Different approaches for the treatment of myopic choroidal neovascular: a network meta-analysis

doi:10.21203/rs.3.rs-1988277/v1

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Different approaches for the treatment of myopic choroidal neovascular: a network meta-analysis

https://doi.org/10.21203/rs.3.rs-1988277/v1

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Purpose: In order to evaluate the efficacy of intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) drugs, photodynamic therapy (PDT), and laser treatment (LT) for anatomical and functional improvement in myopic choroidal neovascularization (mCNV) patients were evaluated in a mesh meta-analysis.

Methods: Two researchers independently searched PubMed, Cochrane Library, Web of Science, CNKI, WanFang Data, Embase, and other databases to screen RCTs and retrospective studies comparing best-corrected visual acuity (BCVA) and foveal center thickness (FCT) changes after mCNV treatment. The retrieval time limit is from the database construction to November 30, 2021. ADDIS1.16.8 and R 3.5.3 software were used to conduct mesh meta-analyses of RCTs and retrospective studies, respectively.

Results: A total of 601 eyes in 8 RCTs involving 6 treatment options: intravitreal bevacizumab (IVB), intravitreal ranibizumab (IVR), intravitreal conbercept (IVC), intravitreal aflibercept (IVA), LT, PDT, sham first followed by IVA (Sham /IVA). The results of the mesh meta-analysis showed that: in the RCTs, IVB and IVR were superior to PDT [MD=0.18, 95%CI (0.01, 0.42)] in improving BCVA of mCNV patients, and all the therapeutic effects from high to low might be intravitreal IVA, IVB, IVR, LT, Sham/IVA, and PDT; the order of FCT thickness reduction from high to low is IVA, IVR, IVB, PDT. In addition, the results of BCVA after long-term treatment in retrospective studies showed that all the therapeutic effects from high to low might be IVA, IVC, IVB /IVR, IVB, IVR, PDT, PDT with IVB /IVR; as for the order of FCT thickness reduction from high to low is IVA, IVC, IVR, IVB, PDT.

Conclusions: Anti-VEGF treatment in patients with long-term improvement in mCNV vision effect is best, using IVB or IVR alone to treat mCNV may be better than IVB or IVR combined with PDT; There was no significant difference in the improvement of visual acuity and macular edema in mCNV patients with different anti-VEGF drugs. Due to the limited number and quality of included literature, the above conclusions need to be confirmed by more large-sample and high-quality articles.

aflibercept

bevacizumab

conbercept

laser treatment

myopic choroidal neovascularization

network meta-analysis ranibizumab

photodynamic therapy

At present, myopia has become a global public health problem,¹ as the main cause of the uncorrected refractive error, which has brought a huge economic burden every year.² A meta-analysis shows that the global potential productivity loss caused by uncorrected myopia was estimated to be $244 billion in 2015.³ High myopia (HM) is defined as ametropia with a diopter (D) ≤-6 or less.⁴ Moreover, HM was associated with a significant increase in visual impairment (VI), irreversible blindness,⁵ and, more frightening still, a significant prevalence. According to a meta-analysis, nearly half of the world's population may suffer from myopia by 2050, of which the HM population will be as high as 10%.⁶ Usually, while HM individuals have characteristic fundus pathological changes such as leopard-shaped fundus and chorioretinal atrophy, we call it pathological myopia (PM),⁷ though there is no broad and clear clinical definition of the latter. Furthermore, compared with ordinary myopia, HM significantly increases the risk of complications caused by PM, such as retinal atrophy, retinal detachment (RD), cataract, glaucoma, myopic macular degeneration, and myopic choroidal neovascular (mCNV).^8–10

mCNV is one of the terrible complications from PM, affecting about 5–11% of PM patients, of which about 15% involve both eyes.⁹ The disease mainly refers to the formation of abnormal neovascularization under the retinal pigment epithelium or retina.¹¹ Besides, the vision of patients who have not been treated for a long time will be significantly reduced or even blind.¹² Therefore, timely treatment of mCNV is very important. Currently, there are several treatments for mCNV, including retinal laser photocoagulation, photodynamic therapy (PDT), intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs, etc. All of them have been shown to be effective in the treatment of mCNV. Matsuda et al. found that after laser treatment (LT), mCNV patients were followed up for 13–60 months, despite the phenomenon of laser photocoagulation scar enlargement in about 80% of patients, almost all patients had no vision loss and were well-controlled.¹³ Also, PDT was shown to improve visual acuity in patients with mCNV during a one-year follow-up.¹⁴ In addition, with the emergence of anti-VEGF drugs and successful application in many other retinal angiogenic diseases, anti-VEGF therapy has gradually become a common treatment for mCNV. Currently, commonly used anti-VEGF drugs include aflibercept, ranibizumab, bevacizumab, and conbercept (which was produced in China and was approved by the State Food and Drug Administration of China in May 2017 for the treatment of mCNV).

Although there have been meta-analyses on mCNV. But they are mainly traditional meta-analyses comparing two treatment methods. For example, Hu et al.¹⁵ compared the efficacy of intravitreal bevacizumab (IVB) and ranibizumab (IVR) in the treatment of mCNV in a meta-analysis and confirmed that both of them were effective treatment measures, though there was no statistical difference between the two treatments as far as possible. Additionally, Wang et al.¹⁶ compared the ranibizumab/bevacizumab with PDT treatment and found that anti-VEGF on mCNV treatment has a better curative effect. However, so far, no mesh meta-analysis has comprehensively compared various treatment methods and the four different anti-VEGF drugs. Therefore, the purpose of this study is to compare and rank the efficacy of several existing mCNV treatment methods, in order to obtain the best method of mCNV treatment and provide useful information for guiding the clinical treatment of the disease.

Flow chart and characteristic table

1.1Literature search results

We preliminarily searched 763 articles, deleted 61 duplicate articles, 617 non-comparative original articles were deleted, excluded 56 articles by reading the title and abstract, excluded 13 articles after reading the full text, and finally included 16 articles that met the criteria. Details are presented in Figure 1.

1.2 Basic characteristics of the included study

A total of 16 articles were included, including 8 RCTs and 8 retrospective studies, involving 1072 eyes. The following is the characteristic table of the original literature (Table 1)

Evidence network diagram

Figure 2A shows the network diagram of 6 different mCNV treatment methods in the BCVA results of RCTs, a total of 6 interventions including IVA, IVR, IVB, PDT, LT, and sham-combined IVA were involved in the mesh meta-analysis; Figure 2B shows the network relationship diagram of different treatment methods for mCNV in the BCVA results from retrospective studies, the mesh meta-analysis involves 7 interventions: IVA, IVR, IVB, IVC, IVB or IVR treatment, PDT treatment alone, and PDT combined with IVB or IVR treatment; Figure 2C shows a network diagram of 4 different treatments(IVB, IVR, IVA, PDT) in RCTs of FCT results. Figure 2D shows a network diagram of 5 different treatments (IVA, IVB, IVC, IVR, PDT) in the FCT results of retrospective studies; The line thickness in the figure is positively correlated with the number of studies directly comparing the two interventions.

The convergence and stability evaluation results of the study were included

The convergence diagnosis diagram and trajectory density diagram are drawn to evaluate the convergence and stability of the model. Before 50000 iterations of the model, the convergence diagnosis diagram and trajectory diagram have converged. The density diagram is a curve with a normal shape and smooth distribution, and the bandwidth value approaches 0, suggesting that the convergence degree of the model is satisfactory and the stability is good.

Results of mesh meta-analysis

4.1 RCTs

4.1.2 Results of BCVA changes

In the 8 articles included, the changes in BCVA in patients were described. In the included study, a significant increase in BCVA from baseline after most treatments were observed. A comprehensive analysis was carried out using Addis and R software

The results of mesh meta-analysis showed that: BCVA improvement after IVB and IVR treatment was better than PDT [MD=0.18, 95%CI (0.02, 0,40)], [MD=0.18, 95%CI (0.01, 0.42)]. There was no statistical significance in the comparison of postoperative hospital stay between other closure methods (The 95%CI contains 0, which means it is not statistically significant), as shown in Table 2.

Node analysis showed that all P > 0.05, reflecting that there was no statistical inconsistency between the results of direct comparison and indirect comparison. See Table3 for the detailed results.

ADDIS and R showed that the order of probability of improving visual acuity by mCNV treatment was IVA>IVB>IVR>LT> Sham /IVA>PDT, See Figure 3 and Table 4 for details.

4.1.2 Results of FCT changes

Among all RCTs, there are 5 articles involving the change of FCT results, including IVB, IVA, IVR, and PDT. We extracted the data on FCT changes before and after mCNV treatment and found that these treatment methods have no statistical difference in reducing FCT. The detailed results are shown in Table 5(The 95%CI contains 0, which means it is not statistically significant); The results of the comparison and ranking of the effects of these four treatment methods show that IVA may have the best effect, followed by IVR and IVB, and PDT may have the worst effect. The detailed results are shown in Figure 4 and Table 6.

4.2 Retrospective studies

4.2.1 Results of BCVA changes

The 8 included articles described BCVA changes after 12 months of treatment. Addis combined with R software was used for comprehensive analysis, Mesh meta results showed no statistical difference among all treatments (95%CI includes 0), See Table 7 for details.

The node analysis method shows that the direct comparison results are consistent with the indirect comparison results (P > 0.05). See table 8 for the details.

ADDIS combined with R shows that after 12 months of treatment with 7 different methods, the order of increasing the probability of BCVA in mCNV patients is IVA > IVC > IVR or IVB > IVB > IVR > PDT with IVB or IVR > PDT. See Figure 5 and Table 9 for details.

4.2.2 Results of FCT changes

A total of 4 retrospective studies involved the changes in FCT results, including IVC, IVB, IVA, IVR, and PDT. We found that these treatment methods had no statistical difference in reducing FCT. The detailed results are shown in table 10; The results of the comparison and ranking of the effects of these five treatment methods show that IVA may have the best effect, followed by IVC, IVR, IVB, and PDT may have the worst effect. See Figure 6 and Table 11 for the detailed results.

In order to comprehensively compare the efficacy of different anti-VEGF drugs, PDT, LT, and even several combination therapy methods, we initially tried to include only RCTs. However, due to the lack of statistically significant results after the combination of all appropriate RCTs, considering the limited current RCTs, therefore, we also conducted the same mesh meta-analysis on retrospective articles in order to find the most suitable clinical treatment method for mCNV, and the results were similar to RCTs. This is the first article to compare the efficacy of different mCNV treatment methods in RCTs and retrospective studies, involving a total of 16 articles. The results of both RCTs and retrospective studies showed that anti-VEGF therapy might be the best choice after a long-term treatment follow-up of about 12 months. According to the sequencing results, since most of the results showed no statistical significance, we could only get the best possible treatment. The results of RCT and retrospective studies show that among anti-VEGF drugs, IVA may have the best effect in restoring the structure and function of mCNV patients. However, due to the lack of statistical significance, this result is only a possible reference, and more literature and higher-quality data are needed to further confirm this result.

mCNV is one of the complications of myopia with severe loss of vision.³⁵ Patients without timely treatment will have very poor vision.³⁶ For a long time in the past, laser therapy has been used to treat CNV, but it is limited to extrafoveal mCNV and not applicable to subfoveal mCNV. This treatment is prone to laser scar expansion and disease recurrence.^37,38 In our study, there is only one article involving LT,²⁴ and due to the small sample size, it only shows that the degree of vision decline of patients is better than PDT treatment, which has no great advantage in improving visual acuity.

Moreover, the first approved mCNV method that could be used in the treatment is PDT. In fact, as early as 2001, a clinical study of mCNV treated 81 eyes with PDT and 39 eyes with glucose for sham treatment for 12 months, finally, it was found that compared with the control group, the visual acuity of mCNV patients treated with PDT tended to be stable or even improved, and there were no obvious adverse reactions, which proved that PDT can be used as an effective treatment for mCNV.¹⁴ However, when followed up to 24 months, the visual acuity of the PDT treatment group was no longer significantly improved compared with the placebo control group, which can be said to be mainly manifested as stable visual acuity, which may be caused by PDT treatment exacerbating the development of choroidal retinal atrophy in myopia patients.³⁹ What`s more, all the articles included in our study that involved PDT treatment were followed up for 12 months, but there were different evaluations on its efficacy. Some studies’ results showed that the BCVA of mCNV patients improved, while others decreased. We speculated that this was related to the small sample size. After all, studies^26,33,34 with a large sample size all showed that BCVA could be improved after 12 months of PDT treatment.

Intravitreal injection of anti-VEGF drugs is considered the first-line treatment of mCNV,⁴⁰ also, at the same time, it is the most economic burden of the treatment method. Conbercept is a new anti-VEGF drug from China, like aflibercept, it is a soluble receptor protein. The difference is that conbercept mainly contains extracellular domain 2 of VEGF receptor 1 and extracellular domains 3 and 4 of VEGF receptor 2, which are fused with Fc part of human immunoglobulin G1,⁴¹ while aflibercept only contains extracellular domain 2 of human VEGF receptor 1.⁴⁰ The efficacy and safety of IVC in the treatment of mCNV have been verified. In a retrospective study in China, 34 mCNV eyes were treated with conbercept and followed up for 12 months. The logMAR BCVA of the patients increased by 4.12 ± 2.69 on average without complications or adverse events.⁴² As with other anti-VEGF drugs, it can be used as a long-term therapeutic agent for mCNV, although its application is limited at present, especially in other countries. Furthermore, aflibercept has been used earlier for the treatment of mCNV, which has also been demonstrated a significant therapeutic effect. Luca et al. performed IVA treatment on 15 eyes of mCNV patients and finally found that the patients not only improved BCVA but also significantly reduced central retinal thickness, as well as decreased levels of vascular endothelial growth factor (VEGF) and placental growth factor (PIGF).⁴³ Besides, bevacizumab is a humanized monoclonal antibody (IgG1) targeting VEGF-A to inhibit angiogenesis, in addition, it is mainly composed of a fab region that binds to the target and an Fc region that performs an effector function.⁴⁴ What's more, ranibizumab is also a humanized monoclonal antibody fragment, but it only contains Fab fragment, which can also inhibit VEGF-A and prevent the formation of new blood vessels.⁴⁵ As one of the most commonly used anti-VEGF drugs, ranibizumab, and bevacizumab are commonly used to compare efficacy with each other, but they are currently considered to have the same efficacy in improving visual acuity in mCNV patients without statistical difference.¹⁵ Thus, the four kinds of VEGF drugs can effectively inhibit the formation of new blood vessels, for the treatment of mCNV hope, but actually what drug effects best is yet to be concluded. Even in this study we just draw in the RCT group that IVB, IVR is superior to the PDT treatment, 4 kinds of anti-VEGF drugs between concrete and also did not have statistically significant results, we think that is likely to be factors such as literature insufficiency, the sample size is too little.

There are several deficiencies in our study. First of all, we want to compare the long-term efficacy of different treatments, so we tried to choose 12 months as a follow-up time. However, only the data in retrospective studies meet the conditions of time unification. In RCTs, there are still two studies with BCVA results followed up for 3 months and 19 months respectively. As for the results of FCT, the data in most articles do not meet the follow-up time of 12 months. Secondly, we only selected the reduction of LogMAR BCVA, and FCT as the outcome index, because most of the included articles only included these indexes, and the changes in visual acuity and FCT are the most important indexes to evaluate the efficacy of mCNV. We tried to include the number of anti-VEGF injections as the outcome index, but the data included in the study is difficult to meet the extraction of this index. Finally, there are too few studies included in this study and the sample size is not large, which is why most of the results in this study are not statistically significant. In the future, we hope that there will be more appropriate studies, and we will update the data in time to get more reliable results.

Anti-VEGF is the most effective drug to improve the retinal structure and function of mCNV patients. However, PDT and laser also have certain therapeutic effects, and patients will not have a heavy economic burden. But, we have only obtained the possible ranking results of efficacy: Aflibercept may be the most effective anti-VEGF drug for the treatment of mCNV, the above results may only have reference significance. After all, there is no statistical difference in the therapeutic effect of four different anti-VEGF drugs. These conclusions need to be confirmed by higher quality and larger sample studies.

Protocol and registration

This study has been pre-registered in the International Prospective Register of Systematic Reviews under the registration number PROSPERO (https://www.crd.york.ac.uk/prospero/): CRD42021287142. This network meta-analysis was conducted and presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.¹⁷

Search Strategy

In order to obtain appropriate randomized controlled trials (RCTs) and retrospective articles as far as possible, we searched PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang, and other databases, the retrieval time limit is from the establishment of each database to November 30, 2021. The language of this article is limited to English, and the retrieval strategy is “myopia” AND “choroid neovascularization” OR “mCNV” AND “pathological myopia” OR “PM” AND “photodynamic therapy” OR “PDT” OR “anti-VEGF” OR “bevacizumab” OR “IVB” OR “aflibercept” OR “IVA” OR “ranibizumab” OR “IVR” OR “conbercept” OR “IVC” OR “laser treatment” OR “laser photocoagulation” OR “mCNV” AND “randomized controlled trials” OR “RCT” OR “retrospective studies”.

Inclusion and exclusion criteria

We included and analyzed RCTs and retrospective studies respectively. These studies are comparative articles on different treatment methods for mCNV patients, mainly including the comparison of best-corrected visual acuity (BCVA) changes before and after treatment.

Inclusion criteria:1. mCNV patients (CNV patients secondary to PM: refractive error ≤ - 6.0 diopter, or axial length greater than 26 mm) received treatment, regardless of race, region, occupation, and age;2. The data were complete, including baseline BCVA and post-treatment BCVA.3. Comparison of the efficacy of at least two treatment methods. Exclusion criteria: 1. Study subjects are not patients with CNV secondary to PM; 2. Single-arm study without a comparison of treatment measures. 3. Non-original articles such as summarization and experience summary; 4. Incomplete data or incomplete data cannot be obtained from the author.

Outcome

The primary outcome was the mean change in BCVA after treatment from baseline, and the visual acuity was logarithmic visual acuity (logMAR) converted from BCVA measurements. The secondary outcome measure was the change in foveal center thickness (FCT) on optical coherence tomography (OCT).

Literature selection and data extraction

In this study, two authors (Yuliang Feng and Jiasong Yang) independently read the title and abstract of the article according to the inclusion and exclusion criteria, exclude the articles that clearly do not meet the requirements, and then determine the final included literature by reading the content of the article in detail. If the two authors disagree in this process, they will consult or discuss and submit it to the third senior researcher for adjudication, Missing data were obtained by contacting the corresponding authors of the included literature.

Statistical analysis

ADDIS 1.16.8(http://www.drugis.org/ index) and R version 3.5.3¹⁸(R Foundation for Statistical Computing, Vienna, Austria) software were used to analyze the data. In this study, quantitative data and mean square deviation (MD) were used as the effect indicator, and the MD and standard deviation (SD) of each group of data were extracted for joint analysis. Point estimates and 95% confidence intervals (CI) of each effect indicator were given. χ2 test (α=0.1) was used to analyze the heterogeneity among the included studies, and I² was used to determine the heterogeneity. If the heterogeneity among the results was small, the fixed-effect model was used for meta-analysis. Otherwise, if the heterogeneity among the results was large, the random-effect model was used for meta-analysis after excluding the influence of obvious clinical heterogeneity, and P<0.05 between each group was considered statistically significant. ADDIS software was used to calculate the potential Scale reduction factor (PSRF) to diagnose the convergence degree of the model. Set the initial value of 4 Markov chains, the initial value of the model is 2.5, refine the iteration step size by 10, adjust the number of iterations by 20000 times, and simulate the number of iterations by 50000 times. Only when the PSRF value tends to 1 indicates that the convergence of the model is satisfactory.

The R software calls "RJAGS", "GEMTC" program package to establish the Bayesian model, and calls "Network" program package to draw the evidence Network diagram of each intervention. The straight line indicates that there is direct comparison evidence between the two interventions, and the wireless connection lacks direct comparison evidence. The thicker the line, the more studies that directly compared the two interventions. The optimal probability ranking curve (SUCRA) value was calculated, the ranking map was drawn to predict the ranking of therapeutic effects of various measures, and the forest map for direct comparison was drawn. For the study of generating Node Split nodes, the Node Split model was first used to test the consistency of direct comparison and indirect comparison. P > 0.05 indicated good consistency and the consistency model was used for analysis. Instead, adopt the inconsistency model.

Author Contributions:

Yajun Wu: responsible for writing and modifying manuscripts; Yuliang Feng and Jiasong Yang: responsible for independent screening of literature; Hua Fan: responsible for data statistics and chart making; Zitong Yu, Xiaolin Xie and Yumeng Dai responsible for proofreading and revising the language of the manuscript; Wensheng Li: responsible for the design of the study and guiding the revision of manuscript

Conflict of Interest Disclosures:

The authors declare no conflict of interest.

Data Sharing Statement

The data in this study are used to support the results of this study and can be obtained at the request of the corresponding authors.

Funding

Aier Eye Hospital Group Scientific Research Fund (AR2001D1).

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First author (year)

Type

Clinical trial

Therapeutic method

Eyes

Change of FCT(μm)

Follow-up time(months)

Change of BCVA (logMAR)

Follow-up time(months)

Pece2015¹⁹

RCT

two arms

IVB

IVR

47±65.9

42.4±71.1

0.01±0.335

-0.12±0.355

Gharbiya2010²⁰

RCT

two arms

IVR

IVB

45±64.9

52±42.7

-0.3±0.222

-0.32±0.168

Howaidy2019²¹

RCT

two arms

IVA

IVR

153.2±77.9

142.2±93.9

-0.15±0.121

-0.16±0.225

Iacono2012²²

RCT

two arms

IVR

IVB

65±106.3

35±73.0

-0.19±0.195

-0.17±0.195

Ikuno2015²³

RCT

two arms

IVA

Sham/IVA

-0.27±0.18

-0.08±0.18

Parodi2010²⁴

RCT

three arms

PDT

IVB

0.02±0.320

0.15±0.320

-0.2±0.320

Ruiz2013²⁵

RCT

two arms

PDT

IVB

14±67.2

53±70.4

0.01±0.337

-0.22±0.304

Wolf2014²⁶

RCT

two arms

PDT

IVR

116

-0.19±0.227

-0.28±0.204

Sayanagi2019²⁷

Retro

two arms

IVA

IVR

141.3±110.5

94.8±103.8

-0.3±0.4100

-0.22±0.463

Lai2012²⁸

Retro

two arms

IVB

IVR

-0.31±0.393

-0.55±0.441

Chen2020²⁹

Retro

two arms

IVC

IVR

30.62±80.9

42.13±85.2

-0.41±0.508

-0.32±0.400

Cha2014³⁰

Retro

two arms

IVR

IVB

-0.24±0.410

-0.21±0.410

Baba2010³¹

Retro

two arms

PDT

IVB

96±86.9

82±46.0

0.03±0.291

-0.26±0.394

Iruno2010³²

Retro

two arms

PDT

IVB

0.16±0.335

-0.19±0.318

Yoon2010³³

Retro

three arms

PDT

IVR / IVB

PDT with IVR/IVB

-0.06±0.474

-0.24±0.450

-0.09±0.482

Parravano2014³⁴

Retro

two arms

PDT

IVR

65.8±107.8

93.7±120.1

-0.01±0.485

-0.13±0.331

Table1. Characteristics of the table.

Note: Retro: Retrospective study; Sham/IVA: The patients were treated with IVA after sham treatment; IVR or IVB: Treatment with IVB or IVR; PDT with IVR or IVB: PDT was used in combination with IVB or IVR.

LT
-0.03 (-0.36, 0.26)	PDT
0.15 (-0.28, 0.60)	0.17 (-0.14, 0.57)	IVA
0.15 (-0.16, 0.47)	0.18 (0.02, 0.40)	-0.00 (-0.33, 0.33)	IVB
0.16(-0.18, 0.49)	0.18 (0.01, 0.42)	0.00 (-0.29, 0.30)	0.00 (-0.15, 0.17)	IVR
-0.05 (-0.57, 0.49)	-0.02 (-0.44, 0.49)	-0.19 (-0.48, 0.10)	-0.19 (-0.64, 0.24)	-0.20 (-0.62, 0.21)	sham/IVA

Table 2. Different treatment methods improve the results of a meta-analysis of BCVA mesh (RCT).

Name	Direct Effect	Indirect Effect	Overall	P-Value
PDT, IVR	-0.10(-0.32,0.13)	-0.33(-0.57, -0.09)	-0.18(-0.42, -0.01)	0.11
PDT, IVB	-0.28(-0.48, -0.09)	-0.05 (-0.31, 0.22)	-0.18(-0.40, -0.02)	0.1
IVB, IVR	-0.05 (-0.20, 0.10)	0.19 (-0.12, 0.49)	-0.00 (-0.17, 0.15)	0.11

Table 3. The consistency of direct comparison and indirect comparison of various treatment methods with BCVA change as the node (RCT).

Treatment	Rank 1	Rank 2	Rank 3	Rank 4	Rank 5	Rank 6
LT	0.27	0.25	0.24	0.11	0.06	0.08
PDT	0.28	0.43	0.23	0.04	0.01	0.00
IVA	0.01	0.07	0.13	0.25	0.18	0.36
IVB	0.00	0.02	0.12	0.28	0.32	0.26
IVR	0.00	0.02	0.08	0.27	0.38	0.25
Sham/IVA	0.44	0.22	0.20	0.05	0.06	0.04

Table 4. Effect ranking diagram of different treatment methods to improve BCVA (RCT).

Note: Rank1-6 corresponds to the color from light to dark in the ranking diagram; The higher the value, in the Rank6 on behalf of the treatment the better the results.

IVA
12.8 (-56.7, 84.2）	IVB
10.9 (-52.1, 73.3)	10.9 (-52.1, 73.3)	IVR
52.0(-35.9, 141.8)	39.0 (-15.1, 93.8	40.8 (-20.9, 105.7)	PDT

Table 5. Different treatment methods improve the results of a meta-analysis of FCT mesh (RCT).

Treatment	Rank 1	Rank 2	Rank 3	Rank 4
IVA	0.57	0.13	0.21	0.09
IVB	0.19	0.37	0.41	0.03
IVR	0.21	0.46	0.29	0.04
PDT	0.03	0.04	0.10	0.84

Table 6. Effect ranking diagram of different treatment methods to improve FCT (RCT).

Note: Rank1-4 corresponds to the color from dark to light in the ranking diagram; The higher the value, in the Rank1 on behalf of the treatment the better the results.

IVA
-0.12 (-0.68, 0.43)	IVB
-0.17 (-0.87, 0.52)	-0.05 (-0.54, 0.43)	IVB or IVR
0.00 (-0.63, 0.65)	0.13 (-0.36, 0.64)	0.16 (-0.47, 0.85)	IVC
-0.09 (-0.56, 0.40)	0.03 (-0.23, 0.30)	0.07 (-0.40, 0.61)	-0.10 (-0.51, 0.32)	IVR
-0.34 (-0.92, 0.22)	-0.22 (-0.50, 0.03)	-0.18 (-0.58, 0.22)	-0.34 (-0.89, 0.14)	-0.25 (-0.57, 0.02)	PDT
-0.31 (-1.03, 0.38)	-0.19 (-0.70, 0.30)	-0.15 (-0.56, 0.28)	-0.32 (-1.01, 0.33)	-0.22 (-0.77, 0.28)	0.04 (-0.40, 0.46)	PDT with IVB or IVR

Table 7. Different treatment methods improve the results of a meta-analysis of BCVA mesh (Retrospective studies).

Treatment	Direct Effect	Indirect Effect	Overall	P-Value
IVB, IVR	-0.12 (-0.42, 0.17)	0.20 (-0.29, 0.69)	-0.03 (-0.30, 0.23)	0.2
IVB, PDT	0.32 (0.02, 0.62)	0.00 (-0.47, 0.49)	0.22 (-0.03, 0.50)	0.21
IVR, PDT	0.12 (-0.28, 0.52)	0.44 (0.02, 0.89)	0.25 (-0.02, 0.57)	0.21

Table 8. The consistency of direct comparison and indirect comparison of various treatment methods with BCVA change as the node (Retrospective studies).

Treatment	Rank 1	Rank 2	Rank 3	Rank 4	Rank 5	Rank 6	Rank7
IVA	0.06	0.06	0.07	0.10	0.11	0.20	0.39
IVB	0.01	0.09	0.17	0.30	0.22	0.15	0.06
IVB/IVR	0.06	0.13	0.30	0.14	0.12	0.14	0.11
IVC	0.04	0.05	0.06	0.10	0.13	0.26	0.36
IVR	0.01	0.04	0.12	0.23	0.35	0.21	0.04
PDT	0.45	0.36	0.14	0.03	0.01	0.00	0.00
PDT with IVB/IVR	0.37	0.28	0.14	0.08	0.06	0.05	0.02

Table 9. Effect ranking diagram of different treatment methods to improve BCVA (Retrospective studies).

Note: Rank1-7 corresponds to the color from light to dark in the ranking diagram; The higher the value, in the Rank7 on behalf of the treatment the better the results.

IVA
87.53 (-50.44, 236.33)	IVB
57.26 (-66.20, 174.77)	-31.11 (-160.84, 94.04)	IVC
47.49 (-51.45, 145.05)	-40.26 (-146.93, 63.59)	-9.06 (-76.84, 60.22)	IVR
75.91 (-43.26, 195.48)	-12.96 (-93.66, 62.15)	18.37 (-78.26, 117.16)	26.75 (-41.75, 95.99)	PDT

Table 10. Different treatment methods improve the results of a meta-analysis of FCT mesh (Retrospective studies).

Treatment	Rank 1	Rank 2	Rank 3	Rank 4	Rank 5
IVA	0.74	0.11	0.08	0.04	0.03
IVB	0.06	0.11	0.11	0.20	0.53
IVC	0.10	0.26	0.28	0.17	0.18
IVR	0.07	0.42	0.35	0.12	0.03
PDT	0.03	0.10	0.18	0.47	0.22

Table 11. Effect ranking diagram of different treatment methods to improve FCT (Retrospective studies).

Note: Rank1-5 corresponds to the color from dark to light in the ranking diagram; The higher the value, in the Rank1 on behalf of the treatment the better the results.

No competing interests reported.

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Different approaches for the treatment of myopic choroidal neovascular: a network meta-analysis

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