Purpose: This post hoc analysis explores the relationship between early retinal anatomical response and long-term anatomical and visual outcomes with ranibizumab in center-involved diabetic macular edema.
Methods: Eyes randomized to the ranibizumab plus prompt laser and ranibizumab plus deferred laser treatment arms in the Protocol I study were categorized according to their proportional reduction (<20 vs. ≥20%) in central retinal thickness (CRT) after 12 weeks. Adjusted and unadjusted analyses assessed the association between early (Week 12) anatomical response and long-term (Weeks 52 and 156) anatomical and best-corrected visual acuity outcomes.
Results: Of 335 study eyes, 118 showed limited (<20%) and 217 showed strong (≥20%) CRT reduction at Week 12. In unadjusted and adjusted analyses, limited early CRT response was negatively and significantly associated with strong CRT response at Weeks 52 and 156. Sensitivity analyses indicated that this association was robust and unrelated to any “floor effect.” In unadjusted analyses, a strong early CRT response was associated with greater long-term improvement in best-corrected visual acuity; after controlling for confounders, the association lost statistical significance.
Conclusion: Early CRT response to ranibizumab is a significant prognostic indicator of medium- to long-term anatomical outcome in center-involved diabetic macular edema.
Diabetic macular edema (DME), a frequent microvascular complication of Type 1 and 2 diabetes,1 is characterized by vascular leakage and accumulation of extracellular fluid in the macula because of breakdown of the blood-retinal barrier.2Disruption of retinal architecture (e.g., vitreoretinal interface abnormalities, loss of retinal inner layer boundaries, cell displacement by cystoid cavities, and neuroretinal detachment) associated with long-standing retinal edema3–6 may result in neuronal cell loss and compromised retinal function.7 Macular edema is the main cause of visual impairment in diabetic patients,8 with symptomatic vision loss occurring when macular thickening involves or threatens the fovea.2
Vascular endothelial growth factor-A (VEGF-A) is a potent vasopermeability factor closely implicated in disruption of the blood-retinal barrier in DME,9–11 making it a promising target for pharmacological intervention. Randomized clinical trials of the intravitreal anti-VEGF-A agents ranibizumab and aflibercept in eyes with center-involved DME have demonstrated their efficacy as monotherapy in comparison with laser photocoagulation in improving visual acuity12–14 and reducing central retinal thickness (CRT).13 Currently, intravitreal anti-VEGF-A agents are the treatment of choice for DME with central involvement.2 Nevertheless, even with the intensive treatment schedules used in clinical trials, the morphologic and visual responses to anti-VEGF-A therapy are often incomplete, with ∼20% to 65% of eyes failing to achieve resolution of retinal thickening12,15–17 and ∼30% to 70% of eyes showing <10-letter improvement in best-corrected visual acuity (BCVA)12,13,15,18–21 after 1 year or 2 years of treatment.
Persistent and/or recurrent macular edema has been implicated as a possible contributory factor to poor visual outcome with ranibizumab therapy in DME.22,23 Optical coherence tomography (OCT) provides an accurate and reliable measure of CRT in DME, enabling quantitative longitudinal monitoring of macular edema and its response to treatment.24,25 In the era of anti-VEGF-A–directed treatment of center-involved DME, OCT-derived retinal thickness has become a widely used quantitative end point in major clinical studies of DME.26 As a demonstration of the importance attached to OCT assessment in the management of DME, the Diabetic Retinopathy Clinical Research Network (DRCR.net) studies of intravitreal ranibizumab in the treatment of DME routinely use OCT-derived CRT response as a measure of treatment efficacy and the need for retreatment.27
Early identification of those patients for whom long-term anti-VEGF-A therapy is likely to confer that only limited visual benefit would enable more timely consideration of additional disease management strategies. To this end, the EARLY (Early Anti-VEGF Response and Long-term efficacy) program, a series of post hoc analyses of data from one of the largest studies of ranibizumab in DME—the Protocol I study15—was undertaken to explore the relationship between early and long-term anatomical and visual acuity outcomes of ranibizumab therapy. The primary objective of the present analysis was to assess whether retinal anatomical response after 12 weeks of ranibizumab therapy offered any indication of likely anatomical response at 1 year and 3 years. A secondary objective was to explore further the possible association between early anatomical and long-term visual acuity outcomes.
Patients and Methods
Protocol I Study Overview
Protocol I was a prospective, multicenter Phase III study conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net) of intravitreal ranibizumab and triamcinolone in patients with center-involved DME (clinicaltrials.govidentifier NCT00445003). The methodology of this study has been detailed elsewhere.15 In brief, study eyes (baseline BCVA of 78 to 24 Early Treatment Diabetic Retinopathy Study letters [approximate Snellen equivalent 20/32[FIGURE DASH]20/320] and time-domain OCT–determined CRT ≥250 µm) were randomly assigned to treatment with 1) intravitreal ranibizumab 0.5 mg plus prompt (within 7[FIGURE DASH]10 days) focal/grid photocoagulation, 2) intravitreal ranibizumab 0.5 mg plus deferred (after ≥24 weeks) focal/grid photocoagulation, 3) intravitreal triamcinolone 4 mg plus prompt focal/grid photocoagulation, or 4) sham injection plus prompt focal/grid photocoagulation. Intravitreal injections were performed at 4-week intervals for the first 12 weeks (or for the first 20 weeks if DME persisted) and as needed thereafter; repeat use of laser was governed by the extent of central macular edema. Use of alternative DME treatments was allowed only if prespecified treatment failure or futility criteria were met. Follow-up examinations, including measurements of BCVA and OCT (Stratus, Carl Zeiss Meditec Inc, Dublin, CA)-derived CRT, were performed every 4 weeks for the first year and every 4 weeks to 16 weeks thereafter. Patient follow-up was planned for 3 years, with the primary efficacy end point being the mean change in BCVA at 1 year.15 Review of study findings at 2 years indicated an efficacy advantage in the ranibizumab treatment arms,28 and patients in the sham injection and intravitreal triamcinolone treatment arms were offered the option of switching to open-label ranibizumab for the third year. Follow-up findings for the subset of eyes randomized to ranibizumab plus prompt or deferred laser treatment were reported at 3 years29 and 5 years.30
Anatomical and Visual Response Analysis
This analysis is based on 3-year follow-up data for those Protocol I study eyes that were randomized to ranibizumab plus prompt or deferred laser treatment and, in addition, provided an observed CRT measurement at Week 12. Eligible eyes were categorized according to their proportional change from baseline in CRT at Week 12: 1) eyes with <20% reduction (“limited early CRT response”) and 2) eyes with ≥20% reduction (“strong early CRT response”). Serial (4-weekly) CRT and BCVA readings over Weeks 12 to 156 were collected for the 2 cohorts; missing readings were imputed using the last-observation-carried-forward technique. Central retinal thickness and BCVA readings obtained after initiation of add-on treatment were also included in the analysis. Anatomical response over the 3-year follow-up period was expressed as the proportion of eyes with ≥20% reduction in CRT from baseline; visual acuity response was expressed as the mean absolute change from baseline in BCVA (Early Treatment Diabetic Retinopathy Study letters). To assess the robustness of any observed association between early and long-term anatomical response (as expressed by the percent reduction in CRT), a sensitivity analysis was conducted in eyes categorized according to the change in logarithmically transformed OCT-derived CRT (logOCT) value (<1 log-step, 1–2 log-step, and >2 log-step improvement) at Week 12. For this analysis, anatomical response over the 3-year follow-up period was expressed as the proportion of eyes with >2 log-step OCT improvement from baseline. A 1-step reduction in logOCT equates to ∼20% reduction in CRT, whereas a 2-step reduction equates to ∼36% reduction in CRT, irrespective of baseline CRT.31 To address the possibility that any demonstrated association between early and late anatomical response might be attributable to the limited scope for CRT reduction in eyes with mild retinal thickening (the “floor effect”), a sensitivity analysis was performed in eyes with baseline CRT ≥350 µm.
Intercohort comparisons of baseline characteristics, as well as anatomical responses (proportion of eyes with ≥20% reduction from baseline in CRT) and visual responses (mean change from baseline in BCVA) over the study period were performed using Student’s t-test or Kruskal–Wallis 1-way analysis of variance for continuous variables and Pearson chi-square test for categorical variables. Multiple linear and logistic regression analyses were performed on long-term (Weeks 52 and 156) anatomical responses (≥20% CRT reduction, and >2 log-step OCT improvement from baseline) and visual acuity outcome (BCVA change from baseline). In addition to early anatomical response (either <20% vs. ≥20% CRT reduction or <1 log-step and 1–2 log-step vs. >2 log-step OCT improvement at Week 12), covariates included in the regression models were age, sex, baseline BCVA and CRT, previous receipt of DME treatment, BCVA change at Week 12, and cumulative number of ranibizumab injections and laser treatments received at Week 52 or 156. P values were determined using Student’s t-test (linear regression) and Wald chi-square test (logistic regression). Statistical analyses were performed with SAS versions 9.3 and 9.4 (SAS Inc, Cary, NC). All tests were 2-tailed and a P value of ≤0.05 was considered statistically significant.
The Protocol I study allocated a total of 375 eyes to treatment with ranibizumab plus either prompt or deferred laser; of these, 335 eyes provided OCT-derived CRT data (and corresponding visual acuity data) at Week 12 and were included in the present analysis.
A limited initial anatomical response to ranibizumab did not preclude a further decrease in CRT with continued treatment. Among the cohort of study eyes with limited early CRT response (n = 118), 37 (31.4%) eyes subsequently achieved a ≥20% reduction in CRT by Week 52 (“slow responders”), whereas the remaining 81 (68.6%) eyes continued to show <20% reduction in CRT at Week 52 (“non-responders”). Subsequent response rates (proportion of eyes with ≥20% reduction in CRT) remained high in slow-responder eyes (91.9 and 86.5% at Weeks 104 and 156, respectively) but, despite a gradual improvement over time, were significantly (P < 0.001) lower in nonresponder eyes (23.5 and 35.8% at Weeks 104 and 156, respectively).
The significant association between early and long-term anatomical response to ranibizumab demonstrated in the unadjusted analysis persisted after controlling for potential confounding variables. Significant differences in demographic and baseline clinical characteristics and treatment intensity were noted between cohorts categorized by their proportional CRT response at Week 12 (Table 1). For example, eyes with ≥20% CRT reduction at Week 12 were younger (mean 61.5 vs. 65.0 years of age; P = 0.002), had lower baseline BCVA (mean 61.6 vs. 65.4 Early Treatment Diabetic Retinopathy Study letters; P = 0.004), and higher baseline CRT (433 vs. 345 µm; P < 0.001) and, as expected from their strong initial anatomical response, received fewer ranibizumab injections (mean 12.7 vs. 15.1; P = 0.005) and laser procedures (mean 1.7 vs. 2.4; P = 0.005) over the 3-year follow-up period than eyes with <20% CRT reduction at Week 12. Multiple logistic regression analysis with adjustment for differences in baseline parameters (age, sex, previous DME treatment, and baseline BCVA and CRT) indicated that <20% CRT reduction at Week 12 showed a significant negative association with ≥20% CRT reduction at Week 52 (odds ratio [OR] 0.11, 95% confidence interval [CI] 0.06–0.19; P < 0.001) and Week 156 (OR 0.35, 95% CI 0.20–0.61; P < 0.001). Of the other covariates included in this regression model, baseline BCVA and baseline CRT were significantly (positively) associated with ≥20% CRT reduction at Week 52, whereas baseline CRT remained significantly associated with ≥20% CRT reduction at Week 156. An expanded regression model that additionally adjusted for differences in treatment intensity over the 3-year study period likewise indicated that <20% CRT reduction at Week 12 was significantly (negatively) associated with ≥20% CRT reduction at Week 52 (OR 0.13, 95% CI 0.07–0.24; P < 0.001) and Week 156 (OR 0.45, 95% CI 0.25–0.81; P = 0.008) (Table 2). In this model, baseline CRT and cumulative number of ranibizumab injections were also significantly associated with ≥20% CRT reduction at Weeks 52 and 156 (Table 2).