WAVE 2002Low.

Methods	Women's Angiographic Vitamin and Estrogen Trial (WAVE). Randomised, double blind, placebo‐controlled trial with two‐by‐two factorial design.
Participants	Country: United States of America and Canada. Number of participants randomised: 423 women mean age 65 years. Inclusion criteria: postmenopausal women as defined by any one of the following criteria: (bilateral oophorectomy at any age or age 45 to 55 with FSH 40 mIU/ml or older than 55 years. Protocol angiogram within four months performed while haemodynamically stable demonstrating at least one vessel segment free of intervention, with 15 to 75% stenosis. If the angiogram was performed within two weeks of a myocardial infarction, the qualifying segment may not be the infarct segment. Exclusion criteria: oestrogen replacement therapy within the past three months. Estrogen vaginal cream permitted if used no more than 25% of the time. Concurrent use of vitamins C and E exceeding the recommended dietary allowance, history of breast cancer or mammogram suggestive of cancer without subsequent negative biopsy, history of endometrial carcinoma without subsequent hysterectomy, any abnormal uterine bleeding or endometrial hyperplasia at baseline, pap smear with dysplasia of cervical intraepithelial neoplasia grade I or greater, uncontrolled diabetes or hypertension, myocardial infarction less than four weeks prior to randomisation, planned or prior coronary artery bypass grafting, fasting triglycerides 500 mg/dl within four months of randomisation, creatinine 2.0 mg/dl, symptomatic gallstones, New York Heart association class IV congestive heart failure or known ejection fraction 25%, history of haemorrhagic stroke or bleeding diathesis, history of pulmonary embolism or idiopathic deep venous thrombosis, history of osteoporosis unless treated with nonhormonal therapy, anticipated survival three years, concurrent participation in other masked clinical trial, participation in an interventional device trial or short‐term postangioplasty antithrombotic trial was permitted so long as follow‐up angiography was not a requirement of that trial.
Interventions	The participants were randomly assigned to receive: group 1: vitamins (vitamin E 400 IU and vitamin C 500 mg) and hormone replacement therapy (HRT) placebo (n = 105); group 2: HRT (women with a prior hysterectomy took one tablet containing conjugated equine estrogens (0.625 mg of Premarin, while the women who had not had a hysterectomy took one tablet containing conjugated equine estrogens and medroxyprogesterone acetate (0.625 mg/2.5 mg of Prempro) and vitamins placebo daily (n = 103); group 3: vitamins C and E and HRT (n = 107); group 4: vitamin placebo and HRT placebo (n = 108); twice daily for a median of three years.
Outcomes	The primary outcome measure was: annualised mean change in minimum lumen diameter from baseline to concluding angiogram of all qualifying coronary lesions averaged for each patient. Patients with intercurrent death or myocardial infarction were imputed the worst rank of angiographic outcome.
Notes	Compliance with treatment was checked by serum assessments. Among the women with angiographic follow‐up, those assigned to HRT took 67% of their prescribed medication according to pill counts, and those assigned to HRT placebo took 70%. The corresponding figures were both 84% for antioxidant vitamins and vitamin placebo. Nine women assigned to placebo oestrogen crossed over to open‐label oestrogen, and one woman assigned to placebo vitamin supplements crossed over to open‐label vitamins. Twenty‐three participants from the placebo group and 29 from the HRT group, 38 from the vitamins, and 27 from the HRT and vitamin group withdrew from the trial. Hormone replacement drugs supplied by Wyeth Pharmaceuticals, Collegeville, Pa.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)	Low risk	Allocation was controlled by a central and independent randomisation unit, so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias) All outcomes	Low risk	The trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)	Low risk	Pre‐defined, or clinically relevant and reasonably expected outcomes are reported on.
Other bias	Low risk	The trial appears to be free of other components that could put it at risk of bias.