Clinical Trials in Surgical Retina

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Article initiated by:

Francesc March de Ribot, MD, PhD

All contributors:

Leo A. Kim, MD, PhD, Koushik Tripathy, MD (AIIMS), Francesc March de Ribot, MD, PhD, Lipi Mittal, MS, FAICO (Refractive Surgery)

Assigned editor:

Koushik Tripathy, MD (AIIMS)

Review:

Assigned status Update Pending

 by Koushik Tripathy, MD (AIIMS) on May 31, 2024.

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Contributing Editors:	add

Clinical trials are pillars of evidence-based medicine. This article summarizes some clinical trials in surgical retina. However, this is not a comprehensive list.

Vitreomacular traction and macular hole

Objectives

The goal was to determine the effect of pneumatic vitreolysis (PVL) in eyes with vitreomacular traction (VMT) with and without full-thickness macular holes (FTMH).

Design

A randomized clinical trial compared PVL with C3F8 gas to observation (sham injection, pressing the hub of a needless synringe against the conjunctiva) for VMT without FTMH (Protocol AG) and a single-arm study assessing PVL for FTMH (Protocol AH). Participants were adults with central VMT (vitreomacular adhesion was ≤3000 μm). In Protocol AG, VA was 20/32 to 20/400. In Protocol AH, eyes had a FTMH (≤250 μm at the narrowest point) and VA of 20/25 to 20/400.

Main Outcome Measures

Central VMT release at 24 weeks (Protocol AG) and FTMH closure at 8 weeks (Protocol AH).

Limitations

The study had to be cancelled for safety concerns. The sample sizes were not met because of early termination. The original sample size calculations were based on anatomic, not visual, outcomes; thus, the power to detect modest differences between treatment groups was relatively low. The follow-up ended after 24 weeks, so data on long-term outcomes are unavailable.

Results

From 2018 to 2020, participants were enrolled in Protocol AG 46, and in Protocol AH, 35. The studies had to be terminated for safety concerns for the high number of retinal detachments (10%) and tears (1.6%). In Protocol AG at 24 weeks, the central VMT release was 78% in the PVL group and 9% in the sham group; the mean change in VA from baseline was 6.7 letters in the PVL group and 6.1 letters in the sham group. In Protocol AH at 8 weeks, the FTMH closure was 29% in the PVL group and, the mean change in VA from baseline was –1.5 letters.

Conclusions

PVL induced hyaloid release solved most of the cases of VMT and one-third of the FTMH. However, the studies were terminated early because of safety concerns related to retinal detachments.

Pearls for clinical practice

PVL for VMT and FTMH carries a high risk of complications.

Other important research articles on VMT and macular hole include:

• The International Vitreomacular Traction Study Group classification of vitreomacular adhesion, traction, and macular hole
• Inverted internal limiting membrane flap technique for large macular holes
• Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes (MIVI-TRUST study)
• Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) Randomized Trial

Endophthalmitis

Endophthalmitis vitrectomy study (EVS)

Objectives

To evaluate the role of early pars plana vitrectomy (VIT) and systemic antibiotics in managing acute post-operative endophthalmitis.

Design

A multicentric, randomized clinical trial involving 420 patients with acute endophthalmitis within 6 weeks post cataract surgery receiving VIT or vitreous tap or biopsy (TAP) or treatment with or without systemic antibiotics (ceftazidime or amikacin).

Main Outcome Measures

Media clarity, clinically and photographically, and visual acuity were assessed using an Early Treatment Diabetic Retinopathy Study visual acuity chart.

Results

No difference in the media clarity or visual acuity was observed in groups with or without systemic antibiotics. There was no difference in visual outcomes with or without VIT in groups with hand movement or better visual acuity. However, there was a three-times increase in the frequency of visual acuity of 20/40 or better (33%), a two-times increase in visual acuity of 20/100 or better and a 50% reduction in the frequency of severe vision loss (20%) with VIT over TAP in groups with initial visual acuity of light perception only. The difference was statistically significant between the two groups with VIT and TAP with a P value of <0.001.

Conclusion

Immediate VIT is not required in patients with initial visual acuity better than light perception, however, it is of benefit in patients with initial visual acuity of light perception only. Intravenous antibiotics did not affect the visual outcomes and hence the exclusion of treatment with systemic antibiotics can prevent the potential side effects, prolonged hospital stays and treatment costs.

Other important studies on endophthalmitis include:

• Use of intracameral moxifloxacin during cataract surgery to prevent endophthalmitis
• Complete and early vitrectomy for endophthalmitis (CEVE)

Diabetic retinopathy

Protocol AB of DRCR.net

Objective

The goal was to compare the initial treatment with intravitreal anti-vascular endothelial growth factor (anti-VEGF), aflibercept and prompt vitrectomy (VIT) with pan-retinal photocoagulation (PRP) for vitreous hemorrhage (VH) in a patient with proliferative diabetic retinopathy (PDR).

Design

A randomized clinical trial

Study place

Thirty nine DRCR retina centers in the US and Canada

Study Population

205 patients with loss of vision due to VH from PDR from November 2016 to December 2017 were randomly assigned to treatment with aflibercept or vitrectomy with PRP.

Main Outcome Measures

Mean visual acuity letter score ranging from 0-100 with a higher score representing better visual acuity over 24 weeks. Assessment of mean visual acuity at 4 weeks and 2 years was the secondary outcome of this study.

Results

The mean visual acuity letter score was 59.3 in the aflibercept group vs 63.0 in the VIT group over 24 weeks. 15 out of 23 showed no significant difference in the secondary outcomes. The mean visual acuity scores were 52.6 and 62.3 in the aflibercept and VIT groups respectively at 4 weeks and 73.7 vs 71.0 at 2 years. 33 % of eyes in the aflibercept group received vitrectomy and 32 % in the vitrectomy group received aflibercept over 2 years subsequently.

Conclusion

There was no statistically significant difference in the primary outcomes in the initial treatment with intravitreal anti-VEGF, aflibercept and vitrectomy with pan-retinal photocoagulation for vitreous hemorrhage in PDR over 24 weeks.

Limitation

This trial did not mention the visual outcomes beyond 2 years and hence long follow-up studies are needed to know the durability of neovascularization regression. Also, the loss to follow-up in the VIT group was more as compared to the aflibercept group which could bias the outcomes over 2 years.

Evaluation of vitrectomy in diabetic macular edema (DME) with VMT [a study by DRCR network]

Objective

The purpose was to evaluate the clinical outcomes of vitrectomy for DME in eyes with moderate visual loss and vitreomacular traction (VMT)

Design and Participants

A prospective non-randomized treatment study where 100 patients with VMT and retinal thickness > 300 microns on optical coherence tomography (OCT), visual acuity 20/63 to 20/400, and no simultaneous extraction of cataract with vitrectomy were enrolled with an additional 300 patients receiving vitrectomy for DME but not meeting the above criteria. The follow-ups were done at 3 months, 6 months and 12 months.

Main Outcome Measure

Visual acuity, retinal thickening measured on OCT and surgical complications were the outcome measures with the primary endpoint at 6 months follow-up.

Results

The median visual acuity was 20/200 and the median central subfield thickness was 491 microns which at 6 months reduced by 160 microns, with 43 % with OCT thickness < 250 microns and 68% with at least 50 % reduction in retinal thickness. Visual outcomes improved by 10 or more letters in 38% of patients and further reduced by 10 or more letters in 22 %. The postoperative complications noted over 6 months were vitreous hemorrhage in 5 eyes, raised intra-ocular pressure in 7 eyes, retinal detachment in 3 eyes and endophthalmitis in 1 eye.

Conclusion

Post vitrectomy, retinal thickness was reduced in the majority of the eyes making it reasonable to perform vitrectomy in eyes with reduced vision due to DME and VMT and in eyes with intractable DME.

Diabetic retinopathy vitrectomy study (DRVS)

Objective

To compare the results of early vitrectomy and conventional management in eyes with recent severe vitreous hemorrhage due to diabetic retinopathy in eyes with good vision.

Design and Participants

A randomized trial where patients aged 18 to 70 years with type 1 or type 2 diabetes mellitus with at least one eye with severe vitreous hemorrhage and visual acuity of 5/200 or less were and those with advanced active PDR (proliferative diabetic retinopathy) and visual acuity of 10/200 or better were eligible.

Results

After a two-year follow-up, 25 % of eyes that underwent early vitrectomy for vitreous haemorrhage had visual acuity of 10/20 or better as compared to 15% in the conventional management group (P value= 0.01). Around 36% of eyes gained visual acuity 10/20 or better in type 1 diabetics with early vitrectomy as compared to 12% in the conventional group. However, no such gains were obtained in type 2 diabetics. After 4 year follow-up, 44 % of eyes gained visual acuity of 10/20 or better compared to 28% of eyes managed conventionally in advanced PDR cases.

Conclusion

DRVS suggested that eyes with or suspected to have very severe proliferative diabetic retinopathy may benefit from early vitrectomy in maintaining or restoring visual acuity.

Myopic traction maculopathy (MTM)

Vitrectomy and internal limiting membrane peeling for MTM

	Vitrectomy + ILM peeling with or without gas tamponade	Vitrectomy + gas tamponade without ILM peeling	Vitrectomy + ILM peeling with gas( C3F8) or balanced salt solution (BSS) tamponade
Objective	To analyze the clinical outcomes of vitrectomy with ILM peeling with or without gas tamponade in myopic foveoschisis	To compare the clinical and anatomical outcomes in eyes with PPV and gas tamponade without ILM peeling	To analyze the clinical and anatomical outcomes in eyes with foveoschisis who underwent vitrectomy and ILM peeling with C3F8 tamponade or BSS tamponade
Design	Retrospective, comparative case series	Retrospective	Retrospective
Method	Seventeen eyes were divided into 2 groups, 9 eyes received gas tamponade and 8 were without gas. Outcome measures were the resolution of foveoschisis measured on OCT, the mean period of resolution and BCVA.	Nine eyes were included and the outcome measures were BCVA change, change in foveal detachment height and resolution of foveoschisis on OCT	Eighteen eyes of 17 patients were divided into Group A, where 7 eyes were filled with BSS, and Group B, where 11 eyes were injected with 18% C3F8 gas.
Result	Eight eyes (88.9%) with gas tamponade and 75% ( 6 eyes) with no gas tamponade showed resolution on OCT which was statistically insignificant (P value = 0.576). The mean period of the resolution was 2.25 months and 4.5 months in gas and no gas groups respectively. (P value = 0.011). The mean BCVA improved significantly in both groups. ( P value= 0.011 and 0.017)	Median BCVA improved from 20/80 to 20/50 in 8 eyes. ( P value= 0.012). The mean improvement in BCVA was 3.6 lines. OCT showed resolution and full foveal reattachment in 77.8% ( 7 eyes) and partial resolution in 22.2 %( 2 eyes). A decrease in the mean height of foveal detachment from 505 um to 21 um ( P value < 0.001) was noted.	Post-operative BCVA was significantly greater than pre-operative BCVA in group B (P value = 0.001). BCVA change at the last visit was significantly greater in group A ( P= 0.025). Both groups did not have worsening of BCVA. All eyes showed anatomical resolution in group B 3 months post vitrectomy as compared to group A where 6 eyes did not show resolution. No eye developed macular hole during surgery or at follow-up visits.
Conclusion	Vitrectomy with ILM peeling without gas tamponade was as effective as vitrectomy with gas tamponade in macular foveoschisis. However, eyes with gas tamponade showed a faster resolution.	Vitrectomy with gas tamponade without ILM peeling showed comparable outcomes as studies with ILM peeling in MTM.	Eyes with foveoschisis undergoing vitrectomy with ILM peeling with C3F8 tamponade showed faster resolution and better gain in visual acuity as compared to BSS.

Macular buckling (MB)

Objective

To evaluate the efficacy of macular buckle in myopic foveoschisis with either hard silicone implant or Ando Plombe.

Design and Methods

Retrospective study where out of 16 eyes, 6 underwent PPV with MB with a hard silicone implant and 10 eyes with Ando macular plombe.

Results

Out of 16 eyes, BCVA improved in 14 eyes (87.5%); and remained stable or worsened in 2 eyes (12.5%). The mean post-operative BCVA improved to 20/80 from 20/125 pre-operative BCVA. Both methods showed a reduction in retinal thickness and a similar rate of complications, the most common being localized retinal pigment epithelium atrophy.

Conclusion

Macular buckling combined with PPV is an effective method of treating myopic foveoschisis with Ando plombe being a relatively easier technique.

Fovea-sparing ILM peeling (FSIP)

Objective

To determine the efficacy and safety of a novel technique of fovea-sparing ILM peeling for foveal retinal detachments in patients with MTM.

Design and Methods

A retrospective analysis of 45 eyes of 45 consecutive patients who underwent vitrectomy along with ILM peeling and gas tamponade was done and they were divided into two groups based on the total area of ILM peeled- 30 eyes underwent complete ILM peeling and 15 eyes underwent fovea-sparing ILM peeling.

Main Outcome Measures

Evaluation of BCVA and the rate of development of full-thickness macular hole (MH).

Results

5 of 30 eyes in group 1(16.7%) developed full-thickness MH compared to zero eyes in group 2. Post-operative BCVA was significantly better in the fovea-sparing ILM peeling group (P=0.04) than the pre-operative BCVA as compared to complete ILM peeling. FSIP group also revealed contraction of the residual ILM and reduction in outer lamellar holes on post-operative OCT examination.

Conclusion

Fovea-sparing ILM peeling is an effective and safe technique for treating foveal detachments in myopic tractional maculopathy as there is reduction in full-thickness MH formation.

Inverted ILM flap technique

Objective

To observe the effect of PPV with inverted ILM flap in macular hole in patients with high myopia with or without retinal detachment (RD).

Design and Methods

A retrospective case series of 10 eyes where 4 eyes with macular hole and RD and 6 eyes with macular hole without RD underwent PPV with inverted ILM peeling to close the macular hole.

Results

In total 80% of cases (8 eyes), 5 eyes without RD and 3 eyes with RD, the macular hole was closed after the surgery. The retina was reattached in 3 out of 4 eyes with RD after the initial surgery. BCVA improved by > 2 lines in 5 eyes (50%), remained the same in 4 eyes (40%) and deteriorated by >2 lines in 1 eye (10%).

Conclusion

Inverted ILM peeling technique may be preferred as one of the treatments in macular holes in high myopia patients with or without RD.

Autologous blood clot (ABC) for macular hole retinal detachment (MHRD)

Objective

To determine the anatomical and functional outcomes of vitrectomy with inverted ILM repositioning (ILMR) and ABC in MHRD in high myopics.

Design and Methods

A retrospective study of 27 highly myopic eyes with MHRD who underwent the above surgical procedure was done. The main outcomes were evaluated by OCT, BCVA and fundus examinations.

Results

The hole was closed and the retina was attached in 26 eyes (96%) after a single surgery, 100% retinal attachment was achieved by performing another vitrectomy 3 months after the initial surgery. 3 eyes with closed holes showed persistent subretinal fluid (SRF) after gas absorption. 2 of these eyes showed complete resolution of SRF during the follow-up period and in 1 eye, the persistent SRF resolved gradually in a 12-month follow-up period. BCVA was significantly improved post-surgery at 3 and 6 months and at the last visit (P =0.001)

Conclusion

PPV with ILMR and ABC is an effective method to treat and improve BCVA in MHRD in high myopia patients.

Retinal detachment (RD)

	SILICONE OIL STUDY REPORT 1	SILICONE OIL STUDY REPORT 11
Objective	To compare surgical outcomes with vitrectomy with silicone oil or sulphur hexafluoride (SF6) in eyes with rhegmatogenous retinal detachment (RRD) and severe PVR	To compare surgical outcomes with vitrectomy with silicone oil or long-acting gas, perfluoro propane (C3F8)in eyes with rhegmatogenous retinal detachment (RRD) and severe PVR
Design	Prospective, randomized surgical clinical trial	Prospective, randomized surgical clinical trial
Main Outcome Measures	Visual acuity, macular attachment and complications	Visual acuity measurement, macular attachment and the incidence of complications
Patients enrolled	101 eyes with RRD and severe PVR receiving vitrectomy for the first time were randomly assigned into two groups- 20% SF6 and 1000 centistokes silicone oil	Cohort 1- 265 eyes with RRD and severe PVR with a follow-up of 3 years were randomized to C3F8 and silicone oil Cohort 2- 249 eyes with attached macula at 36 months and a follow-up up to 6 years
Results	50-60% of eyes with silicone oil had visual acuity > or = 5/200 vs 30-60% with SF6 The frequency of macula attachment was higher in silicone oil group (80%) than SF6 (60%) P value < 0.05 Hypotony and Keratopathy were seen more in eyes with detached macula as compared to eyes with attached macula.	Cohort 1- The rate of retinal attachment was higher in eyes treated with C3F8 from 18-36 months. Cohort 2- The macular attachment was maintained through a 6-year follow-up No difference was observed in the rates of macular attachment, visual acuity > 0r = 5/200 or glaucoma in both the groups. Eyes treated with longer-acting gas, C3F8 had high rates of post-operative hypotony. Less keratopathy was observed in eyes with oil removal as compared to oil-retained eyes.
Conclusion	Silicone oil has a better tamponade effect than SF6 in RD patients with PVR.	Both tamponades with oil and C3F8 were equal in patients with RD with PVR and were better than tamponade with SF6 ( report 1)

Primary retinal detachment (RD) outcome study

	PSEUDOPHAKIC RD OUTCOME STUDY REPORT 3	PHAKIC RD OUCTOME STUDY REPORT 2
Purpose	To evaluate the surgical outcomes of eyes with pseudophakic RD treated with Pars plana vitrectomy (PPV) or PPV with scleral buckle (PPV-SB)	To evaluate the anatomical and visual outcomes in complex phakic RRD eyes treated with PPV, SB or PPV-SB
Design	Retrospective, multi-centeric cohort study	Retrospective, multi-centeric, interventional study
Main Outcome Measures	Single surgery anatomic success (SSAS) which is defined as retinal attachment without tamponade or a need for repeat RD surgery within 90 days and final visual acuity	Primary outcome- SSAS Secondary outcome- Final visual acuity
Results	Out of a total of 893 pseudophakic eyes, 684 (77%) eyes were treated with PPV and 209 eyes (23%) with PPV-SB. SSAS was noted in 84 % of eyes with PPV and 92 % of eyes treated with PPV-SB which was statistically significant ( P value.009) In eyes with macula-on RRD, SSAS was 88% in the PPV group and 100% in PPV-SB whereas it was 81 % in PPV and 89% in the PPV-SB group in macula-off RRD eyes. The mean final visual acuity was similar in both groups.	SSAS was achieved in 155 of 169 cases treated with SB (91.7%), 207 of 249 cases with PPV (83.1%) and 271 of 297 eyes with PPV-SB ( 91.2%). Sb and PPV-SB were found to be superior to PPV in SSAS ( P value.0041). In macula-on RRD, SB had better visual outcomes as compared with PPV and PPV-SB.
Conclusion	To conclude, eyes treated with PPV-SB had better SSAS than eyes treated with PPV in cases of pseudophakic RRD.	In this comparison of moderately complex RRD eyes treated with PPV, SB or PPV-SB, eyes treated with SB had the best visual outcomes and the eyes managed with PPV alone had the worst SSAS.

PIVOT study

Objective

To compare and evaluate the surgical outcomes of eyes treated with pneumatic retinopexy (PnR) vs PPV in eyes with primary RD.

Design

A prospective and randomized trial

Main Outcome Measures

Assessment of Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity at the end of 1 year was the primary outcome of the study. The secondary outcomes were an assessment of subjective visual function by a 25-item National Eye Institute Visual Function Questionnaire, using M-CHARTS to calculate the metamorphopsia score and primary anatomical success.

Results

ETDRS visual acuity was 4.9letters better in the PnR group than PPV at the end of 1 year. Subjective visual function using a 25-item National Eye Institute Visual Function Questionnaire was superior in the PnR group at the end of 3 and 6 months. Metamorphopsia score was superior in eyes treated with PnR than PPV at the end of 12 months and the primary anatomic outcomes were achieved in 80.8% of patients treated with PnR and 93.2% treated with PPV.

Conclusion

Pneumatic retinopexy was found to have superior visual acuity and less metamorphopsia than patients with PPV. Hence, PnR can be considered the first choice of treatment in the management of primary RRD in patients meeting the PIVOT criteria.

REDOS

Objective

To evaluate and compare the surgical outcomes, visual outcomes, quality of life and complications associated with primary RRD management with PPV or PPV-SB and SF6 or C3F8 tamponade.

Design

In an interventional, randomized clinical trial, patients with primary RRD are randomly assigned to PPV or PPV-SB and SF6 or C3F8 tamponade.

Main Outcome Measures

SSAS will be the primary outcome of this study. The secondary outcomes will be the final best corrected visual acuity, Pinhole visual acuity, the status of the retina ( whether attached or detached), severity and incidence of complications, questionnaire results, and onset of RRD recurrence at 8-10  weeks and 6 months.

Current status

An ongoing clinical trial, registered on 18 May 2023.

Central retinal artery occlusion (CRAO)

EAGLE study

Objective

To compare the outcomes of treatment after local intra-arterial fibrinolysis (LIF ) using recombinant tissue plasminogen activator (rtpa) and Conservative standard treatment (CST) in acute non-arteritic CRAO patients.

Design

Randomized, prospective clinical trial

Inclusion criteria

Age 18-75 years, CRAO not older than 20 hours and BCVA <0.5 logarithm of the minimum angle of resolution (logMAR)

Exclusion criteria

Branch retinal artery occlusion, cilioretinal artery

Methods

In the study period between 2002 and 2007, 84 patients were randomized into two groups where 40 patients received CST ( ocular massage, intra-ocular pressure lowering drugs, heparin and isovolumic hemodilution depending on hematocrit) and 44 patients received local intra-arterial fibrinolysis therapy in the form of rtpa in the ophthalmic artery to a maximum of 50 mg.

Main Outcomes

Primary- BCVA at the end of 1 month of treatment using scoring on the Early treatment diabetic retinopathy study (ETDRS)

Secondary- Safety

Results

In both the groups, the mean BCVA change at 1 month was similar and did not differ in both groups (P=0.69). In 60 % CST group and 57.1% LIF group, clinically significant BCVA improvement (>=0.3 logMAR) was noted. 4.3 % ( 2 patients) in CST and 37.1% (13 patients ) in LIF group suffered from adverse reactions.

Conclusion

Due to adverse reactions, the study was stopped after the first analysis and LIF was not recommended for acute non-arteritic CRAO.

Vitreous surgery along with direct central retinal artery massage

Objective

To estimate the efficacy of vitreous surgery along with direct central retinal artery massage for CRAO cases.

Methods

On 10 patients with acute CRAO, 3 ports pars plana vitrectomy (PPV) was performed along with massaging the central bifurcation of the retinal artery on the optic nerve head or within the optic nerve or both using a special probe made up of nickel-titanium. Patients were followed up at 24 hr, 48 hr, 1 week, 2 weeks, 3 weeks, 4 weeks and 2 months post-procedure and BCVA, fundus photograph and FFA were documented.

Result

Out of 10 patients, retinal blood flow improved in 4 cases. In 6 out of 10 cases, no change was observed during the procedure, however, 4 cases showed improved retinal circulation after 24-48 hours while 2 cases still did not show any change. CRAO recurrence was not noted in all 8 cases with improved retinal circulation. BCVA improved by 3 or more lines in 6 out of 10 cases (60%) while 4 cases did not show any improvement in visual acuity at the end of 2 months.

Conclusion

Vitreous surgery with direct central retinal massage seems to be an effective method in improving retinal circulation and visual acuity in patients with acute CRAO.