Chapter 34

Surgical Clinical Trials

Surgical Clinical trials in ophthalmology (particularly vitreoretinal disease) have been a crucial aspect in forming management protocols and determining clinical outcomes. However, surgical trials in general are difficult to design and interpret because of varying surgical preferences, experience levels, and case heterogeneity. Below is a summary of several key trials in vitreoretinal surgery.

Diabetic Retinopathy

Role of Vitrectomy for the Management of Diabetic Macular Oedema in Eyes with Vitreomacular Traction

Protocol D evaluated the role of vitrectomy in 45 eyes with diabetic macular edema (DME) and vitreomacular traction (VMT).[1] Outcome measures were visual acuity, retinal thickening and surgical complications. Following vitrectomy performed for DME and VMT, retinal thickening was reduced in most eyes (nearly 70% of eyes experienced a greater than 50% reduction in thickness). This study informs surgeons that it is reasonable to consider vitrectomy surgery in eyes with reduced vision due to DME and VMT if intravitreal therapy has failed though it is significant to note that this study was designed in the pre anti-VEGF era.

Diabetic Retinopathy Clinical Research Network Writing C, Haller JA, Qin H, Apte RS, Beck RR, Bressler NM, Browning DJ, Danis RP, Glassman AR, Googe JM, Kollman C, Lauer AK, Peters MA, Stockman ME: Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology 2010, 117:1087-93 e3.

Gas vs. Silicone Oil in the Management of Complex Retinal Detachment

The silicone oil study compared surgical outcomes in eyes with PVR retinal detachments where silicone oil was compared against SF6 and long acting gas (C3F8).[2,3] Inclusion criteria were patients with PVR of Grade C-3 or greater according to the Retina Society Classification and visual acuity of light perception or better. The outcome measures were evaluated with visual acuity of 5/200 or greater and macular reattachment for 6 months. Compared to SF6-treated eyes, a greater percentage of people randomized to silicone oil had an attached macula and a visual acuity greater than 5/200. However, no significant differences in visual acuity or rates of complete retinal reattachment, corneal abnormalities or glaucoma were found between the C3F8 and silicone oil groups. Patients in whom long-acting gas was used as tamponade agent had a higher risk of post-operative hypotony.

Vitrectomy with silicone oil or sulfur hexafluoride gas in eyes with severe proliferative vitreoretinopathy: results of a randomized clinical trial. Silicone Study Report 1. Archives of ophthalmology 1992, 110:770-9.

Abrams GW, Azen SP, McCuen BW, 2nd, Flynn HW, Jr., Lai MY, Ryan SJ: Vitrectomy with silicone oil or long-acting gas in eyes with severe proliferative vitreoretinopathy: results of additional and long-term follow-up. Silicone Study report 11. Archives of ophthalmology 1997, 115:335-44.

Scleral Buckle vs. Vitrectomy in the Management of Rhegmatogeneous Retinal Detachment

The scleral buckling versus primary vitrectomy in rhegmatogenous retinal detachments (SPR) study evaluated visual and anatomic outcomes in phakic and pseudophakic eyes using the two modalities. In phakic patients, SB achieved greater improvement in final VA than vitrectomy. Cataract progression was greater with vitrectomy. In the pseudophakic group, primary anatomical success rate was significantly higher in the primary vitrectomy group compared to scleral buckling. It should be noted that this report was published in 2007 prior to the widespread use of micro-incisional sutureless vitrectomy system (MIVS) and also before widefield intra-operative visualisation systems were broadly available worldwide.

More recently, the Primary Retinal Detachment Outcomes (PRO) studies have re-assessed the role of scleral buckle in the management of moderately complex primary rhegmatogenous retinal detachment in the era of MIVS and widefield visualisation systems.[5,6,7] One report from this series found that visual and anatomic outcomes were superior in phakic eyes treated with scleral buckle (solo procedure or combined with PPV) compared to eyes treated with vitrectomy alone. When pseudophakic eyes were assessed it was found that eyes treated with combined vitrectomy and buckle had superior single surgery anatomic success rates than eyes treated with vitrectomy alone. Visual outcomes were however similar for both groups.

Ryan EH, Ryan CM, Forbes NJ, Yonekawa Y, Wagley S, Mittra RA, Parke DW, Joseph DP, Emerson GG, Shah GK, Blinder KJ, Capone A, Williams GA, Eliott D, Gupta OP, Hsu J, Regillo CD: Primary Retinal Detachment Outcomes Study Report Number 2: Phakic Retinal Detachment Outcomes. Ophthalmology 2020, 127:1077-85.

Joseph DP, Ryan EH, Ryan CM, Forbes NJK, Wagley S, Yonekawa Y, Mittra RA, Parke DW, Emerson GG, Shah GK, Blinder KJ, Capone A, Williams GA, Eliott D, Gupta OP, Hsu J, Regillo CD: Primary Retinal Detachment Outcomes Study: Pseudophakic Retinal Detachment Outcomes: Primary Retinal Detachment Outcomes Study Report Number 3. Ophthalmology 2020, 127:1507-14.

Ryan EH, Joseph DP, Ryan CM, Forbes NJK, Yonekawa Y, Mittra RA, Parke DW, Ringeisen A, Emerson GG, Shah GK, Blinder KJ, Capone A, Williams GA, Eliott D, Gupta OP, Hsu J, Regillo CD: Primary Retinal Detachment Outcomes Study: Methodology and Overall Outcomes-Primary Retinal Detachment Outcomes Study Report Number 1. Ophthalmology Retina 2020, 4:814-22.

Pneumatic Retinopexy in the Management of Rhegmatogenous Retinal Detachment

The pneumatic retinopexy versus vitrectomy for the management of primary rhegmatogenous retinal detachment outcomes randomized trial (PIVOT) study evaluated visual and anatomic outcomes using the two techniques in a prospective fashion.[8] Primary anatomic success was greater in the vitrectomy group at 12 months (80.8% vs. 93.2%).  However, visual acuity was greater at 6 months in the pneumatic retinopexy group and rates of vertical metamorphopsia and cataract were lower.  This study provides good evidence that pneumatic retinopexy is a reasonable management option for patients with superior retinal detachments where the offending breaks are located above and between the 4 and 8 o’clock meridians.

Hillier RJ, Felfeli T, Berger AR, Wong DT, Altomare F, Dai D, Giavedoni LR, Kertes PJ, Kohly RP, Muni RH: The Pneumatic Retinopexy versus Vitrectomy for the Management of Primary Rhegmatogenous Retinal Detachment Outcomes Randomized Trial (PIVOT). Ophthalmology 2019, 126:531-9.

Endophthalmitis

Role of Vitrectomy in the Management of Endophthalmitis

Similar to rhegmatogenous retinal detachment, a broad range of surgeon-dependent and pathology-dependent variables modulate anatomic and visual outcomes following the surgical management of endophthalmitis. The endophthalmitis vitrectomy study (EVS)[9] was published in 1995 and compared systemic antibiotic therapy against surgical treatment in the management of endophthalmitis within 6 weeks of cataract surgery. They showed that patients presenting with Light perception vision had significantly better visual gains with vitrectomy management than medical management alone. A more recent study performed a retrospective analysis of visual outcomes in patients that suffered endophthalmitis and were treated with vitrectomy or non-surgical ways.[10] This was a retrospective analysis of 290 consecutive cases that were managed in the era of MIVS (unlike the EVS where patients were treated with 20 gauge vitrectomy) and widefield intra-operative viewing systems. The current study also evaluated the role of intravitreal antimicrobial therapy (not systemic antibiotic therapy) in patients that suffered endopthalmitis following cataract surgery, intravitreal therapy and endogenous systemic disease. In that study, early vitrectomy (within 24 hours) was found to be associated with better visual outcomes.

Summary of Vitreoretinal Surgery Studies

Sr. No Year of Publication Authors Country Study Type No of Patients Main Outcome Measures Main Results/Conclusions
1 2010 Haller J et al. USA-Multicentre DRCR net Protocol D<a class="super" href="#1" data-pop-drop="references-1">[1]</a>: To evaluate vitrectomy for diabetic macular edema (DME) in eyes with at least moderate vision loss and vitreomacular traction. Prospective cohort study 87 1. Visual acuity 2. OCT retinal thickening 3. Surgical complications 1. After vitrectomy for DME and vitreomacular traction, retinal thickening was reduced in most eyes 2. Between 28% and 49% of eyes with characteristics similar to those included in this study are likely to have improvement of visual acuity, while between 13% and 31% are likely to have worsening 3. Retinal thickening was reduced in most eyes (nearly 70% of eyes experienced a greater than 50% reduction in thickness) 4. The surgical complication rate is low and similar to previous studies
2 1990 DRVS group USA -Multicentre DRVS study<a class="super" href="#2" data-pop-drop="references-2">[2]</a> 1. Early vitrectomy vs conventional management for recent severe vitreous haemorrhage 2. Early vitrectomy vs conventional management for eye with good vision but a poor prognosis 1741 1. Visual acuity was main 2. Outcome measure Visual acuity of 10/20 or better was considered “good vision” while less than 5/200 was “poor vision. 1. Early vitrectomy provided a greater chance of prompt recovery of visual acuity, especially in type 1 diabetics and if vision is poor in the fellow eye 2. Early vitrectomy is of benefit especially in those with both fibrous proliferations and at least moderately severe new vessels, in which extensive scatter photocoagulation has been carried out or is precluded by vitreous haemorrhage
3 1997 Abrams GW et al USA-Multicentric Silicone Oil study Report 11<a class="super" href="#3" data-pop-drop="references-3">[3]</a> Evaluate and compare silicone oil vs long acting gas in RD with PVR RCT 265 Changes in visual acuity, recurrent retinal detachment, and incidence of complications. 1. No significant differences in visual acuity (5/200 or better), rates of complete retinal attachment, corneal abnormalities or glaucoma were found 2. Gas-treated eyes had more hypotony 3. Anterior PVR was more prevalent than posterior PVR and former had a worse prognosis
4 2007 Heinrich Heimann et al Europe -Multicentric Scleral buckling vs primary vitrectomy in RRD study group<a class="super" href="#4" data-pop-drop="references-4">[4]</a> –Phakic subtrial – prospective RCT 416 Gain in Visual acuity, post operative development of PVR and cataract and retinal reattachment rate at end of 1 year 1. SB had greater improvement in final VA than those who underwent primary vitrectomy 2. Cataract progression was more significant in vitrectomy arm 3. There is a benefit of SB in phakic eyes with respect to BCVA improvement
5 2007 Heinrich Heimann et al Europe -Multicentric Scleral buckling vs primary vitrectomy in RRD study group<a class="super" href="#4" data-pop-drop="references-4">[4]</a> –Pseudophakic subtrial – prospective RCT 265 Gain in Visual acuity, post operative development of PVR and retinal detachment rate at end of 1 year 1. Primary anatomical success rate was significantly higher in the primary vitrectomy arm group compared to the SB group 2. No significant difference between the groups in terms of functional outcome 3. Primary vitrectomy is treatment of choice in pseudophakic patients
6 2020 Edwin Ryan et al USA multicentre Primary Retinal Detachment Outcomes Study Report 1 - Methodology & Outcomes<a class="super" href="#5" data-pop-drop="references-5">[5]</a> 2335 Single surgery anatomic success (SSAS) Final visual acuity 1. SSAS was noted as 91.2% in SB alone,84.2% in PPV and 90.2% in SB+PPV 2. Average final visual acuities were 20/35 for SB, 20/53 for PPV and 20/61 for SB+PPV (Cases not matched for preop characteristics so can’t be used for comparison of visual outcomes)
7 2020 Edwin H. Ryan, Et al USA multicentre Primary Retinal Detachment Outcomes Study Report Number 2 Phakic Retinal Detachment Outcomes<a class="super" href="#6" data-pop-drop="references-6">[6]</a> Multicentre retrospective interventional cohort study 715 Single surgery anatomic success (SSAS) and Final visual acuity using following 3 arms 1.Scleral Buckle 2.PPV 3.SB+PPV 1. SSAS was noted in 155 of 169 SB cases (91.7%), 207 of 249 PPV cases (83.1%), and 271 of 297 PPV/SB cases (91.2%). 2. Scleral buckle and PPV/SB were superior to PPV for SSAS 3. For phakic moderately complex primary RRDs, PPV versus SB versus PPV/SB, SB had the best visual outcomes, and PPV had the worst SSAS outcomes
8 2020 Daniel P. Joseph et al USA multicentre Primary Retinal Detachment Outcomes Study: Pseudophakic Retinal Detachment Outcomes Primary Retinal Detachment Outcomes Study Report Number 3<a class="super" href="#7" data-pop-drop="references-7">[7]</a> Multicentre retrospective interventional cohort study 1018 Single surgery anatomic success (SSAS) and Final visual acuity using following 2 arms 1.SB+PPV 2.PPV 1. SSAS was greater for PPV-SB than PPV for inferior (96% vs. 82%) and superior (90% vs. 82%) detachments. Mean final VA was similar for PPV (20/47) and PPV-SB (20/46) 2. In pseudophakic RRDs, SSAS was better in patients treated with PPV-SB compared with PPV alone, whereas visual outcomes were similar for both groups
9 2018 Roxane Hillier etal Canada Pneumatic Retinopexy (PnR)versus Vitrectomy(PPV) for management of RRD Outcomes of RCT (PIVOT) Prospective, randomized controlled trial.<a class="super" href="#8" data-pop-drop="references-8">[8]</a> 176 Visual acuity, using ETDRS charts, Subjective visual function, metamorphopsia score, Primary anatomic success 1. VA at 1 year was superior in PnR 79.9 vs 75.0 letters in PPV group 2. Visual function score was higher in PnR group at 3&6 months 3. Metamorphopsia score was superior in PnR group 0.14 vs 0.28 in PPV group 4. Primary anatomic success was same in both the groups
10 1995-1997 Multiple authors USA EVS study<a class="super" href="#9" data-pop-drop="references-9">[9]</a> Role of early PPV vs intravitreal antibiotics in endophthalmitis following cataract surgery with 20/50 < VA < LP (perception) Investigator-initiated, multicentre, randomized clinical trial. 420 Visual acuity (VA) using ETDRS chart and media clarity at 3 and 9 months 1. Visual acuity was better with PPV in patients with LP vision 2. Results were comparable when initial vision was HM or better 3. Intravenous antibiotics did not affect outcome 4. PPV has better outcome when VA is light perception only
11 2020 Sarah Welch et al New Zealand Better visual outcome associated with early vitrectomy in the management of endophthalmitis<a class="super" href="#10" data-pop-drop="references-10">[10]</a> Retrospective study 290 Visual acuity at 9-month follow-up and proportion of subjects with severe vision loss (≤20/200) 1. Cataract Surgery 31.7% and Intravitreal injections 19/% were the most common causes of endophthalmitis 2. Early vitrectomy (within 24 hours) is associated with better visual outcomes (20/100) at 9 months 3. Younger age, poor presenting visual acuity and culture-positive endophthalmitis are associated with poorer visual acuity outcomes

References


  1. Diabetic Retinopathy Clinical Research Network Writing C, Haller JA, Qin H, Apte RS, Beck RR, Bressler NM, Browning DJ, Danis RP, Glassman AR, Googe JM, Kollman C, Lauer AK, Peters MA, Stockman ME: Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology 2010, 117:1087-93 e3.

  2. Vitrectomy with silicone oil or sulfur hexafluoride gas in eyes with severe proliferative vitreoretinopathy: results of a randomized clinical trial. Silicone Study Report 1. Archives of ophthalmology 1992, 110:770-9.

  3. Abrams GW, Azen SP, McCuen BW, 2nd, Flynn HW, Jr., Lai MY, Ryan SJ: Vitrectomy with silicone oil or long-acting gas in eyes with severe proliferative vitreoretinopathy: results of additional and long-term follow-up. Silicone Study report 11. Archives of ophthalmology 1997, 115:335-44.

  4. Heimann H, Bartz-Schmidt KU, Bornfeld N, Weiss C, Hilgers RD, Foerster MH. Scleral Buckling versus Primary Vitrectomy in Rhegmatogenous Retinal Detachment Study G: Scleral buckling versus primary vitrectomy in rhegmatogenous retinal detachment: a prospective randomized multnter clinical study. Ophthalmology 2007, 114:2142-54.

  5. Ryan EH, Ryan CM, Forbes NJ, Yonekawa Y, Wagley S, Mittra RA, Parke DW, Joseph DP, Emerson GG, Shah GK, Blinder KJ, Capone A, Williams GA, Eliott D, Gupta OP, Hsu J, Regillo CD. Primary Retinal Detachment Outcomes Study Report Number 2: Phakic Retinal Detachment Outcomes. Ophthalmology 2020, 127:1077-85.

  6. Joseph DP, Ryan EH, Ryan CM, Forbes NJK, Wagley S, Yonekawa Y, Mittra RA, Parke DW, Emerson GG, Shah GK, Blinder KJ, Capone A, Williams GA, Eliott D, Gupta OP, Hsu J, Regillo CD. Primary Retinal Detachment Outcomes Study: Pseudophakic Retinal Detachment Outcomes: Primary Retinal Detachment Outcomes Study Report Number 3. Ophthalmology 2020, 127:1507-14.

  7. Ryan EH, Joseph DP, Ryan CM, Forbes NJK, Yonekawa Y, Mittra RA, Parke DW, Ringeisen A, Emerson GG, Shah GK, Blinder KJ, Capone A, Williams GA, Eliott D, Gupta OP, Hsu J, Regillo CD. Primary Retinal Detachment Outcomes Study: Methodology and Overall Outcomes-Primary Retinal Detachment Outcomes Study Report Number 1. Ophthalmology Retina 2020, 4:814-22.

  8. Hillier RJ, Felfeli T, Berger AR, Wong DT, Altomare F, Dai D, Giavedoni LR, Kertes PJ, Kohly RP, Muni RH. The Pneumatic Retinopexy versus Vitrectomy for the Management of Primary Rhegmatogenous Retinal Detachment Outcomes Randomized Trial (PIVOT). Ophthalmology 2019, 126:531-9.

  9. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Archives of ophthalmology 1995, 113:1479-96.

  10. Welch S, Bhikoo R, Wang N, Siemerink MJ, Shew W, Polkinghorne PJ, Niederer RL: Better visual outcome associated with early vitrectomy in the management of endophthalmitis. The British journal of ophthalmology 2021.

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