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Glaucoma Surgery Calculator: Limited Additive Effect of Phacoemulsification on Intraocular Pressure in Ab Interno Trabeculectomy Ashley E. Neiweem,1¶ Igor I. Bussel,2¶ Joel S. Schuman,2 Eric N. Brown,2, 3 Nils A. Loewen2✝ 1: Rosalind Franklin University of Medicine and Science, Chicago Medical School, Chicago, United States of America 2: Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, United States of America 3: Department of Ophthalmology, School of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America ¶ authors have equally contributed ✝ corresponding author: Nils A. Loewen, MD, PhD 203 Lothrop St Suite 819 Pittsburgh, PA 15213 Email: [email protected] Phone: 412-605-1541

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Financial Support:

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Research to Prevent Blindness Departmental Grant.

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Individual Grant from Department of Ophthalmology, University of Pittsburgh.

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The sponsor or funding organization had no role in the design or conduct of this research

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Conflict of Interest:

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NAL has received honoraria from Neomedix for wet labs and lectures.

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Address for reprints: Nils A. Loewen, MD, PhD, 203 Lothrop St, Suite 819, Pittsburgh, PA 15213

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Abstract

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Purpose: To compare intraocular pressure (IOP) reduction and to develop a predictive surgery

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calculator based on the results between trabectome-mediated ab interno trabeculectomy in

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pseudophakic patients versus phacoemulsification combined with trabectome-mediated ab interno

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trabeculectomy in phakic patients.

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Methods: This observational surgical cohort study analyzed pseudophakic patients who received

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trabectome-mediated ab interno trabeculectomy (AIT) or phacoemulsification combined with AIT

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(phaco-AIT). Follow up for less than 12 months or neovascular glaucoma led to exclusion. Missing data

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was imputed by generating 5 similar but non-identical datasets. Groups were matched using

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Coarsened exact matching based on age, gender, type of glaucoma, race, preoperative number of

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glaucoma medications and baseline intraocular pressure (IOP). Linear regression was used to examine

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the outcome measures consisting of IOP and medications.

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Results: Of 949 cases, 587 were included consisting of 235 AIT and 352 phaco-AIT. Baseline IOP

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between groups was statistically significant (p≤0.01) in linear regression models and was minimized

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after coarsened exact matching. An increment of 1 mmHg in baseline IOP was associated with a

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0.73±0.03 mmHg IOP reduction. Phaco-AIT had an IOP reduction that was only 0.73±0.32 mmHg

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greater than that of AIT. The resulting calculator to determine IOP reduction consisted of the formula -

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13.54+0.73*(phacoemulsification yes:1, no:0)+0.73*(baseline IOP)+0.59*(secondary open

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angle glaucoma yes:1, no:0)+0.03*(age)+0.09*(medications).

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Conclusions: This predictive calculator for minimally invasive glaucoma surgery can assist clinical

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decision making. Only a small additional IOP reduction was observed when phacoemulsification was

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added to AIT. Patients with a higher baseline IOP had a greater IOP reduction.

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Introduction

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Cataract surgery is often associated with a moderate intraocular pressure (IOP) reduction of 1.5–3

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mmHg in patient with ocular hypertension or glaucoma.[1–3] Minimally invasive glaucoma surgery

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(MIGS) allows to combine IOP lowering with vision improvement from cataract surgery in an age group

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often affected by both. Such a practice pattern has become more common because it is standardized,

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safe[4] and also cost effective.[5] The first randomized controlled trials comparing phacoemulsification

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alone to phacoemulsification combined with implantation of trabecular bypass microstents, a form of

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MIGS, (iStent, Glaukos, Laguna Hills, CA), showed a relatively small additional effect of these implants

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on IOP reduction.[6] Ab interno trabeculectomy with the trabectome (Neomedix Corp; Tustin, CA),

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another MIGS modality, lowers IOP by plasma-mediated ionization and ablation of trabecular

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meshwork (TM) of up to 180° thereby increasing aqueous outflow in eyes with an intact downstream

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drainage system.[4] Both ab interno trabeculectomy (AIT) and phacoemulsification combined with ab

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interno trabeculectomy (phaco-AIT) can be used in patients with different angle opening[7] and

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surgical status.[8] The purpose of the comparison in this study was to assess reduction of IOP after AIT

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performed in pseudophakic patients versus phaco-AIT in phakic patients using a coarsened exact

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matched cohort. Based on results with microstents,[6] we hypothesized that in this matched

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comparison the benefit of adding phacoemulsification to AIT would be associated with a greater

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reduction in IOP and medications during 12 month follow-up. The resulting calculator can help

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clinicians to predict the IOP reduction.

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Methods

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Participants

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Data for this study were collected with approval by the Institutional Review Board of the University of

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Pittsburgh, in accordance with the Declaration of Helsinki and the Health Insurance Portability and

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Accountability Act. No informed consent was necessary for this retrospective, observational cohort

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study. Patient records were anonymized and de-identified prior to analysis. Subjects were divided into

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pseudophakic patients who received AIT and phakic patients who received phaco-AIT. Outcomes were

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determined for all patients with a diagnosis of glaucoma with or without a visually significant cataract,

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who had 12 months of follow-up. The specific target IOP was set on a case-by-case basis by the

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individual treating physician and was the maximum IOP estimated to prevent further nerve damage.

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Patients who were followed for less than 12 months or diagnosed with neovascular glaucoma were

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excluded. Indications for AIT consisted of worsening glaucoma on maximally tolerated topical therapy

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while indications for phaco-AIT were the same or stable glaucoma with desire to reduce medications

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plus a visually significant cataract with visual brightness acuity testing equal or worse than least 0.4

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logMAR (20/50 Snellen). The postoperative medications consisted of 1% pilocarpine four times per day

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for 1 month, then three times per day for 1 month, 1% prednisolone acetate four times per day for 1

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week to be tapered by one drop each week, and a third or fourth generation fluoroquinolone four

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times per day for 1 week. Glaucoma medications could be continued as deemed necessary to achieve

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target pressures. Visual field status of all patients was categorized as early, moderate, or advanced by

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individual glaucoma specialists based on the most recent Humphrey visual field exams (Zeiss, Jena,

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Germany). All patients had a comprehensive slit lamp, gonioscopy and dilated ophthalmoscopy exam

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prior to surgery.

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Statistics

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Demographics were compared by Mann-Whitney U test and chi-squared test for continuous and

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categorical variables, respectively. To avoid eliminating data with missing values multiple imputation

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was used. Missing values of the incomplete dataset were imputed m>1 times, thus creating m

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completed datasets. Second, each of the m completed datasets were independently analyzed. Finally,

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the results from each of the m analysis were pooled into a final result. Missing data such as age, gender

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and race were imputed by generating 5 similar but non-identical datasets. Groups were then matched

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by utilizing Coarsened Exact Matching[9] based on age, gender, type of glaucoma, race, preoperative

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number of glaucoma medications and baseline IOP. Univariate linear regression was performed first

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and those variables that were statistically significant were included in the final multivariate regression

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model. A p-value of less than 0.05 was considered statistically significant. Continuous variables were

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expressed as mean±SD. All analyses were performed using R.[10]

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Results

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Baseline Demographics

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After applying exclusion criteria and matching, a total of 587 patients were included in the study

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consisting of 235 AIT and 352 phaco-AIT (Figure 1). Baseline demographics are shown in Table 1.

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Table 1. Raw data demographics of study population. Demographics for AIT-only and phaco-AIT show significant difference (p < 0.05) for age, gender, baseline IOP, and baseline number of medications in unmatched data. AIT Phaco-AIT p-value (n=368) (n=581) Age

<0.01* Mean±SD

75±10

74±9

Range

(50, 96)

(51, 94)

Gender

0.01*

Male

130 (35%)

248 (43%)

Female

223 (61%)

323 (56%)

Types of Glaucoma ACG

0.19 2 (1%)

11 (2%)

POAG

289 (78%)

442 (76%)

SOAG

77 (21%)

128 (22%)

Race

0.34 African Americans

19 (5%)

29 (5%)

Asians

92 (25%)

166 (29%)

Caucasians

216 (59%)

303 (52%)

10 (3%)

20 (3%)

Others Baseline IOP

<0.01*

Mean±SD

24.1±7.1

20.6±6.6

Range

(10, 51)

(10, 59)

Baseline Number of Glaucoma Medications Mean±SD Range 115 116

<0.01* 2.9±1.1

2.4±1.0

(1, 6)

(1, 5)

ACG (angle closure glaucoma); POAG (primary open angle glaucoma); SOAG (secondary open angle glaucoma).

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Primary open angle glaucoma (POAG) comprised 86% and 89% of AIT and phaco-AIT, respectively.

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Secondary open angle glaucoma (SOAG) included 14% and 11% of AIT and phaco-AIT, respectively.

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From the matched subjects, 75% in AIT and also in phaco-AIT were Caucasian, followed by Asian,

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African American, and others. These values were not statistically significant. Additionally, age, gender,

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baseline number of glaucoma medications, and baseline IOP were found to be statistically different

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(p<0.01) between groups (Table 1). Following Coarsened Exact Matching, these preoperative

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differences between treatment groups were minimized (Table 2).

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Table 2. Matched data demographics of study population. Matched data is shown for both AIT-only and phaco-AIT group demographics. AIT phaco-AIT p-value (n=235) (n=352) Age

0.04* Mean±SD Range

76±9

75±8

(51,96)

(56,94)

Gender

0.15

Female

156 (66%)

212 (60%)

Male

79 (34%)

140 (40%)

Types of Glaucoma ACG

0.34 0 (0%)

0 (0%)

POAG

202 (86%)

313 (89%)

SOAG

33 (14%)

39 (11%)

Race

0.77 African Americans

7 (3%)

7 (2%)

Asians

48 (20%)

78 (22%)

Caucasians

176 (75%)

263 (75%)

4 (2%)

4 (1%)

Others Baseline IOP

<0.01*

Mean±SD

22.6±6.4

19.9±5.9

Range

(10, 46)

(10, 42)

Baseline Number of Glaucoma Medications Mean±SD Range

<0.01* 2.8±1.1

2.4±1.1

(1,6)

(1,5)

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ACG (angle closure glaucoma); POAG (primary open angle glaucoma); SOAG (secondary open angle glaucoma).

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Multiple Imputation and Coarsened Exact Matching

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Missing data in each category are recorded. Data missing from baseline number of medications, type of

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glaucoma, and IOP were 0% for both groups. Conversely, age, gender, and race had missing data

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among both groups. Six percent of AIT had an unknown age, 4% were without defined gender and 8%

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without defined race. Two percent of phaco-AIT had an unknown age, 2% were without defined

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gender, and 11% without race.

Figure 1: Trabectome Surgeries. Cases analyzed after accounting for exclusion criteria (AIT, ab interno trabeculectomy; phaco-AIT, AIT combined with phacoemulsification; IOP, intraocular pressure; POAG, primary open angle glaucoma; SOAG, secondary open angle glaucoma).

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Linear Regression Models

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Linear regression of the multiple imputed, matched data was used to identify the influence of the

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parameters above on the IOP lowering effect of surgery. Univariate linear regression was performed

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first (Table 3) using the variables phacoemulsification, baseline IOP, SOAG, age, number of medications

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at baseline, race and gender (male).

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Table 3. Univariate linear regression of patient parameters of study. A p-value of <0.05 is considered statistically significant. Coefficient Standard Error p-value Phaco

-1.35

0.50

<0.01*

Baseline IOP

0.74

0.03

<0.01*

SOAG

4.17

0.74

<0.01*

Age

0.10

0.03

<0.01*

Baseline # of medications

0.56

0.22

<0.01*

Race 8

Asian

1.10

2.30

0.64

Caucasian

1.94

2.19

0.39

Other

4.84

3.47

0.18

Male

-0.75

0.50

0.14

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Phaco (phacoemulsification); IOP (intraocular pressure); SOAG (secondary open angle glaucoma).

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Of these variables, phacoemulsification, baseline IOP, SOAG, age and number of medications at

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baseline were found to be statistically significant and included in the final multivariate regression

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model (Table 4). Only baseline IOP and phacoemulsification were statistically significant in both models

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(p = 0.02 and p<0.01, respectively).

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Table 4. Multivariate linear regression of patient parameters that were found to be statistically significant (p < 0.05) in univariate linear regression. Coefficient Standard Error p-value Intercept

-13.54

1.67

<0.01*

Phaco

0.73

0.32

0.02*

Baseline IOP

0.73

0.03

<0.01*

SOAG

0.59

0.50

0.24

Age

0.03

0.02

0.10

Baseline # of Medications

0.09

0.14

0.55

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Phaco (phacoemulsification); IOP (intraocular pressure); SOAG (secondary open angle glaucoma).

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Each increment of 1 mmHg in baseline IOP was associated with an IOP reduction of 0.73±0.03 mmHg

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(p<0.01). After adjusting for baseline IOP, age, baseline number of glaucoma medications, and type of

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glaucoma, phacoemulsification conferred an additional IOP reduction of 0.73±0.32 mmHg IOP.

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Preoperative IOP was 22.6±6.4 mmHg in AIT and 19.9±5.8 mmHg in phaco-AIT with 2.8±1.1

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medications in AIT and 2.4±1.1 in phaco-AIT. At one year, IOP in AIT was reduced to 16.9±4.5 mmHg

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(mean±SD) and in phaco-AIT to 15.4±3.6 mmHg (p<0.01), while medications in AIT declined to 1.7±1.2

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and in PT to 2.3±1.3 (p<0.01). Postoperative AIT and phaco-AIT were significantly different at all time 9

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points for both IOP and medications due to the large sample sizes with a narrow confidence interval

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and small standard error (Figure 2).

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Figure 2: IOP and medication plots. Preoperative and postoperative intraocular pressure (IOP; left) and number of glaucoma medications (Meds; right) over the 12 month follow-up for both groups. Represented as mean ± standard error. Statistically significantly different at all time points for both plots (p<0.05).

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Glaucoma Surgery IOP Reduction Calculator

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The calculator predicting the IOP reduction had the formula: -13.54+0.73*(phaco; yes:1,

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no:0)+0.73*(baseline IOP)+0.59*(SOAG; yes:1, no:0)+0.03*(age)+0.09*(medications).

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For example, a 75-year-old pseudophakic patient with POAG with a baseline IOP of 21 and 2 different

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medications receiving AIT alone would be expressed as:

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-13.54+0.73(0)+0.73*(21)+0.59(0)+0.03*(75)+0.09*(2) = 4.22 mmHg reduction in IOP, with a resulting

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postoperative IOP of 16.78 mmHg.

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Conversely, a 75-year-old phakic patient with POAG with the same baseline IOP and medications

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receiving phaco-AIT in a combined approach would have an IOP reduction of -

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13.54+0.73(1)+0.73*(21)+0.59(0)+0.03(75)+0.09(2) = 4.95 mmHg, thus a postoperative IOP of 16.05

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mmHg.

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The linear relationship of pre- and postoperative IOP can be seen in the scattergrams that show every

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single data point (Figure 3).

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Figure 3: Phaco-AIT and AIT scattergrams. Scattergrams of AIT and phaco-AIT after 1 month (left) and 12 months (right). Baseline IOP plotted against IOP at 1 month and 12 months with x=y line. Red line represents linear fit.

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Discussion

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We created a glaucoma surgery calculator to determine the postoperative IOP based on the

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preoperative IOP, type of glaucoma, age, medications, and type of surgery. This first calculator for

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minimally invasive glaucoma surgery (MIGS) can help clinicians to estimate outcomes and anticipate

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the need for postoperative glaucoma medications. Using coarsened exact matching, we found only a

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small additional contribution of phacoemulsification to the considerable IOP reduction from AIT. The

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impact of baseline IOP on total pressure reduction was substantial, adding 0.73 mmHg IOP reduction

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per 1 mmHg higher baseline IOP. Both groups achieved a significant decline in medications.

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The modest IOP reduction sometimes seen after phacoemulsification[1–3] has been hypothesized to

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be mediated by TM and Schlemm's canal distension that increase the outflow facility,[11,12] activation

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of a TM stress response pathway from ultrasound and fluids,[13] a trabeculoplasty-like effect[14,15] or

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resolution of relative pupillary block.[11] The relatively small additional IOP reduction in our study in

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eyes that had phacoemulsification added to AIT is consistent with the concept that this may be

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mediated by the remaining temporal TM.[12,16]

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We caution against use of phacoemulsification alone for the purpose of IOP reduction as recently

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advocated.[11] Because of a relatively more diseased TM in glaucoma, phacoemulsification on its own

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does not lower IOP reliably in such patients.[17] The impact of phacoemulsification on IOP in patients

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with same session TM bypass microstents may be relatively higher compared to ab interno

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trabeculectomy because of more remaining trabecular meshwork[7,8] and fewer drainage segments

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accessed in the former.[18]

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The raw baseline age differences and higher number of medications between AIT and phaco-AIT

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groups match the increased incidence of cataracts and glaucoma with age.[19] Following coarsened

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exact matching, these differences were minimized and allowed a statistically valid comparison with

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linear regression.[20] It was previously assumed that IOP reduction following AIT is independent of

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preoperative IOP[7,8] and only limited by episcleral venous pressure and other downstream

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elements.[21] The linear correlation between pre- and postoperative IOPs seen here suggests that

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patients with higher baseline IOP may have both a higher TM-mediated outflow resistance and a

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somewhat higher outflow resistance that is downstream of the TM.

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This study had limitations. We applied methods commonly used in statistics, coarsened exact matching

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and multiple imputation, to account for missing demographic values and avoid losing data thereby

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increasing the validity and sample size of the study. Additionally, the 12 month follow-up is still a

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relatively short-term follow-up endpoint for patients with good life expectancy and ongoing ocular

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disease. Interpretations of IOP outcomes presented here have to take into account that phaco-AIT

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patients in reality have a mixed indication of vision improvement (phaco) with often optional IOP or

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medication reduction (AIT). As a result, IOPs can be considerably lower if the second of the two

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average glaucoma medication is not eliminated.

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In conclusion, this first glaucoma surgery calculator advises clinicians on IOP after trabectome-

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mediated ab interno trabeculectomy. Phacoemulsification has only a small additional IOP lowering

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effect when combined with trabectome surgery. Patients with higher baseline IOP are expected to

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have a greater IOP reduction.

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Shingleton BJ, Pasternack JJ, Hung JW, O’Donoghue MW. Three and five year changes in intraocular pressures after clear corneal phacoemulsification in open angle glaucoma patients, glaucoma suspects, and normal patients. J Glaucoma. 2006;15: 494–498.

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10. R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2015. 11. Poley BJ, Lindstrom RL, Samuelson TW, Schulze R Jr. Intraocular pressure reduction after phacoemulsification with intraocular lens implantation in glaucomatous and nonglaucomatous eyes: evaluation of a causal relationship between the natural lens and open-angle glaucoma. J Cataract Refract Surg. 2009;35: 1946–1955. 12. Kee C, Moon SH. Effect of cataract extraction and posterior chamber lens implantation on outflow facility and its response to pilocarpine in Korean subjects. Br J Ophthalmol. 2000;84: 987–989. 13. Wang N, Chintala SK, Fini ME, Schuman JS. Ultrasound activates the TM ELAM-1/IL-1/NF-kappaB response: a potential mechanism for intraocular pressure reduction after phacoemulsification. Invest Ophthalmol Vis Sci. 2003;44: 1977–1981. 14. Shazly TA, Latina MA, Dagianis JJ, Chitturi S. Effect of prior cataract surgery on the long-term outcome of selective laser trabeculoplasty. Clin Ophthalmol. 2011;5: 377–380.

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Paperpile.com library used for this content Pritha R, Loewen RT, Yalong D, Parikh H, Loewen NA. Stratification of phaco-trabectome surgery results using a glaucoma severity index. ResearchGate. March 2016. doi:10.13140/RG.2.1.1244.5849. Polat J, Loewen NA. Combined Phacoemulsification and Trabectome for Treatment of Glaucoma. ResearchGate. July 2015. doi:10.13140/RG.2.1.3997.0964. Neiweem AE, Bussel II, Schuman JS, Brown EN, Loewen NA. Glaucoma Surgery Calculator: Limited Additive Effect of Phacoemulsification on Intraocular Pressure in Ab Interno Trabeculectomy. ResearchGate. March 2016. doi:10.13140/RG.2.1.4062.6324. Zhang X, Loewen N, Tan O, et al. Predicting Development of Glaucomatous Visual Field Conversion Using Baseline Fourier-Domain Optical Coherence Tomography. Am J Ophthalmol. 2016;163:29-37. Barry J-C, Loewen N. Zykloplegie-Tropferfahrungen in deutschsprachigen Zentren für Kinderophthalmologie und Strabologie - Umfrageergebnisse 1999. Klinische Monatsblätter für Augenheilkunde. 2001;218(01):26-30. Loewen RT, Roy P, Park DB, et al. A Porcine Anterior Segment Perfusion and Transduction Model With Direct Visualization of the Trabecular Meshwork. Invest Ophthalmol Vis Sci. 2016;57(3):1338-1344. Akil H, Chopra V, Huang A, Loewen N, Noguchi J, Francis BA. Clinical Results of Ab Interno Trabeculotomy Using the Trabectome in Patients with Pigmentary Glaucoma compared to Primary Open Angle Glaucoma. Clin Experiment Ophthalmol. March 2016. doi:10.1111/ ceo.12737. Loewen RT, Roy P, Parikh HA, Dang Y, Schuman JS, Loewen NA. Impact of a Glaucoma Severity Index on Results of Trabectome Surgery: Larger Pressure Reduction in More Severe Glaucoma. PLoS One. 2016;11(3):e0151926. Oatts JT, Wang X, Loewen NA. Effect of alpha-2-agonist premedication on intraocular pressure after selective laser trabeculoplasty. Indian J Ophthalmol. 2015;63(12):891-894. Marcus I, Salchow DJ, Leung SL, Zhou EJ, Tsai JC, Loewen NA. Academic Associate Program Impact on Clinical Study Enrollment in an Academic Ophthalmology Practice. Journal of Academic Ophthalmology. 2013;6(1):69-75. Loewen N. Long-Term Genetic Modification of the Ocular Outflow Tract and the Retinal Pigment Epithelium with Feline Immunodeficiency Viral Vectors. Kaplowitz K, Loewen NA. Trabectome-Mediated Ab Interno Trabeculectomy for Secondary Glaucoma or as a Secondary Procedure. In: Aref AA, Varma R, eds. Advanced Glaucoma Surgery. Essentials in Ophthalmology. Springer International Publishing; 2015:15-29. Parikh H, Bussel II, Schuman JS, Loewen N. Matched Comparison of Phaco-Trabectome to Trabectome in Phakic Patients. In: American Glaucoma Society. Roy P, Loewen R, Parikh H, Dang Y, Schuman J, Loewen N. Stratification of Results of Trabectome with Phacoemulsification by Glaucoma Severity: Larger IOP Reduction in More Advanced Glaucoma. In: American Glaucoma Society. Loewen R, Roy P, Parikh H, Dang Y, Schuman J, Loewen N. 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