Methodological quality of the review: High confidence
Author: Do DV, Wang X, Vedula SS, Marrone M, Sleilati G, Hawkins BS, Frank RN
Region: North America, Europe, Asia and Australia
Sector: Diabetic retinopathy
Sub-sector: Blood pressure control
Equity focus: None specified
Review type: Other review
Quantitative synthesis method: Meta-analysis
Qualitative synthesis method: Not applicable
Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Research has established the importance of blood glucose control to prevent development and progression of the ocular complications of diabetes. Simultaneous blood pressure control has been advocated for the same purpose, but findings reported from individual studies have supported varying conclusions regarding the ocular benefit of interventions on blood pressure.
The primary aim of the review was to summarize the existing evidence regarding the effect of interventions to control or reduce blood pressure levels among diabetics on incidence and progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs. The secondary aim of the review was to compare classes of anti-hypertensive medications with respect to the same outcomes.
In total, authors included 15 randomized controlled trials (RCTs), which were mainly conducted in North America and Europe. In 10 of the 15 RCTs, one group of participants was assigned to one or more anti-hypertensive agents and the control group received placebo. In three trials, intense blood pressure control was compared to less intense blood pressure control. In the remaining two trials, blood pressure control was compared with usual care. Five of the 15 trials enrolled Type 1 diabetics, and 10 trials enrolled Type 2 diabetics. Six trials were sponsored entirely by pharmaceutical companies, seven trials received partial support from pharmaceutical companies, and two studies received support from government-sponsored grants and institutional support.
Study designs, populations, interventions, and lengths of follow-up (range one to nine years) varied among the included trials. Overall, the quality of the evidence for individual outcomes was low to moderate. For the primary outcomes, incidence and progression of retinopathy, the quality of evidence was downgraded due to inconsistency and imprecision of estimates from individual studies and differing characteristics of participants.
Authors reported that evidence from included trials supported a benefit of more intensive blood pressure control intervention with respect to 4 to 5-year incidence of diabetic retinopathy (estimated risk ratio (RR) 0.80; 95% confidence interval (CI) 0.71 to 0.92) and the combined outcome of incidence and progression (estimated RR 0.78; 95% CI 0.63 to 0.97). Authors also noted that the evidence provided less support for a benefit with respect to 4- to 5-year progression of diabetic retinopathy (point estimate was closer to 1 than point estimates for incidence and combined incidence and progression, and the CI overlapped 1; estimated RR 0.88; 95% CI 0.73 to 1.05). Regarding progression to proliferative diabetic retinopathy or clinically significant macular edema or moderate to severe loss of best-corrected visual acuity did not support a benefit of intervention on blood pressure: estimated RRs and 95% CIs 0.95 (0.83 to 1.09) and 1.06 (0.85 to 1.33), respectively, after 4 to 5 years of follow-up. Findings within subgroups of trial participants (Type 1 and Type 2 diabetics; participants with normal blood pressure levels at baseline and those with elevated levels) were similar to overall findings.
The adverse event reported most often (seven of 15 trials) was death, yielding an estimated RR 0.86 (95% CI 0.64 to 1.14). Hypotension was reported from three trials; the estimated RR was 2.08 (95% CI 1.68 to 2.57). Other adverse ocular events were reported from single trials.
Authors concluded that included evidence in the review supports a beneficial effect of intervention to reduce blood pressure with respect to preventing diabetic retinopathy for up to 4 to 5 years. However, the lack of evidence to support such intervention to slow progression of diabetic retinopathy or to prevent other outcomes considered in this review, along with the relatively modest support for the beneficial effect on incidence, weakens the conclusion regarding an overall benefit of intervening on blood pressure solely to prevent diabetic retinopathy.
Authors included RCTs in which: a) participants were assigned to strict blood pressure control, alone or in combination with other interventions, were compared with participants assigned to less strict blood pressure control; b) participants were assigned to blood pressure control were compared with participants assigned to no intervention (placebo); and c) participants were assigned to treatment with on class of anti-hypertensive agents were compared with participants assigned to another class of anti-hypertensive agents.
Primary outcomes consisted of incidence of retinopathy and progression of retinopathy. Follow-up times of interest by the authors was between four and five years after enrollment. However, authors note analyzing primary outcomes at 18 months to two years reported from a few trials. Secondary outcomes were assessed at follow-up times mentioned above. These consisted of: decrease in visual acuity by three or more lines in both eyes on a logMAR chart; and incidence of proliferative diabetic retinopathy or clinically significant macular edema. Authors summarized adverse effects related to blood pressure: death, hypotension, and adverse ocular events; vision-related quality-of-life data as reported from the included studies, when available; and economic data on any cost or cost-effectiveness data, when available. Authors note not applying any restriction on follow-up time, however they considered one year inadequate for the outcomes relevant for the review.
Authors conducted a search on several electronic databases including CENTRAL, Ovid MEDLINE databases, EMBASE, LILACS, the metaRegister of Controlled Trials, ClinicalTri-als.gov, and the World Health Organization International Clinical Trials Registry Platform. Authors did not use any date or language restrictions on the search. In addition, authors reviewed references of included studies as part of the search strategy. Two authors independently screened studies for inclusion, extracted data and assessed the risk of bias of included studies. Risk of bias was assessed according to methods described in chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions.
Authors note that because all outcomes considered for the review were dichotomous, authors estimated risk ratios (RR) with 95% confidence interval (CI) for the primary and secondary outcome measures and adverse events. Heterogeneity was assessed using the Chi2 and I2 values. Publication bias was not assessed as very few studies were identified for inclusion in the review. Meta-analysis conducted used a random-effects-model for four to five years follow-up times, and fixed-effect model for 18 months to two years follow-up times.
Authors recognize that because only RCTs were included in the review, the included trials were heterogeneous in several important respects (for example, sample size, practices do not reflect what is currently in use).
Authors note that specific racial or ethnic distribution was not reported in the description of most included trials. Of those which report the geographical location of the study and compare retinal lesions at baseline among white and Asian participants, none of the trials provided data to suggest that diabetic individuals from different racial or ethnic groups differed in their responses to blood pressure control with respect to the development or progression of retinopathy or to adverse events.
Summary of quality assessment:
Overall, there is high confidence in the conclusions of the review. Authors used thorough methods to identify studies for inclusion. Rigorous methods were used to screen studies for inclusion, extract data and assess the methodological quality of included studies. Authors did not draw strong policy conclusions based on included evidence, and acknowledged limitations of the review.