MRC‐O 1992.
| Methods | Randomised single‐blind placebo‐controlled multi‐site study conducted in general practice setting in England, Scotland, and Wales | |
| Participants | 4396 ambulatory patients 60 years or older; age range 60 to 74; mean 70.3 years; male 42%; 58% female; race not reported. Mean blood pressure at entry: 184/91 mmHg; pulse pressure 94 mmHg
Inclusion criteria: BP entry criteria: systolic BP 160 to 209 mmHg and diastolic BP < 115 mmHg Exclusion criteria: known or suspected secondary hypertension; taking antihypertensive drugs; cardiac failure or any other accepted indication for antihypertensive treatment; receiving treatment for angina pectoris; history of myocardial infarction or stroke within preceding 3 months; impaired renal function; diabetes; asthma; serious intercurrent disease, including malignancy, known to be present at time of examination; serum potassium concentration ≤ 3.4 mmol/L or > 5.0 mmol/L Pre‐existing risk factors: myocardial infarction: excluded if within last 3 months; stroke: excluded if within last 3 months; diabetes: excluded; smoking: 17.5% Follow‐up: 5.8 years |
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| Interventions |
Diuretic arm Step 1 ‐ hydrochlorothiazide 25 mg or 50 mg + amiloride 2.5 mg or 5 mg daily Step 2 ‐ atenolol 50 mg daily Step 3 ‐ nifedipine up to 20 mg daily Step 4 ‐ other drugs Beta blocker arm Step 1 ‐ atenolol 50 mg daily Step 2 ‐ hydrochlorothiazide 25 mg or 50 mg + amiloride 2.5 mg or 5 mg daily Step 3 ‐ nifedipine up to 20 mg daily Step 4 ‐ other drugs Control ‐ matching placebo |
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| Outcomes | Mortality, stroke, CHD, 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 (including withdrawals and losses to follow‐up): placebo group 53%; diuretic arm 48%; beta blocker arm 63% Difference in blood pressure at study end (Treatment ‐ Control) ‐ systolic/diastolic: ‐6.3/‐5.9 mmHg Dropouts due to side effects: control group 82 (3.7%); diuretic arm 160 (14.8%); beta blocker arm 333 (30.2%) Quality of life or functional outcomes: no perceptible negative effect of treatment compared to control on measures of cognitive function 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 74‐year‐old patients |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "all trial entrants were randomly allocated in equal proportions to one of the four treatment categories...." Randomisation was stratified by gender and site; at each site, participants were assigned to therapy based on computer‐generated lists Comment: baseline characteristics were similar |
| Allocation concealment (selection bias) | Unclear risk | Method of allocation concealment was not described |
| Blinding of participant and personnel (performance and detection bias) | High risk | Quote: "this trial was single‐blind; patients did not know in which treatment group they were in; but the doctors and nurses" (page 406) Comment: patients were blinded; providers were not blinded |
| Blinding of outcome assessment | Low risk | Quote: "the records of all patients were "flagged" at Southport NHS center register to ensure notification of death. The diagnostic evidence for each terminating event was assessed by the arbitrator, blind to the treatment regimen. World Health Organization criteria for classification of strokes and coronary events were used. All available documentation was reviewed, including copies of general practitioners' notes, hospital inpatient and outpatient notes, electrocardiographic recordings, necropsy findings, and death certificates" "Data on terminating events were analysed after every 5000 patient years and were reviewed by an independent monitoring and ethics committee" Comment: outcome assessor was blinded |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Quote: "over five and a half years about 25% of people were lost to follow up. The cumulative percentage of people who stopped taking their randomised treatment, including both those withdrawn but continuing on follow up and those lost to follow up, 48% of the diuretic group, 63% of the beta‐blocker group, and 53% of the placebo group" "Overall, the beta‐blocker group had significantly more withdrawals than diuretic groups" Comment: loss to follow‐up was high; only selected reasons for the beta blocker group were provided. Reasons pertinent to respective groups were not mentioned. Insufficient detail was provided to determine if intention‐to‐treat analysis was carried out correctly |
| Selective reporting (reporting bias) | High risk | "A patient's participation in a trial ended with a stroke, whether non‐fatal or fatal; coronary events; other cardiovascular events, and death from any cause" "If a patient had a non‐fatal event followed by a fatal event in the same category, only the fatal event was included in the analyses. If a patient had two events in different categories, for example, a non‐fatal stroke then a coronary event (fatal or non‐fatal), then both were included" Morbidity and mortality data were reported as stated in the objectives |
| Industry sponsorship bias | Low risk | Quote: "the trial was supervised by an MRC working party and coordinated by the MRC Epidemiology and Medical Care Unit at Northwick Park Hospital, Harrow" The source of funding for carrying out the trial was not mentioned, nor was the relation of investigators or any member of the MRC working party to the manufacturers/suppliers of medications for the trial |