HYVET 2008.

Methods	Randomised double‐blind placebo‐controlled multi‐site outpatient study conducted in Western Europe (86 patients), Eastern Europe (2144), China (1526), Australasia (19), and Tunisia (70)
Participants	3845 participants (61% women); age range 80 to 105; mean age = 84 years Pre‐existing factors: cardiovascular disease = 12.0%; hypertension = 89.9%; antihypertensive treatment = 64%; stroke = 6.8%; myocardial infarction = 3.1%; diabetes = 6.8%; heart failure = 2.9%; smoking = 6.5% Blood pressure (BP) entry criteria: mean of the 4 systolic blood pressure measurements taken at the second and third visits (2 at each visit) was between 160 and 199 mmHg. Baseline BP 173.0/90.8 mmHg. Pulse pressure 82.2 mmHg. Target BP was < 150/80 mmHg Exclusion criteria: accelerated hypertension (retinal haemorrhage, exudates, or papilledema); overt clinical congestive heart failure requiring treatment with diuretic, vasodilator, or ACE inhibitor; renal failure; documented cerebral or subarachnoid haemorrhage; condition expected to severely limit survival (e.g. terminal illness), inability to stand up, requiring BP‐lowering treatment for reasons other than hypertension (e.g. angina, peripheral); ischaemia, gout; renal artery stenosis; dementia (Mental Test score < 7/10) Follow‐up: 2.1 years (median 1.8 years)
Interventions	Treatment Step 1 ‐ indapamide 1.5 mg daily Step 2 ‐ perindopril 2 mg daily Step 3 ‐ perindopril 4 mg daily Control ‐ identical appearing placebos for each step
Outcomes	Total stroke, total coronary artery disease, total mortality, total cardiovascular events (including CHF) Dropouts due to side effects: not reported Quality of life or functional status outcomes: not reported
Notes	Difference in blood pressure at study end (Treatment ‐ Control) systolic/diastolic: sitting ‐15.0/‐6.1 mmHg, standing ‐14.7/‐5.4 mmHg. Percentage of participants not on assigned therapy at study end: active treatment 0.8%, placebo 0.6%. Corresponded with the study author to request missing information Data on mortality, cardiovascular mortality and morbidity (includes CHF but excludes TIA), cerebrovascular mortality and morbidity, and CHD mortality and morbidity are available for the 80 years or older subgroup
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation: sequence generation was not reported. Randomisation was stratified according to age (80 to 89 years and 90 years or older) and sex; permuted blocks of 4 and 6 of any 10 participants were used to ensure roughly equal assignment to each of the 2 groups within large centres Comment: method used for randomisation was not mentioned
Allocation concealment (selection bias)	Low risk	An interactive voice response system (IVRS) was employed to tell the investigator which 6‐month drug pack to prescribe
Blinding of participant and personnel (performance and detection bias)	Low risk	The main trial was a randomised double‐blind placebo‐controlled trial Comment: patients and providers were blinded
Blinding of outcome assessment	Low risk	Quote: "the Endpoint Committee will provide an objective blinded evaluation of previously defined end‐points" "All events that were possible end points were reviewed by an independent committee, unaware of the group assignment, using predefined definitions from the protocol" Comment: outcome assessment was done in an independent manner and outcome assessors were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Percentage lost to follow‐up: active treatment 0.3%, placebo 0.6%. Reported on the number of participants lost to follow‐up (16 patients) "...vital status was unknown in 17 patients..." "The primary analysis was performed according to the intention‐to‐treat principle" Comment: small losses to follow‐up; ITT analysis was used
Selective reporting (reporting bias)	High risk	All primary and secondary outcomes mentioned in the objectives were reported in the results. Cannot extract the number of participants in each group who had non‐fatal myocardial infarction Correspondence with the study author Question: "the serious adverse events noted in the publication...are the numbers the total serious adverse events OR was the first event counted and analysed? Answer: it is the total number of SAEs. Patients could contribute more than one SAE" Question: "if a patient had an event after being censored, were those events counted? If not, is it possible to see that data? Answer:it would depend on the event. If it was a recurrent endpoint, then it was not counted (e.g. a further non‐fatal stoke). If the event was a new endpoint (e.g. a fatal MI in someone who had previously had a non‐fatal stroke), then it was counted"
Industry sponsorship bias	Low risk	Quote: "supported by grants from the British Heart Foundation and the Institut de Recherches Internationales Servier. Drs Beckett and Peters and Mr Banya report receiving grant support from the Institut de Recherches Internationales Servier; Dr Staessen, consulting fees from Pfizer, Tanabe, Daiichi‐Sankyo, and Sigma‐Tau and speakers’ fees from Pfizer, Tanabe, and Bayer; Dr Anderson, consulting fees from Boehringer Ingelheim and Servier and speakers’ fees from Boehringer Ingelheim, Servier, AstraZeneca, and Sanofi‐Aventis; Dr Forette, consulting fees from Wyeth Elan, Sanofi‐Aventis, and Bristol‐Myers Squibb and speakers’ fees from Servier, AstraZeneca, and Sanofi‐Aventis; Dr Rajkumar, speakers’ fees from Schering‐Plough, Merck Sharp & Dohme, and Menarini; and Dr Bulpitt, consulting fees from Imperial College Consulting, a consultancy funded by a grant from the Institut de Recherches Internationales Servier" "No other potential conflict of interest relevant to this article was reported" Comment: some of the doctors received consulting fees and speakers' fees from the pharmaceutical companies, though researchers received grants from the British Heart Foundation and the Institut de Recherches Internationales Servier