SCOPE 2003.

Methods	Multisite study. Randomization: patients allocated by a central, computer‐generated randomization schedule in a 1:1 ratio. Patients blinded; providers blinded; outcome assessors blinded. Eight patients lost to follow‐up. % 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: 70‐89 years, average 76.4 years. Mean blood pressure at entry 166/90 mmHg. Blood pressure entry criteria: SBP 160‐179 mmHg or DBP 90‐99 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 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 MI within 6 months; decompensated heart failure; serum AST or ALT > 3 times upper limit of normal (ULN); serum creatinine >180 micromol/l (men) or >140 micromol/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. Study funding: Astra‐Zeneca. 'Executive and Steering committees had full access to all data and were free to suggest analyses, interpret results and write ... independently of study sponsor'.
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	'Patients allocated by central, computer‐generated randomization schedule, in a 1:1 ratio'.
Allocation concealment?	Low risk	'Investigators sent fax with patient data for central randomization and received treatment allocation (patient study number) by return fax'.
Blinding? All outcomes	Low risk	'Patients randomized in double‐blind fashion to receive (active treatment) or matching placebo tablet.' 'Suspected clinical events reported to coordinating centre. Adjudicated by Independent Clinical event Committee. All clinical events strictly and prospectively defined. Every person involved in adjudication ... blinded to ... allocation'
Incomplete outcome data addressed? 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 randomized (all 13 at 1 centre due to concerns on individual patient data; 14 ‐ no study drug dispensed).
Free of selective reporting?	Low risk	Outcomes specified in protocol reported.
Free of other bias?	High risk	84% of placebo group ended study on antihypertensive agent (not ACE or ARB) to ensure ethical treatment of hypertension. Comment: Fewer than anticipated events and lower between group difference in BP reduced power of study to detect outcome differences.