- Email: [email protected]
Measurement of Persistence and Adherence to Regimens of IOP-Lowering Glaucoma Medications Using Pharmacy Claims Data
Measurement of Persistence and Adherence to Regimens of IOP-Lowering Glaucoma Medications Using Pharmacy Claims Data JACOB WILENSKY, MD, RICHARD G. FISCELLA, RPH, MPH, ANGELINE M. CARLSON, PHD, LISA S. MORRIS, PHD, AND JOHN WALT, MBA
● PURPOSE: Determine persistence and adherence of glaucoma patients to therapeutic regimens of prostaglandin/prostamide-class IOP-lowering medications. ● DESIGN: Retrospective, population-based study. ● METHODS: Glaucoma patients in the IMS Health LifeLink database with a pharmacy claim for latanoprost (n ⴝ 1567), travoprost (n ⴝ 381), or bimatoprost (n ⴝ 476) between September, 2001 and March, 2002 who had no claims for IOP-lowering medication in the previous 180 days, and who were persistent during the first 90 days of therapy. Values reported in the quantity dispensed and days supply fields of the database were used in an algorithm that corrected anomalous data and adjusted days supply to calculate the main outcome measures, persistence, and adherence to therapy. ● RESULTS: The percentage of patients persistent for the 12-month observation period was 69.4% (1087/1567) for those prescribed latanoprost, 70.6% (269/381) for those prescribed travoprost, and 68.1% (324/467) for those prescribed bimatoprost. Mean adherence for patients prescribed latanoprost was 75.4% of the year, for those prescribed travoprost, 77.1% of the year, and for those prescribed bimatoprost, 78.2% of the year. The mean number of days adherent for bimatoprost-treated patients (291.2 days) was significantly greater than for latanoprost-treated patients (281.0 days), and not remarkably different from travoprost-treated patients (287.0 days). ● CONCLUSIONS: Overall, patients in this study who were taking IOP-lowering prostaglandin/prostamide medications had a mean adherence rate of 76% on
Accepted for publication Sep 2, 2005. From the University of Illinois at Chicago, Chicago, Illinois (J.W.); Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois (R.G.F.); Data Intelligence Consultants, LLC, Eden Prairie, Minnesota (A.M.C.); IMS Health, Plymouth Meeting, Pennsylvania (L.S.M.); and Allergan Global Health Outcomes, Irvine, California (J.W.). Inquiries to Jacob Wilensky, MD, University of Illinois at Chicago, 1855 West Taylor, Chicago, IL 60612; fax: 312-996-7770; e-mail: [email protected]
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average, suggesting that opportunities remain for improvement of adherence to therapeutic regimens for glaucoma treatment with prostamides and prostaglandins. (Am J Ophthalmol 2006;141:S28 –S33. © 2006 by Elsevier Inc. All rights reserved.)
E
FFECTIVE TREATMENT OF GLAUCOMA PRESENTS A
considerable challenge to health care professionals. To preserve vision, successful pharmacological therapy is necessary to lower intraocular pressure (IOP). This, in turn, requires both patient persistence with therapy (continued use of prescribed medication over time) and adherence to a specific drug regimen (consistent daily use of the prescribed medication as ordered). A number of reasons for poor persistence or adherence have been identified. First, many patients, especially newly diagnosed patients, are asymptomatic; for these patients, use of the medication does not provide an immediately obvious benefit. Other reasons that can contribute to poor persistence or adherence to therapy include difficulty with self-administration of drops for elderly patients, a requirement for multiple doses per day, transient bothersome symptoms after instillation, and simple forgetfulness.1–3 The current generation of prostaglandin and prostamide IOP-lowering drugs offer once per day dosing regimens and reduced adverse effects compared with preceding generations of therapies. Reported rates of persistence with prostaglandin-class glaucoma therapies are better than with preceding generations of IOP-lowering medications,4 – 6 but still vary widely. Many studies that examine this important outcome use retrospective analysis of administrative claims databases.4 – 8 A patient is usually deemed to have discontinued, or to be nonpersistent, if no refill of their prescription appears in the database within a proscribed period of time. Measurement of adherence is more complex. It attempts to assess patients’ compliance with the treatment regimen. Electronic monitoring of medication, as it is dispensed, provides the most direct measure of adherence to a therapeutic regimen, but is expensive and, therefore, lim-
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/06/$32.00 doi:10.1016/j.ajo.2005.09.011
ited in terms of the number of patients that may be assessed.9 Analysis of claims data can provide an estimate of adherence as the number of days on which the patient possesses an adequate supply of medication, that is the number of days upon which the patient would be able to comply with the treatment regimen.10 The amount of medication dispensed when the prescription is filled is expressed as the number of days supply; this is used to determine whether the patient was adherent (had medication available for use) on any given day.11 Adherence measured from claims databases, the approach used in this study, has shown 75% to 85% concordance with patient self-reported compliance in other therapeutic areas.12,13 The use of administrative claims data has the advantage of access to data regarding filled prescriptions for very large numbers of patients. Analysis depends on two data fields generally available in such databases, the quantity of medication dispensed, and the number of days supply of medication dispensed. Unfortunately, administrative claims data may contain inconsistencies in both the quantity dispensed and days supply fields that can ultimately lead to inappropriate estimates of persistence and adherence if not properly adjusted. These fields are usually precise for oral solid therapy dispensed in whole number increments, for example, regimens of one or multiple tablet(s) every day. For ophthalmic solutions and inhaled solutions/suspensions, or for complex dosing regimens, entries in these fields may not accurately reflect actual quantities dispensed or days supplied. For dosage forms such as ophthalmic solutions, the quantity dispensed field can contain inconsistencies if the claims processing form requires whole numbers only; pharmacists must round up or down to the nearest whole number to comply. Thus, claims for a 2.5-ml bottle of ophthalmic solution may report the quantity dispensed as 2 ml or 3 ml. In some cases, the number of bottles of ophthalmic solution dispensed may be erroneously reported instead of the total number of milliliters. In these cases, a 2.5-ml bottle of ophthalmic solution may be reported as a quantity dispensed of 1. Inconsistencies in the days supply field for ophthalmic solutions arise for several reasons: (1) variability among products in the number of drops/ml dispensed by the dropper; (2) variability among products in the amount of “overfill”/bottle; (3) a requirement to report the days supply based on the fixed quantity determined by the package size from the manufacturer; or (4) a requirement that the claim conform to the patient’s insurance benefit, which often limits the days supply to 30 days, despite the fact that the quantity contained in the bottle may be sufficient for a greater number of days. Accordingly, use of claims data to estimate persistency and adherence with regimens of ophthalmic solutions requires an understanding of dispensing requirements, claims adjudication requirements, and insurance benefit structures. This study uses administrative claims data to VOL. 141, NO. 1
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examine persistence and adherence during a 12-month observation period for glaucoma patients prescribed the prostaglandin/prostamide IOP-lowering drugs, latanoprost, travoprost, and bimatoprost. It addresses the inconsistencies between quantity dispensed and days supply data fields by corrections and adjustments to better estimate persistence and adherence to drug therapy.
METHODS CLAIMS RECORDS FROM THE IMS HEALTH LIFELINK: INTE-
grated Claims Solutions database were used in this retrospective, population-based study. LifeLink is a US employer-based database covering approximately 1.8 million lives in 40 different indemnity and preferred provider organization (PPO) health plans. The database represents all medical and pharmacy claims with dates of service beginning January 1, 1991 through all paid medical and pharmacy claims as of December 31, 2003 from all sites of care including outpatient, inpatient, laboratory tests, rehabilitation centers, ambulatory surgical centers, nursing homes, psychiatric care facilities, and pharmacy. The database is de-identified by IMS Health in accordance with privacy regulations pursuant to the Health Insurance Portability and Accountability Act (HIPAA) with encrypted patient and physician identifiers and appropriately modified age and zip code formats. Patients with a glaucoma medical claim (ICD-9-CM codes ⫽ 365.xx) and a pharmacy claim for latanoprost, travoprost, or bimatoprost with a date of service from September 2001 through March 2002 were selected for the analysis. Although the study was initiated in late 2003, to have 18 months of retrospective data, data starting at September 2001 were included in this analysis. The date of the first prescription claim for a prostaglandin/prostamide ophthalmic solution was defined as the index date. Continuous eligibility was required for 180 days before the index date with no evidence of IOP-lowering medication use during that time. These patients were defined as “new therapy starts.” Persistence and adherence were determined for all “new therapy starts” who continued for at least 3 months of therapy following the index date, and who took only a single IOP-lowering drug during the entire observation period. Persistence was defined as continued acquisition (filling or refilling) of therapy during a 12-month period of time. Days persistent was measured from the date of the first claim for a drug of interest through the end of the adjusted days supply of the last claim for a prostaglandin/prostamide drug during the 12-month observation period. Days persistent measured continued use, including gaps in therapy. Adherence was determined as the percentage of days for which there was adjusted days supply, that is, the percentage of days for which the patients possessed medication, as evidence of drug therapy.
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TABLE 1. Days per ml of Glaucoma Medication Calculated by Two Methods Days per ml of Solution
Calculation Method
Latanoprost, Travoprost, or Bimatoprost
Latanoprost Only
Travoprost Only
Bimatoprost Only
7.5 15.5
7.8 15.5
6.5 12.9
7.4 15.8
2.0
2.0
2.1
From days supply value on claim forms From number of days between consecutive fills of prescription Adjustment factor
● ADJUSTMENT OF DATA IN THE QUANTITY DISPENSED AND DAYS SUPPLY FIELDS: To address the possible in-
● ADJUSTMENT OF DAYS SUPPLY DATA:
Using the population retained for this study, the number of days/ml calculated directly from the days supply field of the claims without any adjustments or corrections was, on average, 7.5 days (Table 1). According to this, a 2.5-ml bottle of ophthalmic solution would have lasted approximately 18 days, a much shorter period than would be anticipated. Therefore, use of the average days/ml value calculated from the days supply number reported on claim forms would likely underestimate patients’ persistence and adherence with therapy. To compute an adjustment factor for the days supply value, 14,141 pairs of claims for latanoprost, travoprost, and bimatoprost (from all patients in the database prescribed these medications, not just the “new therapy starts”) were analyzed to determine the average number of days between consecutive fills of prescriptions for the same medication. From this analysis, the average number of days/ml of solution was calculated to be 15.5 days (Table 1). By this calculation, a 2.5-ml bottle of ophthalmic solution would last, on average, approximately 39 days, 21 days longer than the average calculated from the days supply numbers reported on the claim forms. Similarly, the average number of days/ml of solution was calculated for each medication. The ratio between the days/ml calculated for each medication by the two methods was used as a factor to adjust the days supply values obtained from the claim forms.
consistencies between the quantity dispensed and days supply reported on a pharmacy claim for prostaglandin/ prostamide medication, an algorithm was developed to compute persistence and adherence for each subject. Corrections or adjustments were made for two data elements. Quantity adjustments were made if the units in the quantity field were outside of acceptable ranges based on National Drug Code (NDC) values. In cases where the NDC indicated that a 2.5-ml bottle of ophthalmic solution was dispensed and the quantity dispensed field indicated some multiple of that quantity, the dollar amount claimed was used to ensure appropriate adjustment of the quantity dispensed. For example, if the quantity dispensed field was 3 but the dollar amount claimed was three times what one bottle would cost, the quantity dispensed field was adjusted to reflect three bottles rather than 3 ml. To adjust the days supply value, the number of days between consecutive prescription claims were determined for all patients in the database receiving prostaglandin/ prostamide therapy (not just “new therapy starts”) using each drug and bottle size. This produced a mean value of days/ml solution for each drug (presented in Table 1). The days supply values taken from the claims data were then adjusted using a factor that was the ratio of the days/ml values calculated by the two methods. The statistical difference between the numbers of actual mean days adherent were determined using the Student t test.
● PERSISTENCE AND ADHERENCE USING ADJUSTED DAYS SUPPLY VALUES: Of the 2424 patients included in this analysis, 69.3% were persistent with their glaucoma therapy for at least 358 days. That is, their final bottle during the 12-month observation period would have lasted past day 358 following their initial claim for IOP-lowering medication. Only slight differences in persistence were found among patients taking different medications. For patients on latanoprost monotherapy, 69.4% were persistent for at least 358 days, compared with 70.6% of patients on travoprost monotherapy, and 68.1% of patients on bimatoprost monotherapy (Table 2). In an analysis that included additional patients who had not been persistent for the first 90 days, 59% of patients prescribed latanoprost were persistent for at least 358 days, compared with 57% of
RESULTS A TOTAL OF 3822 PATIENTS WERE IDENTIFIED WITH GLAU-
coma and as “new therapy starts.” These patients had at least one pharmacy claim from the IMS database for latanoprost, travoprost, or bimatoprost between September 2001 and March 2002, but no claims for glaucoma medications in the prior 180 days. Of these, 2424 patients met the inclusion criteria: they completed an initial 3-month period of therapy on one drug and used no other drug during the 12-month observation period. Data for these 2424 patients were analyzed for persistence and adherence to the therapeutic regimen. S30
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TABLE 2. Persistence and Adherence of Glaucoma Patients to Their Therapeutic Regimen Latanoprost, n ⫽ 1567
Days Persistent
90–119 120–149 150–179 180–209 210–239 240–269 270–299 300–329 330–357 358⫹ Total Actual mean days adherent
Travoprost, n ⫽ 381
Bimatoprost, n ⫽ 476
Percent of Patients Persistent
Percent of Year Adherent
Percent of Patients Persistent
Percent of Year Adherent
Percent of Patients Persistent
Percent of Year Adherent
2.1 3.1 0.8 1.1 1.9 2.4 3.8 6.8 8.6 69.4 100
25.4 32.5 39.8 51.2 56.0 59.2 64.3 66.3 72.4 82.6 75.4 281.0* ⫾ 69.9
0.8 4.5 0.8 1.6 0.5 2.4 2.6 4.7 11.5 70.6 100
25.8 32.6 42.9 50.6 56 51.6 64.1 63.5 74.2 84.3 77.1 287.0 ⫾ 70.5
1.5 2.1 2.1 2.3 2.7 2.7 3.8 4.0 10.7 68.1 100
25.8 32.6 40.4 47.2 55.7 58.9 64.1 73.6 81.8 85.1 78.2 291.2* ⫾ 67.8
*Student’s t test; P ⱕ .05.
patients prescribed travoprost, and 57% of patients prescribed bimatoprost. Although the percentage of patients in the most persistent category was slightly lower for bimatoprost, they were adherent for more days compared with patients using travoprost or latanoprost. The 324 bimatoprost patients who were persistent for at least 358 days (68.1% of all the patients that used bimatoprost) had medication available for 85.1% of the days in the 12-month observation period, or for 310 days of therapy. For comparison, the 269 most persistent travoprost patients (70.6%) had medication available for 84.3% of the year, or for 308 days of therapy, and the 1087 most persistent latanoprost patients (69.4%) had medication available for 82.6% of the year, or for 302 days of therapy. When patients prescribed any of the three drugs were considered together, they were adherent (had medication available for use) on 76.3% (278 days) of the 12-month period. The actual mean number of days adherent were 281, 287, and 291 days for latanoprost-, travoprost-, and bimatoprost-prescribed patients, respectively (Table 2). Patients prescribed bimatoprost had a significantly greater (P ⱕ .05) number of days with medication available for use compared with those prescribed latanoprost, however no significant difference in overall adherence was found between bimatoprost- and travoprost-prescribed patients (Table 2).
DISCUSSION THIS STUDY WAS DESIGNED TO ASSESS THE PERSISTENCE
and adherence to prescribed prostaglandin or prostamide medication for IOP reduction of “new therapy starts,” defined as glaucoma patients who had no claims for VOL. 141, NO. 1
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ophthalmic medications in the previous 180 days. The data were extracted from a large database of pharmacy claims, were adjusted to correct for possible inaccuracies in reporting on pharmacy claims forms. This was done because pharmacy claims data are subject to several types of inaccuracies as described in the introduction of this article. The amounts dispensed were corrected to the manufacturer’s volumes, and made consistent with the dollar amount charged. An adjustment factor for the average days supply/ bottle was derived from the days/ml calculated from consecutive fills of prostaglandin/prostamide prescriptions of all patients in the database, not just “new therapy starts.” The adjustment factor was almost invariant between latanoprost, bimatoprost, and travoprost, so the adjustment did not skew the results to favor any one of the prostaglandin/prostamide medications. The average adjusted number of days a 2.5-ml bottle of ophthalmic solution would last, 39 days, was approximately twice that reported in the days supply field of the pharmacy claims forms. This adjusted days supply value is consistent with median times between refills reported for 2.5-ml bottles of latanoprost (39 to 41 days), bimatoprost (36 to 46 days), and travoprost (39 to 54 days),14 as well as mean refill times for 2.5-ml bottles of these three medications (43 to 62 days).7 When an adjusted days supply algorithm is applied, the percentage of all new glaucoma patients with an initial persistency of 90 days who were persistent for 358 days or longer was 69.4% for those prescribed latanoprost, 70.6% for travoprost, and 68.1% for bimatoprost. Other published 12-month persistency rates for patients who were prescribed latanoprost ranged from 33% to 70%.5,6,8 Absolute rates of 12-month persistency have not been previously published for travoprost or bimatoprost.
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The present study found little difference in 12-month persistency rates among patients prescribed latanoprost, travoprost, and bimatoprost. Previous comparative studies found greater 12-month persistence for patients prescribed latanoprost than for IOP-lowering medications of different classes, such as -blockers and carbonic anhydrase inhibitors.4 – 6,8 Another comparative study reported that patients prescribed travoprost or bimatoprost were more likely to discontinue than those prescribed latanoprost, but did not provide specific 12-month persistence values7; exactly why that study found such differences (in contrast to the present study) is unclear, but possible contributing factors have been discussed previously.15 Earlier studies typically allowed a 90-day period for refill of the prescription before the patient was considered to have discontinued therapy, whereas the present study allowed gaps of any size in therapy during the 12-month observation period. This difference in methodology could have contributed to greater persistence rates found in the present study, although inspection of the adherence rates as a function of persistence suggests that large gaps in therapy were uncommon, and that imposition of a 90-day limit for refills would probably not have significantly changed the results. This study has several limitations. The study design uses claims data to infer adherence as the availability of medication rather than by directly measuring adherence, for example by electronic monitoring of drops dispensed from each bottle. Patients who were given a prescription but never filled it did not initiate a claim, therefore, they would not have been included. The patients included in the analysis for this study were required to persist for an initial 90-day period with their therapy, that is, refill their prescription at least once during the first 90 days after the initial claim. Since the first 90 days are typically used to try different samples of medications until the most appropriate one is found, including only those patients who had at least one refill during this time period ensured that the study would analyze those cases in which the provider and patient had settled on a suitable long-term drug regimen. Furthermore, most of the patients refill within 90 days. As noted above, the mean or median numbers of days between refills of bimatoprost, latanoprost, and travoprost were found to be 40 to 60 days.7,14 There are no studies indicating whether initial persistence is associated with longer periods of persistence and adherence. In this study, 69.3% of patients who were initially persistent for the first 90 days were still persistent after 358 days or more. When patients who did not meet the requirement for an initial 90-day period of persistence were included in the analysis, the percentage of patients who were persistent for 358 days or more dropped to 58%. For the total population of patients, irrespective of their time of persistence, those prescribed latanoprost were adherent (had medication available) for 281 of the days in the 12-month observation period, whereas travoprost patients were adherent for 287 days, and bimatoprost patients S32
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were adherent for 291 days. Patients prescribed bimatoprost were adherent for significantly more days per year than those prescribed latanoprost (P ⱕ .05). Overall, patients in this study were adherent to their regimen for 76.3% of the days in the 12-month observation period. To our knowledge, rates of adherence to prostaglandin/prostamide therapy derived from a pharmacy claims database in this manner have not been previously published. The levels of persistence and adherence found when using corrected quantity dispensed and adjusted days supply information appear to be a better reflection of patient medication use behaviors than the more commonly used method of employing uncorrected data to calculate these measures. The algorithm used in this study thus has face validity but additional testing is ongoing. It is important to note, however, that even when using adjusted data, patients were found to be nonadherent with their glaucoma therapy approximately 24% of the time in this study. Both persistence and adherence to dosing regimens of the prostaglandin/prostamide class of IOP-lowering drugs could be further improved. In conclusion, rates of persistence and adherence to therapy calculated from administrative databases are likely to underestimate the true rates unless reporting errors are corrected and days supply values are adjusted. After correction and adjustment, the rate of persistence is considerably higher than has been previously reported for most comparable studies of IOP-lowering medications using this data source. Overall, patients in this study on prostaglandin/prostamide medications were adherent 76% of the time, suggesting that while opportunities remain for improvement of adherence to therapeutic regimens for treatment of glaucoma, large gaps in therapy were uncommon. ACKNOWLEDGMENTS
We thank Glenn Trygstad, BS and Sue Ellen Kline, PhD of Data Intelligence Consultants, LLC for programming and data management and initial input into problem formulation, respectively. Allergan, Inc (Irvine, California) funded this study and was involved in the following aspects of the study: reviewing the study design, consultation for data management methodology, contracting the preparation of the manuscript, and the review and approval of the manuscript by coauthor John Walt, who is an employee of Allergan, Inc.
REFERENCES 1. Taylor SA, Galbraith SM, Mills RP. Causes of non-compliance with drug regimens in glaucoma patients: a qualitative study. J Ocul Pharmacol Ther 2002;18:401– 409. 2. Balkrishnan R, Brent Bond J, Byerly WG, Camacho FT, Anderson RT. Medication-related predictors of health-related quality of life in glaucoma patients enrolled in a OF
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medicare health maintenance organization. Am J Geriatr Pharmacother 2003;1:75– 81. Tsai JC, McClure CA, Ramos SE, Schlundt DG, Pichert JW. Compliance barriers in glaucoma: a systematic classification. J Glaucoma 2003;12:393–398. Dasgupta S, Oates V, Bookhart BK, Vaziri B, Schwartz GF, Mozaffari E. Population-based persistency rates for topical glaucoma medications measured with pharmacy claims data. Am J Manag Care 2002;8(Suppl 10):S255–S261. Schwartz GF, Reardon G, Mozaffari E. Persistency with latanoprost or timolol in primary open-angle glaucoma suspects. Am J Ophthalmol 2004;137(Suppl 1):S13–S16. Zhou Z, Althin R, Sforzolini BS, Dhawan R. Persistency and treatment failure in newly diagnosed open angle glaucoma patients in the United Kingdom. Br J Ophthalmol 2004;88:1391–1394. Reardon G, Schwartz GF, Mozaffari E. Patient persistency with ocular prostaglandin therapy: a population-based, retrospective study. Clin Ther 2003;25:1172–1185. Reardon G, Schwartz GF, Mozaffari E. Patient persistency with topical ocular hypotensive therapy in a managed care population. Am J Ophthalmol 2004;137(Suppl 1):S3–S12.
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9. Kass MA, Meltzer DW, Gordon M. A miniature compliance monitor for eyedrop medication. Arch Ophthalmol 1984; 102:1550 –1554. 10. Dezii CM. Persistence with drug therapy: a practical approach using administrative claims data. Manag Care 2001; 10:42– 45. 11. Day D. Use of pharmacy claims databases to determine rates of medication adherence. Adv Ther 2003;20:164 –166. 12. Erickson SR, Coombs JH, Kirking DM, Azimi AR. Compliance from self-reported versus pharmacy claims data with metered-dose inhalers. Ann Pharmacother 2001;35:997– 1003. 13. Kwon A, Bungay KM, Pei Y, et al. Antidepressant use: concordance between self-report and claims records. Med Care 2003;41:368 –374. 14. Platt R, Reardon G, Mozaffari E. Observed time between prescription refills for newer ocular hypotensive agents: the effect of bottle size. Am J Ophthalmol 2004;137:S17– S23. 15. Fiscella RG. Persistency with glaucoma medication. Am J Ophthalmol 2004;138:1093–1094.
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● PURPOSE: Determine persistence and adherence of glaucoma patients to therapeutic regimens of prostaglandin/prostamide-class IOP-lowering medications. ● DESIGN: Retrospective, population-based study. ● METHODS: Glaucoma patients in the IMS Health LifeLink database with a pharmacy claim for latanoprost (n ⴝ 1567), travoprost (n ⴝ 381), or bimatoprost (n ⴝ 476) between September, 2001 and March, 2002 who had no claims for IOP-lowering medication in the previous 180 days, and who were persistent during the first 90 days of therapy. Values reported in the quantity dispensed and days supply fields of the database were used in an algorithm that corrected anomalous data and adjusted days supply to calculate the main outcome measures, persistence, and adherence to therapy. ● RESULTS: The percentage of patients persistent for the 12-month observation period was 69.4% (1087/1567) for those prescribed latanoprost, 70.6% (269/381) for those prescribed travoprost, and 68.1% (324/467) for those prescribed bimatoprost. Mean adherence for patients prescribed latanoprost was 75.4% of the year, for those prescribed travoprost, 77.1% of the year, and for those prescribed bimatoprost, 78.2% of the year. The mean number of days adherent for bimatoprost-treated patients (291.2 days) was significantly greater than for latanoprost-treated patients (281.0 days), and not remarkably different from travoprost-treated patients (287.0 days). ● CONCLUSIONS: Overall, patients in this study who were taking IOP-lowering prostaglandin/prostamide medications had a mean adherence rate of 76% on
Accepted for publication Sep 2, 2005. From the University of Illinois at Chicago, Chicago, Illinois (J.W.); Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois (R.G.F.); Data Intelligence Consultants, LLC, Eden Prairie, Minnesota (A.M.C.); IMS Health, Plymouth Meeting, Pennsylvania (L.S.M.); and Allergan Global Health Outcomes, Irvine, California (J.W.). Inquiries to Jacob Wilensky, MD, University of Illinois at Chicago, 1855 West Taylor, Chicago, IL 60612; fax: 312-996-7770; e-mail: [email protected]
S28
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2006 BY
average, suggesting that opportunities remain for improvement of adherence to therapeutic regimens for glaucoma treatment with prostamides and prostaglandins. (Am J Ophthalmol 2006;141:S28 –S33. © 2006 by Elsevier Inc. All rights reserved.)
E
FFECTIVE TREATMENT OF GLAUCOMA PRESENTS A
considerable challenge to health care professionals. To preserve vision, successful pharmacological therapy is necessary to lower intraocular pressure (IOP). This, in turn, requires both patient persistence with therapy (continued use of prescribed medication over time) and adherence to a specific drug regimen (consistent daily use of the prescribed medication as ordered). A number of reasons for poor persistence or adherence have been identified. First, many patients, especially newly diagnosed patients, are asymptomatic; for these patients, use of the medication does not provide an immediately obvious benefit. Other reasons that can contribute to poor persistence or adherence to therapy include difficulty with self-administration of drops for elderly patients, a requirement for multiple doses per day, transient bothersome symptoms after instillation, and simple forgetfulness.1–3 The current generation of prostaglandin and prostamide IOP-lowering drugs offer once per day dosing regimens and reduced adverse effects compared with preceding generations of therapies. Reported rates of persistence with prostaglandin-class glaucoma therapies are better than with preceding generations of IOP-lowering medications,4 – 6 but still vary widely. Many studies that examine this important outcome use retrospective analysis of administrative claims databases.4 – 8 A patient is usually deemed to have discontinued, or to be nonpersistent, if no refill of their prescription appears in the database within a proscribed period of time. Measurement of adherence is more complex. It attempts to assess patients’ compliance with the treatment regimen. Electronic monitoring of medication, as it is dispensed, provides the most direct measure of adherence to a therapeutic regimen, but is expensive and, therefore, lim-
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/06/$32.00 doi:10.1016/j.ajo.2005.09.011
ited in terms of the number of patients that may be assessed.9 Analysis of claims data can provide an estimate of adherence as the number of days on which the patient possesses an adequate supply of medication, that is the number of days upon which the patient would be able to comply with the treatment regimen.10 The amount of medication dispensed when the prescription is filled is expressed as the number of days supply; this is used to determine whether the patient was adherent (had medication available for use) on any given day.11 Adherence measured from claims databases, the approach used in this study, has shown 75% to 85% concordance with patient self-reported compliance in other therapeutic areas.12,13 The use of administrative claims data has the advantage of access to data regarding filled prescriptions for very large numbers of patients. Analysis depends on two data fields generally available in such databases, the quantity of medication dispensed, and the number of days supply of medication dispensed. Unfortunately, administrative claims data may contain inconsistencies in both the quantity dispensed and days supply fields that can ultimately lead to inappropriate estimates of persistence and adherence if not properly adjusted. These fields are usually precise for oral solid therapy dispensed in whole number increments, for example, regimens of one or multiple tablet(s) every day. For ophthalmic solutions and inhaled solutions/suspensions, or for complex dosing regimens, entries in these fields may not accurately reflect actual quantities dispensed or days supplied. For dosage forms such as ophthalmic solutions, the quantity dispensed field can contain inconsistencies if the claims processing form requires whole numbers only; pharmacists must round up or down to the nearest whole number to comply. Thus, claims for a 2.5-ml bottle of ophthalmic solution may report the quantity dispensed as 2 ml or 3 ml. In some cases, the number of bottles of ophthalmic solution dispensed may be erroneously reported instead of the total number of milliliters. In these cases, a 2.5-ml bottle of ophthalmic solution may be reported as a quantity dispensed of 1. Inconsistencies in the days supply field for ophthalmic solutions arise for several reasons: (1) variability among products in the number of drops/ml dispensed by the dropper; (2) variability among products in the amount of “overfill”/bottle; (3) a requirement to report the days supply based on the fixed quantity determined by the package size from the manufacturer; or (4) a requirement that the claim conform to the patient’s insurance benefit, which often limits the days supply to 30 days, despite the fact that the quantity contained in the bottle may be sufficient for a greater number of days. Accordingly, use of claims data to estimate persistency and adherence with regimens of ophthalmic solutions requires an understanding of dispensing requirements, claims adjudication requirements, and insurance benefit structures. This study uses administrative claims data to VOL. 141, NO. 1
(SUPPL)
REGIMENS
OF
examine persistence and adherence during a 12-month observation period for glaucoma patients prescribed the prostaglandin/prostamide IOP-lowering drugs, latanoprost, travoprost, and bimatoprost. It addresses the inconsistencies between quantity dispensed and days supply data fields by corrections and adjustments to better estimate persistence and adherence to drug therapy.
METHODS CLAIMS RECORDS FROM THE IMS HEALTH LIFELINK: INTE-
grated Claims Solutions database were used in this retrospective, population-based study. LifeLink is a US employer-based database covering approximately 1.8 million lives in 40 different indemnity and preferred provider organization (PPO) health plans. The database represents all medical and pharmacy claims with dates of service beginning January 1, 1991 through all paid medical and pharmacy claims as of December 31, 2003 from all sites of care including outpatient, inpatient, laboratory tests, rehabilitation centers, ambulatory surgical centers, nursing homes, psychiatric care facilities, and pharmacy. The database is de-identified by IMS Health in accordance with privacy regulations pursuant to the Health Insurance Portability and Accountability Act (HIPAA) with encrypted patient and physician identifiers and appropriately modified age and zip code formats. Patients with a glaucoma medical claim (ICD-9-CM codes ⫽ 365.xx) and a pharmacy claim for latanoprost, travoprost, or bimatoprost with a date of service from September 2001 through March 2002 were selected for the analysis. Although the study was initiated in late 2003, to have 18 months of retrospective data, data starting at September 2001 were included in this analysis. The date of the first prescription claim for a prostaglandin/prostamide ophthalmic solution was defined as the index date. Continuous eligibility was required for 180 days before the index date with no evidence of IOP-lowering medication use during that time. These patients were defined as “new therapy starts.” Persistence and adherence were determined for all “new therapy starts” who continued for at least 3 months of therapy following the index date, and who took only a single IOP-lowering drug during the entire observation period. Persistence was defined as continued acquisition (filling or refilling) of therapy during a 12-month period of time. Days persistent was measured from the date of the first claim for a drug of interest through the end of the adjusted days supply of the last claim for a prostaglandin/prostamide drug during the 12-month observation period. Days persistent measured continued use, including gaps in therapy. Adherence was determined as the percentage of days for which there was adjusted days supply, that is, the percentage of days for which the patients possessed medication, as evidence of drug therapy.
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TABLE 1. Days per ml of Glaucoma Medication Calculated by Two Methods Days per ml of Solution
Calculation Method
Latanoprost, Travoprost, or Bimatoprost
Latanoprost Only
Travoprost Only
Bimatoprost Only
7.5 15.5
7.8 15.5
6.5 12.9
7.4 15.8
2.0
2.0
2.1
From days supply value on claim forms From number of days between consecutive fills of prescription Adjustment factor
● ADJUSTMENT OF DATA IN THE QUANTITY DISPENSED AND DAYS SUPPLY FIELDS: To address the possible in-
● ADJUSTMENT OF DAYS SUPPLY DATA:
Using the population retained for this study, the number of days/ml calculated directly from the days supply field of the claims without any adjustments or corrections was, on average, 7.5 days (Table 1). According to this, a 2.5-ml bottle of ophthalmic solution would have lasted approximately 18 days, a much shorter period than would be anticipated. Therefore, use of the average days/ml value calculated from the days supply number reported on claim forms would likely underestimate patients’ persistence and adherence with therapy. To compute an adjustment factor for the days supply value, 14,141 pairs of claims for latanoprost, travoprost, and bimatoprost (from all patients in the database prescribed these medications, not just the “new therapy starts”) were analyzed to determine the average number of days between consecutive fills of prescriptions for the same medication. From this analysis, the average number of days/ml of solution was calculated to be 15.5 days (Table 1). By this calculation, a 2.5-ml bottle of ophthalmic solution would last, on average, approximately 39 days, 21 days longer than the average calculated from the days supply numbers reported on the claim forms. Similarly, the average number of days/ml of solution was calculated for each medication. The ratio between the days/ml calculated for each medication by the two methods was used as a factor to adjust the days supply values obtained from the claim forms.
consistencies between the quantity dispensed and days supply reported on a pharmacy claim for prostaglandin/ prostamide medication, an algorithm was developed to compute persistence and adherence for each subject. Corrections or adjustments were made for two data elements. Quantity adjustments were made if the units in the quantity field were outside of acceptable ranges based on National Drug Code (NDC) values. In cases where the NDC indicated that a 2.5-ml bottle of ophthalmic solution was dispensed and the quantity dispensed field indicated some multiple of that quantity, the dollar amount claimed was used to ensure appropriate adjustment of the quantity dispensed. For example, if the quantity dispensed field was 3 but the dollar amount claimed was three times what one bottle would cost, the quantity dispensed field was adjusted to reflect three bottles rather than 3 ml. To adjust the days supply value, the number of days between consecutive prescription claims were determined for all patients in the database receiving prostaglandin/ prostamide therapy (not just “new therapy starts”) using each drug and bottle size. This produced a mean value of days/ml solution for each drug (presented in Table 1). The days supply values taken from the claims data were then adjusted using a factor that was the ratio of the days/ml values calculated by the two methods. The statistical difference between the numbers of actual mean days adherent were determined using the Student t test.
● PERSISTENCE AND ADHERENCE USING ADJUSTED DAYS SUPPLY VALUES: Of the 2424 patients included in this analysis, 69.3% were persistent with their glaucoma therapy for at least 358 days. That is, their final bottle during the 12-month observation period would have lasted past day 358 following their initial claim for IOP-lowering medication. Only slight differences in persistence were found among patients taking different medications. For patients on latanoprost monotherapy, 69.4% were persistent for at least 358 days, compared with 70.6% of patients on travoprost monotherapy, and 68.1% of patients on bimatoprost monotherapy (Table 2). In an analysis that included additional patients who had not been persistent for the first 90 days, 59% of patients prescribed latanoprost were persistent for at least 358 days, compared with 57% of
RESULTS A TOTAL OF 3822 PATIENTS WERE IDENTIFIED WITH GLAU-
coma and as “new therapy starts.” These patients had at least one pharmacy claim from the IMS database for latanoprost, travoprost, or bimatoprost between September 2001 and March 2002, but no claims for glaucoma medications in the prior 180 days. Of these, 2424 patients met the inclusion criteria: they completed an initial 3-month period of therapy on one drug and used no other drug during the 12-month observation period. Data for these 2424 patients were analyzed for persistence and adherence to the therapeutic regimen. S30
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TABLE 2. Persistence and Adherence of Glaucoma Patients to Their Therapeutic Regimen Latanoprost, n ⫽ 1567
Days Persistent
90–119 120–149 150–179 180–209 210–239 240–269 270–299 300–329 330–357 358⫹ Total Actual mean days adherent
Travoprost, n ⫽ 381
Bimatoprost, n ⫽ 476
Percent of Patients Persistent
Percent of Year Adherent
Percent of Patients Persistent
Percent of Year Adherent
Percent of Patients Persistent
Percent of Year Adherent
2.1 3.1 0.8 1.1 1.9 2.4 3.8 6.8 8.6 69.4 100
25.4 32.5 39.8 51.2 56.0 59.2 64.3 66.3 72.4 82.6 75.4 281.0* ⫾ 69.9
0.8 4.5 0.8 1.6 0.5 2.4 2.6 4.7 11.5 70.6 100
25.8 32.6 42.9 50.6 56 51.6 64.1 63.5 74.2 84.3 77.1 287.0 ⫾ 70.5
1.5 2.1 2.1 2.3 2.7 2.7 3.8 4.0 10.7 68.1 100
25.8 32.6 40.4 47.2 55.7 58.9 64.1 73.6 81.8 85.1 78.2 291.2* ⫾ 67.8
*Student’s t test; P ⱕ .05.
patients prescribed travoprost, and 57% of patients prescribed bimatoprost. Although the percentage of patients in the most persistent category was slightly lower for bimatoprost, they were adherent for more days compared with patients using travoprost or latanoprost. The 324 bimatoprost patients who were persistent for at least 358 days (68.1% of all the patients that used bimatoprost) had medication available for 85.1% of the days in the 12-month observation period, or for 310 days of therapy. For comparison, the 269 most persistent travoprost patients (70.6%) had medication available for 84.3% of the year, or for 308 days of therapy, and the 1087 most persistent latanoprost patients (69.4%) had medication available for 82.6% of the year, or for 302 days of therapy. When patients prescribed any of the three drugs were considered together, they were adherent (had medication available for use) on 76.3% (278 days) of the 12-month period. The actual mean number of days adherent were 281, 287, and 291 days for latanoprost-, travoprost-, and bimatoprost-prescribed patients, respectively (Table 2). Patients prescribed bimatoprost had a significantly greater (P ⱕ .05) number of days with medication available for use compared with those prescribed latanoprost, however no significant difference in overall adherence was found between bimatoprost- and travoprost-prescribed patients (Table 2).
DISCUSSION THIS STUDY WAS DESIGNED TO ASSESS THE PERSISTENCE
and adherence to prescribed prostaglandin or prostamide medication for IOP reduction of “new therapy starts,” defined as glaucoma patients who had no claims for VOL. 141, NO. 1
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ophthalmic medications in the previous 180 days. The data were extracted from a large database of pharmacy claims, were adjusted to correct for possible inaccuracies in reporting on pharmacy claims forms. This was done because pharmacy claims data are subject to several types of inaccuracies as described in the introduction of this article. The amounts dispensed were corrected to the manufacturer’s volumes, and made consistent with the dollar amount charged. An adjustment factor for the average days supply/ bottle was derived from the days/ml calculated from consecutive fills of prostaglandin/prostamide prescriptions of all patients in the database, not just “new therapy starts.” The adjustment factor was almost invariant between latanoprost, bimatoprost, and travoprost, so the adjustment did not skew the results to favor any one of the prostaglandin/prostamide medications. The average adjusted number of days a 2.5-ml bottle of ophthalmic solution would last, 39 days, was approximately twice that reported in the days supply field of the pharmacy claims forms. This adjusted days supply value is consistent with median times between refills reported for 2.5-ml bottles of latanoprost (39 to 41 days), bimatoprost (36 to 46 days), and travoprost (39 to 54 days),14 as well as mean refill times for 2.5-ml bottles of these three medications (43 to 62 days).7 When an adjusted days supply algorithm is applied, the percentage of all new glaucoma patients with an initial persistency of 90 days who were persistent for 358 days or longer was 69.4% for those prescribed latanoprost, 70.6% for travoprost, and 68.1% for bimatoprost. Other published 12-month persistency rates for patients who were prescribed latanoprost ranged from 33% to 70%.5,6,8 Absolute rates of 12-month persistency have not been previously published for travoprost or bimatoprost.
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The present study found little difference in 12-month persistency rates among patients prescribed latanoprost, travoprost, and bimatoprost. Previous comparative studies found greater 12-month persistence for patients prescribed latanoprost than for IOP-lowering medications of different classes, such as -blockers and carbonic anhydrase inhibitors.4 – 6,8 Another comparative study reported that patients prescribed travoprost or bimatoprost were more likely to discontinue than those prescribed latanoprost, but did not provide specific 12-month persistence values7; exactly why that study found such differences (in contrast to the present study) is unclear, but possible contributing factors have been discussed previously.15 Earlier studies typically allowed a 90-day period for refill of the prescription before the patient was considered to have discontinued therapy, whereas the present study allowed gaps of any size in therapy during the 12-month observation period. This difference in methodology could have contributed to greater persistence rates found in the present study, although inspection of the adherence rates as a function of persistence suggests that large gaps in therapy were uncommon, and that imposition of a 90-day limit for refills would probably not have significantly changed the results. This study has several limitations. The study design uses claims data to infer adherence as the availability of medication rather than by directly measuring adherence, for example by electronic monitoring of drops dispensed from each bottle. Patients who were given a prescription but never filled it did not initiate a claim, therefore, they would not have been included. The patients included in the analysis for this study were required to persist for an initial 90-day period with their therapy, that is, refill their prescription at least once during the first 90 days after the initial claim. Since the first 90 days are typically used to try different samples of medications until the most appropriate one is found, including only those patients who had at least one refill during this time period ensured that the study would analyze those cases in which the provider and patient had settled on a suitable long-term drug regimen. Furthermore, most of the patients refill within 90 days. As noted above, the mean or median numbers of days between refills of bimatoprost, latanoprost, and travoprost were found to be 40 to 60 days.7,14 There are no studies indicating whether initial persistence is associated with longer periods of persistence and adherence. In this study, 69.3% of patients who were initially persistent for the first 90 days were still persistent after 358 days or more. When patients who did not meet the requirement for an initial 90-day period of persistence were included in the analysis, the percentage of patients who were persistent for 358 days or more dropped to 58%. For the total population of patients, irrespective of their time of persistence, those prescribed latanoprost were adherent (had medication available) for 281 of the days in the 12-month observation period, whereas travoprost patients were adherent for 287 days, and bimatoprost patients S32
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were adherent for 291 days. Patients prescribed bimatoprost were adherent for significantly more days per year than those prescribed latanoprost (P ⱕ .05). Overall, patients in this study were adherent to their regimen for 76.3% of the days in the 12-month observation period. To our knowledge, rates of adherence to prostaglandin/prostamide therapy derived from a pharmacy claims database in this manner have not been previously published. The levels of persistence and adherence found when using corrected quantity dispensed and adjusted days supply information appear to be a better reflection of patient medication use behaviors than the more commonly used method of employing uncorrected data to calculate these measures. The algorithm used in this study thus has face validity but additional testing is ongoing. It is important to note, however, that even when using adjusted data, patients were found to be nonadherent with their glaucoma therapy approximately 24% of the time in this study. Both persistence and adherence to dosing regimens of the prostaglandin/prostamide class of IOP-lowering drugs could be further improved. In conclusion, rates of persistence and adherence to therapy calculated from administrative databases are likely to underestimate the true rates unless reporting errors are corrected and days supply values are adjusted. After correction and adjustment, the rate of persistence is considerably higher than has been previously reported for most comparable studies of IOP-lowering medications using this data source. Overall, patients in this study on prostaglandin/prostamide medications were adherent 76% of the time, suggesting that while opportunities remain for improvement of adherence to therapeutic regimens for treatment of glaucoma, large gaps in therapy were uncommon. ACKNOWLEDGMENTS
We thank Glenn Trygstad, BS and Sue Ellen Kline, PhD of Data Intelligence Consultants, LLC for programming and data management and initial input into problem formulation, respectively. Allergan, Inc (Irvine, California) funded this study and was involved in the following aspects of the study: reviewing the study design, consultation for data management methodology, contracting the preparation of the manuscript, and the review and approval of the manuscript by coauthor John Walt, who is an employee of Allergan, Inc.
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