MRC‐TMH 1985.

Methods	Randomized single‐blind study comparing 2 treatments and placebo in ambulatory young patients in England, Scotland & Wales.
Participants	17,354 participants (8306 male and 9048 female); mean age 52 years, range 35 to 64 years; ethnicity not reported; male (49%); baseline mean SBP/DBP was 161.4/98.2 mmHg; and pulse pressure was 63 mmHg. The inclusion criteria was SBP < 200 mmHg and DBP 90 to 109 mmHg. 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 three months, presence of angina, intermittent claudication, diabetes, gout, bronchial asthma, serious inter current disease or pregnancy. Follow‐up: 5 years
Interventions	Treatment: bendrofluazide 10 mg daily, propranolol 80 mg to 240 mg daily + methyldopa added if required Control: placebo Note: 288 patients were randomly assigned to observation only, taking no tablets, and were merged with placebo.
Outcomes	Mortality, stroke, CHD, systolic BP and diastolic BP No CHF data
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low 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 provided for sequence generation. Random sequence generation achieved properly and the baseline characteristics were well matched.
Allocation concealment (selection bias)	Low risk	No description of method for allocation concealment provided. Baseline characteristics were well matched.
Blinding of participants and personnel (performance bias) All outcomes	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 ‐ participants were blinded but not the physician.
Blinding of outcome assessment (detection bias) All outcomes	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 nonfatal; coronary events, including sudden death thought to be due to a coronary cause, death known to be due to myocardial infarction, and nonfatal myocardial infarction; other cardiovascular events, including deaths due to hypertension (ICD 400 to 404), and to rupture or dissection of an aortic aneurysm, and death from any other cause. Clinic staff reported these events to the co‐ordinating centre. The records of all patients who suffered nonfatal 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 the study follow‐up, except for death flagging. This induced a censoring attrition bias, limited to the occurrence of nonfatal events of myocardial infarction or stroke.
Selective reporting (reporting bias)	Low risk	No information about pre‐specified outcomes was available on which to make this assessment. However, aim of the study was to study mortality and morbidity, which have been reported.
Other bias	Unclear 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."