Purpose: The efficacy and safety of scleral buckling (SB) versus combination SB and pars plana vitrectomy (SB + PPV) for rhegmatogenous retinal detachment (RRD) repair remains unclear. Methods: A systematic review and meta-analysis was conducted to identify comparative studies published from Jan 2000–Jun 2021 that reported on the efficacy and/or safety following SB and SB + PPV for RRD repair. Final best-corrected visual acuity (BCVA) represented the primary endpoint, while reattachment rates and ocular adverse events were secondary endpoints. A random-effects meta-analysis was performed, and 95% confidence intervals were calculated. Results: Across 18 studies, 3912 SB and 3300 SB + PPV eyes were included. Final BCVA was nonsignificantly different between SB and SB + PPV (20/38 vs. 20/66 Snellen; WMD = −0.11 LogMAR; 95% CI: [–0.29, 0.07]; p = 0.23). Primary reattachment rate was similar between procedures (p = 0.74); however, SB alone achieved a significantly higher final reattachment rate (97.40% vs. 93.86%; RR = 1.03; 95% CI: [1.00, 1.06]; p = 0.04). Compared to SB + PPV, SB alone had a significantly lower risk of postoperative macular edema (RR = 0.69; 95% CI: [0.47, 1.00]; p = 0.05) and cataract formation (RR = 0.34; 95% CI: [0.12, 0.96]; p = 0.04). The incidence of macular hole, epiretinal membrane, residual subretinal fluid, proliferative vitreoretinopathy, elevated intraocular pressure, and extraocular muscle dysfunction were similar between SB and SB + PPV. Conclusions: There was no significant difference in final BCVA between SB + PPV and SB alone in RRD. SB alone offers a slightly higher final reattachment rate along with a reduced risk of macular edema and cataract. Primary reattachment rate and the incidence of other complications were similar between the two procedures.

© 2022 The Author(s). Published by S. Karger AG, Basel

Introduction

Rhegmatogenous retinal detachment (RRD) develops secondary to a retinal break with subsequent influx of subretinal fluid and separation of the neurosensory retina from its underlying retinal pigment epithelium. RRDs are serious ocular emergencies requiring urgent management [1]. The annual incidence of RRD is 10–18 per 100,000 population [2, 3] and 1 per 300 in a lifetime [4]. Predisposing factors include age, family history, trauma, high myopia, previous intraocular surgery, and previous history of RRD [3, 5]. Management of RRD has advanced significantly in the past few decades. The current surgical armamentarium consists of modalities such as pneumatic retinopexy, pars plana vitrectomy (PPV), scleral buckling (SB), or a combination of these procedures with or without laser retinopexy or cryopexy [6].

In SB, segmental or encircling silicone bands attached to the sclera create indentations, thus facilitating reattachment of the retina to the underlying retinal pigment epithelium. SB is an extraocular procedure that has been associated with faster visual recovery and reduced cataract progression compared to PPV [7]. However, SB has reduced primary reattachment rates with increasing age as a result of the lack of formed vitreous [7]. Furthermore, its success depends on accurate external localization of the retinal break on the sclera to ensure proper placement of the buckle [8, 9]. In PPV, vitreous humor is removed to relieve vitreous traction and replaced with a tamponade of fluid, gas, or oil, with laser retinopexy or cryopexy applied to causative breaks [10]. PPV is a microincisional procedure that is associated with a more facile intraoperative identification of retinal tears. However, PPV carries the risk of cataract formation and requires strict postoperative positioning [11, 12].

Both SB and PPV remain important techniques in the armamentarium for RRD management and can be used together to capitalize on the advantages of both procedures. Although SB has certain advantages over PPV, SB alone has more recently grown out of favor among some ophthalmologists who have developed a preference toward standalone PPV [13, 14]. While SB, PPV, and combination SB with PPV (SB + PPV) have been studied extensively in comparative studies, the results are unclear and conflicting with regard to final visual acuity, rates of redetachment, and complications [6, 15-17]. To our knowledge, this is the most comprehensive meta-analysis of randomized controlled trials (RCTs) and observational studies to evaluate the comparative efficacy and safety of SB versus SB + PPV and the first to perform subgroup analyses based on lens and macular attachment status.

MethodsSearch Strategy and Registration

This systematic review and meta-analysis, registered with the International Prospective Register of Systematic Reviews (CRD42020191490), was conducted in compliance with the Preferred Reporting Items of Systematic Reviews (PRISMA) guidelines [18, 19] and the tenets of the Declaration of Helsinki. Searches on Ovid MEDLINE, Embase, Cochrane Library, and Google Scholar from January 2000 to June 2021 were performed to identify published peer-reviewed articles (online suppl. Tables S1a–c; see www.karger.com/doi/10.1159/000524888 for all online suppl. material).

Eligibility Criteria and Study Selection

After the removal of duplicates, article screening was conducted in a two-stage process: titles and abstracts were reviewed followed by full-text evaluation of the remaining articles. Inclusion criteria were (1) comparative RCTs and observational studies; (2) peer-reviewed full-text articles; (3) English language; (4) RRD patients treated using SB alone or SB + PPV; (5) at least one set of reported efficacy and/or safety outcomes for each treatment arm; and (6) at least five eyes per treatment arm. In the case of multiple studies derived from the same study population, data were extracted from publications with the longest follow-up period. However, related older studies were reviewed for any additional baseline or follow-up data which may not have been reported in subsequent reports.

Data Collection and Study Endpoints

Data were extracted from all eligible studies via manuscripts and supplementary files. For missing data, an attempt was made to contact study investigators up to two times with each attempt separated by a minimum of 2 weeks. Missing data were not imputed but rather marked as not available in collection tables. When available, baseline demographic variables included study design, country of origin, number of eyes, age, gender, ethnicity, distribution of right eyes, intervention(s), vitrector gauge, intraoperative gas use and type, lens status, best-corrected distance visual acuity, intraocular pressure (IOP), break details (total number, inferior breaks, detached quadrants), macular attachment, presence of lattice degeneration, vitreous hemorrhage, and proliferative vitreoretinopathy (PVR) grade.

The primary efficacy indicator was best-corrected visual acuity (BCVA), which was collected in Early Treatment for Diabetic Retinopathy Study (ETDRS) letters or LogMAR (logarithm of the minimal angle of resolution) notation as per the data available in the included studies. According to previously published conversions, mean Snellen values were converted to LogMAR [20, 21].

Secondary efficacy indicators included primary (i.e., single surgery) and final reattachment rates, central subfield retinal thickness (CSFT), operation time, number of interventions to achieve reattachment, IOP (final and change), and incidence of intra- and postoperative ocular adverse events (online suppl. Table S2). Efficacy and safety results were based on data at target follow-up and interim time points when available.

Bias Assessment and GRADE

Risk of bias assessment was conducted using the Cochrane RoB 2 tool for randomized trials [22] and the ROBINS-I tool for nonrandomized studies [23]. Conflicts of interest and industry sponsorship were also documented. A conservative threshold of 20% was set to differentiate between high and low loss to follow-up for the missing data domain in the first 12 months of follow-up; this was increased by 5% for every 12 months of additional follow-up [24, 25]. If one trial arm met this criterion but the other arm(s) did not, the risk of bias was rated as high. Trials were excluded if there was a high risk of bias in three or more assessment domains. Critical assessment of the certainty of evidence for each outcome was conducted using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool [26].

Study selection, bias assessment, data collection, analysis, and conflict resolution were performed by three independent reviewers (P.A.H.N., A.S.D., A.P.S.), with any unresolved conflicts addressed in collaboration with another co-author (M.M.P.). Microsoft® Excel (Microsoft Corporation, Redmond, WA, USA) was used to manage the study screening and data collection process.

Data Synthesis and Analysis

In all analyses, eyes were stratified by the initial procedure to which they were assigned, i.e., SB alone or combination SB + PPV irrespective of whether additional procedures were subsequently performed in cases of primary surgical failure. Outcomes were weighted by the number of eyes and the intention-to-treat principle was used when available. A random-effects model in Review Manager (RevMan 5.4.1; Nordic Cochrane Centre, Cochrane, Copenhagen, Denmark) was used in all analyses to account for possible inter-study heterogeneity. Continuous endpoints were summarized as μ ± SD with weighted mean differences (WMDs) calculated using the inverse variance method. Dichotomous endpoints were summarized as percentages of the total sample with risk ratios (RRs) calculated using the Mantel-Haenszel method. The weighted mean was defined as

and weighted standard deviation as

Meta-analysis was only performed if there were at least two trials with data on an efficacy or safety endpoint. For all outcomes, 95% confidence intervals (95% CIs) were reported. A p value ≤0.05 was considered statistically significant. Statistical heterogeneity was investigated using two methods: (1) percentage of variance attributable to heterogeneity via an I2 statistic (significant heterogeneity: >75%) [27] and (2) a χ2 statistic. Review Manager (RevMan 5.4.1; Nordic Cochrane Centre, Cochrane, Copenhagen, Denmark) was used to perform the meta-analysis. The number needed to treat and number needed to harm (NNH) were also reported for relevant outcomes. Subgroup analyses were conducted based on lens status, macular attachment status, studies published in or after 2010, and exclusion of studies which explicitly mention inclusion of significant PVR (grade C or worse) [28]. A leave-one-out sensitivity analysis was also performed.

ResultsBaseline Demographic Characteristics

After identifying 6,076 unique articles, 107 underwent full-text examination and 18 studies met all inclusion criteria (online suppl. Fig. S1) [16, 29-47]. Eight (44.44%) studies explicitly excluded and/or did not have any baseline eyes with PVR grade C or worse, nine (50%) excluded eyes with a history of ocular trauma, seven (38.89%) excluded eyes with macular hole, and nine (50%) excluded eyes with previous vitreoretinal surgery. At baseline, 3,912 (54.24%) eyes underwent SB and 3,300 (45.76%) underwent SB + PPV over a mean target follow-up period of 4.66 months per eye (Table 1). A comparison of the baseline characteristics of SB versus SB + PPV eyes can be found in Table 2. Compared to the SB + PPV group, the SB group was younger by a mean of 6.8 years, had a higher proportion of phakic eyes by 16%, a lower proportion of macula off eyes by 11%, a better mean BCVA of 0.43 LogMAR, and a 9% lower prevalence of PVR. The mean operation time with SB + PPV was nearly twice that of SB.

Table 1.

Baseline demographics of included studies

Table 2.

Comparison of baseline characteristics between SB alone and SB + PPV eyes (for characteristics with values reported by at least two studies)

Risk of Bias Assessment and GRADE

Bias assessment of two included RCTs using the Cochrane RoB2 criteria revealed 70.00% of the five rated domains as being low risk, 30.00% as having some concerns, and none as being high risk (online suppl. Table S3a). There were no concerns regarding randomization or selection of reported results. Using the ROBINS-I criteria for 16 observational studies, 69.64% of the seven assessed domains were rated as low risk, 30.36% as moderate risk, and none as serious or critical risk (online suppl. Table S3b). There were no concerns related to intervention classification, and non-significant concerns related to participant selection, deviation from intended interventions, missing data, and selection of reported results. Eight studies (44.44%) declared conflicts of interest and/or financial support for their study [16, 30, 36, 39, 41-44]. No study was excluded based on the a priori bias exclusion criterion.

GRADE of BCVA revealed a moderate certainty of evidence, whereas there was a high evidence certainty for primary and final reattachment rates (Table 3). Analysis of eight safety outcomes with available data yielded results which were rated as having very low (12.5%), low (37.5%), moderate (37.5%), or high (12.5%) level of evidence certainty with specific outcomes and ratings detailed below.

Table 3.

GRADE summary of findings1

Main Efficacy and Safety Analysis

In the efficacy analysis of all available data (Tables 4,5), there was no significant difference in the mean final BCVA of SB alone (0.28 ± 0.44 LogMAR [20/38 Snellen]) versus SB + PPV (0.52 ± 0.58 LogMAR [20/66 Snellen]; WMD = −0.11 LogMAR; 95% CI: [–0.29, 0.07]; p = 0.23; GRADE: moderate certainty; Fig. 1a). The primary reattachment rates of 87.42% for SB and 87.47% for SB + PPV were nonsignificantly different (RR = 0.99; 95% CI: [0.94, 1.04]; p = 0.74; GRADE: high certainty; Fig. 1b). However, the final reattachment rate was significantly higher with SB versus SB + PPV (97.40% vs. 93.86%; RR = 1.03; 95% CI: [1.00, 1.06]; p = 0.04; SB number needed to treat = 28; GRADE: high certainty; Fig. 1c). Insufficient postoperative data on CSFT, operation time, number of interventions to anatomic success, IOP (final and change) were available, precluding meta-analyses of these endpoints. Additional data at interim follow-up time points from the initial procedure were not available for analysis.

Table 4.

Efficacy endpoint data of included studies

Table 5.

Numeric summary of forest plots

Fig. 1.

Forest plots of the efficacy analyses of SB versus SB + PPV for the surgical management of RRD illustrating the BCVA at last follow-up (a); primary reattachment rate (b); and final reattachment rate (c). CI, confidence interval; SB, scleral buckling; SB + PPV, combined scleral buckling and pars plana vitrectomy.

When assessing the incidence of complications, SB alone had a significantly lower risk of macular edema (11.97% vs. 19.23%; RR = 0.69; 95% CI: [0.47, 1.00]; p = 0.05; NNH = 14; GRADE: high certainty; Fig. 2c) and cataract development or progression (16.05% vs. 48.58%; RR = 0.34; 95% CI: [0.12, 0.96]; p = 0.04; SB NNH = 3; GRADE: moderate certainty; Fig. 2g). The incidence of macular hole (p = 0.53; GRADE: low), epiretinal membrane (p = 0.40; GRADE: moderate), residual subretinal fluid (p = 0.08; GRADE: very low), PVR development or progression (p = 0.21; GRADE: low), elevated IOP (p = 0.78; GRADE: moderate), and diplopia, strabismus, or extraocular muscle dysfunction (p = 0.86; GRADE: low) were similar between SB alone and SB + PPV.

Fig. 2.

Forest plots of the main safety analyses of SB versus SB + PPV for the surgical management of RRD illustrating the incidence of macular hole (a); epiretinal membrane/macular pucker (b); macular edema (c); elevated IOP or ocular hypertension (d); residual subretinal fluid (e); PVR development or progression (f); cataract development or progression (g); diplopia, strabismus, and other EOM dysfunction (h). CI, confidence interval; SB, scleral buckling; SB + PPV, combined scleral buckling and pars plana vitrectomy.

Subgroup Analysis: Publication in 2010 or Later, Lens Status, Macular Attachment Status, Significant PVR

Unless otherwise stated below, efficacy and safety outcomes were similar in the main analysis and subgroups of studies published in or after 2010 (online suppl. Fig. S2, 3) and among eyes with phakic (online suppl. Fig. S4) and pseudophakic lens status (online suppl. Fig. S5), macula on (online suppl. Fig. S6) and off status (online suppl. Fig. S7), and without significant PVR at baseline (online suppl. Fig. S8, 9). The following subgroup findings were significantly different from the main analysis.

In the subgroup analysis of studies published in or after 2010, final BCVA was significantly better with SB alone (SB: 0.29 ± 0.46 [20/39 Snellen] versus SB + PPV: 0.52 ± 0.58 [20/66 Snellen] LogMAR; WMD = −0.16; 95% CI: [–0.28, −0.04]; p = 0.009; online suppl. Fig. S2a), while cataract development or progression was no longer significantly different between SB versus SB + PPV (p = 0.07; online suppl. Fig. S3f). Among pseudophakic eyes, the final reattachment rate was no longer significant between comparators (p = 0.83; online suppl. Fig. S5c). Comparing SB to SB + PPV in macula on and off eyes separately, final reattachment rate was no longer significantly different in the former subgroup (p = 0.31 and 0.04, respectively; online suppl. Fig. 6b, 7b). In eyes with no significant baseline PVR, cataract development or progression was no longer significantly different between SB and SB + PPV (p = 0.07; online suppl. Fig. S9d).

Sensitivity Analysis: Leave-One-Out

Detailed results of a leave-one-out sensitivity analysis can be found in online supplementary Table S4. In the main analysis, the removal of one study at a time resulted in final BCVA being significantly better with SB alone [32] and a higher incidence of IOP elevation with SB + PPV with the cited references removed from analysis [41]. Final reattachment rate [39, 43] as well as the incidence of macular edema [29, 41, 45, 48] and cataract development or progression were no longer significantly different between SB + PPV and SB alone upon individual removal of the cited references from analysis [40-43].

Discussion

SB alone and in combination with PPV are important techniques that are often used to repair RRDs. Despite SB more recently growing out of favor among some ophthalmologists who prefer PPV given the potentially comparable efficacy and safety with a reduced operation time, consensus on a preferred surgical modality has yet to be achieved [8, 13, 14, 49, 50]. Although SB can be considered invasive due to extraocular tissue manipulation and tissue dissection, it is less invasive in terms of intraocular risks relative to PPV. More surgery is not always best; doing only what is necessary may be better for long-term integrity of the retina. Given the advantages and disadvantages for each procedure, this meta-analysis sought to consolidate relevant comparative studies to investigate the efficacy and safety of SB alone versus SB in combination with PPV.

In the main efficacy analysis and subgroup analyses, the primary outcome, final BCVA, demonstrated no statistically significant difference between SB and SB + PPV. However, exclusion of studies published prior to 2010, i.e., one study by Halberstadt et al. [32], resulted in BCVA being significantly better in eyes with RRD treated via SB alone. A better final BCVA among standalone SB eyes is consistent with previous studies comparing SB to PPV and is likely a multifactorial result with cataract formation as a primary reason [1, 11, 51, 52]. Across studies that reported this information, subgroup analysis comparing final BCVA among phakic (SB: 0.38 ± 0.33 LogMAR [20/48 Snellen] vs. SB + PPV 0.33 ± 0.45 LogMAR [20/43 Snellen]; p = 0.77) and pseudophakic (SB: 0.69 ± 0.28 [20/98 Snellen] vs. SB + PPV 0.58 ± 0.30 [20/76 Snellen]; p = 0.21) eyes demonstrated no significant difference. Age, baseline visual acuity, and macular attachment status are other factors that have been found to influence postoperative visual acuity [32, 53]. Compared to SB, eyes which underwent SB + PPV had a higher mean age along with a worse preoperative BCVA and higher proportion of macula off eyes, differences that may potentially influence final outcomes. Moradian et al. [37] noted that better final BCVA in SB eyes may result from a significantly more rapid improvement in the initial postoperative period versus SB + PPV [32, 37]. Overall, earlier visual recovery, reduced postoperative positioning requirements, lower risk of cataract formation, and no impairment of accommodation with SB alone likely mediate final BCVA [7, 11, 51, 54].

Examination of anatomic reattachment rates revealed that SB had a significantly higher final reattachment rate versus SB + PPV, which remained consistent in a subgroup of phakic eyes only, although the difference between groups was small. In phakic eyes, an increased risk of incomplete vitreous removal and intraoperative breaks with PPV may mediate decreased reattachment rates, even if done in combination with SB [17, 55, 56]. In the subgroup of pseudophakic eyes, there is a lower risk of incomplete vitreous removal, which was consistent with the observed lack of significant difference between comparators for both primary and final reattachment rates [57, 58]. Of note, the use of sectoral and/or encircling buckles was inconsistent among studies with some studies not outlining specific details regarding the procedure performed. Our results are contrary to a retrospective study of 1,212 eyes with both RRD and choroidal detachment where SB was found to be a significant risk factor for RRD recurrence at 3 months postoperatively in comparison with PPV with gas, oil, and/or in combination with SB [59]. The authors hypothesize this to be complicated by other factors including middle age, male sex, aphakia, and axial length, which were also found to correlate with higher rates of redetachment. In the present study, the SB + PPV group had a higher mean age along with a higher proportion of males and aphakic eyes, which could potentially contribute to a lower final reattachment rate compared to SB alone. Furthermore, recent modifications to surgical techniques such as chandelier-endoilluminated wide-angle viewing systems may further enhance the ability of SB to visualize retinal breaks and allow improved efficacy with SB [60, 61].

SB alone had a significantly lower risk of cataract development or progression versus SB + PPV in the main analysis, which aligns with previous knowledge about a higher risk of cataract formation in vitrectomized eyes and the indication for SB over PPV in younger patients given a lower risk of impairing accommodation [7]. However, details of endotamponade, laser retinopexy, and cryopexy use were inconsistently reported among included studies [62, 63]. Further, we were unable to assess cataract grade of included eyes at baseline, and predisposing conditions such as diabetes and steroid use, given a paucity of baseline patient and ocular characteristics across included studies [64, 65].

The risk of macular edema was significantly lower with SB versus SB + PPV. Cystoid macular edema (CME) is well-reported following retinal detachment repair with SB and PPV with the incidence of CME post-PPV reported in 2.3–16.3% of cases [66-68] versus 6.9–43% with SB [68-71]. The risk of CME secondary to RRD repair across included studies was unclear given the variable study design and surgical approach along with limited, nonspecific, and nonstandardized reporting of this complication between studies [45, 72]. Pre- and postoperative precautions such as the use of anti-inflammatory medications [66, 73], surgical techniques such as inner limiting membrane peeling [74, 75], and advancements in optical coherence tomography to monitor for developing CME [72] may aid in preventing, diagnosing, and managing CME following RRD repair. Furthermore, a lack of available data on CSFT at baseline and postoperatively made it difficult to calculate mean differences in retinal thickness over time.

The incidence of elevated IOP was similar between SB and SB + PPV in the main analysis; however, leave-one-out analyses revealed a significantly lower risk of IOP elevation with SB. This is consistent with previous studies reporting a higher rate of IOP elevation in vitrectomized eyes, which is usually transient but may also result in a long-term risk of glaucoma [76, 77]. Causes for IOP elevation following retinal surgery are likely related to intraocular tamponade use (i.e., gas vs. silicone) and expansion properties of gas, encircling bands which can impair episcleral circulation or cause ciliary body congestion, synechiae, anterior choroidal swelling, and steroid use [29, 43, 78-80]. Given limited available data from only one-third of included studies, strong conclusions cannot be drawn from our data related to this safety outcome. There were no other significant differences in ocular adverse events identified in the present analysis.

Limitations

There were multiple instances of missing baseline and outcome data including location of breaks, mean number of breaks, time from diagnosis to surgery, and follow-up time. Alongside generally unstandardized reporting of data and outcomes among studies, this may influence the interpretation of findings. Baseline characteristics between SB and SB + PPV including age, gender, baseline BCVA, macula off status, operation time, and PVR presence were not always similar. Also, eyes that did not achieve primary surgical success for whom final follow-up data including BCVA and reattachment rates were available likely had additional procedure(s). Only four studies which reported final success data specified that PPV was the preferred surgical modality for eyes requiring additional procedures, irrespective of initial assignment to SB alone or SB + PPV [29, 30, 35, 43].

Despite a random-effects analysis to account for heterogeneity, the significance of certain comparisons was altered in leave-one-out sensitivity analyses, thus increasing the risk of uncertainty in our findings. As well, only seven studies had data available on final BCVA, the primary outcome of interest, limiting the ability to analyze this primary endpoint across diverse subgroups. A recently published study by Xu et al. [81] provides a comprehensive list of RRD repair-related complications which, if reported in relevant studies, may facilitate improved comparison of RRD interventions. The decision to pursue SB versus SB + PPV was often made by the surgeon, and factors such as baseline demographics and experience with various repair methods may affect patient selection for these procedures. The inclusion of only RCTs and comparative observational studies was to aim for balance in baseline characteristics of patients between the SB and SB + PPV cohorts. Nevertheless, data in this analysis must be regarded as hypothesis-generating and applied to populations rather than at the level of individual patients. Notwithstanding a low-moderate risk of bias for included studies, only 2 of the 17 studies included in the analysis were derived from RCTs. The included observational studies are susceptible to confounding and selection bias, and adjustment for confounding beyond subgroup analysis was not possible in the current analysis. While primary SB is a suitable option in the treatment of RRDs, the increased preference for PPV among ophthalmologists has resulted in a declining amount of research on SB alone or in combination with PPV in recent years [13, 14].

Conclusions

This meta-analysis found that SB may offer a better final BCVA along with reduced risks of cataract development or progression, IOP elevation, and CME postoperatively compared to SB + PPV (GRADE: moderate level of certainty). With a high level of certainty, SB alone was associated with a slightly higher final reattachment rate compared to SB + PPV. While these conclusions may not be true among all patient subgroups, the present study demonstrates that combination SB + PPV may be unnecessary in certain uncomplicated RRDs. In complicated cases, data are less clear on the role of SB + PPV and the decision to pursue combination procedures should be left to the surgeon’s discretion based on individual patient factors. We recommend further evaluation of efficacy and safety outcomes for SB and SB + PPV in diverse subgroups in addition to cost-effectiveness analyses and patient-provider experience measures to guide future clinical decision-making.

Acknowledgments

We thank Drs. Takayuki Baba, Grace Kiew, and João Heitor Marques for providing supplementary unpublished data from their studies which were included in the present analysis.

Statement of Ethics

The paper is exempt from Ethical Committee approval given that it is a meta-analysis of previously published data as opposed to a primary study using direct/individual patient data. This research in its entirety complies with the guidelines for human studies and should include evidence that the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

Conflict of Interest Statement

Prem A.H. Nichani, Arjan S. Dhoot, Arshia Eshtiaghi, Andrew Mihalache, Aman P. Sayal, and Hannah J. Yu: None. Marko M. Popovic: financial support (to institution) – PSI Foundation. Charles C. Wykoff: consulting: Adverum, Allergan, Apellis, Bayer, Genentech, Gyroscope, IVERIC Bio, Chengdu Kanghong Biotechnologies, Kodiak Sciences, NGM Biopharmaceuticals, Novartis, ONL Therapeutics, Opthea, Regeneron, RegenXBio, and Roche and research: Adverum, Aldeyra, Apellis, Bayer, Chengdu Kanghong Biotechnologies, Clearside Biomedical, Gemini Therapeutics, Genentech, Gyroscope, IONIS Pharmaceutical, IVERIC Bio, Kodiak Sciences, NGM Biopharmaceuticals, Novartis, Opthea, Regeneron, RegenXBio, and Roche. Peter J. Kertes: consultant – Bayer, Novartis, Novelty Nobility, and Roche; financial support (to institution) – Novartis and Roche; financial support – Bayer, Boehringer Ingelheim, Novartis, Pfizer, Roche, and Zeiss; and equity owner – ArcticDx. Rajeev H. Muni: consultant – Allergan, Bayer, Novartis, and Roche and financial support (to institution) – Bayer and Novartis.

Funding Sources

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author Contributions

The authors, namely, Prem A.H. Nichani, Arjan S. Dhoot, Marko M. Popovic, Arshia Eshtiaghi, Andrew Milhalache, Aman P. Sayal, Hannah J. Yu, Charles C. Wykoff, Peter J. Kertes, and Rajeev H. Muni, have sufficiently fulfilled the four criteria of authorship as detailed by the International Committee of Medical Journal Editors (ICMJE) Recommendations. Specifically, all named authors substantially contributed to the conception or design of the study, acquisition, analysis, and/or interpretation of the data, assisted in drafting and/or revising the manuscript critically for important intellectual content, provided final approval for this version of the manuscript to be published, and agreed to be accountable for all aspects of the work.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.

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