HYVET 2008.

Study characteristics
Methods	Multisite study. Randomisation: stratified by age, sex, and centre. Participants randomly allocated through interactive voice response system setup by coordinating centre. Participants blinded; investigators blinded; outcome assessors blinded. Planned duration: 5 years.
Participants	Geographic region: Europe, China, Australasia, Tunisia. 195 centres in 13 countries. Study setting: community. N = 3845 (60.5% female). Age: ≥ 80 years, mean 83.6 years. Ethnicity: not reported; 86 western Europe, 2144 eastern Europe, 1526 China, 19 Australasia, 70 Tunisia. Mean sitting blood pressure (BP) at entry: 173.0/90.8 mmHg. BP entry criteria: sustained systolic BP 160 to 199 mmHg (1 month apart); standing systolic BP > 140 mmHg; sitting diastolic BP 90 to 109 mmHg (protocol amendment 2003 < 110 mmHg). Of the total n = 3845 HYVET population (n = 1933 hypertensive treatment group, n = 1912 placebo), n = 3336 were recruited into HYVET COG (n = 1687 hypertensive treatment group, n = 1649 placebo).
Interventions	Minimum 2 month single daily placebo tablet run‐in phase with all other antihypertensive treatment stopped. Treatment: step 1 ‐ indapamide SR 1.5 mg/day; step 2 ‐ indapamide SR 1.5 mg/day and perindopril 2 mg/day; step 3 ‐ indapamide SR 1.5 mg/day and perindopril 4 mg/day. Control: matching placebos. Target sitting systolic BP < 150 mmHg and diastolic < 80 mmHg (sitting systolic BP ≥ 150 mmHg accepted if standing systolic BP < 120 mmHg). Average follow‐up: median 1.8 years (mean, 2.1; range, 0 to 6.5). Difference in BP at end of study (treatment ‐ control) systolic/diastolic: ‐15.0/‐6.1 mmHg (sitting).
Outcomes	Analysed in the review: blood pressure level; incidence of dementia; change in cognitive function (measured by MMSE); incidence of side effects. Not analysed in the review. Primary: fatal and non‐fatal stroke. Secondary: total mortality; cardiovascular mortality; cardiac mortality; stroke mortality; skeletal fracture rate. Other outcomes: incidence of retinal lesions; overt heart failure; renal failure; dissecting aortic aneurysm; acute myocardial infarction (MI). Cognitive function outcomes not specified in original trial protocol.
Notes	Exclusion criteria: known accelerated hypertension; overt clinical congestive heart failure, requiring treatment with diuretic or ACE inhibitor; renal failure (serum creatinine > 150 μmol/L); documented cerebral or subarachnoid haemorrhage in previous 6 months; condition expected to severely limit survival; known secondary hypertension; gout; clinical diagnosis of dementia; nursing home residence; contraindication to trial medication (serum potassium < 3.5 µmol/L or > 5.5 µmol/L); inability to stand or walk. Overall HYVET trial: % not on assigned treatment at 2 years: 0.8% active treatment; 0.6% control group. Of the n = 1687 hypertensive treatment group, n = 1649 placebo recruited to HYVET COG 96 died and 141 declined to continue and 132 died and 146 declined to continue in the two groups respectively, with 5 lost to follow‐up in each group. Due to early termination of the trial, not all participants reached at least one year of follow‐up. Of the n = 3336, only n = 1469 (i.e. 44%) attended their 2‐year follow‐up visit.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: 'Randomisation was stratified according to age and sex; permuted blocks of 4 and 6 of any 10 patients used to ensure roughly equal assignment to each of the two groups within large centres'
Allocation concealment (selection bias)	Low risk	Quote: 'when the coordinating centre has received the entry form on a patient and checked they are eligible, they inform the interactive voice response system (IVRS) to permit randomisation according to schedule. The IVRS then automatically, in real‐time, faxes the centre to inform them that their patient is eligible to enter the trial and that the local investigator can make a call to the system to receive number of the treatment pack that their patient is to receive'
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Active treatment and matching placebo. Allocation concealed from investigator and participant.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Active treatment and matching placebo. Allocation concealed from investigator and participant. End‐Points Committee blinded to treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: 'Data from patients were analysed for the groups to which the patients were assigned, regardless of which study drugs (or which doses) the patients actually received and regardless of other protocol irregularities. Patients from closed centres were included in intention‐to‐treat population and contributed (data) up to the date of closure of the centre'. In the hypertensive treatment group, 303/1687 participants did not complete the study, of which five were lost to follow‐up. In the placebo group, 343/1649 did not complete the study of which, again, five were lost to follow‐up. Comment: Similar numbers for each event for which data were censored between treatment and placebo groups. Only 44% of participants completed a 2‐year follow‐up visit. Quote: 'repeating the analyses with all patients, regardless of whether they had more than one cognitive function assessment, did not affect the results'. Shorter duration of study more of an issue than attrition bias.
Selective reporting (reporting bias)	Low risk	Outcomes specified in the protocols reported in the main results and cognitive sub‐study.
Other bias	Low risk