WELL‐HART 2003.

Methods	Multicentre randomised, double‐blinded, placebo‐controlled trial run at 5 centres in North America. It was run from June 1995 to October 2000 and was designed to test the effects of oral micronised 17β‐oestradiol with or without sequential administered medroxyprogesterone acetate, compared to control, on the progression of atherosclerosis in postmenopausal women with angiographically documented coronary artery disease. Participants were stratified according to the presence or absence of diabetes Recruitment: Not reported Screening: Not reported Randomisation: Computerised random number generator in the data coordinating centre used and adaptive randomisation was used to correct for imbalances between treatment groups in total cholesterol Stratification: According to diabetes status Allocation: not reported Baseline equality of treatment groups: The age in the oestrogen treatment group was significantly lower than the other two treatment groups (P=0.02). Otherwise there were no substantive differences between groups Blinding: The participants, gynaecologists, clinical staff and image analysts were all blinded to treatment assignment Analysis:Only those who could be quantified by quantitative coronary angiography were included Funding Source: NHLBI, Mead Johnson laboratories and Pharmacia and Upjohn
Participants	226 postmenopausal women who had at least one coronary artery lesion. The mean age of the participants were: 64.2 years in the control group (SD 6.2), 61.8 years in the oestrogen group (SD 6.7) [E] and 64.4 years in the oestrogen‐progestin group (SD 6.4) [EP] P = 0.02 Years since menopause: 18.3 years in the control group (SD 10.5), 16.7 years in the oestrogen group (SD 10.3) [E] and 19.7 years in the oestrogen‐progestin group (SD 10.5) [EP] P = 0.23 CVS Risk Factors Smoking status: P = 0.55 Current smoker:7 (9%) [control], 11 (14%) [E], 8 (11%) [EP] Former smoker: 28 (37%) [control], 27 (36%) [E], 34 (46%) [EP] Never smoked: 41 (54%) [control], 38 (50%) [E], 32 (43%) [EP] Diabetes: 40 (53%) [control], 38 (50%) [E], 37 (50%) [EP] P = 0.93 Blood pressure – systolic: 141.6 (SD 22.4) [control], 138.1 (SD 21.7) [E], 142.3 (SD 24.6) [EP] P = 0.49 Blood pressure – diastolic: 75.9 (SD10.5) [control], 76.5 (SD 11.1) [E], 75.3 (SD 12.5) [EP] P = 0.82 BMI: 30.0 (SD 5.4) [control], 30.6 (SD 5.6) [E], 30.2 (SD 5.6) [EP] P = 0.83 Inclusion criteria: Post‐menopausal (as indicated by a serum oestradiol level below 20 pg per millilitre) 75 years or younger LDL level of 100 to 250 mg per decilitre (2.59 to 6.46 mmol/L) total triglyceride level of less than 400 mg per decilitre (4.52 mmol/L) at least one coronary‐artery lesion occluding 30 percent or more of the luminal diameter Women who had undergone PTCA were eligible if they had at least 20 % stenosis in a segment of a coronary artery that was not crossed by the guidewire used for angioplasty Women who had undergone CABG were eligible if they had at least 20 % stenosis in a segment of a coronary artery which was not proximal to a patent graft Exclusion criteria: women who smoked > 15 cigarettes per day a diagnosis of breast cancer or gynaecological cancer within 5 years before screening a life‐threatening disease and a projected survival of less than 5 years a diastolic blood pressure > 110 mm Hg a fasting glucose of more than 200 mg per decilitre thyroid disease a serum creatinine more than 2.5 mg per decilitre (220 µmol/L) heart failure (Killip class III or IV and an ejection fraction below 30%) more than five hot flushes per day which interfered with their daily activities plans to undergo revascularisation within six months of the screening visit baseline coronary angiogram obtained before or less than six months after a revascularisation procedure a MI less than six weeks before the screening visit
Interventions	HT regimen: 1 mg of oral micronised 17β‐oestradiol [E] (Estrace, Mea Johnson) daily, plus a placebo tablet matching medroxyprogesterone acetate for 12 consecutive days of every month HT regimen 2: 1 mg of oral micronised 17β‐oestradiol (Estrace, Mea Johnson) daily, plus 5 mg medroxyprogesterone acetate [P] (Provera, Upjohn) for 12 consecutive days of every month Comparator: two placebo tablets, one matching each of the active drugs for 12 consecutive days of every month
Outcomes	Primary outcomes: Average (per‐participant) change from baseline in the percent stenosis in all lesions evaluated by quantitative coronary angiography Secondary outcomes: Average (per‐participant) change in minimal luminal diameter (on quantitative angiography) Global change score
Notes	LDL was reduced to a target of less than 130 mg per decilitre (3.36 mmol/L) by means of dietary intervention and lipid lowering therapy (usually with a statin) Follow‐up times: median duration 3.3 years Medication compliance: P = 0.28 Control group: 93.6% with oestrogen matched placebo and 98.4% with progestin matched placebo Oestrogen group: 92.6% with oestrogen and 99.9% with progestin matched placebo Oestrogen‐Progestin group: 94.1% with oestrogen and 96.1% with progestin Participants were assessed with visits every month for the first six months and then every other month up until 36 months Methods for verifying medication compliance by pill counts at study visits The number who dropped out or swapped medication: not clear, though four participants used open‐label oestrogen The mean time since menopause that treatment was started for the study population overall was 18.2 years. 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	Stratification according to the presence or absence of diabetes Randomisation with the use of a computerised random‐number generator Adaptive randomisation was used for imbalances among the treatment groups in the total cholesterol
Allocation concealment (selection bias)	Low risk	Data co‐ordinating centre performed randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, gynaecologists and clinical staff were blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Image analysts were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	44 participants dropped out between different treatment groups but in comparable numbers between groups (11 in the control group, 17 in the oestrogen group and 16 in the oestrogen‐progestin group). The reasons for dropping out included: death (n = 5), medical problems (n = 7), open‐label use of oestrogen therapy (n = 4), loss of follow‐up (n = 5) and personal reasons (n = 23)
Selective reporting (reporting bias)	Low risk	No prior published design paper All outcomes specified in current paper were reported
Other bias	Unclear risk	Death and cardiovascular outcomes were not prespecified as outcomes for this study but were reported afterwards as adverse events