Dorzolamide/Timolol-Fixed Combination For Primary Open-Angle Glaucoma: A Protocol For Systematic Review

doi:10.21203/rs.3.rs-37758/v1

Download PDF

Protocol

Dorzolamide/Timolol-Fixed Combination For Primary Open-Angle Glaucoma: A Protocol For Systematic Review

https://doi.org/10.21203/rs.3.rs-37758/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background: Primary open-angle glaucoma (POAG) is a very common disorder, and it is the second leading cause that results in blindness worldwide after cataracts. Previous studies have reported that dorzolamide/timolol-fixed combination (DTFC) can be used in treating POAG. However, there are still inconsistent results. Thus, this study will systematically investigate the efficacy and safety of DTFC on POAG.

Methods: A comprehensive search will be carried out in Cochrane Library, MEDLINE, EMBASE, CINAHI, ACMD, China National Knowledge Infrastructure, and WANGFANG database from origin to the present. There are no limitations related to the language and publication status. Only randomized controlled trials that assessed the efficacy and safety of DTFC for the treatment of POAG will be included. Two researchers will independently undertake record selection, data extraction, and study quality assessment. Any divisions will be solved by discussion with a third researcher. We will perform statistical analysis using RevMan 5.3 software

Discussion: This study will summarize the present evidence to identify the efficacy and safety of DTFC in treating POAG through mean intraocular pressure, best corrected visual acuity, contrast sensitivity, bioelectric activity of the retina, rate of progression of glaucoma, quality of life, and adverse events. The results of this study will help to determine whether DTFC is effective and safety for the treatment of POAG.

Systematic review registration: PROSPERO CRD42020170531.

Ophthalmology

Primary open-angle glaucoma

dorzolamide

timolol

efficacy

safety

Primary open-angle glaucoma (POAG) is a chronic, progressive, and anterior optic neuropathy that is characterized by increased intraocular pressure (IOP), cupping and atrophy of the optic nerve head, and typical visual field defects [1–3]. It is the leading cause of irreversible visual impairment worldwide [4–5], and if left untreated, it can ultimately result in severe or complete vision loss [6]. The prevalence of POAG is estimated between 1.5% and 2% in the USA, with most cases detected over 40 years old [7–8]. It has been estimated that the global number of POAG is about 44 million cases in 2013, and will reach to 53 million by 2020 [9]. There are several known risk factors that result in POAG, such as increased IOP, advanced age, race, decreased corneal thickness, family history, diabetes and myopia [10–12].

POAG is associated with high IOP [13], which leads to degeneration of the optic nerve [13–14]. Interventional treatments, including medical interventions, laser trabeculoplasty and surgery aim at lowering IOP with the target of delaying or halting the progression of POAG [15–17]. Of those, topical medical therapy is the main therapy, and a single topical hypotensive drug is the first line approach. However, more than 40% patients require more than one medication to reach IOP reduction [18]. Fortunately, the fixed combination of single medication is reported to resolve this problem. The dorzolamide/timolol-fixed combination (DTFC) is commonly-prescribed fixed combinations for POAG that has been approved in several countries [19–20]. Dorzolamide is a non-bacteriostatic sulfonamide derivative and topical carbonic anhydrase inhibitor that manages evaluated IOP and relevant ocular hypertension [21]. Timolol is a beta-blocker, which decreases IOP by reducing the production of fluid [22]. DTFC exerts better efficacy than any single medication. Studies suggested that DTFC could help decrease IOP significantly in patients with POAG [23–31]. However, no systematic review has investigated the efficacy and safety of DTFC in treating POAG. Therefore, this study will systematically and comprehensively assess the efficacy and safety of DTFC for the management of POAG.

Aim

This systematic review aims to appraise the efficacy and safety of DTFC for POAG.

Objective

The objective of this systematic review is to comprehensively and systematically search eligible studies and to summarize all available evidence on investigating the efficacy and safety of DTFC compared to other interventions for POAG.

Study design

This systematic review was registered on PROSPERO (CRD42020170531). It has been reported according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) Protocol and checklist (additional file 1) [32]. In brief, this study will be performed in four steps: (a) multiple literature sources will be searched to examine relevant records; (b) titles, abstracts, and full-text identifying will be carried out in accordance with predefined eligibility criteria; (c) all essential data will be extracted; and (d) a recommended study quality assessment tool will be utilized to appraise study quality before a meta-analysis will be pursued.

Eligibility criteria

This study consists of following inclusion criteria: (a) only randomized controlled trials (RCTs) will be eligible if they assess the efficacy and safety of DTFC alone in patients with POAG which meet the criteria; (b) we will include all RCTs involving participants with a confirmed diagnosis of POAG in spite of country, race, gender, age, and severity of POAG; (c) RCTs will be included if they randomize participants to utilize DTFC or to other comparators, such as placebo; (d) studies published up to the present in any language and publication status will be included.

The exclusion criteria are presented as follows: (a) all animal study, review, case report, uncontrolled trial, non-RCTs and quasi-RCTs will be excluded; (b) other types of glaucoma will be excluded if they are elaborated clearly, however, any undefined type of glaucoma will be considered for further identifying; (c) glaucoma secondary to other diseases will be excluded; (d) any other treatment combined with DTFC in the experimental group, and any forms of DTFC as comparator in the control group will be excluded in this study; and (e) trials report one of the outcomes of interest.

Outcome measurements

The outcomes of interest for analysis will include primary outcomes of mean intraocular pressure and best corrected visual acuity; and secondary outcomes of contrast sensitivity, bioelectric activity of the retina, rate of progression of glaucoma, quality of life (as assessed by 36-Item Short Form Survey), and adverse events.

Information sources and search method

A comprehensive search will be performed to identify relevant records from origin to the present in the electronic databases of Cochrane Library, MEDLINE, EMBASE, CINAHI, ACMD, China National Knowledge Infrastructure, and WANFANG databases. We will not apply limitations to the language and publication status. We will only consider RCTs that appraised the efficacy and safety of DTFC for POAG. We have summarized search strategy sample for Cochrane Library (table 1), and will create similar search strategies for other electronic databases. The search terms include “glaucoma”, “intraocular pressure”, “ocular hypertension”, “intraocular hypertension”, “open-angle”, “primary”, “optic neuropathy”, “timolol”, “Timoptic”, “Istalol”, “Timoptic-xe”, “dorzolamide”, “Trusopt”, “fixed”, “combination”, “randomized controlled trials”, “random”, “randomised”, “randomly”, “allocation”, “placebo”, “blind”, “clinical trials”, and “controlled trials”. In addition, we will scrutinize other sources, such as Google Scholar, conference proceedings, and reference lists of included trials.

Table 1

Search strategy used in Cochrane Library database
Number	Search terms
1	Mesh descriptor: (glaucoma, open-angle) explode all trees
2	((glaucoma) or (intraocular pressure) or (ocular hypertension) or (intraocular hypertension) or (open-angle) or (primary) or (optic neuropathy*)):ti, ab, kw
3	Or 1–2
4	Mesh descriptor: (timolol) explode all trees
5	(dorzolamide) explode all trees
6	((timolol) or (Timoptic) or (Istalol) or (Timoptic-xe) or (dorzolamide) or (Trusopt) or (fixed) or (combination)):ti, ab, kw
7	Or 4–6
8	MeSH descriptor: (randomized controlled trials) explode all trees
9	((random) or (randomised) or (randomly) or (allocation) or (placebo) or (blind) or (clinical trials) or (controlled trials)):ti, ab, kw
10	Or 8–9
11	3 and 7 and 10

Study selection

All citations will be imported into Endnote X9 and duplicates will be removed. Two researchers (YXQ and HWL) will independently identify titles/abstracts of sought records to eliminate unrelated studies. Then, full papers of potential trials will be obtained and further inspected against all eligibility criteria. If any differences are identified, we will invite a third researcher (QS) to solve them by discussion and a final decision will be reached. Any reasons for excluded studies will be listed. The process of study selection will be reported following PRISMA statement, and will be exerted in a PRISMA flowchart.

Data extraction and management

Two researchers (XJS and LH) will independently extract data from all included RCTs using a predefined, structured and standard data-extraction form. Any divergences will be resolved through discussion with a third researcher (QS). The extracted information consists of study information (e.g. title, first author, year of publication, and country), patient characteristics (e.g. diagnosis criteria, and eligibility criteria), study methods (e.g. sample size, randomization, blind, and concealment); details of intervention and controls (e.g. treatment types, dosage, and duration), outcome measurements, results, findings, follow-up information, adverse events, and conflict of interest. We will express continuous data using means, standard deviations, standard errors with 95% confidence intervals (CIs), and dichotomous data using frequencies or percentages (%) with 95% CIs.

Dealing with missing data

We will contact primary authors to request any unclear or missing data. If it can not be obtained, we will analyze available data using intention-to-treat analysis, and will discuss its possible affects to the study findings.

Risk of bias assessment

Two researchers (YXQ and HWL) will independently appraise methodological quality for all eligible RCTs using Cochrane Handbook for Systematic Reviews of Interventions Tool [33]. It covers seven aspects, and each item is further rated as “high risk of bias”, “unclear risk of bias” or “low risk of bias”. Any disagreements will be resolved by a third researcher (QS) through consultation and a consensus will be reached.

Quality of evidence rating

Two researchers (XJS and LH) will independently assess the overall strength of the evidence using Grading of Recommendations Assessment, Development and Evaluation tool [34]. It includes study limitations, inconsistency of results, indirectness of evidence, imprecision, and reporting bias [34]. It categorizes the quality of evidence in one of four levels: high quality, moderate quality, low quality, and very low quality [34]. Its results will be demonstrated in the table of Summary of Findings. A third researcher (QS) will help to solve any disagreements.

Statistical analysis

RevMan 5.3 software (Cochrane, London, UK) will be utilized to perform statistical analysis. In terms of treatment effect measures, mean difference (MD) or standardized MD and 95% CIs will be used for continuous outcomes, and risk ratio and 95% CIs will be utilized for dichotomous outcomes. We will appraise the inconsistencies cross studies using I² test [35]. We define I² ≤ 50% as having minor heterogeneity, and will use a fixed-effects model to pool the data [36]; while I² >50% as having remarkable heterogeneity, and will apply a random-effects model to synthesize the data [37]. If it is possible, we will conduct meta-analysis when minor heterogeneity across sufficient data on outcomes is extracted. If the outcome data can not be pooled, we will present a narrative analysis of individual trials. If sufficient data is available, subgroup analyses will be performed to identify the potential sources of heterogeneity according to the variations in study and patient characteristics, different types of interventions and controls, and different study quality. A sensitivity analysis will be conducted to test the stability of conclusions by eliminating low quality trials. If necessary, we will perform a funnel plot and Egger’s regression test to check reporting bias when over 10 RCTs are included.

Dissemination

This study will be published in print, conferences or by peer-reviewed journals.

Amendments

Any changes to this protocol will be noted with reference to saved searches and analysis.

Fixed combination therapy in treating POAG has gained popularity in recent years. At present, DTFC is the first fixed combination that comprises of dorzolamide and timolol, and is currently routinely utilized in clinical practice in treating POAG. To date, several clinical trials have investigated the efficacy and safety of DTFC for the treatment of POAG, and their findings indicate that DTFC can significantly reduce IOP in patients with POAG [23–31]. To the best of our knowledge, rarely data at systematic level is available on assessing efficacy and safety of DTFC for the treatment of POAG. Thus, this systematic review protocol is the first one to specifically explore the efficacy and safety of DTFC alone in treating POAG. We believe that the findings of this study may provide evidence at evidence-based medicine level to determine whether DTFC is effective and safe for the treatment of POAG. Its results may benefit patients, clinicians, and health-related decision-makers.

On the other hand, this proposed study may still have several limitations. First, the study quality of included trials may be poor. Second, there is insufficient number of included studies and their sample size may be low. Third, remarkable heterogeneity across included trials may exert. All those limitations may affect stability and robustness of the study results, and may result in misleading interpretation of study findings.

POAG, primary open-angle glaucoma; DTFC, dorzolamide/timolol-fixed combination; RCTs, randomized controlled trials; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analysis; MD, mean difference; CIs, confidence intervals.

Ethics approval and consent to participate: Not applicable

Consent for publication: Not applicable

Availability of data and material: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current protocol

Competing interests: All authors declare that they have no competing interests.

Funding: This work was supported in part by the Scientific Research Project of Heilongjiang Provincial Department of Health (2013257), Scientific Research Projects of Heilongjiang Provincial Health and Health Committee (2019-327), and 2019 Basic Research Business Expenses Research Project of Heilongjiang Provincial Universities (2019-KYYWF-1345). The funders did not take part in the design, execution, or writing of the study.

Authors’ contributions: YXQ, HWL, QS, XJS and LH conceived the study. XJS and LH contributed with the clinical background and expertise. YXQ, HWL, LH and XJS contributed with the analytical plan and the bias assessment approach. YXQ and HWL performed the literature search plan. YXQ, HWL, XJS and LH drafted the protocol. All authors revised the protocol and approved the final version. HWL supervised the study

Acknowledgements: Not applicable

Availability of data and materials: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current protocol

Authors' information: Yan-Xiu Qi, [email protected]

Hong-wei Liu, [email protected]

Quan Sun, [email protected]

Xing-jie Su, [email protected]

Lin Han, [email protected]

Bertaud S, Aragno V, Baudouin C, Labbé A. Primary open-angle glaucoma. Rev Med Interne. 2019;40(7):445–52.
Erichev VP, Egorov EA. On pathogenesis of primary open-angle glaucoma. Vestn Oftalmol. 2014;130(6):98–104.
Weinreb RN, Leung CK, Crowston JG, et al. Primary open-angle glaucoma. Nat Rev Dis Primers. 2016;2:16067.
Hoffmann EM, Prokosch-Willing V. Primary Open Angle Glaucoma. Klin Monbl Augenheilkd. 2017;234(11):1407–22.
American Academy of Ophthalmology. Primary open-angle glaucoma preferred practice pattern guidelines. Ophthalmology. 2015;123(1):41–111.
Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90(3):262–7.
Friedman DS, Wolfs RC, O'Colmain BJ, et al. Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol. 2004;122:532–8.
Vajaranant TS, Wu S, Torres M, Varma R. The Changing Face of Primary Open-Angle Glaucoma in the United States: Demographic and Geographic Changes From 2011 to 2050. Am J Ophthalmol. 2012;154(2):303–14.
Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121(11):2081–90.
Actis AG, Versino E, Brogliatti B, Rolle T. Risk Factors for Primary Open Angle Glaucoma (POAG) Progression: A Study Ruled in Torino. Open Ophthalmol J. 2016;10:129–39.
Williams AM, Huang W, Muir KW, Stinnett SS, Stone JS, Rosdahl JA. Identifying risk factors for blindness from primary open-angle glaucoma by race: a case-control study. Clin Ophthalmol. 2018;12:377–83.
Zhang L, Xu L, Yang H. Risk factors and the progress of primary open-angle glaucoma. Zhonghua Yan Ke Za Zhi. 2009;45(4):380–4.
Mao WM, Liu Y, Wordinger YH, Clark AF, Pang IH. Novel therapeutic targets for reduction of intraocular pressure in primary open angle glaucoma. Zhonghua Yan Ke Za Zhi. 2016;52(6):471–5.
Inatani M, Iwao K, Inoue T, et al. Long-term relationship between intraocular pressure and visual field loss in primary open-angle glaucoma. J Glaucoma. 2008;17(4):275–9.
Xiao H, Liu X, Zhong Y, Mao Z. The influence of surgical and medical interventions upon optic disc structure in patients with primary open angle glaucoma. Eye Sci. 2011;26(4):185–92.
Xu L, Yu RJ, Ding XM, et al. Efficacy of low-energy selective laser trabeculoplasty on the treatment of primary open angle glaucoma. Int J Ophthalmol. 2019;12(9):1432–7.
Bartelt-Hofer J, Flessa S. Comparative efficacy and cost-utility of combined cataract and minimally invasive glaucoma surgery in primary open-angle glaucoma. Int Ophthalmol. 2020;40(6):1469–79.
Lundberg LU, Thygesen J, Damgaard-Jensen L, Serup L, Kessing SV. Glaucoma patients treated by practicing ophthalmologists in Denmark. Estimated number of patients and the extent of visual field defects. Ugeskr Laeger. 2000;162(21):3028–33.
Higginbotham EJ. Considerations in glaucoma therapy: fixed combinations versus their component medications. Clin Ophthalmol. 2010;4:1–9.
Razeghinejad MR, Sawchyn AK, Katz LJ. Fixed combinations of dorzolamide-timolol and brimonidine-timolol in the management of glaucoma. Expert Opin Pharmacother. 2010;11(6):959–68.
Balfour JA, Wilde MI. Dorzolamide. A review of its pharmacology and therapeutic potential in the management of glaucoma and ocular hypertension. Drugs Aging. 1997;10(5):384–403.
Konstas AG, Mantziris DA, Cate EA, Stewart WC. Effect of timolol on the diurnal intraocular pressure in exfoliation and primary open-angle glaucoma. Arch Ophthalmol. 1997;115(8):975–9.
Rolle T, Tofani F, Brogliatti B, Grignolo FM. The effects of dorzolamide 2% and dorzolamide/timolol fixed combination on retinal and optic nerve head blood flow in primary open-angle glaucoma patients. Eye (Lond). 2008;22(9):1172–9.
Cvenkel B, Stewart JA, Nelson LA, Stewart WC. Dorzolamide/timolol fixed combination versus latanoprost/timolol fixed combination in patients with primary open-angle glaucoma or ocular hypertension. Curr Eye Res. 2008;33(2):163–8.
Konstas AG, Quaranta L, Yan DB, et al. Twenty-four hour efficacy with the dorzolamide/timolol-fixed combination compared with the brimonidine/timolol-fixed combination in primary open-angle glaucoma. Eye (Lond). 2012;26(1):80–7.
Kozobolis V, Panos GD, Konstantinidis A, Labiris G. Comparison of dorzolamide/timolol vs brinzolamide/brimonidine fixed combination therapy in the management of primary open-angle glaucoma. Eur J Ophthalmol. 2017;27(2):160–3.
Babić N, Andreić V, Miljković A, Grković D, Jovanović P. Comparison of the efficacy and safety of fixed combination travoprost/timolol and dorzolamide/ timolol in patients with primary open-angle glaucoma and ocular hypertension. Srp Arh Celok Lek. 2013;141(7–8):441–6.
Eren MH, Gungel H, Altan C, Pasaoglu IB, Sabanci S. Comparison of dorzolamide/timolol and latanoprost/timolol fixed combinations on diurnal intraocular pressure control in primary open-angle glaucoma. J Ocul Pharmacol Ther. 2012;28(4):381–6.
Gulkilik G, Oba E, Odabası M. Comparison of fixed combinations of dorzolamide/timolol and brimonidine/timolol in patients with primary open-angle glaucoma. Int Ophthalmol. 2011;31(6):447–51.
Pajic B, Pajic-Eggspuehler B, Häfliger IO. Comparison of the effects of dorzolamide/timolol and latanoprost/timolol fixed combinations upon intraocular pressure and progression of visual field damage in primary open-angle glaucoma. Curr Med Res Opin. 2010;26(9):2213–9.
Janulevicienë I, Harris A, Kagemann L, Siesky B, McCranor L. A comparison of the effects of dorzolamide/timolol fixed combination versus latanoprost on intraocular pressure and pulsatile ocular blood flow in primary open-angle glaucoma patients. Acta Ophthalmol Scand. 2004;82(6):730–7.
Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;349:g7647.
Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:1–9.
Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–6.
Higgins JPT, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.
Bell A, Fairbrother M, Jones K. Fixed and random effects models: making an informed choice. Qual Quant. 2019;53:1051–74.
Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.

PRISMAPchecklist.doc

Download PDF

Version 1

posted

You are reading this latest preprint version

Dorzolamide/Timolol-Fixed Combination For Primary Open-Angle Glaucoma: A Protocol For Systematic Review

Status:

Version 1

Abstract

Background

Methods/design

Discussion

List Of Abbreviations

Declarations

References

Supplementary Files

Status:

Version 1