ORIGINAL STUDY
Characterization of Glaucoma Medication Adherence in Kaiser Permanente Southern California Jason P. Jones, PhD,* Donald S. Fong, MD, MPH,*w Ervin N. Fang, MD,z Claire A. Mesirov, MPH,* and Vaishali Patel, PharmD, MSy
Purpose: To describe adherence to glaucoma medications. Patients and Methods: Medication adherence was investigated using the computerized records of Kaiser Permanente Southern California, a group model health maintenance organization that provides care to 3.4 million residents of Southern California. Eligible glaucoma patients were diagnosed between 2005 and 2009 and had medical and prescription drug coverage between 2005 and 2009. Utilization and adherence parameters were calculated for each of the 5 years from the incident date. Results: A total of 17,943 newly diagnosed glaucoma patients were identified between the years 2005 and 2009. Of patients diagnosed with glaucoma in 2005, 71% were continuously eligible for 5 years. Medication adherence was calculated using a medication possession ratio. Adherence was bimodal and not normal in distribution. Overall, the mean age of the entire group was 66 years, with 56% being 65 years of age or older. The high adherence group tended to be older, more likely to be female, and more likely to be white. The low adherent group (younger) tended to have more and worse diabetes, renal disease, myocardial infarction, and stroke. Conclusions: The shape of the adherence distribution appears bimodal, so analysis based on parametric measures may not be appropriate. Investigations of adherence should probably be performed separately for the low, mid, and high groups. Key Word: glaucoma, medication, adherence, distribution
(J Glaucoma 2016;25:22–26)
G
laucoma affects more than 60 million people globally, and an estimated 10% of those with glaucoma are blind.1 In the United States, primary open-angle glaucoma affects 2.2 million people and is the most common form of glaucoma.2 Reduction of intraocular pressure (IOP) is a primary goal of glaucoma management and has been shown to reduce the risk of progression of optic nerve damage and visual field loss.3–5 Lowering IOP also reduces the risk of glaucoma development in individuals with ocular hypertension.6 Received for publication May 28, 2013; accepted November 9, 2014. From the *Department of Research and Evaluation, Southern California Permanente Medical Group, Pasadena; wDepartment of Ophthalmology, Southern California Permanente Medical Group, Baldwin Park; zDepartment of Ophthalmology, Southern California Permanente Medical Group, Los Angeles; and yGlobal Health Outcomes Strategy and Research, Allergan, Irvine, CA. Supported by a grant from Allergan Inc. Disclosure: V.P. is an employee of Allergan Inc. The remaining authors declare no conflict of interest. Reprints: Donald S. Fong, MD, MPH, Department of Ophthalmology, SCPMG, 1011 Baldwin Park Blvd, Baldwin Park, CA 91706 (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 101097/IJG.0000000000000205
Ophthalmologists and patients believe that compliance and persistence are common problems for many patients with glaucoma. A systematic review reported that the proportion of patients who were adherent to their prescribed medication ranged from 5% to 80%.7 A recent systematic review found that adherence ranged from 23% to 60% over 12 months.8 The current study investigates medication adherence and associated characteristics in a large population of glaucoma patients.
PATIENTS AND METHODS Medication adherence was investigated using the computerized records of Kaiser Permanente Southern California, a group model health maintenance organization that provides care to 3.4 million residents of Southern California at 13 medical centers. Glaucoma was defined as a new ICD-9 diagnosis of 365.x by an ophthalmologist coupled with a prescription for a glaucoma agent filled within 90 days of diagnosis. To be included into the study, eligible glaucoma patients were 18 years or older, and were diagnosed between 2005 and 2009. They also had to have medical and prescription drug coverage between 2005 and 2009 and at least 365 days of coverage before the study. Exclusion was a prior 365.x diagnosis or 2 consecutive prescription fills for glaucoma agents. The evaluation period for each individual was the period of continuous eligibility during which the incident date was selected. For example, if a member was eligible from 2005 to 2007 and from 2009 to 2010 and the incident date was in 2006, only the period from 2005 to 2007 was considered. All observations and utilization during this period was captured. Baseline characteristics were calculated before the incident date and include demographic characteristics, prior insurance eligibility, and comorbid conditions. Utilization and adherence parameters were calculated for each of the 5 years from the incident date. Utilization was calculated on a per member per year basis and included: outpatient clinic visits, emergency department visits, inpatient admissions, inpatient days, and outpatient ophthalmology visits. General pharmacy utilization was calculated based on the total number of classes (first 2 digits of the GPI code) and unique medications (first 10 digits of the GPI code). Medication adherence was calculated using a medication possession ratio (MPR) for glaucoma, diabetes, hypertension, and lipid medications. A MPR is calculated as the number of days during which a patient had access to medication divided by the number of days in a period of interest. For instance, if a patient had access to medication for 50 out of 100 days, her/his MPR would be 0.5.
22 | www.glaucomajournal.com J Glaucoma Volume 25, Number 1, January 2016 Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Glaucoma
Volume 25, Number 1, January 2016
Standard approaches to calculating the MPR (using the “days supplied” field in the pharmacy claim) are known to be problematic for topical ophthalmic medications because the days supplied often is inaccurate because different bottle fill rates cause problems using the nominal bottle volumes. To adjust for this differential fill rate and its impact on calculation adherence, we considered 3 approaches: we considered (1) not adjusting for the extra volume, (2) adjusting using the estimated duration of the bottle calculated by our internal Kaiser Permanente Pharmacy, and (3) chose to use the overfill volume published by Rylander.9 Statistical testing is not reported because the sample sizes for many comparisons were quite large, resulting in all comparisons being statistically significant. The actual values are reported to allow the reader to determine whether there are clinical differences. The number of comparisons with the annual adherence comparison is limited, so statistical testing was performed using the Spearman rank correlation, a nonparametric measure. This study was reviewed and approved by the Kaiser Permanente Southern California Institutional Review Board.
RESULTS A total of 17,943 newly diagnosed glaucoma patients were identified between the years 2005 and 2009. Of patients diagnosed with glaucoma in 2005, 71% were continuously eligible for 5 years. Because the definition of glaucoma required patients to have medications filled during the first year, we looked at adherence starting in year 2. About 6.6% of patients lost membership in year 2, so they were excluded from the study. Figure 1 shows the distribution of the glaucoma medication adherence in year 2, the first year after study eligibility criteria were applied. Adherence groups were defined as low (MPR < 20%), mid (MPR 20% to 79%),
Characterization of Glaucoma Medication Adherence
and high (MPRZ80%). Surprisingly, the distribution was not normal, but bimodal. The “low,” “medium,” and “high” adherence groups contain 29%, 32%, and 32% of patients, respectively. Patients were followed for up to 5 years, 4 years after inclusion into the study. For utilization and adherence measures, the denominator for each patient was set to the number of days for which (s)he was eligible. For instance, if the patient was eligible for the entire year, the denominator was 365. If the patient was eligible for 90 days, the denominator was 90, for the given year. If eligibility terminated before the beginning of the year, the patient was not included in the calculation. Table 1 shows the demographic, eligibility, and baseline characteristics of the study population by adherence. Overall, the mean age of the entire group was 66, with 56% being 65 years of age or older. Hypertension was common in all groups, followed by diabetes, pulmonary disease, renal disease, and cancer. Heart disease and strokes were also common. The high adherence group tended to be older (62% were 65 y of age or older), more likely to be female, and more likely to be white. The low adherent group (younger) tended to have more and worse diabetes, renal disease, myocardial infarction, and stroke. As expected, glaucoma adherence in the past was highly correlated with future glaucoma adherence with Spearman rank and correlation coefficients ranging from 0.65 to 0.84 (Table 2). Table 3 shows medical and prescription utilization for each adherence group. Overall and ophthalmic-specific utilization was highest in the year of incident glaucoma overall and for each group. On average, patients tended to have outpatient encounters of some type approximately once per month (eg, year 5 outpatient utilization per member per year was 12.56 overall). Low adherent patients tended to have fewer outpatient visits (especially in the ophthalmology department) and more emergency department visits and hospital admissions than the high adherent group. Patients in the cohort averaged 6
FIGURE 1. Glaucoma medication adherence distribution in year 2.
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Volume 25, Number 1, January 2016
TABLE 1. Baseline Demographics, Eligibility, and Baseline Comorbid Conditions n Demographics Age (mean) Age 60 Age 65 + Female Race (white) Race (Hispanic) Race (black) Race (Asian) Race (native American) Race (unknown) Race (other) Median income (mean) Education (12 + y) Education (16 + y) Follow-up Years (mean) Prior year 1y 2y 3y 4y 5y Comorbidity Myocardial infarction Heart failure Peripheral vasc. dis. Stroke Dementia Pulmonary Rheumatism Peptic ulcer dis. Liver (mild) Diabetes Diabetes w/Comp. Paralysis Renal Cancer Liver (severe) Cancer w/Mets. HIV/AIDS Hypertension (ICD-9)
Overall
High
Mid
Low
NA
17,943
5839 33%
5765 32%
5142 29%
1197 6.7%
66.2 70% 57% 52% 49% 23% 18% 10% 0.2% 19% 5% $68.3 K 76% 24%
61.0 55% 41% 55% 47% 24% 14% 10% 0.1% 25% 5% $68.4 K 76% 24%
66.8 72% 58% 52% 52% 21% 15% 9% 0.2% 19% 4% $68.3 K 77% 25%
66.2 70% 56% 51% 49% 23% 19% 9% 0.2% 19% 5% $67.8 K 76% 24%
66.0 70% 56% 51% 50% 23% 16% 9% 0.2% 20% 5% $67.7 K 76% 24%
2.98 100% 93% 68% 46% 28% 13%
3.10 100% 100% 70.0% 49.0% 30.0% 13.0%
3.33 100% 100% 78.0% 55.0% 34.0% 15.0%
3.01 100% 100% 69.0% 46.0% 27.0% 13.0%
0.53 100% 2% 0.0% 0.0% 0.0% 0.0%
8.0% 7.9% 7.7% 9.7% 1.0% 17.3% 3.7% 3.7% 4.9% 29.2% 16.9% 2.0% 13.1% 12.1% 0.4% 2.4% 0.2% 65.0%
7.3% 7.2% 7.2% 8.9% 0.8% 16.8% 3.7% 3.9% 4.9% 26.4% 14.9% 1.5% 12.2% 12.9% 0.4% 2.6% 0.1% 66.4%
7.7% 7.2% 7.4% 9.1% 0.8% 16.7% 3.7% 3.2% 4.7% 28.5% 15.4% 2.1% 12.3% 12.1% 0.3% 2.2% 0.2% 64.8%
9.0% 8.4% 7.7% 10.9% 1.1% 17.9% 3.6% 3.7% 4.9% 32.4% 20.1% 2.3% 14.4% 11.0% 0.4% 2.4% 0.3% 64.4%
8.7% 11.9% 12.2% 10.8% 1.8% 20.1% 3.7% 4.4% 6.8% 32.4% 20.9% 2.1% 16.4% 12.8% 0.8% 3.0% 0.3% 62.2%
to 7 prescription classes and 7 to 8 unique drugs besides their glaucoma medications. Patients in the low adherence group tended to have more medications earlier and fewer later compared with the high adherence group. Table 4 shows the adherence across multiple chronic medication classes (glaucoma, diabetes, hypertension, lipid lowering, and thyroid) for the second year after glaucoma
incidence. Relationships generally are weaker than within glaucoma medications across time. The strongest relationship was between hypertension and lipid lowering agents (Spearman r = 0.44). No other class was strongly related with glaucoma medication adherence (all r < 0.10).
DISCUSSION TABLE 2. Spearman Rank Correlations Between Glaucoma Medication Adherence After Year 1
Adherence Correlation Over Time Years Compared Year Year Year Year Year Year
2 2 2 3 3 4
to to to to to to
Year Year Year Year Year Year
3 4 5 4 5 5
r
n
P
0.82 0.72 0.65 0.83 0.74 0.84
12,132 8327 5086 8327 5086 5086
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
Adherence and compliance are thought to be synonymous and is defined as the “degree or extent of conformity to the recommendations about day-to-day treatment by the provider with respect to the timing, dosage and frequency.”7 Medication persistence is defined as duration of time from start to discontinuation of treatment. Electronic monitoring has been reported to be an objective method, because the date and time for each instance of opening and closing are recorded.10,11 However, electronic monitoring studies are limited by short follow-ups and to not reflect the real world because of the intrusiveness of the monitors. Another measure of adherence is prescription
24 | www.glaucomajournal.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Glaucoma
Volume 25, Number 1, January 2016
Characterization of Glaucoma Medication Adherence
TABLE 3. Utilization and General Medication Adherence by Glaucoma Adherence Group
Overall n
High
17,943
5839 33% Health care utilization (number of visits shown as per patient per year) Outpatient in YP 12.48 12.14 Y1 16.55 16.18 Y2 12.88 13.67 Y5 12.56 13.33 Emergency department in YP 0.43 0.37 Y1 0.53 0.40 Y2 0.53 0.45 Y5 0.55 0.46 Hospital admissions YP 0.19 0.16 Y1 0.27 0.18 Y2 0.31 0.26 Y5 0.32 0.25 Outpatient ophthalmology YP 2.00 1.67 Y1 6.49 6.20 Y2 2.97 3.83 Y5 2.51 3.20 Number of nonglaucoma medication Classes YP 6.56 0.00 Y1 6.88 0.64 Y2 6.35 0.69 Y5 6.00 0.64 Medications YP 8.05 6.54 Y1 8.53 6.93 Y2 7.67 6.33 Y5 7.09 6.10 General adherence (MPR) Diabetes YP 0.19 0.81 Y1 0.19 0.81 Y2 0.21 0.81 Y5 0.21 0.81 Hypertension YP 0.49 0.77 Y1 0.53 0.79 Y2 0.53 0.79 Y5 0.56 0.77 Lipid lowering YP 0.35 0.71 Y1 0.38 0.72 Y2 0.40 0.71 Y5 0.44 0.74
Mid
Low
NA
5765 32%
5142 29%
1197 6.7%
12.23 15.20 12.96 11.99
12.81 15.53 11.37 11.79
13.17 23.58 15.60 15.02
0.39 0.41 0.51 0.54
0.51 0.58 0.62 0.61
0.56 1.11 0.58 0.70
0.16 0.20 0.28 0.31
0.22 0.29 0.39 0.40
0.29 0.70 0.33 0.37
1.72 5.28 2.89 2.36
2.52 5.63 1.68 1.59
2.32 12.60 5.09 3.48
0.00 0.46 0.39 0.42
0.00 0.26 0.02 0.12
0.00 0.60
6.39 6.77 6.64 5.89
6.63 7.02 5.98 5.86
6.93 6.62 6.61 6.82
0.77 0.78 0.78 0.76
0.74 0.75 0.71 0.69
0.74 0.75 0.74 0.75
0.74 0.76 0.76 0.75
0.71 0.71 0.68 0.67
0.74 0.75 0.75 0.75
0.65 0.67 0.65 0.65
0.61 0.61 0.58 0.58
0.66 0.65 0.64 0.64
All numeric summaries other than counts are means. MPR indicates medication possession ratio; YP, year prior; Y1, year 1; Y2, year 2; Y5, year 5.
record review, such as the MPR, a measure of the number of days over a period for which patients have sufficient supply. In a study of pharmacy claims data, 1 study reported the MPR to be 64% over a 22-month period.12 Another reported the proportion of days covered (similar measure to MPR) to be 76% in patients during the first year.13 In a study of gaps in adherence, 89% had a gap of 45 days, 71% had 60 days, and 22% had 120 day gap during a 12-month period of follow-up.14 The current study investigated medication adherence, using MPR in a large population of newly diagnosed Copyright
r
glaucoma patients enrolled in a group model health maintenance organization. Unexpectedly, the pattern of glaucoma adherence is not normally distributed. The shape of the adherence distribution appears bimodal. This bimodal distribution suggests that investigations about adherence should not center on parametric characteristics like the mean or the median. Investigations should probably be performed separately for the low, mid, and high groups. Investigators have suggested that patients who had more visits to an ophthalmologist are more likely to be adherent.15 Another found that missing an ophthalmology
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25
Jones et al
J Glaucoma
TABLE 4. Spearman Rank Correlation Between Glaucoma Medication Adherence and Other Medication Adherence in Year 2
Medication Class Diabetes Hypertension Lipid lowering Thyroid
r
n
P
0.04 0.067 0.083 0.036
8327 5086 16,746 16,746
r0.003 < 0.001 < 0.001 < 0.001
visit was associated with lower compliance to therapy.16 The current study suggests the group with high adherence having slightly higher number of ophthalmology visits at year 1 through year 5. No other associations were observed. Both the low and high adherent groups had significant systemic issues. Hypertension was common in both groups as was pulmonary disease, kidney disease, and cancer. When we looked at nonglaucoma chronic medications (eg, diabetes, antihypertensives), we also found a bimodal shape for the adherence distribution. Adherence to these medications seems unrelated to adherence for glaucoma medications despite apparent relationships between the other classes. The large sample size in the current study provides significant P-values for many associations, but there did not seem to be any other relationship with glaucoma medication adherence. The strength of the current study is the large number of patients and drug use available on a computerized database. In addition, the study was able to examine systemic comorbidities. One limitation of our current study is that clinical measures of interest (eg, IOP and visual fields) are not included. In addition, we did not evaluate treatment modification (eg, switching or augmenting medications), other glaucoma interventions (eg, surgery), and other patient characteristics that may be tied to adherence (eg, movement disorders). Future studies should investigate the impact of adherence and progression using functional measures (eg, visual field). In summary, glaucoma medication adherence is distributed in a bimodal distribution. Patients with high compliance tended to be older, more likely to be female, and more likely to be white. Common comorbid condition included hypertension diabetes and chronic pulmonary disease. The low adherent group was younger and tended to have more and worse diabetes, renal disease, myocardial infarction, stroke, and all other conditions. Studies and interventions of adherence should be focused on the group with low adherence to help improve treatment adherence.
Volume 25, Number 1, January 2016
REFERENCES 1. Quigley HA. Number of people with glaucoma worldwide. Br J Ophthalmol. 1996;80:389–393. 2. Friedman DS, Wolfs RC, O’Colmain BJ, et al. Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol. 2004;122:532–538. 3. Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002; 120:1268–1279. 4. Investigators TA. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130:429–440. 5. Group CNTGS. Comparison of glaucomatous progression between untreated patients with normal tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophtalmol. 1998;126:487–497. 6. Kass MA, Heuer DK, Higginbotham EJ, et al. The ocular hypertension treatment study group: the ocular hypertension treatment study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701–713. 7. Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health. 2008;11:44–47. 8. Lu VH, Goldberg I, Lu CY. Use of glaucoma medications: state of the science and directions for observational research. Am J Ophthalmol. 2010;150:569–574. 9. Rylander NR, Vold SD. Cost anlaysis of glaucoma medications. Am J Ophthalmol. 2008;145:106–113. 10. Robin AL, Novack GD, Covert DW, et al. Adherence in glaucoma objective measurements of once-daily and adjunctive medication use. Am J Ophthalmol. 2007;144:533–540. 11. Hermann MM, Papapconstantinou D, Muether PS, et al. Adherence with brimonidince in patients with glaucoma aware and not aware of electronic monitoring. Acta Ophthalmol. 2011;89:e300–e305. 12. Friedman DS, Quigley HA, Gelb L, et al. Using pharmacy claims data to study adherence to glaucoma medications: methodology and findings of the Glaucoma Adherence and Persistency Study (GAPS). Invest Ophthalmol Vis Sci. 2007;48: 1391–1394. 13. Wilensky J, Riscella RG, Carlson AM, et al. Measurement of persistence and adherence to regimens of IOP lowering glaucoma medications using pharmacy claims data. Am J Ophthamol. 2006;141:s28–s33. 14. Lee PP, Walt JG, Chiang TH, et al. A gap analysis approach to assess patient persistence with glaucoma medication. Am J Ophthalmol. 2007;144:520–524. 15. Gurwitz JH, Yeomans SM, Glynn RJ, et al. Patient noncompliance in the managed care setting. The case of medical therapy for glaucoma. Med Care. 1998;36:357–369. 16. Quigley HA, Friedman DS, Hahn SR. Evaluation of practice patterns for the care of open-angle glaucoma compared with claims data; the Glaucoma Adherence and Persistency Study. Ophthalmol. 2007;114:1599–1606.
26 | www.glaucomajournal.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Characterization of Glaucoma Medication Adherence in Kaiser Permanente Southern California Jason P. Jones, PhD,* Donald S. Fong, MD, MPH,*w Ervin N. Fang, MD,z Claire A. Mesirov, MPH,* and Vaishali Patel, PharmD, MSy
Purpose: To describe adherence to glaucoma medications. Patients and Methods: Medication adherence was investigated using the computerized records of Kaiser Permanente Southern California, a group model health maintenance organization that provides care to 3.4 million residents of Southern California. Eligible glaucoma patients were diagnosed between 2005 and 2009 and had medical and prescription drug coverage between 2005 and 2009. Utilization and adherence parameters were calculated for each of the 5 years from the incident date. Results: A total of 17,943 newly diagnosed glaucoma patients were identified between the years 2005 and 2009. Of patients diagnosed with glaucoma in 2005, 71% were continuously eligible for 5 years. Medication adherence was calculated using a medication possession ratio. Adherence was bimodal and not normal in distribution. Overall, the mean age of the entire group was 66 years, with 56% being 65 years of age or older. The high adherence group tended to be older, more likely to be female, and more likely to be white. The low adherent group (younger) tended to have more and worse diabetes, renal disease, myocardial infarction, and stroke. Conclusions: The shape of the adherence distribution appears bimodal, so analysis based on parametric measures may not be appropriate. Investigations of adherence should probably be performed separately for the low, mid, and high groups. Key Word: glaucoma, medication, adherence, distribution
(J Glaucoma 2016;25:22–26)
G
laucoma affects more than 60 million people globally, and an estimated 10% of those with glaucoma are blind.1 In the United States, primary open-angle glaucoma affects 2.2 million people and is the most common form of glaucoma.2 Reduction of intraocular pressure (IOP) is a primary goal of glaucoma management and has been shown to reduce the risk of progression of optic nerve damage and visual field loss.3–5 Lowering IOP also reduces the risk of glaucoma development in individuals with ocular hypertension.6 Received for publication May 28, 2013; accepted November 9, 2014. From the *Department of Research and Evaluation, Southern California Permanente Medical Group, Pasadena; wDepartment of Ophthalmology, Southern California Permanente Medical Group, Baldwin Park; zDepartment of Ophthalmology, Southern California Permanente Medical Group, Los Angeles; and yGlobal Health Outcomes Strategy and Research, Allergan, Irvine, CA. Supported by a grant from Allergan Inc. Disclosure: V.P. is an employee of Allergan Inc. The remaining authors declare no conflict of interest. Reprints: Donald S. Fong, MD, MPH, Department of Ophthalmology, SCPMG, 1011 Baldwin Park Blvd, Baldwin Park, CA 91706 (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 101097/IJG.0000000000000205
Ophthalmologists and patients believe that compliance and persistence are common problems for many patients with glaucoma. A systematic review reported that the proportion of patients who were adherent to their prescribed medication ranged from 5% to 80%.7 A recent systematic review found that adherence ranged from 23% to 60% over 12 months.8 The current study investigates medication adherence and associated characteristics in a large population of glaucoma patients.
PATIENTS AND METHODS Medication adherence was investigated using the computerized records of Kaiser Permanente Southern California, a group model health maintenance organization that provides care to 3.4 million residents of Southern California at 13 medical centers. Glaucoma was defined as a new ICD-9 diagnosis of 365.x by an ophthalmologist coupled with a prescription for a glaucoma agent filled within 90 days of diagnosis. To be included into the study, eligible glaucoma patients were 18 years or older, and were diagnosed between 2005 and 2009. They also had to have medical and prescription drug coverage between 2005 and 2009 and at least 365 days of coverage before the study. Exclusion was a prior 365.x diagnosis or 2 consecutive prescription fills for glaucoma agents. The evaluation period for each individual was the period of continuous eligibility during which the incident date was selected. For example, if a member was eligible from 2005 to 2007 and from 2009 to 2010 and the incident date was in 2006, only the period from 2005 to 2007 was considered. All observations and utilization during this period was captured. Baseline characteristics were calculated before the incident date and include demographic characteristics, prior insurance eligibility, and comorbid conditions. Utilization and adherence parameters were calculated for each of the 5 years from the incident date. Utilization was calculated on a per member per year basis and included: outpatient clinic visits, emergency department visits, inpatient admissions, inpatient days, and outpatient ophthalmology visits. General pharmacy utilization was calculated based on the total number of classes (first 2 digits of the GPI code) and unique medications (first 10 digits of the GPI code). Medication adherence was calculated using a medication possession ratio (MPR) for glaucoma, diabetes, hypertension, and lipid medications. A MPR is calculated as the number of days during which a patient had access to medication divided by the number of days in a period of interest. For instance, if a patient had access to medication for 50 out of 100 days, her/his MPR would be 0.5.
22 | www.glaucomajournal.com J Glaucoma Volume 25, Number 1, January 2016 Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Glaucoma
Volume 25, Number 1, January 2016
Standard approaches to calculating the MPR (using the “days supplied” field in the pharmacy claim) are known to be problematic for topical ophthalmic medications because the days supplied often is inaccurate because different bottle fill rates cause problems using the nominal bottle volumes. To adjust for this differential fill rate and its impact on calculation adherence, we considered 3 approaches: we considered (1) not adjusting for the extra volume, (2) adjusting using the estimated duration of the bottle calculated by our internal Kaiser Permanente Pharmacy, and (3) chose to use the overfill volume published by Rylander.9 Statistical testing is not reported because the sample sizes for many comparisons were quite large, resulting in all comparisons being statistically significant. The actual values are reported to allow the reader to determine whether there are clinical differences. The number of comparisons with the annual adherence comparison is limited, so statistical testing was performed using the Spearman rank correlation, a nonparametric measure. This study was reviewed and approved by the Kaiser Permanente Southern California Institutional Review Board.
RESULTS A total of 17,943 newly diagnosed glaucoma patients were identified between the years 2005 and 2009. Of patients diagnosed with glaucoma in 2005, 71% were continuously eligible for 5 years. Because the definition of glaucoma required patients to have medications filled during the first year, we looked at adherence starting in year 2. About 6.6% of patients lost membership in year 2, so they were excluded from the study. Figure 1 shows the distribution of the glaucoma medication adherence in year 2, the first year after study eligibility criteria were applied. Adherence groups were defined as low (MPR < 20%), mid (MPR 20% to 79%),
Characterization of Glaucoma Medication Adherence
and high (MPRZ80%). Surprisingly, the distribution was not normal, but bimodal. The “low,” “medium,” and “high” adherence groups contain 29%, 32%, and 32% of patients, respectively. Patients were followed for up to 5 years, 4 years after inclusion into the study. For utilization and adherence measures, the denominator for each patient was set to the number of days for which (s)he was eligible. For instance, if the patient was eligible for the entire year, the denominator was 365. If the patient was eligible for 90 days, the denominator was 90, for the given year. If eligibility terminated before the beginning of the year, the patient was not included in the calculation. Table 1 shows the demographic, eligibility, and baseline characteristics of the study population by adherence. Overall, the mean age of the entire group was 66, with 56% being 65 years of age or older. Hypertension was common in all groups, followed by diabetes, pulmonary disease, renal disease, and cancer. Heart disease and strokes were also common. The high adherence group tended to be older (62% were 65 y of age or older), more likely to be female, and more likely to be white. The low adherent group (younger) tended to have more and worse diabetes, renal disease, myocardial infarction, and stroke. As expected, glaucoma adherence in the past was highly correlated with future glaucoma adherence with Spearman rank and correlation coefficients ranging from 0.65 to 0.84 (Table 2). Table 3 shows medical and prescription utilization for each adherence group. Overall and ophthalmic-specific utilization was highest in the year of incident glaucoma overall and for each group. On average, patients tended to have outpatient encounters of some type approximately once per month (eg, year 5 outpatient utilization per member per year was 12.56 overall). Low adherent patients tended to have fewer outpatient visits (especially in the ophthalmology department) and more emergency department visits and hospital admissions than the high adherent group. Patients in the cohort averaged 6
FIGURE 1. Glaucoma medication adherence distribution in year 2.
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Jones et al
J Glaucoma
Volume 25, Number 1, January 2016
TABLE 1. Baseline Demographics, Eligibility, and Baseline Comorbid Conditions n Demographics Age (mean) Age 60 Age 65 + Female Race (white) Race (Hispanic) Race (black) Race (Asian) Race (native American) Race (unknown) Race (other) Median income (mean) Education (12 + y) Education (16 + y) Follow-up Years (mean) Prior year 1y 2y 3y 4y 5y Comorbidity Myocardial infarction Heart failure Peripheral vasc. dis. Stroke Dementia Pulmonary Rheumatism Peptic ulcer dis. Liver (mild) Diabetes Diabetes w/Comp. Paralysis Renal Cancer Liver (severe) Cancer w/Mets. HIV/AIDS Hypertension (ICD-9)
Overall
High
Mid
Low
NA
17,943
5839 33%
5765 32%
5142 29%
1197 6.7%
66.2 70% 57% 52% 49% 23% 18% 10% 0.2% 19% 5% $68.3 K 76% 24%
61.0 55% 41% 55% 47% 24% 14% 10% 0.1% 25% 5% $68.4 K 76% 24%
66.8 72% 58% 52% 52% 21% 15% 9% 0.2% 19% 4% $68.3 K 77% 25%
66.2 70% 56% 51% 49% 23% 19% 9% 0.2% 19% 5% $67.8 K 76% 24%
66.0 70% 56% 51% 50% 23% 16% 9% 0.2% 20% 5% $67.7 K 76% 24%
2.98 100% 93% 68% 46% 28% 13%
3.10 100% 100% 70.0% 49.0% 30.0% 13.0%
3.33 100% 100% 78.0% 55.0% 34.0% 15.0%
3.01 100% 100% 69.0% 46.0% 27.0% 13.0%
0.53 100% 2% 0.0% 0.0% 0.0% 0.0%
8.0% 7.9% 7.7% 9.7% 1.0% 17.3% 3.7% 3.7% 4.9% 29.2% 16.9% 2.0% 13.1% 12.1% 0.4% 2.4% 0.2% 65.0%
7.3% 7.2% 7.2% 8.9% 0.8% 16.8% 3.7% 3.9% 4.9% 26.4% 14.9% 1.5% 12.2% 12.9% 0.4% 2.6% 0.1% 66.4%
7.7% 7.2% 7.4% 9.1% 0.8% 16.7% 3.7% 3.2% 4.7% 28.5% 15.4% 2.1% 12.3% 12.1% 0.3% 2.2% 0.2% 64.8%
9.0% 8.4% 7.7% 10.9% 1.1% 17.9% 3.6% 3.7% 4.9% 32.4% 20.1% 2.3% 14.4% 11.0% 0.4% 2.4% 0.3% 64.4%
8.7% 11.9% 12.2% 10.8% 1.8% 20.1% 3.7% 4.4% 6.8% 32.4% 20.9% 2.1% 16.4% 12.8% 0.8% 3.0% 0.3% 62.2%
to 7 prescription classes and 7 to 8 unique drugs besides their glaucoma medications. Patients in the low adherence group tended to have more medications earlier and fewer later compared with the high adherence group. Table 4 shows the adherence across multiple chronic medication classes (glaucoma, diabetes, hypertension, lipid lowering, and thyroid) for the second year after glaucoma
incidence. Relationships generally are weaker than within glaucoma medications across time. The strongest relationship was between hypertension and lipid lowering agents (Spearman r = 0.44). No other class was strongly related with glaucoma medication adherence (all r < 0.10).
DISCUSSION TABLE 2. Spearman Rank Correlations Between Glaucoma Medication Adherence After Year 1
Adherence Correlation Over Time Years Compared Year Year Year Year Year Year
2 2 2 3 3 4
to to to to to to
Year Year Year Year Year Year
3 4 5 4 5 5
r
n
P
0.82 0.72 0.65 0.83 0.74 0.84
12,132 8327 5086 8327 5086 5086
< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
Adherence and compliance are thought to be synonymous and is defined as the “degree or extent of conformity to the recommendations about day-to-day treatment by the provider with respect to the timing, dosage and frequency.”7 Medication persistence is defined as duration of time from start to discontinuation of treatment. Electronic monitoring has been reported to be an objective method, because the date and time for each instance of opening and closing are recorded.10,11 However, electronic monitoring studies are limited by short follow-ups and to not reflect the real world because of the intrusiveness of the monitors. Another measure of adherence is prescription
24 | www.glaucomajournal.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Glaucoma
Volume 25, Number 1, January 2016
Characterization of Glaucoma Medication Adherence
TABLE 3. Utilization and General Medication Adherence by Glaucoma Adherence Group
Overall n
High
17,943
5839 33% Health care utilization (number of visits shown as per patient per year) Outpatient in YP 12.48 12.14 Y1 16.55 16.18 Y2 12.88 13.67 Y5 12.56 13.33 Emergency department in YP 0.43 0.37 Y1 0.53 0.40 Y2 0.53 0.45 Y5 0.55 0.46 Hospital admissions YP 0.19 0.16 Y1 0.27 0.18 Y2 0.31 0.26 Y5 0.32 0.25 Outpatient ophthalmology YP 2.00 1.67 Y1 6.49 6.20 Y2 2.97 3.83 Y5 2.51 3.20 Number of nonglaucoma medication Classes YP 6.56 0.00 Y1 6.88 0.64 Y2 6.35 0.69 Y5 6.00 0.64 Medications YP 8.05 6.54 Y1 8.53 6.93 Y2 7.67 6.33 Y5 7.09 6.10 General adherence (MPR) Diabetes YP 0.19 0.81 Y1 0.19 0.81 Y2 0.21 0.81 Y5 0.21 0.81 Hypertension YP 0.49 0.77 Y1 0.53 0.79 Y2 0.53 0.79 Y5 0.56 0.77 Lipid lowering YP 0.35 0.71 Y1 0.38 0.72 Y2 0.40 0.71 Y5 0.44 0.74
Mid
Low
NA
5765 32%
5142 29%
1197 6.7%
12.23 15.20 12.96 11.99
12.81 15.53 11.37 11.79
13.17 23.58 15.60 15.02
0.39 0.41 0.51 0.54
0.51 0.58 0.62 0.61
0.56 1.11 0.58 0.70
0.16 0.20 0.28 0.31
0.22 0.29 0.39 0.40
0.29 0.70 0.33 0.37
1.72 5.28 2.89 2.36
2.52 5.63 1.68 1.59
2.32 12.60 5.09 3.48
0.00 0.46 0.39 0.42
0.00 0.26 0.02 0.12
0.00 0.60
6.39 6.77 6.64 5.89
6.63 7.02 5.98 5.86
6.93 6.62 6.61 6.82
0.77 0.78 0.78 0.76
0.74 0.75 0.71 0.69
0.74 0.75 0.74 0.75
0.74 0.76 0.76 0.75
0.71 0.71 0.68 0.67
0.74 0.75 0.75 0.75
0.65 0.67 0.65 0.65
0.61 0.61 0.58 0.58
0.66 0.65 0.64 0.64
All numeric summaries other than counts are means. MPR indicates medication possession ratio; YP, year prior; Y1, year 1; Y2, year 2; Y5, year 5.
record review, such as the MPR, a measure of the number of days over a period for which patients have sufficient supply. In a study of pharmacy claims data, 1 study reported the MPR to be 64% over a 22-month period.12 Another reported the proportion of days covered (similar measure to MPR) to be 76% in patients during the first year.13 In a study of gaps in adherence, 89% had a gap of 45 days, 71% had 60 days, and 22% had 120 day gap during a 12-month period of follow-up.14 The current study investigated medication adherence, using MPR in a large population of newly diagnosed Copyright
r
glaucoma patients enrolled in a group model health maintenance organization. Unexpectedly, the pattern of glaucoma adherence is not normally distributed. The shape of the adherence distribution appears bimodal. This bimodal distribution suggests that investigations about adherence should not center on parametric characteristics like the mean or the median. Investigations should probably be performed separately for the low, mid, and high groups. Investigators have suggested that patients who had more visits to an ophthalmologist are more likely to be adherent.15 Another found that missing an ophthalmology
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25
Jones et al
J Glaucoma
TABLE 4. Spearman Rank Correlation Between Glaucoma Medication Adherence and Other Medication Adherence in Year 2
Medication Class Diabetes Hypertension Lipid lowering Thyroid
r
n
P
0.04 0.067 0.083 0.036
8327 5086 16,746 16,746
r0.003 < 0.001 < 0.001 < 0.001
visit was associated with lower compliance to therapy.16 The current study suggests the group with high adherence having slightly higher number of ophthalmology visits at year 1 through year 5. No other associations were observed. Both the low and high adherent groups had significant systemic issues. Hypertension was common in both groups as was pulmonary disease, kidney disease, and cancer. When we looked at nonglaucoma chronic medications (eg, diabetes, antihypertensives), we also found a bimodal shape for the adherence distribution. Adherence to these medications seems unrelated to adherence for glaucoma medications despite apparent relationships between the other classes. The large sample size in the current study provides significant P-values for many associations, but there did not seem to be any other relationship with glaucoma medication adherence. The strength of the current study is the large number of patients and drug use available on a computerized database. In addition, the study was able to examine systemic comorbidities. One limitation of our current study is that clinical measures of interest (eg, IOP and visual fields) are not included. In addition, we did not evaluate treatment modification (eg, switching or augmenting medications), other glaucoma interventions (eg, surgery), and other patient characteristics that may be tied to adherence (eg, movement disorders). Future studies should investigate the impact of adherence and progression using functional measures (eg, visual field). In summary, glaucoma medication adherence is distributed in a bimodal distribution. Patients with high compliance tended to be older, more likely to be female, and more likely to be white. Common comorbid condition included hypertension diabetes and chronic pulmonary disease. The low adherent group was younger and tended to have more and worse diabetes, renal disease, myocardial infarction, stroke, and all other conditions. Studies and interventions of adherence should be focused on the group with low adherence to help improve treatment adherence.
Volume 25, Number 1, January 2016
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