MIDAS 1996.

Study characteristics
Methods	Multicenter, randomized, double‐bind, controlled clinical trial
Participants	883 patients in the USA aged ≥ 40 years with DBP 90 to 115 mmHg Mean age 58 years 194 F:689 M
Interventions	Hydrochlorothiazide 12.5 mg to 25 mg twice daily Isradipine 2.5 mg to 5.0 mg twice daily
Outcomes	IMT Any major vascular event (stroke, MI, CHF, angina, sudden death and other cardiovascular disease‐related death) Any major vascular procedure (endarterectomy, CABG and angioplasty) Any non‐major vascular events/procedures (TIA, AF, PVC, femoral/popliteal bypass graft, aortic valve replacement and palpitation) BP at 1 year Duration: 3 years
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Patients... were randomised into 2 treatment groups... The randomisation process was stratified and blocked by clinic to provide equal probability of assignment to either treatment group throughout the study."
Allocation concealment (selection bias)	Unclear risk	No description of allocation concealment was provided, although add‐on enalapril, if used, was administered open‐label.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Study was described as double‐blind, but no additional details provided.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "All reported clinical events were reviewed, adjudicated, and classified by the MIDAS Investigators' Morbidity and Mortality Committee, consisting of 6 clinicians, each from a different clinical centre; all were blinded to the randomisation assignments... Members of this committee were required to reach a unanimous decision, based on clinical judgment, on how each reported event should be classified." Quote: "After completion of the trial, when investigators were unblinded to the results on clinical events obtained by the Morbidity and Mortality Committee, concern was expressed as to whether objective criteria had been consistently applied in adjudication of clinical events, especially those classified as 'hospitalized angina pectoris'. Accordingly an external ad hoc panel of 3 recognized authorities in the fields of cardiology and epidemiology was appointed. Using standard clinical definitions and the hierarchy described herein, this ad hoc committee independently reviewed and adjudicated selected clinical events while blinded to the randomisation assignments of the participants. The final analysis of clinical events reported in this article is based on the classification of events reported by this ad hoc committee." Because unblinding occurred (and was the reason for the ad hoc committee), risk is assessed as unclear.
Incomplete outcome data (attrition bias) All outcomes	High risk	Intention‐to‐treat approach was used. Quote: "[At the study end] Twenty percent of those on isradipine treatment and 18% of those on hydrochlorothiazide treatment had withdrawn from their respective study medications." Relatively high attrition over 3 years.
Selective reporting (reporting bias)	Low risk	All cardiovascular and BP outcomes in the protocol reported.
Use of supplemental drugs	Low risk	Only enalapril permitted for add‐on therapy. Quote: "Those who do not have responses (whose diastolic blood pressure is not controlled) to the first dose of the study drugs will have their doses doubled. The small proportion of participants who then still do not demonstrate adequate blood pressure control will receive open‐label enalapril in doses from 2.5 to 10 mg twice daily."
Industry sponsorship	High risk	Quote: "This study was supported in part by Sandoz Research Institute (SRI), Sandoz Pharmaceuticals, East Hanover, NJ".