• Josefine Clement Freiberg, Alexander von Spreckelsen, Miriam Kolko, Augusto Azuara-Blanco, and Gianni Virgili.
• Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
• Cochrane Db Syst Rev. 2022 Jun 10; 6 (6): CD013817CD013817.

BackgroundGlaucoma is a group of optic neuropathies characterized by progressive degeneration of the retinal ganglion cells, axonal loss and irreversible visual field defects. Glaucoma is classified as primary or secondary, and worldwide, primary glaucoma is a leading cause of irreversible blindness. Several subtypes of glaucoma exist, and primary open-angle glaucoma (POAG) is the most common. The etiology of POAG is unknown, but current treatments aim to reduce intraocular pressure (IOP), thus preventing the onset and progression of the disease. Compared with traditional antiglaucomatous treatments, rho kinase inhibitors (ROKi) have a different pharmacodynamic. ROKi is the only current treatment that effectively lowers IOP by modulating the drainage of aqueous humor through the trabecular meshwork and Schlemm's canal. As ROKi are introduced into the market more widely, it is important to assess the efficacy and potential AEs of the treatment.ObjectivesTo compare the efficacy and safety of ROKi with placebo or other glaucoma medication in people diagnosed with open-angle glaucoma (OAG), primary open-angle glaucoma (POAG) or ocular hypertension (OHT).Search MethodsWe used standard Cochrane methods and searched databases on 11 December 2020.Selection CriteriaWe included randomized clinical trials examining commercially available ROKi-based monotherapy or combination therapy compared with placebo or other IOP-lowering medical treatments in people diagnosed with (P)OAG or OHT. We included trials where ROKi were administered according to official glaucoma guidelines. There were no restrictions regarding type, year or status of the publication.Data Collection And AnalysisWe used standard methodological procedures expected by Cochrane. Two review authors independently screened studies, extracted data, and evaluated risk of bias by using Cochrane's RoB 2 tool.  MAIN RESULTS: We included 17 trials with 4953 participants diagnosed with (P)OAG or OHT. Fifteen were multicenter trials and 15 were masked trials. All participants were aged above 18 years. Trial duration varied from 24 hours to 12 months. Trials were conducted in the USA, Canada and Japan. Sixteen trials were funded by pharmaceutical companies, and one trial provided no information about funding sources. The trials compared ROKi monotherapy (netarsudil or ripasudil) or combination therapy with latanoprost (prostaglandin analog) or timolol (beta-blocker) with placebo, timolol, latanoprost or netarsudil. Reported outcomes were IOP and safety. Meta-analyses were applied to 13 trials (IOP reduction from baseline) and 15 trials (ocular AEs).  Of the trials evaluating IOP, seven were at low risk, three had some concerns, and three were at high risk of bias. Three trials found that netarsudil monotherapy may be superior to placebo (mean difference [MD] 3.11 mmHg, 95% confidence interval [CI] 2.59 to 3.62; I2 = 0%; 155 participants; low-certainty evidence). Evidence from three trials found that timolol may be superior to netarsudil with an MD of 0.66 mmHg (95% CI 0.41 to 0.91; I2 = 0%; 1415 participants; low-certainty evidence). Evidence from four trials found that latanoprost may be superior to netarsudil with an MD of 0.97 mmHg (95% CI 0.67 to 1.27; I2 = 4%; 1283 participants; moderate-certainty evidence).  Evidence from three trials showed that, compared with monotherapy with latanoprost, combination therapy with netarsudil and latanoprost probably led to an additional pooled mean IOP reduction from baseline of 1.64 mmHg (95% CI -2.16 to -1.11; 1114 participants). Evidence from three trials showed that, compared with monotherapy with netarsudil, combination therapy with netarsudil and latanoprost probably led to an additional pooled mean IOP reduction from baseline of 2.66 mmHg (95% CI -2.98 to -2.35; 1132 participants). The certainty of evidence was moderate. One trial showed that,  compared with timolol monotherapy, combination therapy with ripasudil and timolol may lead to an IOP reduction from baseline of 0.75 mmHg (95% -1.29 to -CI 0.21; 208 participants). The certainty of evidence was moderate. Of the trials assessing total ocular AEs, three were at low risk, four had some concerns, and eight were at high risk of bias.  We found very low-certainty evidence that netarsudil may lead to more ocular AEs compared with placebo, with 66 more ocular AEs per 100 person-months (95% CI 28 to 103; I2 = 86%; 4 trials, 188 participants). We found low-certainty evidence that netarsudil may lead to more ocular AEs compared with latanoprost, with 29 more ocular AEs per 100 person-months (95% CI 17 to 42; I2 = 95%; 4 trials, 1286 participants).  We found moderate-certainty evidence that, compared with timolol, netarsudil probably led to 21 additional ocular AEs (95% CI 14 to 27; I2 = 93%; 4 trials, 1678 participants). Data from three trials (1132 participants) showed no evidence of differences in the incidence rate of AEs between combination therapy with netarsudil and latanoprost and netarsudil monotherapy (1 more event per 100 person-months, 95% CI 0 to 3); however, the certainty of evidence was low. Similarly, we found low-certainty evidence that, compared with latanoprost, combination therapy with netarsudil and latanoprost may cause 29 more ocular events per 100 person-months (95% CI 11 to 47; 3 trials, 1116 participants). We found moderate-certainty evidence that, compared with timolol monotherapy, combination therapy with ripasudil and timolol probably causes 35 more ocular events per 100 person-months (95% CI 25 to 45; 1 trial, 208 participants). In all included trials, ROKi was reportedly not associated with any particular serious AEs.Authors' ConclusionsThe current evidence suggests that in people diagnosed with OHT or (P)OAG, the hypotensive effect of netarsudil may be inferior to latanoprost and slightly inferior to timolol. Combining netarsudil and latanoprost probably further reduces IOP compared with monotherapy. Netarsudil as mono- or combination therapy may result in more ocular AEs. However, the certainty of evidence was very low or low for all comparisons except timolol. In general, AEs were described as mild, transient, and reversible upon treatment discontinuation. ROKi was not associated with any particular serious AEs. Future trials of sufficient size and follow-up should be conducted to provide reliable information about glaucoma progression, relevant IOP measurements and a detailed description of AEs using similar terminology. This would ensure the robustness and confidence of the results and assess the intermediate- and long-term efficacy and safety of ROKi.Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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