Question
What are the benefits and risks of rho kinase inhibitor eye drops to treat people with either glaucoma or increased eye pressure?
Key messages
Antiglaucomatous eye drops such as latanoprost and timolol may reduce the eye pressure more compared with treatment with a rho kinase inhibitor, but the difference with timolol is small. When combining rho kinase inhibitors with different types of medicine, the eye pressure may be reduced more. People treated with a rho kinase inhibitor experience more adverse events (side effects) compared with other treatments. Future research in this area should focus on reporting disease progression (how the glaucoma gets worse over time).
What is glaucoma?
Glaucoma is a sight-threatening eye disease that can lead to blindness if left untreated. There are different types of glaucoma and the most common is called primary open-angle glaucoma. High eye pressure is a known risk factor for developing glaucoma.
Medical glaucoma treatment
There are different types of eye drops that can be used to treat glaucoma. All medical treatments of glaucoma work by reducing eye pressure. Latanoprost and timolol are two glaucoma medications, and one of the new types of glaucoma medicine is called a rho kinase inhibitor.
What did we want to find out?
We wanted to examine whether the effectiveness and safety of rho kinase inhibitor eye drops were better or worse than other medicines.
What did we do?
We searched for studies that compared:
- rho kinase inhibitor with placebo (a treatment with no therapeutic effect);
- rho kinase inhibitor with other types of glaucoma treatments (latanoprost and timolol).
Search date
We searched medical databases on 11 December 2020.
What did we find?
We found 17 studies examining 4953 people aged at least 18 years diagnosed with primary open-angle glaucoma or high eye pressure and treated with a rho kinase inhibitor. The studies varied in treatment duration from 24 hours to 12 months. They were conducted in the USA, Canada and Japan. Of the studies, 16 were funded by pharmaceutical companies and one did not provide information about potential funding sources. The effect of treatment was evaluated by measuring the eye pressure and assessing the adverse events of treatment.
The studies did not report data disease progression, but they reported data on the lowering of the pressure within the eye and adverse events. Treatment with latanoprost may be better than rho kinase inhibitor. Treatment with timolol may be slightly better than treatment with rho kinase inhibitor. Furthermore, treatment with both rho kinase inhibitor and latanoprost or timolol probably reduces the eye pressure even more. Overall, the studies reported adverse events very differently. More people treated with rho kinase inhibitors may have experienced eye-related adverse events; however, we are not very certain about these findings. There were no serious adverse events reported for treatment with rho kinase inhibitor.
Main limitations of the evidence
The studies did not report all the outcomes that we were interested in. The studies focused on specific outcomes such as eye pressure and adverse events, whereas we wanted to answer other questions as well. The current evidence was based on few studies. Some studies were conducted in a way that may have introduced errors into the results. Studies varied in the way they measured the outcomes and thus may not be comparable to each other.
The 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.
Glaucoma 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.
To 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).
We used standard Cochrane methods and searched databases on 11 December 2020.
We 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.
We 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.
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.