Accepted Manuscript Predictors of Sustained Intraocular Pressure Elevation in Eyes Receiving Intravitreal Anti-Vascular Endothelial Growth Factor Therapy Nicolas A. Yannuzzi, BA Samir N. Patel, BS Kavita V. Bhavsar, MD Fumitaka Sugiguchi, 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 of Sustained Intraocular Pressure Elevation in Eyes Receiving Intravitreal Anti-Vascular Endothelial Growth Factor Therapy, American Journal of Ophthalmology (2014), doi: 10.1016/j.ajo.2014.04.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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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
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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
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Correspondence: K. Bailey Freund M.D. Vitreous Retina Macula Consultants of New York 460 Park Avenue #5 New York, New York 10022 [email protected] 1-212-861-9797
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Suggested Short Title: Predictors of Sustained Intraocular Pressure Elevation
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Abstract
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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.
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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 longterm 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).
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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 longterm 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 antiVEGF 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.
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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 crosssectional 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. 2
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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).
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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-hundredsixty-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-thirtynine (26%) respondents reported performing anterior chamber paracentesis 3
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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-seventynine (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). Onehundred-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 antiVEGF 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. 4
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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 0.05cc 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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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 P-Value Clinical Factor Adjusted O.R. (95% C.I.) Bevacizumaba 0.627 (0.260-1.512) 0.299 Aflibercepta 2.23 (0.452-11.002) 0.325 Injectors who used 31 2.833 (1.119 – 7.172) 0.028 gauge needlesb High volume, fast 5.561 (1.638 - 18.878) 0.006 injectors 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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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.
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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.
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 of Sustained Intraocular Pressure Elevation in Eyes Receiving Intravitreal Anti-Vascular Endothelial Growth Factor Therapy, American Journal of Ophthalmology (2014), doi: 10.1016/j.ajo.2014.04.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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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
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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
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Correspondence: K. Bailey Freund M.D. Vitreous Retina Macula Consultants of New York 460 Park Avenue #5 New York, New York 10022 [email protected] 1-212-861-9797
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Suggested Short Title: Predictors of Sustained Intraocular Pressure Elevation
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Abstract
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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.
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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 longterm 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).
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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 longterm 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 antiVEGF 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.
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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 crosssectional 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. 2
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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).
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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-hundredsixty-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-thirtynine (26%) respondents reported performing anterior chamber paracentesis 3
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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-seventynine (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). Onehundred-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 antiVEGF 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. 4
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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 0.05cc 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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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 P-Value Clinical Factor Adjusted O.R. (95% C.I.) Bevacizumaba 0.627 (0.260-1.512) 0.299 Aflibercepta 2.23 (0.452-11.002) 0.325 Injectors who used 31 2.833 (1.119 – 7.172) 0.028 gauge needlesb High volume, fast 5.561 (1.638 - 18.878) 0.006 injectors 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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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.
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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.
