key: cord-0962947-w3jiviz9
authors: Racette, Lyne; Abu, Sampson Listowell; Poleon, Shervonne; Thomas, Tracy; Sabbagh, Nouran; Girkin, Christopher A.
title: The impact of the COVID-19 pandemic on adherence to ocular hypotensive medication in patients with primary open-angle glaucoma
date: 2021-10-19
journal: Ophthalmology
DOI: 10.1016/j.ophtha.2021.10.009
sha: 28689853c33bcbb9b800ba01ec575446c8991374
doc_id: 962947
cord_uid: w3jiviz9

OBJECTIVE: Emerging evidence suggests that the COVID-19 pandemic is disrupting health behaviors such as medication adherence. The objective of this study was to determine whether adherence to ocular hypotensive medication was affected by the pandemic and to identify factors associated with this change. DESIGN: In this cohort study, we used a controlled interrupted time series design in which the interruption was the declaration of the COVID-19 pandemic in the United States on March 13, 2020. The 300-day monitoring period, which evenly bracketed this declaration, started on October 16, 2019, and ended on August 10, 2020. PARTICIPANTS: Patients with primary open-angle glaucoma enrolled in an ongoing longitudinal NIH-funded study initiated prior to the onset of the pandemic were selected if they were prescribed ocular hypotensive medication and had adherence data spanning the 300-day period. METHODS: We applied segmented regression analysis using a “slope change following a lag” impact model to obtain the adherence slopes in the periods preceding and following the segmentation. We compared the two slopes using the Davies test. MAIN OUTCOME AND MEASURE: The main outcome measure was daily adherence to ocular hypotensive medication—defined as the number of doses taken divided by the number of doses prescribed, expressed in percent. Adherence was measured objectively using Medication Event Monitoring System (MEMS) caps. We assessed the associations between change in adherence and demographic, clinical, and psychosocial factors. RESULTS: The sample included 79 patients (mean age, 71 years [SD, 8 years]). Segmented regression identified a breakpoint at day 28 following the declaration of the pandemic. The slope in the post-breakpoint period (-0.04%/day) was significantly different from zero (P < 0.001) and from the slope in the period preceding the breakpoint (0.006%/day) (P < 0.001). A significant positive association was observed between the Connor-Davidson Resilience score and the change in slope between the pre- and post-breakpoint periods (P = 0.002). CONCLUSIONS AND RELEVANCE: Adherence to ocular hypotensive medication worsened during the COVID-19 pandemic and appears to be related to patient resilience. This collateral consequence of the pandemic may translate into vision loss that may manifest beyond its containment.

Emerging evidence suggests that the COVID-19 pandemic is disrupting behaviors such as physical activity, sleep and alcohol consumption. In previous seasonal and pandemic influenzas, poorer adherence to antiviral treatment was reported. 1 During the COVID-19 pandemic, changes in medication adherence-a critical health behavior in the management of chronic diseases-have also been reported. [2] [3] [4] Only one of the three studies assessing medication adherence with objective measurements reported improved adherence during the pandemic. Patients with asthma and chronic obstructive pulmonary disease (COPD) showed a 14.5% increase in adherence to daily controller medications between January and March, 2020. 4 This improvement likely reflects an understanding of the importance of controlling these diseases in the midst of a pandemic of respiratory illness. Of the other two studies, one reported a 10% decrease in the number of long acting antipsychotic injections administered within an ambulatory clinic located in Pittsburg, Pennsylvania. 3 The other study analyzed administrative databases and reported higher failed refill rates for chronic disease medications in Italian clinical practice settings from April to May of 2020. 2 Together, these findings suggest that adherence behavior was affected during the pandemic. These findings also raise concern for medication adherence in glaucoma patients, specifically because adherence to prescribed therapy was previously found to be poorer compared to adherence to other medications. 5 Primary open-angle glaucoma (POAG)-a chronic age-related optic neuropathy that is asymptomatic in the early stages-can lead to irreversible blindness if left untreated.

Hypotensive eye drops are prescribed as a first-line treatment to control intraocular pressurethe only known modifiable risk factor for glaucoma progression. While efficacious, 6 adherence to this treatment is challenging for patients, who are required to instill eye drops every day for the duration of their lives. 7 Given the strong association between nonadherence and visual field progression, 8 the primary goal of this study was to assess the impact of the COVID-19 pandemic on adherence to ocular hypotensive therapy in patients with POAG. Adherence-J o u r n a l P r e -p r o o f conceptualized as a dynamic process 9 -is likely to fluctuate in response to stressful situations or changes in personal circumstances. As a result, a secondary goal of this study was to identify factors associated with medication adherence during the pandemic. We assessed the association between demographic, clinical, and psychosocial factors and adherence in the periods preceding and following the onset of the pandemic. Psychosocial factors included resilience, 10 coping styles, 11 illness perception 12 and self-efficacy, 13 which have been associated with adherence and visual function.

The data examined in this study were obtained from an ongoing longitudinal NIH-funded study (referred to as the parent study elsewhere in this report) that fortuitously began prior to the onset of the COVID-19 pandemic. While the primary goal of the parent study was to reduce the time to detection of progression through the development of a joint structure-function model, 14 objective measurements of adherence as well as psychosocial data were obtained as ancillary data. This afforded a unique opportunity to examine the effects of the pandemic on objectively measured medication adherence in patients with POAG.

We used a controlled interrupted time series design in which the date of the COVID-19 emergency declaration in the United States-March 13, 2020-served as the interruption. We selected data from the parent study, in which patients were monitored over a 3-year period.

Information on all demographic variables was obtained by self-report. Eligibility criteria at baseline included the presence of the following in at least one eye: a confirmed diagnosis of POAG, open anterior chamber angle, best-corrected visual acuity of 20/40 or better, spherical correction < 5 diopters (D), cylinder correction < 3 D, and at least one reliable visual field result.

All patients were at least 18 years of age. Participants with a history of intraocular surgery (except uncomplicated cataract or glaucoma surgery), secondary glaucoma, other ocular and J o u r n a l P r e -p r o o f systemic diseases that affect the visual field, cognitive impairment, inability to perform visual field tests reliably, and severe visual field loss defined as mean deviation of -12 dB or worse on a reliable static automated perimetry test were not eligible. Visual field tests were performed with the Humphrey Field Analyzer (Carl Zeiss Meditec, Dublin, CA) using the 24-2 pattern and the Swedish Interactive Thresholding Algorithm. Institutional Review Board approval was obtained from the University of Alabama at Birmingham.

Patients were selected from the parent study if they had been prescribed ocular hypotensive medication throughout the 300 days of the study, which covered the period of October 16, 2019 (150 days preceding the interruption) to August 10, 2020 (150 days following the interruption).

Patients were excluded if they had incomplete adherence data, which could have happened, for example, if a clinical decision was made to undergo surgery or if the patient reported not using their MEMS for a given period while continuing to use their eye drops. The study conformed with the principles and guidelines for the protection of human subjects in biomedical research, adhered to the Health Insurance Portability and Accountability Act and followed the tenets of the Declaration of Helsinki. Written consent was obtained from each participant.

Daily medication adherence was measured using Medication Event Monitoring System (MEMS) caps (Aardex, Switzerland), which electronically register the date and time at which the bottle is opened. The MEMS caps recorded data during the implementation phase of adherence, 15 which follows treatment initiation and describes the extent to which actual dosing corresponds to prescribed dosing. Patients were given one MEMS device for each prescribed ocular hypotensive medication and were instructed to place their eye drop bottle in the MEMS bottle after each instillation. This method has been previously used to assess adherence in patients J o u r n a l P r e -p r o o f with glaucoma. 13, 16 We labelled the MEMS devices with the name of each medication and the research coordinator verified that the correct medication was in the correct MEMS at each study visit. Patients were told that the MEMS caps recorded the date and time at which the bottle was opened and were instructed to use their eye drops as usual. The MEMS caps were not equipped with an LCD display and patients did not receive daily feedback on adherence. The data were downloaded from the MEMS caps at each study visit using a MEMS USB near field communication reader, which allows for seamless data transfer from the MEMS caps to the secure web based MedAmigo platform. When a study visit was missed, the MEMS continued to monitor adherence and the data were downloaded at the next study visit. While study visits were missed during the pandemic, all but four patients had returned for a visit when the dataset used in this study was assembled.

For each patient, a profile was created in MedAmigo that included the number of MEMS caps assigned, the medication regimen associated with each cap, and regimen changes. This information allowed MedAmigo to translate the raw data downloaded from the MEMS caps into percent adherence. Only two patients underwent a change in regimen during the study period.

One patient was excluded due to a clinical decision to stop ocular hypertensive therapy in favor of surgery. The other patient underwent a change in medication class and was excluded to avoid introducing regimen change as a confounding variable. Daily adherence was defined as * 100. The 24-hour period that defined a day was arbitrarily set to start at 3 a.m. and end at 2:59 a.m. to minimize the impact of variability in bedtime hour (e.g., if a patient instilled a bedtime dose at 12:25 a.m., this dose would be counted even though it was technically taken on the next day). Additional instillations were excluded from the calculation, but no penalty was applied. Penalties were also not applied for doses taken outside the prescribed time frame (e.g., we did not apply any penalization for an eye drop instilled at 3 p.m. J o u r n a l P r e -p r o o f that was prescribed to be taken in the morning). When two or more medications were prescribed, an overall percent adherence score was calculated by averaging the mean adherence for each medication.

Two metrics of medication adherence were assessed to capture both its static and dynamic components. Mean adherence was used to provide a summary of adherence over a period of time, and the slope was used to quantify the extent to which adherence changed over time. The breakpoint identified using the segmented regression (described below) was used as a cut-off point in all analyses.

We performed segmented regression analyses to determine whether the COVID-19 pandemic impacted the slope of adherence over time using the 'segmented' package in R. 17, 18 We selected a "slope change following a lag" impact model, 19 which is suitable when there is a delayed change following an event. In this study, we assumed a priori that there would be a delay between the declaration of the pandemic and its resulting impact on medication adherence. We used ordinary least square linear regression because mean adherence-the outcome variable-is continuous. A two-tailed Davies test 20 was performed to determine whether the slopes of the segments preceding and following the onset of the pandemic were significantly different from each other. Autocorrelations in the data were assessed using the Durbin-Watson test. The output of this test ranges from 0 to 4 and values between 1.5 and 2.5 are considered normal.

Change in percent mean adherence Mean adherence was calculated for each patient in the period preceding and following the declaration of the pandemic. The percent change in adherence was calculated as

Negative values indicate a worsening of adherence in the 150 days following the onset of the pandemic. We compared the percent change in adherence between these periods using the Wilcoxon signed-rank test. This analysis was performed using JMP version 15.2.0 statistical software (SAS Institute Inc., Cary, NC).

We assessed the association between demographic, clinical and psychosocial factors and change in percent mean adherence, as well as change in adherence slope, defined as the difference between the slopes in the period preceding and following the segmentation point. The ) was used to measure psychological resilience. 22 Coping was assessed using the 66item Ways of Coping questionnaire, 23 which provides a total score as well as raw scores (frequency of effort) and relative scores (percentage of effort) for the following eight subscales: confrontive coping, distancing, self-controlling, seeking social support, accepting responsibility, escape-avoidance, planful problem solving, and positive reappraisal. Each subscale represents a specific coping strategy. Illness perception was assessed with the 9-item Brief Illness Perception questionnaire. 24 Each question is a subscale that assesses a specific dimension of illness perception: consequences, timeline, personal control, treatment control, identity, coherence, emotional representation, and illness concern. Self-efficacy was measured using the 10-item Glaucoma Medication Adherence Self-Efficacy scale, 25 which assesses patients' confidence in their ability to adhere to their prescribed ocular hypotensive medications. The data from each questionnaire were carefully examined and when response sets were identified, these data were excluded from the analyses. Response sets refer to the tendency of some participants to use a pattern of responses regardless of the question asked (e.g., circling "0" for all questions on a questionnaire) and affect the validity of the results because the answers do not reflect the views of the respondents.

Demographic and clinical data for the 79 participants included in the study are presented in Table 1 . Seventy-one patients (90%) had glaucoma in both eyes and 43 (54%) were prescribed only one glaucoma medication. One patient selected "Other (specify)" for race and reported being Indian. This participant was excluded from the analyses on race.

Change in adherence slope using segmented regression analysis Figure 1 shows the segmented regression analysis applied to the daily mean adherence data.

The optimal segmentation point was at 28 days after the declaration of the pandemic-April 10 , J o u r n a l P r e -p r o o f 2020. The slope before the segmentation was 0.006%/day (P = 0.116) compared to -0.041%/day (P < 0.001) after the segmentation. The Davies test showed that the difference between these slopes (-0.047) was significant (P < 0.001). The Durbin-Watson test yielded a value of 1.6, indicating that adjustments for autocorrelations were not needed. Factors associated with change in mean adherence Table 3 ). In contrast, change in slope was positively associated with the relative score of the planful problem solving (Spearman Rho = 0.30, P = 0.02). Coping data were available for 58 of the 79 patients included in this study. The results for each subscale of illness perception are presented in Table 4 (available at http://www.aaojournal.org) and show no associations with pandemic-related change in adherence. Similarly, glaucoma medication self-efficacy was not associated with change in adherence. Associations between resilience-defined as the process of positive adaptation to adversityand medication adherence were previously reported in some chronic diseases, 10,27,28 but not in glaucoma. The positive association we observed between resilience and medication adherence in the period preceding the pandemic provides evidence for a protective role of resilience against nonadherence to ocular hypotensive medication. The pandemic offered an opportunity to assess whether higher resilience would allow patients to maintain their baseline level of adherence in the face of the adversity imposed by the pandemic. We also found a positive association between resilience and the change in adherence slope. These associations suggest that resilience may be a promising target for improving adherence. We found that higher levels of planful problem solving also enhanced patients' ability to maintain their medication regimen during the pandemic. In contrast, we found that confrontive coping-defined as taking aggressive efforts to change a situation, to the point of being risky and antagonistic-was negatively associated with change in adherence slope. In the context of the pandemic, individuals whose most frequent and predominant style was confrontive coping may have had diminished ability to focus on their medication regimen.

Self-described race was not associated with percent change in mean adherence nor with the decline in adherence observed during the pandemic. However, consistent with previous reports J o u r n a l P r e -p r o o f both in glaucoma 29 and other chronic diseases, 30 This difference may be due to factors such as the stress generated by the experience of systemic or individual racial bias. 31 Other social determinants of health-such as demographic factors, health status, out-of-pocket costs, convenience of refilling prescriptions and socioeconomic status that are captured by the construct of race may also be involved, 32 although a large study of privately insured patients with type 2 diabetes, hypertension and hyperlipidemia showed that the difference in adherence between Black and White patients was not eliminated after adjusting for these factors. 33 Regardless, in the context of the COVID-19

pandemic in glaucoma, further reductions in sub-optimal baseline levels of adherence portend higher rates of disease progression in Black patients. This is particularly concerning in this population which is disproportionately affected by POAG and is more likely to develop POAGrelated visual impairment. 34 As can be appreciated in Figure 3 , crises. 35 In a recent JAMA viewpoint article, Alexander and Qato 36 proposed several strategies that could be implemented to ensure continued access to medication, including expanding the capacity for mail-order and home delivery. Newman-Casey et al 37 reported that patients who used mail orders and pharmacy pick-ups were 90% more likely to maintain good adherence over a four-year period, emphasizing the potential for expanding this type of access to medication. Until such improvements are made, providers should maintain awareness of the negative impact of the pandemic on adherence and highlight this during clinic visits. The patientprovider relationship has previously been described as a facilitator of good adherence, 38 and is a promising vehicle for identifying barriers as they arise in patients, as well as for developing individualized solutions.

In some patients, we observed a change in the timing of eye drop instillations in the periods preceding and following the onset of the pandemic. Panel A of Figure 4 (available at http://www.aaojournal.org) shows an example of a patient whose adherence was stable during the study period, changing from 62% to 59%. The instillation timing of this patient, however, became starkly less consistent after the onset of the pandemic. This irregularity may translate into poorer medication coverage which may impact visual outcomes in the future. Panel B presents the data for the patient whose adherence improved by 72% (the outlier observed on Figure 2 ). Although adherence greatly improved in this patient once the pandemic was declared, only approximately half of the prescribed medication was taken, and at irregular times.

Taken together, these anecdotal examples illustrate that the impact of the pandemic on medication adherence is complex and that its manifestation varies considerably among patients.

This study allowed us to assess the impact of the pandemic on adherence to ocular hypotensive medication and has several strengths. The use of a controlled interrupted time series design in which measurement of the outcome variable-adherence-remained stable throughout the J o u r n a l P r e -p r o o f study period is an important strength of the study. Patients were using MEMS prior to the start of the study period, which provided an excellent baseline, and no new protocols were initiated during the pandemic. Other strengths include the use of MEMS as an objective surrogate measure of medication adherence. While direct observation of medication adherence-either in person or wirelessly-would be ideal, these approaches are more intrusive and alert patients to the fact that their adherence is monitored. This may introduce reactivity bias that can impact patient behavior and translate into higher levels of adherence. 39 The use of MEMS is less invasive than direct observation, provides more accurate estimates than self-report, and provides finer granularity compared to medication possession ratio. Additionally, evidence

shows that the Hawthorne effect-another type of reactivity bias in which patient adherence initially improves when electronic monitoring is used-decreases after approximately two months of using the devices. 40 In this study, adherence was monitored for at least two months prior to study onset in 89% of the patients, and was monitored for at least one month prior to study onset in all patients.

This study also has several limitations. First, the interrupted time series design is vulnerable to the co-occurrence of other events that can impact the outcome variable. For example, in the included in this study did not reach statistical significance due to insufficient statistical power.

Sixth, the study relied on self-report for the obtention of demographic variables, which is a method frequently used in clinical studies but one that can introduce bias. Seventh, this was a single-site study performed in Jefferson County, Alabama, which was the county most impacted during the study period, no significant change in slope was observed in either patient. This suggests that the observed decline in adherence was not a result of the COVID-19 diagnoses.

Finally, the results of the study may not generalize to patients with advanced glaucoma as these patients were not represented in this study.

In conclusion, our findings suggest that medication adherence was adversely affected by the COVID-19 pandemic. This reduction was associated with lower psychometric measures of resilience and more confrontational coping strategies. This may translate into ocular complications and poorer visual outcomes in the months and years following the pandemic.

While the timing and speed of the eventual reversal to pre-pandemic levels of adherence is difficult to predict, the recent surge of the Delta variant suggests an extended recovery period.

Clinicians-in glaucoma and other non-respiratory specialties-should therefore have a raised The difference in slopes before and after the segmentation was significant in Black patients (difference in slopes = -0.08%/day, P < 0.001) as well as in White patients (difference in slopes Table 2 . Associations between demographic, clinical, and psychosocial factors and pre-pandemic mean adherence and slope, and two metrics of change in adherence following the onset of the pandemic. 

A systematic review of factors affecting intended and actual adherence with antiviral medication as treatment or prophylaxis in seasonal and pandemic flu. Influenza Other Respir Viruses

Implications of COVID-19 infection on medication adherence with chronic therapies in Italy: A proposed observational investigation by the Fail-to-Refill project. Risk management and healthcare policy

Long acting injectable antipsychotic medications: Ensuring care continuity during the COVID-19 pandemic restrictions

Changes in medication adherence among patients with asthma and COPD during the COVID-19 pandemic

Improving the prediction of medication compliance: the example of bisphosphonates for osteoporosis

The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration

Electronic monitoring to assess adherence with once-daily glaucoma medications and risk factors for nonadherence: the automated dosing reminder study

The Association between Medication Adherence and Visual Field Progression in the Collaborative Initial Glaucoma Treatment Study

Medication Adherence Trajectories: A Systematic Literature Review

Medication adherence is influenced by resilience in patients with systemic lupus erythematosus

Maladaptive coping strategies and glaucoma progression

Psychosocial determinants of adherence with oral anticancer treatment: 'we don't need no education

Predictors of adherence to glaucoma treatment in a multisite study

Prediction accuracy of a novel dynamic structurefunction model for glaucoma progression

A new taxonomy for describing and defining adherence to medications

Adherence in glaucoma: objective measurements of once-daily and adjunctive medication use

R: A language and environment for statistical computing

Package 'segmented'

Interrupted time series regression for the evaluation of public health interventions: a tutorial

Hypothesis testing when a nuisance parameter is present only under the alternative

Medication adherence program: adherence challenges and interventions in type 2 diabetes

Development of a new resilience scale: the Connor-Davidson Resilience Scale (CD-RISC)

The Ways Of Coping Questionnaire

The brief illness perception questionnaire

Validation of a short version of the glaucoma medication self-efficacy questionnaire

Effect of COVID-19 response policies on walking behavior in US cities

Abuse and resilience in relation to HAART medication adherence and HIV viral load among women with HIV in the United States

Resilience, religiosity and treatment adherence in hemodialysis patients: a prospective study

Risk factors for poor adherence to eyedrops in electronically monitored patients with glaucoma

Predictors of Medication Adherence in Patients with Rheumatoid Arthritis

Understanding how discrimination can affect health

Race and Genetic Ancestry in Medicine -A Time for Reckoning with Racism

Racial and ethnic disparities in medication adherence among privately insured patients in the United States

Primary open-angle glaucoma in blacks: a review

On the frontline against COVID-19: Community pharmacists' contribution during a public health crisis

Ensuring Access to Medications in the US During the COVID-19 Pandemic

Patterns of Glaucoma Medication Adherence over Four Years of Follow-Up

Patient and Provider Perspectives on Glaucoma Treatment Adherence: A Delphi Study in Urban Alabama

A comparison of measures used to describe adherence to glaucoma medication in a randomised controlled trial

Practical and analytic issues in the electronic assessment of adherence

Interrupted time series analysis in drug utilization research is increasing: systematic review and recommendations

The authors thank Kurt Healey, RN, for his insightful inputs at each stage of the study and for critically reviewing the manuscript.J o u r n a l P r e -p r o o f