Dataset Information

Topographical Response of Retinal Neovascularization to Aflibercept or Panretinal Photocoagulation in Proliferative Diabetic Retinopathy: Post Hoc Analysis of the CLARITY Randomized Clinical Trial.

ABSTRACT:

Importance

Eyes with proliferative diabetic retinopathy have a variable response to treatment with panretinal photocoagulation (PRP) or anti-vascular endothelial growth factor agents. The location of neovascularization (NV) is associated with outcomes (eg, patients with disc NV [NVD] have poorer visual prognosis than those with NV elsewhere [NVE]).

Objective

To investigate the distribution of NV in patients with proliferative diabetic retinopathy and the topographical response of NV to treatment with aflibercept or PRP.

Design, setting, and participants

This post hoc analysis of the phase 2b randomized clinical single-masked multicenter noninferiority Clinical Efficacy and Mechanistic Evaluation of Aflibercept for Proliferative Diabetic Retinopathy (CLARITY) trial was conducted from November 1, 2019, to September 1, 2020, among 120 treatment-naive patients with proliferative diabetic retinopathy to evaluate the topography of NVD and NVE in 4 quadrants of the retina on color fundus photography at baseline and at 12 and 52 weeks after treatment.

Exposures

In the CLARITY trial, patients were randomized to receive intravitreal aflibercept (2 mg/0.05 mL at baseline, 4 weeks, and 8 weeks, and as needed from 12 weeks onward) or PRP (completed in initial fractionated sessions and then on an as-needed basis when reviewed every 8 weeks).

Main outcomes and measures

Main outcomes were per-retinal quadrant frequencies of NV at baseline and frequencies of patterns of regression, recurrence, and new occurrence at 12-week and 52-week unmasked follow-up.

Results

The study included 120 treatment-naive patients (75 men; mean [SD] age, 54.8 [14.6] years) with proliferative diabetic retinopathy (there was a 1:1 ratio of eyes to patients). At baseline, NVD with or without NVE was observed in 42 eyes (35.0%), and NVE only was found in 78 eyes (65.0%); NVE had a predilection for the nasal quadrant (64 [53.3%]). Rates of regression with treatment were higher among eyes with NVE (89 of 102 [87.3%]) compared with eyes with NVD (23 of 43 [53.5%]) by 52 weeks, with NVD being more resistant to either treatment with higher rates of persistence than NVE (20 of 39 [51.3%] vs 29 of 100 [29.0%]). Considering NVE, the regression rate in the temporal quadrant was lowest (32 of 42 [76.2%]). Eyes treated with aflibercept showed higher rates of regression of NVE compared with those treated with PRP (50 of 52 [96.2%] vs 39 of 50 [78.0%]; difference, 18.2% [95% CI, 5.5%-30.8%]; P = .01), but no difference was found for NVD (11 of 17 [64.7%] vs 12 of 26 [46.2%]; difference, 18.6% [95% CI, -11.2% to 48.3%]; P = .23).

Conclusions and relevance

This post hoc analysis found that NVD is less frequent but is associated with more resistance to currently available treatments than NVE. Aflibercept was superior to PRP for treating NVE, but neither treatment was particularly effective against NVD by 52 weeks. Future treatments are needed to better target NVD, which has poorer visual prognosis.

Trial registration

isrctn.org Identifier: ISRCTN32207582.

SUBMITTER: Halim S

PROVIDER: S-EPMC7953330 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IMPORTANCE:Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME). OBJECTIVE:To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy. DESIGN, SETTING, AND PARTICIPANTS:Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015. INTERVENTIONS:Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n?=?203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n?=?191 eyes). Eyes in both treatment groups could receive ranibizumab for DME. MAIN OUTCOMES AND MEASURES:The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization. RESULTS:Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P?<?.001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P?<?.001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P?<?.001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P?<?.001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P?<?.001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P?=?.58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified. CONCLUSIONS AND RELEVANCE:Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT01489189.

Project description:PURPOSE:To compare rates and identify predictive factors for events that represent worsening of proliferative diabetic retinopathy (PDR) in eyes treated with panretinal photocoagulation (PRP) or ranibizumab. DESIGN:Randomized clinical trial (55 United States sites). PARTICIPANTS:Three hundred ninety-four study eyes from 305 adults with PDR, visual acuity (VA) 20/320 or better, and no history of PRP. INTERVENTION:Panretinal photocoagulation or intravitreous ranibizumab injections (0.5 mg/0.05 ml). MAIN OUTCOME MEASURES:Time from randomization to a composite PDR-worsening outcome defined as the first occurrence of vitreous hemorrhage, retinal detachment, anterior segment neovascularization, or neovascular glaucoma. RESULTS:Through 2 years, the cumulative probability of worsening PDR was 42% (PRP) versus 34% (ranibizumab; hazard ratio [HR], 1.33; 99% confidence interval [CI], 0.90 to 1.98; P = 0.063). Worse baseline levels of diabetic retinopathy severity (Early Treatment Diabetic Retinopathy Study scale) were associated with increased risk of worsening PDR, regardless of treatment group (64% [high-risk PDR or worse] vs. 23% [moderate PDR or better]; HR, 3.97; 99% CI, 2.48 to 6.36; P < 0.001). In the PRP group, eyes receiving pattern scan versus conventional single-spot PRP also were at higher risk for worsening PDR (60% vs. 39%; HR, 2.04; 99% CI, 1.02 to 4.08; P = 0.008), regardless of the number of spots placed or the number of sittings to complete the initial PRP. Eyes in both groups with vision-impairing (VA 20/32 or worse) center-involved diabetic macular edema (DME) at baseline were required to receive ranibizumab for center-involved DME. Therefore the composite outcome was compared by treatment in the subgroup of eyes that did not have vision-impairing center-involved DME at baseline. For these eyes, the rate of PDR-worsening was greater with PRP than ranibizumab (45% vs. 31%; HR, 1.62; 99% CI, 1.01 to 2.60; P = 0.008). CONCLUSIONS:In eyes with PDR, ranibizumab resulted in less PDR worsening compared with PRP, especially in eyes not required to receive ranibizumab for center-involved DME. Although anti-vascular endothelial growth factor therapy requires a more frequent visit schedule than PRP, these findings provide additional evidence supporting the use of ranibizumab as an alternative therapy to PRP for PDR, at least through 2 years.

Project description:PurposeTo identify baseline factors associated with change in visual acuity or development of vision-impairing central-involved diabetic macular edema (DME) over 2 years when treating proliferative diabetic retinopathy (PDR) with ranibizumab or panretinal photocoagulation (PRP).DesignPost hoc analyses of randomized, multicenter clinical trial data.ParticipantsEyes completing the 2-year visit (n = 328) or without vision-impairing central-involved DME at baseline (n = 302) in Diabetic Retinopathy Clinical Research Network Protocol S.MethodsIntravitreous ranibizumab (0.5 mg/0.05 ml) or PRP.Main outcome measuresChange in visual acuity (area under the curve) and development of vision-impairing (20/32 or worse) central-involved DME over 2 years.ResultsAfter multivariable model selection with adjustment for baseline visual acuity and central subfield thickness, no factors were identified as associated with change in visual acuity or development of vision-impairing central-involved DME within the ranibizumab group. In the PRP group, worse change in visual acuity was more likely with higher hemoglobin A1c level (-0.6 letters per 1% increase; 95% confidence interval [CI], -1.2 to -0.1 letters; continuous P = 0.03), more severe diabetic retinopathy (difference between high-risk PDR or worse vs. moderate PDR or better, -2.8 letters [95% CI, -5.5 to -0.2 letters]; continuous P = 0.003), and higher mean arterial pressure (difference between ≥100 mmHg vs. <100 mmHg, -2.0 letters [95% CI, -4.6 to 0.5 letters]; continuous P = 0.009). Development of vision-impairing central-involved DME was more likely with higher hemoglobin A1c level (hazard ratio [HR] per 1% increase, 1.31 [95% CI, 1.13-1.52]; continuous P < 0.001), more severe diabetic retinopathy (HR for high-risk PDR or worse vs. moderate PDR or better, 1.46 [95% CI, 0.73-2.92]; continuous P = 0.03), and the presence of cystoid abnormalities within 500 μm of the macula center (HR, 2.90 [95% CI, 1.35-6.24]; P = 0.006).ConclusionsFor eyes managed with PRP, higher hemoglobin A1c level and more severe diabetic retinopathy were associated with less vision improvement and an increased risk of vision-impairing central-involved DME developing. When managing PDR with ranibizumab, eyes gained vision, on average, with no baseline characteristics identified as associated with visual acuity or central-involved DME outcomes.

Project description:ImportanceVitreous hemorrhage from proliferative diabetic retinopathy can cause loss of vision. The best management approach is unknown.ObjectiveTo compare initial treatment with intravitreous aflibercept vs vitrectomy with panretinal photocoagulation for vitreous hemorrhage from proliferative diabetic retinopathy.Design, setting, and participantsRandomized clinical trial at 39 DRCR Retina Network sites in the US and Canada including 205 adults with vison loss due to vitreous hemorrhage from proliferative diabetic retinopathy who were enrolled from November 2016 to December 2017. The final follow-up visit was completed in January 2020.InterventionsRandom assignment of eyes (1 per participant) to aflibercept (100 participants) or vitrectomy with panretinal photocoagulation (105 participants). Participants whose eyes were assigned to aflibercept initially received 4 monthly injections. Both groups could receive aflibercept or vitrectomy during follow-up based on protocol criteria.Main outcomes and measuresThe primary outcome was mean visual acuity letter score (range, 0-100; higher scores indicate better vision) over 24 weeks (area under the curve); the study was powered to detect a difference of 8 letters. Secondary outcomes included mean visual acuity at 4 weeks and 2 years.ResultsAmong 205 participants (205 eyes) who were randomized (mean [SD] age, 57 [11] years; 115 [56%] men; mean visual acuity letter score, 34.5 [Snellen equivalent, 20/200]), 95% (195 of 205) completed the 24-week visit and 90% (177 of 196, excluding 9 deaths) completed the 2-year visit. The mean visual acuity letter score over 24 weeks was 59.3 (Snellen equivalent, 20/63) (95% CI, 54.9 to 63.7) in the aflibercept group vs 63.0 (Snellen equivalent, 20/63) (95% CI, 58.6 to 67.3) in the vitrectomy group (adjusted difference, -5.0 [95% CI, -10.2 to 0.3], P = .06). Among 23 secondary outcomes, 15 showed no significant difference. The mean visual acuity letter score was 52.6 (Snellen equivalent, 20/100) in the aflibercept group vs 62.3 (Snellen equivalent, 20/63) in the vitrectomy group at 4 weeks (adjusted difference, -11.2 [95% CI, -18.5 to -3.9], P = .003) and 73.7 (Snellen equivalent, 20/40) vs 71.0 (Snellen equivalent, 20/40) at 2 years (adjusted difference, 2.7 [95% CI, -3.1 to 8.4], P = .36). Over 2 years, 33 eyes (33%) assigned to aflibercept received vitrectomy and 34 eyes (32%) assigned to vitrectomy received subsequent aflibercept.Conclusions and relevanceAmong participants whose eyes had vitreous hemorrhage from proliferative diabetic retinopathy, there was no statistically significant difference in the primary outcome of mean visual acuity letter score over 24 weeks following initial treatment with intravitreous aflibercept vs vitrectomy with panretinal photocoagulation. However, the study may have been underpowered, considering the range of the 95% CI, to detect a clinically important benefit in favor of initial vitrectomy with panretinal photocoagulation.Trial registrationClinicalTrials.gov Identifier: NCT02858076.