HYVET pilot 2003.

Methods	Randomized, open, multisite trial conducted in Europe. Most patients enrolled were from Bulgaria 1130 (88%), 39 (3%) in Spain, 39 (3%) in Romania, 32 (2.5%) in the UK, 20 (1.5%) in Poland, and smaller numbers in 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 four readings) 160 to 219 mmHg, diastolic blood pressure 95 to 109 mmHg (later changed to 90 to 109 mmHg), standing systolic blood pressure > 140 mmHg (average of two readings). Mean blood pressure at entry: systolic blood pressure averaged 181.5 + 11.3 mmHg (range 160–217 mmHg) and entry diastolic pressure averaged 99.6 + 3.4 mmHg (range 90–114 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 had a previous myocardial infarction, 4.5% a previous stroke, and 20.7% drank more than 1 unit of alcohol per day. Smoking: 4.2% The target blood pressures were a sitting systolic pressure less than 150 mmHg plus a sitting diastolic pressure less than 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., the presence of gout, renal artery stenosis, dementia (abbreviated mental test score, 7/10), and a condition expected to limit survival severely Follow‐up: 13 months
Interventions	Treatment: Step1: 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.
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 to 89 years, and > 90 years). Baseline characteristics were 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." Comment: method used for allocation concealment was not specified and probably not done as it was an open‐label pilot study.
Blinding of participants and personnel (performance bias) All outcomes	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 (detection bias) All outcomes	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 patients lost to follow‐up low and reasons for attrition were not mentioned, although the 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 nonfatal event." Comment: all endpoints were reported in the results section.
Other bias	Low risk	Quote: "The pilot trial was supported by the British Heart Foundation."