- Email: [email protected]
Endophthalmitis Rates after Bilateral Same-Day Intravitreal Anti–Vascular Endothelial Growth Factor Injections
Accepted Manuscript Endophthalmitis Rates after Bilateral Same Day Intravitreal Anti-Vascular Endothelial Growth Factor Injections Durga S. Borkar, MD, Anthony Obeid, MD, MPH, Daniel C. Su, MD, Philip P. Storey, MD, MPH, Xinxiao Gao, MD, Carl D. Regillo, MD, FACS, Richard S. Kaiser, MD, Sunir J. Garg, MD, Jason Hsu, MD, Allen Chiang, MD, James P. Dunn, MD, Mitchell Fineman, MD, David Fischer, MD, Omesh Gupta, MD, MBA, Allen Ho, MD, Michael Klufas, MD, Joseph Maguire, MD, Sonia Mehta, MD, Carl Park, MD, Arunan Sivalingam, MD, Marc Spirn, MD, William Tasman, MD, James Vander, MD PII:
S0002-9394(18)30326-X
DOI:
10.1016/j.ajo.2018.06.022
Reference:
AJOPHT 10568
To appear in:
American Journal of Ophthalmology
Received Date: 3 June 2018 Revised Date:
20 June 2018
Accepted Date: 26 June 2018
Please cite this article as: Borkar DS, Obeid A, Su DC, Storey PP, Gao X, Regillo CD, Kaiser RS, Garg SJ, Hsu J, for the Wills Post Injection Endophthalmitis (PIE) Study Group, Chiang A, Dunn JP, Fineman M, Fischer D, Gupta O, Ho A, Klufas M, Maguire J, Mehta S, Park C, Sivalingam A, Spirn M, Tasman W, Vander J, Endophthalmitis Rates after Bilateral Same Day Intravitreal Anti-Vascular Endothelial Growth Factor Injections, American Journal of Ophthalmology (2018), doi: 10.1016/j.ajo.2018.06.022. 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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Abstract Purpose: To evaluate practice patterns for bilateral same day intravitreal anti- vascular
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endothelial growth factor (VEGF) injections and determine the rate of unilateral and bilateral post-injection endophthalmitis after bilateral same day intravitreal anti-VEGF injections. Design: Retrospective cohort study
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Methods: The records of a large academic private practice were electronically queried for all office visits during which bilateral intravitreal anti-VEGF injections were performed between
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April 1, 2012 and August 21, 2017 for patients with a diagnosis of neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion. Demographic information and indication for injection were recorded for each patient and office visit. Charts of patients with endophthalmitis were reviewed, and information was collected on
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presentation exam, culture data, and visual outcomes.
Results: During the study period, 101,932 bilateral same day intravitreal anti-VEGF injections were performed over 50,966 office visits for 5,890 patients. The mean (standard deviation) age
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of patients in this cohort was 74.2 (14.1) years and 60.6% of patients were female. The two most common indications for injection were neovascular age-related macular degeneration
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(54.3% of patients) and diabetic macular edema (35.4% of patients). Twenty-eight cases of endophthalmitis (0.027% of total injections) occurred during the study period. There were no cases of bilateral endophthalmitis, and no patients had more than one occurrence of endophthalmitis. Conclusions: In this large cohort of patients undergoing bilateral same day intravitreal antiVEGF injections, there were no cases of bilateral endophthalmitis. Additionally, the overall rate
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of unilateral endophthalmitis was low and comparable to prior studies of unilateral injections.
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These results support the safety of bilateral same day intravitreal anti-VEGF treatment.
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Endophthalmitis Rates after Bilateral Same Day Intravitreal Anti-Vascular Endothelial Growth Factor Injections
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The Retina Service, Wills Eye Hospital, Philadelphia, PA
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Financial Support: None
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Durga S. Borkar1, MD, Anthony Obeid, MD, MPH1, Daniel C. Su, MD1, Philip P. Storey, MD, MPH1, Xinxiao Gao, MD1, Carl D. Regillo, MD, FACS1, Richard S. Kaiser, MD1, Sunir J. Garg, MD1, Jason Hsu, MD1 for the Wills Post Injection Endophthalmitis (PIE) Study Group
Conflict of Interest: D.B, A.O, D.S, P.S, X.G have no conflicts of interest.
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C.R. Research grants: Genentech, Regeneron, Novartis, Allergan, Alcon; Consulting: Genentech, Allergan, Alcon, Novartis, Iconic R.K. Consulting: PanOptica
S.G. Research grants: Aerpio, Allergan, Eyegate; Consulting: Deciphera, Santen
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J.H. Research grants: Roche/Genentech and Santen; Consulting: Ophthotech
Meeting presentation: This study is scheduled to be presented as a paper presentation at the American Society of Retina Specialists Annual Meeting, Vancouver, BC July 2018
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Short Title: Endophthalmitis after Bilateral Same Day Anti-VEGF Injections
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Corresponding Author: Jason Hsu, MD Retina Service, Wills Eye Hospital 840 Walnut Street Suite 1020 Philadelphia, PA 19107 Phone number: +1(215) 928 3092 Email: [email protected]
Abbreviations and acronyms: AMD, age-related macular degeneration; DME, diabetic macular edema; ICD, international classification of disease; RVO, retinal vein occlusion; VEGF, vascular endothelial growth factor.
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Introduction Intravitreal anti-VEGF injections are currently the most commonly performed procedure in medicine, with 2.3 million injections performed for Medicare beneficiaries alone in 2014.1 The most common indications for anti-VEGF therapy, neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME), often require chronic, bilateral treatment.2,3 This leads to both increased physician and patient burden in terms of office visits. As a result, methods to provide more efficient care are needed. For patients undergoing bilateral treatment, many retina specialists will perform bilateral same day intravitreal injections to help minimize office visits for patients. The most recent survey of retina specialists nationally revealed that 46% of retina specialists routinely perform bilateral same day injections.4 Some practitioners prefer to avoid bilateral same day injections due to fear of possible bilateral endophthalmitis as well as the possibility of increased systemic absorption of anti-VEGF. To date, few studies have been performed evaluating rates of endophthalmitis following bilateral same day intravitreal anti-VEGF injection, and all of these studies have reviewed less than 2,000 intravitreal injections.5-10 Given the low rates of endophthalmitis following intravitreal injection and large sample size needed11-23, a larger study investigating this topic is warranted. The purpose of this study was to assess the rate and outcomes of unilateral and bilateral endophthalmitis in a large cohort of patients receiving bilateral same day anti-VEGF therapy.
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Methods Institutional Review Board approval was obtained from the Wills Eye Hospital review board. All work was performed in accordance with the Health Insurance Portability and Accountability Act of 1996 and adhered to the tenets of the Declaration of Helsinki. The electronic medical records of the Mid Atlantic Retina practice were queried for all office visits during which bilateral same day intravitreal anti-VEGF injections were performed between April 1, 2012 and August 21, 2017 using Current Procedural Terminology codes. International Classification of Diseases, 9th and 10th Editions (ICD-9 or ICD-10) codes were used to determine the indication for each injection. Missing diagnoses or differing diagnoses between the two eyes were also noted. Basic demographic information was also extracted for each patient included in the study. All anti-VEGF injections were administered in an office-based setting by a vitreoretinal fellow or a fellowship-trained retina specialist. Bevacizumab injections were administered using prepackaged syringes from a compounding pharmacy, while aflibercept syringes were loaded from single-use vials during the office visit. Ranibizumab injections were administered using either syringes loaded from single-use vials during the office visit or prefilled syringes later in the study period. The preinjection preparation typically consisted of two rounds of topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine, Alcon Labs, Fort Worth, Texas, USA) or 0.5% tetracaine hydrochloride (Tetracaine, Alcon Labs, Fort Worth, Texas, USA) and 5% povidone-iodine (Betadine 5%, Alcon Labs, Fort Worth, Texas, USA) applied topically to the conjunctiva. Based on patient preference, some patients also received an additional 1-2% subconjunctival lidocaine injection followed by 5% povidone-iodine. Typically, eyelid retraction was performed using a bimanual eyelid retraction technique, which has been previously 2
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Results
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described.24,25 Although choice of injection quadrant could vary, injections were generally performed in the inferotemporal quadrant with conjunctival displacement performed at the discretion of the treating physician. Injections were performed 3.0-4.0 mm from the limbus using a 30- or 31-gauge needle. Bilateral injections were set up by the technician concurrently and performed in the same procedure room. The same bottles of anesthetic and betadine were used for each eye. The second injection was performed immediately after the first injection. The choice of which eye, right or left, was injected first was left to the treating physician’s discretion. ICD-9 and ICD-10 codes for endophthalmitis were used to electronically identify cases of endophthalmitis within 30 days of intravitreal injection. If additional procedures were performed in this post-injection period, such as glaucoma or cataract surgery, these cases were excluded from the study. All possible cases of endophthalmitis from this electronic search were individually reviewed to confirm a diagnosis of presumed infectious endophthalmitis. For each case, laterality, injection number, anti-VEGF agent, indication for anti-VEGF injection, preendophthalmitis Snellen visual acuity, presentation clinical exam, treatments, and posttreatment Snellen visual acuity at 1, 3, 6, and 12 months were reviewed. Presumed infectious endophthalmitis was defined based on a clinical decision to proceed with either a vitreous or anterior chamber tap and injection of intravitreal antibiotics or a pars plana vitrectomy with injection of intravitreal antibiotics. Cases of post-injection inflammation that were treated with topical steroids and close monitoring alone without injection of intravitreal antibiotics were not included. All statistical analyses were conducted using SPSS, Version 24 (SPSS, Inc, Chicago, IL, USA). Categorical variables were compared using a chi-square test and continuous variables were compared using a two-sample t-test. A p-value less than 0.05 was considered statistically significant.
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During the study period, 101,932 bilateral same day intravitreal anti-VEGF injections were performed over 50,966 office visits for 5,890 patients. The baseline demographic and clinical characteristics are described in Table 1. The average age of the study population at the time of first injection was 74.2 years (SD=14.1 years) and 60.6% of the study population was female. The most common indication for injection was neovascular AMD (54.3% of patients, Table 1), while the second most common was diabetic macular edema (35.4% of patients, Table 1). Of the 101,932 intravitreal anti-VEGF injections included in the study, 55,051 (54.0%, Table 2) ranibizumab injections, 32,542 (31.9%, Table 2) aflibercept injections and 14,339 bevacizumab injections (14.1%, Table 2) were performed. Nearly two thirds of injections were for neovascular AMD. Ranibizumab was the most common agent used for neovascular AMD treatment, while aflibercept was the most common treatment choice for DME. Temporal trends were noted throughout the study period. While the number of bevacizumab injections remained fairly constant each year, there was a significant increase in the number of aflibercept injections starting in 2014 which corresponded to an annual decrease in the number of ranibizumab injections performed each year starting in 2014 (Figure 1). Over
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time, the number of bilateral same day injections performed increased, ranging from 870 injections per month in 2012 to approximately 2300 injections per month in 2017 (Figure 2). Twenty-eight cases of unilateral endophthalmitis were identified and confirmed by individual chart review, corresponding to a rate of 0.027% (approximately 1 in 3,700 injections). No cases of bilateral endophthalmitis were identified, and no patients had more than one case of endophthalmitis during the study period. The basic clinical and demographic characteristics of these cases are described in Table 3 and were similar to the overall study cohort. There were five cases of endophthalmitis after bevacizumab injection (0.035%), ten cases of endophthalmitis after ranibizumab injection (0.018%) and thirteen cases of endophthalmitis after aflibercept injection (0.039%). There was no statistically significant difference between the rates of endophthalmitis (p=0.15) among the three anti-VEGF agents. Similarly, there was no significant difference in the rates of endophthalmitis based on the diagnosis of neovascular AMD (0.033%) versus diabetic macular edema (0.019%, p=0.20) Twenty-five of twenty-eight patients (89%) presented within the first week after injection. Three patients (11%) presented more than three weeks after intravitreal injection. All patients in this series were initially treated with vitreous (or anterior chamber) tap and injection of intravitreal antibiotics on the day of presentation. Culture data was not available for all patients if it was done at an outside laboratory and not documented in the available exam notes. Eleven patients (39%) subsequently underwent pars plana vitrectomy and two of these patients had a retinal detachment requiring surgery. Baseline and twelve-month visual acuity outcomes are described in Table 3. Sixteen patients (57%) resumed bilateral same day intravitreal injections within one year of endophthalmitis diagnosis.
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Discussion In this study evaluating more than 100,000 bilateral same day intravitreal injections, the overall rate of endophthalmitis was 0.027% of total injections. There were no cases of bilateral endophthalmitis, and no patients had endophthalmitis more than once during the study period. Overall, 57% of patients elected to resume bilateral same day intravitreal injections within one year of endophthalmitis diagnosis. While there was no direct comparison to endophthalmitis rates after unilateral injections in this same population, there are multiple reports on the rates of endophthalmitis after predominantly unilateral intravitreal anti-VEGF injections, including studies from this practice.21,26,27 The overall rate of presumed infectious endophthalmitis in this study is near the lower end of the range reported from prior large studies of post-injection endophthalmitis, including multiple meta-analyses, with rates ranging from 0.008% to 0.092%.11-23,28 While some prior studies distinguish between infectious and noninfectious endophthalmitis, we considered cases to be presumed infectious if an injection of intravitreal antibiotics was performed. This is important to note in evaluating the rate of endophthalmitis in this study, as most retina specialists have a low threshold to treat with intravitreal antibiotics as a precautionary measure even if sterile endophthalmitis is high on the differential. The sample sizes of previous studies which specifically evaluated bilateral same day intravitreal injections ranged between 208 and 1534 intravitreal injections, but some studies were not limited to anti-VEGF injections alone.3,5-10 In these studies, the rates of unilateral endophthalmitis were between 0.0% and 0.48%. The studies with no cases of endophthalmitis 4
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were relatively small and acknowledge that larger studies are needed. No cases of bilateral endophthalmitis were noted. However, there has been a report of two cases of Staphylococcus epidermidis bilateral endophthalmitis following bilateral same day intravitreal bevacizumab.29 This study found no significant difference in the rates of endophthalmitis among the three anti-VEGF agents, which is similar to prior studies.27,30 Anecdotally, providers may be more concerned about bilateral same day bevacizumab injections given its off label indication and preparation by a compounding pharmacy. While prior endophthalmitis outbreaks have been associated with multidose contamination31,32, the Food and Drug Administration’s efforts to regulate compounding pharmacies are intended to lower this risk. This study has some limitations. The retrospective nature of the study with multiple treating physicians implies some degree of variability in injection technique and endophthalmitis management. Additionally, since billing codes were used to identify the indication and agent for each intravitreal injection, some injection encounter information such as indication was sporadically missing from the practice database. However, these injections make up a very small percentage of the overall large number of injections included in this study. As with any retrospective study of endophthalmitis, it is possible that some cases of endophthalmitis may not have been captured due to errors in coding, Although a case could have also been missed if follow up was with another retina provider, the practice has several locations over three states with a very large catchment area, decreasing the possibility of this. The percentage of bevacizumab injections in this study is significantly lower than what has been reported in larger U.S. populations, which may limit generalizability to all populations.2 However, prior studies have not demonstrated any difference in endophthalmitis based on drug choice.27 Furthermore, the patient population in this study predominantly received injections for neovascular AMD. Similarly, prior studies have suggested that endophthalmitis rates do not vary between AMD and DME26, and this is supported by our results as well. Despite these limitations, this study has several strengths. It is more than fifty times larger than prior studies of bilateral same day intravitreal injections, and a large sample size is imperative for studying a rare complication such as endophthalmitis. Data was collected from over twenty providers in the practice at various locations adding to the diversity of the study population and increasing generalizability. Although multiple providers are in the study, the practice has a standardized preparation protocol for intravitreal injections. While this study has the strength of the large sample size of other prior studies using administrative datasets created from billing codes, it also has the benefit of detailed chart review to confirm cases of endophthalmitis rather than relying on coding alone to assess for this outcome. In summary, our study of over 100,000 bilateral same day intravitreal anti-VEGF injections found a low rate of unilateral endophthalmitis comparable to prior studies of unilateral injections and no cases of bilateral endophthalmitis. These results lend support to the safety of this practice when great caution is taken to prevent infection at every step of the procedure. By performing bilateral same day injections, practitioners can significantly decrease the number of office visits necessary for treatment of patients with bilateral pathology. In fact, prior studies which have surveyed patients with bilateral pathology found that almost all patients in these studies preferred bilateral same-day intravitreal injections to staggered unilateral injections.7,9,10 As the number of patients requiring intravitreal anti-VEGF treatment 5
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continues to grow, efforts to validate practice patterns which improve efficiency for both patients and providers are imperative.
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Appendix 1: Wills Post-Injection Endophthalmitis (PIE) Study Group Members *Note: All members have the same affiliation- The Retina Service, Wills Eye Hospital
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Allen Chiang, MD James P. Dunn, MD Mitchell Fineman, MD David Fischer, MD Omesh Gupta, MD, MBA Allen Ho, MD Michael Klufas, MD Joseph Maguire, MD Sonia Mehta, MD Carl Park, MD Arunan Sivalingam, MD Marc Spirn, MD William Tasman, MD James Vander, MD
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Acknowledgements a. Funding/Support: None b. Financial Disclosures: C.R. Research grants: Genentech, Regeneron, Novartis, Allergan, Alcon; Consulting: Genentech, Allergan, Alcon, Novartis, Iconic R.K. Consulting: PanOptica S.G. Research grants: Aerpio, Allergan, Eyegate; Consulting: Deciphera, Santen J.H. Research grants: Roche/Genentech and Santen; Consulting: Ophthotech c. Other Acknowledgements: None
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References 1. McLaughlin MD, Hwang JC. Trends in Vitreoretinal Procedures for Medicare Beneficiaries, 2000 to 2014. Ophthalmology. 2017;124(5):667-673. 2. Parikh R, Ross JS, Sangaralingham LR, Adelman RA, Shah ND, Barkmeier AJ. Trends of Anti-Vascular Endothelial Growth Factor Use in Ophthalmology Among Privately Insured and Medicare Advantage Patients. Ophthalmology. 2017;124(3):352-358. 3. Giocanti-Auregan A, Tadayoni R, Grenet T, et al. Estimation of the need for bilateral intravitreal anti-VEGF injections in clinical practice. BMC Ophthalmol. 2016;16:142. 4. Green-Simms AE, Ekdawi NS, Bakri SJ. Survey of intravitreal injection techniques among retinal specialists in the United States. Am J Ophthalmol. 2011;151(2):329-332. 5. Okoye O, Okonkwo O, Oderinlo O, Hassan K, Ijasan A. Bilateral concomitant intravitreal anti-vascular endothelial growth factor injection: Experience in a Nigerian tertiary private eye care facility. Niger J Clin Pract. 2016;19(4):544-548. 6. Davis RP, Schefler AC, Murray TG. Concomitant bilateral intravitreal anti-VEGF injections for the treatment of exudative age-related macular degeneration. Clin Ophthalmol. 2010;4:703-707. 7. Mahajan VB, Elkins KA, Russell SR, et al. Bilateral intravitreal injection of antivascular endothelial growth factor therapy. Retina. 2011;31(1):31-35. 8. Lima LH, Zweifel SA, Engelbert M, et al. Evaluation of safety for bilateral same-day intravitreal injections of antivascular endothelial growth factor therapy. Retina. 2009;29(9):1213-1217. 9. Bakri SJ, Risco M, Edwards AO, Pulido JS. Bilateral simultaneous intravitreal injections in the office setting. Am J Ophthalmol. 2009;148(1):66-69 e61. 10. Abu-Yaghi NE, Shokry AN, Abu-Sbeit RH. Bilateral same-session intravitreal injections of anti-vascular endothelial growth factors. Int J Ophthalmol. 2014;7(6):1017-1021. 11. Daien V, Nguyen V, Essex RW, et al. Incidence and Outcomes of Infectious and Noninfectious Endophthalmitis after Intravitreal Injections for Age-Related Macular Degeneration. Ophthalmology. 2018;125(1):66-74. 12. McCannel CA. Meta-analysis of endophthalmitis after intravitreal injection of antivascular endothelial growth factor agents: causative organisms and possible prevention strategies. Retina. 2011;31(4):654-661. 13. Lyall DA, Tey A, Foot B, et al. Post-intravitreal anti-VEGF endophthalmitis in the United Kingdom: incidence, features, risk factors, and outcomes. Eye (Lond). 2012;26(12):15171526. 14. Fileta JB, Scott IU, Flynn HW, Jr. Meta-analysis of infectious endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmic Surg Lasers Imaging Retina. 2014;45(2):143-149. 15. Gregori NZ, Flynn HW, Jr., Schwartz SG, et al. Current Infectious Endophthalmitis Rates After Intravitreal Injections of Anti-Vascular Endothelial Growth Factor Agents and Outcomes of Treatment. Ophthalmic Surg Lasers Imaging Retina. 2015;46(6):643-648. 16. Meredith TA, McCannel CA, Barr C, et al. Postinjection endophthalmitis in the comparison of age-related macular degeneration treatments trials (CATT). Ophthalmology. 2015;122(4):817-821.
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Dossarps D, Bron AM, Koehrer P, Aho-Glele LS, Creuzot-Garcher C, net F. Endophthalmitis After Intravitreal Injections: Incidence, Presentation, Management, and Visual Outcome. Am J Ophthalmol. 2015;160(1):17-25 e11. Moshfeghi AA, Rosenfeld PJ, Flynn HW, Jr., et al. Endophthalmitis after intravitreal vascular [corrected] endothelial growth factor antagonists: a six-year experience at a university referral center. Retina. 2011;31(4):662-668. Day S, Acquah K, Mruthyunjaya P, Grossman DS, Lee PP, Sloan FA. Ocular complications after anti-vascular endothelial growth factor therapy in Medicare patients with agerelated macular degeneration. Am J Ophthalmol. 2011;152(2):266-272. Casparis H, Wolfensberger TJ, Becker M, et al. Incidence of presumed endophthalmitis after intravitreal injection performed in the operating room: a retrospective multicenter study. Retina. 2014;34(1):12-17. Shah CP, Garg SJ, Vander JF, et al. Outcomes and risk factors associated with endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmology. 2011;118(10):2028-2034. Nentwich MM, Yactayo-Miranda Y, Schwarzbach F, Wolf A, Kampik A, Mino de Kaspar H. Endophthalmitis after intravitreal injection: decreasing incidence and clinical outcome8-year results from a tertiary ophthalmic referral center. Retina. 2014;34(5):943-950. Chen E, Lin MY, Cox J, Brown DM. Endophthalmitis after intravitreal injection: the importance of viridans streptococci. Retina. 2011;31(8):1525-1533. Fineman MS, Hsu J, Spirn MJ, Kaiser RS. Bimanual assisted eyelid retraction technique for intravitreal injections. Retina. 2013;33(9):1968-1970. Rahimy E, Fineman MS, Regillo CD, et al. Speculum versus Bimanual Lid Retraction during Intravitreal Injection. Ophthalmology. 2015;122(8):1729-1730. Rayess N, Rahimy E, Shah CP, et al. Incidence and clinical features of post-injection endophthalmitis according to diagnosis. Br J Ophthalmol. 2016;100(8):1058-1061. Rayess N, Rahimy E, Storey P, et al. Postinjection Endophthalmitis Rates and Characteristics Following Intravitreal Bevacizumab, Ranibizumab, and Aflibercept. Am J Ophthalmol. 2016;165:88-93. Moshfeghi AA. Endophthalmitis following intravitreal anti-vascular endothelial growth factor injections for neovascular age-related macular degeneration. Semin Ophthalmol. 2011;26(3):139-148. Tabatabaii A, Ahmadraji A, Khodabande A, Mansouri M. Acute bilateral endophthalmitis following bilateral intravitreal bevacizumab (avastin) injection. Middle East Afr J Ophthalmol. 2013;20(1):87-88. VanderBeek BL, Bonaffini SG, Ma L. Association of compounded bevacizumab with postinjection endophthalmitis. JAMA Ophthalmol. 2015;133(10):1159-1164. Goldberg RA, Flynn HW, Jr., Isom RF, Miller D, Gonzalez S. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol. 2012;153(2):204-208 e201. Goldberg RA, Flynn HW, Jr., Miller D, Gonzalez S, Isom RF. Streptococcus endophthalmitis outbreak after intravitreal injection of bevacizumab: one-year outcomes and investigative results. Ophthalmology. 2013;120(7):1448-1453.
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Figure 1: Trends in anti-VEGF Injections by Agent
Figure 2: Number of Bilateral Injections by Year
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Figure 1: Figure showing number of injections performed each year by agent at a large academic private practice with locations in PA, NJ, and DE between April 1, 2012 and August 21, 2017. While the number of bevacizumab injections remained fairly constant during the study period, there was a steady increase in aflibercept injections starting in 2014 and corresponding to a decline in ranibizumab injections. 2017 is not included as the full calendar year is not included in the study period.
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Figure 2: Figure displaying the number of bilateral injections performed each year at a large academic private practice with locations in PA, NJ, and DE between April 1, 2012 and August 21, 2017. The figure shows a steady increase in the number of bilateral injections performed.
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2319 (39.4) 3571 (60.6)
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1 (0.02) 172 (2.9) 1248 (21.2) 1250 (21.2) 3219 (54.7)
100 (1.7) 475 (8.1) 24 (0.4) 4721 (80.2) 570 (9.7) 3197 (54.3) 2083 (35.4) 242 (4.1) 98 (1.7) 270 (4.6)
Denominator for all percentages is 5,890 patients
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74.2 (14.1)
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Age (y), Mean SD Age category (y) <18 18-44 45-64 65-74 75+ Gender Male Female Race Asian African American Hispanic/Latino White Unknown/other Diagnosis Neovascular AMD Diabetic Macular Edema Retinal Vein Occlusion Multiple Etiologies Missing
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Baseline Characteristic
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Bevacizumab Ranibizumab
Neovascular AMD
7,076 (49.3)
Aflibercept
Total Injections
19,213 (59.0)
68,946 (67.6)
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So me sub DME 5,730 (40.0) 9,099 (16.5) 11,679 (35.9) 26,508 (26.0) grou RVO 319 (2.2) 1,655 (3.0) 588 (1.8) 2,562 (2.5) p tota Multiple 665 (4.6) 1,433 (2.6) 958 (2.9) 3,056 (3.0) ls Missing etiology 549 (3.8) 207 (0.4) 104 (0.3) 860 (0.8) for num Total Injections 14,339 55,051 32,542 101,932 ber of injections may be odd numbers as there were some patients in the study who received a different anti-VEGF agent in each eye.
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42,657 (77.5)
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Total (%)
Number of Cases
28
Age (y), Mean SD
75.9(17.1)
Male
White
27 (96.4)
Asian
1 (3.6)
Laterality 13 (46.4)
Left
15 (53.6)
Diagnosis Neovascular AMD
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10 (35.7)
23 (82.1)
DME
5 (17.9)
Visual Acuity at Causative Injection 20/20-20/40
12 (42.9)
20/50-20/200 20/400 or worse
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11 (39.3) 5 (17.9)
Visual Acuity at 12 Months1 20/20-20/40
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20/400 or worse
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Bilateral Injections Resumed
11 (42.3) 10 (38.5) 16 (57.1)
2 patients did not have 12 month follow up data available (n=26)
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S0002-9394(18)30326-X
DOI:
10.1016/j.ajo.2018.06.022
Reference:
AJOPHT 10568
To appear in:
American Journal of Ophthalmology
Received Date: 3 June 2018 Revised Date:
20 June 2018
Accepted Date: 26 June 2018
Please cite this article as: Borkar DS, Obeid A, Su DC, Storey PP, Gao X, Regillo CD, Kaiser RS, Garg SJ, Hsu J, for the Wills Post Injection Endophthalmitis (PIE) Study Group, Chiang A, Dunn JP, Fineman M, Fischer D, Gupta O, Ho A, Klufas M, Maguire J, Mehta S, Park C, Sivalingam A, Spirn M, Tasman W, Vander J, Endophthalmitis Rates after Bilateral Same Day Intravitreal Anti-Vascular Endothelial Growth Factor Injections, American Journal of Ophthalmology (2018), doi: 10.1016/j.ajo.2018.06.022. 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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Abstract Purpose: To evaluate practice patterns for bilateral same day intravitreal anti- vascular
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endothelial growth factor (VEGF) injections and determine the rate of unilateral and bilateral post-injection endophthalmitis after bilateral same day intravitreal anti-VEGF injections. Design: Retrospective cohort study
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Methods: The records of a large academic private practice were electronically queried for all office visits during which bilateral intravitreal anti-VEGF injections were performed between
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April 1, 2012 and August 21, 2017 for patients with a diagnosis of neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion. Demographic information and indication for injection were recorded for each patient and office visit. Charts of patients with endophthalmitis were reviewed, and information was collected on
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presentation exam, culture data, and visual outcomes.
Results: During the study period, 101,932 bilateral same day intravitreal anti-VEGF injections were performed over 50,966 office visits for 5,890 patients. The mean (standard deviation) age
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of patients in this cohort was 74.2 (14.1) years and 60.6% of patients were female. The two most common indications for injection were neovascular age-related macular degeneration
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(54.3% of patients) and diabetic macular edema (35.4% of patients). Twenty-eight cases of endophthalmitis (0.027% of total injections) occurred during the study period. There were no cases of bilateral endophthalmitis, and no patients had more than one occurrence of endophthalmitis. Conclusions: In this large cohort of patients undergoing bilateral same day intravitreal antiVEGF injections, there were no cases of bilateral endophthalmitis. Additionally, the overall rate
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of unilateral endophthalmitis was low and comparable to prior studies of unilateral injections.
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These results support the safety of bilateral same day intravitreal anti-VEGF treatment.
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Endophthalmitis Rates after Bilateral Same Day Intravitreal Anti-Vascular Endothelial Growth Factor Injections
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The Retina Service, Wills Eye Hospital, Philadelphia, PA
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Financial Support: None
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Durga S. Borkar1, MD, Anthony Obeid, MD, MPH1, Daniel C. Su, MD1, Philip P. Storey, MD, MPH1, Xinxiao Gao, MD1, Carl D. Regillo, MD, FACS1, Richard S. Kaiser, MD1, Sunir J. Garg, MD1, Jason Hsu, MD1 for the Wills Post Injection Endophthalmitis (PIE) Study Group
Conflict of Interest: D.B, A.O, D.S, P.S, X.G have no conflicts of interest.
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C.R. Research grants: Genentech, Regeneron, Novartis, Allergan, Alcon; Consulting: Genentech, Allergan, Alcon, Novartis, Iconic R.K. Consulting: PanOptica
S.G. Research grants: Aerpio, Allergan, Eyegate; Consulting: Deciphera, Santen
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J.H. Research grants: Roche/Genentech and Santen; Consulting: Ophthotech
Meeting presentation: This study is scheduled to be presented as a paper presentation at the American Society of Retina Specialists Annual Meeting, Vancouver, BC July 2018
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Short Title: Endophthalmitis after Bilateral Same Day Anti-VEGF Injections
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Corresponding Author: Jason Hsu, MD Retina Service, Wills Eye Hospital 840 Walnut Street Suite 1020 Philadelphia, PA 19107 Phone number: +1(215) 928 3092 Email: [email protected]
Abbreviations and acronyms: AMD, age-related macular degeneration; DME, diabetic macular edema; ICD, international classification of disease; RVO, retinal vein occlusion; VEGF, vascular endothelial growth factor.
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Introduction Intravitreal anti-VEGF injections are currently the most commonly performed procedure in medicine, with 2.3 million injections performed for Medicare beneficiaries alone in 2014.1 The most common indications for anti-VEGF therapy, neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME), often require chronic, bilateral treatment.2,3 This leads to both increased physician and patient burden in terms of office visits. As a result, methods to provide more efficient care are needed. For patients undergoing bilateral treatment, many retina specialists will perform bilateral same day intravitreal injections to help minimize office visits for patients. The most recent survey of retina specialists nationally revealed that 46% of retina specialists routinely perform bilateral same day injections.4 Some practitioners prefer to avoid bilateral same day injections due to fear of possible bilateral endophthalmitis as well as the possibility of increased systemic absorption of anti-VEGF. To date, few studies have been performed evaluating rates of endophthalmitis following bilateral same day intravitreal anti-VEGF injection, and all of these studies have reviewed less than 2,000 intravitreal injections.5-10 Given the low rates of endophthalmitis following intravitreal injection and large sample size needed11-23, a larger study investigating this topic is warranted. The purpose of this study was to assess the rate and outcomes of unilateral and bilateral endophthalmitis in a large cohort of patients receiving bilateral same day anti-VEGF therapy.
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Methods Institutional Review Board approval was obtained from the Wills Eye Hospital review board. All work was performed in accordance with the Health Insurance Portability and Accountability Act of 1996 and adhered to the tenets of the Declaration of Helsinki. The electronic medical records of the Mid Atlantic Retina practice were queried for all office visits during which bilateral same day intravitreal anti-VEGF injections were performed between April 1, 2012 and August 21, 2017 using Current Procedural Terminology codes. International Classification of Diseases, 9th and 10th Editions (ICD-9 or ICD-10) codes were used to determine the indication for each injection. Missing diagnoses or differing diagnoses between the two eyes were also noted. Basic demographic information was also extracted for each patient included in the study. All anti-VEGF injections were administered in an office-based setting by a vitreoretinal fellow or a fellowship-trained retina specialist. Bevacizumab injections were administered using prepackaged syringes from a compounding pharmacy, while aflibercept syringes were loaded from single-use vials during the office visit. Ranibizumab injections were administered using either syringes loaded from single-use vials during the office visit or prefilled syringes later in the study period. The preinjection preparation typically consisted of two rounds of topical anesthesia with 0.5% proparacaine hydrochloride (Alcaine, Alcon Labs, Fort Worth, Texas, USA) or 0.5% tetracaine hydrochloride (Tetracaine, Alcon Labs, Fort Worth, Texas, USA) and 5% povidone-iodine (Betadine 5%, Alcon Labs, Fort Worth, Texas, USA) applied topically to the conjunctiva. Based on patient preference, some patients also received an additional 1-2% subconjunctival lidocaine injection followed by 5% povidone-iodine. Typically, eyelid retraction was performed using a bimanual eyelid retraction technique, which has been previously 2
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Results
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described.24,25 Although choice of injection quadrant could vary, injections were generally performed in the inferotemporal quadrant with conjunctival displacement performed at the discretion of the treating physician. Injections were performed 3.0-4.0 mm from the limbus using a 30- or 31-gauge needle. Bilateral injections were set up by the technician concurrently and performed in the same procedure room. The same bottles of anesthetic and betadine were used for each eye. The second injection was performed immediately after the first injection. The choice of which eye, right or left, was injected first was left to the treating physician’s discretion. ICD-9 and ICD-10 codes for endophthalmitis were used to electronically identify cases of endophthalmitis within 30 days of intravitreal injection. If additional procedures were performed in this post-injection period, such as glaucoma or cataract surgery, these cases were excluded from the study. All possible cases of endophthalmitis from this electronic search were individually reviewed to confirm a diagnosis of presumed infectious endophthalmitis. For each case, laterality, injection number, anti-VEGF agent, indication for anti-VEGF injection, preendophthalmitis Snellen visual acuity, presentation clinical exam, treatments, and posttreatment Snellen visual acuity at 1, 3, 6, and 12 months were reviewed. Presumed infectious endophthalmitis was defined based on a clinical decision to proceed with either a vitreous or anterior chamber tap and injection of intravitreal antibiotics or a pars plana vitrectomy with injection of intravitreal antibiotics. Cases of post-injection inflammation that were treated with topical steroids and close monitoring alone without injection of intravitreal antibiotics were not included. All statistical analyses were conducted using SPSS, Version 24 (SPSS, Inc, Chicago, IL, USA). Categorical variables were compared using a chi-square test and continuous variables were compared using a two-sample t-test. A p-value less than 0.05 was considered statistically significant.
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During the study period, 101,932 bilateral same day intravitreal anti-VEGF injections were performed over 50,966 office visits for 5,890 patients. The baseline demographic and clinical characteristics are described in Table 1. The average age of the study population at the time of first injection was 74.2 years (SD=14.1 years) and 60.6% of the study population was female. The most common indication for injection was neovascular AMD (54.3% of patients, Table 1), while the second most common was diabetic macular edema (35.4% of patients, Table 1). Of the 101,932 intravitreal anti-VEGF injections included in the study, 55,051 (54.0%, Table 2) ranibizumab injections, 32,542 (31.9%, Table 2) aflibercept injections and 14,339 bevacizumab injections (14.1%, Table 2) were performed. Nearly two thirds of injections were for neovascular AMD. Ranibizumab was the most common agent used for neovascular AMD treatment, while aflibercept was the most common treatment choice for DME. Temporal trends were noted throughout the study period. While the number of bevacizumab injections remained fairly constant each year, there was a significant increase in the number of aflibercept injections starting in 2014 which corresponded to an annual decrease in the number of ranibizumab injections performed each year starting in 2014 (Figure 1). Over
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time, the number of bilateral same day injections performed increased, ranging from 870 injections per month in 2012 to approximately 2300 injections per month in 2017 (Figure 2). Twenty-eight cases of unilateral endophthalmitis were identified and confirmed by individual chart review, corresponding to a rate of 0.027% (approximately 1 in 3,700 injections). No cases of bilateral endophthalmitis were identified, and no patients had more than one case of endophthalmitis during the study period. The basic clinical and demographic characteristics of these cases are described in Table 3 and were similar to the overall study cohort. There were five cases of endophthalmitis after bevacizumab injection (0.035%), ten cases of endophthalmitis after ranibizumab injection (0.018%) and thirteen cases of endophthalmitis after aflibercept injection (0.039%). There was no statistically significant difference between the rates of endophthalmitis (p=0.15) among the three anti-VEGF agents. Similarly, there was no significant difference in the rates of endophthalmitis based on the diagnosis of neovascular AMD (0.033%) versus diabetic macular edema (0.019%, p=0.20) Twenty-five of twenty-eight patients (89%) presented within the first week after injection. Three patients (11%) presented more than three weeks after intravitreal injection. All patients in this series were initially treated with vitreous (or anterior chamber) tap and injection of intravitreal antibiotics on the day of presentation. Culture data was not available for all patients if it was done at an outside laboratory and not documented in the available exam notes. Eleven patients (39%) subsequently underwent pars plana vitrectomy and two of these patients had a retinal detachment requiring surgery. Baseline and twelve-month visual acuity outcomes are described in Table 3. Sixteen patients (57%) resumed bilateral same day intravitreal injections within one year of endophthalmitis diagnosis.
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Discussion In this study evaluating more than 100,000 bilateral same day intravitreal injections, the overall rate of endophthalmitis was 0.027% of total injections. There were no cases of bilateral endophthalmitis, and no patients had endophthalmitis more than once during the study period. Overall, 57% of patients elected to resume bilateral same day intravitreal injections within one year of endophthalmitis diagnosis. While there was no direct comparison to endophthalmitis rates after unilateral injections in this same population, there are multiple reports on the rates of endophthalmitis after predominantly unilateral intravitreal anti-VEGF injections, including studies from this practice.21,26,27 The overall rate of presumed infectious endophthalmitis in this study is near the lower end of the range reported from prior large studies of post-injection endophthalmitis, including multiple meta-analyses, with rates ranging from 0.008% to 0.092%.11-23,28 While some prior studies distinguish between infectious and noninfectious endophthalmitis, we considered cases to be presumed infectious if an injection of intravitreal antibiotics was performed. This is important to note in evaluating the rate of endophthalmitis in this study, as most retina specialists have a low threshold to treat with intravitreal antibiotics as a precautionary measure even if sterile endophthalmitis is high on the differential. The sample sizes of previous studies which specifically evaluated bilateral same day intravitreal injections ranged between 208 and 1534 intravitreal injections, but some studies were not limited to anti-VEGF injections alone.3,5-10 In these studies, the rates of unilateral endophthalmitis were between 0.0% and 0.48%. The studies with no cases of endophthalmitis 4
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were relatively small and acknowledge that larger studies are needed. No cases of bilateral endophthalmitis were noted. However, there has been a report of two cases of Staphylococcus epidermidis bilateral endophthalmitis following bilateral same day intravitreal bevacizumab.29 This study found no significant difference in the rates of endophthalmitis among the three anti-VEGF agents, which is similar to prior studies.27,30 Anecdotally, providers may be more concerned about bilateral same day bevacizumab injections given its off label indication and preparation by a compounding pharmacy. While prior endophthalmitis outbreaks have been associated with multidose contamination31,32, the Food and Drug Administration’s efforts to regulate compounding pharmacies are intended to lower this risk. This study has some limitations. The retrospective nature of the study with multiple treating physicians implies some degree of variability in injection technique and endophthalmitis management. Additionally, since billing codes were used to identify the indication and agent for each intravitreal injection, some injection encounter information such as indication was sporadically missing from the practice database. However, these injections make up a very small percentage of the overall large number of injections included in this study. As with any retrospective study of endophthalmitis, it is possible that some cases of endophthalmitis may not have been captured due to errors in coding, Although a case could have also been missed if follow up was with another retina provider, the practice has several locations over three states with a very large catchment area, decreasing the possibility of this. The percentage of bevacizumab injections in this study is significantly lower than what has been reported in larger U.S. populations, which may limit generalizability to all populations.2 However, prior studies have not demonstrated any difference in endophthalmitis based on drug choice.27 Furthermore, the patient population in this study predominantly received injections for neovascular AMD. Similarly, prior studies have suggested that endophthalmitis rates do not vary between AMD and DME26, and this is supported by our results as well. Despite these limitations, this study has several strengths. It is more than fifty times larger than prior studies of bilateral same day intravitreal injections, and a large sample size is imperative for studying a rare complication such as endophthalmitis. Data was collected from over twenty providers in the practice at various locations adding to the diversity of the study population and increasing generalizability. Although multiple providers are in the study, the practice has a standardized preparation protocol for intravitreal injections. While this study has the strength of the large sample size of other prior studies using administrative datasets created from billing codes, it also has the benefit of detailed chart review to confirm cases of endophthalmitis rather than relying on coding alone to assess for this outcome. In summary, our study of over 100,000 bilateral same day intravitreal anti-VEGF injections found a low rate of unilateral endophthalmitis comparable to prior studies of unilateral injections and no cases of bilateral endophthalmitis. These results lend support to the safety of this practice when great caution is taken to prevent infection at every step of the procedure. By performing bilateral same day injections, practitioners can significantly decrease the number of office visits necessary for treatment of patients with bilateral pathology. In fact, prior studies which have surveyed patients with bilateral pathology found that almost all patients in these studies preferred bilateral same-day intravitreal injections to staggered unilateral injections.7,9,10 As the number of patients requiring intravitreal anti-VEGF treatment 5
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continues to grow, efforts to validate practice patterns which improve efficiency for both patients and providers are imperative.
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Appendix 1: Wills Post-Injection Endophthalmitis (PIE) Study Group Members *Note: All members have the same affiliation- The Retina Service, Wills Eye Hospital
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Allen Chiang, MD James P. Dunn, MD Mitchell Fineman, MD David Fischer, MD Omesh Gupta, MD, MBA Allen Ho, MD Michael Klufas, MD Joseph Maguire, MD Sonia Mehta, MD Carl Park, MD Arunan Sivalingam, MD Marc Spirn, MD William Tasman, MD James Vander, MD
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Acknowledgements a. Funding/Support: None b. Financial Disclosures: C.R. Research grants: Genentech, Regeneron, Novartis, Allergan, Alcon; Consulting: Genentech, Allergan, Alcon, Novartis, Iconic R.K. Consulting: PanOptica S.G. Research grants: Aerpio, Allergan, Eyegate; Consulting: Deciphera, Santen J.H. Research grants: Roche/Genentech and Santen; Consulting: Ophthotech c. Other Acknowledgements: None
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References 1. McLaughlin MD, Hwang JC. Trends in Vitreoretinal Procedures for Medicare Beneficiaries, 2000 to 2014. Ophthalmology. 2017;124(5):667-673. 2. Parikh R, Ross JS, Sangaralingham LR, Adelman RA, Shah ND, Barkmeier AJ. Trends of Anti-Vascular Endothelial Growth Factor Use in Ophthalmology Among Privately Insured and Medicare Advantage Patients. Ophthalmology. 2017;124(3):352-358. 3. Giocanti-Auregan A, Tadayoni R, Grenet T, et al. Estimation of the need for bilateral intravitreal anti-VEGF injections in clinical practice. BMC Ophthalmol. 2016;16:142. 4. Green-Simms AE, Ekdawi NS, Bakri SJ. Survey of intravitreal injection techniques among retinal specialists in the United States. Am J Ophthalmol. 2011;151(2):329-332. 5. Okoye O, Okonkwo O, Oderinlo O, Hassan K, Ijasan A. Bilateral concomitant intravitreal anti-vascular endothelial growth factor injection: Experience in a Nigerian tertiary private eye care facility. Niger J Clin Pract. 2016;19(4):544-548. 6. Davis RP, Schefler AC, Murray TG. Concomitant bilateral intravitreal anti-VEGF injections for the treatment of exudative age-related macular degeneration. Clin Ophthalmol. 2010;4:703-707. 7. Mahajan VB, Elkins KA, Russell SR, et al. Bilateral intravitreal injection of antivascular endothelial growth factor therapy. Retina. 2011;31(1):31-35. 8. Lima LH, Zweifel SA, Engelbert M, et al. Evaluation of safety for bilateral same-day intravitreal injections of antivascular endothelial growth factor therapy. Retina. 2009;29(9):1213-1217. 9. Bakri SJ, Risco M, Edwards AO, Pulido JS. Bilateral simultaneous intravitreal injections in the office setting. Am J Ophthalmol. 2009;148(1):66-69 e61. 10. Abu-Yaghi NE, Shokry AN, Abu-Sbeit RH. Bilateral same-session intravitreal injections of anti-vascular endothelial growth factors. Int J Ophthalmol. 2014;7(6):1017-1021. 11. Daien V, Nguyen V, Essex RW, et al. Incidence and Outcomes of Infectious and Noninfectious Endophthalmitis after Intravitreal Injections for Age-Related Macular Degeneration. Ophthalmology. 2018;125(1):66-74. 12. McCannel CA. Meta-analysis of endophthalmitis after intravitreal injection of antivascular endothelial growth factor agents: causative organisms and possible prevention strategies. Retina. 2011;31(4):654-661. 13. Lyall DA, Tey A, Foot B, et al. Post-intravitreal anti-VEGF endophthalmitis in the United Kingdom: incidence, features, risk factors, and outcomes. Eye (Lond). 2012;26(12):15171526. 14. Fileta JB, Scott IU, Flynn HW, Jr. Meta-analysis of infectious endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmic Surg Lasers Imaging Retina. 2014;45(2):143-149. 15. Gregori NZ, Flynn HW, Jr., Schwartz SG, et al. Current Infectious Endophthalmitis Rates After Intravitreal Injections of Anti-Vascular Endothelial Growth Factor Agents and Outcomes of Treatment. Ophthalmic Surg Lasers Imaging Retina. 2015;46(6):643-648. 16. Meredith TA, McCannel CA, Barr C, et al. Postinjection endophthalmitis in the comparison of age-related macular degeneration treatments trials (CATT). Ophthalmology. 2015;122(4):817-821.
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Figure 1: Trends in anti-VEGF Injections by Agent
Figure 2: Number of Bilateral Injections by Year
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Figure 1: Figure showing number of injections performed each year by agent at a large academic private practice with locations in PA, NJ, and DE between April 1, 2012 and August 21, 2017. While the number of bevacizumab injections remained fairly constant during the study period, there was a steady increase in aflibercept injections starting in 2014 and corresponding to a decline in ranibizumab injections. 2017 is not included as the full calendar year is not included in the study period.
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Figure 2: Figure displaying the number of bilateral injections performed each year at a large academic private practice with locations in PA, NJ, and DE between April 1, 2012 and August 21, 2017. The figure shows a steady increase in the number of bilateral injections performed.
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2319 (39.4) 3571 (60.6)
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1 (0.02) 172 (2.9) 1248 (21.2) 1250 (21.2) 3219 (54.7)
100 (1.7) 475 (8.1) 24 (0.4) 4721 (80.2) 570 (9.7) 3197 (54.3) 2083 (35.4) 242 (4.1) 98 (1.7) 270 (4.6)
Denominator for all percentages is 5,890 patients
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74.2 (14.1)
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Age (y), Mean SD Age category (y) <18 18-44 45-64 65-74 75+ Gender Male Female Race Asian African American Hispanic/Latino White Unknown/other Diagnosis Neovascular AMD Diabetic Macular Edema Retinal Vein Occlusion Multiple Etiologies Missing
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Baseline Characteristic
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Bevacizumab Ranibizumab
Neovascular AMD
7,076 (49.3)
Aflibercept
Total Injections
19,213 (59.0)
68,946 (67.6)
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So me sub DME 5,730 (40.0) 9,099 (16.5) 11,679 (35.9) 26,508 (26.0) grou RVO 319 (2.2) 1,655 (3.0) 588 (1.8) 2,562 (2.5) p tota Multiple 665 (4.6) 1,433 (2.6) 958 (2.9) 3,056 (3.0) ls Missing etiology 549 (3.8) 207 (0.4) 104 (0.3) 860 (0.8) for num Total Injections 14,339 55,051 32,542 101,932 ber of injections may be odd numbers as there were some patients in the study who received a different anti-VEGF agent in each eye.
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42,657 (77.5)
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Total (%)
Number of Cases
28
Age (y), Mean SD
75.9(17.1)
Male
White
27 (96.4)
Asian
1 (3.6)
Laterality 13 (46.4)
Left
15 (53.6)
Diagnosis Neovascular AMD
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10 (35.7)
23 (82.1)
DME
5 (17.9)
Visual Acuity at Causative Injection 20/20-20/40
12 (42.9)
20/50-20/200 20/400 or worse
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11 (39.3) 5 (17.9)
Visual Acuity at 12 Months1 20/20-20/40
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20/400 or worse
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Bilateral Injections Resumed
11 (42.3) 10 (38.5) 16 (57.1)
2 patients did not have 12 month follow up data available (n=26)
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