SHEP 1991.

Study characteristics
Methods	Multisite study. Double‐blind, placebo‐controlled stepped‐care treatment programme. Study duration: 5 years. Randomisation: stratified by site and by antihypertensive medication status at initial contact; participants randomly allocated by coordinating centre. Participants blinded; providers blinded; morbidity and mortality assessors blinded. Type of trial: randomised, placebo‐controlled. Percentage lost to follow ‐up: < 1%. Percentage not on assigned therapy at study end: placebo group: 44%; treatment group: 10%
Participants	Geographic region: United States of America. Study setting: community. N = 4736 (55.8% female). Age range 60 to > 80 years, mean 71.6 (SD 6.7). Race: White non‐Hispanic (79.2%), Black (13.8%), Hispanic (1.8%), Asian (4.3%), other (0.9%). Education level: mean 11.7 years (SD 3.5). Diagnosis: systolic hypertension. Mean blood pressure at entry: 170/77 mmHg. Blood pressure (BP) entry criteria: systolic BP 160 to 219 mmHg and diastolic BP < 90 mmHg.
Interventions	Control: matching placebo. Treatment: step 1 ‐ chlorthalidone 12.5 or 25 mg daily; step 2 ‐ atenolol 25 or 50 mg or reserpine 0.05 or 0.10 mg daily. Average length of follow up: 4.5 years. Difference in blood pressure at study end (Treatment ‐ Control) systolic/diastolic: ‐11.1/‐3.4 mmHg.
Outcomes	Analysed in the review: incidence of dementia; quality of life; incidence of side effects including depression; blood pressure level. Not analysed in the review: total mortality; total stroke; sudden cardiac death; rapid cardiac death; non‐fatal myocardial infarction (MI); fatal MI; left ventricular failure; other cardiovascular death; transient ischaemic attack (TIA); coronary artery bypass grafting or angioplasty; renal dysfunction. Dropouts due to side effects: control group: 7%; treatment group: 13%. 90% of hypertensive treatment group group and 44% of placebo group on active hypertensive treatment at end of 5 years. Number of participants in groups at end of 5 years: 773/2365 hypertensive treatment group, 738/2371 placebo group. Quality of life or functional outcomes: no perceptible negative effect of treatment compared to control on measures of cognitive, physical and emotional function.
Notes	Exclusions: history and/or signs 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 ischaemic attack (TIA) with bruit matched with TIA localisation, 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.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: 'After verification of eligibility ... randomly allocated by coordinating centre to one of two treatment groups. Randomisation stratified by centre and antihypertensive medication use at initial contact.' Comment: Probably adequate
Allocation concealment (selection bias)	Low risk	Quote: 'Random assignment ... made by coordinating centre and transmitted to local centre by telephone after verification of eligibility.' Comment: probably adequately concealed.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: 'Participants randomised in a double‐blind manner to once‐daily dose of active drug treatment or matching placebo.' Data on study endpoints collected by investigators and confirmed by a panel of three physicians blind to allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: 'Participants randomised in a double‐blind manner to once‐daily dose of active drug treatment or matching placebo.' Data on study endpoints collected by investigators and confirmed by a panel of three physicians blind to allocation.
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: 'All analyses were by treatment assignment at randomisation.' Comment: Subsequent publication (Di Bari 2001) addressed effect of differential dropout between treatment and control groups and concluded that the cognitive evaluations were biased toward the null effect by differential dropout.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes reported.
Other bias	High risk	About 35% of participants in the placebo group took antihypertensive medication during the study for pre‐defined BP levels.