Could Intensive Blood Pressure Control Really Reduce Diabetic Retinopathy Outcomes? Evidence from Meta-Analysis and Trial Sequential Analysis from Randomized Controlled Trials

Abstract

Introduction: 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 (ME).

Methods: A number of electronic databases were searched including PubMed, EMBASE, CINAHL, Cochrane Library, conferences and proceedings. Randomized controlled trials comparing intensive blood pressure targets with conventional blood pressure targets in patients with type 2 diabetes were included. The definition of intensive versus conventional blood pressure targets was from the pertinent original studies. Meta-analyses and trial sequential analyses of randomized trials were analyzed in STATA.

Results: Eight trials randomizing 6989 patients were assessed and reviewed in full text; 3749 vs. 3240 were in each arm (intensive vs. conventional). All trials had a low risk of bias. Intensive blood pressure control supported a 17% reduction in the incidence of DR (relative risk 0.83, 95% confidence interval 0.72-0.95). 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. Heterogeneity was absent (I² = 0%; P = 0.56). 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). TSA showed that insufficient evidence had been found, although the Z value line appeared to have a tendency of approaching the futility boundaries. There were also no statistically significant effects on the incidence of PDR and ME (TSA-adjusted CI 0.84-1.12).

Conclusion: 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%.

Keywords: Diabetic retinopathy; Intensive blood pressure control; Trial sequential analysis.

Fig. 1

Flow chart of study selection. RCTs randomized controlled trials

Fig. 2

Effect of intensive blood pressure target versus control group on incidence of DR; 95% CI, filled square (for each group) and open diamond (for all studies combined). Broken vertical line represents summary RR of the total pooled data

Fig. 3

Required information size to demonstrate or reject 15% relative risk reduction in the effect of strict blood pressure targets on incidence of DR with an alpha of 5% and beta of 20% is 9184 patients (vertical red line). The red dashed lines represent the trial sequential monitoring boundaries and the futility boundaries. The solid blue line is the cumulative Z curve

Fig. 4

Effect of intensive blood pressure target versus control group on progression of DR; 95% CI filled square (for each group) and open diamond (for all studies combined). Broken vertical line represents summary RR of the total pooled data

Fig. 5

Required information size to demonstrate or reject 15% relative risk reduction (a priori estimate) of the effect of strict blood pressure targets on progression of DR (with a control group proportion of 16.8%, alpha of 5%, and beta of 20%) is 7157 patients (vertical red dashed line). The red dashed lines represent the trial sequential monitoring boundaries and the futility boundaries. The solid blue line is the cumulative Z curve

Fig. 6

Effect of intensive blood pressure target versus control group on the incidence of PDR or macular edema; 95% CI filled square (for each group) and open diamond (for all studies combined). Broken vertical line represents summary RR of the total pooled data

Fig. 7

Required information size to demonstrate or reject 15% relative risk reduction of the effect of a strict blood pressure target on the incidence of PDR or macular edema (with a control group proportion of 13.1%, alpha of 5%, and beta of 20%) is 11,572 patients (vertical red dashed line). The red dashed lines represent the trial sequential monitoring boundaries and the futility boundaries. The solid blue line is the cumulative Z curve