HERS 1998.

Methods	Stated purpose: to determine if combined HT alters risk for CHD events in postmenopausal women with established coronary disease Stratification: by clinical centre Blinding: participants, clinical centre staff, outcome assessors, data analysts, funders blinded Unblinding: When required for safety or symptom control, participants reported directly to gynaecology staff, who were located separately from clinical staff, did not communicate with them about breast or gynaecological problems and were not involved in outcome ascertainment. No. of women screened for eligibility: 3463, of whom 43% were excluded (ineligible, declined to participate, did not return for appointment or did not comply with placebo run‐in therapy) No. randomised: 2763 No. analysed: 2763 Losses to follow‐up: vital status known for all women at end of trial. 59 women did not complete follow‐up (32 in experimental arm, 27 in placebo arm). Adherence to treatment by women evaluated: by self‐report: at 1 year: 82% HT arm, 91% control arm; at 3 years: 75% HT arm, 81% control arm; by pill count in HT arm: at 1 year: 79%; at 3 years: 70% HT arm Analysis by intention to treat: yes (also analysed by treatment received, with inclusion limited to women with > 80% compliance) No. of centres: 20 Years of recruitment: February 1993‐September 1994 Design: parallel Funding: pharmaceutical (Wyeth‐Ayerst) UNBLINDED CONTINUATION OF HERS 1998: N.B. Follow‐up continued unblinded, as an open‐label observational study 2321 women (93% of 2510 surviving HERS participants) followed up for a further 2.7 years ‐ originally planned for additional 4 years, but executive committee decided no further useful information likely to emerge No. analysed: 2311 for vital status Losses to follow‐up: 10 women (1%) not contacted at final follow‐up (2 in HT arm, 8 in control arm); of these, vital status known for 5 Adherence to treatment: Among women originally assigned to the HT group, 45% reported at least 80% compliance during the sixth year of follow‐up. Among women originally assigned to placebo, 8% reported taking HT at 6 years.
Participants	Included Postmenopausal women younger than 80 years, with a uterus, with coronary disease (myocardial infarction, coronary artery bypass surgery, percutaneous coronary revascularisation or angiographic evidence of at least 50% narrowing of 1 or more major arteries, as documented by baseline ECG or hospital discharge summary), likely to be available for follow‐up for at least 4 years Excluded Women whose coronary event occurred within 6 months of randomisation, use of hormone therapy within 3 months of randomisation, serum triglycerides ≥ 300 mg/dL, history or baseline findings suggestive of venous thromboembolism, breast cancer, endometrial cancer, cervical cancer, uncontrolled hypertension, uncontrolled diabetes, severe congestive heart failure, other life‐threatening disease, alcoholism, drug abuse, history of intolerance of HT, any preexisting condition indicating unsuitability for long‐term HT or placebo therapy, > 80% compliance with placebo medication during run‐in phase Mean age: 67 years (SD 7) Age range: 44‐79 Means of recruitment: lists of cardiac patients, mass mailing, direct advertising Baseline equality of treatment groups: more women in control arm on statins at randomisation (67% vs 54%). When adjusted in analyses ‐ made no statistically significant difference Country: USA
Interventions	HT arm: conjugated equine oestrogen 0.625 mg with medroxyprogesterone acetate 2.5 mg Control arm: placebo identical in appearance Continuous oral regimen Adherence to treatment defined as > 80% compliance with medication or placebo Duration: 4.2 years, mean FOR UNBLINDED CONTINUATION OF HERS 1998: Continuation planned for an additional 4 years but stopped after mean additional 2.7 years, as no additional useful data anticipated
Outcomes	Coronary events (MI or coronary death) Venous thromboembolism Fracture Gallbladder disease Endometrial, breast or ovarian cancer Death
Notes	Power calculation: 90% power to observe 24% reduction in coronary events at an average of 4.2 years' (P = 0.05) follow‐up Further unblinded follow‐up 2.7 years (HERS II) ‐ see below
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random numbers in blocks of 4
Allocation concealment (selection bias)	Low risk	Computer displayed after participant details entered
Incomplete outcome data (attrition bias) All outcomes	Low risk	Vital status known for all women at end of trial. 59 women did not complete follow‐up (32 in experimental arm, 27 in placebo arm). Analysed by intention to treat
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, clinical centre staff, data analysts and funders blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors blinded
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Low risk	More women in control arm on statins at randomisation (67% vs 54%). When adjusted in analyses ‐ made no statistically significant difference