WAVE 2002.

Methods	Objective:  To determine whether HT or antioxidant vitamin supplements, alone or in combination, influence the progress of coronary artery disease in post‐menopausal women as measured by angiography.   Multicentre, 2 x 2, randomised, factorial, placebo‐controlled (RCT) trial involving seven hospital sites; five in the United States and two in Canada.  The trial recruitment was conducted from July 1997 to July 1999), with a mean follow‐up of 2.8 (SD: ± 0.9 years.  The primary aim of the trial was to assess the effects of oestrogen and/or progestin with or without antioxidant vitamins for preventing angiographic progression of coronary artery disease. Coronary artery disease was defined as having al least one coronary segment with stenosis of ≥ 15% and 75% in a vessel ≥ 2 mm in diameter at baseline, with the angiograph conducted within four months of trial recruitment.  The primary outcome was therefore change in the minimum lumen diameter (MLD) of the vessels from baseline, as assessed by quantitative coronary angiography at follow‐up. Clinical CVD events and health related quality of life were all assessed as secondary outcomes   Recruitment: Recruited at clinical sites in USA and Canada Screening: Not reported Randomisation: Computer‐randomised, permuted block design with random blocks of two and four Stratification: Clinical centre, hysterectomy status Allocation: Remotely by phone call to study co‐ordinating centre Baseline equality of treatment groups: Higher prevalence of diabetes and higher fasting blood glucose levels in the HT group Blinding: Participants, investigators and staff at clinical centres blinded except (when necessary) the study gynaecologist.  Adverse effects managed by gynaecologist not involved in outcome assessment who had access to treatment assignment if necessary, with permission of coordinating centre (unblinding). Analysis: No (98% of women analysed by ITT). Funding Source: National Heart, Lung and Blood Institute contract, General Clinical Research Center grant, USA.
Participants	Four hundred and twenty‐three post‐menopausal women with angiographically verified coronary disease were randomised to receive either (1) daily conjugated oestrogen alone for participants who had undergone a hysterectomy; (2) daily conjugated oestrogen in combination with medroxyprogesterone acetate; (3) vitamins E and C, or (4) placebo. Post‐menopausal status was defined as having bilateral oophorectomy at any age, being younger than 55 years old with a follicle‐stimulating hormone level of 40 IU/ml or higher, or being older than 55 years.  Included women were 66% White and 34% non‐White (Black or other; specific origins not reported). In terms of risk factors for CVD: 37% had diabetes; 76% had hypertension; 39% were current smokers; 43% had suffered a previous MI, and 37.5% were current HT users.  The mean BMI was 30.7 kg/m2; mean systolic blood pressure was 139 (SD: 21) mm Hg and the mean diastolic blood pressure 76 (SD: 10.5) mm Hg. The HT and placebo HT groups were well‐balanced in terms of baseline characteristics, apart from the exception of the active HT group having a statistically significantly higher prevalence of diabetes and higher fasting blood glucose levels   Exclusion criteria: Use of oestrogen replacement therapy within the past three months apart from oestrogen vaginal cream if used no more than 25% of the time use of vitamins C and E exceeding the recommended dietary allowance and unwillingness to stop taking them evidence of potential breast, uterine, or cervical cancer; any abnormal uterine bleeding or endometrial hyperplasia at baseline MI less than four weeks prior to randomisation prior or planned coronary artery bypass graft surgery fasting triglycerides levels higher than 500 mg/dL (5.65 mmol/L) creatinine level higher than 2.0 mg/dL (176.8 µmol/L0) symptomatic gallstones New York Heart Association class IV congestive heart failure or a left ventricular ejection fraction known to be less than 25% history of hemorrhagic stroke, bleeding diathesis, pulmonary embolism, idiopathic deep venous thrombosis, or untreated osteoporosis
Interventions	HT regimens: 1)  0.625 mg conjugated equine oestrogen daily plus placebo for women who had undergone a hysterectomy (continuous dosage regimen). 2)  0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate daily plus placebo for women who had not undergone a hysterectomy (continuous dosage regimen). 3)  400 IU vitamin E twice daily (800 IU) plus 500 mg vitamin C twice daily (1 g) Comparator: two placebo tablets daily. Adherence to treatment: Evaluated for 159/211 who had angiographic follow‐up: HT group took 67% of medication, placebo group took 70%; 9/108 women in placebo group crossed to open‐label oestrogen   Losses to follow‐up: Five (three in HT group, two in placebo group)   Follow‐up times: Baseline, three months, and then every six months. Patients underwent a coronary angiography at baseline and trial exit.  Other investigations performed at baseline were: 12‐lead electrocardiogram; breast and pelvic examinations, mammography, Papanicolaou smears and fulfilment of the five health‐related quality of life questionnaires (HRQoL). Baseline assays included: fasting glucose, insulin, HbA1c, fibrinogen, lipid profile, vitamins C and E and estrone. HRQoL questionnaires: Five HRQoL questionnaires were completed at baseline and at 18 months by participants. The specific questionnaires completed were: (1) the Medical Outcome Study Short Form (SF‐36); (2) Centre for Epidemiological Studies‐Depression Scale; (3) Seattle Angina Questionnaire; (4) Duke Activity Scale Index, and (5) The Medical Outcomes Study Sleep Questionnaire
Outcomes	Mean change from baseline in MLD of all qualifying angiographic segments Death from any cause Death from CVD Non‐fatal MI Stroke Secondary outcomes: Deep vein thrombosis Health‐related quality of life
Notes	The sample size calculation was predicated on the ability to detect differences between groups in the primary outcome measure, change in the minimum lumen diameter of all qualifying angiographic segments, as assessed by quantitative coronary angiography. The trial was therefore not powered to detect differences in CVD clinical events between the treatment groups. Additionally, as the factorial design revealed no interactions between treatment groups, results for the two HT versus placebo treatment groups (i.e. oestrogen alone or oestrogen in combination with progestin) were pooled and presented as aggregate numbers of 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. Data were not published regarding the time that treatment was started in relation to the menopause or what age the menopause took place. The study author was contacted and advised that these data would be available from NIH. NIH were contacted but as yet these data have not been released. The mean age of study participants was reported, 65 years (SD 9) in the active group and 66 years (SD 9) in the control group. 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	Computer randomised, permuted block design with random blocks of two and four
Allocation concealment (selection bias)	Low risk	Remotely by phone call to study coordinating centre
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, investigators and staff at clinical centres blinded except (when necessary) the study gynaecologist
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants, investigators and staff at clinical centres blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Losses to follow‐up five (three in HT group, two in placebo group), 98% of women analysed by intention to treat
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Unclear risk	Groups balanced at baseline, apart from HT group had a higher prevalence of diabetes and higher fasting blood glucose levels