Research Article - Journal of Clinical Ophthalmology (2020) Volume 4, Issue 2

Endolaserless vitrectomy with aflibercept for proliferative diabetic retinopathy-related vitreous hemorrhage (LASER LESS TRIAL):1-Year Results.

¹Southeast Retina Center, Augusta 30909, Georgia, USA

²Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, Georgia, USA

Corresponding Author:

Dr. Dennis M Marcus
Southeast Retina Center 3685 Wheeler Rd
Ste 201 Augusta, GA 30909, USA
Tel: (706) 650-0061
Fax: (706) 650-0064
E-mail: dmarcus@southeastretina.com

Accepted date: June 02, 2020

Citation: Marcus DM, Starnes D, Walia H, et al. Endolaserless vitrectomy with aflibercept for proliferative diabetic retinopathy-related vitreous hemorrhage (LASER LESS TRIAL):1-Year Results. J Clin Ophthalmol 2020;4(2):254-265.

Abstract

Objective: We report the 1-year safety and efficacy results of vitrectomy without endolaser for proliferative diabetic retinopathy (PDR)-related vitreous hemorrhage (VH).

Methods: All eyes received one preoperative and intraoperative IAI (2 mg). The q8week group received postoperative IAI every 4 weeks through week 16 followed by q8week IAI. The q16week group received postoperative IAI every 4 weeks through week 8 followed by q16week IAI. All patients were examined every 4 weeks; PRN IAI for PDR progression or diabetic macular edema (DME) was allowed.

Results: Thirty-one eyes from 40 patients were randomized. Through 52 weeks, endophthalmitis, progression of traction retinal detachment, iris/angle neovascularization and neovascular glaucoma were not observed. The q8week and q16week groups received an average of 8.4 and 5.4 injections, respectively, through 52 weeks. Adverse events at any time through 52 weeks such as worsened visual acuity>30 letters (6 eyes), new rhegmatogenous retinal detachment (1 eye), and recurrent VH (4 eyes) occurred infrequently and were more common in the q16week group. Preoperative average visual acuity (VA) was 37 letters (20/200) for randomized eyes. Endolaserless vitrectomy resulted in statistically significant 52-week visual acuity 33 letter gain to 72 letters (20/40). Visual acuity outcomes favored (not statistically significant) the q8week group where average acuity was 77 letters (20/32) with a 52-week 40 letter gain versus 66 letters (20/50) with a 52-week 24 letter gain in the q16week group.

Conclusion: Endolaserless vitrectomy with aflibercept demonstrates 52-week safety with significant VA improvement.

Keywords

Endolaser, Pars plana vitrectomy, Proliferative diabetic retinopathy, Anti-vascular endothelial growth factor, Vitreous hemorrhage.

Abbreviations

EPDR: Proliferative Diabetic Retinopathy; VH: Vitreous Hemorrhage; DME: Diabetic Macular Edema; BCVA: Best Corrected Visual Acuity; VEGF: Vascular Endothelial Growth Factor; PRP: Pan-Retinal Photocoagulation; PPV: Pars Plana Vitrectomy; IAI: Intravitreal Aflibercept Injection; DRCR: Diabetic Retinopathy Clinical Research; DRVS: Diabetic Retinopathy Vitrectomy Study; HVF: Humphrey Visual Field; OCT: Optical Coherent Tomography; VA: Visual Acuity

Introduction

Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is now established as optimal therapy for centerinvolved diabetic macular edema (DME) [1-4]. Anti-VEGF’s ability to reduce retinal neovascularization during DME treatment has led to investigation of anti-VEGF therapy for PDR [5-9] and PDR-related vitreous hemorrhage [10-13]. For over 4 decades, PRP has remained the standard therapy for PDR. However, anti- VEGF therapy has emerged as an alternative therapy for PDR eyes not requiring vitrectomy [5,7-9]. Diabetic Retinopathy Clinical Research (DRCR) Protocol S compared anti-VEGF ranibizumab to PRP for PDR not requiring vitrectomy [5,8].

DRCR Protocol S concluded that their findings supported either anti-VEGF therapy or PRP as viable PDR treatment [8]. The PROTEUS study showed that adding ranibizumab to PRP was more effective than PRP alone in regressing neovascularization in eyes with high-risk PDR [9]. The CLARITY trial further supports anti-VEGF aflibercept therapy in PDR eyes [7]. When PDR was present in eyes being treated for DME in DRCR Protocol T, aflibercept resulted in greater PDR regression rates compared to ranibizumab and Bevacizumab [6].

Given the above information, intravitreal aflibercept injection (IAI) may represent a useful therapy before, during, and after vitrectomy for PDR-related vitreous hemorrhage. We previously reported the short-term 4-month results with endolaserless vitrectomy and aflibercept for eyes with PRP-naïve PDR-related VH [11-13]. Herein, we report 52-week safety and efficacy results for our expanded cohort of 40 eyes.

Materials and Methods

This is a phase I/II, open-label, randomized, prospective, single center interventional study. Eligible subjects were identified and provided with a copy of informed consent. Informed consent documentation and relevant supporting information was submitted and approved by the Institutional Review Board (IRB)/Ethics Committee (EC).

Study population

Adult subjects with Type 1 or Type 2 diabetes mellitus and PDR-related VH requiring vitrectomy. Vitrectomy need was determined by a non-study, standard of care visit prior to the screening study visit. Exclusion criteria are listed in Table 1.

Table 1. Exclusion criteria.

Study design

Only one eye per patient was eligible and was randomly assigned after vitrectomy with equal probability to either a q8week or q16week treatment group. Figure 1 presents the injection and randomization schedule.

Figure 1: Aflibercept (2mg) Treatment Schedule: 21 randomized patients with PRP-naïve eyes undergoing vitrectomy for PDR-related vitreous hemorrhage randomized in 1:1 ratio. PRN: pro re nata; Scr:
screen; SX: surgery; POD1: post-operative day 1; POWK: post-operative week 1.

Intraoperative methods and assessment

Eyes underwent 23-gauge PPV. After removal of VH, eyes were intraoperatively evaluated for randomization eligibility. Eyes ineligible for randomization, as determined intraoperative, did not receive intraoperative IAI, but did receive intraoperative endolaser and were followed postoperatively.

Visit schedule

Figure 2 summarizes the visit schedule.

Figure 2: Visit Schedule. FA: Fluorescein Angiography; FP: Fundus Photography; Scr: screen; SX: Surgery; POD1: post-operative day 1; POWK1: post-operative week 1.

Post-operative PDR treatment and monitoring

PDR was monitored and assessed for progression by postoperative clinical exam and q12 week standard 7-field fundus photography and Optos wide-field fluorescein angiography/photography. If progression of PDR occurred at a visit where IAI was not mandatory, IAI was required at that visit and in 4 weeks. If regression of the progressed PDR was not evident after 2 consecutive monthly IAI, then PRP could be administered. Criteria for PDR progression and regression are summarized in Table 2.

Table 2. Criteria for PDR progression and regression.

DME treatment and monitoring

Eyes with clinical and optical coherent tomography (OCT) DME in the q8week group were to receive appropriate IAI per label as part of the mandatory schedule through 16 weeks. Starting at week 12 and week 20 in the q16 and q8week groups, respectively, eyes were eligible to receive additional 2mg IAI (monthly) for the treatment of DME (Table 3).

Table 3. Criteria for additional monthly IAI for DME.

Outcome Measurements

Primary outcomes

Primary safety outcomes are summarized in Table 4.

Table 4. Primary safety outcomes.

Secondary outcomes

Secondary outcomes are summarized in Table 5. Qualitative angiographic outcomes were evaluated based on size and leakage intensity of hyper fluorescence. Qualitative photographic outcomes were based on photographic DME/exudate size and thickness.

Table 5. Secondary outcomes.

Visual field outcomes were evaluated by the mean cumulative score and change for the combined 30-2 and 60-4 Humphrey visual field (HVF) decibel thresholds from week 4 to week 52.

Results/Observations

Study participants

Forty eyes from 40 subjects were enrolled. Baseline demographics are presented in Table 6. All eyes received preoperative IAI at enrollment. Two intraoperative retinal tears, in two eyes, were treated with intraoperative retinal cryopexy. Five of the 31 randomized eyes required membrane peel for nonmacular traction. Average surgical time was 21 minutes (range: 12-47 minutes) for randomized eyes. Twenty-five of 31 (81%) randomized subjects completed their 52-week follow-up visit. Figure 3 summarizes patient randomization and retention.

Figure 3: Participant randomization and retention. Last observation carried forward (LOCF) from week 48 was used for this participant for week 52 analysis.

Table 6. Baseline Demographics for 31 randomized eyes. One subject declined vitrectomy after enrollment and receipt of pre-operative IAI. This subject continues follow-up for safety as a nonrandomized eye. One subject was unable to undergo vitrectomy after enrollment and receipt of pre-operative IAI due to accelerated hypertension at time of surgery. This subject has been lost to follow-up since the decision to not undergo surgery. Thirty-eight of 40 enrolled eyes underwent vitrectomy surgery. Seven of those 39 eyes were not randomized due to intraoperative evidence of previous peripheral retinal ablation (2 eyes), traction retinal detachment involving the macula (2 eyes), significant nasal fibrovascular proliferation and noncentral nonmacular traction retinal detachment (1 eye), cataracts and retrolental hemorrhage (1 eye), and intraoperative tears (1 eye). These seven non-randomized eyes received intraoperative endolaser and did not receive intraoperative IAI and continue follow-up for safety as nonrandomized eyes.

Primary safety outcomes

Adverse primary safety outcomes are summarized in Table 7. All adverse events are summarized in Table 8. Treatment schedules for two subjects experiencing recurrent vitreous hemorrhages are presented in Figures 4 and 5.

Figure 4: Vitreous hemorrhage case presentation, VH: Vitreous Hemorrhage.

Figure 5: Vitreous hemorrhage case presentation; VH: Vitreous Hemorrhage.

Table 7. Primary safety outcomes results through 52 weeks.

Table 8. Adverse events.

Injection treatment requirement and compliance

An average of 8.4 (range: 2 to 10) and 5.4 (range: 2 to 9) total injections though 52 weeks were administered to the q8week and q16week treatment groups, respectively (Table 9).

Table 9. Follow-up and injection compliance.

Visual acuity outcomes

Endolaserless vitrectomy with IAI resulted in statistically significant VA gain for all eyes and in both groups (Table 10, Figure 6). Baseline preoperative VA letter score for 31 randomized eyes was 37 letters (20/200) (range: 0 to 84 letters). For 26 randomized eyes in both groups with 52-week followup, baseline preoperative VA letter score was 40 letters (20/160) (range: 0 to 84 letters). At 52 weeks, the average best corrected visual acuity (BCVA) score improved to 72 letters (20/40) with an average change in BCVA of +33 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline (range: -10 to 90 letters) (p<0.00004; one tailed t-test). For randomized eyes in the q8week group with 52-week follow-up, average BCVA improved to 77 letters (20/32) with an average letter gain of +40 ETDRS letters (range: -10 to 90 letters) (p<0.0009; one-tailed t-test). For randomized eyes in the q16week group with 52-week follow-up, average BCVA improved to 66 letters (20/50) with an average letter gain of +24 letters (range: -6 to 85 letters) (p<0.0097; one-tailed t-test). Baseline letter score did not show a statistically significant difference between the two groups (35 letters q8week and 42 letters q16week) (p<0.882; two-tailed t-test). Letter score change from baseline favored the q8week group (40 letter gain q8week versus 24 letter gain q16week) but this was not statistically significant (p<0.480; two-tailed t-test).

Figure 6: Average visual acuity.

Table 10. Visual acuity change from baseline.

OCT Outcomes

Baseline OCT was performed at 4 weeks postoperatively in 31 randomized eyes with no statistically significant difference between the two groups but thinner in the q16week group (336 um q8week group and 282 um q16week group) (p<0.408; twotailed t-test). Endolaserless vitrectomy with IAI resulted in statistically significant OCT thinning from week 4 to week 52 for all eyes in the q8week but not in the q16week group (Table 11, Figure 7). For 26 randomized eyes at 52-week follow-up, average OCT central subfoveal thickness (CST) was 264 um (range: 147 to 338 um), which displayed an average thinning of 33 um from the baseline OCT 4-week postoperative visit (p<0.000014; onetailed t-test). For randomized eyes in the q8week group with 52-week follow-up, average 52 week OCT CST was 270 um with an average thinning of 53 um from baseline (p<0.004; onetailed t-test). For randomized eyes in the q16week group with 52 week follow-up, average 52 week OCT CST was 255 um with an average thinning of 12 um from baseline (p<0.165; one-tailed t-test). Fifty-two week OCT thickness change (53 um thinning q8week group and 12 um thinning q16week group) from baseline favored the q8week group (not statistically significant) (p<0.312; two-tailed t-test)

Figure 7: Average OCT values.

Table 11. Average OCT values through 52 weeks post-operatively.

Eight of 31 randomized eyes (5 in q8week group and 3 in q16week group) demonstrated DME intraoperatively. At 4 weeks and 52 weeks postoperatively, OCT CST>300 um was observed in 11 of 31 randomized eyes (7 in q8week group and 4 in q16week group) and 4 of 25 randomized eyes (2 in q8week group and 2 in q16week group), respectively. Clinical DME at 52 weeks postoperatively was observed in 3 of 25 eyes (1 in the q8week group and 2 in the q16week group) (Table 12).

Table 12. Clinical DME evaluation and incidence.

Fundus Photographic (FP) and Wide-Field Fluorescein angiographic (FA) grading

Fundus photographic and wide-field fluorescein angiographic grading is presented in Table 13.