Accepted Manuscript

Predictors of Sustained Intraocular Pressure Elevation in Eyes Receiving IntravitrealAnti-Vascular Endothelial Growth Factor Therapy

Nicolas A. Yannuzzi, BA Samir N. Patel, BS Kavita V. Bhavsar, MD FumitakaSugiguchi, BS K. Bailey Freund, MD

PII: S0002-9394(14)00233-5

DOI: 10.1016/j.ajo.2014.04.029

Reference: AJOPHT 8907

To appear in: American Journal of Ophthalmology

Received Date: 3 January 2014

Revised Date: 28 April 2014

Accepted Date: 30 April 2014

Please cite this article as: Yannuzzi NA, Patel SN, Bhavsar KV, Sugiguchi F, Freund KB, Predictors ofSustained Intraocular Pressure Elevation in Eyes Receiving Intravitreal Anti-Vascular Endothelial GrowthFactor Therapy, American Journal of Ophthalmology (2014), doi: 10.1016/j.ajo.2014.04.029.

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Predictors of Sustained Intraocular Pressure Elevation in Eyes Receiving Intravitreal Anti-Vascular

Endothelial Growth Factor Therapy Nicolas A. Yannuzzi, BA12, Samir N. Patel, BS12, Kavita V. Bhavsar, MD2345, Fumitaka Sugiguchi, BS12, K. Bailey Freund, MD2345 1 - Weill Cornell Medical College, New York, NY 2 - LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Institute, New York, NY 3 - Vitreous Retina Macula Consultants of New York, NY 4 - Department of Ophthalmology, New York University School of Medicine, New York, NY 5 - Department of Ophthalmology, Columbia University College of Physicians and Surgeons, New York, NY Correspondence: K. Bailey Freund M.D. Vitreous Retina Macula Consultants of New York 460 Park Avenue #5 New York, New York 10022 kbfnyf@aol.com 1-212-861-9797 Suggested Short Title: Predictors of Sustained Intraocular Pressure Elevation

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Abstract Purpose: To determine the intravitreal anti-vascular endothelial growth factor (VEGF) injection techniques and preferences within the retinal community and to identify potential factors associated with the development of sustained intraocular pressure (IOP) elevation in patients treated with intravitreal anti-VEGF therapy for neovascular age-related macular degeneration (AMD). Design: Cross-sectional, physician survey. Methods: Five-hundred-thirty retina specialists spanning both private and academic practices were surveyed regarding current anti-VEGF intravitreal injection protocols including the anti-VEGF drug of choice, needle gauge, injection volume, injection technique, and self-reported prevalence of sustained IOP elevation. Multivariate logistic regressions were performed to assess the potential influence of these factors on long-term IOP. Results: Two-hundred-ninety-two (55%) specialists reported believing that intravitreal anti-VEGF therapy may cause sustained IOP elevation. Of these responses, the most common reported prevalence was 1-2% (48%) followed by 3-5% (34%). There was no relationship between the frequency of sustained IOP elevation and anti-VEGF drug of choice. Physicians who injected greater than 0.05cc in less than one second were 5.56 times more likely to observe a high frequency of sustained IOP elevation (p=0.006, 95% C.I. 1.64-18.89). Conclusions: Based on physician survey data, serial anti-VEGF injections using higher injection volumes with a rapid injection technique may potentially lead to sustained IOP elevation. The underlying mechanism for this complication may be injury to the trabecular meshwork resulting from rapid elevations in IOP. Further investigation of the relationship between injection techniques and sustained IOP elevation in the form of retrospective or prospective clinical studies is warranted.

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Introduction Therapies targeting vascular endothelial growth factor (VEGF) have

revolutionized the treatment of neovascular age-related macular degeneration (AMD) and other visually threatening retinal diseases, including retinal vein occlusion and diabetic macular edema, where over-expression of VEGF, vascular leakage, and neovascularizarion have been identified as pathogenic mechanisms that may be addressed with therapy. In these diseases, anti-VEGF agents have been shown to be efficacious and to have a favorable safety profile. Given the need for frequent injections over the course of a disease, particularly in neovascular AMD, novel reports of long-term risks are surfacing. Intraocular pressure (IOP) elevation is a significant concern in chronic anti-VEGF therapy and is incompletely characterized.1-6

Transient increases in IOP have been studied extensively in the setting of anti-VEGF therapy. This work has revealed that patients experience short-term pressure spikes after injection that normalize within 30 minutes without further intervention in the majority of cases.7-9 In contrast, sustained IOP elevation has been investigated, but its mechanism is poorly understood.1-6 Several associations have been described including male gender,6 short intervals between injections,6 a previous history of glaucoma,10 and the total number of injections administered.5,11 To the best of our knowledge, there are no prior studies in the literature on the influence of injection protocols on the risk of sustained IOP elevation.

This survey was performed primarily to determine the intravitreal anti-VEGF injection techniques and preferences within the retinal community. The second objective was to conduct statistical analysis to identify potential candidate risk factors for developing sustained elevations in IOP that could be examined further in future studies. Methods Data Collection A database of 2,638 retina specialists was created from existing membership data of the American Society of Retina Specialists (ASRS), the Macula Society, and the Retina Society. Participants that spanned both private and academic practices were emailed an invitation to the survey hosted by SurveyMonkey (Palo Alto, CA). This cross-sectional survey consisted of 15 questions including the number of monthly injections administered for neovascular AMD, the preferred anti-VEGF agent, the needle gauge used and volume of medication injected, the injection technique, the use of anterior chamber paracentesis, the use of a cotton tipped applicator to prevent reflux, IOP monitoring practices both before and after injection, and the use of IOP lowering drops prior to injection. Participants were also polled on the speed of administration, the practice of softening the globe with pressure during anesthetic preparation, the prevalence of sustained IOP elevation, and the proposed mechanism of pressure elevation. Sustained IOP elevation was defined as persistent elevation in pre-injection IOP of > 5 mmHg above baseline (prior to the first anti-VEGF treatment) on at least two consecutive visits. The order of the answer choices to the suggested mechanism of sustained IOP elevation was randomized with each respondent as not to create bias towards one selection. Since all surveys were anonymous and no patient identifiers were recorded in any manner, the Western IRB ruled that the survey met the conditions for exemption.

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Statistical Analysis Univariate relationships between the frequency of observing sustained IOP

elevation and (1) drug type used, (2) needle gauge used, (3) volume of medication injected, (4) injection technique used, (5) speed of injection, (6) performance of anterior chamber paracentesis, (7) prevention of reflux with a cotton tipped applicator, (8) administration of IOP lowering drops, and (9) softening the globe with pressure prior to injection were analyzed. Specific variables based on the likert-type scale (6-9) were dichotomized to never/sometimes and most of the time/always for univariate analysis. Compound variables for injection characteristics were also analyzed. Volume of medication injected, size of needle gauge, and speed of injection were dichotomized into high volume (> 0.05 cc) versus low volume (≤ 0.05 cc), low gauge (< 31 gauge) versus high gauge (≥ 31 gauge), and fast speed (< 1 second) vs. slow speed (≥ 1 second), respectively. All were calculated using the two-sample t-test or Wilcoxon rank sum test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables.

Specific clinical characteristics were further assessed for a potential independent effect on the frequency of observing sustained IOP elevation. Variables that resulted in a p-value < 0.2 from the univariate analyses were further evaluated using a multivariable logistic regression model to adjust for confounding factors. An assessment of collinearity between predictors was performed prior to the specification of the final multivariate model. If two predictive factors were collinear (variance inflation factor value > 10), then the one that was more closely related to the frequency of observing sustained IOP elevation in the univariate analysis was explored in the multivariate model. The number of subjects in the different outcome groups limited the number of variables that could be explored in the multivariate model. All p-values are two-sided with statistical significance evaluated at the 0.05 alpha level. Ninety-five percent confidence intervals (95% C.I.) for adjusted odds ratios (O.R.) were constructed to assess the precision of the obtained estimates. All analyses were performed in SPSS Version 22 (SPSS Inc., Chicago, IL). Results Survey Data

Five-hundred-thirty-nine of the 2,638 retina specialists polled (20.4%) responded to the survey. Survey results are reported in Figure 1. Nine (2%) respondents reported that they do not routinely administer injections and were eliminated from subsequent analysis. Three-hundred-eighty-seven (72%) specialists administered greater than 50 injections per month. Two-hundred-seventy-eight (52%) physicians most frequently used bevacizumab, 184 (35%) ranibizumab, and 68 (13%) aflibercept. Three-hundred-sixty-eight (69%) physicians used a 30 gauge needle, while the next most common needle sizes were 32 G, 31 G, and 27 G respectively. A single physician reported also using 33 gauge needles. Three-hundred-sixty-one (68%) injectors elected to use a dosage volume of 0.05cc, while the next most common volume was a little more than 0.05cc.

Four-hundred-seventy-one (89%) respondents used a perpendicular injection technique, while the remaining 59 (11%) used an angled technique. One-hundred-thirty-nine (26%) respondents reported performing anterior chamber paracentesis

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immediately following injections at least sometimes, while 391 (74%) reported never performing this procedure. Two-hundred-ninety-two (55%) specialists reported covering the injection site with a cotton tipped applicator after injecting to prevent reflux at least sometimes, while 238 (45%) elected not to use this technique. Four-hundred-seventy-nine (90%) physicians reported routinely checking IOP prior to injecting most of the time or more often, yet only 136 (26%) reported routinely checking IOP after injecting most of the time or more often.

Eighty-one (15%) specialists elected to use IOP lowering drops prior to injections, while 449 (85%) never use IOP lowering drops. Three-hundred-forty-six (65%) respondents reported injecting at a moderate speed (about a second), while the next most common technique was a fast injection speed (less than a second). One-hundred-seven (20%) respondents reported softening the eye with pressure during anesthetic preparation of the globe.

Two-hundred-ninety-two (55%) specialists reported believing that intravitreal anti-VEGF therapy may cause sustained IOP elevation. Of the 292 physicians who reported believing in sustained IOP elevation, we asked the prevalence within their practice as well as the most likely mechanism. Eleven (4%) never observed it, 141 (48%) observed it rarely (1-2%), 99 (34%) observed it occasionally (3-5%), and 41 (14%) observed it in 6% or more of their patients. We also asked each physician the most likely mechanism of sustained IOP elevation. Mechanical obstruction to outflow by high molecular-weight protein aggregates was the most common response cited by 95 (33%) respondents, followed by mechanical trauma to the trabecular meshwork from repeated pressure spikes with each injection which was cited by 72 (25%) participants.

Notably, 14 (5%) physicians commented that multiple mechanisms are likely to be responsible depending on the individual patient. Several physicians proposed other mechanisms that were not included as choices in our survey including the belief that sustained IOP elevation is related to the natural history of increasing IOP with aging, or that there may be mechanical injury to the trabecular meshwork by traction from insertion of dull needles. Statistical Analysis

Of those who observed sustained IOP elevation, the study population was dichotomized into those who reported frequent observation of sustained IOP elevation (> 5%) and those who observed it infrequently (≤ 5%). The frequent observation group consisted of 35 respondents (12.5%), while the infrequent observation group consisted of 245 respondents (87.5%) as shown in Figure 2. Clinical predictors of sustained IOP elevation with p < 0.2 from the univariate analysis are shown in Table 1 and included anti-VEGF drug type, needle gauge, high volume and fast injectors (greater than 0.05cc in less than 1 second), the decision to perform anterior chamber paracentesis, and the decision to administer IOP lowering drops. The two groups were similar (p > 0.2 from the univariate analysis) with respect to clinical characteristics that included angled versus perpendicular injection technique, high versus low volume injection amounts, fast versus slow injection speed, prevention of reflux with a cotton tipped applicator, and softening the globe with pressure prior to injection (Table 2). Furthermore, the two groups were similar with respect to injectors who used high volumes and high gauges (31 or 32 gauge), fast speed and high gauges, and high volume, high gauges, and fast speed.

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A multivariate logistic regression model for independent predictors of observing a high frequency of sustained IOP elevation was performed. A chi-square test found a statistically significant association between the needle gauge and the drug type used (bevacizumab injectors were more likely to use 31G needles than other drug type users), χ2(6) = 23.682; p < 0.001 (Cramer’s V = 0.206, p < 0.01). Therefore, the following variables were included, based on a priori considerations and the findings of the univariate analysis: drug type used, needle gauge used, and injectors who used a high volume with a fast speed.

The results of the multivariable logistic regression are presented in Table 3. There was no relationship between those who observed a high frequency of sustained IOP elevation and the drug type used. Respondents using 31 gauge needles were 2.83 times more likely to observe a high frequency of sustained IOP elevation than those who used 27, 30, or 32 gauge needles (p=0.028, 95% C.I. 1.12-7.17). Additional analysis showed that there was no statistically significant relationship between high frequency observers of sustained IOP elevation and injectors using high gauges (O.R.: 1.133, 95% CI 0.517 – 2.484).

High volume, fast injectors, however, were 5.56 times more likely to observe a high frequency of sustained IOP elevation (p=0.006, 95% C.I. 1.64-18.89). To test the strength of this association, we computed this regression with multiple other cutoff points delineating what we defined as low and high frequency observers of sustained IOP elevation. When the cutoff point was placed at >0%, >2%, >5%, and >10% prevalence, this association held with O.R. ranging between 4.92 and 6.83 and p-values <0.05 in each case.

Discussion

This survey was designed to investigate the intravitreal anti-VEGF injection protocols of retinal physicians. Further, it was also intended to generate candidate risk factors for the development of sustained IOP elevation that could be investigated further in future studies. As a survey, it does not contain purely objective data obtained from the clinical record, and thus its results must be interpreted critically.

Our data indicate that most retina specialists observe sustained IOP elevation at a frequency of 1-5%. This estimate falls in the lower range of previous studies based on objective clinical data which have reported rates from 3.45%-11%.2-6 Not all investigators have detected this phenomenon. Notably, Wehrli et al. found that the incidence of sustained IOP elevation after intravitreal anti-VEGF therapy was 0.5%-1% incidence per eye per year and did not differ between treated eyes and controls.12

There are a limited number of studies on clinical predictors of sustained IOP elevation. Hoang et al. previously reported that eyes receiving ≥ 29 injections were 16.1 times more likely to experience this complication in comparison to those who had received ≤ 12 injections.5 Other predictors previously investigated include male gender,6 interval between injections,6 and total number of injections administered.5,11

Reports on whether certain anti-VEGF agents are more prone to causing sustained IOP elevation have been inconsistent. Choi et al. found no significant difference between bevacizumab, ranibizumab, and pegaptanib with respect to this complication.4 In a separate study, Adelman et al. found that sustained IOP elevation could occur with both bevacizumab and ranibizumab.3 In contrast, Good et al. reported

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an increased risk in eyes receiving only bevacizumab (9.9%) in comparison to eyes receiving ranibizumab (3.1%).2 However, post-hoc analysis revealed that the power of the difference was only 0.037 at the 0.05 level so the authors were unable to conclude if bevacizumab had a higher risk of IOP elevation than ranibizumab. It has been hypothesized that aflibercept might lead to a lower incidence of sustained IOP elevation as the drug requires fewer injections, but currently there are insufficient data to support this premise.10 In our survey, we found that high frequency observers of sustained IOP elevation were more likely to use bevacizumab and less likely to use aflibercept and ranibizumab than low frequency observers but this was not statistically significant in either the univariate or multivariate analysis.

While there have not been any previous studies evaluating the impact of injection technique and needle gauge on sustained IOP elevation, several studies have investigated the effects of different injection practices on short-term IOP. Höhn et al. examined the impact of a straight scleral incision in comparison to a tunneled sclera injection technique in patients receiving ranibizumab injections. Tunneled scleral incisions had an average of 11 mmHg greater mean increase in IOP than straight scleral incisions.13 In our survey, we found no significant correlation between an angled or perpendicular injection technique and sustained IOP elevation.

Higher gauge needles have been favored in intravitreal injections due to the requirement for less force to penetrate the sclera14 and their propensity to induce less pain and tissue trauma.15 However, Kim et al. showed that short-term IOP elevation was greater with 30 and 32 gauge needles in comparison to 27 gauge needles immediately after injection though time to pressure normalization did not differ.16 In Kim et al.’s study, injections done with 30 and 32 gauge needles consisted of bevacizumab or ranibizumab while injections done with 27 gauge needles were either pegatanib or triamcinolone. Even though the injections done with smaller bore needles contained less volume (0.05cc) than those with 27 gauge needles (0.09cc or 0.1cc), the higher gauge needles were thought to have greater pressure spikes because they had less vitreous reflux. The authors hypothesized that if large volumes were injected with a small needle that did not allow for significant reflux, a high short-term elevation in IOP would be expected.

In a separate study evaluating the association between needle size, post-injection reflux, and IOP spikes following intravitreal injections (currently under review), our group showed that eyes receiving intravitreal anti-VEGF therapy with 32-gauge needles had a lower incidence of post-injection reflux and higher mean intraocular pressure immediately following injection compared to the eyes injected with larger 30-gauge needles. Of note, the incidence of immediate post-injection IOP spikes of 50 mmHg or higher was 42% in the eyes injected with 32-gauge needle compared to only 9% in the eyes injected with 30-gauge needles.

Rodriguez et al. examined both short-term intraocular pressure and reflux with different syringes and injection techniques.17 There was no difference between incision technique or reflux volume and intraocular pressure. However, there was greater reflux with 26 and 27 gauge needles in comparison to 29 and 30 gauge needles. A straight technique also had greater vitreous reflux than beveled approaches. In our survey, we found that 31 gauge needle users were significantly more likely to observe sustained IOP elevation than the accumulation of other needle gauge users including 27G, 30G, and 32G. We hypothesized that decreased reflux with higher gauge

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needles could possibly account for increased short-term pressure spikes and subsequent injury to the trabecular meshwork causing sustained IOP elevation. While the association between 31 gauge needles and sustained IOP elevation was significant, we did not observe an increase in the incidence of sustained IOP elevation in 32 gauge users in comparison to 27, 30, or 31 gauge users, a finding which we cannot explain. Further, we did not detect a significant difference between low gauge (<31G) and high gauge (≥ 31G) users with respect to sustained IOP elevation. We then tested whether the use of high gauge needles in conjunction with a technique to prevent reflux was associated with sustained IOP elevation but did not find a significant effect. The strongest association was between high volume, fast injectors and an increased frequency of sustained IOP elevation. Physicians who injected more than 0.05cc in less than 1 second were greater than 5 times more likely to experience sustained IOP elevation in our multivariate analysis, and this finding was robust and replicated across multiple cutoff points for low and high frequency observers. However, injecting high volumes or a fast technique alone was not predictive of sustained IOP elevation. Potentially these two variables have a synergistic effect causing high volume per unit time administration of agent that results in damage to the trabecular meshwork that may account for sustained IOP elevation.

Anterior chamber paracentesis has generally not been recommended in intravitreal injections of any volume as described in Aiello’s intravitreal injection guidelines.18 Dwinger et al. also recommended against routine paracentesis even with large volume 0.1cc injections of triamcinolone since only moderate transient pressure elevations were detected and all normalized by 24 hours.19 In our series, low frequency observers of sustained IOP elevation were more likely to perform anterior chamber paracentesis (71.8% versus 62.9% in high frequency observers) though this difference was not statistically significant.

Several studies have shown that softening the globe during anesthetic preparation might temper short-term IOP elevation. Gregori et al. reported that decompressing the eye with a cotton swab prior to injection resulted in less transient IOP elevation.20 Morlet et al. showed that mercury bag decompression of the eye for 15 minutes before injection resulted in a lower mean IOP increase in patients receiving 0.1cc ganciclovir.21 In contrast, we observed no significant differences in softening the globe with pressure during anesthetic preparation between the two groups (12.2% versus 11.4% in high frequency observers). It has previously been shown that using dorzolamide/timolol or brinzolamide/timolol drops prior to intravitreal injections may reduce short-term IOP elevation.22 In our survey, we observed that high frequency observers (8.6%) were more likely to administer IOP lowering drops than low frequency observers (1.2%).

Our survey also indicates that the mechanism of sustained IOP elevation remains controversial with professional opinions split among multiple mechanisms. The most common response was mechanical obstruction by high molecular weight protein aggregates. This hypothesis is supported by Liu et al. who reported that compounded, repackaged bevacizumab held in plastic syringes contained protein aggregates and silicone oil microdroplets.23 These substances could potentially block aqueous outflow or may be responsible for causing an inflammatory trabeculitis as was reported by Sniegowski et al. following anti-VEGF injection.24 Kahook et al. also hypothesized that

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large particulate matter in compounded bevacizumab could lead to obstruction of aqueous outflow and elevation in IOP, thus favoring a bevacizumab phenomenon.25 In another study Kahook et al. postulated that sustained IOP elevation is due to anti-VEGF effect since in vitro, bevacizumab was found to be harmful to the trabecular meshwork cells, but that this effect was not detected with ranibizumab.26 Finally, other investigators have hypothesized that the phenomenon can be explained by the damage to the trabecular meshwork with repeated transient IOP spikes.27

While our survey reveals that certain injection practices may influence the development of sustained IOP elevation, the design of the study has significant limitations. With a cross-sectional survey, we are unable to derive causation from the data. Furthermore, due to a 20% response rate, there is potential for a non-responder bias that could have affected the results of our analyses. Additional limitations include the subjective nature and biases encountered when using self-reported outcomes and exposures. For instance, a quantitative estimate of the prevalence of sustained IOP elevation in a physician practice cannot be accurately ascertained without a chart review, and the self-reported data from this survey is only a surrogate for this measure. Further, physician survey responses to injection practices signify only a snapshot in time and may have changed significantly over time. These changes would not be detected with our design.

In conclusion, this survey provides useful information on current intravitreal injection practices. It does not, however, reveal the etiology of sustained IOP elevation or refute other contributing factors previously identified by investigators. Nevertheless, our most robust statistical finding was that a high volume, fast injection technique may lead to persistent IOP elevation. The underlying mechanism of this relationship may be due to high velocity drug flow and transient IOP spikes causing injury to the trabecular meshwork. Assigning causation to this factor alone would be premature. The clinical conundrum of sustained IOP elevation certainly is explained by multiple variables, many of which could not be accounted for in our survey design. Further exploration in the form of detailed retrospective and prospective clinical studies of the relationship between injection technique and IOP is needed.

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Acknowledgements/Disclosures A. Funding/Support: This work was supported by the Macula Foundation (New

York, New York) and the LuEsther T. Mertz Retinal Research Center (New York, New York).

B. Financial Interest Disclosure: K. Bailey Freund – Genentech, Inc: Consultant, Honoraria; Heidelberg Engineering: Consultant, Honoraria; Regeneron Pharmaceuticals, Inc: Consultant, Honoraria; Bayer HeathCare: Consultant, Honoraria. Nicolas A. Yannuzzi – None. Samir N. Patel – None. Kavita V. Bhavsar – None, Fumitaka Sugiguchi – None.

C. Author Contributions: Design and conduct of the study (NAY, KVB, KBF), collection (NAY, SNP, FS), management, analysis, and interpretation of the data (NAY, SNP, KVB, KBF), preparation, review and approval of the manuscript (NAY, SNP, KVB, KBF).

D. Other Acknowledgements: None

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Figure Captions Figure 1: Clinical Characteristics of Injection Practices by Retinal Physicians and Prevalence of Observed Sustained Intraocular Pressure Elevation in Eyes Receiving Intravitreal Anti-Vascular Endothelial Growth Factor Therapy A cross sectional survey was administered to retinal specialists regarding injection protocols, prevalence of intraocular pressure elevation, and the suggested mechanism of the phenomenon. Five-hundred-thirty-nine physicians reported the number of injections they administer per month. The 9 non-injectors were removed from the remaining categories. The final two panels only include those physicians who reported believing in sustained intraocular pressure elevation. Figure 2: Derivation of the High and Low Prevalence Observers of Sustained Intraocular Pressure Elevation in Eyes Receiving Intravitreal Anti-Vascular Endothelial Growth Factor Therapy for the Univariate and Multivariate Statistical Analysis Of the 539 respondents, the study population was limited to participants who stated they believed intravitreal anti-vascular endothelial growth factor therapy can cause sustained intraocular pressure elevation, reported prevalence, and regularly checked pressure. These 280 physicians were further dichotomized into low and high prevalence observers for subsequent univariate and multivariate statistical analysis.

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Tables Table 1: Clinical Characteristics of Injection Practices by Frequency of Observation of Sustained Intraocular Pressure Elevation in Eyes Receiving Intravitreal Anti-Vascular

Endothelial Growth Factor Therapy (Univariate Analysis with p<0.20) High Frequency

Observersa (35, 12.5%)

Low Frequency Observersb (245,

87.5%) P-Valuec

Drug type Bevacizumab 23 (65.7%) 119 (48.6%) 0.058

Aflibercept 2 (5.7%) 40 (16.3%) 0.100 Ranibizumab 10 (28.6%) 86 (35.1%) 0.446

Needle Gauge 27 1 (2.9%) 7 (2.9%) 1 30 22 (62.9%) 167 (68.1%) 0.531 31 9 (25.7%) 27 (11.0%) 0.027 32 3 (8.5%) 44 (18.0%) 0.227

High volume, fast injectorsd

5 (14.3%) 9 (3.7%) 0.020

Perform anterior chamber paracentesis

22 (62.9%) 176 (71.8%) 0.119

Administration of intraocular pressure lowering drops

3 (8.6%) 3 (1.2%) 0.028

a. Refers to physicians who observed ≥ 5% sustained intraocular pressure elevation in their practice. b. Refers to physicians who observed < 5% sustained intraocular pressure elevation in their practice. c. The Fisher exact test and chi-square test were used when comparing two categorical variables. The Fisher exact test was used over a chi-square test if the expected cell value was less than 5. d. Refers to physicians who injected greater than 0.05cc of volume in less than 1 second. Caption: Univariate analysis was conducted on injection practices of high frequency (>5%) and low frequency (≤5%) observers of sustained intraocular pressure elevation in eyes receiving intravitreal anti-vascular endothelial growth factor therapy. Factors with p<0.20 are reported above.

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Table 2: Clinical Characteristics of Injection Practices by Frequency of Observation of Sustained Intraocular Pressure Elevation in Eyes Receiving Intravitreal Anti-Vascular

Endothelial Growth Factor Therapy (Univariate Analysis with p>0.20) High Frequency

Observers (35, 12.5%)

Low Frequency Observers (245,

87.5%) P-Valuea

Angled injection technique

6 (17.2%) 30 (12.2%) 0.420

Perpendicular injection technique

29 (82.8%) 215 (87.8%) 0.420

High volumeb 12 (34.3%) 70 (28.6%) 0.487 Fast injection

speedc 11 (31.4%) 54 (22.0%) 0.219

Prevention of reflux with a cotton tipped

applicator

13 (37.1%) 110 (44.9%) 0.387

Softening the globe with pressure

during anesthetic prep

4 (11.4%) 30 (12.2%) 1.000

High volume, high gauged

4 (11.4%) 13 (5.3%) 0.244

Fast speed, high gaugee

3 (8.6%) 20 (8.2%) 1.000

High volume, high gauge, fast speedf

2 (5.7%) 12 (4.9%) 0.690

a. The Fisher exact test and chi-square test were used when comparing two categorical variables. The Fisher exact test was used over a chi-square test if the expected cell value was less than 5. b. Refers to physicians who injected > 0.05cc. c. Refers to physicians who injected in < 1 second. d. Refers to physicians who injected > 0.05cc with either 31 or 32 gauge needles. e. Refers to physicians who injected in < 1 second with either 31 or 32 gauge needles. f. Refers to physicians who injected > 0.05cc in < 1 second with either 31 or 32 gauge needles. Caption: Univariate analysis was conducted on injection practices of high frequency (>5%) and low frequency (≤5%) observers of sustained intraocular pressure elevation in eyes receiving intravitreal anti-vascular endothelial growth factor therapy. Factors with p>0.20 are reported above.

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Caption: A multivariate logistic regression model for independent predictors of observing a high frequency of sustained intraocular pressure elevation was performed to evaluate the impact of anti-vascular endothelial growth factor agent, needle gauge, and a high volume, fast injection method on sustained intraocular pressure elevation in eyes receiving intravitreal anti-vascular endothelial growth factor therapy.

Table 3: Multivariate Analysis of the Injection Practices of High Frequency Observers of Sustained Intraocular Pressure Elevation

in Eyes Receiving Intravitreal Anti-Vascular Endothelial Growth Factor Therapy

Clinical Factor Adjusted O.R. (95% C.I.)

P-Value

Bevacizumaba 0.627 (0.260-1.512) 0.299 Aflibercepta 2.23 (0.452-11.002) 0.325

Injectors who used 31 gauge needlesb

2.833 (1.119 – 7.172) 0.028

High volume, fast injectors

5.561 (1.638 - 18.878) 0.006

a. Ranibizumab drug users serve as the reference category for drug type. b. The reference category includes injectors who used 27 gauge, 30 gauge, or 32 gauge needles.

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K. Bailey Freund, MD is a Clinical Professor of Ophthalmology at New York University School of Medicine and a senior partner at Vitreous Retina Macula Consultants of New York. Dr. Freund is on the Editorial Board of the journal Retina. He has authored over 160 peer-reviewed scientific manuscripts and numerous book chapters. He is a recipient of the Young Investigator Award from the Macula Society.

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Nicolas A. Yannuzzi is a medical student at Weill Cornell Medical College. He received his BA in Biochemical Sciences from Harvard College and is expecting his MD degree in May, 2014. At Cornell, he was elected to Alpha Omega Alpha. He is scheduled to begin internship at Memorial Sloan-Kettering Cancer Institute followed by residency at Bascom Palmer Eye Institute.