Symptomatic vitreomacular adhesion (sVMA) typically occurs with incomplete posterior vitreous detachment (PVD) and leads to subsequent loss or distortion of vision (1–3). sVMA can further result in the occurrence of vitreomacular traction (VMT), often coinciding with macular hole (MH) and epiretinal membrane (ERM).

Based on its etiology, treatment of sVMA requires the release of vitreous body traction on the retina. The current standard management option for treating these adhesions is pars plana vitrectomy (PPV), which involves removing the vitreous surgically (4, 5). However, even small-gauge procedure PPV can lead to serious complications including retinal detachment, retinal tears, endophthalmitis, and postoperative cataract formation. A biological agent for non-invasive treatment of VMA known as ocriplasmin (Jetrea; ThromboGenics NV, Leuven, Belgium, UK) was approved as the first drug of its kind by the US Food and Drug Administration on October 17, 2012 (6, 7). Ocriplasmin is composed of the catalytic domain of human plasmin with proteolytic activity against protein components of the vitreous body and vitreoretinal interface. It dissolves the protein matrix responsible for VMA. The approval of ocriplasmin for clinical use was based on the MIVI-TRUST study (8). Since then, randomized controlled trials (RCTs) including MIVI-IIT and OASIS (9, 10), prospective cohort studies, and observational studies including INJECT, ORBIT, and OVIID-1 (11–13) have analyzed the efficacy of and adverse reactions to ocriplasmin. Resulting data show that non-surgical induction of PVD using ocriplasmin can offer the benefits of VMA release and MH closure while eliminating the risks associated with a surgical procedure.

Subgroup analyses on pharmacologic VMA resolution showed that subjects with certain baseline characteristics had higher VMA resolution rate included absence of ERM, presence of MH, small adhesion diameter, phakic lens status, gender, and age (11, 13, 14). Meta-analysis of Jackson et al. further demonstrated that presence of ERM and broad VMA, increasing age, and male gender were associated with decreased treatment response in RCT reports (15).

This study includes a complete search for existing data in this meta-analysis to evaluate the efficacy and safety profile of ocriplasmin for the treatment of sVMA with/without MH, across subgroups defined by the presence of ERM and MH, and also to identify factors which may affect the effectiveness of ocriplasmin including MH diameter, age, gender, and others. Based on our findings, we proposed the optimal profile of patient for treatment with ocriplasmin.

This study is fully compliant with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (16). This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021228893).

We identified 5 RCTs and 50 cohort studies including 4,159 participants. Our results demonstrated that treatment with ocriplasmin increased the likelihood of VMA release and MH closure and was associated with improvements in BCVA and questionnaire-assessed visual function. No increased risk in overall AEs was found between ocriplasmin treatment and control. The results also showed that VMAR was more likely in patients with absence of ERM. Patients with smaller MH diameter were more likely to achieve MH closure. Our findings have comprehensively demonstrated the effectiveness of ocriplasmin in VMA and MH treatment as well as patient-related factors affecting outcomes and included guidance on selection of suitable patients to receive ocriplasmin treatment in clinic.

Posterior vitreous detachment is a physiological age-related process and incomplete PVD could cause VMA due to the persistent adhesion of the vitreous to the macula, especially the fovea. Persistent asymptomatic VMA may progress to VMT, also known as sVMA, causing retinal structure deformation such as macular edema and MH and accompanied by metamorphopsia, decreased visual acuity, and other symptoms. The RCTs included in this study indicated that treatment with ocriplasmin was more likely than control intervention to result in VMA release and MH closure, reduce the requirement for PPV, and achieve visual improvement, consistent with a previous meta-analysis (19). One RCT study on wAMD (18), showed that the VMA release of patients with wAMD was lower than previously demonstrated by other RCT studies, suggesting that VMA secondary to wAMD may be less responsive to ocriplasmin. However, this study found that ocriplasmin treatment and its causing VMA release decreased the number of antivascular endothelial growth factor injection in patients with wAMD.

Furthermore, we analyzed VFQ-25 composite scores changes found in the OASIS and the MIVI-TRUST trials (20, 21). Ocriplasmin treatment was associated with visual function improvement not only in BCVA, but also in this participant-reported questionnaire-based outcome. These scores reflect the influence of visual disability and visual symptoms on generic health domains and indicate the effect of treatment on activities related to daily visual functions (22, 23). The findings are relevant to clinical decision-making, since outcomes reported by patients are powerful tools to verify the effects of a treatment on health and daily-life activities of patients, both in terms of benefits and potential adverse effects.

The strengths of this meta-analysis include the comprehensive search strategy and retrieval of all the relevant trials and the focus on detecting the optimal patient profile for ocriplasmin treatment. In the UK, the National Institute for Health and Care Excellence (NICE) guidance recommends the use of ocriplasmin for treating VMT in adults without ERM, who have a MH ≤ 400 μm diameter and/or severe symptoms (24). Several studies have demonstrated that ocriplasmin therapy might be more beneficial for patients with sVMA with specific characteristics such as relatively small adhesion diameter and absence of ERM (25). More recently, Jackson et al. included 5 RCTs in an IPD meta-analysis and found that VMA release is more likely in younger, female patients and eyes with MH and less likely in the presence of ERM, broad VMA (>1,500 μm), DR, or pseudophakia (15). In this study, we also reported that patients with absence of ERM, the treatment of ocriplasmin was more likely to induce VMA release (Figure 4). Patients with MH were more likely to experience VMA release after ocriplasmin injection, since ERM and large VMA adhesion diameters seemed to be rare in the presence of MH. However, even if a patient with MH achieves VMA release, without MH closure, PPV is subsequently required to close the MH, which would still be considered a treatment failure. For patients with MH, small diameter MH (≤ 250 μm) was more likely to get nonsurgical closure (Figure 5). Therefore, as recommended by the NICE guidelines, patients with smaller MH may have a higher closure rate.

In this study, we extracted raw data from the included studies providing baseline characteristics of each participant and applied the ROC curves and the AUROCs analysis. By using the IPD of included studies, we estimated the cutoff values and evaluated the performance of these factors as predictors of VMA release after ocriplasmin therapy in a total of 120 patients. Further, the predict ability for female patients with VMA diameter < 506 μm and without ERM was 0.84. So, in clinical practice, when we encounter patients with sVMA and consider whether to use ocriplasmin for them, the gender of patient, ERM formation, and VMA diameter were brought into the formula (P_Release). P_Release represents the estimated probability of VMA release. If P_Release is more than 0.68, the patient might probably achieve VMAR after with ocriplasmin therapy. We further provided several examples and their P_release value in Supplementary Table 6 for reference. These findings would help doctors about patient selection strategy.

It has been recognized that sVMA may be associated with other conditions such as AMD, DR, or RVO (18, 26, 27). These pathogenic factors may lead to an abnormally strong adhesion between the posterior vitreous cortex and macula. As mentioned earlier, the therapeutic effect of ocriplasmin for secondary VMA may be poorer than that for idiopathic VMA. In this study, we attempted to analyze whether AMD, DR, or RVO may affect the therapeutic effect of ocriplasmin, but a paucity of information on health status of patient in the included studies prevented this analysis.

Several other sVMA treatment modalities exist; observation often being the first approach. Studies report that 11 to 40% of sVMA cases resolve spontaneously (28, 29), with unpredictable timeframes. Moreover, sVMA may lead to anomalies of retinal morphology, being responsible for metamorphopsia or loss of visual acuity, which increases with duration. Previous meta-analyses evaluated VMA treatment by intravitreal gas injections and found VMAR in 84% and MH closure in 59% after perfluoropropane (C₃F₈) gas injection (30) or VMA resolution in 47% of cases with or without associated MH 1 month after the injection C₃F8 or SF₆ (31). Other studies have found VMA release in 36% of eyes treated with air injection (32). Recently, the first RCT for evaluating the safety and efficacy of intravitreal gas (C₃F₈) injection was terminated early because of safety concerns related to retinal detachments and retinal tears (33). So, the safety issue of intravitreal gas injection still requires great attention. More studies are needed to increase understanding of the benefits of different approaches to management of sVMA including observation, PPV, ocriplasmin, and intravitreal gas injections.

A potential limitation of this meta-analysis is that few trials compared different approaches of managing sVMA including PPV, intravitreal gas injection, ocriplasmin, and observation (32, 34, 35). It was, therefore, not possible for us to compare efficacy directly between these strategies. There might introduce some bias in the predict ability in IPD analysis for only based on 5 studies with limited sample size. Also, few studies observed recurrence after ocriplasmin therapy (36). In future studies, attention should be paid to recurrence rates and timeframes in ocriplasmin-induced patients with VMAR. In addition, highly myopic patients with VMA require special attention, since treatment may be challenging in this group (37). Insufficient study to date involves observation and follow-up after ocriplasmin treatment in this group of patients. Most of the existing study has been carried out in Europe and North America and the effects in other regions and races remain unclear. More long-term follow-up data and further analyses are needed to understand therapeutic effects in VMA induced by various etiologies.

Evidence from the 5 RCTs and 50 cohort studies included here suggests that ocriplasmin is a suitable approach for treating sVMA. As clinicians, we should be increasingly cognizant of appropriate patient selection for ocriplasmin treatment and should take into account various factors such as MH, ERM, VMA diameter, age, and sex.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

XC contributed to the study design, manuscript writing, literature search, data abstraction, and finalization. ML contributed to the literature review, data abstraction, manuscript writing, and statistical analysis. RY contributed to the literature review and statistical analysis. WW contributed to the manuscript writing and review. YW contributed to the study design, manuscript writing, and review. All authors contributed to the article and approved the submitted version.

This study was supported by the National Natural Science Foundation of China under (Grant Nos. 82101128 and 81870686) and the Beijing Municipal Natural Science Foundation under (Grant No. 7184201). The funders had no role in the design or conduct of the study, collection, management, analysis, or interpretation of the data, preparation, review, or approval of the manuscript, or the decision to submit the manuscript for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Reviewer FL declared shared affiliation with the authors to the handling Editor at time of review.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.