Risk Factors for Visual Field Progression in the Low-pressure Glaucoma Treatment Study
CARLOS GUSTAVO DE MORAES, JEFFREY M. LIEBMANN, DAVID S. GREENFIELD, STUART K. GARDINER, ROBERT RITCH, AND THEODORE KRUPIN, ON BEHALF OF THE LOW-PRESSURE GLAUCOMA TREATMENT STUDY GROUP To investigate risk factors associated with visual ﬁeld progression in the Low-pressure Glaucoma Treatment Study, a prospective trial designed to compare the effects of the alpha2-adrenergic agonist brimonidine tartrate 0.2% to the beta-adrenergic antagonist timolol maleate 0.5% on visual function in low-pressure glaucoma. ● DESIGN: Prospective cohort study. ● METHODS: Low-pressure Glaucoma Treatment Study patients with >5 visual ﬁeld tests during follow-up were included. Progression was determined using pointwise linear regression analysis, deﬁned as the same 3 or more visual ﬁeld locations with a slope more negative than 1.0 dB/year at P < 5%, on 3 consecutive tests. Ocular and systemic risk factors were analyzed using Cox proportional hazards model and further tested for independence in a multivariate model. ● RESULTS: A total of 253 eyes of 127 subjects (mean age, 64.7 10.9 years; mean follow-up, 40.6 12 months) were analyzed. Eyes randomized to timolol progressed faster than those randomized to brimonidine (mean rates of progression, 0.38 0.9 vs 0.02 0.7 dB/y, P < .01). In the ﬁnal multivariate model adjusting for all tested covariates, older age (hazard ratio [HR] 1.41/decade older, 95% conﬁdence interval [CI] 1.05 to 1.90, P .022), use of systemic antihypertensives (HR 2.53, 95% CI 1.32 to 4.87, P .005), and mean ocular perfusion pressure (HR 1.21/mm Hg lower, 95% CI 1.12 to 1.31, P < .001) were associated with progression whereas randomization to brimonidine revealed a protective effect (HR 0.26, 95% CI 0.12 to 0.55, P < .001). ● CONCLUSIONS: While randomization to brimonidine 0.2% was protective compared to timolol 0.5%, lower
Accepted for publication April 24, 2012. From the Einhorn Clinical Research Center, New York Eye and Ear Inﬁrmary, New York, New York (C.G.D.M., J.M.L., R.R.); Department of Ophthalmology, New York University School of Medicine, New York, New York (C.G.D.M., J.M.L.); Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Palm Beach Gardens, Florida (D.S.G.); Devers Eye Institute, Legacy Health, Portland, Oregon (S.K.G.); Department of Ophthalmology, New York Medical College, Valhalla, New York (R.R.); Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (T.K.); and The Chicago Center for Vision Research, Chicago, Illinois (T.K.). Inquiries to Carlos Gustavo De Moraes, 310 East 14th St, New York, NY 10003; e-mail: [email protected]
mean ocular perfusion pressure increased the risk for reaching a progression outcome in the Low-pressure Glaucoma Treatment Study. This suggests that the beneﬁcial effect of randomization to the brimonidine arm was independent of possible differences in ocular perfusion pressures between the 2 treatment arms. The current results and large number of drop-outs in the brimonidine 0.2% arm suggest that more research is necessary before altering clinical practice paradigms. (Am J Ophthalmol 2012;154:702–711. © 2012 by Elsevier Inc. All rights reserved.)
terized by structural and functional abnormalities of the optic nerve.1–3 Even though intraocular pressure (IOP) is the most important modiﬁable risk factor for disease onset and progression,4 – 8 glaucoma can exist even among individuals for whom IOP measurements are within the statistically deﬁned “normal range.”9 –12 Although an artiﬁcial construct, low-pressure (normal-tension, normal-pressure, or low-tension) glaucoma is a widely used term to classify the disease in patients with glaucomatous optic neuropathy with or without visual ﬁeld loss whose pressures are within the 95th percentile of the normal distribution of IOP measurements in the healthy population (IOP 22 mm Hg using Goldmann applanation tonometry).9 The Low-pressure Glaucoma Treatment Study13–15 is a multicenter, double-masked, prospective, randomized clinical trial that aimed to investigate visual ﬁeld outcomes in low-pressure glaucoma patients treated with either a topical beta-adrenergic antagonist (timolol maleate 0.5%) or alpha2-adrenergic agonist (brimonidine tartrate 0.2%). The results of this trial revealed that subjects randomized to topical brimonidine 0.2% had better preservation of visual function than those receiving timolol 0.5% despite similar IOP levels.15 It is unclear, however, whether this outcome was attributable to different mechanisms of drug action or whether other risk factors, including IOP, also played a signiﬁcant role. In the present study, we investigated baseline and intercurrent risk factors for visual ﬁeld progression among participants enrolled in the Low-pressure Glaucoma Treatment Study.
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LAUCOMA IS A PROGRESSIVE DISORDER CHARAC-
ELSEVIER INC. ALL
PATIENTS AND METHODS
THE METHODOLOGY OF THE LOW-PRESSURE GLAUCOMA
Treatment Study, including baseline characteristics and study design, has been described in detail elsewhere.13–15 In brief, the Low-pressure Glaucoma Treatment Study Group was a multicenter, prospective clinical trial in which patients were randomized to treatment with topical brimonidine tartrate 0.2% vs timolol maleate 0.5%. The institutional review boards at all 13 participating centers approved the study protocol and informed consent was obtained.
● INCLUSION AND EXCLUSION CRITERIA: Study patients had previously diagnosed low-pressure glaucoma that fulﬁlled the following eligibility criteria: all known untreated IOP 21 mm Hg; open iridocorneal angles; at least 2 reproducible visual ﬁelds with glaucomatous defects in 1 or both eyes on automated perimetry (Humphrey Field Analyzer; Carl Zeiss Meditec, Inc, Dublin, California, USA), with the location of the ﬁeld defect being consistent with the photographic appearance of the optic nerve head; and age 30 years. To determine eligibility based on IOP, all patients receiving IOP-lowering treatment underwent a 4-week washout without therapy. Baseline IOP (measured with a calibrated Goldmann applanation tonometer) had to be 21 mm Hg in both eyes with 5 mm Hg difference between the eyes on an ofﬁce diurnal curve (8:00 AM, 10:00 AM, 12:00 PM, 4:00 PM) assessed prior to randomization. Ocular exclusion criteria included the following: a history of IOP 21 mm Hg in the patient record, bestcorrected visual acuity worse than 20/40 in either eye, a history of angle closure or an occludable angle by gonioscopy, prior glaucoma incisional surgery, inﬂammatory eye disease, prior ocular trauma, diabetic retinopathy or other diseases capable of causing visual ﬁeld loss or optic nerve deterioration, extensive glaucomatous visual ﬁeld damage with a mean deviation worse than 16 decibels (dB), or a clinically determined threat to central ﬁxation in either eye. Systemic exclusion criteria included a resting pulse 50 beats/minute; severe or uncontrolled cardiovascular, renal, or pulmonary disease that would preclude safe administration of a topical beta-adrenergic antagonist; and a prior myocardial infarction or stroke. Continuation of systemic medications that could affect IOP was allowed as long as the doses remained constant throughout the trial. ● RANDOMIZATION, TREATMENT, AND MASKING:
higher patient attrition in the brimonidine group attributable to an expected rate of adverse events of approximately 20%, randomization and delivery of medications (provided by Allergan, Inc, Irvine, California, USA) to the sites were stratiﬁed in blocks of 7 (4 to brimonidine and 3 to timolol). The randomization list was maintained and masked study medications were provided in new 10-mL white bottles labeled with the assigned randomization number directly to the clinical centers by an independent pharmacy (Fountain Valley Cancer Center Pharmacy, Fountain Valley, California, USA). Ocular treatment other than the study medication was not permitted. Investigators, patients, and the visual ﬁeld reading and coordinating centers were all masked to patient assignment. Endpoints requiring discontinuation from the study included: treated IOP 21 mm Hg that was repeated within 1 month, safety concern as judged by the treating physician, symptomatic ocular allergic adverse events (hyperemia, pruritus, stinging, and/or conjunctival folliculosis) requiring medication cessation, retinal events that could alter visual acuity or visual ﬁeld (eg, age-related macular degeneration), the occurrence of systemic (eg, respiratory or cardiovascular) adverse events that prevented the administration of topical timolol, nonocular intolerable events associated with topical brimonidine (eg, xerostomia, fatigue, drowsiness), or if the patient moved or declined continued participation. Collection of data from discontinued patients ceased at their ﬁnal study visit. Data up to this point were included in the analysis, but discontinued patients were no longer followed as part of the study.
● STUDY VISITS: Patients were examined at 1 and 4 months after initiation of treatment. Subsequent visits were at 4-month ( 2 weeks) intervals. Pre- and postrandomization morning visits recorded the following: ocular and systemic history, blood pressure, pulse, corrected visual acuity, IOP, slit-lamp examination, and optic disc evaluation for cup-to-disc ratio and the presence or absence of disc hemorrhage. Gonioscopy and stereoscopic optic disc photographs were performed annually. Fullthreshold standard achromatic perimetry (Humphrey 24-2) visual ﬁeld was performed at 4-month intervals according to protocol guidelines.
Patients were randomly assigned to receive monotherapy with either brimonidine tartrate 0.2% containing benzalkonium chloride (Alphagan; Allergan, Inc, Irvine, California, USA) or timolol maleate 0.5% containing benzalkonium chloride (Timoptic; Merck & Co Inc, West Point, Pennsylvania, USA) twice daily in both eyes, including the morning before each visit. To allow for RISK FACTORS
The main outcome measure was visual ﬁeld progression in 1 eye as determined by pointwise linear regression.15 Visual ﬁeld progression analysis was performed using Progressor software (Medisoft, Inc, Leeds, UK).16 Visual ﬁeld analyses were performed by an independent reading center (Devers Eye Institute, Legacy Health System, Portland, Oregon, USA) masked to the treatment assignment. Linear regression of the sensitivity (in dB) was performed at each test location to obtain the rate of change at that location, based on all ﬁelds up to and including the last examination. Default Progressor criteria 703
● OUTCOME MEASURES:
VOL. 154, NO. 4
TABLE 1. Low-pressure Glaucoma Treatment Study: Comparison of Clinical Characteristics Between Patients Randomized to Timolol Maleate 0.5% and Brimonidine Tatrate 0.2%a
Timolol (n 69) Brimonidine (n 58)
Age (years) Sex (male/female) Follow-up time (months) Positive family history for glaucoma (%) Use of systemic antihyptertensives (%) Use of systemic beta-blockers (%) Treatment for diabetes mellitus (%) Positive history of migraine (%) Positive history of Raynaud phenomenon (%) Spherical equivalent (diopters) Lens status (per eye) (pseudophakic eyes, %) At least 1 disc hemorrhage detected (%) Number of eyes with recurrent disc hemorrhages Cup-to-disc ratio Central corneal thickness ( m) Untreated diurnal curve IOP (mm Hg) Mean Peak Fluctuation Treated follow-up IOP (mm Hg) Mean Peak Fluctuation Mean % IOP reduction from baseline (%) Baseline blood pressure (mm Hg) Systolic Diastolic Follow-up blood pressure (mm Hg) Mean systolic Mean diastolic Fluctuation systolic Fluctuation diastolic Mean ocular perfusion pressure (mm Hg) Average follow-up Fluctuation follow-up Heart rate (beats/min) Follow-up mean Follow-up ﬂuctuation IOP intraocular pressure. a All data are presented as mean b Independent samples t test. c Fisher exact test.
65.2 10.8 26/43 41.1 11.6 25 (36) 32 (46) 11 (16) 6 (8) 3 (4) 10 (14) 0.64 2.6 10 (7) 12 (8) 10 (7) 0.72 0.1 547.8 38.6 15.2 16.7 1.28 13.9 16.4 1.59 8 132.3 76.9 128.7 75.8 10.9 6.4 48.4 3.7 66.0 5.68 2.5 2.7 0.7 2.3 2.6 0.5 10 17.0 9.2 13.1 6.9 6.1 3.8 5.5 2.7 6.7 3.3
63.3 11.1 27/31 40.4 12.4 17 (29) 24 (41) 6 (10) 11 (18) 6 (10) 5 (8) 0.55 2.2 16 (13) 6 (5) 3 (2) 0.67 0.1 540.6 29.0 16.2 17.7 1.37 14.1 17.0 1.86 12 128.9 74.7 129.4 74.5 10.9 6.2 47.7 3.2 70.9 6.26 1.9 2.0 0.6 1.9 2.3 0.6 10 18.2 10.7 14.0 7.9 5.6 3.3 5.8 2.4 10.1 3.5
.18b .36c .68b .45c .59c .43c .11c .29c .41c .78b .08c .33c .15c .03b .10b .01b .04b .30b .38b .03b .01b .01b .13b .08b .68b .14b .95b .55b .32b .19b .01b .18b
standard deviation unless otherwise speciﬁed.
were used to deﬁne a signiﬁcant negative slope (at least 1.0 dB/year for inner points and 2.0 dB/year for edge points) at the P 5% level.15–17 Edge points for the Humphrey 24-2 ﬁeld included the 2 outer nasal locations, 1 above and 1 below the horizontal. Criteria for visual ﬁeld progression required conﬁrmation at the next 2 examinations of a signiﬁcant negative slope at the same 3 or more test locations. For eyes not reaching a progression endpoint, we used the time to last follow-up visit (either the 704 AMERICAN JOURNAL
ﬁnal scheduled visit or the censored one). Progressing visual ﬁeld locations were not required to be contiguous. Because of these criteria, progression could not be determined until 5 visual ﬁeld tests had been collected (the 16-month visit). Consequently, for the purposes of this manuscript, only those eyes with enough visual ﬁeld tests to determine a progression outcome (yes/no) were included in the analysis (1 at baseline plus 4 tests following randomization). OPHTHALMOLOGY OCTOBER
We examined clinical characteristics that predicted the development of visual ﬁeld progression. The following demographic and ocular parameters were investigated: age at baseline, sex, family history of glaucoma, central corneal thickness (CCT), cup-to-disc ratio (estimated during slitlamp examination), refractive error spherical equivalent (SE), and lens status. Pre-randomization data collected and investigated for risk assessment were: IOP mean, peak, and ﬂuctuation during the diurnal curve; baseline pulse; systolic (SBP) and diastolic blood pressure (DBP); presence of systemic comorbidities (migraine, Raynaud phenomenon, systemic hypertension, and diabetes mellitus); and use of systemic medications (categorized as systemic antihypertensives, systemic beta-blockers, and antidiabetic agents). Post-randomization variables consisted of series length (ie, follow-up time), detection of at least 1 optic disc hemorrhage on stereophotographs any time during follow-up, and mean, peak, and ﬂuctuation of IOP and blood pressure during follow-up. For numerical variables, the mean was calculated by averaging all values recorded during the follow-up period. Fluctuation was deﬁned as the standard deviation (SD) of all measurements in the same interval. Mean ocular perfusion pressure (MOPP) was estimated by the equation MOPP 2/3 [DBP 1/3 (SBP – DBP)] – IOP.18 Data on systemic comorbidities and medications were obtained from participants’ self-reports. Descriptive statistics are presented with frequency tables and graphs, whereas estimates of center and dispersion are described as mean and SD, respectively. Cox proportional hazards model was used to investigate the risk of progression (progression: yes or no, based on the progression criteria described above) based on follow-up time (progression endpoint or data censoring for progressing and nonprogressing eyes, respectively). Variables with P .10 in the univariate model were entered in a multivariate model. Generalized estimating equations were used to control for inter-eye relationships.19 Since one of the assumptions of regression analyses is that the predictors should not be strongly and signiﬁcantly correlated with one another (ie, no colinearity),20 if pairs of predictor variables had moderate to strong signiﬁcant correlation, the variable with the most signiﬁcant P value in the univariate analysis was entered in the multivariate model. Cox proportional hazards multivariate model was performed using a backward elimination approach based on likelihood ratios. Variables in the saturated multivariate model with P .10 were subsequently removed and variables were entered in the model if P .05. Alpha level was set at 5% (2-sided) and computerized statistical analyses were performed using SPSS for Windows (version 16.1; IBM SPSS Statistics Inc, Armonk, New York, USA). VOL. 154, NO. 4 RISK FACTORS
FIGURE 1. Low-pressure Glaucoma Treatment Study: Comparison of mean deviation (MD) rates of change (dB/y) between progressing (light gray) and nonprogressing eyes (dark gray) based on the pointwise linear regression criteria. The black curve corresponds to Gaussian curves based on the estimates from study patients.
● STATISTICAL ANALYSIS:
FIGURE 2. Low-pressure Glaucoma Treatment Study: Comparison of mean deviation (MD) rates of change (dB/y) between eyes on timolol 0.5% (dark gray) and brimonidine 0.2% (light gray). The black curve corresponds to Gaussian curves based on the estimates from study patients.
ONE HUNDRED NINETY-THREE PATIENTS WERE ASSESSED
for eligibility in the Low-pressure Glaucoma Treatment Study, of which 178 were randomized to treatment with either timolol or brimonidine. The characteristics of these patients are described in detail elsewhere.13–15 Of those, 253 eyes of 127 subjects (mean age, 64.7 10.9 years; 705
TABLE 2. Low-pressure Glaucoma Treatment Study: Cox Proportional Hazards Univariate Analysis Testing the Association Between Each Variable and the Hazards of Visual Field Progression Based on Pointwise Linear Regression Criteria
Parameter HR 95% Conﬁdence Interval P Value
Randomization (brimonidine) Age (per decade older) Sex (female) Positive family history for glaucoma Use of systemic antihypertensives Use of systemic beta-blockers Treatment for diabetes mellitus Positive history of migraine Positive history of Raynaud phenomenon Spherical equivalent (per diopter more positive) Lens status (pseudophakic) Disc hemorrhage detection Cup-to-disc ratio (per 0.1-unit increase) Central corneal thickness (per m thicker) Heart rate (beats/min, per unit higher) Follow-up mean Follow-up ﬂuctuation HR hazard ratio.
0.29 1.21 1.48 1.04 1.65 1.71 0.79 0.33 0.83 1.00 0.41 2.14 1.16 1.00 0.98 0.95
0.14 to 0.58 0.90 to 1.62 0.82 to 2.69 0.57 to 1.90 0.63 to 2.91 0.85 to 3.43 0.31 to 2.02 0.04 to 2.46 0.30 to 2.32 0.89 to 1.11 0.10 to 1.70 0.90 to 5.08 0.95 to 1.41 0.99 to 1.01 0.95 to 1.02 0.86 to 1.04
.001 .078 .192 .882 .082 .131 .629 .284 .732 .964 .222 .082 .127 .212 .552 .333
TABLE 3. Low-pressure Glaucoma Treatment Study: Cox Proportional Hazards Univariate Analysis Testing the Association Between Intraocular Pressure and Blood Pressure Parameters and the Hazards of Visual Field Progression Based on Pointwise Linear Regression Criteria
Parameter Progression Stable HR 95% Conﬁdence Interval P Value
Untreated baseline diurnal IOP (per mm Hg higher) Mean Peak Fluctuation Treated follow-up IOP (per mm Hg higher) Mean Peak Fluctuation Mean % IOP reduction from baseline (per 0.1% greater) Baseline blood pressure (per mm Hg lower) Systolic Diastolic Follow-up blood pressure Mean systolic (per mm Hg lower) Mean diastolic (per mm Hg lower) Fluctuation systolic (per mm Hg higher) Fluctuation diastolic (per mm Hg higher) Mean ocular perfusion pressure Baseline (per mm Hg higher) Average follow-up (per mm Hg lower) Fluctuation follow-up (per mm Hg higher) HR hazard ratio; IOP intraocular pressure.
15.8 17.4 1.38 13.9 16.6 1.38 11 130.9 75.9 125.5 73.1 11.7 6.9 47.1 46.4 4.0
2.6 2.3 0.8 2.0 2.2 0.8 10 18.3 9.3 11.8 5.3 6.2 3.5 7.1 4.6 2.5
15.6 17.7 1.31 14.0 16.7 1.31 9 130.7 76.0 129.8 75.7 10.7 6.2 47.4 48.4 3.4
2.2 2.8 0.6 2.2 2.6 0.6 10 17.5 10.1 13.8 7.7 5.8 3.6 8.0 5.8 2.6
1.05 1.00 1.15 1.00 1.00 1.06 1.08 0.99 0.99 1.02 1.08 1.03 1.04 0.98 1.10 1.08
0.92 to 1.19 0.96 to 1.04 0.79 to 1.67 0.88 to 1.13 0.90 to 1.11 0.67 to 1.70 0.91 to 1.29 0.98 to 1.01 0.96 to 1.02 1.01 to 1.05 1.03 to 1.13 0.98 to 1.08 0.96 to 1.13 0.94 to 1.01 1.04 to 1.17 0.96 to 1.22
.437 .903 .462 .926 .991 .780 .343 .740 .508 .016 .001 .228 .286 .31 .001 .196
women, 58%; European ancestry, 71%) had at least 5 visual ﬁeld tests and met the inclusion and exclusion criteria for this study. The following results, therefore, refer to this subset of eyes with the minimum number of ﬁelds 706 AMERICAN JOURNAL
required for PLR trend analysis.21 Table 1 shows the clinical characteristics of this population. Of the 127 participants, 69 (54%) were randomized to timolol and 58 (46%) to brimonidine (P .20). FortyOPHTHALMOLOGY OCTOBER
TABLE 4. Low-pressure Glaucoma Treatment Study: Cox Proportional Hazards Multivariate Model Using a Backward Elimination Approach Based on Likelihood Ratiosa
Parameter HR 95% Conﬁdence Interval P Value
Randomization (brimonidine) Age (per decade older) Use of systemic antihypertensives Mean ocular perfusion pressure during follow-up (per mm Hg lower) HR hazard ratio. Variables were entered in the model if P model.
0.26 1.41 2.53 1.21
0.12 to 0.55 1.05 to 1.90 1.32 to 4.87 1.12 to 1.31
.001 .022 .005 .001
.05 and removed if P
.10 in the saturated multivariate
eight eyes (48/253; 19%) of 40 patients (40/127; 31%) met the predeﬁned PLR progression criteria (31 patients randomized to timolol; 9 patients randomized to brimonidine, P .01, Fisher exact test). Patients were followed for a mean of 40.6 12 months. As expected, the rate of mean deviation (MD) change (dB/y) was signiﬁcantly faster in eyes that met our progression criteria than in those that did not ( 0.87 0.7 vs 0.04 0.8 dB/y, P .01). Figures 1 and 2 show the distribution of MD rates of change between progressing and nonprogressing eyes, as well as between the timolol ( 0.38 0.9 dB/y) and brimonidine (0.02 0.7 dB/y) groups, respectively (P .01). In this subset of participants with at least 5 visual ﬁeld tests, eyes on brimonidine had signiﬁcantly higher diurnal mean and peak IOP measurements prior to treatment randomization (respectively, 16.2 1.9 vs 15.2 2.5 mm Hg, P .01; and 17.7 2.0 vs 16.7 2.7 mm Hg, P .04) even though treated mean pressures during follow-up were similar between the 2 groups (14.1 1.9 vs 13.9 2.3 mm Hg, P .38). However, eyes on brimonidine had statistically greater IOP ﬂuctuation (1.86 0.6 vs 1.59 0.5 mm Hg, P .01) and higher peaks (17.0 2.3 vs 16.4 2.6 mm Hg, P .03) during follow-up. Univariate analysis (Tables 2 and 3) revealed the following variables to be associated with visual ﬁeld progression at P .25: age, lens status, use of systemic antihypertensives, use of systemic beta-adrenergic antagonists, disc hemorrhage, cup-to-disc ratio, CCT, mean SBP during follow-up, mean DBP during follow-up, SBP ﬂuctuation, MOPP during follow-up, ocular perfusion pressure ﬂuctuation, baseline heart rate, and randomization. To investigate whether an interaction between randomization and MOPP signiﬁcantly inﬂuenced the model, an interaction term (MOPP randomization) was included in the multivariate model. However, this variable did not reach statistical signiﬁcance in the model (HR 1.03/mm Hg, 95% conﬁdence interval [CI] 0.88 to 1.19, P .69). We also tested the interaction between IOP mean, peak, and ﬂuctuation and treatment randomization to investigate if the impact of IOP on visual ﬁeld progression differed between patients assigned to timolol or brimonidine. We VOL. 154, NO. 4 RISK FACTORS
found no signiﬁcant association between the interaction terms and progression (mean IOP randomization, hazard ratio [HR] 0.75/mm Hg, 95% CI 0.535 to 1.076, P .12; peak IOP randomization, HR 0.82/mm Hg, 95% CI 0.62 to 1.08, P .17; IOP ﬂuctuation randomization, HR 1.26/mm Hg, 95% CI 0.49 to 3.23, P .62). There was signiﬁcant correlation between the following pairs of variables: average MOPP vs mean follow-up IOP (r 0.36, P .001); average MOPP vs mean follow-up SBP (r 0.75, P .001); average MOPP vs mean follow-up DBP (r 0.78, P .001); average MOPP vs MOPP ﬂuctuation (r 0.16, P .01); and mean follow-up SBP vs mean follow-up DBP (r 0.40, P .001). Given this signiﬁcant association among related variables and its more signiﬁcant association with progression in the univariate analysis, we opted to include MOPP in the multivariate analysis to circumvent colinearity. In the multivariate analysis (Table 4), older age (HR 1.41/decade older, 95% CI 1.05 to 1.90, P .022), use of systemic antihypertensives (HR 2.53, 95% CI 1.32 to 4.87, P .005), and lower MOPP during follow-up (HR 1.21/mm Hg, 95% CI 1.12 to 1.31, P .001) were associated with increased risk of progression, whereas randomization to brimonidine was signiﬁcantly associated with decreased risk of progression (HR 0.26, 95% CI 0.12 to 0.55, P .001).
THE PURPOSE OF THIS STUDY WAS TO IDENTIFY RISK FAC-
tors for progression in the Low-pressure Glaucoma Treatment Study. We found a signiﬁcant association between the use of topical timolol maleate 0.5% and the risk of progression in patients with low-pressure glaucoma compared to the use of brimonidine tartrate 0.2%, which was independent from other known risk factors for glaucoma progression (eg, disc hemorrhage, older age, and lower systemic blood pressure) despite similar mean IOP during follow-up. This ﬁnding suggests that brimonidine may 707
have an effect on IOP-independent mechanisms that decrease or delay the rate of visual ﬁeld deterioration in patients with glaucoma associated with IOPs in the statistically normal range and that this effect is independent of ocular perfusion pressure. The differentiation between low- and high-pressure glaucoma is arbitrary. One of the limitations of this classiﬁcation is the fact that it overlooks the continuum of IOP measurements and sets an arbitrary cut-off value to deﬁne a multifactorial optic neuropathy. It also disregards the sources of error (limitations of the technique itself and inﬂuence of CCT and corneal curvature, for instance)22,23 and variability (related to the circadian rhythm and long-term ﬂuctuation)24,25 of IOP measurements. These limitations notwithstanding, numerous studies have described evidence suggesting clinical differences between patients whose pressure lies above or below this arbitrary cut-off value.26 –29 For instance, low-pressure glaucoma appears to be more common among women and myopic individuals,9,12 may affect the central/paracentral visual ﬁeld more often,27–29 and is more commonly associated with systemic conditions such as migraine and Raynaud phenomenon;12,30 and disc hemorrhages may be detected more often.12,17 We determined that a lower MOPP during follow-up was signiﬁcantly associated with visual ﬁeld progression in our model and this effect was not signiﬁcantly affected by other covariates, such as use of systemic antihypertensives and randomization arm (Table 4). An imbalance between IOP mechanical stress and blood supply leads to hypoxia, which may be responsible, at least partially, for axonal damage and retinal ganglion cell death.30 Even though the calculation of estimated MOPP is subject to criticism—it extrapolates the mean arterial pressure measured in the brachial artery to be the same as that in the ophthalmic artery and disregards the effects of changes in body position during the day and night—it appears to be a relatively robust estimator of the effects of low systemic blood pressure on the optic nerve.5,30,31 In consonance with our ﬁndings, the Early Manifest Glaucoma Trial (EMGT)5 and the Barbados Eye Study (BES)32 found a signiﬁcant association between low systemic blood pressure and the risk of progressive and incident glaucoma, respectively. Also, the role of lower systolic perfusion pressure in the EMGT was signiﬁcant in the group with lower baseline IOP but not in the group with higher measurements,5 which supports our hypothesis that for eyes with statistically low IOP, IOPindependent risk factors may be more relevant predictors of progression. By examining the interaction between randomization group and MOPP, our data support the notion that the more detrimental effect of timolol on visual ﬁeld outcomes compared with brimonidine in low-pressure glaucoma is independent of its effect on perfusion pressure, as had been previously postulated.33,34 It is possible, however, that overtreatment of systemic hypertension may be injurious 708 AMERICAN JOURNAL
to the MOPP, similarly to what has been reported in internal medicine.35–37 Patients who are overtreated for systemic hypertension—sometimes because of the alleged “white-coat hypertension”—are at increased risk of coronary ischemia and mortality.36 This phenomenon is graphically represented as a “J” curve in which there is an upturn of cardiac problems and death at both low and high blood pressure.35 Low blood pressure leads to compensatory vasoconstriction of peripheral organs and tissues38,39—in the eye, the retinal and choroidal circulation—and reduction of the true MOPP, as opposed to the estimated (brachial) MOPP. An increase in vascular resistance diminishes blood ﬂow to the optic nerve head, which is a watershed zone.40 Nevertheless, it is important to stress that our study did not aim to investigate the speciﬁc role of systemic antihypertensives on glaucoma progression, as we did not collect information on the dosage, length of treatment, and 24-hour blood pressure monitoring of these patients. Future studies ought to speciﬁcally address the interaction between overtreatment of systemic hypertension and MOPP and whether there could be a deleterious effect on glaucomatous neurodegeneration. In consonance with ﬁndings of the randomized clinical trials in glaucoma,4,5,7,8 older age was a signiﬁcant predictor of visual ﬁeld progression in the present study. In the multivariate analysis, the risk of progression increased by 43% for each decade older. The EMGT also found a more signiﬁcant role of older age in the group of patients with lower baseline IOP—resembling low-pressure glaucoma patients—when compared to those with more elevated IOP.5 Once IOP is lowered to a certain level, it is possible that other IOP-independent factors (such as age) become more signiﬁcant. Aging is associated to longer exposure to exogenous hazards and systemic comorbidities, and may increase the susceptibility of the optic nerve complex to IOP stress. We did not ﬁnd a signiﬁcant association between IOP or CCT and visual ﬁeld progression in this cohort. This ﬁnding is not likely to be attributable to a confounding effect of more aggressive treatment of eyes with higher IOP or decreased CCT, given the standardized treatment protocol followed in this trial. Nonetheless, the Collaborative Normal-Tension Glaucoma Study Group12 found a significant role of IOP even in a population of patients with low IOP. Our results should not be compared with that trial, given that their comparison was between treated and untreated arms, whereas all patients in our study were treated. Also, we only performed pretreatment diurnal curves and the role of short- and long-term IOP variability was not taken into account in our analyses. Despite these considerations, it is possible that once the IOP is reduced to low values, as in this study (mean follow-up IOP was 14 mm Hg), the importance of other risk factors may become either more apparent or important for determining progression. Moreover, by investigating the interaction between randomization and mean follow-up IOP on OPHTHALMOLOGY OCTOBER
progression, our ﬁndings suggest that it is unlikely that the different outcomes we observed between patients treated with timolol or brimonidine were attributable to different effects of these drugs on daytime IOP. The lack of data on the effect of each drug on nighttime or early-morning IOP prevents us from concluding whether the different outcomes could be attributable to different effectiveness in dampening the circadian IOP variation. Previous studies have shown similar effectiveness of both drugs in lowering the IOP even when assessed with diurnal curves. Also, it has been shown that both timolol and brimonidine have limited effectiveness for lowering nocturnal IOP in the supine position.41– 43 It is particularly interesting that the brimonidine group had higher untreated mean and peak IOP at baseline as well as higher peak and ﬂuctuation during follow-up and still progressed at slower rates than the timolol group. Despite being statistically signiﬁcant, it is controversial whether such small differences ( 1.0 mm Hg) are clinically signiﬁcant, especially when looking at pooled data. Despite the observed protective effect of brimonidine compared to timolol in patients with low-pressure glaucoma, the incidence of adverse reaction to brimonidine was higher than for timolol. This caused the average follow-up time in the study to be reduced below that planned. Development of alternative neuroprotective agents with fewer adverse effects would be desirable. This observation notwithstanding, patients on brimonidine who did not develop signiﬁcant ocular allergy progressed at slower rates than those on timolol in the present cohort. In
addition, for those patients who tolerated brimonidine well, the risk of progression was reduced independently of other demographic or physiologic factors. Furthermore, for this ancillary analysis of the Low-pressure Glaucoma Treatment Study, we selected a subset of patients with at least 5 visual ﬁeld tests during follow-up, which ended up leading to signiﬁcant baseline differences between treatment groups—which was not observed in our previous publication including all participants.15 This limitation notwithstanding, all analyses were adjusted for these potential confounders and we were unable to identify their signiﬁcant role in the rates of progression in both the univariate and multivariate models. In summary, treatment of low-pressure glaucoma with topical brimonidine 0.2% preserved the visual ﬁeld better than topical timolol 0.5% in the Low-pressure Glaucoma Treatment Study, despite similar mean IOP during the study. Lower MOPP and use of systemic antihypertensives were also independently associated with disease progression. These ﬁndings suggest that the beneﬁcial effect of brimonidine compared to timolol in the current study was attributable to factors other than any differences in IOP control or differences in ocular perfusion, and is consistent with a neuroprotective effect in the brimonidine arm. This last hypothesis needs to be conﬁrmed with additional study before this information can be used to suggest changes to current glaucoma treatment paradigms. Lastly, MOPP may be an additional modiﬁable risk factor that deserves additional research and clinical attention.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF Interest. Financial disclosures: C.G. De Moraes: grant support, Edith C. Blum Foundation, New York Glaucoma Research Institute; JM Liebmann: consultant/advisor, Alcon Laboratories, Inc; Allergan, Inc; Diopsys Corporation; Merz Pharmaceuticals, Inc; Optovue, Inc; Quark Pharmaceuticals, Inc; Topcon Medical Systems; grant support, Carl Zeiss Meditec, Diopsys Corporation, Heidelberg Engineering, National Eye Institute, New York Glaucoma Research Institute, Optovue, Topcon Medical Systems; D.S. Greenﬁeld: consultant/advisor, Allergan, Inc; Alcon, Inc; Topcon, Inc; Merz; SOLX; grant support, National Eye Institute, Carl Zeiss Meditec, Optovue, Heidelberg Engineering; R Ritch: consultant/advisor, iSonic, Aeon Astron, Drais Pharmaceutical, Medacorp; lecture fees: Pﬁzer, Merck; patents/royalty, Ocular Instruments, Inc.; T Krupin: consultant/advisor, Allergan, Inc. Publication of this article was supported by funding provided by Allergan, Inc, Irvine, California; the Chicago Center for Vision Research, Chicago, Illinois; Research to Prevent Blindness, Inc, New York, New York; and Ralph and Sylvia Ablon Research Fund of the New York Glaucoma Research Institute, New York, New York. Study medications were provided by Allergan, Inc. Dr De Moraes is the Edith C. Blum Foundation Research Scientist, New York Glaucoma Research Institute, New York, New York. Involved in design and conduct of the study (T.K., R.R., J.M.L., D.S.G.); collection, management, analysis, and interpretation of the data (T.K., R.R., J.M.L., D.S.G., S.K.G., C.G.D.M.); and preparation, review, or approval of the manuscript (T.K., R.R., J.M.L., D.S.G., S.K.G., C.G.D.M.). The institutional review boards at all 13 participating centers approved the prospective study protocol and patients gave informed consent to participate in this research study. Clinical trial (www.clinicaltrials.gov) ID: NCT00317577. MEMBERS OF THE LOW-PRESSURE GLAUCOMA STUDY GROUP University Eye Specialists, Chicago, Illinois. Theodore Krupin, Lisa F. Rosenberg, Jon M. Ruderman, and John W. Yang. New York Eye & Ear Inﬁrmary, New York, New York. Celso Tello, Jeffrey M. Liebmann, and Robert Ritch. Wills Eye Hospital, Philadelphia, Pennsylvania. Jonathan S. Myers, L. Jay Katz, George L. Spaeth, Richard P. Wilson, and Marlene R. Moster. Indiana University, Indianapolis, Indiana. Louis B. Cantor. Cullen Eye Institute, Baylor College, Houston, Texas. Ronald L. Gross. Private Practice, Rapid City, South Dakota. Monte S. Dirks. Brooke Army Medical Center, San Antonio, Texas. Steven R. Grimes. Bascom Palmer Eye Institute, University of Miami School of Medicine, Palm Beach Gardens, Florida. David S. Greenﬁeld and Harmohina Bagga. University of Florida–Gainesville, Gainesville, Florida. Mark B. Sherwood. University of Chicago, Chicago, Illinois. Marianne E. Feitl. Little Rock Eye Clinic, Little Rock, Arkansas. J. Charles Henry. Wheaton Eye Clinic, Wheaton, Illinois. David K. Gieser. Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania. Jody R. Piltz-Seymour.
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REPORTING VISUAL ACUITIES
The AJO encourages authors to report the visual acuity in the manuscript using the same nomenclature that was used in gathering the data provided they were recorded in one of the methods listed here. This table of equivalent visual acuities is provided to the readers as an aid to interpret visual acuity ﬁndings in familiar units.
Table of Equivalent Visual Acuity Measurements
Snellen Visual Acuities 4 Meters 6 Meters 20 Feet Decimal Fraction LogMAR
4/40 4/32 4/25 4/20 4/16 4/12.6 4/10 4/8 4/6.3 4/5 4/4 4/3.2 4/2.5 4/2
6/60 6/48 6/38 6/30 6/24 6/20 6/15 6/12 6/10 6/7.5 6/6 6/5 6/3.75 6/3
20/200 20/160 20/125 20/100 20/80 20/63 20/50 20/40 20/32 20/25 20/20 20/16 20/12.5 20/10
0.10 0.125 0.16 0.20 0.25 0.32 0.40 0.50 0.63 0.80 1.00 1.25 1.60 2.00
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0.1 0.2 0.3
From Ferris FL III, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. Am J Ophthalmol 1982;94:91–96.
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