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. 2023 Mar 28;2023(3):CD006127. doi: 10.1002/14651858.CD006127.pub3

ACCORD Eye.

Study characteristics
Methods Study design: substudy of ACCORD – a 2 x 2 factorial RCT
Unit of randomization and analysis: individual
Number randomized:

  • Total: 10,251 in ACCORD; 3537 enrolled in the ACCORD Eye study and 1590 in the ACCORD Eye blood pressure trial; 1263 participants in the blood pressure trial with 4‐year follow‐up data were analyzed for diabetic retinopathy outcomes in ACCORD Eye

  • Per group: blood pressure trial (n = 1263): 647 (intensive) and 616 (standard) analyzed for diabetic retinopathy outcomes. Visual acuity outcomes analyzed for 1546 participants: 798 (intensive) and 748 (standard).


Sample size calculation: target of 4065, which would have given 80% power to detect a 20% relative reduction with intensive blood pressure control as compared with standard blood pressure control (power of 77% for the blood pressure question for ACCORD Eye with 1263 enrolled participants, per ad hoc calculation)
Participants Country: USA and Canada
Study period: randomization in ACCORD began January 2001 (for Vanguard centers), was restarted February 2003, and ended October 2005; follow‐up completed June 2009; 8‐year follow‐up of ACCORD Eye survivors 2010 to 2014
Type of diabetes: type 2
Participants’ status at baseline inACCORD Eyeblood pressure trial except as noted:

  • Age, mean (SD): 61.3 (6.1) intensive, 61.5 (6.6) standard

  • Gender, % women: 48% intensive, 45% standard 

  • Race/ethnicity: 31.4% non‐white participants in intensive group,  32.6% non‐white participants in standard group

  • Diabetes duration, year, mean (SD): 10.1 (7.0) intensive, 10.3 (7.5) standard

  • Smokers, % current: 13.8% intensive, 12.5% standard

  • Blood pressure, mean (SD): 

    • SBP 138 (17) mmHg intensive, 139 (15) mmHg standard

    • DBP 76 (10) mmHg intensive, 77 (10) mmHg standard

  • Hypertension, %: not reported

  • Glycated hemoglobin, mean (SD): 8.4 ± 1.1 intensive, 8.2 (1.0) standard

  • BMI, mean (SD): 32.7 (5.7) intensive, 32.2 (5.3) standard

  • Severity of retinopathy: intensive group: 50.9% none; 16.3% mild; 30.2% moderate NPDR; 0.5% severe NPDR; 2.2% PDR. Standard group: 47.9% none; 19.0% mild; 32.1% moderate NPDR; 0.2% severe NPDR; 0.8% PDR

  • Medical history:

    • Myocardial infarction, %: not reported

    • Stroke, %: not reported


Equivalence of groups at baseline: imbalances on gender, cholesterol level, blood pressure, diabetic retinopathy
Inclusion criteria: type 2 diabetes (> 3 months); glycated hemoglobin level of ≥ 7.5%; and high risk for cardiovascular disease (established cardiovascular disease or had known risk factors); retinal photographs at baseline (for ACCORD Eye)
Exclusion criteria: history of PDR that had been treated with laser photocoagulation or vitrectomy
Interventions Intervention 1: intensive blood pressure control (intervention) arm targeted SBP < 120 mmHg. The recommendation was to start with a combination of a diuretic and either an ACEi or a beta‐blocker at randomization. Drug doses to be increased or additional antihypertensive medications added, or both, at "milepost" visits in the intensive group until goal was reached.
Intervention 2: standard blood pressure control arm targeted SBP 130 to 139 mmHg. Medication dose titration or the addition of another drug was indicated whenever SBP was ≥ 160 mmHg at a single visit or ≥ 140 mmHg at 2 successive visits.
Treatment algorithms for both arms described in Cushman 2007.
Length of follow‐up:

  • Planned: 4 years

  • Actual: 4 years; 8 years for a subset of survivors
Outcomes Primary outcome, as specified for this review: progression of diabetic retinopathy
Secondary outcomes, as specified for this review: development of PDR necessitating photocoagulation therapy or vitrectomy; macular edema; moderate vision loss from baseline to 4 years (i.e. loss of ≥ 3 lines on logMAR visual acuity charts)
Other diabetic retinopathy outcomes: legal blindness (20/160 or worse), severe vision loss (5/200)
Retinopathy diagnosis and monitoring: "The fundus photographs were evaluated by trained graders, who were unaware of the treatment assignments, at the Fundus Photograph Reading Center (University of Wisconsin, Madison), on the basis of the photographic standards defined for the Early Treatment Diabetic Retinopathy Study (ETDRS) and graded according to an abbreviated and modified version of the ETDRS Final Retinopathy Severity Scale for Persons, which combines  the severity levels from both eyes for each person."
Participants (eyes) examined for the outcomes: 1263 for retinopathy, 1746 for visual acuity
Intervals at which outcomes were assessed: visual acuity assessed at baseline, years 2, 4, 6, and 8 or at the study close‐out visit; retinopathy assessed at baseline, 4 and 8 years
Cost of the interventions: not reported
Quality of life: not reported
Adverse outcomes: death, CV events, renal failure, hypotension
Other outcomes reported: none from ACCORD Eye
Notes Sources of funding: government; industry‐donated study medications, equipment, and supplies
Declaration of interest: several authors declared interests related to pharmaceutical companies
Class(es) of antihypertensive agents assigned: not specified
Degree of blood pressure control achieved: intensive: median SBP < 120 mmHg (115 to 120); standard: median SBP < 140 mmHg (135 to 140)
Trial registration: NCT00542178
Other: participants were also randomized to intensive (maintenance of glycated hemoglobin < 6.0%) or standard (glycated hemoglobin 7.0% to 7.9%) glycemic control
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk “An Internet‐based, web browser randomization procedure will be employed in ACCORD” (protocol). Algorithm used to generate random sequence was not described clearly.
Allocation concealment (selection bias) Low risk "Randomization was performed centrally on the study's web site with the use of permuted blocks to maintain concealment of future study‐group assignments"
Masking (performance bias and detection bias)
Primary outcomes Low risk The blood pressure component of ACCORD was an unmasked, open‐label randomized trial. However:
"The fundus photographs were evaluated by trained graders, who were unaware of the treatment assignments ..."
Masking (performance bias and detection bias)
Secondary outcomes Unclear risk Not reported whether visual acuity assessors and ophthalmologists were masked to interventions
Incomplete outcome data (attrition bias)
Primary outcome Low risk 291 of 1263 participants (23%), 155 assigned to intensive blood pressure control and 136 assigned to standard blood pressure control, had missing 4‐year outcome data; number of deaths included in 291 not found.
"there was no evidence of significant differences regarding the amount of missing data, and the results of sensitivity analyses supported those of the primary analyses." Used logistic regression methods for multiple imputation
Incomplete outcome data (attrition bias)
Secondary outcomes Low risk See above
Selective reporting (reporting bias) Unclear risk Progression to PDR or CSME, or both, not reported.
Other bias Unclear risk 65 of 3537 (1.8%) of randomized participants enrolled were subsequently excluded from the trial due to detection of exclusion criteria after randomization. "... baseline fundus photographs could not be obtained within four months of randomization."
Conflicts of interest for the Data and Safety Monitoring Board members are unclear.
"For the Eye Substudy (in a subset of 4065 participants), the baseline eye exam/fundus photography can be performed up to 2 months post‐randomization." (protocol)