SHEP‐P 1989.

Methods	Randomised double‐blind placebo‐controlled multi‐site study in community ambulatory patients in USA
Participants	551 participants; 63% female; age range: > 60 (15% > 80); mean 72 years; race: white (82%); non‐white (18%); male (37%); mean blood pressure at entry 172/75 mmHg; pulse pressure 93 mmHg. Pre‐existing risk factors: myocardial infarction 4%; stroke 1%; smoking 11% Inclusion criteria: SBP 160 to 219 mmHg and DBP < 90 mmHg Exclusion criteria: coronary bypass surgery within 2 years; heart attack within 6 months; stroke with residua; current treatment with antihypertensive drugs, insulin, or anticoagulants; allergy to study medications; specified arrhythmias or a pacemaker; uncontrolled congestive heart failure; serum creatinine level 2.0 mg/dL or more; alcohol abuse; cancer or other life‐threatening disease; chronic obstructive pulmonary disease; peripheral vascular disease with tissue injury; senile dementia; residence in a nursing home; carotid bruit with history of transient ischaemic attacks; history of malignant hypertension Follow‐up: 3 years
Interventions	Treatment Step 1 ‐ chlorthalidone 25 to 50 mg daily (87%) Step 2 ‐ randomised to hydralazine 25 mg twice daily, reserpine 0.05 mg twice daily, or metoprolol 50 mg twice daily (13%) Control ‐ placebo
Outcomes	Mortality, CHD, stroke, CHF, systolic BP, diastolic BP Dropouts due to side effects reported at 12 months Quality of life or functional outcomes not reported
Notes	Percentage not on assigned therapy at study end: placebo group 40% and treatment group 30%. Difference in blood pressure at study end (Treatment ‐ Control) systolic/diastolic: ‐17/‐5 mmHg. Dropouts due to side effects (at 12 months; data not reported for end of study): control group 2 (1.8%); treatment group 7 (1.6%) Information was obtained for subgroups from publications using individual patient data from the INDANA database (Gueyffier 1999) Data on mortality, cardiovascular mortality and morbidity (does not include TIA), cerebrovascular mortality and morbidity, and CHD mortality and morbidity are available for 60 to 79 years and 80 years or older subgroups
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “the pilot study of the Systolic Hypertension in the Elderly Program was a randomized, double‐blind, placebo‐controlled trial of drug therapy for isolated systolic hypertension” (Perry et al Stroke 1989; 20: page 4) “Each randomization was carried out by telephone between the clinic staff and the coordinating center data manager, who checked that eligibility criteria were met before assigning the participant to chlorthalidone or placebo. We used an adaptive randomization procedure that varied treatment assignment probabilities by 10% in one or the other direction in order to balance the step I study groups within race, sex, age and baseline systolic BP strata” Comment: randomisation was carried out in a proper manner, and baseline characteristics were matching, although minor differences were seen in the medical history and physical examination, which were relatively small and could not affect the outcome
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not described
Blinding of participant and personnel (performance and detection bias)	Low risk	Quote: "the pilot study of systolic hypertension in the Elderly Program (SHEP‐PS) was a randomized, double‐blind, placebo‐controlled trial, following participants for an average of 34 months" "Upon randomization into the study, participants entered the step‐up protocol and received 25 mg/day of chlorthalidone or placebo (supplied as identical capsules by USV Pharmaceutical Corp)" “Participants receiving step I placebo who had not reached goal underwent a dummy randomization, and all received step II placebo twice daily. Twelve weeks later, the dosage for participants who still had not reached goal was doubled” Comment: participants and treating physicians were blinded
Blinding of outcome assessment	Low risk	Quote: "when the necessary documentation for a morbid event was assembled at the Coordinating Center, it was copied and mailed to the three members of the Morbidity and Mortality Committee (a neurologist and two internists). Working independently and without knowledge of the participant's treatment group assignment, each member made a diagnosis based on the criteria of Table 1. The diagnosis of "no event" was also acceptable and was the final diagnosis for five suspected morbid events. A diagnosis was accepted when the three members agreed unanimously" Comment: outcome assessment was done in an independent manner; outcome assessors were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: “at the end of SHEP‐PS, the vital status of all participants was known; 512 were alive” “Analysis was by intention to treat according to randomization to Step I medication (chlorthalidone or placebo), regardless of whether a Step II medication was added subsequently” "We specified an “intention to treat” rule (with study groups divided by the randomized assignment regardless of subsequent crossovers) and a plan for replacing any missing annual visit BP with the last available value" Comment: there was no loss to follow‐up
Selective reporting (reporting bias)	High risk	All cardiovascular events such as stroke, left ventricular failure, transient ischaemic attack, myocardial infarction, sudden death, angina pectoris, coronary artery surgery, and peripheral vascular disease were reported in the results section "For any participant who had two or more events, one was designated the study event based on a hierarchal classification headed by death followed by four categories of nonfatal events in rank order of stroke, other hypertensive events, atherosclerotic events, and non‐cardiovascular events. When there were two events in one category, the event that occurred first was used" Comment: not all events were reported if they occurred in the same category
Industry sponsorship bias	Low risk	Quote: "sponsorship: this study was supported by the National Heart, Lung and Blood Institute: The National Institute of Ageing; in part by the National Institute of Mental Health" Comment: conflict of interest was declared and source of funding was not provided; because the study is not industry sponsored, we assessed it as having low risk of bias