77

1 Centro di Ricerca Clinica e Laboratorio per il Glaucoma e la Cornea, Clinica Oculistica, Di.N.O.G., University of Genova, Genova,

Italy.2

Global Health Outcomes Strategy and Research, Allergan, Inc., Irvine, California.3

Analytica International, New York, New York.

JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICSVolume 25, Number 1, 2009© Mary Ann Liebert, Inc.DOI: 10.1089/jop.2008.0079

Pharmacotherapy Compliance in Patients with Ocular Hypertension or Primary Open-Angle Glaucoma

Carlo E. Traverso,1 John G. Walt,2 Lee S. Stern,3 and Margarita Dolgitser 3

Abstract

Purpose: The aim of this study was to compare rates of pharmacotherapy coverage in patients with ocular hypertension (OH) and patients with primary open-angle glaucoma (POAG).Methods: Retrospective cohort study analysis of a nationally representative, multimanaged health plan data-base (PharMetrics; 1998–2005) which included 4818 medicated OH patients and 52,985 medicated POAG patients with at least 1 year of continuous enrollment and at least one prescription for IOP-lowering medication during the fi rst year of follow-up. Patients selected for the current study were nested within the cohort of OH patients (n = 36,767) and POAG patients (n =72,412) previously reported. Of the previously reported OH cohort, only 13.1% of patients fi lled at least one prescription, as compared to 73.2% of the previously reported POAG cohort. Medication coverage was defi ned as the percent of days during which a patient was in possession of IOP-lowering therapy over the fi rst year of follow-up (medication coverage = number of covered days/365). Compliant patients were defi ned as those with ≥ 75th percentile medication coverage.Results: POAG patients had slightly longer mean length of enrollment in the database (2.5 years, SD = 1.2) than did OH patients (2.4 years, SD = 1.1; P < 0.0001). The mean medication coverage was 50% for the POAG cohort (SD = 0.26) and 40% for the OH cohort (SD = 0.25; P < 0.0001). In multivariate models controlling for key covari-ates of interest, POAG patients were 1.9 (95% CI: 1.7 to 2.0) times more likely to be compliant with their pharma-cotherapy than OH patients.Conclusion: In general, pharmacotherapy coverage was poor. Patients with POAG, a more severe condition, were signifi cantly more covered with pharmacotherapies than patients with OH. It is important to implement strategies to help improve patient coverage prior to occurrence of more severe disease.

Introduction

Ocular hypertension (OH) is a condition characterized by elevated intraocular pressure (IOP). It affects 3–6

million Americans,1 and if not properly managed, can pre-dispose to primary open-angle glaucoma (POAG), a chronic potentially debilitating eye disease. It is estimated that over 2 million Americans currently suffer from POAG, and because of the rapidly aging population that number will increase to over 3 million by 2020.2–4 POAG causes progressive damage to retinal ganglion cells and the optic nerve, eventually lead-ing to loss of nerve fi bers, a permanent decrease in visual fi elds, and possible blindness. As such, POAG is the second most common cause of legal blindness in the United States, and one of the three leading causes worldwide.5,6

POAG imposes a substantial cost burden on the health-care system, with annual estimates ranging from $1.5 billion to $1.9 billion.5,7 This burden includes not only the cost of direct treatment, but also the treatment of associated comor-bidities and overall health-care expenses, such as long-term care and admission to skilled nursing facilities.8 Within the fi rst year of diagnosis, patients with POAG incur signifi -cantly higher total and condition-related health-care costs as compared to those with OH.9 Due to the higher costs of POAG compared to OH, there is a social incentive to avert disease progression of OH to POAG.

It has been shown that medical treatment can delay and possibly prevent the onset of POAG in individuals with increased IOP.1,10 As intraocular pressure currently is the

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TRAVERSO ET AL.78

index date, and the 1 year of follow-up was defi ned as the index year. Patients with an ICD-9 diagnosis code for POAG (365.11) during the index year or any time prior to index date were excluded.

A cohort of medicated POAG cases was identifi ed for the purpose of comparative analysis of pharmacotherapy com-pliance. Patients in this cohort were included if they had at least two ICD-9 codes for POAG (365.11) at any time during the follow-up period in any diagnosis position (primary, sec-ondary, tertiary, and quaternary) on any claim line, were at least 18 years of age on the date that they fi rst received a POAG diagnosis, had at least one prescription for an IOP-lowering medication during the fi rst year of follow-up, and were continuously enrolled for at least 1 year after fi rst POAG diagnosis. Just as in the OH cohort, the index date was defi ned as the date of fi rst diagnosis, and the index year refers to the one year of continuous follow-up. Those with an ICD-9 diagnosis codes for OH (365.04) any time following the index date were excluded from this cohort. The study design is summarized in Fig. 1. All statistical analysis was conducted in SAS Version 9.1.21

Descriptive statistics

Baseline demographics, including age, gender, payer type, product type, region, and year of index date were examined for both the OH and POAG cohorts.

All descriptive statistics were compared between the OH and POAG cohorts using a Chi-Square analysis for categori-cal variables and an unpaired t-test for continuous variables.

Comorbidities and procedures

Comorbid conditions for both cohorts were identifi ed during the index year by the presence of at least two ICD-9 codes for each condition. Both ocular comorbidities (cata-ract, cataract surgery, diabetic retinopathy, and blindness) and systemic comorbidities (hypertension, cardiovascu-lar disease, diabetes mellitus, cerebrovascular disease, and dementia) were analyzed.

The proportion of POAG and OH patients a procedure (visual fi eld exam, comprehensive eye exam, trabeculo-plasty, or trabeculectomy) was identifi ed by at least one CPT code during the year post-index date.

Statistical differences in comorbidities and procedures between OH and POAG cohorts were determined using a Chi-Square test.

Compliance analysis

Medicated OH or POAG patients were defi ned as patients who fi lled at least one prescription for IOP-lowering phar-macotherapy during the index year of follow-up. Time from diagnosis date to fi rst IOP-lowering prescription was com-pared between the OH and POAG patients. In order to assess medication compliance while accounting for multiple simul-taneous prescriptions, switches, and add-ons, Medication Coverage was calculated for patients in both the OH and POAG cohorts; coverage was defi ned as the percent of days during which a patient was in possession of any glaucoma medication over the fi rst year of follow-up.22 The 75th per-centile of coverage (for both cohorts) served as the compli-ance/noncompliance cutoff.

only treatable risk factor for POAG, therapy is targeted at decreasing IOP with ocular antihypertensive medications.5

While pharmacological therapy is available to treat OH and POAG, patient compliance with medications is para-mount in slowing disease progression. One recent study showed that enhanced compliance with pharmacotherapy reduces the odds of negative outcomes, such as the need for glaucoma surgery.11 Further, patients with POAG who were more compliant with pharmacotherapy have been shown to incur signifi cantly lower glaucoma-related health-care charges than those who were less compliant.12

In other disease areas, it has been demonstrated that compliance is typically associated with better outcomes. For example, diabetics who were nonadherent to medication had statistically and clinically worse outcomes,13 higher hospital-ization rates, and greater health-care costs 14 as compared to patients who were adherent. Likewise, medical compliance has been associated with a signifi cant decrease in fractures in patients with osteoporosis,15 and better blood pressure control in patients with systemic hypertension.16,17

In one study, patients in the early stages of POAG were shown to be less compliant with pharmacotherapy prior to experiencing POAG-related symptoms, specifi cally a gradual loss of visual fi eld; compliance increased after the appearance of symptoms.18 Given this fi nding, there may be incentive to promote compliance with pharmacotherapy in OH patients, prior to the manifestation of symptoms, in order to prevent progressing to more severe, and more costly, POAG. Therefore, the purpose of this study was to assess and compare pharma-cotherapy compliance in patients with OH to that of patients with POAG by using retrospective claims data to assess real-world treatment rates in a managed care setting.

Methods

Study design

This retrospective cohort study examined patients with OH and POAG using the PharMetrics Anonymous Patient-Centric database. This source-linked claims database is a repository of health information on over 50 million covered lives belonging to 64 national and regional United States (US) managed care organizations, with linkage to medical and pharmacy data. The data are longitudinal and represen-tative of the US national multimanaged care population on a variety of demographics, including age, gender, and product type. Institutional Review Board (IRB)/Ethics Committee approval was not required for this study.19

Study population

Patient data were evaluated between 1998 and 2005. To formulate the cohort of medicated OH cases, patients were extracted from the PharMetrics database using the following inclusion criteria: at least two International Classifi cation of Diseases Ninth Revision (ICD-9)20 diagnosis codes for OH (365.04) at any time during the follow-up period in any diag-nosis position (primary, secondary, tertiary, and quater-nary) on any claim line, at least 18 years of age on the date of fi rst OH diagnosis, at least one prescription for an IOP-lowering medication during the fi rst year of follow-up, and a minimum of 1 year of continuous enrollment after fi rst OH diagnosis. The date of fi rst diagnosis was defi ned as the

10-JOP_25-1_0079.indd 78 2/26/2009 4:13:51 AM

PHARMACOTHERAPY COMPLIANCE IN PATIENTS WITH OH OR POAG 79

cardiovascular disease, diabetes mellitus, cerebrovascular disease, and dementia) than patients with OH (Table 2).

A larger proportion of POAG patients than OH patients underwent a visual fi eld exam, comprehensive eye exam, trabeculoplasty, or trabeculectomy (Table 3).

Compliance analysis

During the index year, 13.1% (n = 4,818) compared to 73.2% (n = 52,985) of the previously reported OH and POAG cohorts were receiving IOP-lowering medication, respectively (P < 0.0001).9 The mean time from diagno-sis date to index date was somewhat longer for the OH patients (89.7 days) than for the POAG patients (77.9 days; P < 0.0001).

The mean medication coverage was signifi cantly higher for the POAG cohort (50%, SD = 0.26) than for the OH cohort (40%, SD = 0.25; P < 0.0001). The 75th percentile of coverage for all medicated patients (OH and POAG) was 71.3%.

Multivariate modeling

Multivariate modeling results are reported in Table 4. POAG patients were 1.9 (95% CI: 1.7 to 2.0) times more likely to be compliant with their pharmacotherapy than OH patients, after adjusting for key covariates of interest (P > 0.0001).

Patients with comorbid cardiovascular disease, stroke or cerebrovascular disease, and dementia were signifi cantly less likely to be compliant with their IOP-lowering phar-macotherapy than those without these comorbid conditions (Table 4).

Those patients who had undergone cataract surgery were 1.2 (95% CI: 1.1 to 1.3) times less likely to be compliant with their IOP-lowering pharmacotherapy than those who had not had cataract surgery.

As age increased, so did the likelihood of compliance with pharmacotherapy.

Multivariate modeling

Multivariate logistic regression models determined the effects of disease state (OH vs. POAG) on patient compliance during the index year, while controlling for key covariates of interest (all descriptive statistics, ocular and systemic comor-bidities, and duration of enrollment in PharMetrics). Models were run in medicated OH and POAG patients. Initially, all potential covariates were included in the multivariate mod-els; however only those covariates with a P-value <0.2 were retained and controlled for in the fi nal models.

Results

Descriptive statistics

The fi nal study population consisted of 4,818 OH patients and 52,985 POAG patients who met the study criteria. Patients with OH were statistically different from those with POAG over a variety of demographic factors (Table 1). Patients with OH were signifi cantly younger (mean age 54, SD = 11) than patients with POAG (mean age 60, SD = 14; P < 0.0001). The majority of both OH and POAG patients were female (54.9% vs. 54.4%, respectively; P = 0.4967) and most OH and POAG patients were from the Midwest (42.4% and 34.1%, respec-tively; P < 0.0001). A higher proportion of OH patients compared to POAG patients were covered by commercial insurance (71.1% vs. 56.6%), while more POAG patients were covered in Medicare risk plans than OH patients (30.6% vs. 11.4%). Additionally, POAG patients had slightly longer mean length of enrollment in the database (2.5 years, SD = 1.2) than did OH patients (2.4 years, SD = 1.1; P < 0.0001).

Comorbidities and procedures

In univariate analyses not controlling for the effects of age, patients with POAG were more likely to have both ocu-lar comorbidities (cataract, cataract surgery, diabetic retinop-athy, blindness) and systemic comorbidities (hypertension,

OH Cohort

POAG Cohort

First OH diagnosis

First POAG diagnosis Last claim in PharMetrics

At Least 1 year of Continuous EnrollmentAND at least one IOP-lowering prescription

Index Date(1998–2005)

FIG. 1. Study design. Patients with ocular hypertension or primary open-angle glaucoma were selected if they had at least 1 year of continuous enrollment between 1998 and 2005 in the PharMetrics database and at least one prescription for IOP-lowering medication within the fi rst year of follow-up.

10-JOP_25-1_0079.indd 79 2/26/2009 4:13:51 AM

TRAVERSO ET AL.80

The strengths of this study include the large sample sizes, allowing us to draw important conclusions from the trends we observed and the representative nature of the data. There are however inherent limitations with a study based on ret-rospective claims data. While race is strong risk factor for developing glaucoma,5,23 this information was not available within the database and was therefore not controlled for in the multivariate models. In addition, we were unable to vali-date disease status using pertinent clinical data, such as IOP measurements or the physicians’ clinical impressions. It was not possible to control for physician ordering of discontinua-tion of medication if it was no longer necessary following laser procedures or surgery. Also, information regarding medica-tions or treatment given outside of the specifi c enrolled man-aged care plan is not available in the database.

Although we demonstrated a signifi cant difference in compliance between OH and POAG patients, there may be confounders in this relationship that are not refl ected in the claims data. For example, severe intolerance to medication may lead to its discontinuation, or a physician may prescribe nonpharmacological treatment instead of offering educa-tion tools to improve their compliance; this would lead to an underestimation of the degree of compliance. Conversely, the coverage methodology used in this study as a proxy for patient compliance was unable to take into account patients who, while in possession of medication, may not follow their medication regimen correctly.

There are several possible reasons as to why patients with POAG are more compliant with pharmacotherapy than patients with OH. A recent meta-analysis showed that in dis-ease conditions that are not directly life-threatening, patients in worse health tend to be more compliant with medical therapy than patients in better health.24 This is exemplifi ed by a number of chronic conditions, such as systemic hyper-tension, hypercholesterolemia, diabetes, and osteoporosis, which have an asymptomatic early phase, eventually pro-gressing to more severe disease.25–27 From the point of view of the patient, it is the presence of symptoms that instills the perception that a disease actually poses a serious threat to their health. In OH and in early stages of POAG, patients will experience no symptoms until the disease progresses and advanced visual fi eld damage has occurred.28

Tsai and colleagues have described a number of barriers to adherence, the most common of which are situational/environmental (for approximately half of glaucoma patients) or related to drug treatment regimen (for approximately one-third).29 Another study found a decrease in therapy compliance with the addition of another medical therapy.30 This fi nding suggests that the simpler the regimen, the more likely the patient will adhere to that regimen.

Previous studies have shown that patients who are not compliant with their medications are more likely to experi-ence worse outcomes and to use more health-care resources. For example, Stewart and colleagues showed that the chance of maintaining eyesight is diminished in patients with POAG who do not adhere to their medications.31 Patients who pro-gress to more advanced stage of a disease may require addi-tional pharmacological therapies or surgical intervention, leading to higher health-care costs. In this regard, Lee and colleagues found that resource utilization increases with dis-ease severity and suggested that delaying the progression of POAG could potentially reduce health-care burden.32 Even when considering other chronic and initially asymptomatic

Discussion

This retrospective study used real-world claims data to compare pharmacotherapy compliance of medicated patients with OH to that of medicated patients with POAG in a large cohort of patients. After controlling for key covari-ates, patients with POAG were signifi cantly more likely to be compliant with their medication than patients with OH.

Since POAG is a progressively more severe disease than OH, we expected to fi nd that POAG patients were older and more affl icted with comorbidites than OH patients, and our results validated this fi nding. Patients with POAG were approximately 8 years older than patients with OH and exhibited higher rates of cataracts, diabetic retinopathy, blindness, hypertension, cardiovascular disease, diabetes mellitus, cerebrovascular disease, and dementia. The num-ber of ophthalmic procedures performed in OH and POAG patients is in line with what would be expected for these patients.

Table 1. Descriptive Statistics of OH and OAG Cohorts

Variable (%)OH Cohort (n = 4,818)

POAG Cohort (n = 52,985) P-value

Age ≥65 years 12.4 31.0 <0.0001Gender Male Female

45.154.9

45.654.4

0.4967

Region East Midwest South West

26.342.421.310.1

28.634.125.811.6

<0.0001

Payer type Commercial Medicare risk Self-insured Medicaid Other/unknown

71.111.44.83.19.7

56.630.64.72.15.9

<0.0001

Product type HMO PPO POS Indemnity Other/unknown

38.840.212.81.76.4

54.827.610.91.75.0

<0.0001

Year of index date 1998 1999 2000 2001 2002 2003 2004

3.74.78.7

12.722.832.614.8

5.16.313.119.221.126.09.3

<0.0001

Length of enrollment, mean (SD)

2.4 (1.1) 2.5 (1.2) <0.0001

OH, ocular hypertension; POAG, primary open-angle

glaucoma; HMO, health maintenance organization; PPO, preferred

provider organization; POS, point of service organization.

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PHARMACOTHERAPY COMPLIANCE IN PATIENTS WITH OH OR POAG 81

Research shows that there are no specifi c characteristics that could serve to easily identify a patient at risk of non-compliance.33 It is therefore important that health-care pro-viders give all of their patients the necessary educational information regarding their condition. This should include clear disclosure about the current state of their disease and continuing patient education (CPE) during the course of the disease before irreversible damage and vision loss occurs. Educational interventions should be personalized and sim-ple and may involve a range of resources, including the fam-ily or community.18,34

It is important to implement strategies to help improve patient compliance prior to occurrence of more severe dis-ease. The delay of disease progression while in the early stages of OH through better disease management may sub-stantially reduce the economic burden of glaucoma on the health-care system.35

Acknowledgment

This study was funded by Allergan, Inc. (Irvine, CA).

disease processes, including systemic hypertension and osteoporosis, compliance is associated with improved clini-cal performance and outcomes for the patient and decreased health-care costs.14–17

One striking result of our work is the fi nding of a very low compliance even in the POAG group. This problem should be addressed in the real world in order to increase the effi cacy of any medical treatment.

Table 2. Percentage of Patients with Comorbidities

Comorbidity OH Cohort (n =4,818)

POAG Cohort (n =52,985) P-value

Ocular comorbidities Cataract 15.4% 19.3% <0.0001Cataract surgery 4.2% 4.8% 0.0774Diabetic retinopathy 5.3% 4.0% <0.0001Blindness 0.4% 0.4% 0.6523

Systemic comorbidities Hypertension 35.8% 40.3% <0.0001Cardiovascular disease 7.6% 12.2% <0.0001Diabetes mellitus 22.0% 21.9% 0.8840Cerebrovascular disease 0.7% 1.6% <0.0001

Dementia 0.3% 0.9% <0.0001

Table 3. Percentage of Patients with Procedures

ProcedureOH Cohort (n = 4,818)

POAG Cohort (n = 52,985) P-value

Comprehensive eye exam

70.0% 72.1% 0.0021

Visual-fi eld exam 67.6% 70.0% 0.0003Trabeculoplasty 1.0% 4.6% <0.0001Trabeculectomy 0.2% 2.1% <0.0001

Table 4. Multivariate Logistic Regression Model Predicting Compliance

Patient cohort Covariate Odds ratio (95% CI) P-value

Medicated OH and POAG patients

(n = 57,803)

OH (OH vs. POAG) 0.53 (0. 49–0.58) <0.0001Comorbidity (Yes vs. No) Cataract surgery 0.82 (0.74–0.91) <0.0001 Cardiovascular disease 0.84 (0.79– 0.89) <0.0001 Stroke/cerebrovascular disease 0.85 (0.73–0.99) 0.0356 Dementia 0.76 (0.62–0.94) 0.0114Region (Yes vs. East) West 0.82 (0.76–0.88) <0.0001 Midwest 1.08 (1.03–1.14) 0.0030 South 1.06 (1.00–1.12) 0.0481Payer type (Yes vs. Commercial) Medicare risk 1.12 (1.04–1.20) 0.0029 Self-insured 1.26 (1.14–1.38) <0.0001 Medicaid 1.53 (1.35–1.74) <0.0001 Other 1.14 (1.05–1.23) 0.0026Product type (Yes vs. PPO, HMO or other) POS 0.95 (0.89–1.02) 0.1287 Indemnity 1.04 (0.90–1.21) 0.5958Age (continuous, years) 1.02 (1.02–1.02) <0.0001

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TRAVERSO ET AL.82

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23. Quigley, H.A., and Broman, A.T. The number of people with

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24. DiMatteo, M.R., Haskard, K.B., and Williams, S.L. Health beliefs,

disease severity, and patient adherence: A meta-analysis. Med. Care 45:521–528.

25. Cortet, B., and Benichou, O. Adherence, persistence, concor-

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27. Rudd, P. Compliance with antihypertensive therapy: Raising

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31. Stewart, W.C., Chorak, R.P., Hunt, H.H., and Sethuraman, G.

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disease in glaucoma. Arch. Ophthalmol. 124:12–19, 2006.

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for optimizing patient compliance. Curr. Opin. Ophthalmol. 17:190–195, 2006.

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Received: July 10, 2008Accepted: September 10, 2008

Reprint Requests: Lee S. SternDirector, Global Health Outcomes

Analytica International450 Park Avenue South, 12th Floor

New York, NY 10016

E-mail: lstern@analyticaintl.com

Disclosure Statement

The following disclosures apply to the authors: John G. Walt is a full-time employee of Allergan, and Lee S. Stern and Margarita Dolgitser are employed by Analytica International, which received funding from Allergan for their involvement in this study.

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