SHEP 1991.

Methods	Randomized, double‐blind, placebo controlled multisite study in community ambulatory patients conducted in USA.
Participants	4736 participants (55.8% female); age range 60 to > 80 mean: 72 years; male 43%; race: white non‐Hispanic (79.2%), Black (13.8%), Hispanic (1.8%), Asian (4.3%), other (0.9%); mean blood pressure at entry: 170/77 mmHg Pre‐existing risk factors: myocardial infarction: 4.9%; stroke: 1.4%; diabetes: 10.1%; smoking: 12.7%; Blood pressure (BP) entry criteria: systolic BP 160 ‐ 219 mm Hg and diastolic BP < 90 mm Hg. Baseline mean SBP/DBP was 170/77 mmHg and pulse pressure was 93 mmHg. Exclusion criteria: history, signs, or both, of major cardiovascular diseases likely to require pharmacologic and other treatment (e.g. previous myocardial infarction, coronary artery surgery, major arrhythmias, conduction defect, recent stroke, carotid artery disease, history of transient ischemic attack (TIA) with bruit matched with TIA localization, two or more TIAs and signs or symptoms in a single neurological distribution); other major diseases (e.g. cancer, alcoholic liver disease, established renal dysfunction) with competing risk factors for the primary endpoint ‐ stroke; presence of medical management problems (e.g. insulin dependent diabetes, history of dementia, evidence of alcohol abuse); bradycardia; people maintained on beta‐blockers, diuretics, other antihypertensive drugs, anticoagulants, or experimental drugs on recommendation of their physicians. Follow‐up: 4.5 years
Interventions	Treatment: Step 1 ‐ chlorthalidone 12.5 mg or 25 mg daily Step 2 ‐ atenolol 25 mg or 50 mg or reserpine 0.05 mg or 0.10 mg daily Control: placebo
Outcomes	Mortality, stroke, CHD, CHF, systolic BP and diastolic BP Dropouts due to side effects Quality of life or functional outcomes
Notes	Percentage not on assigned therapy at study end: placebo group: 44%, and treatment group: 10%. Difference in blood pressure at study end (Treatment ‐ Control) systolic/diastolic: ‐11.1/‐3.4 mmHg. Dropouts due to side effects: Control group: 7%; Treatment group: 13%. Quality of life or functional outcomes: no perceptible negative effect of treatment compared to control on measures of cognitive, physical, and emotional function.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Stratified randomization by antihypertensive drug treatment status at initial contact and by center produced two SHEP groups—assigned to active treatment and placebo—comparable at baseline.” "Each randomisation was carried out by telephone." “Both treatment groups were generally comparable to the several traits assessed.” Comment: randomization was adequately done and baseline characteristics of two groups were well matched.
Allocation concealment (selection bias)	Low risk	Quote: "The random assignment to one of the two study groups was to be made by the Coordinating Center and transmitted to the clinical center by telephone after verification of eligibility (inclusion and exclusion criteria). Each participant was to be assigned a drug bottle number for the first step and dosage of the treatment program. A randomization report was then to be mailed to each clinical center." Comment: patients were randomly allocated by co‐ordinating centre and allocation concealment seems to be performed adequately.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "SHEP was a long term, multicenter, randomized, double‐blind, placebo‐controlled trial sponsored by the National Heart, Lung and Blood Institute and National Institute of Ageing." "Participants were to be randomized at each center to either chlorthalidone or matching placebo in a double‐blind manner." “Drug dosage was doubled (including matching placebo) for participants failing to achieve the SBP goal at follow‐up visits.” Comment: neither participants nor treating physicians were aware of the treatment given.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “Occurrence of study events listed above was confirmed by a coding panel of three physicians blind to randomization allocation.” "The SHEP endpoint committee, which was masked to results by treatment group and individual participant treatment assignment, coded strokes, causes of death, and selected nonfatal outcomes. Documented criteria (1, 2a, 2b) were used in assessing outcomes. At each of its meetings, the DSMB was satisfied that the ascertainment of outcomes was not biased." "The progress of the study and the safety of the participants were reviewed on a regular basis by an independent data and safety monitoring board." Comment: morbidity and mortality outcome assessment was carried out independently
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "By July 1990, there were 661 initial reports of strokes and deaths. Of these, 90.3%, or 587, had complete information of which 579 had been coded by the endpoint committee. By December 1990, there were 721 reports of strokes and deaths, and 94.9%, or 684, had complete information and 666 had been coded. Primary outcome determination was complete for 99.8% of the participants." “All analyses are to be based on participants’ original treatment group assignment (i.e. the intention‐to‐treat principle)." Comment: complete follow‐up of 99.8% patients therefore it is assessed as low risk of bias.
Selective reporting (reporting bias)	Low risk	Comment: The primary endpoints, such as nonfatal and fatal stroke over a 5‐year period; secondary endpoints such as nonfatal myocardial infarction and fatal coronary heart disease, and major CVD morbidity and mortality were reported.
Other bias	Low risk	Quote: "The SHEP trial was supported by contracts with the National Heart, Lung and Blood Institute and the National Institute on Aging. Drugs were supplied by the Lemmon Co., Sellersville, Pa; Wyeth laboratories/Ayerst laboratories and AH Robims Co.; Richmond Va; Stuart Pharmaceuticals, Welmington, Del. It is pleasure to acknowledge the contribution of the investigators and the staff at the 16 clinical centers and coordination and service centers of the SHEP Cooperative Research Group." Comment: study sponsored by the NHLBI; no conflict of interest was declared.