NRs, while there was no significant difference in the IOP-reducing efficacy of travoprost and latanoprost. No serious adverse events occurred with the treatment of the four PGAs. The prevalence of conjunctival hyperemia due to bimatoprost or tafluprost was significantly higher than that of latanoprost. Other adverse events had no significant difference between the four drugs. Conclusion The existing studies cannot prove that latanoprost, travoprost, bimatoprost, and tafluprost have different responsiveness in OAG/OHT patients. Switching to bimatoprost or travoprost cannot achieve a significant improvement in responsiveness in LNRs. Bimatoprost has a better IOP-reducing efficacy than latanoprost and travoprost. No serious adverse events occurred during treatment with any medication we studied.


Introduction
Glaucoma is the most common irreversible blindness-inducing disease on a global scale, characterized by a chronic and progressive optic neuropathy and visual field loss [1]. Intraocular pressure (IOP) is the main risk factor for optic nerve damage, and regulation of IOP is the only clinically proven treatment that can delay disease progression [2]. Previous research has demonstrated that lowering of the IOP by 1 mmHg can reduce the risk of glaucomatous progression by approximately 10% [3]. Topical use of ocular hypotensive agents is typically the first therapeutic option in glaucoma. Since the 1990s, prostaglandin F2α analogues (PGAs) have gradually replaced β-blockers as the first-choice therapy due to their high clinical efficacy to reduce IOP, minimal side effects, and once-daily dosage regimens, consequently facilitating patient compliance [4,5].
PGAs mainly decrease IOP by increasing outflow facility through an IOP-independent uveoscleral pathway. Some studies have revealed that they can also affect the IOP-dependent conventional trabecular meshwork (TM) outflow pathway [5,6]. Among the PGAs used in the clinic, latanoprost and travoprost are ester prodrug analogs of prostaglandin F2α (PGF2α).
ough usually classified as prostaglandin analogues, bimatoprost is an amide prodrug of 17-phenyl-PGF2α (similar to PGF2α) [1,7]. Tafluprost is a unique PGF2α analog. e major modification of tafluprost is the substitution of the C-15 hydrogen and hydroxyl group with two fluorine atoms [8]. PGAs can bind to prostaglandin receptors EP and FP in the ciliary muscle, induce ciliary muscle relaxation, and increase uveoscleral outflow facility.
ese drugs also increase cell contractility of the TM as well as decrease endothelial cell contractility within Schlemm's canal, mediating aqueous humor outflow through the conventional pathway [9]. PGAs can degrade the extracellular matrix (ECM), which results in ECM turnover in the uvea and TM and ultimately reduces outflow resistance [10].
PGAs have been proven effective in decreasing IOP and are widely used in the treatment of glaucoma. However, after PGA therapies, some patients do not demonstrate a significant reduction in IOP,or fail to achieve the target IOP. Such patients are usually defined as nonresponders. Although there is no clear definition, nonresponders typically refer to patients with an IOP reduction of <15% from baseline after treatment [11]. It was reported that, in American and European populations, 12-41% of patients with glaucoma demonstrated low response to latanoprost, and such patients are defined as latanoprost nonresponders (LNRs). In Singapore, these data are approximately 5.4% [12]. Martínez and colleagues [13] reported that approximately 11% of Hispanics are LNRs. It was reported that the efficacy of latanoprost is significantly undermined in elderly patients and in European and American populations [4]. However, other studies revealed that age and baseline IOP are not factors affecting patient responsiveness to PGAs [14,15]. Several studies demonstrated that replacing latanoprost with bimatoprost or travoprost can further decrease IOP in LNRs [16][17][18]. is can be due to varying PGA not acting on the same receptor [19]. Some researchers postulated that bimatoprost interacts with a unique receptor that is unassociated with other PGA receptors. However, this "undefined receptor" has not yet been cloned [1,10].
is meta-analysis aimed to evaluate the responsiveness of latanoprost (0.005 mg/mL), travoprost (0.004 mg/mL), bimatoprost (0.03 mg/mL), and tafluprost (0.0015 mg/mL) eye-dropbased therapies in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT) and whether substituting latanoprost with other PGAs can further reduce the IOP in LNRs. is study also evaluated the IOP-reducing efficacy and safety of the four PGAs in patients with OAG or OHT.

Literature Search Strategy.
A thorough literature search was carried out separately by two researchers on PubMed, Embase, and the Cochrane Controlled Trials Register. e publication time of the selected articles was before 1990, with the type of study restricted to randomized controlled trials (RCTs). e keyword input strategy was "open angle glaucoma" OR "ocular hypertension" AND "latanoprost" OR "travoprost" OR "bimatoprost" OR "tafluprost." Manual examination of reference lists was carried out, for relevant original research to supplement the study. Following reading the title and abstract, whenever a research study article was deemed relevant to this research, the full text was read. e primary clinical endpoint was the number of responders at the end of each study. A responder was defined as a patient with an IOP reduction of ≥15% or ≥20% from baseline, after therapy. When both the data of IOP reduction ≥15% or 20% were described in a study, the data of IOP reduction ≥20% were extracted. e secondary clinical endpoint was the IOP reduction at the endpoint from baseline. Safety evaluation included five common adverse events: conjunctival hyperemia, hypertrichosis, ocular burning, ocular itching, and foreign-body sensation.

Inclusion
2.5. Quality Assessment. Two researchers blindly evaluated the quality of the studies reported in the scientific literature with the Methodological Quality Assessment (Modified Jadad Score). If the results differed, it was resolved through discussion with a third senior researcher. e quality assessment included four items: random sequence generation (appropriate: 2, unclear: 1, and inappropriate: 0), concealment of allocation (appropriate: 2, unclear: 1, and inappropriate: 0), blind (double blind: 2, single blind: 1, and open label: 0), and withdrawals and dropouts (described: 1 and not described: 0). If the Jadad score of a document was ≤3, we defined the study as "low quality." If the score was between 4 and 7, we defined the research as "high quality."

Data Analysis.
e Stata SE-64 ® software (StataCorp, College Station, TX, USA) was used for data analysis. We used the relative risk (RR) to summarize dichotomous results and the weighted mean difference (WMD) to summarize continuous results. When the IOP reduction and the standard deviation (SD) value were not available from the original document, we utilized the following formula to calculate [20]: (1) e heterogeneity was analyzed by I 2 statistics. P < 0.05 was defined as an index of heterogeneity. When I 2 > 50%, we considered that heterogeneity was confirmed and we chose a random-effects model for pooling the data in such a situation. When I 2 ≤ 50%, we chose a fixed-effect model. Due to the limitation of the number of included studies, we did not perform sensitivity analysis and publication bias evaluation.

Study Selection.
A total of 889 documents were retrieved and 588 documents remained (following removal of duplicates), of which 236 documents were initially selected following reading the title and abstract. According to the applied inclusion and exclusion criteria, we selected 14 documents deemed as relevant and censored the full text, including references. Two articles were excluded as the research content did not match with this study. One article was excluded due to incomplete data. Finally, 11 articles containing 10 RCTs were included in this meta-analysis [8,11,[16][17][18][21][22][23][24][25][26]. e detailed search strategy is outlined in Figure 1. Choplin [11] and Noecker [21] studied the same population, though the authors extracted differing outcome variables. A total of 1381 patients were included, with an average age of 60.1 years, of which 45.1% were men. e follow-up time range was from one to six months. Race included white, black, Hispanic, Asian, and Native Hawaiian.
e included studies did not analyze patient compliance issues. However, since all the included studies were prospective RCTs and the patient data lost to follow-up were excluded, the analytical assumption placed in this study was that there existed full patient compliance. e detailed data of each study are highlighted in Table 1.

Quality Assessment.
According to the revised Jadad scale, two of the studies were defined as "low quality" and the other eight studies were defined as "high quality." e average score of the included studies was five points. Due to the limitation of the number of included studies, we did not employ a funnel plot to assess publication bias. e specific score of each study is highlighted in Table 2.

Efficacy of PGAs in OAG/OHT