A simple mathematical approach to identifying baseline predictors of the effectiveness of carbonic anhydrase inhibitors in intraocular pressure reduction

Selective laser trabeculoplasty (SLT) emerges as a first-line treatment for newly diagnosed open-angle glaucoma and ocular hypertension. However, the interindividual response to SLT considerably varied. Large-scale clinical investigations concerning predictive factors for SLT effectiveness are limited. This study aimed to identify baseline predictors of the percentage intraocular pressure (IOP)-lowering effectiveness of SLT using an alternative mathematical approach. Mathematical equations of IOP under the steady state of aqueous humour flow were formulated. The conclusive equation integrates physiological variables, including trabecular outflow facility, uveoscleral outflow fraction, plasma protein concentration, albumin/globulin ratio, mean arterial pressure, episcleral venous pressure, and plasma osmolarity. The equation was employed to estimate the percentage of IOP reduction following SLT and subsequently subjected to global sensitivity analysis to determine significant predictors of the IOP-lowering effect of SLT using the Monte Carlo simulation of 8,192 samples. In the current model, a 50% improvement in the trabecular outflow facility impacted by SLT is associated with a mean percentage IOP reduction of 16.6%. Lower baseline trabecular outflow facilities were the strongest predictors, showing a correlation with greater effectiveness of SLT in terms of percentage of IOP reduction. The second most influential factor includes baseline uveoscleral outflow fraction, followed by baseline episcleral venous pressure. Specifically, lower baseline uveoscleral outflow fraction and episcleral venous pressure were found to be correlated with increased effectiveness of SLT. Baseline levels of plasma protein concentration, albumin/globulin ratio, mean arterial pressure, and plasma osmolarity have minimal impact on SLT success or failure. This study identifies baseline trabecular outflow facilities as the strongest predictor of SLT effectiveness. The results suggested that pre-SLT medical treatment that augments uveoscleral outflow and/or trabecular outflow facilities could compromise the effectiveness of subsequent SLT in terms of percentage IOP reduction compared to those who never received pre-SLT medication.

To assess whether an association exists between pretreatment corneal hysteresis (CH) and the magnitude of intraocular pressure (IOP) and medication burden reduction following microinvasive glaucoma surgery (MIGS). Retrospective chart review of 84 eyes from 57 patients with CH measurements who underwent trabecular meshwork MIGS in a glaucoma practice in New York City with follow-up visits at 3-6 and 9-12 months. MIGS included canaloplasty, goniotomy, microbypass stents, or a combination thereof. The lowest and middle CH tertiles experienced significantly reduced mean IOP at 3-6-month follow-ups (p = .007, < .001), whereas the highest tertile did not (p = .06). At 9-12-month follow-ups, a significant mean IOP reduction only persisted in the middle tertile (p = .001). For medication burden reduction, only the highest CH tertile experienced significant mean reductions at both 3-6- and 9-12-month follow-ups (p = .015, .028). Notably, 7 patients in the lowest CH tertile failed MIGS and required an additional surgical or laser procedure within 24 months of MIGS, whereas only 3 patients failed in the other tertiles (likelihood ratio < .05). Multivariate analysis excluding MIGS failures demonstrated an inverse association between CH and the magnitude of post-operative IOP reduction at both 3-6- and 9-12-month follow-ups when controlling for baseline IOP and medication changes (p = .002, .026). There was an inverse association between pretreatment CH and the magnitude of IOP reduction following surgery. There is also evidence of an increased need for repeat surgery or other intervention in patients with lower CH who undergo MIGS.

A randomized, investigator-masked, 4-week study comparing timolol maleate 0.5%, brinzolamide 1%, and brimonidine tartrate 0.2% as adjunctive therapies to travoprost 0.004% in adults with primary open-angle glaucoma or ocular hypertension

Glaucoma is a leading cause of irreversible blindness worldwide and is estimated to affect nearly 70 million people and to cause blindness in about 7 million people. The pathology shared by the heterogeneous group of glaucoma disorders is progressive optic nerve damage that is characterized by ‘cupping’ of the optic disk. This progressive glaucomatous optic atrophy gradually leads to visual field loss. The precise mechanisms leading to optic nerve axon damage have not been fully elucidated. Intuitively, direct treatment of the optic nerve is an obvious therapeutic strategy; however, there are no completed clinical trials that have tested the proof-of-concept that ‘neuroprotection’ is a viable treatment for glaucoma. At present, ophthalmologists treat the only known modifiable risk factor for glaucoma, clinically significant elevated intraocular pressure (IOP). Given our current understanding of the human genome and glaucoma therapeutics, the question is, are there genetic determinants for the pharmacodynamic variation in drug response to glaucoma medications? In order to begin to answer this question we need to assess the following two issues: (1) What is the evidence that lowering IOP is important for ‘protecting’ the susceptible optic nerve in patients with glaucoma? (2) What are the variables in assessing the IOP response to glaucoma medications? The first issue has been addressed in five randomized clinical trials, and the results provide strong evidence that reducing IOP slows the progression of glaucomatous optic neuropathy. In the Advanced Glaucoma Intervention Study (AGIS), there was a clear IOP ‘dose–response’ relationship with visual field progression which showed a striking lack of visual field progression in patients who had a mean IOP of 12.3 mmHg. In the other four trials, the treatment interventions, which included medications, laser or filtration surgeries, were based on either setting a minimum target pressure [Ocular Hypertension Treatment Study (OHTS) and Early Manifest Glaucoma Trial Group (EMGT)], calculated target pressure (Collaborative Initial Glaucoma Treatment Study) or percent IOP lowering (OHTS, EMGT and Collaborative Normal Tension Glaucoma Study). Based on these trials, there has been a shift in reporting the effectiveness of glaucoma drugs. Prior to 1996 most glaucoma pharmacology trials reported efficacy as a ‘mean IOP’ and the standard deviations or standard errors of the mean. Now, more studies report on ‘percent IOP reduction’ as an index of response to glaucoma medications. The second issue may be addressed by investigating the basic pharmacology of glaucoma therapeutics. There are five major classes of glaucoma medications: muscarinic cholinergic agonists, carbonic anhydrase inhibitors, b-adrenergic receptor (AR) antagonists, a2-AR agonists, and prostaglandin F receptor agonists. Though nonselective AR agonists had been used, their use is now extremely limited because they are not as effective compared to the newer drugs. The mechanism of action of these drugs is directed either to decrease the production of the clear intraocular fluid (aqueous humor) by the ciliary body or to enhance the outflow of aqueous humor through the trabecular meshwork and/or uveoscleral pathway (Figure 1). Elevated IOP is usually caused by outflow obstruction, and not from increased aqueous humor secretion. There are some susceptible optic nerves that sustain damage at normal IOPs. Despite our understanding of the pharmacology of these medications, we cannot explain the variable IOP response to glaucoma drugs between patients. The IOP response to a drug has been reported in numerous formats: mean IOP pretreatment, mean IOP post-treatment, change in IOP, target IOP, percent change in IOP, effect on diurnal IOP, ‘clinical success,’ percent subjects achieving a specified target IOP, and ‘nonresponders’ (Figure 2). Important considerations to interpret the drug effect properly include: IOP at drug peak and trough effect, contralateral effect in monocular placebo-controlled trials, regression to the mean, placebo effect, and definitions of ‘clinical success’ and ‘nonresponders.’ In pharmacology trials, the safety and efficacy data of a drug are based on a biased population of ‘homogeneous subjects’ who met specific inclusion and exclusion criteria. Although these criteria are important to minimize confounding effects of various ocular conditions, systemic diseases and medications, such study designs explain why unusual and infrequent drug reactions are identified in a ‘post-marketing’ setting when the drug is widely used in patients who deviate The Pharmacogenomics Journal (2003) 3, 197–201 & 2003 Nature Publishing Group All rights reserved 1470-269X/03 $25.00

Background/Aim. The cataract surgery in eyes with and without glaucoma results in the sustained intraocular pressure (IOP) reduction but it is still unknown which glaucomatous patients will achieve clinically significant reduction. The preoperative IOP and some ocular biometric parameters have been shown as potential predictors of the postoperative IOP reduction. The aim of our prospective intervention study was to evaluate that relationship in medically controlled patients with the pseudoexfoliation glaucoma (PXG) and in the nonglaucomatous patients. Methods. Thirty-one PXG patients (31 eyes) and 31 nonglaucomatous patients (31 eyes), all with clinically significant cataract, were enrolled. The preoperative IOP, anterior chamber depth (ACD), axial length (AL), lens thickness (LT), lens position (LP) [LP = ACD + 0.5 LT], relative lens position (RLP) [RLP = LP / AL] and the pressure-to-depth ratio (PD ratio) [PD ratio = preoperative IOP/preoperative ACD] were evaluated as potential predictors of the IOP change in the 6th postoperative month. Results. In the 6th postoperative month, in the PXG group, the IOP reduction was -3.23 ? 3.41 mmHg (-17.67 ? 16.86%) from the preoperative value of 16.27 ? 3.08 mmHg and in the control group, the reduction was -2.26 ? 1.71 mmHg (-15.06 ? 10.93%) from the preoperative value of 14.53 ? 2.04 mmHg. In the PXG group, the significant predictors of the absolute and the percentage IOP reduction were the preoperative IOP, AL, and PD ratio. In the same group, RLP was shown as a significant predictor of absolute change in the IOP in multi-variate analysis, and the percentage IOP change in both the univariate and the multivariate analyses. In the control group, the preoperative IOP and the PD ratio were the only significant parameters that could predict absolute change in the postoperative IOP. Conclusion. The cataract surgery leads to the IOP reduction both in the PXG and nonglaucomatous eye. Predictors monitored in this study are widely available and simply calculable parameters that can be potentially used in managing glaucoma.

Management of iris melanoma with secondary glaucoma.

To evaluate the relationship between lens position parameters and intraocular pressure (IOP) reduction after cataract surgery in nonglaucomatous eyes with open angles. The main outcome of the prospective study was percentage of IOP change, which was calculated using the preoperative IOP and the IOP 4 months after cataract surgery in nonglaucomatous eyes with open angles. Lens position (LP), defined as anterior chamber depth (ACD) + 1/2 lens thickness (LT), was assessed preoperatively using parameters from optical biometry. Preoperative IOP, central corneal thickness, ACD, LT, axial length (AXL), and the ratio of preoperative IOP to ACD (PD ratio) were also evaluated as potential predictors of percentage of IOP change. The predictive values of the parameters we found to be associated with the primary outcome were compared. Four months after cataract surgery, the average IOP reduction was 2.03 ± 2.42 mm Hg, a 12.74% reduction from the preoperative mean of 14.5 ± 3.05 mm Hg. Lens position was correlated with IOP reduction percentage after adjusting for confounders (P = 0.002). Higher preoperative IOP, shallower ACD, shorter AXL, and thicker LT were significantly associated with percentage of IOP decrease. Although not statistically significant, LP was a better predictor of percentage of IOP change compared to PD ratio, preoperative IOP, and ACD. The percentage of IOP reduction after cataract surgery in nonglaucomatous eyes with open angles is greater in more anteriorly positioned lenses. Lens position, which is convenient to compute by basic ocular biometric data, is an accessible predictor with considerable predictive value for postoperative IOP change.

ObjectiveTo compare the pattern of intraocular pressure (IOP) reduction following selective laser trabeculoplasty (SLT) versus argon laser trabeculoplasty (ALT) in open-angle glaucoma (OAG) patients, and to investigate the ability of initial IOP reduction to predict mid-term success.MethodsA prospective, nonrandomized, interventional case series was carried out. Consecutive uncontrolled OAG glaucoma patients underwent SLT or ALT; the same preoperative medical regimen was maintained during follow-up. Data collected included age, type of OAG, pre- and postoperative IOP, number of glaucoma medications, and surgical complications. Post-treatment assessments were scheduled at day 1 and 7 and months 1, 3, and 6.ResultsA total of 45 patients (45 eyes) were enrolled [SLT group (n = 25); ALT group (n = 20)]. Groups were similar for age, baseline IOP, and number of glaucoma medications (P ≥ 0.12). We found no significant differences in mean IOP reduction between SLT (5.1 ± 2.5 mmHg; 26.6%) and ALT (4.4 ± 2.8 mmHg; 22.8%) groups at month 6 (P = 0.38). Success rates (IOP ≤ 16 mmHg and IOP reduction ≥25%) at last follow-up visit were similar for SLT (72%) and ALT (65%) groups (P = 0.36). Comparing the pattern of IOP reduction (% of IOP reduction at each visit) between groups, we found a greater effect following SLT compared with ALT at day 7 (23.7% ± 13.7% vs 8.1% ± 9.5%; P < 0.001). No significant differences were observed at other time points (P ≥ 0.32). Additionally, the percentage of IOP reduction at day 7 and at month 6 were significantly correlated in the SLT group (R2 = 0.36; P < 0.01), but not in the ALT group (P = 0.89). Early postoperative success predicted late success in most SLT cases (82%). No serious complications were observed.ConclusionAlthough mid-term results suggest SLT and ALT as effective and equivalent alternatives, a greater initial IOP reduction was observed following SLT. In addition, the initial IOP reduction was a good predictor of mid-term success in patients undergoing SLT, but not ALT.

To study the effectiveness of unilateral selective laser trabeculoplasty (SLT) on the both eyes of patients with primary open-angle glaucoma (POAG). This was a self-controlled clinical study. Thirty-two patients of 32 eyes with OAG who used same anti-glaucoma medications for both eyes were included aat the Department of Ophthalmology Peking University third Hospital from February 2010 to April 2014. SLT was performed for the poorly controlled eye for each patient. Patients were examined before operation and 1 hour, 1 week, 1 month, 3 months and 6 months after operation. The intraocular pressure was examined after 1 hour of SLT. The rest time points were examined by visual acuity, intraocular pressure (IOP), slit lamp microscope, fundus ophthalmoscope and visual field. The paired t test (Bonferroni) was used to compare the IOP at each time point after SLT with the baseline IOP before SLT. Single factor analysis of variance was used to compare the percentage of IOP drop. Linear correlation analysis was used to analyze the amplitude of the decrease of IOP between treated eyes and untreated eyes at 6-month post-operatively and analyze the IOP between preoperative eyes and 6-month post-operative eyes. The magnitude of the decrease of IOP in patients with glaucoma medication and 6 months after surgery was analyzed. We also analyzed the types of antiglaucoma medications and IOP reductions range for 6 month after SLT. The preoperative mean IOP was (18.9±2.5) mmHg (1 mmHg=0.133 kPa) in the treated eye of patients with OAG. Mean IOP reduction for 1 week, 1, 3, and 6 months after SLT were (1.7±2.9) mmHg, (2.5±2.5) mmHg, (3.5±2.8) mmHg, (3.4±2.5) mmHg and the percentage of IOP reduction were (8±16) %, (13±13) % (18±14) %, (18±12) % respectively (compared with the baseline, P< 0.05) . With the success criteria of IOP reduction ≥3.0 mmHg or ≥20%, the success rate of SLT in the treated eye after 1 week, 1, 3, 6 months was 38%, 52%, 50% and 60% respectively. For the untreated fellow eyes, the preoperative mean IOP was (17.3±2.4) mmHg. Mean IOP reduction for 1 week, 1month, 3 month, and 6 month after SLT were (1.1±2.0) mmHg, (1.0±2.7) mmHg, (2.6±2.2) mmHg and (2.5±2.2) mmHg respectively (compared with the baseline, P<0.05) . There was a positive correlation between preoperative IOP and IOP reduction either in the treated or in the untreated eyes at 6-month post-SLT (R=0.63, P<0.01; R=0.60, P<0.01) . There was a positive correlation in IOP reduction between treated eyes and untreated eyes at 6-month post-operative (R=0.66, P<0.01). All patients didn't need further treatment such as another laser treatment or surgery. Anti-glaucoma medications were remained unchanged after SLT. In poorly anti-glaucoma medication controlled Chinese POAG eyes with mean IOP about 18.0 mmHg, unilateral STL can reduce the IOP about 18% at 6-month post-operative for the treated eyes. There was also a continuous IOP reduction effects for the fellow eyes.(Chin J Ophthalmol, 2016, 52: 410-415).

To investigate factors associated with changes in optic nerve head (ONH) topography after acute intraocular pressure (IOP) reduction in patients with primary open-angle glaucoma (POAG). Untreated POAG patients (IOP >21 mm Hg) were prospectively enrolled. Systemic and ocular information were collected, including central corneal thickness (CCT) and corneal hysteresis (CH). All patients underwent confocal scanning laser ophthalmoscopy and tonometry (Goldmann) before and 1 h after pharmacological IOP reduction. The mean of three measurements was considered for analysis. Changes in each ONH topographic parameter were assessed (one eye was randomly selected), and those that changed significantly were correlated with patient's systemic and ocular characteristics. A total of 42 patients were included (mean age, 66.7 ± 11.8 years). After a mean IOP reduction of 47.3 ± 11.9%, significant changes were observed in cup area and volume, and in rim area and volume (P < 0.01), but not in mean cup depth (P = 0.80). Multiple regression analysis (controlling for baseline IOP and magnitude of IOP reduction) showed that CH (r(2) = 0.17, P < 0.01) and diabetes diagnosis (r(2) ≥ 0.21, P < 0.01) were negatively correlated with the magnitude of changes in ONH parameters, whereas the cup-to-disc ratio was positively correlated (r(2) = 0.30, P < 0.01). Age, race, disc area, and CCT were not significant (P ≥ 0.12). Including all significant factors in a multivariable model, only the presence of diabetes remained significantly associated with all ONH parameters evaluated (P < 0.01). Different systemic and ocular factors, such as diabetes, CH, and the relative size of the cup, seem to be associated with the magnitude of changes in ONH topography after acute IOP reduction in POAG patients. These associations partially explain the ONH changes observed in these patients and suggest that other factors are possibly implicated in an individual susceptibility to IOP.

Update on Microinvasive Glaucoma Surgery.

Numerous studies have provided conflicting evidence to explain the ocular hypotensive mechanism of action of epinephrine. Although epinephrine has been shown consistently to increase outflow facility, its effects on aqueous flow and uveoscleral outflow are not as clear. The purpose of this study was to clarify the effects of multiple doses of topical epinephrine on aqueous humor dynamics in human eyes. This was done by evaluating the four main parameters that determine steady state intraocular pressure. These parameters were assessed at baseline and after a week of twice-daily treatment of epinephrine hydrochloride 2% to one eye. Twenty-six human volunteers were enrolled in the study. Intraocular pressure was measured by pneumatonometry, aqueous flow and trabecular outflow facility by fluorophotometry, episcleral venous pressure by venomanometry and uveoscleral outflow by mathematical calculation. In epinephrine-treated eyes compared to baseline, intraocular pressure and aqueous flow were reduced from 21.2 +/- 0.3 to 17.1 +/- 0.2 mmHg (19%, p = .01) and 3.3 +/- 0.2 to 2.9 +/- 0.2 microl/min (12%, p = .03), respectively. Trabecular outflow facility obtained by fluorophotometry was increased from 0.18 +/- 0.02 to 0.26 +/- 0.03 microl/min/mmHg (44%, p = .02). Topical epinephrine did not significantly affect uveoscleral outflow or episcleral venous pressure. In conclusion, multiple topical doses of epinephrine lowered intraocular pressure in human volunteers by reducing aqueous humor formation and increasing trabecular outflow facility. The increase in uveoscleral outflow suggested by other studies was not observed.

BackgroundTo identify success predictors and to study the role of the fellow untreated eye as a co-variable for adjustment of intraocular pressure (IOP) outcomes following selective laser trabeculoplasty (SLT) in early open-angle glaucoma (OAG) patients.MethodsA case series was carried out. Patients with uncontrolled early OAG or ocular hypertension (inadequate IOP control requiring additional treatment) underwent SLT (one single laser session) performed by the same surgeon in a standardized fashion. The same preoperative medical regimen was maintained during follow-up for all patients. Post-treatment assessments were scheduled at week 1 and months 1, 2, and 3. In order to account for possible influence of IOP fluctuation on laser outcomes, post-laser IOP values of the treated eye of each patient were also analyzed adjusting for IOP changes (between visits variation) of the untreated fellow eye (adjusted analysis). Pre and post-laser IOP values were compared using paired t-test. Factors associated with the magnitude of IOP reduction were investigated using multiple regression analysis.ResultsA total of 45 eyes of 45 patients were enrolled. Mean IOP was reduced from 20.8 ± 5.1 to 14.9 ± 2.9 mmHg at month 3 (p < 0.001). Adjusted success rate (defined as IOP reduction ≥ 20%) was 64% and mean percentage of IOP reduction was 23.1 ± 14.3% at last follow-up visit. Considering unadjusted post-laser IOP values, it was found a 20% greater absolute IOP reduction (median [interquartile range] 6 mmHg [4–7] vs 5 mmHg [3–7]; p = 0.04), with a success rate of 76%. Although baseline IOP was significantly associated with both adjusted and unadjusted post-laser IOP reduction, a stronger association was found when unadjusted IOP values were considered (p < 0.001 and R2 = 0.35; p < 0.001 and R2 = 0.67, respectively). Age, mean deviation (MD) index, central corneal thickness and type of glaucoma were not significant predictors (p ≥ 0.150).ConclusionsIn this group of patients with early OAG or ocular hypertension, our short-term results confirmed SLT as a safe and effective alternative for IOP reduction. Although better outcomes were found in eyes with higher preoperative IOP, this effect was mitigated when results were adjusted to the fellow untreated eye (to the influence of between visits-IOP fluctuations).

To compare clinical outcomes between gonioscopy-assisted transluminal trabeculotomy (GATT) and trabeculectomy (TRAB) in patients with advanced-stage pseudoexfoliation glaucoma (PEXG). This comparative study comprised 62 patients who underwent GATT (N = 31) or TRAB (N = 31) for advanced-stage PEXG. Primary outcome was cumulative probability of surgical success at the end of 12-month follow-up. Success was determined as intraocular pressure (IOP) reduction ≥ 30% from baseline, IOP between 6 and 18mmHg and IOP upper limits for IOP < 15mmHg and < 12mmHg, separately. Secondary outcomes were IOP reduction, antiglaucoma medication (AGM) use, and complications in the study. Age, sex, cup/disc ratio, mean deviation, pattern standard deviation, and retinal nerve fiber layer thickness did not significantly differ between the groups (p > 0.05 for all). The probability of cumulative surgical success at the end of 12months was similar between the two groups for IOP < 15mmHg and < 18mmHg but significantly higher after TRAB (92.0%) than GATT (82.5%) for IOP < 12mmHg (log-rank test p = 0.035). Percentage of IOP reduction from baseline was similar between the groups (53.1 ± 18.6% in GATT group and 53.0 ± 16.6% in TRAB group, p = 0.98) at the end of 12months. No significant difference in the mean number of AGM was present at the 12-month visit (1.3 ± 1.4 in GATT and 1.1 ± 1.4 in TRAB, p = 0.65). At the end of 12months, IOP reduction rate was similar between GATT and TRAB. Cumulative surgical success was higher after TRAB than GATT for IOP < 12mmHg.

To assess the effectiveness of selective laser trabeculoplasty (SLT) in Indian eyes with open-angle glaucoma (OAG). Single-center, prospective, interventional study. Patients undergoing SLT from January 2014 to June 2018 for OAG were included in the study. Treatment-naive naive as well as patients on antiglaucoma medications (AGM) with suboptimal intraocular pressure (IOP) control were included. The main outcome measure was the percentage reduction in IOP. Complete success was defined as IOP reduction > 20% from baseline after 12 months or reduction in the number of AGM. Qualified success was defined as > 20% IOP reduction at 12 months with AGM. Secondary outcomes were occurrence of adverse events and factors predicting treatment outcomes. A total of 104 eyes of 62 Indian patients underwent SLT for OAG. Eighty-three (79.81%) eyes were treatment-naïve, and 21 (20.19%) eyes were on AGM. The median (IQR) baseline IOP was 20 (16-26) mmHg. At 12 months, the median IOP was 16 (4-19) mmHg, the median decrease in IOP was 4 (0-6.5) mmHg, and the percentage reduction in IOP was 17.42% (0%-30.76%). Maximum IOP reduction was noted at 12 months. Overall, success was achieved in 48 (46.15%) patients. Five eyes (4.8%) experienced minor SLT-related complications. Age, gender, prior use of AGM, type of OAG, and higher baseline IOP were not found to be predictive factors for treatment outcome. SLT was found to be a relatively safe and effective procedure in Indian eyes with OAG.