ABCD (2).

Study characteristics
Methods	Study design: 1 of 2 parallel‐group RCTs conducted within ABCD Unit of randomization and analysis: individual Number randomized, total: 470 hypertensive participants Per group: 237 to intensive therapy and 233 to moderate therapy; second randomization to nisoldipine or enalapril Sample size calculation: sample size calculation was based on glomerular filtration rate; power was not reported
Participants	Country: USA Study period: accrual: March 1991 to May 1993; follow‐up planned for 5 to 7 years after March 1991 Type of diabetes: type 2 Participants’ status at baseline: Age, mean (SD): 58.0 (8.4) years in intensive therapy group, 57.7 (8.3) years in moderate therapy group Gender, % women: 33% in intensive therapy group, 32% in moderate therapy group Race/ethnicity: overall 66.3% non‐Hispanic white; 17% African‐American; 13.4% Hispanic; 1.9% Asian; 1% other Duration of diabetes, years, mean (SD): 8.9 (7.1) intensive group, 8.3 (6.2) moderate group Smokers, % current: not reported Blood pressure, mean (SD): SBP 156 (16.1) mmHg intensive group, 154 (16.9) mmHg moderate group DBP 98 (6.4) mmHg intensive group, 98 (6.4) mmHg moderate group Glycated hemoglobin, mean (SD): 11.6 (3.2) intensive group, 11.5 (3.5) moderate group BMI, mean (SD): 31.8 (5.1) intensive group, 31.7 (6.3) moderate group Severity of retinopathy: overall 38.5% no retinopathy; 52.5% NPDR; 4.5% PDR; 4.5% ungradable Medical history: Myocardial infarction, %: 0% (< 6 months) Stroke, %:  0% (< 6 months) Equivalence of intervention groups at baseline: well balanced Inclusion criteria: type 2 diabetes diagnosed by WHO criteria, aged 40 to 74 years at study enrollment, DBP ≥ 90 mmHg and off all antihypertensive medication, willing to participate in study, and likely to complete 5 to 7 years of study Exclusion criteria: pregnancy or lactation (women), allergies to study medications, heart disease including uncorrected heart block, myocardial infarction, angina or heart failure, malignant hypertension, peripheral vascular disease, aortic dissection, on dialysis or other kidney disease, liver disease
Interventions	Intervention 1: intensive blood pressure control Goal DBP 75 mmHg Participants were randomized again to either nisoldipine 10 mg/day, titrated to 20, 40, and then 60 mg/day (plus placebo for enalapril), or enalapril 5 mg/day titrated to 10, 20, and then 40 mg/day (plus placebo for nisoldipine) as the initial antihypertensive medication. Additional antihypertensive medications were added in an open‐label, step‐wise manner initially with metoprolol, then hydrochlorothiazide, and then until the target blood pressure was achieved. Addition of medications was at the discretion of the medical director, but the additional medications could not include calcium channel blockers or ACEi. Intervention 2: moderate blood pressure control Goal DBP 89 mmHg Both interventions: additional antihypertensive medications were added in open‐label, step‐wise manner, initially with metoprolol, hydrochlorothiazide, and then until the target blood pressure was achieved. Addition of medications was at the discretion of the medical director, but the additional medications could not include calcium channel blockers or ACEi. Length of follow‐up: Planned: 5 to 7 years Actual: 4.7 years mean
Outcomes	Primary outcome, as specified for this review: incidence of retinopathy by 2 and 5 years follow‐up, progression of retinopathy by 2‐step and 3‐step worsening from baseline, based on photo gradings by the Wisconsin Retinal Reading Center Secondary outcomes, as specified for this review: none reported Other diabetic retinopathy outcomes: none reported Retinopathy diagnosis and monitoring: "All retinal films were interpreted and graded by the Fundus Photograph Reading Center at the University of Wisconsin without knowledge of the treatment arm. The graders used the protocol of the Early Treatment Diabetic Retinopathy Study (ETDRS)." Participants (eyes) examined for the outcomes: 470 Intervals at which outcomes were assessed: based on retinal photographs taken at 2‐ and 5‐year follow‐up Cost of interventions: not reported Quality of life: not reported Adverse outcomes: death Other outcomes reported from the study: glomerular filtration rate, urinary albumin excretion, left ventricular hypertrophy, neuropathy, and cardiovascular events
Notes	Source of funding: industry (Bayer) and government (NIDDK) Declaration of interest: not reported Run‐in length: 7 to 11 weeks on placebo Class(es) of antihypertensive agents assigned: calcium channel blocker, ACEi Degrees of blood pressure control achieved: SBP:means 132 mmHg in intensive group, 138 mmHg in moderate group DBP:means 78 mmHg in intensive group, 86 mmHg in moderate group
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“Randomization using permuted block randomization within strata was used to ensure equal sample sizes within all arms of the study.”
Allocation concealment (selection bias)	Low risk	“The random assignment to intensive versus moderate treatment with either active nisoldipine coat‐core or enalapril medication was made by telephone by the Data Coordinating Center and the Clinical Coordinating Center.”
Masking (performance bias and detection bias) Primary outcomes	Low risk	“The drugs and placebos were administered in a double‐blind manner. If the single study medication assigned did not achieve the target blood pressure, then open‐label antihypertensive medications were added in a stepwise fashion until the target blood pressure was achieved.” “All retinal films are interpreted and staged at the Wisconsin Retinal Reading Center without knowledge of the group to which the patient has been randomized.”
Incomplete outcome data (attrition bias) Primary outcome	High risk	No specific information on withdrawals, exclusions, or losses to follow‐up was reported. However, figures in each report of outcomes show numbers of participants at each examination through 5 years that suggest ~40% of those enrolled were lost to follow‐up sometime during the 5‐year period. No analysis to account for attrition
Selective reporting (reporting bias)	Unclear risk	Unclear with available information. Percentages reported without explicit denominators for outcomes during 5 years.
Other bias	High risk	“Financial support was provided by Bayer Pharmaceutical Company.” “Supported by the Bayer Pharmaceutical Company and by a grant (DK50298‐02) from the National Institute of Diabetes and Digestive and Kidney Diseases." “We are indebted to the members of the Data and Safety Monitoring Committee for their guidance: Paul W. Whelton, M.D., Tulane University, New Orleans; ... and Kevin Higgins, M.D., Bayer Pharmaceuticals, West Haven, Conn.”