HALL 1998.

Methods	Objective:  to assess the effects of HT on angina and HRQoL in women with ischaemic heart disease   Single‐centre, randomised, controlled (RCT) trial involving one hospital site in Sweden. The trial was a three‐arm trial comprising: one group who received 50 µg transdermal 17ß‐oestradiol daily for 18 days followed by 5 mg of combined treatment with medroxyprogesterone acetate orally; the second group who received 0.625 mg conjugated oestrogens (CEE) orally for 18 days followed by a combination with oral 5 mg medroxyprogesterone acetate daily, and the third group who received placebo.  Due to not confounding the results of other trials in which oestrogens/progestins have been provided orally, the data presented in this trial are from the groups that received only oral medication (i.e. groups two and three).  The length of follow‐up of the trial was one year.  The primary outcome was angina, with death from CVD causes, MI, and the number of angioplasties and CABG performed reported as secondary outcomes   Recruitment: Not reported Screening: Not reported Randomisation: Not reported Stratification: Not reported Allocation: Not reported Baseline equality of treatment groups:  Only limited baseline characteristics reported for the treatment groups, and no statistical comparisons made between groups.  Probable baseline imbalance between treatment groups for age (placebo group older than HT group); weight (placebo group heavier than HT group); number of years since menopause (placebo group higher number than HT group) Blinding: Not reported Analysis: Unclear. No statistical tests for between group differences conducted Funding Source: Hospital grant funded
Participants	Forty post‐menopausal women with existing coronary artery disease (HT: 20; placebo: 20) with a mean age of 60 years (range: 44 ‐ 75) underwent treatment with either HT or placebo for a year. No definition of what constituted post‐menopausal status and whether the trial included patients with a hysterectomy was reported. The mean BMI among the 40 women included in the trial was 30 kg/m2 (range: 20.0 to 40.7 years); the mean time of menopause was 12.5 years (range: 2 to 26); 9.5% were former smokers, 5.5% were never smokers and 5.5% were present smokers.  In terms of diagnosis of CVD: 55% had a previous MI; 27.5% previous bypass surgery; 22.5% previous percutaneous transluminal coronary angioplasty (PTCA) (balloon dilation); 0% had type I diabetes; 10% had type II diabetes; 32.5% had hypertension, and 12.5% had claudication  Inclusion criteria:  No inclusion criteria were reported Exclusion criteria: No inclusion criteria were reported
Interventions	HT regimen: 0.625 mg conjugated oestrogens (CEE) orally for 18 days followed by a combination with oral 5 mg medroxyprogesterone acetate daily (sequential dosage regimen) Comparator: identical placebo capsule daily The overall compliance with study intervention was not reported Follow‐up times:  Baseline, three, six, 12 months and four to six weeks after completion of the trial. Pre‐treatment investigations included gynaecological history and occurrence of climacteric symptoms, Pap smear and mammography (if not performed within two years prior to recruitment).  Blood samples were analysed for oestradiol, estrone, estrone sulphate and follicle stimulating hormone at baseline, three, six, 12 months and four to six weeks after trial completion.  Additionally, a cardiac history, physical examination, and symptoms of angina pectoris were performed using the Canadian Heart Association protocol before trial entry.  Minimal Health Related Quality of Life (HRQoL) data were measured at baseline and at one‐year follow‐up.  The domains covered were:  (1) well being; (2) mucous membrane changes; (3) climacteric symptoms; (4) breast tenderness; (5) negative mood changes; (6) headache, and (7) bleeding irregularities. The outcomes of these were not reported in the paper Withdrawals: 20%; 10% HT and 30% placebo
Outcomes	Death from CVD cause Angina Fatal MI Angioplasty Coronary artery bypass
Notes	No sample size calculation was performed and it is unlikely that the trial was powered adequately to detect significant differences in clinical event rates between the HT and placebo groups. No definition of how clinical events were defined or ascertained was reported.  Additionally, no statistical analyses to assess differences in clinical event rates between the groups were performed. It is therefore unclear, whether the groups differed significantly in the number and types of events experienced.  The length of trial follow‐up (one year) was unlikely to be long enough to ascertain either the longer‐term effects of HT use compared to placebo, or for other important CVD events to be assessed. The control group population started treatment on average 13.3 (SD 7.8) years after their menopause with the hormone group starting on average 11.6 (SD 6.7) years after. Events were not reported individually or according to starting treatment < 10 or > 10 years since the menopause. For the subgroup analysis of when treatment was started the entirety of events in this study were analysed as if all participants had started treatment more than 10 years after their menopause
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Methods of randomisation not reported; imbalance in baseline participant characteristics between groups
Allocation concealment (selection bias)	High risk	Methods of allocation concealment not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of participants and study personnel not reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessors not reported, but may not influence ascertainment of outcomes
Incomplete outcome data (attrition bias) All outcomes	High risk	Analyses do not appear to be undertaken on an ITT basis, it is unclear whether withdrawals were included in the analyses, and no statistical tests for between group differences conducted
Selective reporting (reporting bias)	Unclear risk	The paper reports the results for the main outcome of interest, angina, but it is unclear whether any other outcomes were prespecified but not reported. It appears that just the events that occurred in the trial were reported, rather than these being defined a priori for consideration in the trial. Additionally, HRQoL was measured within the trial, but the results of the assessments were not reported
Other bias	Unclear risk	It is unlikely that the trial was powered to detect differences in clinical events between the HT and placebo treatment groups.  Furthermore, no statistical analyses were undertaken to assess differences in clinical event rates between the trial arms. Therefore, the lack of significant differences in event rates between the two groups should be treated with caution