Could intensive blood pressure control really reduce diabetic retinopathy outcomes? Evidence from meta-analysis and trial sequential analysis from randomized controlled trials

Methodological quality of the review: Medium confidence

Author: Zhou JB, Song ZH, Bai L, Zhu XR, Li HB, Yang JK

Region: United Stated of America (USA), Italy, Slovenia, Denmark, United Kingdom (UK) and Canada.

Sector: Diabetic retinopathy

Sub-sector: Risk factor

Equity focus:  None specified

Review type: Other review

Quantitative synthesis method: Meta-analysis

Qualitative synthesis method: Not applicable

Background:

Objectives:

To explore the accumulated evidence concerning the effect of intensive blood pressure control on the incidence and progression of diabetic retinopathy (DR), proliferative diabetic retinopathy (PDR) and macular edema (MA).

Main findings:

Eight trials randomizing 6,989 patients were included in the review: 3,749 vs. 3,240 were in each arm (intensive versus conventional). Authors attributed low risk of bias to all trials. Authors reported that intensive blood pressure control supported a 17% reduction in the incidence of DR (relative risk 0.83, 95% confidence interval 0.72–0.95). Authors’ trial sequential analyses confirmed that sufficient evidence indicated a relative risk reduction above 17% for the incidence of DR when intensive blood pressure control was targeted.

Authors reported no heterogeneity within studies (I2 = 0%; P = 0.56). In addition, authors reported no statistically significant effect was found for intensive blood pressure targeting on the progress of DR (relative risk 0.94, 95% confidence interval 0.81–1.08). Authors noted that trial sequential analysis (TSA) showed that insufficient evidence had been found, although the Z value line appeared to have a tendency of approaching the futility boundaries. In addition, findings from authors analysis showed that there were no statistically significant effects on the incidence of PDR and ME (TSA-adjusted CI 0.84–1.12).

Authors concluded that intensive blood pressure control reduced the relative risk of incidence of DR by 17%; the available data were insufficient to prove or refute a relative risk reduction for the progression of DR or incidence of PDR and ME at a magnitude of 15%.

Authors note that this study findings for daily clinical practice should be emphasized, and in addition, they state that understanding whether diabetic individuals have a lower risk of DR with the strict blood pressure targets will help diabetologists to provide effective clinical counseling for patients. Blood pressure optimization should be done in primary care or by a diabetologist before the patients even see the ophthalmologist.

Methodology: 

Inclusion criteria consisted of randomized controlled trials (RCTs) investigating the effect of strict blood pressure targeting on the incidence, progression of DR, or incidence of PDR and ME.

Authors searched the following databases MEDLINE, EMBASE, and the Cochrane Controlled Trials Register for articles from inception to April 2018 using a search strategy as follows: [diabetic retinopathy, proliferative diabetic retinopathy (PDR), macular edema, diabetic maculopathy, retinal disorders, retinal disease, diabetic eye disease, or vision loss], (randomized, random, placebo-controlled, double-blind), (hypertension or blood pressure) and (angiotensin II type 1 receptor blockers, adrenergic alpha antagonist, adrenergic beta antagonists, diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, antihypertensive agents).

Two authors independently screened studies for inclusion and extracted data of included studies. Authors note diving included trials into those with low and high risk of bias according to Cochrane Handbook risk of bias tool.

Authors assessed the within- and between-study variation or heterogeneity by testing Cochran’s Q statistic. Authors quantified heterogeneity with I² metric, they estimated pooled OR using fixed effects and random effects models. Random effects was used when heterogeneity was present among studies. Authors note assessing for publication bias using the Egger’s regression test. A trial sequential analysis was conducted by the authors.

Applicability/external validity:

Authors did not assess applicability/external validity of findings.

Geographic focus:

Authors included studies from high income settings and it is not clear if authors included studies conducted in low- and middle-income countries.

Summary of quality assessment:

Overall, there is medium confidence in the conclusions about the effects of this review. Although authors used appropriate methods to screen studies and extract data of included studies, authors did not conduct a thorough search of the literature to ensure all eligible RCTs were identified and included in the review.