0.890.94
Kaplan et al. (1998)1.220.71–2.090.510.22–1.150.42
Varas‐Lorenzo et al. (2000)0.730.51–1.030.720.59–0.890.99
Petitti et al. (2000) (estrogen)1.000.7–1.40.800.6–1.20.80
Grodstein et al. (2000)0.820.72–0.940.610.52–0.710.74
All studies combined0.670.63–0.730.820.74–0.92
Epidemiological studyPast use versus never useCurrent use versus never useCurrent use versus past use
Rate ratio95% CIRate ratio95% CIRate ratio95% CI
Hernandez‐Avila (1990)0.600.2–2.10.700.4–1.41.17
Rosenberg et al. (1993)0.900.7–1.30.800.4–1.30.89
Psaty et al. (1994) (estrogen)0.690.44–1.070.660.44–1.000.96
Sidney et al. (1997)1.010.64–1.600.890.52–1.530.88
Heckbert et al. (1997)0.740.57–0.960.700.55–0.890.94
Kaplan et al. (1998)1.220.71–2.090.510.22–1.150.42
Varas‐Lorenzo et al. (2000)0.730.51–1.030.720.59–0.890.99
Petitti et al. (2000) (estrogen)1.000.7–1.40.800.6–1.20.80
Grodstein et al. (2000)0.820.72–0.940.610.52–0.710.74
All studies combined0.670.63–0.730.820.74–0.92

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Table III.

Rate ratios of acute MI/CHD by duration of HRT use among current users in all epidemiological studies and the WHI study using never users and past users as the reference

Duration of HRT use(in years)Observational studiesWHI study
No. of studiesCurrent use versus never useCurrent use versus past useRate ratio95% CI
Rate ratio95% CIRate ratio95% CI
≤170.790.58–1.080.990.69–1.421.781.08–2.96
1–590.620.52–0.740.760.61–0.941.220.91–1.63
>590.650.56–0.750.790.66–0.930.780.40–1.52
Duration of HRT use(in years)Observational studiesWHI study
No. of studiesCurrent use versus never useCurrent use versus past useRate ratio95% CI
Rate ratio95% CIRate ratio95% CI
≤170.790.58–1.080.990.69–1.421.781.08–2.96
1–590.620.52–0.740.760.61–0.941.220.91–1.63
>590.650.56–0.750.790.66–0.930.780.40–1.52

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Table III.

Rate ratios of acute MI/CHD by duration of HRT use among current users in all epidemiological studies and the WHI study using never users and past users as the reference

Duration of HRT use(in years)Observational studiesWHI study
No. of studiesCurrent use versus never useCurrent use versus past useRate ratio95% CI
Rate ratio95% CIRate ratio95% CI
≤170.790.58–1.080.990.69–1.421.781.08–2.96
1–590.620.52–0.740.760.61–0.941.220.91–1.63
>590.650.56–0.750.790.66–0.930.780.40–1.52
Duration of HRT use(in years)Observational studiesWHI study
No. of studiesCurrent use versus never useCurrent use versus past useRate ratio95% CI
Rate ratio95% CIRate ratio95% CI
≤170.790.58–1.080.990.69–1.421.781.08–2.96
1–590.620.52–0.740.760.61–0.941.220.91–1.63
>590.650.56–0.750.790.66–0.930.780.40–1.52

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FAQs

What was wrong with the WHI study? ›

2.1.

The WHI reported an increased risk of breast cancer in the women treated with a combination of conjugated estrogen and medroxyprogesterone acetate [17], a risk that was significantly higher than in placebo users after 5.6 years of treatment (approximately 6–7 years) [37,38].

What were the results of the women's health Initiative concerning hormone therapy? ›

The WHI demonstrated that the use of estrogen plus progestin hormone therapy after menopause increased the risk for heart disease, stroke, blood clots, breast cancer, and dementia.

What lessons were learned from the women's health Initiative regarding hormone replacement therapy and menopause? ›

Estrogen plus progestin therapy, but not estrogen therapy, increased the risk of breast cancer with a suggestion of greater risk when initiated close to the menopause. Menopausal HT increased the risk of CHD in women more than 20 years distant from menopause, particularly in women with vasomotor symptoms.

When was WHI published? ›

In 1991, the National Heart, Lung, and Blood Institute, part of NIH, launched the Women's Health Initiative (WHI) to understand better how these diseases affect post-menopausal women and to reduce the number of women who develop and die from these diseases.

Why was the WHI study terminated early? ›

A firestorm in women's health ensued when the EPT arm of the WHI was prematurely terminated because of 'increases in breast cancer, coronary heart disease, stroke, and pulmonary embolism in study participants on estrogen plus progestin compared to women taking placebo pills.

Why was the women's health Initiative stopped early? ›

Understanding Why the WHI Hormone Therapy Trial Ended Early

Overall, the data demonstrated an increased risk of stroke among the E-Alone group. For every 10,000 women in the E-Alone group, 12 additional strokes occurred compared to the control group.

Why or why not should a woman take hormone replacement therapy? ›

HRT may be used short-term to treat menopausal symptoms. Long-term use is discouraged because the risk for heart attack, stroke and breast cancer increases the longer HRT is used.

Why is HRT so controversial? ›

Proponents of bioidentical HRT state that the problem with synthetic hormones is that they are too different from our own; they stimulate additional 'unnecessary' hormone receptors and fail to replace some of the critical functions of our natural hormones, creating potentially serious side effects.

What are the disadvantages of hormonal replacement therapy? ›

An increased risk of endometrial cancer (only if you still have your uterus and are not taking a progestin along with estrogen). Increased risk of blood clots and stroke. Increased chance of gallbladder/gallstone problems. Increased risk of dementia if hormone therapy is started after midlife.

› article › abstract ›

Two aspects of the design contributed to the adverse events: [1] The decision to administer continuous combined conjugated equine estrogen (CEE)/medroxyprogeste...
The authors of the WHI studies and the National Heart Lung and Blood Institute (NHLBI) concluded that E+P treatment increased the risks of coronary heart diseas...
Abstract. Over the last 40 years, there has been increasing epidemiological evidence that post‐menopausal treatment with sex steroids in physiological doses may...

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