`
`-
`
`HHS Public Access
`Author manuscript
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`
`
`Published in final edited form as:
`Ophthalmol Retina. 2019 August ; 3(8): 656–662. doi:10.1016/j.oret.2019.03.023.
`
`Real World Trends in Intravitreal Injection Practices Among
`American Retina Specialists
`
`Rahul Chaturvedi, BS1, Kendall W. Wannamaker, MD2, Paul J. Riviere, BS5, Arshad M.
`Khanani, MD, MA3, Charles C. Wykoff, MD, PHD4, Daniel L. Chao, MD, PhD6
`1UC San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093
`
`2UT Health Science Center San Antonio
`
`3Sierra Eye Associates, 950 Ryland Street Reno, NV
`
`4Retina Consultants of Houston, Blanton Eye Institute, Houston Methodist Hospital, Houston,
`Texas
`
`5Department of Radiation Medicine and Applied Sciences, UC San Diego, La Jolla, CA 92093
`
`6Shiley Eye Institute, Andrew Viterbi Department of Ophthalmology, University of California San
`Diego, La Jolla, CA 92093
`
`Abstract
`
`Purpose: To analyze practice patterns employed for intravitreal injections (IVI) by retinal
`specialists in the United States.
`
`Design: Cross-sectional online survey.
`
`Participants: Retina specialists in the United States who responded to a web-based survey.
`
`Methods: Retinal specialists in the United States were contacted via email to complete a web-
`based, anonymous 24-question survey. Multivariate analysis was performed on a selected question
`of interest focused on choice of anesthetic used for IVI.
`
`Main Outcome Measures: Differences in IVI practices, such as antibiotic preferences, and
`different odds of anesthetic use by demographic variables with 95% confidence intervals (CI).
`
`Results: A total of 281 retinal specialists responded to the survey (17% response rate).
`Respondents had an average age of 53 years with an average of 20 years in practice. Respondents
`practiced in 42 states, with 90% practicing in an urban or suburban area. For anesthesia, 14%
`utilized a topical anesthetic with cotton swab compression, 27% a subconjunctival anesthetic, and
`31% an anesthetic gel. Age, gender, geographic location, and practice setting did not appear to
`significantly impact choice of anesthetic for IVI. 66% of respondents always used a lid speculum,
`
`Address for reprints: 9415 Campus Point Drive, La Jolla, CA 92093-0946. Correspondence to: Dr. Daniel L. Chao, UC San Diego
`Health, 9415 Campus Point Drive, La Jolla, CA 92093-0946, Phone: (858)-534-6290, d6chao@ucsd.edu.
`Publisher's Disclaimer: 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 citable 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.
`Conflict of Interest: No conflicting relationship exists for any author
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 2
`
`21% administered topical antibiotics prior to injection, 36% wore a mask, 73% wore gloves, and
`45% always dilated the eyes prior to injection. The majority of respondents utilized a 30-gauge
`needle and injected in the inferior temporal quadrant (70%). 45% would always perform bilateral
`injections the same day if indicated. After the injection, 14% administered post op NSAIDs, 28%
`administered post-op antibiotics, and 31% routinely checked intraocular pressure after injection.
`
`Conclusions: This study provides real-world trends in practices for IVI among retina specialists
`in the United States. In addition, age, gender, practice type, or geographic location did not
`influence anesthetic choice for IVI.
`Precis
`This large survey of intravitreal injection practices among retina specialists in the United States
`illustrates current real world trends and preferences among retina specialists.
`
`Introduction
`
`Intravitreal Injections (IVI) have now been accepted as the standard of care for delivering
`therapeutics to the retina. Since 2006, there has been rapid increase in the number of
`intravitreal injections, estimated to have been around 5.9 million in 2016.1 There is a wide
`spectrum of approaches employed for preparation, technique, antibiotic usage, and post
`injection examinations for intravitreal injections.2,3 These practices generally involve
`considerations for preventing endophthalmitis, improving patient comfort, and optimizing
`clinical workflow. The most concerning risk associated with IVI has been the development
`of endophthalmitis. Employing different techniques before, during and after IVI procedures,
`such as the decision to use povidone-iodine either in addition to or instead of prophylactic
`antibiotics, can affect the rates of endophthalmitis.4 Additional complications of IVI include
`an elevated intraocular pressure, ocular hemorrhage, rhegmatogenous retinal detachment,
`and cataract formation.4–7
`
`While various guidelines have been published by various groups for evidence based
`practices surrounding IVI, it is unclear how these practices are incorporated in the real
`world.2,3 Furthermore it is unknown whether demographic characteristics, such as age,
`gender, or practice setting can affect certain practices, such as choice of anesthetic used for
`IVI. The purpose of this study is to survey current practices surrounding intravitreal
`injections in the United States and to analyze differences based on various demographic
`parameters for choice of anesthetic used in IVI.
`
`A subset of retina specialists in the United States were contacted via email to complete a
`cross-sectional 24 question, internet-based survey aimed at better understanding pre-
`procedure methodologies, materials used, medications used, and post-procedure protocols
`related to IVI. This subset was identified by cross referencing names from the American
`Society of Retina Specialists Find a Retina Specialist webpage (https://www.asrs.org/find-a-
`specialist) (USA as a search term)n to contact information obtained from publicly available
`sources as well as other retina specialists.
`
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`Methods
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 3
`
`The survey was created in the Qualtrics Research Core Platform, a web-based platform that
`allows data storage in a password-protected database and export data into CSV, PDF, and
`Powerpoint formats. The survey was entirely anonymous and thus no identifiable
`information was acquired or stored in the database and is compliant with current HIPAA
`guidelines. The first page of the survey was an informed consent page and required every
`participant to agree to the informed consent to be eligible to complete the survey. This
`research study has been certified as exempt from IRB review by the UC San Diego Human
`Research Protections Program and permits the administration of the web-based survey to
`retinal specialists. The research study adhered to the tenets of the Declaration of Helsinki.
`
`On November 5th, 2018 , emails were sent out to 1676 retina specialists in the United States,
`of which 34 emails immediately were returned. Thus, the survey was successfully sent out to
`1642 participants, of which 281 completed the survey. Between November 5th and
`December 11th, two email reminders to complete the survey were sent to the retina
`specialists. The second email reminder stated that the survey would be closed within 7 days.
`The survey response collection was stopped on December 14th, 2018 and results were
`analyzed on December 17th, 2018.
`
`For choice of anesthetic used for IVI, we used logistic regression to quantify and evaluate
`the relationship between demographic covariates and responses. Response to a question was
`treated as a binary (yes/no) with non-responders excluded from the analysis. All
`demographic covariates of interest were included in the multivariate regression, which
`include age, gender, geographic location, and practice setting. We reported odds ratios with
`relation to reference groups as discussed in the results section, as well as 95% confidence
`intervals and p-values using the Wald test. All statistics were performed using R version
`3.5.2 (https://cran r-project.org/).”
`
`Results
`
`Demographics
`
`There were a total of 281 individuals (17% response rate) who responded to the survey by
`the allotted deadline, which was stated in the final reminder email. Some of the respondents
`chose not to respond to select questions in the survey. The age range of respondents was 29
`to 78, with an average age of 53. Eighty-five percent of respondents identify as male
`(240/281) and 13% as female (37/281). Among the respondents, 11% have been in practice
`between 0 and 5 years post-fellowship (31/279), 14% between 6 and 10 (39/279), 11%
`between 11 and 15 (32/279), 15% between 16 and 20 (41/279), and 49% for 21 or more
`years (136/279), with an average practice length of 20 years post-fellowship and practice
`length range between 1 and 46 years. In terms of geographic distribution, physicians from 42
`different states responded to the survey, with the largest representation from California
`(15%, 4½74), Florida (9%, 24/274), Texas (7%, 19/274), and New York (7%, 18/274). Fifty-
`two percent of respondents categorized the setting of their practice as suburban (146/281),
`42% as Urban (117/281), 5% as Rural (15/281) and 1% as other (3/281). With respect to
`practice setting, 40% work in a “Retina-only practice with greater than 2 retina specialists in
`the group” (112/280), 20% in a “Multi-specialty ophthalmology group” (57/280), 20% in an
`“Academic/University medical group” (56/280), 16% in “Solo or less than 3 retinal
`
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 4
`
`specialists in a retinal only group” (45/280), and 4% in a “Large multi-specialty medical
`group” (10/280). Around half of the respondents perform between 30–80 IVI per week
`(138/281), 20% perform between 0 and 30 IVI per week (57/281), and 31% perform 80 or
`more IVI per week (86/281).
`
`Pre-Injection Procedures
`
`The results for the pre-injection practices are detailed in Table 1. Briefly, seventy-two
`percent of respondents reported a nurse or assistant present in the room to help in
`preparation (20½81). There was a wide array of responses with respect to the type(s) of
`anesthetics used prior to injection. Among respondents, 16% reported using a topical
`anesthetic only (46/281), 14% using a topical anesthetic and cotton swab compression
`(40/281), 31% using an anesthetic gel only or in addition to a topical anesthetic (88/281),
`and 27% using a subconjunctival anesthetic only or in addition to a topical anesthetic
`(77/281). We then performed further a multivariate analysis looking specifically at this
`question of type of anesthetic used. The variables included in the analysis were age, gender,
`years practiced, geographic location, and practice setting. We did not find a statistically
`significant association of age, gender, years practiced, or geographic region on retinal
`specialists’ choice of anesthetic regimen for IVI (p>0.05 for all variables and are available
`upon request).
`
`The majority of respondents used a lid speculum every time they performed an IVI (67%,
`187/281), while 22% never used one (62/281). In terms of applying betadine on the eye,
`63% of respondents dropped betadine from a bottle (177/281). If a patient stated that they
`have a betadine allergy, 58% still used betadine as they believe the allergy did not exist
`(16½78), while 36% chose a strategy not offered in the choices (100/278). Among those
`who chose to handle the allergy with alternative means, 22% stated that they would
`administer antibiotics either before or after the injection (22/100), and 21% would minimize
`exposure of Betadine to only the injection site or by decreasing the concentration (21/100).
`
`In other aspects, the majority used gloves every time (73%, 145/199) and swabbed eyelids
`and eyelashes with betadine every time (59%, 117/199). However, only 36% used a mask
`every procedure (72/199) and only 21% used topical antibiotics prior to injection (42/199).
`While 45% of respondents dilated the eyes prior to injection (127/281) every procedure,
`37% only dilated the eyes half or less than half the time (104/281) prior to injection. The
`majority of respondents did not perform anterior chamber paracentesis for patients at risk for
`conditions such as Glaucoma (63%, 177/280).
`
`Injection Procedures
`
`While the majority of respondents used a 30-gauge needle (61%, 170/279), 21% elected to
`use a 31-gauge needle (59/279) (Table 2). Most respondents injected in the inferior temporal
`quadrant (70%, 195/279), though 27% chose to inject in the superior temporal quadrant
`(74/279). If a patient required bilateral injections, 31% stated they would perform it on the
`same day in every situation (88/281), while 25% would never perform it on the same day
`(69/281). Most of the retinal specialists who responded did not measure the distance from
`
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 5
`
`the limbus upon injecting (69%, 195/281), though 20% utilized calipers (55/281). There was
`a bimodal distribution on whether to place a cotton tip over the injection site immediately
`following injection. While 55% never placed a cotton tip immediately over the spot
`(153/281), 37% of respondents placed a cotton tip over the injection site every time
`(103/281).
`
`Post-Injection Procedures
`
`Half of the survey respondents utilized Balanced Salt Solution (BSS) to irrigate betadine out
`of the eyes (50%, 14½81), while 30% chose “Other” means not listed (84/281), and 20%
`used 3mL 0.9% sodium chloride (56/281) (Table 3). Among those who chose other means,
`35% of them used the commercially available “Eye Wash” solution (29/84). Among
`respondents, 31% stated that they routinely checked IOP (38/123), 28% routinely
`administered a topical antibiotic (34/123), and 46% routinely performed “Other” procedures
`post-injection (57/123). Among those that responded “Other,” 21% checked for visual acuity
`in some manner (counting fingers, hand motion, etc) (12/57).
`
`Discussion
`
`The number of intravitreal injections performed each year continues to increase as the
`prevalence of retinal vascular diseases such as age-related macular degeneration (AMD),
`diabetic retinopathy, and retinal occlusion continue to grow. While a number of previous
`surveys of IVI practice have been performed, to the best of our knowledge, this is the largest
`survey that has been performed that details the specific anesthetic agents, antibiotic usage,
`and various other techniques employed while performing IVI. In particular, in the United
`States, the last survey was conducted in 2011 by Green-Simms et al.2 A more recent survey
`detailing IVI techniques was conducted in Israel in 2016 as well.8 We also reviewed the
`results from the last five years of the PAT survey from the American Society of Retina
`Specialists (2014–2018), and only 6 questions over the entire 5 years overlapped with
`questions in the survey . Though these surveys have assessed important information about
`best practices for IVI, they do not detail important information regarding specific anesthetics
`used, betadine allergies, nor assess differences in techniques based on demographic
`parameters. In this study we performed additional multivariate analysis to assess the effect of
`demographic variables on anesthetic choice for IVI, and did not find that age, gender,
`practice type, or geographic location influenced anesthetic choice for IVI.
`
`Pre-Injection Methodology
`
`The study found that the majority of respondents had a nurse or assistant present in the room
`to help prepare for the injections, which can lead to increased efficiency and decreased
`errors in preparation.9 Interestingly, anesthetic choice did not differ based on gender, age,
`practice setting, or geographic location. Previous studies have not demonstrated a significant
`difference in pain score between the different types of anesthetic used for IVI10,11.
`
`The majority of respondents utilized a lid speculum, which can help to avoid lid reflex
`closure and subsequent exposure of microbes to the injection site. For those respondents that
`
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 6
`
`never utilized a lid speculum or use it less often, there are alternative approaches available
`such as the “Lid Splinting Approach” that may be helpful in decreasing contamination.12
`Many respondents elected to change their protocol if a patient reported a betadine allergy,
`even though previous studies have demonstrated increased risk for developing more serious
`conditions such as endophthalmitis when electing not to use betadine.13
`
`There is no consensus on whether to use, drapes, betadine to swab eyelids and eyelashes,
`gloves, and masks during every IVI. Among the respondents who use at least one of these
`items every procedure, 21% administered topical antibiotics, despite the increasing body of
`literature that shows the rates of endophthalmitis being similar when using antibiotics drops
`prophylactically as compared to control.14 Other studies have demonstrated the possibility of
`there being inherent harm to utilizing antibiotics pre-injection through increasing resistance
`to bacterial organisms.15,16 There was a minority of respondents who reported regularly
`using masks, but there are studies that show significant associations between speech and
`post-injection infection rates in the setting of intravitreous injections.17,18 Though not many
`respondents performed AC paracentesis in patients with glaucoma, previous studies indicate
`there may be benefit in performing AC paracentesis in high-risk individuals with glaucoma
`and or cotton tip decompression.19–21
`
`Injection Methodology
`
`Some previous studies have shown no significant difference between using 27 and 30-gauge
`needles in terms of patient pain scores.22 In contrast, alternate studies find that there is a
`significant decrease in reported pain when using a 30-gauge needle versus a 27-gauge.23
`Though there is conflicting evidence as to whether the 30-gauge needle leads to less pain,
`physicians prefer using the 30-gauge, which is also corroborated by this study. There does
`not seem to be a difference in patients’ reported pain scores when comparing 30 and 31
`gauge needles, and 33 to 30 gauge needles.24,25
`
`Over a quarter of respondents chose to inject in the superior temporal quadrant; however,
`recent studies have shown that the superior temporal quadrant is the most painful for patients
`and should be avoided if possible.26 While those that performed more IVI per week tended
`to perform more bilateral injections on the same day, the majority elect not to. Though it is
`possible to perform bilateral IVI safely, studies have shown that each eye should be treated
`as a separate procedure to decrease complication rates.27 While most respondents did not
`measure the distance from the limbus, previous studies have shown that injecting posterior to
`4.5 mm from the limbus can lead to retinal tears, and thus beginning residents and fellows
`may find it useful to measure the distance with a caliper or alternate tool at least in the
`beginning stages of their practice.8,28
`
`Post-Injection Methodology
`
`Though most respondents never placed a cotton tip over the injection site following IVI,
`previous guidelines recommend the placement of a cotton tip on the injection site to prevent
`possible reflux.29 The majority of respondents did not perform a dilated fundus exam.
`Though there are not many studies documenting the association between a dilated exam and
`
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 7
`
`specific outcomes, it can be beneficial in terms of viewing the retinal artery perfusion post
`injection.30 With regard to irrigating betadine out of the eye, previous studies have shown
`that Povidone-iodine (PI) is associated with greater discomfort as compared to other
`antiseptic agents such as aqueous chlorhexidine.31
`
`Though most respondents did not administer topical NSAIDs or steroids after injection,
`there is some evidence that NSAIDs post injection for macular edema can lead to mild
`decreases in central retinal thickness and may reduce the number of anti-VEGF therapies
`administered in patients who require IVI frequently.32 NSAIDs have also been shown to
`reduce pain at 6 hours and 24 hours after the administration of IVI.33 NSAIDs can thus be
`considered as a post injection measure, especially for patients who experience higher than
`normal pain levels with the procedure. One point of debate in the community is whether to
`use antibiotics post-injection. Previous studies demonstrate that post IVI antibiotic
`administration can lead to increased resistance to virulent organisms such as coagulase
`negative Staphylococcus.34 Furthermore, checking IOP or assessing for light perception can
`be an important way to ensure that the central retinal artery remains perfused.30
`
`There are multiple limitations to this study. The response rate was relatively low (17% of
`those surveyed). While we attempted to recruit a large sample size, response bias and other
`factors could skew the results of the survey. While it would be interesting to look at
`multivariate analysis for multiple questions for this survey, we decided to only look at type
`of anesthetic used, to avoid false positives from multi-hypothesis testing. Additionally, this
`survey was sent to a large subset of retina specialists in the United Stateswhich could
`introduce bias in responses. In conclusion, we believe this study provides an updated survey
`of current practices of retina specialists in the United States, and provides critical
`information regarding current real world practices for intravitreal injection administration.
`
`Acknowledgements / Disclosures
`
`We thank all of the participating retina specialists for taking time to answer this online survey. None of the authors
`have any relevant financial disclosures related to this subject.
`
`Financial Support: None
`
`Appendix
`
`Survey
`
`Demographic information
`
`1.
`
`2.
`
`What is your age?
`
`To which gender identity do you most identify with?
`
`•
`
`•
`
`•
`
`Female
`
`Male
`
`Prefer not to answer
`
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 8
`
`3.
`
`4.
`
`5.
`
`How many years have you been practicing post training in the field of
`ophthalmology?
`
`In which state do you practice medicine in the field of ophthalmology?
`
`Which of the following practice settings do you work in?
`
`•
`
`•
`
`•
`
`•
`
`•
`
`Multispecialty ophthalmology group
`
`Large multi-specialty medical group (nonacademic, e.g. Kaiser)
`
`Academic/university medical group
`
`Retina only practice (>2 retina specialists in group)
`
`Solo or less than 3 retina specialists in a retina only group
`
`6.
`
`How would you describe the setting of the practice that you work in?
`
`•
`
`•
`
`•
`
`•
`
`Urban
`
`Suburban
`
`Rural
`
`Other: please explain
`
`Pre-Injection
`
`1.
`
`Is a nurse or assistant present in the room to help prepare the patient for the
`injection?
`
`•
`
`•
`
`•
`
`Yes
`
`No
`
`Sometimes
`
`2.
`
`Please select the type(s) of anesthesia used prior to injection:
`
`•
`
`•
`
`•
`
`•
`
`•
`
`topical proparacaine
`
`topical proparacaine plus cotton swab compression
`
`lidocaine gel
`
`subconjunctival lidocaine
`
`other (please explain):
`
`3.
`
`What percentage of the time do you use a lid speculum?
`
`•
`
`•
`
`•
`
`•
`
`0%
`
`25%
`
`75%
`
`100%
`
`4.
`
`How do you apply betadine on the eye?
`
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 9
`
`•
`
`•
`
`•
`
`•
`
`Cotton tip applicator
`
`Drop from a betadine bottle
`
`Use a TB syringe
`
`Other (please explain):
`
`5.
`
`What do you do if a patient states they have a “betadine allergy?”
`
`•
`
`•
`
`•
`
`•
`
`I still use betadine as there is no such thing as a betadine allergy
`
`Use chlorhexidine
`
`Refuse to inject them and refer patient to somewhere else
`
`Other (please explain):
`
`6.
`
`Please select all materials used during every procedure:
`
`•
`
`•
`
`•
`
`•
`
`•
`
`Topical antibiotic prior to injection
`
`Drape
`
`Swab eyelids and eyelashes with betadine
`
`Gloves
`
`Mask
`
`7.
`
`What percentage of the time do you dilate the eyes prior to injection?
`
`•
`
`•
`
`•
`
`•
`
`•
`
`0%
`
`25%
`
`50%
`
`75%
`
`100%
`
`8.
`
`What percentage of the time do you perform AC paracentesis for patients at risk
`for damage from elevated intraocular pressures (e.g. glaucoma).
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`0%
`
`25%
`
`50%
`
`75%
`
`100%
`
`I perform ocular decompression with a cotton tip
`
`Other (please explain):
`
`9.
`
`How many intravitreal injections do you perform per week?
`
`•
`
`0–5
`
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 10
`
`•
`
`•
`
`•
`
`5–30
`
`30–80
`
`80+
`
`Injection
`
`1.
`
`Which of the following needle gauges do you typically use for anti-VEGF
`injections?
`
`•
`
`•
`
`•
`
`•
`
`•
`
`27
`
`30
`
`31
`
`33
`
`Other (please explain):
`
`2.
`
`Which quadrant do you typically inject in?
`
`•
`
`•
`
`•
`
`•
`
`Superior temporal quadrant
`
`Inferior temporal quadrant
`
`Superior nasal quadrant
`
`Inferior nasal quadrant
`
`3.
`
`What percentage of the time do you perform bilateral injections the same day if
`the patient requires injections in both eyes?
`
`•
`
`•
`
`•
`
`•
`
`•
`
`0%
`
`25%
`
`50%
`
`75%
`
`100%
`
`4.
`
`How do you measure the distance from the limbus?
`
`•
`
`•
`
`•
`
`•
`
`Calipers
`
`I use another device to measure the distance (e.g. Tb syringe)
`
`I do not measure the distance and approximate instead
`
`Other (please explain):
`
`5.
`
`What percentage of the time do you place a cotton tip over the site immediately
`following injection?
`
`•
`
`•
`
`0%
`
`25%
`
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 11
`
`•
`
`•
`
`•
`
`50%
`
`75%
`
`100%
`
`6.
`
`What percentage of the time do you do a dilated exam when doing injections?
`
`•
`
`•
`
`•
`
`•
`
`•
`
`0%
`
`25%
`
`50%
`
`75%
`
`100%
`
`Post-Injection
`
`1.
`
`What do you use to irrigate betadine out of the eye?
`
`•
`
`•
`
`•
`
`3 mL 0.9% sodium chloride
`
`BSS
`
`Other (Please explain):
`
`2.
`
`Do you routinely use any of the following after injection?
`
`•
`
`•
`
`•
`
`•
`
`Topical NSAIDS/steroids after injection
`
`Topical antibiotics
`
`Check IOP
`
`Other (please explain):
`
`3.
`
`Is there anything else you would like to add about your intravitreal injection
`practice that was not covered?
`
`Pre-injection Practices of American Retina Specialists
`
`Table 1.
`
`Question
`
`Nurse or Assistant Present
`
`Responses
`
`Always Present
`
`Sometimes Present
`
`Never Present
`
`Anesthetic Choice
`
`Topical Anesthetic Only
`
`Topical Anesthetic and Cotton Swab Compression
`
`Anesthetic Gel Only or Anesthetic Gel and Topical Anesthetic
`Combination
`
`n
`
`201 / 281
`
`26 / 281
`
`54 / 281
`
`46 / 281
`
`40 / 281
`
`88 / 281
`
`%
`
`72
`
`9
`
`19
`
`16
`
`14
`
`31
`
`Subconjunctival Anesthetic Only or Subconjunctival and Topical
`Anesthetic Combination
`
`77 / 281
`
`27
`
`Lid Speculum Usage
`
`Always Use
`
`Alternate Combination Not Listed
`
`30 / 281
`
`187 / 281
`
`11
`
`67
`
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 12
`
`Question
`
`Betadine Application
`
`Responses
`
`Use 75% of the Time
`
`Use 25% of the Time
`
`Never Use
`
`Cotton Tip Applicator
`
`Drop from a Betadine Bottle
`
`TB Syringe
`
`Alternate Method
`
`Betadine Allergy
`Response to Patient with
`Allergy
`
`Still Use Betadine since an Allergy Does Not Exist
`
`Use Chlorhexidine
`
`Refuse Injection and Refer to Different Location
`
`Materials Used Every
`Procedure
`
`Dilation of Eyes Prior to
`Injection
`
`Alternate Method
`
`Topical Antibiotics
`
`Drape
`
`Swab Eyelids and Eyelashes with Betadine
`
`Gloves
`
`Mask
`
`Always Dilate
`
`n
`
`16 / 281
`
`16 / 281
`
`62 / 281
`
`50 / 281
`
`177 / 281
`
`21 / 281
`
`33 / 281
`
`161 / 278
`
`15 / 278
`
`2 / 278
`
`100 / 278
`
`42 / 199
`
`13 / 199
`
`117 / 199
`
`145 / 199
`
`72 / 199
`
`127 / 281
`
`%
`
`6
`
`6
`
`22
`
`18
`
`63
`
`8
`
`12
`
`58
`
`5
`
`1
`
`36
`
`21
`
`7
`
`59
`
`73
`
`36
`
`45
`
`18
`
`Author Manuscript
`
`Author Manuscript
`
`AC Paracentesis For At-
`Risk Patients
`
`Dilate 75% of the Time
`
`Dilate 50% of the Time
`
`Dilate 25% of the Time
`
`Never Dilate
`
`Never Perform
`
`Perform 25% of the Time
`
`Table 2.
`
`50 / 281
`
`40 / 281
`
`41 /281
`
`23 / 281
`
`177 / 281
`
`28 / 281
`
`14
`
`15
`
`8
`
`63
`
`10
`
`Injection Practices of American Retina Specialists
`
`Question
`
`Needle Gauge Preference
`
`Responses
`
`27 Gauge
`
`30 Gauge
`
`31 Gauge
`
`33 Gauge
`
`Other
`
`Injection Quadrant
`
`Superior Temporal
`
`n
`
`3 / 279
`
`170 / 279
`
`59 / 279
`
`18 / 279
`
`29 / 279
`
`74 / 279
`
`Inferior Temporal
`
`195 / 279
`
`Superior Nasal
`
`Inferior Nasal
`
`0%
`
`25%
`
`0 / 279
`
`10 / 279
`
`69 / 281
`
`34 / 281
`
`Percentage of Time
`Physician Performs
`Bilateral Injections if
`Required
`
`%
`
`1
`
`61
`
`21
`
`7
`
`10
`
`27
`
`70
`
`0
`
`4
`
`25
`
`12
`
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 13
`
`Question
`
`Responses
`
`50%
`
`75%
`
`100%
`
`Calipers
`
`n
`
`19 / 281
`
`71 / 281
`
`88 / 281
`
`55 / 281
`
`Method for Measuring
`Distance From Limbus
`
`Percentage of Time
`Physician Places Cotton
`Tip over Injection Site
`
`Percentage of Time
`Physician Performs
`Dilated Exam
`
`Alternate Device (e.g. Tb syringe)
`
`29 / 281
`
`Do Not Measure
`
`Other
`
`0%
`
`25%
`
`50%
`
`75%
`
`100%
`
`0%
`
`25%
`
`50%
`
`75%
`
`100%
`
`195 / 281
`
`2 / 281
`
`153 / 281
`
`15 / 281
`
`1 / 281
`
`9 / 281
`
`103 / 281
`
`33 / 281
`
`65 / 281
`
`42 / 281
`
`53 / 281
`
`88 / 281
`
`%
`
`7
`
`25
`
`31
`
`20
`
`10
`
`69
`
`1
`
`55
`
`5
`
`<1
`
`3
`
`37
`
`12
`
`23
`
`15
`
`19
`
`31
`
`Post-Injection Practices of American Retina Specialists
`
`Table 3.
`
`Question
`
`Responses
`
`n
`
`Irrigation Method for
`Betadine
`
`3 mL 0.9% Sodium Chloride
`
`56 / 281
`
`Balanced Salt Solution (BSS)
`
`141 / 281
`
`Routinely Used Materials
`and Methods
`
`Other
`
`84 / 281
`
`Topical NSAIDs/Steroids
`
`17 / 123
`
`Topical Antibiotics
`
`Check IOP
`
`Other
`
`34 / 123
`
`38 / 123
`
`57 / 123
`
`%
`
`20
`
`50
`
`30
`
`14
`
`28
`
`31
`
`46
`
`Abbreviations:
`
`IVI
`
`Intravitreal Injections
`
`References
`
`1. Williams George A. MD, Royal Oak M. IVT Injections: Health Policy Implications. Review of
`Ophthalmology. https://www.reviewofophthalmology.com/article/ivt-injections-health-policy-
`implications. Published 2014.
`2. Green-Simms AE, Ekdawi NS, Bakri SJ. Survey of intravitreal injection techniques among retinal
`specialists in the United States. Am J Ophthalmol. 2011. doi:10.1016/j.ajo.2010.08.039
`
`Ophthalmol Retina. Author manuscript; available in PMC 2020 August 01.
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Author Manuscript
`
`Novartis Exhibit 2214.013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chaturvedi et al.
`
`Page 14
`
`3. Grzybowski A, Told R, Sacu S, et al. 2018 Update on Intravitreal Injections: Euretina Expert
`Consensus Recommendations. Ophthalmologica. 2018. doi:10.1159/000486145
`4. Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal
`injection of anti-VEGF agents: A review of literature. Eye. 2013. doi:10.1038/eye.2013.107
`5. Tolentino M Systemic and Ocular Safety of Intravitreal Anti-VEGF Therapies for Ocular
`Neovascular Disease. Surv Ophthalmol. 2