ERA 2000.

Methods	Objective: To evaluate the effects of HT on the progression of coronary atherosclerosis Multicentered three‐armed randomised controlled (RCT) trial involving six hospital sites in the United States. The trial was conducted from January 1996 to December 1997, with a mean follow‐up of 3.2 ± 0.6 years. The primary aim of the trial was to assess the effects of oestrogen replacement therapy with or without low‐dose progestin on angiographic progression or regression of coronary atherosclerosis in post‐menopausal women. The primary outcome was therefore change in the minimum diameter of the major epicardial segments, as assessed by quantitative coronary angiography. Clinical CVD events were all assessed as secondary outcomes Recruitment: Media announcements, contact through hospital records and admissions, screening logs from other studies Screening: Not stated Randomisation: Computerised in random blocks Stratification: According to lipid lowering therapy at baseline and hospital where angiogram was performed Allocation: Computer displayed treatment assignment after eligible participant details entered Baseline equality of treatment groups: No substantive differences between study groups at baseline Blinding: Participants, clinic staff and all outcomes assessment blinded. Treatment assignment available to designated member of data management staff. Questions relating to adverse effects directed to gynaecology physician and nurse not connected with study Analysis: ITT Funding Source: Grants from National Heart, Lung and Blood Institute and NationalCenter for Research Resources General Clinical Research Center, study medications from Wyeth‐Ayerst Research
Participants	Three hundred and nine post‐menopausal women with angiographically verified coronary disease were randomised to receive either (1) daily conjugated oestrogen alone (n = 100), (2) daily conjugated oestrogen in combination with medroxyprogesterone acetate (n = 105), or daily placebo (n = 105).  Coronary artery disease was defined as at least one stenosis of 30% in any single coronary artery.   The mean age of the women was 65.8 years (range: 41.8 ‐ 79.9), with a mean number of years since menopause of 22.5. Post‐menopausal status was defined as the presence of one of the following conditions: (1) an age of at least 55 without natural menses for at least five years; (2) no natural menses for at least one year and a serum follicle‐stimulating hormone level of more than 40 IU per litre; (3) documented bilateral oophorectomy; or self reported bilateral oophorectomy, a follicle‐stimulating hormone level of more than 40 IU per litre, and a serum oestradiol level of less than 25 pg per mm (91.1 pmol/L). 61% of the women had undergone a hysterectomy and 30.4% an oophorectomy  At baseline 9% of women were taking oestrogen, and therefore underwent a three‐month ‘wash out ‘period prior to randomisation Included women were 82% White, 14% Black, and 4% of other racial origin. 49% had a history of MI and 47% a history of having undergone an angioplasty In terms of risk factors for CVD: 28% had diabetes; 67% had hypertension; 18% were current smokers; and 57% had a BMI > 27.5 kg/m2. The mean systolic blood pressure of the women was 130 mm Hg and the mean diastolic blood pressure 71.8 mm Hg. There were no statistically significant differences between the three treatment groups at baseline Inclusion criteria: Stated above, but only women who were 80% or more medication compliant in the one month prior to randomisation were eligible for participation in the trial  Exclusion criteria: known or suspected breast cancer or endometrial carcinoma previous or planned coronary artery bypass surgery a history of deep vein thrombosis or pulmonary embolism symptomatic gallstones serum aspartate aminotransferase level more than 1.5 times the normal value triglyceride level of more than 400 mg/dL (4.52 mmol/L) while fasting serum creatinine level of more than 2.0 mg per decilitre (176.8 µmol per litre) more than 70% stenosis of the left main coronary artery uncontrolled hypertension uncontrolled diabetes
Interventions	HT regimen: 1) 0.625 mg conjugated equine oestrogen daily and a placebo tablet daily (continuous dosage regimen) 2) 0.625 mg conjugated equine oestrogen plus medroxyprogesterone acetate and placebo tablet daily (continuous dosage regimen) Comparator: two placebo tablets daily (continuous dosage regimen) Participants were classified as medication compliant if they took ≥ 80% of their medication throughout the trial. Medication adherences in the 248 participants evaluated was: 74% in the oestrogen alone group (measured in 79% of participants); 84% in the combination therapy group (measured in the 84% of participants) and 86% in the placebo group (measured in 80% of participants). Additionally, five women in the placebo group initiated HT treatment outside the trial   Follow‐up times: three months, six months and then every six months thereafter. Pre‐treatment investigations included serum electrolytes, haemoglobin levels, hematocrit, platelet count and prothrombin, a 12‐lead electrocardiogram and angiogram (if needed).  Other investigations included annual mammography and gynaecological examinations, including Papanicolaou smears and endometrial aspiration or vaginal ultrasound, to detect sub‐clinical hyperplasia
Outcomes	Primary outcomes: Death from any cause Death from CVD disease Non‐fatal MI Fatal MI Stroke Angina (hospitalisation) Any CVD event Secondary outcomes: Venous thromboembolism
Notes	The sample size calculation was predicated on the ability to detect differences between groups in the primary outcome measure, change in the minimum diameter of the major epicardial segments, as assessed by quantitative coronary angiography.  It is therefore possible that the trial was not powered to detect differences between the three treatment groups on clinical events.  It is therefore not possible to state whether there is any excess risk/benefit for the use of either oestrogen alone or in combination with medroxyprogesterone acetate compared to placebo on the basis of the results reported from the trial. The control group population started treatment on average 23.1 years after their menopause with the oestrogen group starting on average 22.1 years and the combination oestrogen and medroxyprogesterone group starting 23.8 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)	Low risk	Computerised in random blocks
Allocation concealment (selection bias)	Low risk	Computer displayed treatment assignment after eligible participant details entered
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and clinicians blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	No losses to follow‐up for clinical adverse events. Analysed by ITT
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	More in unopposed oestrogen group using nitrates at baseline, otherwise prognostic balance between groups