INSIGHT 2000.

Study characteristics
Methods	Randomized, double‐blind trial
Participants	6321 patients from 8 countries (western Europe and Israel) aged 55 to 80 years with BP ≥ 150/95 mmHg or ≥ 160 mmHg SBP Mean age 65 years 3392 F:2929 M
Interventions	Nifedipine 30 mg daily Co‐amilozide (hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily)
Outcomes	Composite endpoint of death from any cardiovascular or cerebrovascular cause, together with non‐fatal stroke, MI, and HF Total mortality Death from vascular cause Non‐fatal vascular events (including TIA, angina, renal failure) BP at 1 year AEs Duration: 1.75 years
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study used dynamic randomization (minimization). Quote: "As well as the risk factors in table 1, randomisation also took into account patients’ sex, age, and whether or not they were receiving aspirin." 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	Unclear risk	Study was double‐blind. Quote: "All patients received one active and one placebo tablet taken at the same time of day." No further information provided on blinding of personnel and no details provided on the blinding or dose increases and add‐on therapy for patients or personnel.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "An independent critical events committee assessed all endpoints according to prespecified criteria. The members of this committee were unaware of the treatment group and blood pressure of each patient."
Incomplete outcome data (attrition bias) All outcomes	High risk	An intention‐to‐treat analysis was used. Total withdrawals were large and different between the 2 groups: 39.9% in the nifedipine group and 33.5% in the thiazide group. This high and different attrition in the 2 groups could lead to bias.
Selective reporting (reporting bias)	Unclear risk	Prespecified criteria no longer available on website; unable to assess.
Use of supplemental drugs	High risk	Additional treatment was consistent across first three steps, but was then based on clinician's choice. Quote: "There were four optional, dose‐titration steps... These extra dose steps were: dose doubling of the randomised drug; addition of atenolol 25 mg daily (or enalapril 5 mg daily if atenolol contraindicated); dose‐doubling of the additional drug; and addition of any other antihypertensive drug (other than calcium‐channel blockers or diuretics). These titration steps could be done in that order at any visit".
Industry sponsorship	High risk	Quote: "The study was funded conducted and reported by Bayer AG".