VA‐NHLBI 1978.

Methods	Randomized, double‐blind, placebo‐controlled trial conducted in ambulatory patients in USA
Participants	Mean age 37.5 years, range 21 to 50 years. 25% patients were African‐Americans. Male (81%). Baseline mean DBP was 93.3 mmHg. Inclusion criterion: DBP 85 to 105 mmHg. Target < 85 mmHg Exclusion criteria: significant cardiovascular renal abnormalities, insulin‐requiring diabetes, treatment with vasoactive drugs, a concomitant 'fatal' disease, a history of depression or of recent (within the last 2 years) gout or peptic ulcer, and finally any conditions felt to make noncompliance likely Follow‐up: 2 years
Interventions	Treatment: Step 1. chlorthalidone 50 mg Step 2. 100 mg (53% chlorthalidone alone) Step 3. chlorthalidone 100 mg + reserpine 0.25 mg Control: placebo
Outcomes	Mortality, stroke, CHD, CHF, and diastolic BP
Notes	No intervention on diet, smoking, or other behavioral factors.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "At the conclusion of the trial period, subjects were randomly assigned either active or placebo treatment, and this medication was substituted for the identical placebo of the trial period and administered in double‐blind fashion." Comment: method for random sequence generation was not specified; table for baseline characteristics of the 2 groups were not provided.
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment was not mentioned; could not assess baseline characteristics of the 2 groups.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The Cooperative Studies Program Central Research Pharmacy was responsible for distribution of coded double‐blind study drug to each clinical center and for assuring proper handling of these drugs when they were distributed to the individual subjects." "The blinded active and placebo drugs were both designated by small letters in parentheses, whereas the known drugs were designated by underlined capital letters: C, 2C, 1/2C and R. The protocol defined three standard successive therapeutic steps: (c), (2c), and (2c)+(r). Each subject began (c) when he was randomized." "The study biostatistician supervised data management and reporting. The data center supplied each clinical center with instruction manuals, data forms, randomization numbers, and individual subject identification labels for all forms, drug bottles, sample containers, electrocardiograms, and x‐rays." Comment: trial stated as double‐blind and probably patient and physician were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessor was not stated.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "By preliminary count there were 98 losses to study in the active group and 104 in the placebo group, making the total cumulative dropout rate equal to 20% with a dropout being defined as a subject with an appointment overdue for more than 60 days." Comment: dropout rates 19.3% (98/508) in treatment group and 20.6% (104/504) in the placebo group. Reasons for the loss to follow‐up was not stated separately for each group.
Selective reporting (reporting bias)	Unclear risk	Protocol was not available. Comment: major and minor morbid events were reported along with adverse events for each group.
Other bias	Low risk	Quote: "This project was jointly supported by the Cooperative Studies Program of the Medical Research Service of the Veterans Administration and by an Interagency Agreement (2 Y01‐HV‐40012‐04) awarded by the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health, Education, and Welfare." "A feasibility trial to investigate the practicality of determining the advantages and disadvantages of prompt pharmacologic treatment for mild hypertension was jointly funded by the Veterans Administration and the National Heart, Lung and Blood Institute."