EWPHBPE 1989.

Methods	Multi‐site randomised placebo‐controlled double‐blind trial conducted in Europe stratified by age, sex, presence or absence of cardiovascular complications, and site Study setting: hospitals (geriatric); physician offices; nursing homes
Participants	840 ambulatory patients 60 years or older 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% Ambulatory elderly patients: N = 840 (69.8% female); age range 60 to 97; mean 72.0 years; ethnicity not reported Baseline SBP/DBP was 183/101 mmHg; pulse pressure was 82 mmHg Inclusion criteria: SBP 160 to 239 mmHg and DBP 90 to 119 mmHg; mean blood pressure at entry 182/101 mmHg; pre‐existing factors: smoking 16.4%. Blood pressure (BP) entry criteria: systolic BP 160 to 239 mmHg and diastolic BP 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 disease 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 to 50 mg + triamterene 50 to 100 mg daily Step 2 ‐ methyldopa 250 to 2000 mg daily Control: placebo
Outcomes	Total mortality ‐ death from any cause Cardiovascular mortality ‐ CHD mortality plus cerebrovascular mortality CHD (coronary heart disease) mortality ‐ fatal myocardial infarction and ischaemic heart disease, sudden death and fatal arrhythmia, fatal heart failure Cerebrovascular mortality ‐ fatal stroke Dropouts due to side effects: not stated Quality of life or functional outcomes: not stated
Notes	Percentage not on assigned therapy at study end: placebo group > 35%; treatment group > 35% Difference in blood pressure at study end (Treatment ‐ Control) systolic/diastolic: ‐22/‐10 mmHg Information was obtained for subgroups from publications using individual patient data from the INDANA database (Gueyffier 1999) Data were available for mortality outcomes only but not for cardiovascular events, cerebrovascular events, or CHD events in 60 to 79 or 80 years or older subgroups; therefore overall data for 60 years or older available for the first‐line drugs for hypertension review have been used. Cardiovascular mortality and morbidity outcome does not include TIA
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear 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 randomisation was utilised but method of random allocation was not stated
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported
Blinding of participant and personnel (performance and detection bias)	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	Low risk	Quote: "data were sent to the coordinating 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" Comment: 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 intercurrent illnesses (mainly neoplasms). Withdrawal was less frequent in the actively treated group" "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 yr, 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‐eg, 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 were 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% of patients in the placebo group and 14.2% of those in the treatment group were lost to follow‐up. Data on non‐fatal events in patients who dropped out of the trial were not available
Selective reporting (reporting bias)	High risk	Participants were censored if they had "one of the specific study terminating events, including death, non‐fatal 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 terminating fatal events (cardiovascular, non‐cardiovascular, non‐renal, renal, and other causes) as well as non‐fatal, morbid cardiovascular terminating events and non‐fatal, non‐morbid cardiovascular terminating events were reported in the results section, censoring of participants led to high risk of bias
Industry sponsorship 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, this study was not funded by the manufacturer