EWPHE 1985.

Methods	Multisite randomized, placebo‐controlled, double‐blind trial conducted in Europe, stratified by age, sex, presence or absence of cardiovascular complications, and site.
Participants	840 ambulatory elderly patients; 69.8% female; age range: 60 to 97; mean: 72.0 years; Ethnicity not reported. Baseline SBP/DBP was 183/101 mmHg and pulse pressure was 82 mmHg. Geographic region: Europe (Belgium (25%), United Kingdom (19%), Finland (17%), France (14%), Italy (7%), The Netherlands (7%), Ireland (6%), Portugal (3%), Norway (2%), West‐Germany (1%). Study setting: hospitals (geriatric); physician offices; nursing home. Inclusion criteria: SBP 160 to 239 mmHg and DBP 90 to 119 mmHg Exclusion criteria: curable causes of high blood pressure; certain complications of hypertension (i.e. retinopathy grade III or IV, congestive heart failure, history of cerebral or subarachnoid haemorrhage); concurrent diseases, such as hepatitis or cirrhosis, gout, malignancy, and diabetes mellitus requiring insulin treatment Follow‐up: 7 years. Average follow‐up: placebo 4.63 years; treatment 4.69 years
Interventions	Treatment: Step 1 ‐ hydrochlorothiazide 25 mg to 50 mg + triamterene 50 mg to 100 mg daily; Step 2 ‐ methyldopa 250 mg to 2000 mg daily Control: matching placebo
Outcomes	Mortality, stroke, CHD, CHF, systolic BP and diastolic BP Dropouts due to side effects: not stated Quality of life or functional outcomes: not stated
Notes	Only ITT data included. Difference in blood pressure at study end (Treatment ‐ Control) systolic/diastolic: ‐22/‐10 mmHg Percentage of participants not on assigned therapy at study end: placebo group: > 35%; treatment group: > 35%
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The 840 patients were randomised to placebo (N = 424) or active treatment (N = 416). The placebo and active treatment groups were similar in sex ratio, age, sitting blood pressure at randomisation, weight, and percentage with cardiovascular complications on admission to the trial." Comment: stratified randomization was utilized but method of random allocation was not stated. Baseline characteristics were matched.
Allocation concealment (selection bias)	Low risk	Stratified randomization was utilized but method of random allocation was not stated. Baseline characteristics were matched.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "A double‐blind randomised placebo‐controlled trial of antihypertensive treatment was conducted in patients over the age of 60." "Tablets and matching placebos are identical in shape, taste and colour." Comment: both patients and physicians were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Data were sent to the co‐ordinating office every three months on specially designed forms, and deaths and other terminating events were classified independently by two investigators into previously agreed categories. These investigators were not aware of the treatment group to which the patients had been assigned. After leaving the double‐blind part of the trial, the surviving patients were followed up until July 1984, but only date and cause of death were recorded." Comments: outcome assessors were blinded.
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "The intention‐to‐treat analysis was restricted to the cause and date of death because data on non‐fatal events in patients who dropped out from randomised treatment were not available." "During randomised treatment 128 patients defaulted from follow‐up and 52 refused to continue their randomised treatment for various reasons, but continued to attend. 38 patients were withdrawn from randomised treatment because of serious inter current illnesses (mainly neoplasms). Withdrawal was less frequent in the actively treated group (P = 0.022)." "One centre with 21 patients withdrew from the trial before its end. In another centre, the double‐blind phase was terminated in 29 patients, each followed for 5 years, because this was the duration to which the patients had agreed. 11 patients were withdrawn from randomised treatment by the local investigators owing to a moderate increase in blood pressure that did not, however, reach the previously established study‐terminating criteria. Similarly, 17 patients were withdrawn by the local investigators on discovery that the patients were no longer hypertensive during a brief period without treatment. In 6 patients, the treatment code was broken, e.g. at the request of an anaesthetist. 2 patients had treatment stopped in error, and 2 others were withdrawn because the double‐blind drug supply was not available. There were 291 patients still in the double‐blind part of the trial when it was stopped in the summer of 1984." "Both analyses on randomised treatment in the double‐blind part of the trial (on‐randomised treatment or per‐protocol analysis) and an overall intention‐to‐treat analysis was performed. The latter was confined to mortality owing to the difficulty in determining morbidity outside the period of double‐blind follow‐up." Comment: 16.3% patients in the placebo group and 14.2% in treatment group were lost to follow‐up and data on nonfatal events in patients who dropped out of the trial were not available.
Selective reporting (reporting bias)	High risk	Patients were censored if they had "one of the specific study terminating events, including death, nonfatal cerebral or subarachnoid haemorrhage, development of hypertensive retinopathy grade III or IV, dissecting aneurysm, congestive heart failure not controllable without diuretics or antihypertensive drugs, hypertensive encephalopathy, severe increase in left ventricular hypertrophy, and a rise in blood pressure exceeding the defined limits." Comment: although all the terminating fatal events (cardiovascular, non‐cardiovascular non‐renal, renal, and other causes), as well as nonfatal, morbid cardiovascular terminating events and nonfatal, non‐morbid cardiovascular terminating events were reported in the results section, censoring of patients lead to high risk of bias.
Other bias	Low risk	Quote: "This study is supported by the Belgian Hypertension Committee and the World Health Organization. Tablets of alpha methyldopa and placebo were supplied by Merck, Sharp and Dohme; capsules of hydrochlorothiazide and triamterene by Smith, Kline and French." Comment: Conflict of interest was not reported. However, it was not funded by the manufacturer.