MRC‐TMH 1985.

Methods	Randomised single‐blind trial comparing 2 treatments and placebo in ambulatory young patients in England, Scotland, and Wales
Participants	17,354 participants (8306 male and 9048 female) with mean age 52 years; range 35 to 64 years Ethnicity not reported. Male 52%. Baseline mean SBP/DBP 161.4/98.2 mmHg; pulse pressure 63 mmHg Inclusion criteria: SBP < 200 mmHg and DBP 90 to 109 mmHg Patients in 60‐ to 64‐year‐old age group ‐ thaizide = 686; beta blocker = 729; placebo = 1398 Exclusion criteria: secondary hypertension; taking antihypertensive treatment; normally accepted indications for antihypertensive treatment (such as congestive cardiac failure) present; myocardial infarction or stroke within the previous 3 months; presence of angina, intermittent claudication, diabetes, gout, bronchial asthma, serious intercurrent disease, or pregnancy Follow‐up: 5 years
Interventions	Treatment arms: bendrofluazide 10 mg daily or propranolol 80 to 240 mg daily. Methyldopa could be added if required Control: placebo Note: 288 participants were randomly assigned to observation only, taking no tablets, and were merged with placebo
Outcomes	Mortality, stroke, CHD, systolic BP, diastolic BP No congestive heart failure data
Notes	Data for the 60‐ to 64‐year‐old subgroup were obtained from the INDANA database through personal communication with Francois Gueyffier The definition of total cardiovascular events did not include heart failure
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "patients were randomly allocated at entry... Randomisation was in stratified blocks of eight within each sex, 10 year age group, and clinic" Comment: no information was provided for sequence generation
Allocation concealment (selection bias)	Unclear risk	No description of method for allocation concealment was provided
Blinding of participant and personnel (performance and detection bias)	High risk	Quote: "four treatments: the thiazide diuretic bendrofluazide; placebo tablets that looked like bendrofluazide; the beta blocker propranolol; and placebo tablets that looked like propranolol. The two placebo groups were treated as one in all analyses" Quote: "when the protocol was written, it was judged unreasonable to ask general practitioners to undertake such adjustments in a double blind study, and the trial was therefore single blind only" Comment: participant was blinded but not the physician
Blinding of outcome assessment	Low risk	Quote: "the evidence on which the diagnosis of each terminating event was based was assessed by an arbitrator ignorant of the treatment regimen... The arbitrator used WHO criteria for classification" "All events were assessed by an independent arbiter who was blind to the treatment regimen" "Each electrocardiogram tracing was read by two observers who were blind to the treatment regimen; the second reader was also blind to the first reader's coding. If these two readers disagreed, a third reader was used" Comment: adjudication was independent and blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "all analyses presented here are based on randomised treatment ("intention to treat") categories. Thus data for all participants are presented as if the individual was still in the treatment group to which he was originally randomised, although substantial percentages of patients (see below) were in fact withdrawn from their randomly allocated regimen during follow up" Quote: "the total five and a half year cumulative percentages of men who stopped taking their randomised treatment, including both those withdrawn from their randomly allocated regimen but continuing on follow up and those lapsing from the trial, were 43% of the bendrofluazide group, 42% of the propranolol group, and 47% of the placebo group. For women the figures were 33%, 40%, and 40% respectively. The cumulative percentages of people not taking either primary active drug by five and a half years were smaller: 33% of men originally randomised to bendrofluazide and 34% of men randomised to propranolol and 28% and 31% respectively of women" Quote: "events terminating a patient’s participation were: stroke, whether fatal or non‐fatal; coronary events, including sudden death thought to be due to a coronary cause, death known to be due to myocardial infarction, and non‐fatal myocardial infarction; other cardiovascular events, including deaths due to hypertension (ICD 400‐404) and to rupture or dissection of an aortic aneurysm; and death from any other cause. Clinic staff reported these events to the coordinating centre. The records of all patients who suffered non‐fatal terminating events and of any others who lapsed from the trial, whatever the reason, were “flagged” at the Southport NHS central register to ensure notification of death)" Comment: myocardial infarction and stroke were reasons for terminating study follow‐up, except for death flagging. This induces a censoring attrition bias, limited to the occurrence of non‐fatal events, myocardial infarction, or stroke
Selective reporting (reporting bias)	Low risk	No information about prespecified outcomes is available on which to make this assessment. However the aim of the study was to study mortality and morbidity, which have been reported
Industry sponsorship bias	High risk	Conflict of interest was not reported "The working party thanks the general practitioners and nurses collaborating in the trial; the staff at the coordinating centre; the staff of the Wolfson Research Laboratories, Queen Elizabeth Medical Centre, Birmingham, for carrying out the biochemical analyses; Duncan, Flockhart and Co Ltd for tablets of bendrofluazide and placebo; Imperial Chemical Industries Ltd for financial support and for tablets of propranolol and placebo; Ciba Laboratories for supplies of guanethidine; and Merck Sharp and Dohme Ltd for a mobile screening unit, funds for its staffing, and supplies of methyldopa"