a Division of Epidemiology and Public Health and Trent Institute for Health Services Research, University of Nottingham, Nottingham, UK
b Division of Medicine and Therapeutics, University of Leicester, Leicester, UK
* Correspondence to: Professor Richard Logan, Division of Epidemiology and Public Health, University Hospital, Queens Medical Centre, Nottingham NG7 2UH, UK. Tel: +44 115 970 9308; fax: +44 115 970 9316
E-mail address: richard.logan{at}nottingham.ac.uk
Received 23 April 2003; revised 8 September 2003; accepted 19 September 2003
Abstract
Aims To examine the relationship between hormone replacement therapy (HRT) and acute myocardial infarction (AMI) adjusting for coronary risk factors and social and behavioural confounders that might indicate a healthy user effect and could account for the discrepancy between randomized and observational studies of HRT use.
Methods A case-control study of 864 women aged between 3565 suffering an AMI with two age matched community controls from the same geographical area. Information was collected by interview and from general practitioner records. Conditional logistic regression was used to calculate odds ratios (OR) adjusted for diabetes, hypertension, smoking, alcohol, social class, family history and a health conscious behaviour score.
Results HRT use was recorded for 34% of non-fatal AMI cases and 39% of controls with the adjusted OR for ever-use of HRT versus never-use being 0.74 (95% CI 0.550.99). The pattern of risk of AMI was similar for oestrogen only and combined HRT. During the first 12 months of HRT use there was a small increase in risk of AMI with the adjusted OR being 1.14 (0.721.80). HRT use for 1360 months was associated with a small reduction in AMI risk (adjusted OR 0.85, 0.551.29). Only HRT used for >60 months was associated with a substantial risk reduction (adjusted OR 0.42, 0.240.73). Data for deceased cases and controls showed a similar pattern.
Conclusion HRT use whether as oestrogen only or combined hormones was only associated with a significant reduction in risk when used for greater than 60 months. These findings could reflect a dual effect of HRT on AMI risk by prothrombotic and anti-atherogenic mechanisms. Neither oestrogen only or combined HRT can be recommended for prevention of coronary artery disease.
Key Words: Myocardial infarction Hormone replacementtherapy
1. Introduction
Use of hormone replacement therapy (HRT) is widespread in many countries.1Observational studies have suggested that HRT use reduces the risk of acute myocardial infarction (AMI) and other manifestations of coronary artery disease but evidence from randomized trials has not supported this.25
This disparity between observational and randomized studies could reflect a complex relationship between HRT use and risk of AMI or it could reflect unrecognized biases in the observational studies. As HRT users tend to be more educated, more health aware and have favourable coronary risk profiles, a healthy user selection bias has been proposed. Nevertheless while the randomized studies have now found no evidence of heart disease protection from HRT use for up to 5 years they have been less able to examine the effects of longer term HRT use.
The aim of our study was to examine the relationship between both combined and oestrogen only HRT and risk of AMI while adjusting for any healthy usereffect.
2. Methods
This population based case-control study included both fatal and non-fatal AMI cases occurring in women living in the East Midlands, UK.
2.1. Recruitment of AMI cases
Cases were aged between 3565 and were of European ethnicity only as HRT use was uncommon in women of other ethnicities in this area. They were identified from admissions to the eight hospitals serving Derby, Leicester, Mansfield and Nottingham. All cases had suffered a first AMI between 1 April 1995 (1 May in Leicester, 1 October in Mansfield, 1 August 1996 in Derby) and 31 December 1998. Patients having a recurrent AMI were excluded in case their heart disease had influenced the prescribing of HRT.
Live cases were identified from coronary care unit databases, hospital discharges and clinical biochemistry records in Derby, Leicester and Mansfield and in Nottingham from the Nottingham Heart Attack Register.8AMI was confirmed when two of the following were present: a history of cardiac type chest pain; a doubling of two cardiac enzymes; evolving ST-T wave changes with new Q waves. Deceased cases were certified as having had an AMI as their underlying cause of death (ICD-9 410) and were identified from the Coroners offices and the Health Authorities local mortality data.
2.2. Recruitment of controls
For each case, the relevant Health Authority provided a list of all women with the same date of birth. Two controls were chosen from the list using a random number generator. They were excluded if they were not resident in the East Midlands, were not European or had had an AMI. In these instances, or if a control declined to participate, the next randomly chosen control was selected.
2.3. Data collection
Cases and controls were interviewed in their homes by trained fieldworkers using a structured questionnaire. The questionnaire covered demographics, details of HRT use, medical history including operations and regular medication, menstrual, obstetric and contraceptive history, and uptake of screening programmes up to the date of the AMI for the case and her matched controls. Information on heart disease risk factors such as smoking, alcohol intake, diet, physical activity and family history of heart disease or stroke was also collected.
At the end of each interview, participants were asked for permission to take a blood sample for measurement of high-density lipoprotein, and total cholesterol.
At interview, written consent was obtained to examine a case or controls general practice (GP) records. Information was abstracted up to the date of AMI including date started and stopped for each HRT preparation used, uptake of cancer screening programmes, medical history, and other drug prescriptions. The same information was also abstracted from GP records of deceased cases and their controls.
All details of HRT use were taken from the GP records, except for 18 women whose GP records were not available, of whom six reported using HRT (three cases and three controls) at interview. For these six women, information on HRT use obtained at interview was used. Ever use of HRT was defined as having had one or more HRT prescriptions recorded in their GP notes and HRT was defined and categorized according to the British National Formulary.
Duration of HRT use was obtained from the sum of the total number of HRT prescriptions in each womans GP record, and recency of use for each case and matched controls was dated from the time of the cases MI.
Ethical approval for this study was obtained from the Local Research Ethics Committees in Derby, Leicester, Mansfield and Nottingham.
2.4. Statistical analysis
We estimated that the sample size required to detect a relative risk of 0.7 (or rule out a risk of
1.4), with
=0.05 and ß=0.1 (90% power) assuming HRT exposure of 30% in the controls, was 650 cases and 1300 controls. To allow for subgroup analysis, the proposed numbers were increased to 750 cases and 1500 controls.
Conditional logistic regression for matched data9using the matching variable age as a stratifying factor was carried out using Statistical Package for the Social Sciences (SPSS) version 9.0 and Egret for Windows version 2.03. Relative risks were estimated by odds ratios (ORs) with 95% confidence intervals (CIs). Significance levels quoted are two-sided.
The variables considered as potential confounders were history of diabetes, history of hypertension, smoking (cigarette years of exposure), frequency of alcohol consumption, social class, health conscious behaviour score, family history of heart disease/stroke in either a parent and/or a sibling before the age of 60, body mass index, cholesterol level, previous hysterectomy and amount of energetic activity per week. All of these except body mass index, cholesterol level, previous hysterectomy and amount of energetic activity per week were found to be confounders and were adjusted for in the analyses. Participants with missing data were excluded from parts of the analyses that included those data.
The health conscious behaviour score was calculated from data on uptake of cervical and breast cancer screening and on frequency of fresh fruit and vegetable consumption. Reported consumption of fresh fruit or vegetables more than three times a week scored 1 and a record of attendance for a cervical smear scored 1. For breast cancer screening, women over 50 were scored 1 if they had had a mammogram, and for those under 50, breast self-examination was scored 1. Thus the total scores for each woman ranged from 0 to 3 with higher scores reflecting healthier behaviour.
3. Results
3.1. Recruitment rates
A total of 666 women having a non-fatal acute AMI were identified and 559 (84%) participated in the study. Of the 1632 controls selected, 1118 were interviewed (Fig. 1). For 88% of cases there was at least one first or second control interviewed and 68% of all controls interviewed were either first or second controls.
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3.2. Characteristics of live cases and their controls
As shown in Table 1the majority (61%) of participants were aged 5564 years. There was a trend for an increasing risk of AMI with lower socio-economic status (trend 2=8.52, P<0.01), increasing BMI (trend
2=3.63, P=0.06), decreasing frequency of alcohol consumption (trend
2=6.82, P<0.01), increasing numbers of cigarettes smoked (trend
2=111.0, P< 0.001) and decreasing health conscious behaviour score (trend
2=21.9, P<0.001). There was also an increased risk of AMI with a history of diabetes, hypertension, and a family history of AMI (defined as having a sibling or parent having an AMI before age 60).
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3.3. HRT use and non-fatal AMI
Ever use of HRT was recorded in the general practice notes in 34% of live cases and in 39% of their controls (Table 2). In 8% of cases and 13% of controls use was current at the time of the cases AMI and in 5% of cases and 10% of controls HRT had been used for more than 60 months. The adjusted odds ratios for ever use of HRT compared to never use was 0.74 (95% CI 0.550.99 ) based on the data collected from all 559 interviewed live cases and their 1118 controls.
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3.4. Duration of HRT use
In the analyses shown in Table 2there was a trend for risk of AMI to decrease with duration of use beyond 1 year(P<0.001) with an adjusted odds ratio for HRT use of longer than 60 months of 0.42 (95% CI 0.240.73). The risk of AMI was not significantly affected by HRT use for less than 12 months. When duration of use was analysed(Table 3) the reduction in risk of AMI with prolonged use was similar whatever type of HRT was used although it was greater for women using combined HRT rather than oestrogen only.
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The effect of non-response bias was estimated by calculating the odds ratio for ever use of HRT for all cases (interviewed, non interviewed and deceased cases) and corresponding controls. For the 39 living cases and 172 controls where no information was available it was assumed that the proportions who had ever used HRT were the same as those in the non interviewed living cases and corresponding controls. On this basis we estimated that of 864 (559 interviewed, 198 deceased cases and 107 non-interviewed live cases) women identified as having had an AMI in this period 262 (30%) had used HRT at some point compared with 707 (35%) of the 2025 controls (1118 controls for interviewed cases, 393 for deceased cases and 514 non-interviewed) giving an unadjusted OR of 0.81 (95% CI 0.680.96).
4. Discussion
This study has confirmed the major known risk associations for AMI, both positive (smoking, diabetes, family history, hypertension) and negative (alcohol) and shown that only prolonged HRT use (>5 years) is associated with any substantial reduction in risk of AMI (OR=0.42, CI 0.240.73). Hormone replacement therapy use for shorter periods was associated with an initial small increase in AMI risk followed by a decrease but neither was significant at the 5% level. The data for fatal AMI were closely similar but could not be adjusted in the same way. In addition estimates of risk were similar for oestrogen and combined oestrogen-progestogen formulations.
This finding of an apparent protection from AMI with prolonged use of HRT is consistent with a large body of evidence from observational research.2A major issue in all these observational studies has been the possibility of confounding by a healthy user selection bias.6,7,10Our composite health conscious behaviour score, derived from dietary fruit and vegetable intake plus uptake of cervical and breast screening, had a strong, independent inverse association with risk of AMI. The two screening tests are provided free as part of organized national screening programmes; uptake is therefore a marker of health awareness and willingness to use health services. In the final model containing the classical coronary risk factors, the health conscious behaviour score and social class, there was evidence of a similar degree of protection by HRT use as has been shown in meta-analyses of earlier observational studies,2and more recent reports.11,12We also considered the possibility of non-response bias; that HRT usage by deceased cases and by living cases and controls who refused to be interviewed might systematically differ from the cases interviewed. Our best combined estimate of the OR for ever use of HRT including these groups still indicated a protective effect.
The relationship between HRT use and CHD risk seen in observational studies has not been replicated in randomized controlled trials. The Heart and Estrogen-progestin Replacement Study (HERS) compared the effects of conjugated Estrogens and medroxyprogesterone acetate against placebo in post menopausal women with documented CHD and found no overall difference in any cardiovascular outcome over a mean of 4 years follow-up.3However, a statistically significant time effect was seen; there were more CHD events in the HRT group than the placebo group during the first year and fewer in years 45. In later analysis, including an additional unblinded follow up of 2.7 years, the apparent reduction in risk with prolonged HRT use was not sustained.13However, analysis of the open-label phase was progressively complicated by crossover between treatment groups, significantly higher statin use in the placebo group and other potential confounding factors.
In the Womens Health Initiative randomized control trial (WHI) the hazard ratio for incident CHD (non-fatal AMI or CHD death) was 1.29 (adjusted 95% CI 0.851.97) in healthy post-menopausal women randomized to combined HRT compared to placebo4although all-cause mortality did not differ in the two groups. Venous thromboembolic disease was also increased as was fatal or non-fatal stroke. The incidence curves for CHD and pulmonary embolism separated soon after randomization, those for stroke only after 12 years. CHD incidence curves converged slightly after 6 years of follow-up, though by this point numbers were small and again there had been substantial crossover; 42% of the HRT group had discontinued treatment and 11% of the placebo group had started active treatment. The results from the WHI trial are concordant with results from observational studies16for stroke, pulmonary embolism, hip fractures, breast cancer and colorectal cancer.
Our study, and the comparison of results from observational studies and the WHI study cited above,16indicate that selection bias does not appear to explain the rather consistent observational evidence that HRT is associated with a duration-dependent lowering of AMI risk. From what is known of pathogenesis, HRT may have dual effects, opposite in direction and with differing timescales. Acute myocardial infarction is the end result of atherogenesis followed by thrombosis. Combined HRT use has multiple effects on plasma fibrinogen, antithrombin II, protein S plasminogen-activator inhibitor type 1 and factor VII, but the net effect is prothrombotic.14This was clearly shown in the WHI study by the significantly increased incidence of venous thrombosis and pulmonary embolism beginning early after the start of HRT.4On the other hand HRT treatment induces favourable changes in the lipid profile sufficient to reduce CHD risk in the longer term. In both the HERS trial3and the WHI trial4the combined HRT regimens produced highly significant decreases in LDL cholesterol (1314%) and increases in HDL cholesterol (78%) by the end of the first year of treatment. It is therefore biologically plausible that the CHD hazard function should be non-linear over time. In principle, the prospective nature of an RCT will be more apt to detect acute effects of exposure on CHD event rate, and the case-control design better able to pick up late effects of prolonged past exposure.
However, neither the RCT nor case-control data currently available are adequate to resolve such a mixed exposure-risk relationship during prolonged HRT use. Observational studies are vulnerable to the possibility of residual confounding, as the initiation and continuation of HRT use are both subtly influenced by behavioural characteristics. Randomized trials, on the other hand, suffer from progressive null bias due to crossover between use and non-use of HRT. Moreover, since the effect of HRT on CHD risk is small (7 CHD events per 10,000 person years in WHI, for example)4all analyses to date have been at the limits of statistical power.
On the evidence now available, HRT use is not indicated for either the primary or secondary prevention of coronary heart disease. Any potential long term benefit in lipid profile will be exceeded by statin treatment. The primary indication will continue to be the relief of menopausal symptoms.15In prolonged use, the overall balance of risks (breast cancer, stroke, thromboembolic disease) and benefits (reduction in colorectal cancer and osteoporotic fracture) will be the subject of individual judgement.
Acknowledgments
This study would not have been possible without the contributions of Dr Terry Brown, Georgina Jones and Rebecca Pearce, study co-ordinators initially, Dr David Gray and the staff of the Nottingham Heart Attack Register and Gwyn Campion, Gail Faulkner, IreneMilburn, Jenny Park and Anne Williams who carried out the interviews. We are also grateful to the general practitioners in the East Midlands for their help. C.E.D.C., R.F.A.L. and K.L.W. were responsible for designing the study and supervising its conduct. R.K. was study co-ordinator. S.A. performed the statistical analyses. All authors contributed to writing the report.
Footnotes
1 This study was funded by the NHS R&D Programme on Cardiovascular Disease and Stroke
References