HYVET P 2003.

Methods	Randomised open multi‐site trial conducted in Europe. Most patients enrolled were from Bulgaria 1130 (88%), with 39 (3%) from Spain, 39 (3%) from Romania, 32 (2.5%) from the UK, 20 (1.5%) from Poland, and smaller numbers from Finland, Lithuania, Ireland, Greece, and Serbia
Participants	Study setting: both primary and secondary care 1283 participants (63% women); age range 79.5 to 96.1; mean age = 84 years; race: not stated Blood pressure (BP) entry criteria: systolic blood pressure (average of 4 readings) 160 to 219 mmHg, diastolic blood pressure 95 to 109 mmHg (later changed to 90 to 109 mmHg), and standing systolic blood pressure > 140 mmHg (average of 2 readings). Mean blood pressure at entry: systolic blood pressure averaged 181.5 ± 11.3 mmHg (range 160 to 217 mmHg) and entry diastolic pressure averaged 99.6 ± 3.4 mmHg (range 90 to 114 mmHg). Pulse pressure was 82 mmHg. Target blood pressure was < 150/80 mmHg Pre‐existing factors: patients were not obese, with an average body mass index of 25 kg/m²; 48% had been previously treated, 3.0% had a previous myocardial infarction, 4.5% had a previous stroke, and 20.7% drank more than 1 unit of alcohol per day Smoking: 4.2% Target blood pressures were sitting systolic pressure < 150 mmHg plus sitting diastolic pressure < 80 mmHg Exclusion criteria: serum creatinine > 150 mol/L, accelerated hypertension, congestive heart failure requiring treatment, inability to stand, cerebral or subarachnoid haemorrhage in past 6 months, need for blood pressure‐decreasing treatment because of angina etc., presence of gout, renal artery stenosis, dementia (abbreviated mental test score 7/10 (4)), and a condition expected to limit survival severely Follow‐up: 13 months
Interventions	Treatment Step 1 ‐ diuretic (usually bendrofluazide 2.5 mg), an ACE inhibitor (usually lisinopril 2.5 mg), or no treatment Step 2 ‐ involved doubling the dose of the first drug Step 3 ‐ involved adding diltiazem slow‐release 120 mg daily Step 4 ‐ involved adding diltiazem slow‐release 240 mg daily Control ‐ no treatment
Outcomes	Total stroke, total mortality, cardiovascular mortality, cardiac mortality, sitting systolic BP and diastolic BP Dropouts due to side effects: not reported Quality of life or functional status outcomes: not reported
Notes	"As the trial was a pilot trial with limited numbers and a short period of follow‐up, interim analyses were not performed. Similarly, although power calculations are published, they are not relevant to the pilot trial. All analyses are presented on an intention‐to‐treat basis" "The main weaknesses of the pilot trial were that it was an open study and also was not conducted to the standards of Good Clinical Practice. The problem with the use of an open design is that both patient and investigator know the treatment given. This can lead to bias in several different ways. Investigator bias may affect what is written on a death certificate: for example, if the patient has both a myocardial infarction and a stroke before death, the investigator may tend to record a stroke as the underlying cause of death if the patient is receiving no treatment and blood pressure is high" Percentage of patients not on assigned therapy at study end: diuretic 97%, ACEI 96%, no treatment 99.2% Difference in blood pressure at study end (Treatment ‐ Control): sitting BP difference between diuretic/ACEI and no treatment ‐23/‐11 mmHg; standing BP difference between diuretic and no treatment ‐23/‐11 mmHg; and difference between ACEI and no treatment ‐24/‐12 mmHg Data on mortality, cardiovascular mortality and morbidity (includes fatal and non‐fatal stroke, fatal MI, other fatal ischaemic heart disease, sudden death, fatal congestive heart failure, fatal atherosclerosis, fatal pulmonary embolism, fatal hypertension, fatal aortic aneurysm but does not include TIA), cerebrovascular mortality and morbidity (includes fatal and non‐fatal stroke), and CHD mortality and morbidity (includes fatal MI, sudden death, and death due to other ischaemic heart disease and congestive heart failure) are available for the 80 years or older subgroup
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "in the pilot trial, patients older than 80 years and with hypertension were allocated randomly but equally to groups to receive a diuretic‐based regimen, an angiotensin‐converting enzyme (ACE)‐based regimen or to no treatment" "The unit of randomisation was the individual and the SAS Random Allocation of Treatments Balanced in Blocks Program was used to generate the schedule." Restricted random allocation to groups was used to ensure equal allocation per group within each centre and allocation to groups was performed centrally. Stratified into four groups on the basis of sex and age (80–89 years and ≥ 90 years)" Comment: randomisation done; baseline characteristics similar in all treatment groups
Allocation concealment (selection bias)	High risk	Quote: "restricted random allocation to groups was used to ensure equal allocation per group within each centre and allocation to groups was performed centrally" "The pilot HYVET trial was an open design that worked well, but concerns were expressed that only the results of a double‐blind trial conducted to Good Clinical Practice guidelines would be acceptable in the 21st century" (page 2409) Comment: method used for allocation concealment was not specified; this probably was not done, as it was an open‐label pilot study
Blinding of participant and personnel (performance and detection bias)	High risk	"The trial recruited individuals from both primary and secondary care and was of an open design" Comment: patients and providers were not blinded
Blinding of outcome assessment	High risk	Outcome assessors were not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Of the 1283 patients who were assigned to groups, only 27 (2.1%) were lost to follow‐up (had no end‐of‐trial information)" (diuretic 2%, ACEI 2%, no treatment 2%) "Of the 426 patients allocated randomly to a diuretic‐based treatment, 385 (88.5%) were alive and provided information at the end of the trial. The corresponding numbers were 397 (89.8%) for ACE based treatment and 394 (90.1%) for no treatment" "Both the investigators’ and the patients’ knowledge of treatment may affect the withdrawal rates, for example favouring the removal from the trial of a patient who is receiving no treatment but has high blood pressure that approaches but does not exceed a terminating outcome" Comment: number of participants lost to follow‐up low and reasons for attrition not mentioned, although small attrition could not have affected the outcome
Selective reporting (reporting bias)	Low risk	Quote: "the main endpoints of the trial were stroke events, total mortality and cardiovascular, cardiac and stroke mortality" "As this was an open study, the randomised treatment could be continued after a non‐fatal event" Comment: all endpoints were reported in the results section
Industry sponsorship bias	Low risk	Quote: "the pilot trial was supported by the British Heart Foundation"