VA‐II 1970.

Methods	Randomized, double‐blind, placebo‐controlled study conducted in ambulatory men in USA.
Participants	380 men, mean age 52 years, range not reported. 42% participants were African‐Americans. 100% men. Baseline mean SBP/DBP 162/104 mmHg and pulse pressure 58 mmHg. Inclusion criterion: DBP 90‐114 mmHg. Exclusion criteria: history of severe hypertensive complication such as a cerebral or subarachnoid haemorrhage, hypertensive neuroretinopathy, dissecting aneurysm or renal failure, but did not include atherosclerotic complications such as coronary artery disease or cerebrovascular thrombosis; people with surgically curable hypertension, unrelated fatal diseases such as malignant tumours, people unwilling or unable to return to clinic and poorly motivated or otherwise unco‐operative or unreliable people. Follow‐up: 3.7 years.
Interventions	Treatment: step 1: hydrochlorothiazide 100 mg + reserpine 0.2 mg; step 2: hydralazine 75‐150 mg. Control: placebo.
Outcomes	All‐cause mortality, CHD, stroke, CHF, SBP and DBP.
Notes	Study is referenced as VA COOP in Mulrow 1998 review. The review provides data on total cardiovascular mortality + morbidity, cerebrovascular mortality + morbidity, and CHD mortality + morbidity in people aged ≥ 60 years. However, data on all‐cause mortality were not provided in Mulrow 1998 review. Quotes: "The study was terminated in the subgroup of 143 patients whose diastolic blood pressures averaged 115 through 129 mm Hg prior to randomization." "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."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low 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: although method used for random sequence generation not stated it was probably done. Tables 1 and 2 indicated that the two groups were comparable according to the indicated variables.
Allocation concealment (selection bias)	Low risk	Quote: "Accepted patients were then randomly assigned double‐blind to either active drugs or placebos." Comment: method used for allocation concealment not reported; however, baseline characteristics well matched.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quotes: "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‐blind where participants and physicians were not aware of treatment allocated to either group.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quotes: "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 probably blinded.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quotes: "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 mentioned; though reasons were not given separately for the 2 groups. How data were analyzed in these participants not reported.
Selective reporting (reporting bias)	Unclear risk	Comment: protocol not available. Mortality (various causes of death) and morbidity (various terminating morbid events other than death) data reported.
Other bias	Unclear risk	Conflicts of interest not reported.