SHEP 1991.
| Methods | Randomised double‐blind placebo‐controlled multi‐site 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 to 219 mmHg and diastolic BP < 90 mmHg. Baseline mean SBP/DBP was 170/77 mmHg and pulse pressure was 93 mmHg Exclusion criteria: 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, 2 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 |
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| Interventions |
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 Control ‐ placebo |
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| Outcomes | Mortality, stroke, CHD, CHF, systolic BP, diastolic BP Dropouts due to side effects Quality of life or functional outcomes |
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| 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 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 |
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| 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: randomisation was adequately done and baseline characteristics of 2 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: participants were randomly allocated by co‐ordinating centre, and allocation concealment seems to have been performed adequately |
| Blinding of participant and personnel (performance and detection bias) | 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: both participants and treating physicians were not aware of the treatment given |
| Blinding of outcome assessment | 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" (page 982; Probstfield et al 1989) 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: there was complete follow‐up of 99.8% of patients; therefore assessed as low risk of bias |
| Selective reporting (reporting bias) | Low risk | Comment: primary endpoints such as non‐fatal and fatal stroke over a 5‐year period; secondary endpoints such as non‐fatal myocardial infarction and fatal coronary heart disease and major CVD morbidity and mortality were reported |
| Industry sponsorship 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 was sponsored by the NHLBI; no conflict of interest was declared |