HYVET 2008.

Methods	Multisite study. Randomization: stratified by age, sex, and centre. Participants randomly allocated through interactive voice response system setup by coordinating centre. Patients blinded; investigators blinded; outcome assessors blinded. Planned duration: 5 years. Lost to follow‐up: 6 in active treatment; 11 in control group. % not on assigned treatment at 2 years: 0.8% active treatment; 0.6% control group.
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: 173.0/90.8mmHg. BP entry criteria: sustained systolic BP 160‐199mmHg (1 month apart); standing systolic BP >140mmHg; sitting diastolic BP 90‐109mmHg (protocol amendment 2003 <110mmHg).
Interventions	Minimum 2 month single daily placebo tablet run‐in phase with all other antihypertensive treatment stopped. Treatment: step 1 ‐ indapamide SR 1.5mg/day; step 2 ‐ indapamide SR 1.5mg/day and perindopril 2mg/day; step 3 ‐ indapamide SR 1.5mg/day and perindopril 4mg/day. Control: matching placebos. Target sitting systolic BP<150mmHg and diastolic<80mmHg (sitting systolic BP ≥150mmHg accepted if standing systolic BP <120mmHg). Average follow‐up: median 1.8 years (mean, 2.1; range, 0‐6.5). 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 >150μmol/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 <3.5mmol/l or >5.5mmol/l); inability to stand or walk. Funding: British Heart Foundation and the Institut de Recherches Internationales Servier.
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	'patients underwent randomization, provided all inclusion and exclusion criteria were met. Randomization stratified according to age and sex; permuted blocks of 4 and 6 of any 10 patients used to ensure roughly equal assignment to each group within large centres'
Allocation concealment?	Low risk	'when coordinating centre has received entry form and checked they are eligible, they inform interactive voice response system (IVRS) to permit randomization according to schedule. IVRS automatically faxes, in real‐time, centre to inform that patient is eligible and that local investigator can call system to receive number of treatment pack patient is to receive'
Blinding? 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 addressed? All outcomes	Low risk	'data analyzed for the groups to which patients were assigned, regardless of which study drugs (or doses) patient actually received and regardless of other protocol irregularities. Patients from closed centres were included in intention‐to ‐treat population and contributed (data) up to date of closure' Comment: Similar numbers for each event for which data were censored between treatment and placebo groups.
Free of selective reporting?	Low risk	Outcomes specified in the protocols reported in the main results and cognitive substudy.
Free of other bias?	High risk	Study was stopped early based on the significant reduction in the primary outcome at prespecified interim analysis by independent data monitoring committee. Comment: The shorter than planned follow‐up may bias ability to detect effect of treatment on cognitive change and dementia.