VA‐II 1970.

Methods	Multi‐site study Randomisation: stratified by diastolic blood pressure (i.e. 90 to 114 mmHg and 115 to 129 mmHg); group allocation determined by sealed envelope containing randomised assignment. Assignment was determined by a statistician utilising a random number table Patients blinded; providers blinded
Participants	Geographic region: United States of America Study setting: recruited from Veterans Affairs hospitals and seen in outpatient clinics n = 81 (0% female) Age range 60 to 75; mean not reported Race: white (57.6%), black (41.3%), Asian (1.1%); for entire study group (i.e. these data not reported for > 60 years subgroup) Mean blood pressure at entry: 176/103 mmHg; pre‐existing factors: not reported Blood pressure (BP) entry criteria: diastolic BP 90 to 114 mmHg Exclusions: severe hypertension; surgically curable hypertension; uremia; concomitant fatal diseases such as carcinoma; haemorrhages, exudates, or papilledema in the optic fundi; history of cerebral or subarachnoid haemorrhage; dissecting aneurysm; congestive heart failure resistant to digitalis and mercurial diuretics; patients who wished to return to the care of their private physicians; patients unable to attend clinic regularly; patients of dubious reliability such as alcoholics, vagrants, and poorly motivated patients
Interventions	Treatment Step 1 ‐ hydrochlorothiazide 50 mg and reserpine 0.1 mg twice daily Step 2 ‐ hydralazine 25 mg 3 times daily up to 150 mg/d Control ‐ placebo Average follow‐up: 3.3 years
Outcomes	Coronary heart disease (CHD) morbidity and mortality (M&M) ‐ myocardial infarction or sudden death Cerebrovascular M&M ‐ cerebrovascular accidents Cardiovascular M&M ‐ CHD M&M plus cerebrovascular M&M plus congestive heart failure and aneurysms Dropouts due to side effects: for entire study group (i.e. these data not reported for > 60 years of age subgroup) Control group: 3.1%; treatment group: 5.9% Quality of life or functional status outcomes: not reported
Notes	Difference in blood pressure at study end (Treatment ‐ Control) diastolic: ‐17 mmHg; systolic: ‐27 mmHg % lost to follow‐up: 14.7% for entire study group (i.e. these data not reported for > 60 years of age subgroup) % not on assigned therapy at study end: not reported "The study was terminated in the subgroup of 143 patients whose diastolic blood pressures averaged 115 through 129 mm Hg prior to randomization. Termination of the study of this group as previously reported was necessitated by the high incidence of morbid events in the control as compared to the treated patients, demonstrating at a relatively early date a highly significant (P < 0.001) effect of treatment" "Many uncooperative and unreliable patients were identified and eliminated from the trial on the basis of pill counts, urine fluorescence test results, and irregularity of clinic attendance during a pre randomization observation period. Treatment obviously would not have been as effective in a group of patients less carefully selected with regard to their desire to cooperate. The population was further limited in that it excluded female patients and patients with labile hypertension whose diastolic blood pressures averaged lower than 90 mm Hg during the fourth through the sixth day of hospitalization" This study is identified as VA COOP 1970 in the Mulrow 1998 review; the Mulrow 1994 publication; and Musini 2009
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "three hundred and eighty male hypertensive patients with diastolic blood pressures averaging 90 to 114 mm Hg were randomly assigned to either active antihypertensive agents or placebos" Comment: method used for random sequence generation not stated
Allocation concealment (selection bias)	Unclear risk	Quote: "accepted patients were then randomly assigned double‐blind to either active drugs or placebos" (page 1144) Comment: method used for allocation concealment not reported
Blinding of participant and personnel (performance and detection bias)	Low risk	Quote: "accepted patients were then randomly assigned double‐blind to either active drugs or placebos" "Active drugs consisted of two types of tablets, one being a combination tablet containing 50 mg hydrochlorothiazide and 0.1 mg reserpine which was given twice daily. The other was 25 mg of hydralazine hydrochloride given three times daily. The latter medication was raised to 50 mg three times daily if the diastolic blood pressure remained at 90 mm Hg or higher. Obviously, practically all of the patients in the placebo group had their "doses" raised to this level" "Patients in the control group received placebos identical in taste and appearance to the active drugs" "In order to avoid losses to protocol because of side effects presumably caused by one or the other of the two agents, provision was made to permit substitution of a tablet which contained either reserpine or hydrochlorothiazide alone and omitted the offending medication. These special tablets were made available on request of a participating physician. Similar appearing placebo tablets were made available for the control patients and the physician did not know whether the substitution represented active drugs or placebos" Comment: trial was double‐blinded whereby participants and physicians were not aware of the treatment allocated to either group
Blinding of outcome assessment	Low risk	Quote: "the records of the patients reported as having assessable morbid events were reviewed by two consulting physicians who had not participated in the trial" "All available data pertaining to each organic complication, except the type of protocol treatment and the level of blood pressure, were presented to the reviewers and their decisions regarding the occurrence and classification of an event according to the definitions given in the protocol (see list of assessable events at the end of the communication) were accepted as final" Comment: outcome assessors were probably blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "fifty‐six or 15% of the 380 randomized patients were classified as drop‐outs during the course of the trial. Of this number 27 had been randomized to receive placebos and 29 to receive active drugs. The average period of follow up prior to dropping out was 17.6 months with a range from less than 1 month to 49 months" "Thus, the earliest entrants were observed for 5.5 years and the latest entrants for a minimum of 1 year. The average potential duration of observation, disregarding losses and terminations, was 3.9 years for the control group and 3.7 years for the treated patients. However, because of the losses and terminations due to elevated diastolic blood pressure described below, the actual duration of post randomization observation was 3.3 years for the control group and 3.2 years for the treated patients" Comment: reasons for dropouts were mentioned, although the reasons were not given separately for the 2 groups. How data for these patients were analysed is not reported
Selective reporting (reporting bias)	Unclear risk	Comment: protocol is not available Mortality (various causes of death) and morbidity (various terminating morbid events other than death) data were reported
Industry sponsorship bias	High risk	COI has not been reported "The special medications used in this investigation were prepared by William E. Wagner, MD, of Ciba Pharmaceutical Co., Summit, NJ

ACE: angiotensin‐converting enzyme.

ACEI: angiotensin‐converting enzyme inhibitor.

BP: blood pressure.

CHD: coronary heart disease.

CHF: congestive heart failure.

CVD: cardiovascular disease.

DBP: diastolic blood pressure.

ECG: electrocardiogram.

ITT: intention‐to‐treat.

IVRS: interactive voice response system.

M&M: morbidity and mortality.

MI: myocardial infarction.

SAE: serious adverse event.

SBP: systolic blood pressure.

TIA: transient ischaemic attack.