VHAS 1997.

Study characteristics
Methods	Multicenter, randomized, parallel‐group trial
Participants	1414 patients in Italy aged 40 to 65 years with hypertension (msSBP ≥ 160 and msDBP ≥ 95 mmHg) Mean age 54 years 722 F:690 M
Interventions	Chlorthalidone 25 mg daily Verapamil 240 mg daily
Outcomes	ECG Serum glucose, creatinine total and HDL‐C, triglycerides, urate, BUN, AST, ALT, sodium and potassium AEs Cardiovascular events (stroke, MI, TIA, angina, HF, revascularization procedures) BP at 1 year Duration: 2 years
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study indicates that patients were randomly allocated to treatment groups, but no further information provided regarding the method of randomization.
Allocation concealment (selection bias)	Unclear risk	No description of allocation concealment was provided.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "After the first 6 months of double‐blind treatment, the patients returned to being administered their previous treatment according to an open design for an additional 18 months (open treatment)." No details provided on measures used to achieve double‐blinding.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "The details of cardiovascular events were verified, according to predetermined criteria, by experts blind to the randomised treatment assigned". Unclear if physicians conducting the clinical examinations throughout the study were blind to treatment.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "1464 entered the run‐in period and 1414 were allocated randomly to double‐blind treatment. All of them made at least one visit during the treatment period and could be included in intention‐to‐treat analyses... In total 1099 patients completed the 2‐year treatment period; 315 dropped out (21.6% of the verapamil group and 22.9% of the chlorthalidone group)." Unclear how missing data were accounted for in participants who dropped out. Per‐protocol analysis also reported.
Selective reporting (reporting bias)	Low risk	Assessment is based on predetermined criteria for cardiovascular events.
Use of supplemental drugs	Low risk	Only captopril permitted as add‐on treatment. Quote: "After 1 month, we added 25 mg captopril once a day to the double‐blind treatment for patients whose blood pressures had not been lowered to the goal values (a DBP while sitting < 90 mmHg or < 95 mmHg with a reduction of at least 10% from baseline values). After the second month we increased the captopril dose to 25 mg twice a day for patients whose blood pressures had not yet responded to the combined treatment."
Industry sponsorship	High risk	No specific indication of any funding or sponsorship in primary manuscript but in 1998 paper substudy in the Journal of Hypertension (16(11):1667‐76) quote: "This study was supported by a scientific grant from Knoll Farmaceutici Spa and Ravizza Farmaceutici Spa".

ABPM: ambulatory blood pressure monitoring; ACE: angiotensin converting enzyme; AER: albumin excretion rate; AEs: adverse events; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BP: blood pressure; BUN: blood urea nitrogen; CABG: coronary artery bypass graft; CHD: coronary heart disease; CHF: chronic heart failure; CVD: cardiovascular disease; DBP: diastolic blood pressure; ECG: electrocardiogram; F: female; HDL: high‐density lipoprotein; HF: heart failure; IMT: intimal‐medial thickness; ITT: intention‐to‐treat; LDL: low‐density lipoprotein; LVMI: left ventricular mass index; M: male; MI: myocardial infarction; MRC: medical research council; ms: mean sitting; OGTT: oral glucose tolerance test; PP: per protocol; PVC: premature ventricular complex; SBP: systolic blood pressure; TIA: transient ischemic attack; UACR: urine albumin‐creatinine ratio; WDAE: withdrawal due to adverse event