HYVET 2008.

Methods	Randomized double‐blind placebo‐controlled multisite 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 four systolic blood pressure measurements taken at the second and third visits (two 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, unable to stand up, require BP lowering treatment for reasons other than hypertension e.g. angina, peripheral ischemia, gout, renal artery stenosis, those with 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: 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 patients not on assigned therapy at study end: active treatment 0.8%, placebo 0.6%. Corresponded with the author for missing information.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization: Sequence generation was not reported. Randomization 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 patients were used to ensure roughly equal assignment to each of the two groups within large centres. Comment: method used for randomization was not mentioned. Baseline characteristics were similar in the two groups
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 participants and personnel (performance bias) All outcomes	Low risk	The main trial was a randomized, double‐blind, placebo‐controlled trial. Patients and providers were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The Endpoint Committee will provide an objective blinded evaluation of previously defined endpoints." "All events that were possible endpoints were reviewed by an independent committee, unaware of the group assignment, using predefined definitions from the protocol." Comment: outcome assessment done in an independent manner and outcome assessor was 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 patients 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 loss to follow‐up and ITT analysis used
Selective reporting (reporting bias)	High risk	All the primary and secondary outcomes mentioned in the objectives were reported in the results. Could not extract the number of patients in each group that had nonfatal myocardial infarctions. Correspondence with the 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 analyzed? 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 those 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 nonfatal stroke), then it was.
Other 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 doctors received consulting fee and speakers' fees from the pharmaceutical companies, although the research received grants from the British Heart Foundation and the Institut de Recherches Internationales Servier.