The influence of topical non-steroidal anti-inflammatory drugs on the intraocular pressure lowering effect of topical prostaglandin analogues-A systemic review and meta-analysis.

PURPOSE: This study aimed to review previous articles and evaluate the influence of topical non-steroidal anti-inflammatory drugs (NSAIDs) on intraocular pressure (IOP) in glaucoma patients who were treated with prostaglandin analogues (PGs).
METHOD: The presenting study was designed as a meta-analysis of previous research. Databases include PubMed, Web of science, Cochrane library, and Embase were searched with keywords of "intraocular pressure, prostaglandin analogues, NSAIDs, latanoprost, travoprost, bimatoprost, tafluprost, unoprostone, latanoprostene bunod, ketorolac, diclofenac, nepafenac, bromfenac, flurbiprofen". Inclusion criteria were: 1. Study population were glaucoma patients; 2. Comparison between PGs monotherapy and PGs in combination with topical NSAIDs; 3. Changes of IOP as final outcomes. Studies with non-randomized design, treatments combining other anti-glaucomatous drugs, or unavailable absolute IOP were excluded from the analysis. Estimated difference in IOP were calculated using STATA 14.0. RESULT: Seven studies were retrieved for this meta-analysis. Since there is a significant heterogeneity (I2 = 94%) in these studies, random-effect model was used to calculate pooled standardized mean differences (SMD). Our results showed a significantly favorable IOP lowering effect in glaucoma patients treated with combination of topical NSAIDs and PGEs (SMD: 1.3 and -0.03, 95% CI: 0.29 to 2.38 and -0.32 to 0.26, Z = 2.50 and 0.23, p = 0.013 and 0.820, respectively).
CONCLUSION: Results of our meta-analysis suggested that topical NSAIDs may enhance the IOP lowering effect of topical PGs in glaucoma patients.

Introduction

Glaucoma is a progressive optic neuropathy that can cause irreversible loss of vision [1]. Several risk factors are associated with the development of glaucoma, of which only high intraocular pressure (IOP) and large diurnal fluctuations in intraocular pressure can be manipulated [1, 2]. Therefore, the mainstay of treatment for this disease focuses on controlling these factors. Prostaglandin (PG) analogues are well-known topical anti-glaucoma medications, with excellent potency in reducing IOP, good circadian IOP control and few side effects [3-5]. PG analogues reduce IOP by increasing uveoscleral outflow, which involves relaxation of ciliary muscles and remodeling of the extracellular matrix within the ciliary muscles and sclera [6].

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are used clinically to reduce postoperative ocular inflammation, prevent macula edema after cataract surgery, and maintain intraoperative mydriasis during cataract surgery [7-10]. As a cyclooxygenase (COX) inhibitor, NSAIDs inhibit the production of PGs [11]. Since the underlying mechanism of these two drugs are theoretically opposite, there were some debates regarding whether we should avoid NSAID or discontinue PG if a glaucoma patient suffers from macular edema after surgery. Patient’s intraocular pressure could become relatively hard to be controlled if we discontinue PG. On the other hand, long-term macular edema would result in visual decline in patients. It is important to clarify whether IOP control is affected by concomitant treatment with topical NSAIDs and PG analogues in glaucoma patients or not [12-17]. Therefore, the aim of this study was to review previous articles and evaluate the influence of topical NSAIDs on IOP in glaucoma patients being treated with PG analogues via a literature review and meta-analysis.

Methods

Literature search

A literature search of PubMed, ISI Web of Science, EMBASE, and Cochrane library databases was performed to identify relevant studies. The search combined keywords related to NSAIDs (ketorolac, diclofenac, nepafenac, bromfenac, flurbiprofen), PG analogues (latanoprost, travoprost, bimatoprost, tafluprost, unoprostone, latanoprostene bunod) and IOP. Google Scholar and the websites of professional associations were also searched for information. Once relevant articles had been identified, their reference lists were also searched for additional articles. The final search was carried out in June 2020 without restricting the publication year, language, or methodology.

Inclusion and exclusion criteria

We included publications that met the following inclusion criteria: (i) study design—randomized clinical trials (RCTs); (ii) population—patients with glaucoma; (iii) intervention—topical NSAIDs with PG analogues vs placebo vs PG analogues; and (iv) outcome variables—evaluating changes in IOP. Studies involving oral NSAIDs combined with PG analogues were excluded.

Outcome measurements

Data on differences in the IOP between eyes treated with PG analogue monotherapy and PG analogues in combination with topical NSAIDs were obtained and analyzed. Positive numerals indicated that the IOP lowering effect of PG analogues was enhanced (i.e. the IOP in eyes treated with combination therapy was lower than the IOP in eyes treated with PG analogue monotherapy), and negative numerals indicated that the IOP lowering effect was reduced after adding topical NSAIDs.

Study selection

After the literature searches had been combined and duplicates removed, the title and abstract of each unique article was systematically screened for eligibility. After applying the aforementioned inclusion/exclusion criteria, the full text of each article was read and analyzed. A flowchart illustrating the study selection process is shown in Fig 1.

Fig 1

Flowchart of publication search and selection.

Data extraction

Two reviewers (KJL and DKH) extracted data from the eligible studies using a standardized paper form. Any discrepancies between the reviewers’ results were resolved by consensus. For each eligible article, the first author, publication year, study location, study period, study design, baseline characteristics, treatment regimen, inclusion and exclusion criteria, and outcome were extracted.

Quality assessment

Quality assessment was performed according to the risk-of-bias tool outlined in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0) [18]. Six key aspects that influence the quality of an RCT were assessed: sequence generation, allocation concealment, patient blinding, personnel and outcome assessors, management of incomplete outcome data, and completeness of outcome reporting, as well as other potential threats to validity. For each parameter, “yes” indicated a low risk of bias, “no” indicated a high risk of bias, and “unclear” indicated an unclear or unknown risk of bias.

Statistical analysis

Stata 14.0 was used for the meta-analysis. The standardized mean difference (SMD) and 95% confidence interval (CI) were calculated. Heterogeneity between the results of different studies was examined using the I2 statistic, and P < 0.05 and I2 > 50% were considered to indicate statistically significant heterogeneity. If the included studies were not heterogeneous, the fixed-effects model was used for the analysis, otherwise a random-effects model was used.

Results

Identification of eligible studies

A total of 386 potentially relevant articles were identified, of which 375 were excluded because of duplication, animal studies, or in-vitro experimental studies, and the remaining 11 studies were retrieved for full text review. Two of these 11 studies which investigated oral NSAIDs were excluded [13, 19]. Among the remaining nine studies, seven focused on glaucomatous patients and two focused on healthy subjects. To unify the results, we also excluded these two studies on healthy subjects [20, 21]. The remaining seven full text articles were included in the final analysis [12, 14–17, 22, 23].

Study characteristics

The main characteristics of the seven included RCTs are shown in Table 1. These studies were published between 2005 and June 2019 and were conducted in various countries: two in Italy, two in Turkey, one in Japan, one in Iran, and one in China. The number of enrolled cases ranged from 13 to 35. There was no sex bias in these studies. The mean age of the participants in these studies ranged from 32.4±4.7 to 65.2±8.8 years. All of the participants received monotherapy with PG analogue eye drops before the experiment to reduce IOP fluctuations, except for the study by Costagliola in 2005 [22] in which the patients received topical 0.5% timolol for the first 2 weeks and then switched to PG analogues for the next 8 weeks. These patients were then further randomized into treatment and control groups. In the treatment group, all patients received NSAID eye drops in addition to PG analogues, while the control group only received PG analogue monotherapy.

Table 1

Characteristics of the included RCT studies.

Author (year)	Journal	Location	Medication		Type of patient	Primary endpoint	No. of eyes		Sex (male/female)		Age
			Glaucoma	NSAID			NSAID	Control	NSAID	Control
C. Costagliola (2005)	Exp Eye Res	Italy	Timolol/ Latanoprost	Diclofenac	POAGa	10 weeks	32	32	16/16	16/16	55.4±5.11
T. Chiba (2006)	Br J Ophthalmol	Japan	Latanoprost	Bromfenac	POAG/ OHb	18 weeks	13	13	6/7	6/7	65.2±8.8
C. Costagliola (2008)	Curr Eye Res	Italy	Latanoprost	Ketorolac	POAG	1 day	16	16	9/7	9/7	59.45±4.55
R. Sorkhabi (2011)	J Glaucoma	Iran	Latanoprost	Diclofenac	POAG	2 weeks	22	22	12/10	12/10	60.55±9.46
E. Turan-Vural (2011)	Ophthalmologica	Turkey	Latanoprost/Travoprost/ Brimatoprost	Ketorolac	POAG/ Pseudo-exfoliation glaucoma	2 weeks	30	30	15/15	15/15	60.8±11.5
P. Özyol (2016)	J Glaucoma	Turkey	Latanoprost/ Travoprost/ Brimatoprost	Nepafenac	POAG	2 weeks	35	35	20/15	20/15	60.28±7.51
Z. Simin (2018)	J Ophthalmol	China	Latanoprost	Pranoprofen	POAG	10weeks	24	24	13/11	10/14	32.4±4.7

aPOAG = primary open angle glaucoma

bOH = ocular hypertension

Quality and bias assessment of studies

The included RCTs had certain risks of bias, mainly the lack of blinding (Table 2). Sequence generation was appropriate in five studies, and allocation concealment was agreed in all studies. Four studies clearly elaborated upon patient blinding, while only three studies clearly showed assessor blinding. All studies were judged to have a low risk of bias from selective reporting, because it was clear that all the main pre-specified outcomes had been reported.

Table 2

Results of quality and bias assessment of the included studies.

Author (year)	Sequence generation	Allocation concealment	Blinding		Adequate assessment of each outcome		Selective reporting avoided	No other bias
			Patient	Assessor
C. Costagliola (2005)	Yes	Yes	Yes	Yes		Yes	Yes	Yes
T. Chiba (2006)	Unclear	Yes	Yes	Yes		Yes	Yes	Yes
C. Costagliola (2008)	Yes	Yes	Yes	Yes		Yes	Yes	Yes
R. Sorkhabi (2011)	Yes	Yes	Yes	Unclear		Yes	Yes	Yes
E. Turan-Vural (2011)	Yes	Yes	Unclear	No		Yes	Yes	Yes
P. Özyol (2016)	Yes	Yes	Unclear	No		Yes	Yes	Yes
Z. Simin (2018)	Yes	Yes	Unclear	Unclear		Yes	Yes	Yes

IOP outcome

Changes in IOP following concomitant treatment with NSAIDs and PG analogues were detailed in all studies. Five studies demonstrated positive values of IOP changes, indicating enhanced IOP reduction with added NSAIDs [12, 15, 17, 22, 23], while the other two reported negative values [14, 16]. There was significant heterogeneity (I2 = 94%) among the studies. The random-effects model revealed a favorable IOP lowering effect in glaucoma patients treated with a combination of topical NSAIDs and PG analogues compared to PG analogue monotherapy (SMD: 1.3 and -0.03 mmHg, 95% CI: 0.29 to 2.38 and -0.32 to 0.26, Z = 2.50 and 0.23, p = 0.013 and 0.820, respectively). The detailed forest plots are shown in Figs 2 and 3.

Fig 2

Forest plot depicting the meta-analysis for the SMD (standardized mean difference) in IOP in the glaucoma patients treated with a combination of topical NSAIDs and PGs.

The SMD was calculated by Cohen method and the overall SMD favors the additional IOP lowering by this synergic effect. Most studies were treated with topical PGs alone for 4 weeks before combination therapy as baseline IOP, and the treatment IOP was measured as the peak reduction of the IOP in each study after the combination therapy. The treatment/baseline IOP was calculated in mmHg. The unit of SMD is in mmHg.

Fig 3

Forest plot depicting the meta-analysis for the SMD (standardized mean difference) in IOP in the glaucoma patients treated with PG monotherapy.

The data only involved four articles because the other three articles did not provide precise data for calculations. The patients in this forest plot is the control group when comparing with patients in Fig 2. The SMD cross zero without treatment preference. The control/baseline IOP was calculated in mmHg. The unit of SMD is in mmHg.

Discussion

In this meta-analysis, we found that there was a further IOP lowering effect when adding additional NSAIDs to PG analogues compared to PG analogue monotherapy in glaucoma patients. Although topical NSAIDs are used clinically to reduce ocular inflammation or macula edema, no clear mechanism on how it may influence IOP has ever been reported.

The influence of topical NSAIDs on eyes with glaucoma under PG analogue therapy is still controversial. A reduced IOP lowering effect was reported by Chiba [14] and Sorkhabi [16], who proposed that the induction of endogenous PGs by exogenous PG analogues was diminished after the application of additional NSAIDs. In contrast, an enhanced IOP lowering effect was reported when adding NSAIDs to PG analogues in the studies by Costagliola [12, 22], Ozyol [15], Turan-Vural [17], and Simin [23]. They proposed that NSAIDs can inhibit the production of endogenous PGs, thereby up-regulating receptor densities and causing a further reduction in IOP.

After adjusting the meta-analysis, our study still favored a synergistic effect when using NSAIDs and PG analogues simultaneously in glaucoma patients. We hypothesize that the mechanism of an enhanced IOP lowering effect when adding NSAIDs to PG analogues may be explained as follows. In the study by Hardy et al [24], non-selective (ibuprofen) and selective (valeryl salicylate, DuP697 and NS398) COX-1 and COX-2 inhibitors were given intravenously to monitor changes in the concentrations of PGE2 and PGF2a and also changes in prostaglandin E (EP) and prostaglandin F (FP) receptors in retinal vasculature in newborn pigs. The results showed reductions in the concentrations of PGE2 and PGF2a in conjunction with increases in EP and FP receptors. Li et al also demonstrated increases in EP and FP receptor densities in brain synaptosomes in newborn pigs after treatment with ibuprofen or indomethacin [25]. Therefore, exogenous PGs in glaucoma patients may potentiate the IOP reduction effect through an increase in FP receptor expression following NSAID treatment.

Moreover, Maihöfner et al reported that patients with primary open-angle glaucoma (POAG) and steroid-induced glaucoma tended to lose COX-2 expression in the nonpigmented secretary epithelium of the ciliary body compared with normal eyes [26]. There is a general consensus that COX-2 plays an important role in PG formation. This may imply that POAG patients have reduced endogenous PG formation with subsequent FP receptor upregulation, and this may be more obvious in glaucomatous eyes because FP receptors are over-expressed in glaucomatous tissue [27]. This explanation may be similar to that proposed by Costagliola with regards to the upregulation of receptors after the addition of topical NSAIDs to PG analogues [22].

The results of two studies in our meta-analysis contradict our hypothesis. Chiba [14] reported that an elevated IOP was noted 4–6 weeks after applying topical NSAIDs to topical PG analogues compared to a control group (topical PG analogues only). However, the increase in IOP between these two groups did not reach statistical significance. Moreover, a trend of decreasing IOP was found in both groups after the 6th week. In addition, R. Sorkhabi [16] et. al. reported a statistically significant increase in IOP was only found in the 2nd week after adding topical NSAIDs to topical PG analogues. Moreover, a decrease in IOP was noted beyond 2 weeks. These contradicting results may be due to racial differences, as Asian people have a higher rate of non-response to PG analogues than European or American people [28]. The reason may due to a higher uveoscleral flow in Caucasians when comparing with Asian populations, and thus a lower response rate to uveoscleral drugs such as prostaglandins may be found among Asians [29]. However, the underlying mechanism is still unclear, and further studies are needed to investigate this issue.

There are several limitations to this study, including the small number of enrolled studies. Only seven randomized trials were found and included in this meta-analysis. Although our analysis achieved enough statistical power, the publication bias may exist in our study [30]. In addition, different kinds of NSAIDs and PG analogues were used in different studies. Although there were some subtle differences in applying different PG analogues clinically, there were too few studies to categorize them into different groups for comparison. Moreover, our findings may only be applicable to glaucoma patients, as there were no differences in IOP between the normal subjects who received topical PG analogues alone and topical NSAIDs with PG analogues [20].

Moreover, systemic prostaglandins have been applied in cardiology for managing pulmonary hypertension [31], in obstetrics for inducing childbirth or abortion [32], in urology for treating erectile dysfunction [33], in pediatrics for preventing closure of ductus arteriosus in newborns [34], and some other fields. Our analysis raises a question that if the synergic effect also exists in such systemic conditions. Hence, related research in other fields could be done in the future.

In conclusion, this meta-analysis suggests that topical NSAIDs may enhance the IOP lowering effect of topical PG analogues in glaucoma patients. Therefore, the short-term usage of topical NSAIDs may not be contraindicated in glaucoma patients receiving PG analogues to control IOP.

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15 Jun 2020

PONE-D-20-12499

The influence of topical non-steroidal anti-inflammatory drugs on the intraocular pressure lowering effect of topical prostaglandin analogues - a systemic review and meta-analysis

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Additional Editor Comments:

Due to the small sample size, not many studies to meta-analyze, one reviewer was less enthusiastic. This might be better in a specialty journal where it would be read? Both reviewers had significant concerns that need to be carefully and completely addressed. If a revision is attempted, it will be important to make clear that this is a very small samples size, which limits interpretation.

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Reviewer #1: The authors present a meta-analysis of the IOP outcomes from use of PGAs and NSAIDs. The manuscript is technically sound but suffers from a low number of available articles to use on the analysis. Furthermore, more than half the studies had unclear methods of blinding in respective RCTs. This makes a good meta-analysis difficult. Furthermore, this manuscript would be more appropriate for a specialty journal.

1) Although no PGA/NSAID studies on Unoprostone, Vyzulta, or flurbiprofen may exist it would be more complete to search for those as well.

2) Results section : "...NSAIDS were evacuated." evacuated should be "excluded. "

3) Figures 2 and 3 have no legends. Each should have a specific legend that describes the data listed and what the SMD is. I assume that this is IOP.

Overall, a nice manuscript with an important concept the NSAIDs can be used with PGAs. However, there are just very few RCTs to subject to a meta-analysis. This could be of interest to a Glaucoma specialty journal.

Reviewer #2: It may be beneficial for the readers to include the actual IOP change rather than just the SMD. This ca be incorporated either in Table 2 or on the side of the Forest plot itself.

A comment on the magnitude of difference to be expected with the addition of NSAID to a prostaglandin with be clinically useful. What is the unit for the calculated SMD of 1.64; is it mmHg? This can be included in the table and the IOP outcome paragraph.

Simin study (discussion para 2, quoted reference 7) sems a bit problematic. For one, it does not match with reference 7 in the list of references and I am unable to locate it anywhere else in the references to look it up. Additionally, it seems that the prostaglandin group which by the description provided is just a recheck after not adding anything/adding placebo has a SMD of 2.55 in that group. Is there any explanation in the paper for this IOP lowering? When compared to the NSAID added group with a SMD of 2.93 and significant overlap in confidence interval, I’m not sure the study fits the preceding statement of “enhanced IOP lowering effect was reported when adding NSAIDs to PG analogues”. Please review the SMD numbers for accuracy or perhaps consider revising the interpretation.

Page 13, end of para 3: A higher uveoscleral flow in Caucasians and higher trabecular flow in Chinese (Asian) populations may be related to lower response rates of uveoscleral drugs such as prostaglandins in Asians (Fan et al, BJO Dec 2019). Authors may consider including the reference as a possible explanation for the difference.

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Reviewer #1: No

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31 Jul 2020

Dear editor:

Thank you for considering our work entitled “The influence of topical non-steroidal anti-inflammatory drugs on the intraocular pressure lowering effect of topical prostaglandin analogues - a systemic review and meta-analysis”. We really appreciate the time and effort you and reviewers have dedicated to providing insightful feedback on ways to strengthen our paper. We have incorporated changes that reflect the detailed suggestions you and the reviewer have graciously provided. Following are the point-by-point responses to each reviewer’s comments.

Additional Editor Comments:

Due to the small sample size, not many studies to meta-analyze, one reviewer was less enthusiastic. This might be better in a specialty journal where it would be read? Both reviewers had significant concerns that need to be carefully and completely addressed. If a revision is attempted, it will be important to make clear that this is a very small samples size, which limits interpretation.

Response:

Thanks for your valuable comment and reminding. Prostaglandin analogues and NSAID are two of the most commonly used eyedrops in clinical practice of ophthalmology. The former is a crucial anti-glaucomatous medication and the latter is for preventing/treating macular edema after ocular surgery. More than half of the ophthalmologists have experience in these two drugs. Since the underlying mechanism of these two drugs are theoretically opposite, there were some debates regarding whether we should avoid NSAID or discontinue PG if a glaucoma patient suffers from macular edema after surgery. Patient’s intraocular pressure could become relatively hard to be controlled if we discontinue PG. On the other hand, long-term macular edema would result in visual decline in patients as well. Although the clinical trials regarding this topic are scarce, we really think it is important and significant to clarify and highlight the synergic effect of these two medications so that ophthalmologist doesn’t have to avoid or discontinue them in glaucoma patients who need both of the medications.

Besides, although this meta-analysis focused on topical NSAIDs and PG analogues in ophthalmology, we could also draw attention in the other fields. For example, systemic prostaglandins have been applied in cardiology for managing pulmonary hypertension, in obstetrics for inducing childbirth or abortion, in urology for treating erectile dysfunction, in pediatrics for preventing closure of ductus arteriosus in newborns, and some other fields. It is also debatable if we should avoid systemic NSAIDs in these patients. Our analysis raises a question that if the synergic effect also exists in such systemic conditions. More clinical or experimental studies in the other fields might be inspired by our results. Therefore, we sincerely hope our work could be published in a famous comprehensive journal such as PLoS ONE and share our results to readers in every fields. We’ve added some clinical significance in the manuscript. (Line 315 to 321, page 9-10)

We agreed that the sample size is small in this study. We’ve modified the DISCUSSION part and highlight this limitation in the manuscript in accordance to your suggestions. (Line 303 to 305, page 9)

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

Response:

We already rewrote our manuscript to meet the requirement of this journal, and we apologized for our mistake on the sentence “data from this study are available upon request”. Since this is a meta-analysis, all data were available to the public.

Reviewer 1’s comments:

The authors present a meta-analysis of the IOP outcomes from use of PGAs and NSAIDs. The manuscript is technically sound but suffers from a low number of available articles to use on the analysis. Furthermore, more than half the studies had unclear methods of blinding in respective RCTs. This makes a good meta-analysis difficult. Furthermore, this manuscript would be more appropriate for a specialty journal.

Response: Thank for your valuable comments. As we’ve answered the editor’s comment previously in this letter, “Prostaglandin analogues and NSAID are two of the most commonly used eyedrops in clinical practice of ophthalmology. The former is a crucial anti-glaucomatous medication and the latter is for preventing/treating macular edema after ocular surgery. More than half of the ophthalmologists have experience in these two drugs. Since the underlying mechanism of these two drugs are theoretically opposite, there were some debates regarding whether we should avoid NSAID or discontinue PG if a glaucoma patient suffers from macular edema after surgery. Patient’s intraocular pressure could become relatively hard to be controlled if we discontinue PG. On the other hand, long-term macular edema would result in visual decline in patients as well. Although the clinical trials regarding this topic are scarce, we really think it is important and significant to clarify and highlight the synergic effect of these two medications so that ophthalmologist doesn’t have to avoid or discontinue them in glaucoma patients who need both of the medications.

Besides, although this meta-analysis focused on topical NSAIDs and PG analogues in ophthalmology, we could also draw attention in the other fields. For example, systemic prostaglandins have been applied in cardiology for managing pulmonary hypertension, in obstetrics for inducing childbirth or abortion, in urology for treating erectile dysfunction, in pediatrics for preventing closure of ductus arteriosus in newborns, and some other fields. It is also debatable if we should avoid systemic NSAIDs in these patients. Our analysis raises a question that if the synergic effect also exists in such systemic conditions. More clinical or experimental studies in the other fields might be inspired by our results.”

Although the sample size is relatively small in this meta-analysis, they still provide enough statistical power (Journal of Educational and Behavioral Statistics 2010, 35(2), 215–247.) On the other hand, we agreed with you that the low number and detail information of available RCTs is a main drawback in this study that we should carefully interpret the results. We’ve modified the DISCUSSION part and highlight this limitation in the manuscript in accordance to your comment. (Line 303 to 305, page 9)

1. Although no PGA/NSAID studies on Unoprostone, Vyzulta, or flurbiprofen may exist it would be more complete to search for those as well.

Response: Thank you very much for this suggestion. We’ve re-performed the literature review adding unoprostone, Vyzulta, and flurbiprofen as keywords. Unfortunately, no additional clinical trial was found based on the new criteria. We’ve revised the Methods in the manuscript with this change in searching criteria. (Line 113-117, page 3)

2. Results section : "...NSAIDS were evacuated." evacuated should be "excluded. "

Response: Thanks for your reminding. We’ve corrected the typo. (Line 173, Page 5)

3. Figures 2 and 3 have no legends. Each should have a specific legend that describes the data listed and what the SMD is. I assume that this is IOP.

Response: We’ve added legends into figure 2 and 3 in accordance to your comment. (Line 217-230, page 7). SMDs in the figure represent the standardized mean difference of IOP (mmHg), which were calculated with Cohen method. We apologized for making the confusion. We’ve added the footnotes in the figure and the explanation in the manuscript. (Line 215-230, page 7; figure 2; and figure 3)

Overall, a nice manuscript with an important concept the NSAIDs can be used with PGAs. However, there are just very few RCTs to subject to meta-analysis. This could be of interest to a Glaucoma specialty journal.

Response: We really appreciate your valuable comments and considerations. As we’ve answered in the previous comments, we think the statistical power of this meta-analysis was enough despite the small number of available trials. We sincerely hope our work could be published in PLoS ONE since the results of this study might inspire many ophthalmologists and medical physicians in the other field as well.

Reviewer 2’s comments:

It may be beneficial for the readers to include the actual IOP change rather than just the SMD. This can be incorporated either in Table 2 or on the side of the Forest plot itself.

Response: Thanks. We’ve included the information of IOP in baseline and after treatments in each trial and incorporated these data into figure 2 and figure 3 in accordance to your suggestions.

A comment on the magnitude of difference to be expected with the addition of NSAID to a prostaglandin with be clinically useful. What is the unit for the calculated SMD of 1.64; is it mmHg? This can be included in the table and the IOP outcome paragraph.

Response: The unit of the SMD (standardized mean difference) in the results are mmHg. Our results showed that adding topical NSAID on prostaglandin analogue may additionally decrease 1.3mmHg of IOP in patients with glaucoma. We apologized for the confusion and lack of the explanation in the original manuscript. We’ve added the explanation in the table and manuscript in accordance to your suggestion. “The unit of SMD is in mmHg.“ (Line 223 and 230, Page 7)

Simin study (discussion para 2, quoted reference 7) sems a bit problematic. For one, it does not match with reference 7 in the list of references and I am unable to locate it anywhere else in the references to look it up. Additionally, it seems that the prostaglandin group which by the description provided is just a recheck after not adding anything/adding placebo has a SMD of 2.55 in that group. Is there any explanation in the paper for this IOP lowering? When compared to the NSAID added group with a SMD of 2.93 and significant overlap in confidence interval, I’m not sure the study fits the preceding statement of “enhanced IOP lowering effect was reported when adding NSAIDs to PG analogues”. Please review the SMD numbers for accuracy or perhaps consider revising the interpretation.

Response: Thank you so much for this valuable comment. We carefully reviewed the methods of Simin’s study again in accordance to your comment and found that the original “baseline” IOPs in this study were measured before PGE treatments, which was markedly different from the other studies, in which the “baseline” IOPs were measured under PGE therapy right before adding the NSAID. Hence the original results of Simin’s study should not directly compare with the others.

To overcome this fundamental problem, we’ve modified patients’ baseline IOPs in Simin’s study to the IOPs measured after 4 weeks of prostaglandin monotherapy and re-done the meta-analysis again. Fortunately, the significantly synergic effect was still observed in the combine therapy group, with only a little bit decrease of overall standardized mean difference (from 1.64 to 1.33 mmHg). The overall standardized mean difference in PGE monotherapy remained non-significance (from 0.61 to -0.03 mmHg).

We apologize for the mistake and have already revised the manuscript and figure based on these new results.

Page 13, end of para 3: A higher uveoscleral flow in Caucasians and higher trabecular flow in Chinese (Asian) populations may be related to lower response rates of uveoscleral drugs such as prostaglandins in Asians (Fan et al, BJO Dec 2019). Authors may consider including the reference as a possible explanation for the difference.

Response: Thank you for the suggestion. We’ve added this valuable reference in our manuscript in accordance to your comment. (Line 295-298, page 9)

Again, thank you very much for considering our manuscript through Reviewer’s most valuable comments. We have worked hard to answer each query and accordingly have carefully made revisions. We hope that this revised version is qualified to be accepted for publication.

Sincerely,

De-Kuang Hwang

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

2 Sep 2020

The influence of topical non-steroidal anti-inflammatory drugs on the intraocular pressure lowering effect of topical prostaglandin analogues - a systemic review and meta-analysis

PONE-D-20-12499R1

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Reviewer #1: All comments have been addressed

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Reviewer #1: Yes

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Reviewer #1: This is a revised manuscript presenting a meta-analysis of the IOP effects of PGAs with concurrent NSAID use. Overall, an improved manuscript in which the authors have addressed prior comments. Concurrent of these 2 classes of medications doesn't seem to adversely affect IOP.

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4 Sep 2020

PONE-D-20-12499R1

The influence of topical non-steroidal anti-inflammatory drugs on the intraocular pressure lowering effect of topical prostaglandin analogues - a systemic review and meta-analysis

Dear Dr. Hwang:

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