SCOPE 2003.

Study characteristics
Methods	Multisite study. Randomisation: participants allocated by a central, computer‐generated randomisation schedule in a 1:1 ratio. Participants blinded; providers blinded; outcome assessors blinded. Eight participants lost to follow‐up. Percentage not on assigned therapy at study end: 84% control group, 75% treatment group. Duration of trial: 5 years.
Participants	Geographic region: Europe, Canada, USA and Israel. Study setting: community. N = 4964. 64% female. Age range: 70 to 89 years, average 76.4 years. Mean blood pressure at entry 166/90 mmHg. Blood pressure entry criteria: SBP 160 to 179 mmHg or DBP 90 to 99 mmHg, or both. Mini‐Mental State Examination score of 24 or above.
Interventions	Control: matching placebo. Treatment: step 1 ‐ candesartan 8 mg daily; step 2 ‐ candesartan 16 mg daily; step 3 ‐ hydrochlorothiazide 12.5 mg daily. Other drugs, except angiotensin‐converting enzyme inhibitors and AT1‐receptor blockers, could be added later. Mean duration of trial: 44.6 months. Difference in blood pressure at study end (Treatment‐Control) systolic/diastolic: ‐3.2/‐1.6 mmHg
Outcomes	Analysed in the review: blood pressure level, incidence of dementia, cognitive change measured by MMSE, incidence of side effects. Not analysed in the review: major cardiovascular events (cardiovascular deaths, non‐fatal myocardial infarction (MI), non‐fatal stroke), total mortality, fatal and non‐fatal stroke, new onset diabetes mellitus. Dropouts due to side effects (no significant difference between groups): placebo: 17%; treatment: 15%. Quality of life or functional status outcomes: both treatment regimens were well tolerated.
Notes	Exclusions: Related to hypertension: secondary hypertension, SBP > 180 mmHg, orthostatic hypotension, need for antihypertensive treatment other than hydrochlorothiazide during run‐in; stroke or myocardial infarction (MI) within 6 months; decompensated heart failure; serum AST or ALT > 3 times upper limit of normal (ULN); serum creatinine >180 µmol/L (men) or > 140 µmol/L (women); contraindication to study drug or hydrochlorothiazide; serious concomitant diseases affecting survival; alcoholism or drug abuse. Related to dementia: dementia; treatment with drugs for dementia; conditions which preclude MMSE; vitamin B12 deficiency treated < 12 months; hypothyroidism treated < 12 months; neurosyphilis or AIDS; severe brain disorder which may interfere with cognitive function; certain mental disorders; psychopharmacological treatment started within 6 months. 'Executive and Steering committees had full access to all data and were free to suggest analyses, interpret results and write ... independently of study sponsor'. Of the n = 2477 and n = 2460 in the hypertensive treatment group and placebo groups, dementia incidence was available for n = 2416 and n = 2409, respectively.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: 'Patients allocated by central, computer‐generated randomisation schedule, in a 1:1 ratio to candesartan or control treatment'.
Allocation concealment (selection bias)	Low risk	Quote: 'Patients allocated by central, computer‐generated randomisation schedule, in a 1:1 ratio to candesartan or control treatment'. 'The investigator sent fax with patient data for central randomisation and received treatment allocation (i.e. patient study number) by return fax'.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: 'All patients [received] the study drug ... or matching placebo similar in appearance and taste'. 'All suspected clinical events [were reported to] the coordinating centre ... dementia events were adjudicated by the Independent Clinical Event Committee.' 'All clinical events were strictly and prospectively defined.' 'Every person involved in the adjudication process was blinded with respect to the patient's treatment group allocation'
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: 'All patients [received] the study drug ... or matching placebo similar in appearance and taste'. 'All suspected clinical events [were reported to] the coordinating centre ... dementia events were adjudicated by the Independent Clinical Event Committee.' 'All clinical events were strictly and prospectively defined.' 'Every person involved in the adjudication process was blinded with respect to the patient's treatment group allocation'
Incomplete outcome data (attrition bias) All outcomes	Low risk	6 in treatment group and 2 in control group lost to follow‐up at study end; included in intention‐to‐treat analysis. 27 excluded of 4964 randomised (all 13 at 1 centre due to concerns on individual participant data; 14 ‐ no study drug dispensed).
Selective reporting (reporting bias)	Low risk	Outcomes specified in protocol reported.
Other bias	High risk	84% of participants in the placebo group ended the study on an antihypertensive agent (not ACE or ARB) to ensure the ethical treatment of hypertension. Comment: Fewer than anticipated events and lower between group differences in BP reduced power of study to detect outcome differences.