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`Nonadherence or Nonpersistence to
`Intravitreal Injection Therapy for Neovascular
`Age-Related Macular Degeneration
`A Mixed-Methods Systematic Review
`
`Mali Okada, MMed,1 Paul Mitchell, PhD,2 Robert P. Finger, MD, PhD,3 Bora Eldem, MD,4
`S. James Talks, MRCP, FRCOphth,5 Ceri Hirst, PhD,6 Luciano Paladini, MD,7 Jane Barratt, MSc, PhD,8
`Tien Yin Wong, MD, PhD,9,10 Anat Loewenstein, MD11
`
`Topic: Systematic review of risk factors for nonadherence and nonpersistence to intravitreal antievascular
`endothelial growth factor (VEGF) injection therapy for neovascular age-related macular degeneration (nAMD).
`Clinical Relevance: Lack of adherence (nonadherence) or undertreatment (nonpersistence) with respect to
`evidence from clinical trials remains a significant barrier to optimizing real-world outcomes for patients with
`nAMD. Contributing factors and strategies to address this are poorly understood.
`Methods: Studies that reported factors for nonadherence and nonpersistence to anti-VEGF therapy as well
`as studies examining strategies to improve this were included. Trial eligibility and data extraction were conducted
`according to Cochrane review methods. Risk of bias was assessed using the Mixed Method Assessment Tool
`and certainty of evidence evaluated according to the GRADE Confidence in the Evidence from Reviews of
`Qualitative Research tool. Data were collated descriptively.
`Results: Of the 1284 abstract results screened, 124 articles were assessed in full and 37 studies met the
`inclusion criteria. Definitions of nonadherence and nonpersistence varied or were not reported. Nonpersistence
`occurred early, with up to 50% of patients stopping treatment by 24 months. High rates of nonadherence were
`similarly reported, occurring in 32% to 95% of patients. Certainty of this finding was downgraded to a moderate
`level because of the heterogeneity in definitions used across studies. Multiple factors determine nonadherence
`and nonpersistence, including at the condition, therapy, patient, social/economic, and health systems/healthcare
`team levels. Moderate quality evidence points to lower baseline vision and poorer response to treatment as
`condition-related variables. The effects of other factors were of lower certainty, predominantly due to small
`numbers and potential biases in retrospective assessment. Although many factors are not modifiable (e.g., patient
`comorbidity), other factors are potentially correctable (e.g., lack of transport or mismatched patient expectations).
`Evidence on strategies to improve adherence and persistence is limited, but where available, these have proven
`effective.
`Conclusions: Awareness of factors related to poor patient adherence and persistence in nAMD could help
`identify at-risk populations and improve real-world outcomes. Further work is required to develop uniform definitions
`and establish high-quality evidence on interventions that can be easily implemented. Ophthalmology 2021;128:234-
`247 ª 2020 by the American Academy of Ophthalmology
`
`Supplemental material available at www.aaojournal.org.
`
`Intravitreal antievascular endothelial growth factor (VEGF)
`injections have revolutionized the treatment of neovascular
`age-related macular degeneration (nAMD).1,2 Landmark
`clinical trials have demonstrated that anti-VEGF injections
`stabilize disease, and initial and prolonged visual gains are
`common.3,4
`intravitreal
`frequent
`Treatment of nAMD requires
`injections. Although the early pivotal trials used a monthly
`injection regimen, given the difficulties with such intensive
`treatment, other more flexible regimens have since been
`
`developed, with pro re nata (PRN) and treat-and-extend
`(T&E) protocols the most commonly used.2
`Real-world evidence suggests that even with these “less
`taxing” alternate dosing regimens, outcomes seen in practice
`mostly do not reach the levels achieved in trial settings, with
`the discrepancy possibly due to lack of adherence to clinical
`trial regimens (defined in this article as nonadherence) or
`lack of persistence with following recommended clinical
`trial regimens over time (defined as nonpersistence). For
`example, a recent meta-analysis of real-world observational
`
`234
`
`ª 2020 by the American Academy of Ophthalmology
`Published by Elsevier Inc.
`
`https://doi.org/10.1016/j.ophtha.2020.07.060
`ISSN 0161-6420/20
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`Okada et al
`
` Adherence to Intravitreal Injections for nAMD
`
`data based on approximately 26 000 patients reported a
`mean visual gain of only þ5.0 Early Treatment of Diabetic
`Retinopathy Study letters after 12 months of treatment, with
`a mean number of 5.4 injections over 8.3 visits.5 This is well
`below the þ11.3 letters seen in the ANCHOR trial with
`ranibizumab6 and þ8.9 letters in
`monthly intravitreal
`VIEW1/VIEW 2 studies7 with intravitreal aflibercept
`every 8 weeks. Long-term results from both clinical trials
`and registry data also confirm this finding, with more
`frequent
`injections consistently showing better visual
`outcomes.8,9
`Given the importance of encouraging ongoing and
`frequent injections, there is a relative lack of awareness
`among physicians and the health community of the barriers
`that lead to the inter-related phenomenon of nonadherence
`and nonpersistence of anti-VEGF treatment in nAMD in the
`real world. Terminology and agreed definitions may not
`exist. There is even less discussion on strategies to correct or
`counteract these barriers. Previous studies have attempted to
`look at this from a local practice level or focused only on the
`patient experience.10,11 However, a comprehensive analysis
`has not been performed to date. The purpose of
`this
`systematic review is
`to assess
`the factors affecting
`treatment nonadherence and nonpersistence to intravitreal
`anti-VEGF injections in nAMD.
`
`Methods
`
`This systematic review was conducted in accordance with the
`principles set out
`in the Cochrane Handbook for Systematic
`Reviews of Interventions.12 The protocol for this systematic review
`was registered with the international PROSPERO database (ID:
`172653) before data extraction. Our results and methods are
`presented in reference to the Preferred Reporting Items for
`Systematic Reviews and Meta-Analyses
`(http://www.prisma-
`statement.org, accessed 26 May 2019). All work adhered to the
`principles of the Declaration of Helsinki.
`
`Eligibility Criteria for Considering Studies for
`This Review
`
`Studies were eligible to be included in this systematic review based
`on the following criteria as set out in the Patient, Intervention,
`Comparator, and Outcome paradigm (Table 1). No eligibility
`restrictions were placed on the basis of the type of anti-VEGF
`used or the treatment regimen used. The minimum definitions of
`nonadherence and nonpersistence were not set in advance to allow
`for maximal inclusion of studies examining this topic. However, it
`was accepted that the term “nonadherence” was synonymous with
`“noncompliance.” Likewise,
`the term “nonpersistence” was
`interchangeable with “discontinuation,” “cessation,” “lost
`to
`follow-up,” or “dropout.” Both quantitative and qualitative studies
`were eligible for inclusion to comprehensively address all aspects
`of the research question.
`Studies were excluded if they assessed retinal conditions other
`than nAMD or evaluated interventions for nAMD other than
`intravitreal anti-VEGF injections. Conference abstracts were also
`excluded because of the inability to critically assess findings.
`The primary outcome measure for this review was reasons or
`risk factors for treatment nonadherence and nonpersistence after at
`least 1 intravitreal anti-VEGF injection. Secondary outcome
`measures included efficacy of strategies to improve treatment
`adherence and persistence, as well as the rates of nonadherence and
`
`nonpersistence. Further assessments were made for factors that
`may be identified as general barriers to treatment.
`
`Search Methods for Identifying Studies
`
`The following databases were searched: MEDLINE, EMBASE,
`Cochrane Central Register of Controlled Trials (CENTRAL),
`clinicaltrials.gov online database, and Google Scholar. Databases
`were last searched and results updated on March 19, 2020. In
`addition,
`the reference lists from eligible studies were also
`reviewed to identify any additional suitable reports. No language
`restrictions were imposed, but if the report was not in English, the
`text was translated to allow for data extraction and full analysis of
`the risk of bias. There were no limits placed on publication date,
`but all studies had to be original and available in full. The search
`string for each database is provided in the Supplementary Material
`(Appendix and Table S1, available at www.aaojournal.org).
`References
`from the search results were imported into a
`reference management program (Zotero v5.0.66, open-source
`software, https://www.zotero.org).
`
`Study Selection
`
`After the database search, the studies were screened by appraising
`title and abstracts. Those studies that were considered to be
`consistent with the search criteria were analyzed in full text to
`confirm their eligibility. Two reviewers assessed the search results
`independently (M.O. and C.H.), and consensus was reached if there
`were any differences.
`
`Data Collection and Quality of Evidence
`Assessment
`
`Data from each eligible study were extracted and collected in a
`standardized Word (Microsoft Office, Microsoft Corp, Redmond,
`WA) document form (Table S2, available at www.aaojournal.org).
`Study origins and treatment setting (e.g., country, hospital clinic),
`patient demographics (e.g., age and baseline visual acuity), and
`treatment details including type of anti-VEGF and regimen used
`were recorded. Factors or correlates reported in the study relating
`to treatment nonadherence or nonpersistence were evaluated.
`Additionally, any strategies evaluated to improve the adherence or
`persistence were also extracted. The methodological quality of
`each study was assessed according to the Mixed Methods
`Appraisal Tool version 2018 because it can be used across quali-
`tative, quantitative, and mixed-methods studies.13 The overall
`quality and certainty of the evidence in the systematic review
`were evaluated using a modified GRADE approach to include
`qualitative evidence synthesisdthe GRADE Confidence in the
`Evidence from Reviews of Qualitative Research tool.
`
`Data Synthesis and Analysis
`
`treatment nonadherence and nonpersistence, where
`Rates of
`available, were summarized with the proportion of patients
`reported for each outcome divided by the total number at risk in the
`reported study population. Results were reported individually for
`each study. Meta-analysis was not possible because of the varia-
`tions in methodology for reporting outcomes across studies (e.g.,
`differences in inclusion criteria with patient death, patient transfer
`for some studies but not others), differences in time period (total
`nonpersistence over several years vs. yearly rates), and lack of raw
`data for some studies to enable reanalysis. As an alternative, rates
`were tabulated according to each study and the data range
`provided. Factors for nonadherence and nonpersistence were also
`extracted from each study. These were broken down into 5
`domains based on the standardized World Health Organization
`
`235
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`PICO
`Component
`
`Patients
`
`Intervention
`
`Comparison
`Outcomes
`
`P
`
`I
`
`C
`O
`
`Ophthalmology Volume 128, Number 2, February 2021
`
`Table 1. Eligibility Criteria Based on the PICO Strategy
`
`Inclusion Criteria
`
`Exclusion Criteria
`
`Studies including patients diagnosed with nAMD
`
`Patients received at least 1 intravitreal injection of
`ranibizumab and/or bevacizumab and/or aflibercept
`
`Studies not reporting outcomes separately for patients
`with nAMD
`Studies with patients receiving intravitreal injections
`other than anti-VEGF (e.g., triamcinolone) or other
`treatment (e.g., photodynamic therapy)
`Not applicable
`No specific exclusions
`
`to improve
`
`Not applicable
`1) Studies reporting the rates of NA/NP and
`factors for NA/NP
`strategies
`2) Studies
`addressing
`adherence and persistence
`3) Studies
`assessing
`barriers
`therapy
`
`to
`
`intravitreal
`
`NA ¼ nonadherence; nAMD ¼ neovascular age-related macular degeneration; NP ¼ nonpersistence; VEGF ¼ vascular endothelial growth factor.
`
`multidimensions of adherence: (1) patient related; (2) condition
`related; (3) therapy related; (4) healthcare team and health system
`related; and (5) social/economic factors.14 Factors were analyzed
`qualitatively according to theme, but also quantitatively with an
`odds ratio or percentage, where reported. Nonpersistence or
`nonadherence due to patient death or
`transfer of care was
`excluded from analysis. If possible,
`intentional discontinuation
`by treating physician from disease stability or remission was
`separated from unintentional nonpersistence in the analysis.
`
`with a few more recent studies including intravitreal aflibercept or
`ranibizumab on a T&E regimen (Table 2). This reflects the timing
`of treatment initiation of these patients, with most receiving their
`first anti-VEGF injection before 2013 (Table S3, available at
`www.aaojournal.org). Most studies assessed patients treated in a
`tertiary hospital
`(university-affiliated hospitals or dedicated
`retinal
`clinic)
`as
`opposed
`to
`a
`local
`clinic
`(general
`comprehensive clinic) (Table 2).
`
`Results
`
`Search Results
`
`A total of 1436 studies were retrieved from the databases, yielding
`1284 unique records after removal of duplicates. Initial screening
`of the titles and abstracts identified 124 potential studies for full-
`text review, with 35 remaining eligible after assessment of the
`full-text report. Two additional studies were identified via a manual
`search of the reference lists, with a total of 37 reports included in
`the final analysis. Figure 1 presents a Preferred Reporting Items for
`Systematic Reviews and Meta-Analysesebased flow diagram
`showing the number of records identified and excluded at each
`stage.
`Studies were excluded for the following reasons: (1) did not
`examine nAMD specifically or included other interventions; (2)
`addressed other domains in health-related quality of life; and (3)
`cost-effective analysis or modeling of intravitreal injections on
`visual or quality of life outcomes without any correlation to impact
`on treatment adherence or persistence.
`
`Study Characteristics
`Of the 37 eligible studies, the majority (n ¼ 33) assessed the
`factors for treatment nonadherence and nonpersistence, and a
`further 4 studies reported barriers to treatment without additional
`assessment of adherence and persistence.15,16 Only 2 of the final
`studies explored strategies to improve treatment nonadherence
`and nonpersistence. Study characteristics are summarized in
`Table 2.
`The studies were mainly European and US based, with a
`predominantly White population; only 3 reports involved patients
`from Asian countries.17-19 The majority of studies assessed patients
`treated with intravitreal ranibizumab on a PRN dosing regimen,
`
`236
`
`Definitions
`
`There was significant variation in the terminology and definitions of
`nonadherence and nonpersistence used across all studies. Definitions
`were not reported in some studies.16,20,21 Synonyms used for
`nonadherence included “noncompliance,”22,23 “absenteeism,”24 and
`“nonattendance.”25
`Synonyms
`for
`nonpersistence
`included
`“treatment discontinuation/cessation”18,26,27 and “lost to follow-up”
`Nonadherence was variably defined as follows:
` No treatment or consultation with a measure of visual acuity
`and OCT at least every 6 weeks28
` Extreme violation of prescribed treatment22
` Nonattendance of every clinic appointment19
` Receiving less than the recommended 8 injections over 12
`months25
` Deviation from treatment recommendations (by patient or
`physician) with gap in treatment or consultation by more
`than 8 weeks29
` Visit outside of the prescribed 28 days  7 days window
`Nonpersistence was variably defined as follows:
` Treatment discontinuation before 12 months,30
`study
`period,26,27 or permanently31
` No treatment or visit at clinic for more than 4 months,32 6
`months,15,33,34 or 12 months35,36
` No follow-up by any ophthalmologist for 3 months28
` No follow-up within a 12-month period after receiving at
`least 1 anti-VEGF injection37
` Loss of follow-up of at least 24 months18
`In some cases,
`intentional nonpersistence, either due to
`assessed treatment futility or treatment success with inactive
`disease, as agreed to by patient and treating physician, was not
`explicitly differentiated from patients who were lost
`to
`follow-up.
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`Okada et al
`
` Adherence to Intravitreal Injections for nAMD
`
`Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analysesebased flow diagram of screening process. nAMD ¼ neovascular age-related
`macular degeneration.
`
`Prevalence of Nonadherence and
`Nonpersistence
`
`Nonadherence to treatment or monitoring appointments was
`high with variable rates depending on how strictly it was defined
`(32%e95%).25,28,29 In one study, which assessed nonadherence as
`no treatment or consultation at least every 6 weeks when using a
`PRN protocol, almost all patients (n ¼ 346, 95.6%) fulfilled this
`criteria over a 12-month period, with a mean of 2.1  1.1
`gaps.28 When determined by self-report however,
`rates of
`perceived nonadherence were lower, with patients in another study
`estimating their rates of nonadherence at 15.7% (n ¼ 143) and
`caretakers estimating this at a higher 25.8% (n ¼ 230).19
`Unsurprisingly, the observed rates of nonadherence were lower
`
`the
`trial setting, with a secondary analysis of
`in a clinical
`Comparison of Age-Related Macular Degeneration Treatment
`Trial reporting only 10.0% of 1060 patients not attending a study
`visit on time when defined as an average visit
`interval of 4
`weeks  7 days over a 24-month period.38 However, when the
`longest
`interval between 2 visits was calculated, 83.3% of
`patients still had at least 1 visit interval that was not on time.
`Patients who discontinued treatment due to disease remission or
`treatment futility as judged by their physician accounted for 3% to
`30% of all patients with nAMD who commenced treatment. After
`excluding these patients,
`the remaining rates of reported non-
`intentional treatment nonpersistence varied from 3% to 57% at 12
`months, with lower rates when nonpersistence was defined as lack
`of follow-up visits rather than lack of anti-VEGF treatment.35
`
`237
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`Ophthalmology Volume 128, Number 2, February 2021
`
`Planned Frequency
`of Visits
`
`NR
`4 wks
`4 wks
`
`NR
`NR
`4 wks
`4 wks
`4 wks
`NR
`NR
`NR
`NR
`4 to 12 wks (8e24 wks if
`patient refuses additional
`treatment)
`NR
`4 to 6 wks (12e24 weeks
`if no signs of disease
`activity)
`NR
`4 wks
`4e8 wks
`NR
`NR
`4e8 wks
`8 wks
`4 wks
`4 wks
`
`4 wks (8e12 wks if no
`signs of disease activity)
`4e6 wks
`4e16 wks
`4 wks (ranibizumab), 8
`wks (aflibercept)
`NR
`NR
`NR
`
`NR
`
`Table 2. Summary Characteristics of Eligible Studies Assessing Treatment Adherence or Persistence
`
`238
`
`Study
`
`Country
`
`Clinic Type
`
`Study Design
`
`Methodology
`
`Patients
`
`Angermann 2019
`Bobykin 2014
`Boulanger-
`Scemama 2015
`Boyle 2018
`Curtis 2012
`Droege 2013
`Ehlken 2018
`Ehlken 2018a
`Heimes 2016
`Holz 2015
`Husler 2013
`Jansen 2018
`Kim 2017
`
`Austria
`Russia
`France
`
`Australia
`United States
`Germany
`Germany
`Germany
`Germany
`Multinational
`Switzerland
`United States
`South Korea
`
`Krivosic 2017
`Kruger Falk 2013
`
`France
`Denmark
`
`Lad 2014
`Massamba 2015
`McGrath 2013
`Nunes 2010
`Obeid 2018
`Oishi 2011
`Ozturk 2018
`Polat 2017
`Ramakrishnan
`2020
`Rasmussen 2013
`
`Rasmussen 2017
`Sii 2018
`Subhi 2017
`
`Varano 2015
`Vaze 2014
`Westborg 2018
`
`United States
`France
`Australia
`Brazil
`United States
`Japan
`United Kingdom
`Turkey
`United States
`
`Denmark
`
`Denmark
`United Kingdom
`Denmark
`
`Multinational
`Australia
`Sweden
`
`Tertiary
`NR
`Tertiary
`
`Mixed
`NR
`Tertiary
`Tertiary
`Mixed
`NR
`NR
`Mixed
`Local
`Tertiary
`
`NR
`Tertiary
`
`NR
`Tertiary
`Local
`Tertiary
`Local
`Tertiary
`Tertiary
`NR
`Mixed
`
`Tertiary
`
`Tertiary
`
`Tertiary
`
`NR
`Local
`NR
`
`Wintergerst 2018
`
`Germany
`
`Tertiary
`
`Retrospective observational
`Retrospective observational
`Retrospective þ telephone survey
`
`Cross-sectional survey
`Retrospective database
`Cross-sectional survey
`Retrospective observational
`Retrospective þ Prospective
`Retrospective observational
`Retrospective observational
`Cross-sectional survey
`Self-administered questionnaire
`Retrospective observational
`
`Quantitative
`Mixed
`Mixed
`
`Qualitative
`Quantitative
`Qualitative
`Mixed
`Mixed
`Mixed
`Quantitative
`Qualitative
`Qualitative
`Quantitative
`
`841
`6
`60
`
`6
`284 380
`77
`466
`362
`72
`1514
`28
`NR
`64
`
`Drug
`
`NR
`RBZ
`RBZ
`
`NR
`RBZ/BEV/PEG
`RBZ
`RBZ/BEV/AFL
`RBZ or BEV
`RBZ
`RBZ
`RBZ
`NR
`RBZ or BEV
`
`Regimen
`
`PRN
`PRN
`PRN
`
`NR
`NR
`PRN
`PRN
`PRN or fixed
`PRN
`NR
`NR
`NR
`PRN
`
`Retrospective observational
`Retrospective observational
`
`Quantitative
`Mixed
`
`163
`399
`
`NR
`RBZ
`
`NR
`PRN
`
`Retrospective database
`Prospective cohort
`Retrospective þ telephone survey
`Retrospective þ phone interview
`Retrospective observational
`Retrospective þ phone interview
`Retrospective observational
`Retrospective þ telephone survey
`Secondary analysis of RCT
`Retrospective þ telephone survey
`
`Retrospective observational
`Cross-sectional survey
`Retrospective observational
`
`Cross-sectional survey
`Retrospective observational
`Retrospective observational
`Retrospective þ telephone survey
`
`Quantitative
`Quantitative
`Mixed
`Mixed
`Quantitative
`Mixed
`Mixed
`Mixed
`Quantitative
`
`Mixed
`
`Quantitative
`Qualitative
`Quantitative
`
`Qualitative
`Qualitative
`Quantitative
`
`Mixed
`
`459.237
`29
`85
`19
`2003
`86
`21
`125
`1178
`
`381
`
`269
`53
`59
`
`143
`105
`472
`
`55
`
`RBZ or BEV
`RBZ
`RBZ
`BEV
`NR
`RBZ or PEG
`AFL
`RBZ
`RBZ or BEV
`
`RBZ
`
`RBZ or AFL
`RBZ (assumed)
`RBZ or AFL
`
`NR
`RBZ
`RBZ or AFL
`
`NR
`
`NR
`PRN
`T&E
`NR
`NR
`PRN
`Fixed
`PRN
`PRN or monthly
`
`PRN
`
`PRN
`PRN
`PRN
`
`NR
`NR
`PRN, T&E, or
`fixed
`NR
`
`AFL ¼ aflibercept; BEV ¼ bevacizumab; NR ¼ not reported; PEG ¼ pegaptanib; PRN ¼ pro re nata; RBZ ¼ ranibizumab; RCT ¼ randomized controlled trial; T&E ¼ treat-and-extend.
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`Okada et al
`
` Adherence to Intravitreal Injections for nAMD
`
`Studies of nonpersistence to treatment beyond 24 months were
`limited,
`but where
`available,
`recorded
`high
`rates
`of
`nonpersistence
`(Table
`3). Within
`the first
`24 months,
`KaplaneMeier survival curves demonstrated the onset of non-
`persistence for the majority of patients to occur early within the
`first 6 months.
`
`Factors Affecting Treatment Nonadherence
`
`for nonadherence to treatment or monitoring
`Risk factors
`appointments were assessed in 6 studies.19,24,25,28,29 Condition-
`related factors such as worse visual acuity at baseline was
`associated with an increase (odds ratio, 2.37; P ¼ 0.05) in
`nonadherence,29 but this was not statistically significant in another
`study by the same authors.28 Patients whose vision improved with
`treatment of >3 lines also were more likely to be adherent (19.9%
`vs. 12.0%, P ¼ 0.04), although the converse (i.e., loss of vision)
`did not appear to influence adherence pattern in at least 1 study.29
`Of all patient-related variables, patient illness (21.0%e42.8%)
`accounted for a significant cause of nonadherence.19,25 Many
`patients also reported fear of injections as a major barrier to
`treatment (n ¼ 30, 21%), with a small number also reporting
`discomfort after injections as a reason for avoidance.19
`A substantial cause for nonadherence overall related to health
`system factors. Patients stated sometimes forgetting their appoint-
`ment (15%), the appointments were too frequent or inconvenient
`(10%), or there was insufficient clinic capacity with no available
`appointments in the time frame the patient required (47%).19,25
`Social factors play a significant role for most patients, with
`many citing a lack of caretakers to take them to appointments
`(25.9%). Only 1 study examined cost factors, with less than 10%
`reporting financial burden as the primary issue for nonadherence.19
`Seasonal factors also may play a role, with 1 study recording
`almost half of all patients (n ¼ 29, 46%) missing at least 1 visit
`during the traditional French summer holiday period.24 This may
`be due to patients weighing the benefits of holidays against their
`eye health.
`
`Factors Affecting Treatment Nonpersistence
`
`In general, the reasons for nonpersistence reflected those seen for
`nonadherence (Table 4). Baseline visual acuity was a strong
`condition-specific factor, with worse baseline vision in the
`affected eye conferring higher risk of nonpersistence of 1.4 to 8.1
`times. However, there was no consistent threshold level of visual
`acuity where this risk increased. Poor response to treatment and
`worse final visual acuity were also associated with higher rates of
`nonpersistence. There was conflicting evidence as to whether
`bilateral disease was a risk factor, with some studies suggesting a
`3.7-fold increased risk of discontinuation if bilateral injections
`were required,28,30 whereas other studies suggested that bilaterality
`was a protective factor.37
`The therapy regimen may contribute to risk of nonpersistence.
`In a Japanese study using PRN treatment, patients who were only
`given a single injection, instead of 3 loading doses at initiation, had
`a higher risk of nonpersistence.17
`Patient-related factors accounted for a significant cause of
`nonpersistence. In particular, older age was an issue, with the risk
`increasing per decade of life. The highest risk occurred in those
`aged more than 90 years with a 3-fold increased risk compared
`with those younger than 80 years of age. General ill health or
`presence of other systemic comorbidities was also associated with
`risk of nonpersistence independent of age. There was no difference
`due to patient gender or the presence of other ocular comorbidities.
`Patients also reported fear of injections as a barrier to treatment,
`although the extent to which this was responsible varied between
`
`239
`
`Regeneron Exhibit 1182.007
`Regeneron v. Novartis
`IPR2021-00816
`
`10.8e31.3
`
`7.0e71.0
`61.7e65.6
`3.6e57.4
`
`244743(71.0)
`234239(65.6)
`213645(57.4)
`174094(44.7)
`
`112647(61.7)
`104165(53.6)
`
`(%)
`Range
`
`(n[459237)
`
`Lad
`
`(n[284380)
`
`Curtin
`
`1043(46.8)
`
`60(31.4)
`
`16(13.8)
`
`10(7.0)
`
`68(18.8)
`
`503(50.8)
`
`532(23.9)
`
`16(13.8)
`
`37(3.6)
`
`60(10.8)
`
`36(4.2)
`
`63(31.3)
`
`60
`48
`36
`24
`18
`12
`
`6
`
`(n¼362)
`2018
`Ehlken
`
`(n¼932)
`Westborg
`
`(n¼2227)
`
`Holz
`
`(n¼191)
`Heimes
`
`(n¼116)
`
`Subhi
`
`2017(n¼1027)
`
`Rasmussen
`
`(n¼555)
`Rasmussen
`
`2013
`
`(n¼855)
`KrugerFalk
`
`(n¼95)
`Droege
`
`(n¼201)
`Boluanger
`
`Months
`
`ProportionofPatientNonpersistentwithTreatmentatEachTimePoint
`
`N,%
`
`Table3.ReportedRatesofNonpersistencetoTreatmentorMonitoringVisitsoverTime(ExcludingPatientDeathorTransferofCare)
`
`

`

`Ophthalmology Volume 128, Number 2, February 2021
`
`Table 4. Risk Factors for Treatment or Visit Nonpersistence
`
`Risk Factors
`
`Studies
`
`Risk of NP (OR or Primary Reason
`for NP as % of Responses)
`
`Effect of Risk Factor
`(Qualitative Studies)
`
`Condition-Related Factors
`Bilaterality
`
`Worse baseline VA
`
`Worse baseline VA in fellow eye
`
`Worse final VA
`
`No change in VA to treatment
`
`Patient-Related Factors
`Older age
`
`Non-White ethnicity
`
`Systemic illness
`
`Ocular comorbidities
`Fear of injections
`
`Perception injections not helpful or not
`needed
`
`240
`
`Obeid
`Ehlken
`Rasmussen 2018
`Oishi
`Westborg
`Polat
`McGrath
`Bobykin
`Boulanger
`Ehlken 2018
`Westborg
`Bobykin
`Oishi
`Sii
`Droege
`Ehlken 2018
`Obeid
`Polat
`Vaze
`Nunes
`
`Obeid
`
`Ehlken 2018
`Rasmussen 2018
`Westborg
`Subhi
`Rasmussen 2013
`McGrath
`Bobykin
`Wintergerst
`Husler
`Boulanger
`Obeid
`
`Westborg
`Oishi
`Droege
`Rasmussen 2013
`McGrath
`Kruger Falk
`Vaze
`Nunes
`Heimes
`Wintergast
`Huser
`
`Polat
`Droege
`Kruger Falk
`Vaze
`Wintergast
`Huser
`Polat
`Rasmussen 2013
`McGrath
`Kruger Falk
`Vaze
`Nunes
`Wintergast
`Huser
`
`0.69 OR
`3.704 OR
`3.70 OR
`8.1 OR
`1.42 OR
`0 vs. 22.6%
`
`42.5 vs. 51.0 letters
`OR 2.37
`
`1.58 OR 81e85
`2.29 OR 86e90
`3.31 OR > 90
`OR 1.04
`OR 1.05
`
`13.0%
`82.0 vs. 76.6 yrs
`1.47 OR African American
`2.63 OR Asian American
`3.07 OR other ethnicity
`1.27 OR
`
`16.7%
`41.5%
`0.48 OR
`5.6%
`42.3%
`15.8%
`26%
`25%
`8.9%
`
`29.6%
`5.3%
`2.8%
`11.5%
`25%
`8.9%
`21.6%
`
`10.4%
`8.3%
`23.1%
`42.1%
`11%
`21.7%
`
`Increased risk
`
`No difference
`Increased risk
`
`No difference
`Decreased risk
`Increased risk
`Increased risk if in worse eye
`Increased risk
`Increased risk
`Increased risk
`Increased risk
`Increased risk
`Increased risk
`
`No difference
`Increased age > 90 yrs
`Increased age
`No difference
`Increased > 80 yrs
`Increased
`
`Increased risk
`
`Increased risk
`
`Regeneron Exhibit 1182.008
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`Okada et al
`
` Adherence to Intravitreal Injections for nAMD
`
`Table 4. (Continued.)
`
`Risk Factors
`
`Loss of motivation
`
`Therapy-Related Factors
`Treatment regimen
`
`Same day injection
`Anti-VEGF drug type
`
`Health Systems and Healthcare Team Factors
`Lack of information
`
`Did not like or trust physician
`
`Tertiary center
`
`Dissatisfaction with treatment center
`Longer distance from home to treatment
`center
`
`Follow-up burden
`
`Fixed appointments
`Difficulties with appointments
`Social/Economic Factors
`Lower socioeconomic status
`Social isolation or lack of carer
`
`Lack of insurance status
`
`Financial burden
`
`Lack of transport
`
`Studies
`
`Droege
`Heimes
`
`Hanemoto
`Droege
`
`Krivosic
`Subhi
`Westborg
`
`Nunes
`Huser
`Varano
`Kruger Falk
`Huser
`Westborg
`Rasmussen 2018
`Polat
`Polat
`Obeid
`
`Boyle
`McGrath
`Boulanger
`Polat
`Boyle
`Subhi
`Droege
`Rasmussen
`Kruger Falk
`Vaze
`Huser
`Rasmussen 2018
`Nunes
`
`Obeid
`Polat
`Oishi
`Droege
`Wintergerst
`Huser
`McGrath
`Heimes
`Wintergast
`Polat
`Oishi
`Boyle
`Droege
`McGrath
`Vaze
`Wintergast
`Huser
`Holz
`Spooner
`
`Droege
`Rasmussen
`Vaze
`Nunes
`Heimes
`Wintergast
`
`Risk of NP (OR or Primary Reason
`for NP as % of Responses)
`
`Effect of Risk Factor
`(Qualitative Studies)
`
`38%
`5%
`
`Decreased burden for T&E vs. PRN
`Decreased burden for PRN vs.
`monthly
`Decreased risk
`No difference
`
`Increased risk
`
`Increased risk > 50 km
`
`Increased with shorter intervals
`Increased risk
`
`Increased risk
`
`Increased risk
`
`Increased risk
`
`No difference
`
`Increased risk
`Increased risk (indirect costs)
`
`Increased burden (direct and indirect
`costs)
`
`Increased risk
`
`1.45 OR RBZ vs. AFL
`
`26.3%
`4.3%
`
`2.8%
`8.7%
`1.30 OR
`0.33 OR
`17.6%
`R value ¼ 0.227
`1.33 OR 21e30 miles
`1.55 OR > 30 miles
`
`2.48 OR
`Median distance 18 vs. 40 km
`16%
`
`18.9%
`
`8.3%
`7.7%
`13.0%
`0.44 OR
`10.5%
`
`1.52 OR
`16%
`
`61.5%
`
`8.9%
`
`3%
`5%
`20.8%
`
`34.8%
`8.1%
`7.7%
`10%
`13%
`2%
`
`46.3%
`
`7.7%
`5.3%
`38%
`27%
`
`AFL ¼ aflibercept; NP ¼ nonpersistence; OR ¼ odds ratio; PRN ¼ pro re nata; RBZ ¼ ranibizumab; T&E ¼ treat-and-extend; VA ¼ visual acuity;
`VEGF ¼ vascular endothelial growth factor.
`
`241
`
`Regeneron Exhibit 1182.009
`Regeneron v. Novartis
`IPR2021-00816
`
`

`

`Ophthalmology Volume 128, Number 2, February 2021
`
`3% and 30% overall. However, patient perception that the treat-
`ment was not helpful or not required was a strong risk factor, ac-
`counting for up to 42% in some series.39 However, the studies did
`not clarify if this was related to an expectation of improvement
`with treatment
`and subsequent disappointment when only
`stability of vision was achieved. This is in keeping with the
`finding that patients who ceased treatment often reported lack of
`information about the treatment plan or the expected outcomes of
`treatment versus natural history.39,40
`Health system and socioeconomic-related factors represented a
`significant cause for treatment nonpersistence as reported by pa-
`tients. Lack of transport or distance to the treatment center was a
`key factor in most studies, accounting for 5% to 46% of responses.
`In contrast, in Denmark, where the government funds transport to
`the hospital, only 1 of the 4 Danish studies included in the review
`reported transport as an issue. Follow-up burden was also reported
`as a significant factor, but the specifics of whether this was regimen
`related was not explored. The impact of cost or the financial burden
`on treatment persistence was variable, accounting for as low as 2%
`in 1 large multi-country study26 and as high as 30% in others.41 Of
`note, in Sweden, where treatment for nAMD is cover