This secondary analysis of the Comparison of Age-Related Macular Degeneration Treatment Trial randomized clinical trial assesses the association of patient adherence and visual acuity in individuals with neovascular age-related macular degeneration.
Key Points
Question
What is the association between visit adherence and visual outcomes in individuals with neovascular age-related macular degeneration?
Findings
In a secondary analysis of the Comparison of Age-Related Macular Degeneration Treatment Trial randomized clinical trial of 1178 individuals, patients were expected to attend visits every 4 weeks; each missed visit was associated with an average visual acuity letter score decline of 0.7. Compared with patients who were on time, those who averaged between 36 and 60 days and more than 60 days between visits lost 6.1 and 12.5 letters, respectively.
Meaning
Visit adherence may contribute to visual acuity outcomes in neovascular age-related macular degeneration.
Abstract
Importance
Visit adherence has been shown to play a significant role in patient health outcomes. The effect of missing visits on visual acuity (VA) in individuals with neovascular age-related macular degeneration has yet to be characterized.
Objective
To quantify the association between patients’ adherence to randomized clinical trial visits and VA in individuals with neovascular age-related macular degeneration based on 4 visit adherence metrics.
Design, Setting, and Participants
This is a secondary analysis of the Comparison of Age-Related Macular Degeneration Treatment Trial randomized clinical trial. Individuals with age-related macular degeneration were recruited from 44 clinical centers in the United States between February 2008 and December 2009. The 2-year study protocol required 1 visit every 4 weeks (every 21-35 days for a total of 26 visits) for monthly vs pro re nata treatments of bevacizumab vs ranibizumab. Analysis took place from November 2018 through May 2019.
Exposures
Visit adherence was measured in 4 ways: total number of missed visits, average number of days (avg days) between each visit, longest duration in days (max days) between visits, and visit constancy (the tally of 3-month periods with at least 1 visit attended). Average and max days were also categorized as on time (28-35 days), late (36-60 days), and very late (>60 days).
Main Outcomes and Measures
Change in Early Treatment Diabetic Retinopathy Study VA between the baseline and the last visit. Linear multivariate regression models were applied to analyze the association between visit adherence and change in VA, controlling for age, sex, baseline VA, anti–vascular endothelial growth factor drug, number of injections, and dosing regimen.
Results
Of 1178 patients, the mean (SD) age was 79.1 (7.3) years, and 727 (61.7%) were women. The mean (SD) number of missed visits was 2.4 (3.1). Overall, 1091 patients (92.6%) had complete visit constancy during the entire study period. Average days were categorized with 1060 patients (90.0%) classified as on time, 108 (9.2%) were late, and 10 (0.8%) were very late. For max days between visits, 197 patients (16.7%) were on time, 773 (65.6%) were late, and 208 (17.7%) were very late. After controlling for covariates, the late (avg days = −6.1; max days = −2.0) and very late (avg days = −12.5; max days = −5.9) groups saw fewer letters in both the avg and max days categories than patients in the on-time group (P < .001).
Conclusions and Relevance
These results provide evidence to support the concept that visit adherence contributes to VA outcomes in neovascular age-related macular degeneration. The magnitude of the association of visit adherence with VA outcomes in this clinical scenario suggests that substantial effort should be expended to strive for visit adherence or therapeutic strategies that reduce the visit burden without compromising VA outcomes.
Trial Registration
ClinicalTrials.gov Identifier: NCT00593450
Introduction
Medication adherence has become an important metric in assessing treatment efficacy.1,2,3,4 Specific to ophthalmology, this issue has been most commonly assessed with regard to glaucoma medication adherence and persistence.5,6,7,8,9 While it seems self-evident that the best outcomes would naturally follow from the patients who are most adherent to the prescribing guidelines put forth by their physician, the potential association between regular physician visits and outcomes is less obvious. Visit adherence is an idea that is gaining traction across medicine but has been most extensively studied in patients with HIV. Numerous studies have shown that increased adherence with regularly scheduled visits is not only associated with reduced viral loads but also improved survival.10,11,12,13
With the advent of intravitreal injections of anti–vascular endothelial growth factor (anti-VEGF), visual acuity (VA) outcomes have dramatically improved in patients with neovascular age-related macular degeneration (nAMD).14 However, the cost of this advancement includes a tremendous treatment burden to the patient, mandating frequent trips to the ophthalmologist’s office. A big goal in reducing this burden has been to optimize treatment regimens based on monthly, pro re nata, or treat-and-extend schedules. However, each regimen relies on patients adhering to their scheduled follow-up appointments for disease monitoring and treatment.15,16 Unlike patients with HIV who can have a prescription filled by physicians other than their infectious disease physician, patients with nAMD only have 1 option for receiving their vision-saving treatment, and showing up for their visit is integral to this process.
Since anti-VEGF treatment for nAMD began in 2006, multiple real-world studies, or studies from clinical practices rather than clinical trials, in the United States and Europe describe a nonadherence or a loss to follow-up rate ranging from 18% to 57% among patients with nAMD receiving anti-VEGF injections.17,18,19,20 Factors attributed to poor visit adherence include older age, medical comorbidities, problems with transportation to clinic visits, fear of intravitreal injections, and lack of disease awareness.21,22,23 While the causes of poor visit adherence have been evaluated, the effect of missing visits on VA in patients with nAMD has yet to be characterized, to our knowledge.
The importance of this issue has become even more pressing with the impending changes in insurance reimbursement. Recently, it has been reported that Medicare’s future goal will be to shift financial risks to the physician while also accounting for patient outcomes.24 Nowhere in ophthalmology will this conflict arise more than when treating patients with nAMD. Despite a decade of experience, the optimization of injection frequency has yet to be realized. Currently, real-world patients with AMD have poorer VA results than randomized clinical trials suggest.25 One possibility for this difference is the reduced frequency of visits. Here, we perform a secondary analysis of the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) to evaluate the association between patient visit adherence and VA in nAMD.
Methods
Data Source
Data were obtained from the publicly available CATT data files. The CATT trial has been well described elsewhere.26 Briefly, this was a 2-year study that examined the comparative effectiveness of bevacizumab vs ranibizumab and of monthly vs as-needed treatments for nAMD. Participants were recruited from 44 clinical centers in the United States between February 2008 and December 2009. For the purposes of this analysis, the important details of the study methodology required that after randomization, patients were expected to follow up every 4 weeks (±7 days) for 26 follow-up visits total over the entirety of the 2-year study. Institutional review board approval was not needed because the data used are freely available online. Analysis took place from November 2018 through November 2019.
Visit Adherence and Constancy
Because the association between visits and visual outcomes has yet to be fully explored, multiple measures were created to determine which, if any, would be associated with VA. For those patients who withdrew from the study, visit adherence and VA were only assessed as of the final visit for which data were collected. For patients who died, assessment of visit adherence was stopped at the time of death and the final VA was carried forward. The first metric created is also the simplest, assessing the number of visits that were missed. For this metric, the patient was expected to be seen every 4 weeks and was given an anticipated visit window similar to that of the study allowance of ±7 days. Patients seen off schedule were then given credit for the visit in the nearest window. Next, the length of time between visits was calculated by taking the average amount of days (avg days) in between each visit. The third metric created examined the longest interval between visits in days (max days) for each patient. Lastly, visit constancy (the tally of 3-month periods with at least 1 visit attended) has been proven to be associated with mortality and viral load in patients with HIV.11,12 Although the results of the HARBOR study suggest this metric may not be as valuable, given its effectiveness outside of ophthalmology, visit constancy was tested here as well.27 The avg and max days variables were then made into categorical variables based on patients who were on time (28-35 days), late (36-60 days), and very late (>60 days). Similarly, visit constancy was tested as a binary variable with either 100% visit constancy vs less than 100% constancy because very few patients had less than perfect visit constancy, which limited the ability to assess visit constancy’s association with VA.
Outcomes
The primary outcome was the change in Early Treatment Diabetic Retinopathy Study VA between the baseline study visit and the last visit recorded for each patient. Linear univariate and multivariate regression models were applied to analyze the association between all visit adherence parameters and change in VA. Covariates controlled for included age, sex, baseline VA, anti-VEGF agent (bevacizumab vs ranibizumab), and number of injections and dosing assignment (monthly vs pro re nata). For the dosing assignment variable, patients who were rerandomized at 1 year into the pro re nata arm were considered pro re nata for this study. Statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc). All P values were 2-sided, and significance was set at .05.
Results
A total of 1178 patients in the CATT cohort had visit data and were analyzed in this study. The patients had a mean (SD) age of 79.1 (7.3) years, and 727 (61.7%) were women. Overall, 1060 patients (90.0%) adhered to an appointment every 28 to 35 days, in accordance with the study protocol. The mean (SD) days between appointments was 31.9 (9.1) days, as expected given the high visit retention and outlined study protocol. The longest duration between 2 visits ranged from 28 to 558 days (mean [SD], 51.8 [30.8] days). The mean (SD) number of missed visits was 2.4 (3.1). A total of 1091 patients (92.6%) had 100% visit constancy during the study period, with at least 1 visit in each 3-month interval (Table 1).
Table 1. Visit Adherence in Patients With nAMD in the CATT Study.
| Characteristic | No. (%) |
|---|---|
| Total No. | 1178 |
| No. of missed visits | |
| Mean (SD) | 2.4 (3.1) |
| Median (IQR) | 2.0 (1.0-3.0) |
| Average time between visits, d | |
| Mean (SD) | 31.9 (9.1) |
| Median (IQR) | 30.3 (29.2-32.1) |
| On time (28-35 d) | 1060 (90.0) |
| Late (36-60 d) | 108 (9.2) |
| Very late (>60 d) | 10 (0.8) |
| Maximum time between visits, d | |
| Mean (SD) | 51.8 (30.8) |
| Median (IQR) | 42.0 (37.0-56.0) |
| On time (28-35 d) | 197 (16.7) |
| Late (36-60 d) | 773 (65.6) |
| Very late (>60 d) | 208 (17.1) |
| Visit constancya | |
| <100% | 87 (7.4) |
| 100% | 1091 (92.6) |
Abbreviations: CATT, Comparison of Age-Related Macular Degeneration Treatment Trial; IQR, interquartile range; nAMD, neovascular age-related macular degeneration.
Defined as at least 1 visit attended per 3-month interval.
In univariate analysis, each missed visit was associated with a 0.6-letter decline in VA (95% CI, −0.9 to −0.3; P < .001). Linear multivariate analysis showed a similar result with each missed visit being associated with a 0.7-letter decrease in VA after 2 years. With regard to average days of follow-up, 1060 patients (90.0%) were classified as on time, 108 (9.2%) were late, and 10 (0.8%) were very late. The unadjusted final VA changes for these groups were +6.3, +1.1, and −10.8 letters, respectively (late: unadjusted VA, −5.2 [95% CI, −8.6 to −1.8]; very late: unadjusted VA, −17.1 [95% CI, −27.8 to −6.4]; P < .001). After controlling for baseline VA, age, sex, anti-VEGF agent, number of injections, and dosing schedule, the late group was −6.1 letters worse (95% CI, −9.6 to −2.8) and the very late group was −12.5 letters worse (95% CI, −23.0 to −2.1) than the on-time group (P < .001).
The max days between visits showed similar results to the avg days results. Of 1178 patients, 197 (16.7%) were on time and did not have an interval between visits longer than 35 days. Most patients (773 [65.5%]) had at least 1 late follow-up of 36 to 60 days. A total of 208 patients (17.7%) were very late and had at least 1 period where no visit occurred for more than 60 days. These groups averaged +7.8, +6.2, and +1.7 letters in change in final VA, respectively. After controlling for other variables, in comparison with the on-time group, the late group lost 2.0 letters (95% CI, −4.6 to 0.6), and the very late group lost 5.9 letters (95% CI, −9.2 to −2.7) (P < .001). Lastly, failure to attend at least 1 visit in 1 or more 3-month intervals was associated with a 5.8-letter decrease in VA (95% CI, −9.6 to −2.0; P = .003). In multivariable analysis, having 1 or more 3-month periods without a visit lead to a 5.1-letter loss compared with 100% visit constancy (95% CI, −8.9 to −1.3; P = .009) (Table 2).
Table 2. Change in VA of the Study Eye and Visit Adherence.
| Characteristic | No. (%) | Change in ETDRS Letters in the Study Eye | ||||
|---|---|---|---|---|---|---|
| VA Change, Mean (SD) | Univariate Analysis | Multivariate Analysisa | ||||
| Estimate (SE) | P Valueb | Estimate (SE) | P Valueb | |||
| Total No. of missed visits | NA | NA | –0.6 (0.2) | <.001 | –0.7 (0.2) | .009 |
| Average time between visits, d | ||||||
| On time (28-35) | 1060 (90.0) | 6.3 (16.7) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| Late (36-60) | 108 (9.2) | 1.1 (20.2) | −5.2 (1.7) | −6.1 (1.7) | ||
| Very late (>60) | 10 (0.8) | −10.8 (29.1) | −17.1 (5.4) | −12.5 (5.3) | ||
| Maximum time between visits, d | ||||||
| On time (28-35) | 197 (16.7) | 7.8 (15.5) | 1 [Reference] | <.001 | 1 [Reference] | <.001 |
| Late (36-60) | 773 (65.6) | 6.2 (17.0) | −1.6 (1.4) | −2.0 (1.3) | ||
| Very late (>60) | 208 (17.1) | 1.7 (19.2) | −6.1 (1.7) | −5.9 (1.7) | ||
| Visit constancy (8 visits total) | ||||||
| 100% | 1091 (92.6) | 6.1 (16.9) | 1 [Reference] | .003 | 1 [Reference] | .009 |
| <100% | 87 (7.4) | 0.3 (20.3) | –5.8 (1.9) | −5.1 (1.9) | ||
Abbreviations: ETDRS, Early Treatment Diabetic Retinopathy Study; NA, not applicable; VA, visual acuity.
Adjusted by baseline VA, age, sex, anti–vascular endothelial growth factor drug, number of injections, and dosing assignment.
Linear trend P value.
Discussion
Given the high likelihood of substantial VA loss from untreated nAMD, it is not surprising that visit adherence would play an important role in visual outcomes. We found that all assessed measures of visit adherence and constancy had an association with visual outcomes. The most extreme visual outcomes with an adjusted difference of 12.5 letters occurred between those patients with the average amount of days between visits to be considered on time (28-35 days) and those who were very late (>60 days between visits). Numerous studies have assessed the rate at which patients who are receiving injections for nAMD do not follow up, including a recent report that showed that 22% of patients who started receiving injections had at least 1 year of being lost to follow-up.17,18,19,20 While a loss in the mean improvement in VA as visit adherence decreases in clinical practice among patients who participated in randomized clinical trials has been reported, the quantitative effects of visit adherence on VA have not been well characterized.
Numerous aspects of this study need to be considered when evaluating the results. The most prominent of which is that a randomized clinical trial was used as the study setting for the analysis. Two primary benefits were realized by this choice. First, the design of the randomized clinical trials allowed for specific visit windows to be created, which greatly facilitated defining when visits were missed or not. While this information was vital in validating the metrics used to test visit adherence, it is also important to note that 3 of the 4 metrics (avg days, max days, and visit constancy) do not require knowing exactly when the next follow-up visit was scheduled. This will be critical in applying visit adherence metrics to real-world data sets. Second, precise standardized Early Treatment Diabetic Retinopathy Study VA measurements were taken at every visit. This ensured that when the acuity outcomes were described, there would be little concern over the validity of finding differences that were less than 5 letters (or 1 Snellen line) of vision.
While these aspects enhanced the validity of the findings, the randomized clinical trial nature of the study similarly posed a challenge. The median number of missed visits was only 2 visits, and only 10.0% of patients did not have an average follow-up considered to be on time. This contrasts sharply with the previously cited real-world studies,17,18,19,20 which would argue that these numbers should be much higher. While it cannot be known for certain why the visit adherence was higher in CATT compared with real-world studies, it is likely that having a randomized clinical trial population, which is commonly younger and healthier than real-world counterparts, as well as study coordinators whose primary function is to ensure study retention contributed to the high rate of visit adherence seen. Despite this low variability in visit adherence and relative uniformity across the study population, we still found significant associations in each of the metrics assessed.
One interpretation for the findings of this study could argue that the patients who followed up more frequently simply received more injections, which led to the differences in final acuity. Certainly, more frequent visits imply injections occurred more frequently; however, visit adherence was associated with visual outcomes even after controlling for the number of injections each patient received. This suggests a more nuanced association likely exists between injections and visits. While monthly CATT patients received injections regardless of need, thus driving up the number of overall injections within the study, it is also likely that missed visits were missed opportunities to assess disease activity in its earliest state, prior to lasting VA damage was realized. Clearly injections are a mandatory step for maintaining best VA; however, these results suggest more attention should be paid to emphasizing adherence to follow-up, rather than trying to predict a specific number of injections required for any given patient.
Limitations
Limitations of this study also need to be acknowledged. First, these metrics were only assessed in the setting of monthly and pro re nata treatment regimens. It is unclear if a treat-and-extend regimen was studied how, if at all, the associations seen would change. Similarly, these metrics were tested in a randomized clinical trial, and it is unclear how these associations would be impacted if applied to a real-world population. It is possible that the increased variability leads to even stronger associations with VA outcomes, but this is not certain. Next, while this study found significant associations, this should not imply causation. Certainly, finding these associations within the context of controlling for the medication used, treatment regimen (pro re nata vs monthly), and baseline VA suggests a causal role for visit adherence is possible; this cannot be definitively stated. Lastly, these data were created from a randomized clinical trial over the initial 2 years of AMD management. Additional work will be needed to determine if these metrics maintain their association with VA over longer periods.
Conclusions
This study found 4 different metrics that could be used to assess visit adherence that were all associated with VA outcomes. While this association may seem intuitive, we are now able to define the association between visit adherence and VA outcomes. Future work should continue to expand on these metrics and their ability to be applied to real-world populations. The magnitude of the effect of visit adherence on VA outcomes in this clinical scenario suggests that substantial effort should be expended to strive for visit adherence or new therapies that reduce the visit burden without compromising VA outcomes.
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