Syst Eur 1997.

Methods	Multisite study. Randomization: stratified by centre, sex and previous cardiovascular complications. Patients randomly allocated to placebo or active treatment by a centralised system or local computer system. Patients blinded; providers blinded; outcome assessors blinded. Study duration: 5 years. Lost to follow‐up: 2% at 2 years. % not on assigned therapy at study end (2 years) including open follow‐up and lost to follow‐up: placebo group: 27%; treatment group: 18%
Participants	Geographic region: 23 countries across western and eastern Europe, mainly from Finland, Bulgaria, the Russian Federation, Belgium, Italy, Israel, UK, France, Estonia, Lithuania, Spain, Poland and Romania. Study setting: community based and referral clinic. n = 4695 (66.8% female) Age range: ≥60 years; mean 70.3 years. Race: not reported. Mean BP at entry: 174/86 mmHg. BP entry criteria: sitting systolic BP 160‐219 mmHg and sitting diastolic BP< 95 mmHg. Standing systolic BP at least 140 mmHg.
Interventions	Treatment: Step 1 ‐ nitrendipine 10‐40 mg/day; Step 2 ‐ enalapril 5‐20 mg/day and/or hydrochlorothiazide 12.5‐25 mg/day. Control: matching placebos with stepped therapy schedule similar to treatment groups. Mean daily doses: nitrendipine 28.2 mg; enalapril 13.5 mg; hydrochlorothiazide 21.2 mg. Average follow‐up: 2 years (median). Difference in blood pressure at end of study (Treatment ‐ Control) systolic/diastolic: ‐10.1/‐4.5 mmHg at 2 years.
Outcomes	Analysed in the review: Blood pressure level. Not analysed in the review: Total mortality; coronary heart disease (CHD) mortality; CHD morbidity and mortality (M&M); cerebrovascular mortality; cerebrovascular M&M; cardiovascular mortality; cardiovascular M&M. Dropouts due to side effects (no significant difference between groups): placebo: < 7.3%; treatment: < 7.8%. Quality of life or functional status outcomes: Across 4 years of follow‐up, patients receiving active treatment were more likely to report problems on the Social Interaction scale than placebo treated patients (OR 1.32, 95% CI 1.02, 1.69). There were no significant differences between active and placebo treatment in the other Sickness Impact Profile dimensions or in the measure of depression.
Notes	Exclusions: hypertension secondary to a disorder that needed specific medical or surgical treatment; retinal haemorrhage or papilloedema; congestive heart failure; dissecting aortic aneurysm; serum creatinine concentration at presentation of 180 micromols/l or more; history of severe nose bleeds, stroke or MI in the year before the study; dementia; substance abuse; any disorder prohibiting a sitting or standing position; any severe concomitant or non‐cardiovascular disease.
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	'After stratification by centre, sex, and previous cardiovascular complications, ... randomly assigned eligible patients ... by means of a computerised random function.'
Allocation concealment?	Low risk	'Randomization by coordinating centre of patients satisfying all entry criteria and in whom none of the exclusion criteria are present'
Blinding? All outcomes	Low risk	'Placebo tablets were identical to study drugs, with similar schedule'. 'Endpoint committee was unaware of patients treatment status'
Incomplete outcome data addressed? All outcomes	Low risk	Open follow‐up of patients who withdrew from treatment; if this was not possible, data collected annually on vital status, endpoints and antihypertensive medication use. Comment: Similar numbers of non‐supervised open and lost‐to follow‐ups in each group; higher number of supervised open follow‐ups in placebo group.
Free of selective reporting?	Low risk	Prespecified outcomes reported
Free of other bias?	High risk	Study stopped early after second prespecified interim analysis found significant decrease in primary outcome (stroke) in active treatment group. 144 subjects in placebo group and 72 subjects in active treatment group taking open‐label antihypertensives at final visit.