Applegate 1991.

Study characteristics
Methods	Study design: multicenter, randomised, double‐blind, active‐control, parallel‐group trial Total duration of study: 3 years. Details of any 'run‐in' period: "eligibility was determined during an initial screening period of three to eight weeks' duration. Participants who had been taking antihypertensive medications at the beginning of the screening period underwent a short wash‐out period. All participants then underwent a three‐ to eight‐week placebo period during which the blood pressure entry criteria were evaluated." Number of study centres and location: 9 clinical centres located across the USA Study setting and date of study: outpatients; 9 July 1988 to 12 December 1989
Participants	Number randomised: 883 participants Number lost to follow‐up/withdrawn: "20% of those on isradipine treatment and 18% of those on hydrochlorothiazide (HCTZ) treatment had withdrawn from their respective study medications" Number analysed: 883 participants Number of interest: 883 participants Mean age: 58.7 years Age range: 40 years and older Gender: 687 men and 196 women Severity of condition: no details given Diagnostic criteria: "only diastolic BP (DBP) was used to determine the presence of hypertension. Hypertension was defined as an average DBP of from 90 mmHg to 115 mmHg" Smoking history: 340 former smokers and 176 current smokers Inclusion criteria "1) Men and women over the age of 40 years; 2) average sitting diastolic blood pressure greater than 90 mmHg and less than 115 mmHg on each of the last three visits of the placebo run‐in period; 3) presence of one or more atherosclerotic lesions in the extracranial carotid artery, demonstrated by quantitative B‐mode ultrasound scanning at baseline with a maximum plaque thickness of between 1.3 mm and 3.5 mm; 4) total serum cholesterol and triglyceride levels within a week prior to randomisation" Exclusion criteria "1) Determination that the patient was considered unlikely to complete the 3‐year treatment period; 2) presence of any form of secondary hypertension; 3) presence of malignant or accelerated hypertension; 4) presence of symptomatic orthostatic hypotension; 5) an average sitting diastolic blood pressure < 115 mmHg at any visit during the screening or placebo wash‐out period; 6) presence of unstable or poorly controlled angina pectoris; 7) history of a cerebrovascular accident, MI, or TIA within the past three months; 8) previous carotid endarterectomy on the side of the qualifying plaque; 9) potential need for diuretic therapy over a 3‐year period, including a history of mild heart failure; 10) presence of cardiac arrhythmias of sufficient severity as to place the patient at risk for an adverse outcome during the course of the study; 11) presence of insulin‐dependent diabetes mellitus; 12) presence of any severe disease or use of any medication that might confound the study results or interfere with completion of the study."
Interventions	Intervention: 2.5 mg or 5 mg isradipine twice daily Comparison: 12.5 mg or 25 mg HCTZ twice daily Concomitant medications: "the small proportion of participants who did not demonstrate adequate blood pressure control with dose‐doubling were given open‐label enalapril in doses ranging from 2.5 mg to 10 mg twice daily." Excluded medications: no details given
Outcomes	Primary outcome: reducing the rate of progression of early extracranial carotid artery atherosclerosis Secondary outcomes: "defined specifically for the purpose of identifying the effect, if any, on the specific segments of carotid artery. These end points were rate of progression in IMT of the following: (1) "normal" arterial walls, defined as the mean of those walls with IMTs less than 1.0 mm at baseline; (2) "borderline" walls with mean IMTs between 1.0 and 1.3 mm at baseline; (3) "diseased" walls with mean IMTs between 1.3 and 3.5 mm at baseline; (4) the 4 walls of the common carotid artery; (5) the 4walls of the carotid bifurcation; (6) the 4 far walls of the common and bifurcation combined; (7) the single wall with the greatest maximum IMT at baseline; and (8) the single wall with the greatest maximum increase." Time points reported "Follow‐up visits every 2 months during the first year and every 3 months during the remaining 2 years. B‐mode ultrasonography of carotid arteries was performed twice at baseline, twice at the final visit, and once every 6 months in the interim."
Notes	Funding for trial: MIDAS is sponsored by Sandoz Pharmaceuticals Corporation Notable conflicts of interest of trial authors: "Although the Sandoz Research Institute is responsible for centralizing data entry and editing, all data analysis will be conducted by the Operations/Analysis Center at the Bowman Gray School of Medicine. The scientific direction for the study rests with the Investigators' Committee. A Policy and Data Monitoring Committee, with no voting member from Sandoz or any of the participating institutions, is charged with monitoring the trial for safety and efficacy, and with approving the final report of the trial results." Protocol: no details given
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomization process was stratified and blocked by clinic to provide equal probability of assignment to either treatment group throughout the study."
Allocation concealment (selection bias)	Low risk	Quote: "The randomization process was stratified and blocked by clinic to provide equal probability of assignment to either treatment group throughout the study."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Qualifying participants were randomized at the baseline visit and began a 36‐week double‐blind drug treatment period."
Blinding of outcome assessment (detection bias) All outcomes	Low 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 center; all were blinded to the randomization assignments."
Incomplete outcome data (attrition bias) All outcomes	Low risk	All prespecified outcomes reported
Selective reporting (reporting bias)	Low risk	All outcome measures were reported in the results section
Other bias	Low risk	No other source of bias detected