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Evaluation of Health Care Costs and Utilization Patterns for Patients With Gout
Clinical Therapeutics/Volume 34, Number 3, 2012
Evaluation of Health Care Costs and Utilization Patterns for Patients With Gout Haesuk Park, MPharm1; Karen L. Rascati, PhD1; Karim Prasla, PharmD, MS, BCPS2; and Tyrone McBayne, PharmD3 1
Health Outcomes and Pharmacy Practice Division, The University of Texas College of Pharmacy, Austin, Texas; 2Scott & White Health Plan, Health Economics and Outcomes Research, Temple, Texas; and 3 Takeda Pharmaceuticals America, Inc., Deerfield, Illinois ABSTRACT Background: The prevalence of gout has been increasing. Serum uric acid (sUA) levels ⱖ6 mg/dL have been associated with high morbidity and increased health care utilization. Objective: To assess the costs and patterns of health care resource utilization for patients with gout, categorized into 3 cohorts based on sUA levels. Methods: We retrospectively analyzed laboratory, pharmacy, and medical service claims data (January 2005 to June 2010) for patients ⱖ18 years old. Inclusion criteria were at least 2 sUA levels and at least 1 primary gout diagnosis (International Classification of Disease-9th revision code 274.xx), and/or at least 1 prescription for gout-specific medications. Outcomes including costs, health care resource utilization, and medication adherence and persistence were assessed for the 1-year postindex period and summarized for the 3 cohorts based on sUA levels: ⬍6 mg/ dL, 6 to 8.99 mg/dL, and ⱖ9 mg/dL. Costs were adjusted based on preindex utilization and baseline characteristics. Results: Three hundred fifty-two patients met the inclusion criteria: cohort 1 (sUA ⬍6 mg/dL), n ⫽ 38, mean age 59 years; cohort 2 (sUA 6 – 8.99 mg/dL), n ⫽ 231, mean age 61 years; and cohort 3 (sUA ⱖ9 mg/dL), n ⫽ 83, mean age 62 years. Mean adjusted gout-related health care costs were $332, $353, and $663, respectively (P ⬍0.05); mean adjusted all-cause health care costs were $11,365, $11,551, and $14,474, respectively, for the 3 cohorts (P ⬍0.05). sUA levels were positively associated with the percent of patients who had at least 1 hospitalization and the mean number of hospitalizations and emergency department visits (P ⬍ 0.05). Significantly more patients with sUA ⬍6 mg/dL achieved adherence rates of ⱖ80% and had a longer mean duration of continuous treatment compared
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with patients with sUA between 6 and 8.99 mg/dL or ⱖ9.0 mg/dL (P ⬍0.05). Conclusions: Patients with high levels of sUA had higher gout-related and all-cause health care costs, more all-cause hospitalizations, and emergency department visits, but they also exhibited poorer adherence and persistence. (Clin Ther. 2012;34: 640 – 652) © 2012 Elsevier HS Journals, Inc. All rights reserved. Key words: adherence, gout, gouty arthropathy, health care costs, retrospective studies, serum uric acid.
INTRODUCTION Gout arises from poor urate metabolism. Monosodium urate crystals are deposited in joints and soft tissues, causing inflammatory arthritis. More than 5 million people in the United States are affected by gout, and the annual burden of illness for new cases of gout has been estimated at over $27 million (2002 US dollars).1 The prevalence of gout has increased in recent decades. These increases can be explained, in part, by the increasing frequency of risk factors for gout and hyperuricemia, such as obesity, hypertension, and hyperlipidemia, and by increasing longevity.2– 4 A study using data from the 2007 to 2008 National Health and Nutrition Examination Survey found that the prevalence of gout was 3.9% (8.3 million) among US adults, with 2.0% and 5.9% prevalence among women (2.2 million) and men (6.1 million), respectively.4 Gout usually presents acutely with the clinical symptoms of painful, warm, erythematous, and monoarticular joint inflammation.5 When serum uric acid Accepted for publication January 26, 2012. doi:10.1016/j.clinthera.2012.01.020 0149-2918/$ - see front matter © 2012 Elsevier HS Journals, Inc. All rights reserved.
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H. Park et al. (sUA) levels are elevated, chronic progression may occur, in which the patient has frequent recurrent attacks or further development to a state of chronic gouty arthritis.5 A survey of US rheumatologists, conducted in 2004 to 2005 by Schlesinger et al,6 found that patients with gout were most often treated with combination therapy. The most common combination of medications for an acute attack is nonsteroidal antiinflammatory drugs (NSAIDs) with intra-articular corticosteroids, followed by NSAIDs with oral corticosteroids, and NSAIDs with oral colchicine. Xanthine oxidase inhibitors are routinely used for chronic gout management, more commonly after 2 acute attacks. Urate-lowering therapy is aimed at reducing the sUA concentration to ⱕ6.0 mg/dl, well below the concentration at which extracellular body fluids are saturated with urate (6.8 mg/dL).7 Sarawate et al8 found that patients with sUA ⱖ6.0 mg/dL were 59% more likely to be identified with a gout flare, and 49% more likely to be associated with multiple gout flares compared with patients with sUA levels ⬍6.0 mg/dL. Several studies assessed the economic burden of gout among different patient populations. Managed care databases were used to estimate costs associated with gout.5,9,10 Brook et al5 found that annual health benefit costs for an employed population were $3165 higher for patients with gout, compared with those without gout. Wu et al9 found that for elderly gout patients, aged ⱖ65 years, 12-month costs per patient for gout-related health care were $876 (2005 US dollars), or about 6% of all-cause health care costs ($14,734). The group with a very high sUA level had significantly higher regression-adjusted total 12-month all-cause health care costs and gout-related costs compared with those with a low sUA level ($3103 and $276 higher, respectively). Halpern et al10 found that baseline sUA was an important predictor of gout flare costs among gout patients in a national managed health care plan. Baseline sUA of 6 to 8.99 mg/dL and sUA ⱖ9 mg/dL were associated with 2.1 and 2.2 times higher costs, respectively, compared with baseline sUA ⬍6.0 mg/dL.10 These studies, however, examined the association between sUA levels and health care costs without considering the medication-taking behaviors of patients with gout.9,10 Poor compliance with urate-lowering drugs has been recognized, but there are few published studies evaluating comorbidities, adherence, persistence, and treatment patterns among patients with gout.11–13
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Sarawate et al11 and Riedel et al12 investigated adherence with allopurinol among managed care patients with gout. Harrold et al13 evaluated adherence with allopurinol, probenecid, or sulfinpyrazone for gout patients using 2 integrated delivery systems. Although adherence and persistence are important for preventing the painful and damaging effects of gout, little is known about the dynamics of gout medication-taking behaviors associated with sUA levels.13 Clearly, the costs of morbidity associated with gout are high, and disease severity, including sUA levels, affects these costs. More research is needed to assess and understand the interaction of these factors. The existing literature has not provided a comprehensive picture of the economic burden of gout and gout medicationtaking behaviors associated with sUA. The first objective of this retrospective analysis, which used a managed care patient database, was to examine the utilization and costs of health care services for patients with gout, categorized into the 3 cohorts based on sUA levels. The second objective was to describe the association between medicationtaking behaviors and sUA levels for patients who were prescribed gout medications. Specifically, the objectives were to compare 3 cohorts of patients, categorized according to 3 ranges of sUA levels: mean sUA ⬍6 mg/dL, mean sUA 6 to 8.99 mg/dL, and mean sUA ⱖ9 mg/dL.
PATIENTS AND METHODS Data Sources Data in this study were obtained from Scott & White Healthcare (Temple, Texas). Scott & White Healthcare is an integrated health delivery system in central Texas; it includes a mid-size staff-model health plan (Scott & White Health Plan) that covers 200,000 lives, including commercial and Medicare members.
Study Population Patients included in this study were at least 18 years of age, with 1 diagnosis for gout (International Classification of Disease-Ninth Revision [ICD-9] code 274.xx) and/or at least 1 gout-specific medication and at least 2 sUA test levels within a 1-year period between January 1, 2005 and June 30, 2010 (Figure 1A). A gout ICD-9 diagnosis was identified in the primary or secondary diagnosis code fields, and a gout-specific pharmacy claim was identified by a Generic Code Number during the study period. Patients with diagnosis
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Patients included in Scott & White Health Plan during 2005–2010 (N = 180,000)
Patients with at least 2 sUA test levels during 2005– 2010 (n = 713) Patients aged ≥ 18 years (n = 694) Patients with either (1) 1 diagnosis of gout (ICD-9 274.xx) or (2) gout-specific pharmacy claim excluding malignancies diagnosis (n = 461)
Patients continuous enrolled 6 month before and 1 year after the index date ( n = 352) sUA < 6 mg/dL (n = 38)
sUA 6–8.99 mg/dL (n = 231)
sUA ≥ 9 mg/dL (n = 83)
Patients had at least one claim for gout-specific medications for the 1-year post-index period (N = 242) sUA < 6 mg/dL n = 25
6 ≤ sUA < 9 mg/dL n =158
sUA ≥ 9 mg/dL n = 59
A. Patients characteristics, utilization and economic outcomes
B. Gout medicationtaking behaviors
Figure 1. Patient selection for gout patients with (A) at least two serum uric acid (sUA) levels and (B) with gout-specific medications. ICD-9 ⫽ International Classification of Diseases, Ninth Revision.
code(s) for malignancies were excluded. The index date was defined as the earliest date among first diagnosis of gout, first gout-related pharmacy claim, or first sUA test date between July 1, 2005 and June 30, 2009. Data for patients continuously enrolled in the Scott & White Health Plan 6 months before and 1 year after the index date were analyzed. Medical service data, prescription data, laboratory data, and demographic data were extracted. The sUA level was calculated using the mean of the first 2 sUA testing results, which was used to categorize patients into the 3 cohorts: (1) ⬍6.0 mg/dL, (2) 6 to 8.99 mg/dL, and (3) ⱖ9.0 mg/dL. The cutoff points were chosen based on previous studies.9,10,14 The recommended optimal sUA level is ⬍6 mg/dL.7,8 The level ⱖ9 mg/dL was chosen because of the high incidence of gouty arthritis beyond this level compared with a lower sUA level.9,10,14 Institutional review board approval was obtained from both Scott & White Healthcare and The University of Texas at Austin.
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Patient Demographic Characteristics Demographic characteristics (ie, age, gender, and insurance type), comorbidity severity scores, and presence of chronic diseases (ie, cardiovascular disease, chronic kidney disease, diabetes mellitus, hypertension, and obesity) were included. Two methods were used to calculate comorbidity severity scores: the Charlson Comorbidity Index (CCI), which uses ICD-9 codes,15 and the Chronic Disease Score (CDS), which uses prescription data.16 The CCI contains 19 categories of comorbidities, in which each category has an associated weight based on the adjusted risk of 1-year mortality. The CDS is a risk-adjusted metric based on age, sex, and history of dispensed drugs.16 Previous studies concluded it was possible to have potential risk factors that were not captured in any single comorbidity index, because each comorbidity measure considers different risks.17 Previous all-cause health care utilization and costs for the 6-month period before the index date were estimated.
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Utilization Outcomes Health care utilization was measured by the percentage of patients who used any medical services and used any prescription drugs for a 1-year postindex period. Mean numbers of visits for medical services and prescriptions were also calculated. Medical services consisted of inpatient, outpatient, physician, and emergency department (ED) visits. Pharmacy utilization included gout-specific and all-cause prescriptions.
Economic Outcomes Costs were defined as the total allowed amount, including the amount paid to the provider plus member cost sharing (ie, co-payment). Medical costs per person per year (PPPY) were calculated for goutrelated medical services (ICD-9 code 274.xx) and all-cause medical services. Pharmacy costs PPPY were calculated for gout-specific medications (allopurinol, colchicine, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination), and all-cause medications. Health care costs were estimated from the total cost using both medical and pharmacy claims data during the 1-year postindex period after the sUA index date. All costs were inflation adjusted to 2010 dollars.
Gout Medication-Taking Behaviors Gout medication-taking behaviors, defined in terms of medication adherence, persistence, and treatment patterns for the 1-year postindex period, were identified from pharmacy claims data. Medication use was measured for all gout-specific medications including allopurinol, colchicine, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination. The NSAIDs and corticosteroids were not included in the gout-specific medication category, as these medications could be used for diseases other than gout. In addition, some NSAIDs might also be obtained over the counter, the use of which is not possible to capture using claims data.
Medication Adherence Medication adherence was defined by proportion of days covered (PDC), which is the number of days during the study period (365 days) that the patient had at least 1 gout-specific medication on hand.18 The PDC method looks at each day during 365 days to determine whether a patient has ⱖ1 dispensed
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gout-specific medications, resulting in a simple binary measure indicating the presence or absence of medications each study day.19 The PDC has been used to assess adherence to a class of medications. Advantages to using the PDC is that it does not overcount switches between drugs, nor does it overcount medication use in the case of therapeutic duplication for a single condition.19 The PDC was dichotomized, with adherence defined as PDC ⱖ80% (ie, ⱖ292 days of at least 1 gout medication on hand each day within the 365 days after the first gout medication was filled); nonadherence was defined as PDC ⬍80%.
Medication Persistence Medication persistence was defined as the duration of therapy from the index date until discontinuation.18,20 Persistence in gout-specific medication was calculated by summing the number of days from the filling of the first gout medication to the end date of the last gout medication claim (fill date plus days supply) before 30- and 60-day gaps.
Medication Treatment Patterns Monotherapy was defined as therapy with 1 of the gout-specific medications for the 1-year postindex period. Polytherapy was defined as therapy with ⬎1 gout-specific medication for the 1-year postindex period. The prevalence of monotherapy and polytherapy were measured as the proportion of patients who met the definitions over the 1-year follow-up period.
Data Analyses Descriptive statistics included means (SD) and relative frequencies for continuous and categorical data, respectively. Individual variables were compared among the 3 cohorts based on mean sUA levels. Dichotomous variables (eg, gender, insurance type, “yes” or “no” for each disease category, and health care service utilization) were compared using 2 tests. Continuous variables (eg, age, persistence, mean numbers of health care utilizations, and costs) were compared using ANOVA and the Kruskal-Wallis test, a nonparametric alternative to ANOVA. Normally distributed data was analyzed using ANOVA, whereas non-normally distributed data was analyzed using Kruskal-Wallis. Annual health care costs for the 3 cohorts were calculated using a 2-part model.21 In the first part, logistic
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Table I. Patient demographic characteristics by serum uric acid (sUA) cohort.
Characteristics sUA, mean (SD) Demographics Age, y, mean (SD) Male, n (%) Medicare Insurance type, n (%) Previous comorbidities Cardiovascular disease, n (%) Chronic kidney disease, n (%) Diabetes, n (%) Hypertension, n (%) Obesity, n (%) Charlson Comorbidity Index, mean (SD) Chronic disease score, mean (SD)
Cohort 1
Cohort 2
Cohort 3
sUA ⬍6 mg/dL (n ⫽ 38)
sUA 6–8.99 mg/dL (n ⫽ 231)
sUA ⱖ9 mg/dL (n ⫽ 83)
5.02 (0.78)
7.66 (0.79)
10.19 (1.15)
P ⬍0.0001
59 (15) 27 (71.1%) 13 (34.2%)
61 (15) 177 (76.6%) 87 (37.7%)
62 (16) 51 (61.5%) 35 (42.2%)
0.567 0.029 0.683
8 (21.1%) 1 (2.6%) 9 (23.7%) 20 (52.6%) 2 (5.3%)
58 (25.1%) 20 (8.7%) 53 (22.9%) 131 (56.7%) 5 (2.2%)
26 (31.3%) 9 (10.8%) 30 (36.1%) 60 (72.3%) 4 (4.8%)
0.408 0.321* 0.060 0.028 0.356*
0.89 (1.20) 3.89 (3.23)
0.96 (1.27) 4.63 (3.61)
1.28 (1.68) 5.51 (4.32)
0.159 0.063
*Sample size too small for robust statistical tests.
regression was used to predict the likelihood of having a health care cost greater than zero during the 1-year postindex period. A generalized linear model with log link function after Box-Cox test was used in the second part to estimate the mean annual health care costs for patients with positive health care costs. Mean adjusted costs estimated from 2-part models were computed by multiplying the adjusted probability obtained from the logistic regression model (part 1) with the predicted cost from the general linear model (part 2). Cohort 1 (sUA ⬍6 mg/dL) served as the reference cohort, controlling for baseline covariates. Covariates were chosen a priori for all models on the basis of clinical relevance and baseline differences between cohorts. The Modified Park test was used to determine the most appropriate distribution for each cost.22 A bootstrap re-sampling method was used to estimate the 95% CIs of the health care cost differences among the 3 cohorts. An a priori 2-tailed ␣ level of 0.05 was used for all statistical tests. All analyses were conducted using SAS software (version 9.2; SAS Institute Inc., Cary, North Carolina) and Stata (version 11.1; Stata Corp., College Station, Texas).
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RESULTS Patient Demographic Characteristics A total of 352 patients were identified as meeting inclusion criteria (Figure 1A): 38 patients (10.8%) had a mean sUA level ⬍6 mg/dL; 231 patients (65.6%) had a mean sUA level between 6 and 8.99 mg/dL; and the remaining 83 patients (23.6%) had a mean sUA level of ⱖ9 mg/dL (Table I). For the patients with sUA ⬍6 mg/dL, the mean age was 59 (15) years, 71% were male, and the mean CCI was 0.89 (1.20). For patients with sUA levels between 6 and 8.99 mg/dL, the mean age was 61 (15) years, 77% were male, and the mean CCI was 0.96 (1.27). For patients with sUA ⱖ9.0 mg/ dL, the mean age was 62 (16) years, 61% were male, and the mean CCI was 1.28 (1.68). Although the patients’ demographic characteristics, including age, insurance type, and comorbidity scores (CCI and CDS), were comparable across the 3 sUA cohorts, patients with the highest sUA levels (ⱖ9 mg/dL) were more likely to be women (P ⫽ 0.029), and were more likely to have a diagnosis of hypertension (72%) relative to the other 2 cohorts (52.6% and 56.7%; P ⫽ 0.028). The mean (median) time from first to second sUA test
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Table II. All-cause health care utilization and costs during the 6-month preindex period by serum uric acid (sUA) cohort.
Health Care Services Total All-Cause Health Care Utilization No. of patients with at least 1 visit, n (%) Hospitalization ED Physician Outpatient Pharmacy No. of visits, mean (SD) Hospitalization ED Physician Outpatient Pharmacy No. of unique prescription drugs, mean (SD) Total no. of prescription drugs, mean (SD) Total All-Cause Health Care Cost ($), mean (SD) Total medical costs Pharmacy costs Total health care costs
Cohort 1
Cohort 2
Cohort 3
sUA ⬍6 mg/dL (n ⫽ 38)
sUA 6–8.99 mg/dL (n ⫽ 231)
sUA ⱖ9 mg/dL (n ⫽ 83)
1 (2.6%) 7 (18.4%) 26 (68.4%) 23 (60.5%) 29 (76.3%)
24 (10.4%) 40 (17.3%) 161 (69.7%) 155 (67.1%) 173 (74.9%)
11 (13.3%) 15 (18.1%) 56 (67.5%) 51 (61.5%) 61 (73.5%)
P
0.200*,† 0.979*,† 0.928* 0.537* 0.941*
0.32 (1.95) 0.21 (0.47) 3.26 (3.95) 3.00 (3.39) 5.29 (4.52)
0.39 (1.39) 0.29 (0.75) 3.12 (4.19) 3.34 (4.51) 6.29 (6.32)
0.83 (3.33) 0.35 (0.98) 4.08 (4.62) 4.54 (8.64) 9.48 (8.80)
0.215‡ 0.990‡ 0.406‡ 0.992‡ 0.001§
4.13 (3.71)
4.57 (4.35)
6.00 (5.04)
0.026§
7.89 (8.04)
9.86 (10.20)
14.81 (14.01)
0.001§
$5994 (11,525) $923 (1129) $6917 (11,883)
0.419‡ 0.121‡ 0.219‡
$4582 (11,666) $462 (576) $5044 (11,603)
$4204 (8508) $689 (1251) $4893 (8698)
ED ⫽ emergency department. *P values compare differences across the 3 cohorts using Pearson 2 test. † Sample size too small for robust statistical tests. ‡ P values compare differences across the 3 cohorts using Krusal-Wallis test due to non-normality. § P values compared differences across the 3 cohorts using ANOVA.
was approximately 126 days (93 days) for all measured cohorts. It should be noted that some results were based on information from small sample sizes, as indicated in Tables I to IV; therefore, robust statistical tests could not be conducted for some variables.
Utilization Outcomes Utilization and costs during the 6-month preindex period were similar across the 3 sUA categories except for the mean number of unique all-cause prescription drugs
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and total pharmacy claims (Table II). Patients with sUA ⱖ9.0 mg/dL had a mean of 6.00 (5.04) unique all-cause prescription drugs, significantly higher than that for patients with sUA ⬍6.0 mg/dL (4.13 [3.71]) and for patients with sUA of 6 to 8.99 mg/dL (4.57 [4.35]) (P ⫽ 0.026). Patients with sUA ⱖ9.0 mg/dL had a mean of 14.81 (14.01) total all-cause pharmacy claims, significantly higher than that of 7.89 [8.04] for patients with sUA ⬍6.0 mg/dL and 9.86 [10.20] for patients with sUA of 6 to 8.99 mg/dL (P ⫽ 0.001).
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Table III. All-cause and gout-related health care utilization during the 1-year postindex period by serum uric acid (sUA) cohort.
Health Care Services Total All-Cause Health Care Utilization No. of patients with at least 1 visit, n (%) Hospitalization ED Physician Outpatient Pharmacy No. of visits, mean (SD) Hospitalization ED Physician Outpatient Pharmacy No. of unique prescription drugs, mean (SD) Total no. of prescription drugs, mean (SD) Gout-Related Health Care Utilization No. of patients with at least 1 visit, n (%) Hospitalization ED Physician Outpatient Pharmacy No. of visits, mean (SD) Hospitalization ED Physician Outpatient Pharmacy No. of unique prescription drugs, mean (SD) Total no. of prescription drugs, mean (SD)
Cohort 1
Cohort 2
Cohort 3
sUA ⬍6 mg/dL (n ⫽ 38)
sUA 6–8.99 mg/dL (n ⫽ 231)
sUA ⱖ9 mg/dL (n ⫽ 83)
7 (18.4%) 12 (31.6%) 28 (73.7%) 33 (86.8%) 32 (84.2%)
28 (12.1%) 65 (28.1%) 198 (85.7%) 197 (85.3%) 194 (84.0%)
21 (25.3%) 35 (42.2%) 71 (85.5%) 74 (89.2%) 69 (83.1%)
0.84 (1.88) 0.39 (0.68) 8.34 (8.19) 7.34 (7.17) 18.74 (14.87) 8.84 (6.25) 26.68 (22.26)
0.94 (3.89) 0.51 (1.25) 8.10 (8.76) 8.73 (9.15) 18.68 (15.04) 9.04 (6.64) 29.26 (24.64)
1.67 (4.09) 0.86 (1.33) 9.89 (10.10) 11.12 (13.15) 25.84 (20.14) 11.65 (8.13) 41.94 (33.84)
2 (5.3%) 1 (2.6%) 12 (31.6%) 16 (42.1%) 25 (65.8%)
1 (0.4%) 12 (5.2%) 116 (50.2%) 91 (39.4%) 158 (68.4%)
1 (1.2%) 11 (13.3%) 42 (50.6%) 42 (50.6%) 59 (71.1%)
0.13 (0.66) 0.03 (0.16) 0.74 (1.66) 0.71 (1.25) 4.26 (4.13) 0.82 (0.69) 4.37 (4.21)
0.00 (0.07) 0.07 (0.32) 1.04 (1.53) 0.77 (1.35) 3.35 (3.98) 0.91 (0.74) 3.55 (4.33)
0.04 (0.33) 0.14 (0.39) 1.34 (2.00) 1.25 (1.77) 4.00 (4.30) 1.08 (0.84) 4.19 (4.54)
P
0.017*,† 0.063* 0.158* 0.675* 0.981* 0.019‡ 0.026‡ 0.541‡ 0.333‡ 0.003§ 0.011§ 0.001§
0.034*,† 0.025*,† 0.092* 0.208* 0.827* 0.034†,‡ 0.028†,‡ 0.089‡ 0.065‡ 0.268§ 0.112§ 0.357§
ED ⫽ emergency department. *P values compare differences across the 3 cohorts using Pearson 2 test. † Sample size too small for robust statistical tests. ‡ P values compare differences across the 3 cohorts using Kruskal-Wallis tests due to non-normality. § P values compare differences across the 3 cohorts using ANOVA. Pharmacy included allopurinol, colchicine, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination.
Table III demonstrates all-cause and gout-related utilization during the 1-year postindex period. The mean number of gout-specific prescriptions for newly started gout drug therapy did not differ among the 3 cohorts, with a total mean of 3.79 (4.37). The mean number of all-cause prescriptions for patients with the highest sUA levels (ⱖ9 mg/dL) was 41.94 (33.84), sig-
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nificantly greater than that of 26.68 (22.26) for patients with sUA ⬍6 mg/dL and 29.26 (24.64) for patients with sUA of 6 to 8.99 mg/dL (P ⫽ 0.001). The sUA levels were positively associated with the percentage of patients who had at least 1 all-cause hospitalization and with the mean number of all-cause hospitalizations and ED visits. The percentages of patients with
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Table IV. All-cause and gout-related health care costs during the 1-year postindex period by serum acid (sUA) cohort. Cohort 1
Cohort 2
Cohort 3
sUA ⬍6 mg/dL (n ⫽ 38)
sUA 6–8.99 mg/dL (n ⫽ 231)
sUA ⱖ9 mg/dL (n ⫽ 83)
P*
Total All-Cause Health Care Cost, $, mean (SD) Hospitalization ED Physician Outpatient Other Total medical service Pharmacy Total health care costs
$1195 (2947) $1307 (5773) $1856 (4177) $4223 (5707) $764 (3162) $9344 (12,427) $1072 (1118) $10,417 (12,868)
$2370 (9784) $427 ($1536) $1447 (2656) $3984 (5818) $1231 (4792) $9459 (15,914) $1696 (2741) $11,155 (16,428)
$5133 (16,555) $818 (1865) $1465 (1915) $4910 (6655) $1636 (5044) $13,962 (22,303) $2446 (3093) $16,408 (22,857)
0.024 0.025 0.437 0.595 0.004 0.027 0.061 0.011
Gout-Related Health Care Cost, $, mean (SD) Hospitalization ED Physician Outpatient Other Total medical service Pharmacy‡ Total health care costs
$128 (753) $4 (23) $63 (173) $150 (349) $15 (95) $361 (1069) $39 (44) $399 (1071)
$0 (5) $30 (151) $96 (162) $211 (810) $2 (17) $339 (828) $28 (36) $368 (832)
$40 (366) $62 (185) $135 (242) $265 (623) $18 (96) $521 (827) $34 (41) $555 (835)
0.033† 0.025† 0.064 0.168 0.299 0.004 0.476 0.008
Health Care Services
ED ⫽ emergency department. *P values compare differences across the 3 cohorts using Kruskal-Wallis tests. † Sample size too small for robust statistical tests. ‡ Pharmacy included allopurinol, colchicine, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination.
ⱖ1 claim for any type of hospitalization were 25.3% in the cohort with sUA ⱖ9 mg/dL, 18.4% among those with sUA ⬍6 mg/dL, and 12.1% among those with sUA between 6 and 8.99 mg/dL (P ⫽ 0.017). Patients with sUA ⱖ9.0 mg/dL had a mean of 1.67 (4.09) hospitalizations for any cause, which was significantly higher compared with patients with sUA ⬍6.0 mg/dL (0.84 [1.88]) or those with sUA of 6 to 8.99 mg/dL (0.94 [3.89]) (P ⫽ 0.019). The mean numbers of all-cause ED visits were 0.86 for patients with sUA ⱖ9.0 mg/ dL, 0.39 for those with sUA ⬍6.0 mg/dL, and 0.51 for those with sUA of 6 to 8.99 mg/dL (P ⫽ 0.026). The percentages of patients who had gout-related health care utilization (hospital and ED visits) were
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statistically different between cohorts, but the number of events per group was small, so results might not be clinically relevant.
Economic Outcomes All-cause and gout-related health care costs during the 1-year postindex period by sUA levels are shown in Table IV. Mean unadjusted 1-year goutspecific prescription costs and all-cause prescription costs among the 3 cohorts were not significantly different. However, mean unadjusted 1-year gout-related medical service costs for patients with sUA ⱖ9 mg/dL was $521, significantly higher than costs for patients with sUA ⬍6 mg/dL ($361) or for patients
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18,000 16,000 $14,474
Health care costs ($)
14,000 12,000
All-cause health care cost $11,365
$11,551 Gout-related health care cost
10,000 8000 6000 4000 2000 $332
$353
$663
0 sUA <6 mg/dL
sUA 6–8.99 mg/dL
sUA ≥9 mg/dL
Figure 2. Adjusted all-cause and gout-related health care costs for the 1-year post-index period.
with sUA between 6 and 8.99 mg/dL ($339) (P ⫽ 0.004). Similarly, mean unadjusted 1-year all-cause medical service costs for patients with sUA ⱖ9 mg/dL was $13,962, significantly higher than the costs for patients with sUA ⬍6 mg/dL ($9344) or sUA of 6 to 8.99 mg/dL ($9459) (P ⫽ 0.027). Figure 2 presents results from analyses of mean adjusted costs after controlling for age, gender, insurance, CCI, presence of hypertension, and number of all-cause prescriptions for the 6-month preindex period. Positive relationships were found between sUA levels and adjusted gout-related and adjusted all-cause health care costs. Mean adjusted gout-related health care costs for patients with sUA ⱖ9 mg/dL was $663, $310 higher than the cost for patients with sUA ⬍6 mg/dL (P ⬍0.05), although there was no significant difference between costs for patients with sUA of 6 to 8.99 mg/dL and those with sUA ⬍6 mg/dL. Similarly, mean adjusted all-cause health care costs for patients with sUA ⱖ9 mg/dL ($14,474) was significantly higher than the cost for patients with sUA ⬍6 mg/dL ($11,365) (P ⬍0.05). Mean adjusted all-cause health care costs for patients with sUA of 6 to 8.99 mg/dL ($11,551) and patients with sUA ⬍6 mg/dL did not significantly differ. Adjusted gout-related costs represented 2.09%, 3.06%, and 4.58% of total adjusted health care costs for the 1-year postindex period among patients with sUA levels
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⬍6.0 mg/dL, sUA between 6.00 and 8.99 mg/dL, and sUA ⱖ9.0 mg/dL, respectively.
Gout Medication-Taking Behaviors Of a total of 352 gout patients, 242 (68.8%) had at least 1 claim for gout-specific medications (allopurinol, colchicine, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination) over the first year (Figure 1B). Gout-specific medications were taken by a similar proportion of patients across the 3 cohorts: 65.8% for patients with sUA ⬍6.0 mg/dL; 68.4% for patients with sUA between 6 and 8.99 mg/dL; and 71.1% for patients with sUA ⱖ9.0 mg/dL (P ⬎0.05). Medication adherence measured using the PDC over the first year of gout-specific therapy was significantly inversely associated with the sUA levels. More patients with sUA ⬍6 mg/dL (56.0%) achieved adherence rates of ⱖ80% relative to patients with sUA of 6 to 8.99 mg/dL (24.1%) or ⱖ9.0 mg/dL (22.0%) (P ⫽ 0.002) (Table V). The mean PDCs for the 3 cohorts were 72.6%, 46.0%, and 49.9%, respectively (P ⫽ 0.001). Medication persistence in gout medication until the first 30- or 60-day gap in taking gout-specific medication was also significantly associated with sUA levels. Patients with sUA ⬍6.0 mg/dL had a longer mean duration of continuous treatment before ⱖ60-
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Table V. Gout medication-taking behaviors by serum uric acid (sUA) cohort.*
Medication-Taking Behaviors Adherence (n ⫽ 242) Proportion of days covered No. of patients ⱖ80%, n (%) Mean, (SD) Persistence (n ⫽ 242) Mean (SD) days until treatment gap, 30 days 60 days Treatment Patterns (n ⫽ 242) Monotherapy (n ⫽ 156), n (%) Polytherapy (n ⫽ 86), n (%)
Cohort 1
Cohort 2
Cohort 3
sUA ⬍6 mg/dL (n ⫽ 25)
6–8.99 mg/dL (n ⫽ 158)
sUA ⱖ9 mg/dL (n ⫽ 59)
14 (56.0%) 72.6 (27.0)
38 (24.1%) 46.0 (33.9)
13 (22.0%) 49.9 (31.3)
0.002† 0.001‡
215.3 (150.4) 255.4 (136.1)
140.6 (133.4) 163.9 (135.6)
138.5 (132.4) 177.7 (135.6)
0.032‡ 0.008‡
19 (76.0%) 6 (24.0%)
107 (67.7%) 51 (32.3%)
30 (50.9%) 29 (49.2%)
0.031†
P
*Gout medication included allopurinol, colchicines, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination. † P values compare differences across the 3 cohorts using Pearson 2 test. ‡ P values compare differences across the 3 cohorts using ANOVA.
day discontinuation (255 [136] days) compared with patients with sUA levels between 6 and 8.99 mg/dL (164 [136] days) or patients with sUA levels ⱖ9.0 mg/dL (178 [136] days) (P ⫽ 0.008). About two-thirds of the patients (64.5%) had only 1 gout-specific medication (monotherapy), whereas the rest had a combination of ⱖ2 gout-specific medications (polytherapy). The prevalence of monotherapy was negatively associated with higher sUA levels. Patients with sUA levels ⬍6 mg/dL (76.0%) were more likely to continue with monotherapy than patients with sUA levels between 6 and 8.99 mg/dL (67.7%) or patients with sUA levels ⱖ9.0 mg/dL (50.9%) (P ⫽ 0.031). In those patients prescribed monotherapy (n ⫽ 156), allopurinol was the most prevalent gout therapy (n ⫽ 115; 74%), followed by colchicine (n ⫽ 40; 26%). A higher percentage of patients with sUA ⬍6 mg/dL received allopurinol (90%) compared with the other 2 cohorts (70.1% for patients with sUA ⬍6 mg/dL and 76.7% for patients with sUA of 6 to 8.99 mg/dL) (data not shown).
DISCUSSION This retrospective analysis examined utilization, costs, and the medication-taking behaviors of patients with
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gout, stratified by sUA levels, in a single integrated health system population, Scott & White Healthcare. Although several retrospective analyses reported the association between high sUA levels (ie, ⱖ6.0 mg/dL) and increased utilization and costs in gout patients, the findings from each study were somewhat different.9,10,14 Wu et al9 found the mean regression-adjusted gout-related costs were significantly higher for patients with sUA ⱖ9 mg/dL compared with sUA ⬍6 mg/dL, whereas there was no significant difference in costs between the cohorts of sUA of 6 to 8.99 mg/dL and sUA ⬍6.0 mg/dL. Halpern et al14 reported that gout-related costs associated with baseline sUA of 6 to 8.99 mg/dL were higher than costs for sUA ⬍6.0 mg/ dL, but there was no significant difference in costs between sUA ⬍6 mg/dL and sUA ⱖ9.0 mg/dL. Another study by Halpern et al10 found that gout-related costs for patients with baseline sUA of 6 to 8.99 mg/dL or sUA ⱖ9 mg/dL were significantly higher compared with patients with sUA ⬍6.0 mg/dL (P ⬍0.05 and P ⬍0.01, respectively). Possible explanations for these differences could be differences in study populations, definitions of index date, and how sUA levels were determined. Wu et al9
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Clinical Therapeutics used the day of the first sUA level as the index date and this index date level as the sUA for the patient; goutrelated health care costs were measured in the 12 months after the index date. Halpern et al10,14 used the day of the first chronologic gout-related diagnosis or pharmacy claim as the index date and defined the patient’s sUA level as the preceding result closest to the index date. In addition, previous studies used only 1 sUA level to examine the effect of sUA on outcome measures. Changes could occur in sUA levels (eg, associated with alcohol drinking or weight loss), regardless of the use of antihyperuricemic drugs.23 In our study, the index date was defined as the first chronologic gout-related diagnosis, gout-related pharmacy claim, or sUA result to ensure that no gout-related health care services were recorded before the index date. To capture clinically relevant sUA levels that reflected early treatment, the mean of the first 2 sUA results were used. Unlike the previous studies cited, we used the sample inclusion criteria of a diagnosis of gout and/or pharmacy claim for a gout medication with at least 2 sUA tests to provide a more reliable measure of sUA levels for each patient. This study found that patients with more advanced gout disease, defined as sUA ⱖ9.0 mg/dL, had similar prescription costs, but higher medical service costs compared with the other 2 cohorts. In addition, after adjustment for the covariates measured in our study, patients with high sUA levels (ⱖ9.0 mg/dL) had significantly higher gout-related and all-cause health care costs ($310 and $3109 higher, respectively) compared with those with low sUA levels (⬍6.0 mg/dL). In addition, results indicated that poor adherence to newly-initiated gout-specific pharmacotherapy was common in gout patients; ⬍25% of patients with the highest sUA (ⱖ9 mg/dL) and only slightly more than half of patients with the lowest sUA levels (⬍6 mg/dL) were adherent (defined as a PDC of at least 80%). This result was consistent with previous studies, which found that adherence to urate-lowering drugs was generally poor, ranging from 44% to 64% in the study populations.11–13 As expected, patients in the very high sUA level cohort (ⱖ9 mg/dL) and in the high sUA level cohort (6 – 8.99 mg/dL) had significantly lower adherence than patients in the lowest sUA level cohort (⬍6 mg/dL). Based on these findings, it was possible that medication therapy was underutilized in gout patients not achieving sUA goals of ⬍6 mg/dL, resulting in higher medical services.
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Studies using administrative claims have a number of limitations. Because this was an observational study, we could not conclude that nonadherence or poor persistence with gout medications resulted in high sUA levels, poor clinical outcomes, and high health care costs. However, this relationship warrants further consideration and prospective investigation. Additional limitations of this study were inherent in inclusion criteria of a diagnosis of gout and/or pharmacy claim for a gout medication with at least 2 sUA tests. Despite some advantages of using the mean of 2 sUA levels, it was possible that the time periods observed to obtain the second reading might have been different between cohorts. However, we found that there were no statistically significant differences in the time from first sUA to second sUA testing among cohorts (P ⫽ 0.065). Only patients with at least 2 sUA levels were included in the analysis, resulting in a sample size smaller than anticipated compared with all gout patients. Particularly, the number of patients with low sUA levels (sUA ⬍6.0 mg/dL) was much smaller than the other 2 cohorts, which introduced increased statistical variance. This might also indicate that sUA was typically not being managed to clinical standards, as well. Previous studies showed that ⬍20% of patients had relevant sUA results in the datasets.8,9,14 The incomplete laboratory results might limit the generalizability of the study results for all gout patients. Moreover, when estimating gout-related pharmacy costs, we included only allopurinol, colchicine, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination. NSAIDs and corticosteroids, common medications used in gout, were not included in the gout-specific medication category, because these medications could be used for diseases other than gout and/or obtained over the counter. This might underestimate the gout-related pharmacy costs. Another limitation was that although the final cost analysis was adjusted for comorbidities, intrinsic disease severity differences might still influence the results. For instance, unmeasured confounding variables such as body mass index, alcohol consumption, and family history1 not captured in administrative claims might be related to the outcomes. Finally, the study population was derived from a single health care institution and might not be representative of all gout patients.
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CONCLUSIONS This retrospective study showed that high sUA levels (ⱖ9 mg/dL) were associated with increased utilization and costs in gout patients. Nonadherence to gout medications occurred in the majority of the study population. Higher sUA levels were associated with lower medication adherence and lower persistence for patients newly starting gout medication therapy.
ACKNOWLEDGMENTS The authors wish to thank the medical informatics team at Scott & White Health Plan Prescription Services Division who provided the claims and laboratory data. Dr. Park was involved in all aspects of the analysis and writing of the article. Dr. Rascati served as the principal investigator from the proposal development stage to completion and was responsible for obtaining study funding and study design. Dr. Prasla was involved from proposal development and provided the data and feedback on the analysis and the article. Dr. McBayne reviewed all the work and provided input throughout the process. All authors had full access to the data, vouch for the veracity and completeness of the data and the data analysis, and take responsibility for its integrity. The article was written in its entirety by the authors.
CONFLICTS OF INTEREST This study was funded by Takeda Pharmaceuticals America, Inc., Deerfield, Illinois. Drs. Park and Rascati (The University of Texas at Austin) received a research grant from Takeda Pharmaceuticals America, Inc. Dr. Prasla is an employee of Scott & White Health Plan, Health Economics and Outcomes Research, Temple, Texas. Dr. McBayne is an employee of Takeda Pharmaceuticals America, Inc.
REFERENCES 1. Kim KY, Ralph Schumacher H, Hunsche E, et al. A literature review of the epidemiology and treatment of acute gout. Clin Ther. 2003;25:1593–1617. 2. Arromdee E, Michet C, Crowson CS, et al. Epidemiology of gout: is the incidence rising? J Rheumatol. 2002;29:2403– 2406. 3. Mikuls TR, Saag KG. New insights into gout epidemiology. Curr Opin Rheumatol. 2006;18:199 –203. 4. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: The National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011;63:3136 –3141.
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5. Brook RA, Kleinman NL, Patel PA, et al. The economic burden of gout on an employed population. Curr Med Res Opin. 2006;22:1381–1389. 6. Schlesinger N, Moore DF, Sun JD, Schumacher HR, Jr. A survey of current evaluation and treatment of gout. J Rheumatol. 2006;33:2050 –2052. 7. Wortmann RL. Recent advances in the management of gout and hyperuricemia. Curr Opin Rheumatol. 2005;17:319 – 324. 8. Sarawate CA, Patel PA, Schumacher HR, et al. Serum urate levels and gout flares: analysis from managed care data. J Clin Rheumatol. 2006;12:61– 65. 9. Wu EQ, Patel PA, Yu AP, et al. Disease-related and all-cause health care costs of elderly patients with gout. J Manag Care Pharm. 2008;14:164 –175. 10. Halpern R, Fuldeore MJ, Mody RR, et al. The effect of serum urate on gout flares and their associated costs: an administrative claims analysis. J Clin Rheumatol. 2009; 15:3–7. 11. Sarawate CA, Brewer KK, Yang W, et al. Gout medication treatment patterns and adherence to standards of care from a managed care perspective. Mayo Clin Proc. 2006;81: 925–934. 12. Riedel AA, Nelson M, Joseph-Ridge N, et al. Compliance with allopurinol therapy among managed care enrollees with gout: a retrospective analysis of administrative claims. J Rheumatol. 2004;31:1575–1581. 13. Harrold LR, Andrade SE, Briesacher BA, et al. Adherence with urate-lowering therapies for the treatment of gout. Arthritis Res Ther. 2009;11:R46. 14. Halpern R, Mody RR, Fuldeore MJ, et al. Impact of noncompliance with urate-lowering drug on serum urate and gout-related healthcare costs: administrative claims analysis. Curr Med Res Opin. 2009;25:1711–1719. 15. Charlson ME, Charlson RE, Peterson JC, et al. The Charlson comorbidity index is adapted to predict costs of chronic disease in primary care patients. J Clin Epidemiol. 2008;61:1234 –1240. 16. Clark DO, Von Korff M, Saunders K, et al. A chronic disease score with empirically derived weights. Med Care. 1995;33: 783–795. 17. Baser O, Palmer L, Stephenson J. The estimation power of alternative comorbidity indices. Value Health. 2008;11;946 – 955. 18. McHorney CA, Victor Spain C, Alexander CM, Simmons J. Validity of the adherence estimator in the prediction of 9-month persistence with medications prescribed for chronic diseases: a prospective analysis of data from pharmacy claims. Clin Ther. 2009;31:2584 –2607. 19. Martin BC, Wiley-Exley E, Richards S, et al. Contrasting measures of adherence with simple drug use, medication switching, and therapeutic duplication. Ann Pharmacother. 2009;43:36 – 44.
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Clinical Therapeutics 20. Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health. 2008;11:44 – 47. 21. Mullahy J. Much ado about two: reconsidering retransformation and the two-part model in health econometrics. J Health Econ. 1998;17:247– 281. 22. Manning WG, Mullahy J. Estimating log models: to transform or not to transform? J Health Econ. 2001; 20:461– 494. 23. Terkeltaub RA. Gout. N Engl J Med. 2003;349:1647–1655.
Address correspondence to: Karen L. Rascati, PhD, Eckerd/Turley Centennial Professor of Pharmacy, The University of Texas College of Pharmacy, 2409 University Avenue PHR 3.209 Austin, Texas. E-mail: krascati@ mail.utexas.edu.
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Evaluation of Health Care Costs and Utilization Patterns for Patients With Gout Haesuk Park, MPharm1; Karen L. Rascati, PhD1; Karim Prasla, PharmD, MS, BCPS2; and Tyrone McBayne, PharmD3 1
Health Outcomes and Pharmacy Practice Division, The University of Texas College of Pharmacy, Austin, Texas; 2Scott & White Health Plan, Health Economics and Outcomes Research, Temple, Texas; and 3 Takeda Pharmaceuticals America, Inc., Deerfield, Illinois ABSTRACT Background: The prevalence of gout has been increasing. Serum uric acid (sUA) levels ⱖ6 mg/dL have been associated with high morbidity and increased health care utilization. Objective: To assess the costs and patterns of health care resource utilization for patients with gout, categorized into 3 cohorts based on sUA levels. Methods: We retrospectively analyzed laboratory, pharmacy, and medical service claims data (January 2005 to June 2010) for patients ⱖ18 years old. Inclusion criteria were at least 2 sUA levels and at least 1 primary gout diagnosis (International Classification of Disease-9th revision code 274.xx), and/or at least 1 prescription for gout-specific medications. Outcomes including costs, health care resource utilization, and medication adherence and persistence were assessed for the 1-year postindex period and summarized for the 3 cohorts based on sUA levels: ⬍6 mg/ dL, 6 to 8.99 mg/dL, and ⱖ9 mg/dL. Costs were adjusted based on preindex utilization and baseline characteristics. Results: Three hundred fifty-two patients met the inclusion criteria: cohort 1 (sUA ⬍6 mg/dL), n ⫽ 38, mean age 59 years; cohort 2 (sUA 6 – 8.99 mg/dL), n ⫽ 231, mean age 61 years; and cohort 3 (sUA ⱖ9 mg/dL), n ⫽ 83, mean age 62 years. Mean adjusted gout-related health care costs were $332, $353, and $663, respectively (P ⬍0.05); mean adjusted all-cause health care costs were $11,365, $11,551, and $14,474, respectively, for the 3 cohorts (P ⬍0.05). sUA levels were positively associated with the percent of patients who had at least 1 hospitalization and the mean number of hospitalizations and emergency department visits (P ⬍ 0.05). Significantly more patients with sUA ⬍6 mg/dL achieved adherence rates of ⱖ80% and had a longer mean duration of continuous treatment compared
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with patients with sUA between 6 and 8.99 mg/dL or ⱖ9.0 mg/dL (P ⬍0.05). Conclusions: Patients with high levels of sUA had higher gout-related and all-cause health care costs, more all-cause hospitalizations, and emergency department visits, but they also exhibited poorer adherence and persistence. (Clin Ther. 2012;34: 640 – 652) © 2012 Elsevier HS Journals, Inc. All rights reserved. Key words: adherence, gout, gouty arthropathy, health care costs, retrospective studies, serum uric acid.
INTRODUCTION Gout arises from poor urate metabolism. Monosodium urate crystals are deposited in joints and soft tissues, causing inflammatory arthritis. More than 5 million people in the United States are affected by gout, and the annual burden of illness for new cases of gout has been estimated at over $27 million (2002 US dollars).1 The prevalence of gout has increased in recent decades. These increases can be explained, in part, by the increasing frequency of risk factors for gout and hyperuricemia, such as obesity, hypertension, and hyperlipidemia, and by increasing longevity.2– 4 A study using data from the 2007 to 2008 National Health and Nutrition Examination Survey found that the prevalence of gout was 3.9% (8.3 million) among US adults, with 2.0% and 5.9% prevalence among women (2.2 million) and men (6.1 million), respectively.4 Gout usually presents acutely with the clinical symptoms of painful, warm, erythematous, and monoarticular joint inflammation.5 When serum uric acid Accepted for publication January 26, 2012. doi:10.1016/j.clinthera.2012.01.020 0149-2918/$ - see front matter © 2012 Elsevier HS Journals, Inc. All rights reserved.
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H. Park et al. (sUA) levels are elevated, chronic progression may occur, in which the patient has frequent recurrent attacks or further development to a state of chronic gouty arthritis.5 A survey of US rheumatologists, conducted in 2004 to 2005 by Schlesinger et al,6 found that patients with gout were most often treated with combination therapy. The most common combination of medications for an acute attack is nonsteroidal antiinflammatory drugs (NSAIDs) with intra-articular corticosteroids, followed by NSAIDs with oral corticosteroids, and NSAIDs with oral colchicine. Xanthine oxidase inhibitors are routinely used for chronic gout management, more commonly after 2 acute attacks. Urate-lowering therapy is aimed at reducing the sUA concentration to ⱕ6.0 mg/dl, well below the concentration at which extracellular body fluids are saturated with urate (6.8 mg/dL).7 Sarawate et al8 found that patients with sUA ⱖ6.0 mg/dL were 59% more likely to be identified with a gout flare, and 49% more likely to be associated with multiple gout flares compared with patients with sUA levels ⬍6.0 mg/dL. Several studies assessed the economic burden of gout among different patient populations. Managed care databases were used to estimate costs associated with gout.5,9,10 Brook et al5 found that annual health benefit costs for an employed population were $3165 higher for patients with gout, compared with those without gout. Wu et al9 found that for elderly gout patients, aged ⱖ65 years, 12-month costs per patient for gout-related health care were $876 (2005 US dollars), or about 6% of all-cause health care costs ($14,734). The group with a very high sUA level had significantly higher regression-adjusted total 12-month all-cause health care costs and gout-related costs compared with those with a low sUA level ($3103 and $276 higher, respectively). Halpern et al10 found that baseline sUA was an important predictor of gout flare costs among gout patients in a national managed health care plan. Baseline sUA of 6 to 8.99 mg/dL and sUA ⱖ9 mg/dL were associated with 2.1 and 2.2 times higher costs, respectively, compared with baseline sUA ⬍6.0 mg/dL.10 These studies, however, examined the association between sUA levels and health care costs without considering the medication-taking behaviors of patients with gout.9,10 Poor compliance with urate-lowering drugs has been recognized, but there are few published studies evaluating comorbidities, adherence, persistence, and treatment patterns among patients with gout.11–13
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Sarawate et al11 and Riedel et al12 investigated adherence with allopurinol among managed care patients with gout. Harrold et al13 evaluated adherence with allopurinol, probenecid, or sulfinpyrazone for gout patients using 2 integrated delivery systems. Although adherence and persistence are important for preventing the painful and damaging effects of gout, little is known about the dynamics of gout medication-taking behaviors associated with sUA levels.13 Clearly, the costs of morbidity associated with gout are high, and disease severity, including sUA levels, affects these costs. More research is needed to assess and understand the interaction of these factors. The existing literature has not provided a comprehensive picture of the economic burden of gout and gout medicationtaking behaviors associated with sUA. The first objective of this retrospective analysis, which used a managed care patient database, was to examine the utilization and costs of health care services for patients with gout, categorized into the 3 cohorts based on sUA levels. The second objective was to describe the association between medicationtaking behaviors and sUA levels for patients who were prescribed gout medications. Specifically, the objectives were to compare 3 cohorts of patients, categorized according to 3 ranges of sUA levels: mean sUA ⬍6 mg/dL, mean sUA 6 to 8.99 mg/dL, and mean sUA ⱖ9 mg/dL.
PATIENTS AND METHODS Data Sources Data in this study were obtained from Scott & White Healthcare (Temple, Texas). Scott & White Healthcare is an integrated health delivery system in central Texas; it includes a mid-size staff-model health plan (Scott & White Health Plan) that covers 200,000 lives, including commercial and Medicare members.
Study Population Patients included in this study were at least 18 years of age, with 1 diagnosis for gout (International Classification of Disease-Ninth Revision [ICD-9] code 274.xx) and/or at least 1 gout-specific medication and at least 2 sUA test levels within a 1-year period between January 1, 2005 and June 30, 2010 (Figure 1A). A gout ICD-9 diagnosis was identified in the primary or secondary diagnosis code fields, and a gout-specific pharmacy claim was identified by a Generic Code Number during the study period. Patients with diagnosis
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Patients included in Scott & White Health Plan during 2005–2010 (N = 180,000)
Patients with at least 2 sUA test levels during 2005– 2010 (n = 713) Patients aged ≥ 18 years (n = 694) Patients with either (1) 1 diagnosis of gout (ICD-9 274.xx) or (2) gout-specific pharmacy claim excluding malignancies diagnosis (n = 461)
Patients continuous enrolled 6 month before and 1 year after the index date ( n = 352) sUA < 6 mg/dL (n = 38)
sUA 6–8.99 mg/dL (n = 231)
sUA ≥ 9 mg/dL (n = 83)
Patients had at least one claim for gout-specific medications for the 1-year post-index period (N = 242) sUA < 6 mg/dL n = 25
6 ≤ sUA < 9 mg/dL n =158
sUA ≥ 9 mg/dL n = 59
A. Patients characteristics, utilization and economic outcomes
B. Gout medicationtaking behaviors
Figure 1. Patient selection for gout patients with (A) at least two serum uric acid (sUA) levels and (B) with gout-specific medications. ICD-9 ⫽ International Classification of Diseases, Ninth Revision.
code(s) for malignancies were excluded. The index date was defined as the earliest date among first diagnosis of gout, first gout-related pharmacy claim, or first sUA test date between July 1, 2005 and June 30, 2009. Data for patients continuously enrolled in the Scott & White Health Plan 6 months before and 1 year after the index date were analyzed. Medical service data, prescription data, laboratory data, and demographic data were extracted. The sUA level was calculated using the mean of the first 2 sUA testing results, which was used to categorize patients into the 3 cohorts: (1) ⬍6.0 mg/dL, (2) 6 to 8.99 mg/dL, and (3) ⱖ9.0 mg/dL. The cutoff points were chosen based on previous studies.9,10,14 The recommended optimal sUA level is ⬍6 mg/dL.7,8 The level ⱖ9 mg/dL was chosen because of the high incidence of gouty arthritis beyond this level compared with a lower sUA level.9,10,14 Institutional review board approval was obtained from both Scott & White Healthcare and The University of Texas at Austin.
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Patient Demographic Characteristics Demographic characteristics (ie, age, gender, and insurance type), comorbidity severity scores, and presence of chronic diseases (ie, cardiovascular disease, chronic kidney disease, diabetes mellitus, hypertension, and obesity) were included. Two methods were used to calculate comorbidity severity scores: the Charlson Comorbidity Index (CCI), which uses ICD-9 codes,15 and the Chronic Disease Score (CDS), which uses prescription data.16 The CCI contains 19 categories of comorbidities, in which each category has an associated weight based on the adjusted risk of 1-year mortality. The CDS is a risk-adjusted metric based on age, sex, and history of dispensed drugs.16 Previous studies concluded it was possible to have potential risk factors that were not captured in any single comorbidity index, because each comorbidity measure considers different risks.17 Previous all-cause health care utilization and costs for the 6-month period before the index date were estimated.
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Utilization Outcomes Health care utilization was measured by the percentage of patients who used any medical services and used any prescription drugs for a 1-year postindex period. Mean numbers of visits for medical services and prescriptions were also calculated. Medical services consisted of inpatient, outpatient, physician, and emergency department (ED) visits. Pharmacy utilization included gout-specific and all-cause prescriptions.
Economic Outcomes Costs were defined as the total allowed amount, including the amount paid to the provider plus member cost sharing (ie, co-payment). Medical costs per person per year (PPPY) were calculated for goutrelated medical services (ICD-9 code 274.xx) and all-cause medical services. Pharmacy costs PPPY were calculated for gout-specific medications (allopurinol, colchicine, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination), and all-cause medications. Health care costs were estimated from the total cost using both medical and pharmacy claims data during the 1-year postindex period after the sUA index date. All costs were inflation adjusted to 2010 dollars.
Gout Medication-Taking Behaviors Gout medication-taking behaviors, defined in terms of medication adherence, persistence, and treatment patterns for the 1-year postindex period, were identified from pharmacy claims data. Medication use was measured for all gout-specific medications including allopurinol, colchicine, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination. The NSAIDs and corticosteroids were not included in the gout-specific medication category, as these medications could be used for diseases other than gout. In addition, some NSAIDs might also be obtained over the counter, the use of which is not possible to capture using claims data.
Medication Adherence Medication adherence was defined by proportion of days covered (PDC), which is the number of days during the study period (365 days) that the patient had at least 1 gout-specific medication on hand.18 The PDC method looks at each day during 365 days to determine whether a patient has ⱖ1 dispensed
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gout-specific medications, resulting in a simple binary measure indicating the presence or absence of medications each study day.19 The PDC has been used to assess adherence to a class of medications. Advantages to using the PDC is that it does not overcount switches between drugs, nor does it overcount medication use in the case of therapeutic duplication for a single condition.19 The PDC was dichotomized, with adherence defined as PDC ⱖ80% (ie, ⱖ292 days of at least 1 gout medication on hand each day within the 365 days after the first gout medication was filled); nonadherence was defined as PDC ⬍80%.
Medication Persistence Medication persistence was defined as the duration of therapy from the index date until discontinuation.18,20 Persistence in gout-specific medication was calculated by summing the number of days from the filling of the first gout medication to the end date of the last gout medication claim (fill date plus days supply) before 30- and 60-day gaps.
Medication Treatment Patterns Monotherapy was defined as therapy with 1 of the gout-specific medications for the 1-year postindex period. Polytherapy was defined as therapy with ⬎1 gout-specific medication for the 1-year postindex period. The prevalence of monotherapy and polytherapy were measured as the proportion of patients who met the definitions over the 1-year follow-up period.
Data Analyses Descriptive statistics included means (SD) and relative frequencies for continuous and categorical data, respectively. Individual variables were compared among the 3 cohorts based on mean sUA levels. Dichotomous variables (eg, gender, insurance type, “yes” or “no” for each disease category, and health care service utilization) were compared using 2 tests. Continuous variables (eg, age, persistence, mean numbers of health care utilizations, and costs) were compared using ANOVA and the Kruskal-Wallis test, a nonparametric alternative to ANOVA. Normally distributed data was analyzed using ANOVA, whereas non-normally distributed data was analyzed using Kruskal-Wallis. Annual health care costs for the 3 cohorts were calculated using a 2-part model.21 In the first part, logistic
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Table I. Patient demographic characteristics by serum uric acid (sUA) cohort.
Characteristics sUA, mean (SD) Demographics Age, y, mean (SD) Male, n (%) Medicare Insurance type, n (%) Previous comorbidities Cardiovascular disease, n (%) Chronic kidney disease, n (%) Diabetes, n (%) Hypertension, n (%) Obesity, n (%) Charlson Comorbidity Index, mean (SD) Chronic disease score, mean (SD)
Cohort 1
Cohort 2
Cohort 3
sUA ⬍6 mg/dL (n ⫽ 38)
sUA 6–8.99 mg/dL (n ⫽ 231)
sUA ⱖ9 mg/dL (n ⫽ 83)
5.02 (0.78)
7.66 (0.79)
10.19 (1.15)
P ⬍0.0001
59 (15) 27 (71.1%) 13 (34.2%)
61 (15) 177 (76.6%) 87 (37.7%)
62 (16) 51 (61.5%) 35 (42.2%)
0.567 0.029 0.683
8 (21.1%) 1 (2.6%) 9 (23.7%) 20 (52.6%) 2 (5.3%)
58 (25.1%) 20 (8.7%) 53 (22.9%) 131 (56.7%) 5 (2.2%)
26 (31.3%) 9 (10.8%) 30 (36.1%) 60 (72.3%) 4 (4.8%)
0.408 0.321* 0.060 0.028 0.356*
0.89 (1.20) 3.89 (3.23)
0.96 (1.27) 4.63 (3.61)
1.28 (1.68) 5.51 (4.32)
0.159 0.063
*Sample size too small for robust statistical tests.
regression was used to predict the likelihood of having a health care cost greater than zero during the 1-year postindex period. A generalized linear model with log link function after Box-Cox test was used in the second part to estimate the mean annual health care costs for patients with positive health care costs. Mean adjusted costs estimated from 2-part models were computed by multiplying the adjusted probability obtained from the logistic regression model (part 1) with the predicted cost from the general linear model (part 2). Cohort 1 (sUA ⬍6 mg/dL) served as the reference cohort, controlling for baseline covariates. Covariates were chosen a priori for all models on the basis of clinical relevance and baseline differences between cohorts. The Modified Park test was used to determine the most appropriate distribution for each cost.22 A bootstrap re-sampling method was used to estimate the 95% CIs of the health care cost differences among the 3 cohorts. An a priori 2-tailed ␣ level of 0.05 was used for all statistical tests. All analyses were conducted using SAS software (version 9.2; SAS Institute Inc., Cary, North Carolina) and Stata (version 11.1; Stata Corp., College Station, Texas).
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RESULTS Patient Demographic Characteristics A total of 352 patients were identified as meeting inclusion criteria (Figure 1A): 38 patients (10.8%) had a mean sUA level ⬍6 mg/dL; 231 patients (65.6%) had a mean sUA level between 6 and 8.99 mg/dL; and the remaining 83 patients (23.6%) had a mean sUA level of ⱖ9 mg/dL (Table I). For the patients with sUA ⬍6 mg/dL, the mean age was 59 (15) years, 71% were male, and the mean CCI was 0.89 (1.20). For patients with sUA levels between 6 and 8.99 mg/dL, the mean age was 61 (15) years, 77% were male, and the mean CCI was 0.96 (1.27). For patients with sUA ⱖ9.0 mg/ dL, the mean age was 62 (16) years, 61% were male, and the mean CCI was 1.28 (1.68). Although the patients’ demographic characteristics, including age, insurance type, and comorbidity scores (CCI and CDS), were comparable across the 3 sUA cohorts, patients with the highest sUA levels (ⱖ9 mg/dL) were more likely to be women (P ⫽ 0.029), and were more likely to have a diagnosis of hypertension (72%) relative to the other 2 cohorts (52.6% and 56.7%; P ⫽ 0.028). The mean (median) time from first to second sUA test
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Table II. All-cause health care utilization and costs during the 6-month preindex period by serum uric acid (sUA) cohort.
Health Care Services Total All-Cause Health Care Utilization No. of patients with at least 1 visit, n (%) Hospitalization ED Physician Outpatient Pharmacy No. of visits, mean (SD) Hospitalization ED Physician Outpatient Pharmacy No. of unique prescription drugs, mean (SD) Total no. of prescription drugs, mean (SD) Total All-Cause Health Care Cost ($), mean (SD) Total medical costs Pharmacy costs Total health care costs
Cohort 1
Cohort 2
Cohort 3
sUA ⬍6 mg/dL (n ⫽ 38)
sUA 6–8.99 mg/dL (n ⫽ 231)
sUA ⱖ9 mg/dL (n ⫽ 83)
1 (2.6%) 7 (18.4%) 26 (68.4%) 23 (60.5%) 29 (76.3%)
24 (10.4%) 40 (17.3%) 161 (69.7%) 155 (67.1%) 173 (74.9%)
11 (13.3%) 15 (18.1%) 56 (67.5%) 51 (61.5%) 61 (73.5%)
P
0.200*,† 0.979*,† 0.928* 0.537* 0.941*
0.32 (1.95) 0.21 (0.47) 3.26 (3.95) 3.00 (3.39) 5.29 (4.52)
0.39 (1.39) 0.29 (0.75) 3.12 (4.19) 3.34 (4.51) 6.29 (6.32)
0.83 (3.33) 0.35 (0.98) 4.08 (4.62) 4.54 (8.64) 9.48 (8.80)
0.215‡ 0.990‡ 0.406‡ 0.992‡ 0.001§
4.13 (3.71)
4.57 (4.35)
6.00 (5.04)
0.026§
7.89 (8.04)
9.86 (10.20)
14.81 (14.01)
0.001§
$5994 (11,525) $923 (1129) $6917 (11,883)
0.419‡ 0.121‡ 0.219‡
$4582 (11,666) $462 (576) $5044 (11,603)
$4204 (8508) $689 (1251) $4893 (8698)
ED ⫽ emergency department. *P values compare differences across the 3 cohorts using Pearson 2 test. † Sample size too small for robust statistical tests. ‡ P values compare differences across the 3 cohorts using Krusal-Wallis test due to non-normality. § P values compared differences across the 3 cohorts using ANOVA.
was approximately 126 days (93 days) for all measured cohorts. It should be noted that some results were based on information from small sample sizes, as indicated in Tables I to IV; therefore, robust statistical tests could not be conducted for some variables.
Utilization Outcomes Utilization and costs during the 6-month preindex period were similar across the 3 sUA categories except for the mean number of unique all-cause prescription drugs
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and total pharmacy claims (Table II). Patients with sUA ⱖ9.0 mg/dL had a mean of 6.00 (5.04) unique all-cause prescription drugs, significantly higher than that for patients with sUA ⬍6.0 mg/dL (4.13 [3.71]) and for patients with sUA of 6 to 8.99 mg/dL (4.57 [4.35]) (P ⫽ 0.026). Patients with sUA ⱖ9.0 mg/dL had a mean of 14.81 (14.01) total all-cause pharmacy claims, significantly higher than that of 7.89 [8.04] for patients with sUA ⬍6.0 mg/dL and 9.86 [10.20] for patients with sUA of 6 to 8.99 mg/dL (P ⫽ 0.001).
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Table III. All-cause and gout-related health care utilization during the 1-year postindex period by serum uric acid (sUA) cohort.
Health Care Services Total All-Cause Health Care Utilization No. of patients with at least 1 visit, n (%) Hospitalization ED Physician Outpatient Pharmacy No. of visits, mean (SD) Hospitalization ED Physician Outpatient Pharmacy No. of unique prescription drugs, mean (SD) Total no. of prescription drugs, mean (SD) Gout-Related Health Care Utilization No. of patients with at least 1 visit, n (%) Hospitalization ED Physician Outpatient Pharmacy No. of visits, mean (SD) Hospitalization ED Physician Outpatient Pharmacy No. of unique prescription drugs, mean (SD) Total no. of prescription drugs, mean (SD)
Cohort 1
Cohort 2
Cohort 3
sUA ⬍6 mg/dL (n ⫽ 38)
sUA 6–8.99 mg/dL (n ⫽ 231)
sUA ⱖ9 mg/dL (n ⫽ 83)
7 (18.4%) 12 (31.6%) 28 (73.7%) 33 (86.8%) 32 (84.2%)
28 (12.1%) 65 (28.1%) 198 (85.7%) 197 (85.3%) 194 (84.0%)
21 (25.3%) 35 (42.2%) 71 (85.5%) 74 (89.2%) 69 (83.1%)
0.84 (1.88) 0.39 (0.68) 8.34 (8.19) 7.34 (7.17) 18.74 (14.87) 8.84 (6.25) 26.68 (22.26)
0.94 (3.89) 0.51 (1.25) 8.10 (8.76) 8.73 (9.15) 18.68 (15.04) 9.04 (6.64) 29.26 (24.64)
1.67 (4.09) 0.86 (1.33) 9.89 (10.10) 11.12 (13.15) 25.84 (20.14) 11.65 (8.13) 41.94 (33.84)
2 (5.3%) 1 (2.6%) 12 (31.6%) 16 (42.1%) 25 (65.8%)
1 (0.4%) 12 (5.2%) 116 (50.2%) 91 (39.4%) 158 (68.4%)
1 (1.2%) 11 (13.3%) 42 (50.6%) 42 (50.6%) 59 (71.1%)
0.13 (0.66) 0.03 (0.16) 0.74 (1.66) 0.71 (1.25) 4.26 (4.13) 0.82 (0.69) 4.37 (4.21)
0.00 (0.07) 0.07 (0.32) 1.04 (1.53) 0.77 (1.35) 3.35 (3.98) 0.91 (0.74) 3.55 (4.33)
0.04 (0.33) 0.14 (0.39) 1.34 (2.00) 1.25 (1.77) 4.00 (4.30) 1.08 (0.84) 4.19 (4.54)
P
0.017*,† 0.063* 0.158* 0.675* 0.981* 0.019‡ 0.026‡ 0.541‡ 0.333‡ 0.003§ 0.011§ 0.001§
0.034*,† 0.025*,† 0.092* 0.208* 0.827* 0.034†,‡ 0.028†,‡ 0.089‡ 0.065‡ 0.268§ 0.112§ 0.357§
ED ⫽ emergency department. *P values compare differences across the 3 cohorts using Pearson 2 test. † Sample size too small for robust statistical tests. ‡ P values compare differences across the 3 cohorts using Kruskal-Wallis tests due to non-normality. § P values compare differences across the 3 cohorts using ANOVA. Pharmacy included allopurinol, colchicine, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination.
Table III demonstrates all-cause and gout-related utilization during the 1-year postindex period. The mean number of gout-specific prescriptions for newly started gout drug therapy did not differ among the 3 cohorts, with a total mean of 3.79 (4.37). The mean number of all-cause prescriptions for patients with the highest sUA levels (ⱖ9 mg/dL) was 41.94 (33.84), sig-
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nificantly greater than that of 26.68 (22.26) for patients with sUA ⬍6 mg/dL and 29.26 (24.64) for patients with sUA of 6 to 8.99 mg/dL (P ⫽ 0.001). The sUA levels were positively associated with the percentage of patients who had at least 1 all-cause hospitalization and with the mean number of all-cause hospitalizations and ED visits. The percentages of patients with
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Table IV. All-cause and gout-related health care costs during the 1-year postindex period by serum acid (sUA) cohort. Cohort 1
Cohort 2
Cohort 3
sUA ⬍6 mg/dL (n ⫽ 38)
sUA 6–8.99 mg/dL (n ⫽ 231)
sUA ⱖ9 mg/dL (n ⫽ 83)
P*
Total All-Cause Health Care Cost, $, mean (SD) Hospitalization ED Physician Outpatient Other Total medical service Pharmacy Total health care costs
$1195 (2947) $1307 (5773) $1856 (4177) $4223 (5707) $764 (3162) $9344 (12,427) $1072 (1118) $10,417 (12,868)
$2370 (9784) $427 ($1536) $1447 (2656) $3984 (5818) $1231 (4792) $9459 (15,914) $1696 (2741) $11,155 (16,428)
$5133 (16,555) $818 (1865) $1465 (1915) $4910 (6655) $1636 (5044) $13,962 (22,303) $2446 (3093) $16,408 (22,857)
0.024 0.025 0.437 0.595 0.004 0.027 0.061 0.011
Gout-Related Health Care Cost, $, mean (SD) Hospitalization ED Physician Outpatient Other Total medical service Pharmacy‡ Total health care costs
$128 (753) $4 (23) $63 (173) $150 (349) $15 (95) $361 (1069) $39 (44) $399 (1071)
$0 (5) $30 (151) $96 (162) $211 (810) $2 (17) $339 (828) $28 (36) $368 (832)
$40 (366) $62 (185) $135 (242) $265 (623) $18 (96) $521 (827) $34 (41) $555 (835)
0.033† 0.025† 0.064 0.168 0.299 0.004 0.476 0.008
Health Care Services
ED ⫽ emergency department. *P values compare differences across the 3 cohorts using Kruskal-Wallis tests. † Sample size too small for robust statistical tests. ‡ Pharmacy included allopurinol, colchicine, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination.
ⱖ1 claim for any type of hospitalization were 25.3% in the cohort with sUA ⱖ9 mg/dL, 18.4% among those with sUA ⬍6 mg/dL, and 12.1% among those with sUA between 6 and 8.99 mg/dL (P ⫽ 0.017). Patients with sUA ⱖ9.0 mg/dL had a mean of 1.67 (4.09) hospitalizations for any cause, which was significantly higher compared with patients with sUA ⬍6.0 mg/dL (0.84 [1.88]) or those with sUA of 6 to 8.99 mg/dL (0.94 [3.89]) (P ⫽ 0.019). The mean numbers of all-cause ED visits were 0.86 for patients with sUA ⱖ9.0 mg/ dL, 0.39 for those with sUA ⬍6.0 mg/dL, and 0.51 for those with sUA of 6 to 8.99 mg/dL (P ⫽ 0.026). The percentages of patients who had gout-related health care utilization (hospital and ED visits) were
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statistically different between cohorts, but the number of events per group was small, so results might not be clinically relevant.
Economic Outcomes All-cause and gout-related health care costs during the 1-year postindex period by sUA levels are shown in Table IV. Mean unadjusted 1-year goutspecific prescription costs and all-cause prescription costs among the 3 cohorts were not significantly different. However, mean unadjusted 1-year gout-related medical service costs for patients with sUA ⱖ9 mg/dL was $521, significantly higher than costs for patients with sUA ⬍6 mg/dL ($361) or for patients
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18,000 16,000 $14,474
Health care costs ($)
14,000 12,000
All-cause health care cost $11,365
$11,551 Gout-related health care cost
10,000 8000 6000 4000 2000 $332
$353
$663
0 sUA <6 mg/dL
sUA 6–8.99 mg/dL
sUA ≥9 mg/dL
Figure 2. Adjusted all-cause and gout-related health care costs for the 1-year post-index period.
with sUA between 6 and 8.99 mg/dL ($339) (P ⫽ 0.004). Similarly, mean unadjusted 1-year all-cause medical service costs for patients with sUA ⱖ9 mg/dL was $13,962, significantly higher than the costs for patients with sUA ⬍6 mg/dL ($9344) or sUA of 6 to 8.99 mg/dL ($9459) (P ⫽ 0.027). Figure 2 presents results from analyses of mean adjusted costs after controlling for age, gender, insurance, CCI, presence of hypertension, and number of all-cause prescriptions for the 6-month preindex period. Positive relationships were found between sUA levels and adjusted gout-related and adjusted all-cause health care costs. Mean adjusted gout-related health care costs for patients with sUA ⱖ9 mg/dL was $663, $310 higher than the cost for patients with sUA ⬍6 mg/dL (P ⬍0.05), although there was no significant difference between costs for patients with sUA of 6 to 8.99 mg/dL and those with sUA ⬍6 mg/dL. Similarly, mean adjusted all-cause health care costs for patients with sUA ⱖ9 mg/dL ($14,474) was significantly higher than the cost for patients with sUA ⬍6 mg/dL ($11,365) (P ⬍0.05). Mean adjusted all-cause health care costs for patients with sUA of 6 to 8.99 mg/dL ($11,551) and patients with sUA ⬍6 mg/dL did not significantly differ. Adjusted gout-related costs represented 2.09%, 3.06%, and 4.58% of total adjusted health care costs for the 1-year postindex period among patients with sUA levels
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⬍6.0 mg/dL, sUA between 6.00 and 8.99 mg/dL, and sUA ⱖ9.0 mg/dL, respectively.
Gout Medication-Taking Behaviors Of a total of 352 gout patients, 242 (68.8%) had at least 1 claim for gout-specific medications (allopurinol, colchicine, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination) over the first year (Figure 1B). Gout-specific medications were taken by a similar proportion of patients across the 3 cohorts: 65.8% for patients with sUA ⬍6.0 mg/dL; 68.4% for patients with sUA between 6 and 8.99 mg/dL; and 71.1% for patients with sUA ⱖ9.0 mg/dL (P ⬎0.05). Medication adherence measured using the PDC over the first year of gout-specific therapy was significantly inversely associated with the sUA levels. More patients with sUA ⬍6 mg/dL (56.0%) achieved adherence rates of ⱖ80% relative to patients with sUA of 6 to 8.99 mg/dL (24.1%) or ⱖ9.0 mg/dL (22.0%) (P ⫽ 0.002) (Table V). The mean PDCs for the 3 cohorts were 72.6%, 46.0%, and 49.9%, respectively (P ⫽ 0.001). Medication persistence in gout medication until the first 30- or 60-day gap in taking gout-specific medication was also significantly associated with sUA levels. Patients with sUA ⬍6.0 mg/dL had a longer mean duration of continuous treatment before ⱖ60-
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Table V. Gout medication-taking behaviors by serum uric acid (sUA) cohort.*
Medication-Taking Behaviors Adherence (n ⫽ 242) Proportion of days covered No. of patients ⱖ80%, n (%) Mean, (SD) Persistence (n ⫽ 242) Mean (SD) days until treatment gap, 30 days 60 days Treatment Patterns (n ⫽ 242) Monotherapy (n ⫽ 156), n (%) Polytherapy (n ⫽ 86), n (%)
Cohort 1
Cohort 2
Cohort 3
sUA ⬍6 mg/dL (n ⫽ 25)
6–8.99 mg/dL (n ⫽ 158)
sUA ⱖ9 mg/dL (n ⫽ 59)
14 (56.0%) 72.6 (27.0)
38 (24.1%) 46.0 (33.9)
13 (22.0%) 49.9 (31.3)
0.002† 0.001‡
215.3 (150.4) 255.4 (136.1)
140.6 (133.4) 163.9 (135.6)
138.5 (132.4) 177.7 (135.6)
0.032‡ 0.008‡
19 (76.0%) 6 (24.0%)
107 (67.7%) 51 (32.3%)
30 (50.9%) 29 (49.2%)
0.031†
P
*Gout medication included allopurinol, colchicines, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination. † P values compare differences across the 3 cohorts using Pearson 2 test. ‡ P values compare differences across the 3 cohorts using ANOVA.
day discontinuation (255 [136] days) compared with patients with sUA levels between 6 and 8.99 mg/dL (164 [136] days) or patients with sUA levels ⱖ9.0 mg/dL (178 [136] days) (P ⫽ 0.008). About two-thirds of the patients (64.5%) had only 1 gout-specific medication (monotherapy), whereas the rest had a combination of ⱖ2 gout-specific medications (polytherapy). The prevalence of monotherapy was negatively associated with higher sUA levels. Patients with sUA levels ⬍6 mg/dL (76.0%) were more likely to continue with monotherapy than patients with sUA levels between 6 and 8.99 mg/dL (67.7%) or patients with sUA levels ⱖ9.0 mg/dL (50.9%) (P ⫽ 0.031). In those patients prescribed monotherapy (n ⫽ 156), allopurinol was the most prevalent gout therapy (n ⫽ 115; 74%), followed by colchicine (n ⫽ 40; 26%). A higher percentage of patients with sUA ⬍6 mg/dL received allopurinol (90%) compared with the other 2 cohorts (70.1% for patients with sUA ⬍6 mg/dL and 76.7% for patients with sUA of 6 to 8.99 mg/dL) (data not shown).
DISCUSSION This retrospective analysis examined utilization, costs, and the medication-taking behaviors of patients with
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gout, stratified by sUA levels, in a single integrated health system population, Scott & White Healthcare. Although several retrospective analyses reported the association between high sUA levels (ie, ⱖ6.0 mg/dL) and increased utilization and costs in gout patients, the findings from each study were somewhat different.9,10,14 Wu et al9 found the mean regression-adjusted gout-related costs were significantly higher for patients with sUA ⱖ9 mg/dL compared with sUA ⬍6 mg/dL, whereas there was no significant difference in costs between the cohorts of sUA of 6 to 8.99 mg/dL and sUA ⬍6.0 mg/dL. Halpern et al14 reported that gout-related costs associated with baseline sUA of 6 to 8.99 mg/dL were higher than costs for sUA ⬍6.0 mg/ dL, but there was no significant difference in costs between sUA ⬍6 mg/dL and sUA ⱖ9.0 mg/dL. Another study by Halpern et al10 found that gout-related costs for patients with baseline sUA of 6 to 8.99 mg/dL or sUA ⱖ9 mg/dL were significantly higher compared with patients with sUA ⬍6.0 mg/dL (P ⬍0.05 and P ⬍0.01, respectively). Possible explanations for these differences could be differences in study populations, definitions of index date, and how sUA levels were determined. Wu et al9
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Clinical Therapeutics used the day of the first sUA level as the index date and this index date level as the sUA for the patient; goutrelated health care costs were measured in the 12 months after the index date. Halpern et al10,14 used the day of the first chronologic gout-related diagnosis or pharmacy claim as the index date and defined the patient’s sUA level as the preceding result closest to the index date. In addition, previous studies used only 1 sUA level to examine the effect of sUA on outcome measures. Changes could occur in sUA levels (eg, associated with alcohol drinking or weight loss), regardless of the use of antihyperuricemic drugs.23 In our study, the index date was defined as the first chronologic gout-related diagnosis, gout-related pharmacy claim, or sUA result to ensure that no gout-related health care services were recorded before the index date. To capture clinically relevant sUA levels that reflected early treatment, the mean of the first 2 sUA results were used. Unlike the previous studies cited, we used the sample inclusion criteria of a diagnosis of gout and/or pharmacy claim for a gout medication with at least 2 sUA tests to provide a more reliable measure of sUA levels for each patient. This study found that patients with more advanced gout disease, defined as sUA ⱖ9.0 mg/dL, had similar prescription costs, but higher medical service costs compared with the other 2 cohorts. In addition, after adjustment for the covariates measured in our study, patients with high sUA levels (ⱖ9.0 mg/dL) had significantly higher gout-related and all-cause health care costs ($310 and $3109 higher, respectively) compared with those with low sUA levels (⬍6.0 mg/dL). In addition, results indicated that poor adherence to newly-initiated gout-specific pharmacotherapy was common in gout patients; ⬍25% of patients with the highest sUA (ⱖ9 mg/dL) and only slightly more than half of patients with the lowest sUA levels (⬍6 mg/dL) were adherent (defined as a PDC of at least 80%). This result was consistent with previous studies, which found that adherence to urate-lowering drugs was generally poor, ranging from 44% to 64% in the study populations.11–13 As expected, patients in the very high sUA level cohort (ⱖ9 mg/dL) and in the high sUA level cohort (6 – 8.99 mg/dL) had significantly lower adherence than patients in the lowest sUA level cohort (⬍6 mg/dL). Based on these findings, it was possible that medication therapy was underutilized in gout patients not achieving sUA goals of ⬍6 mg/dL, resulting in higher medical services.
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Studies using administrative claims have a number of limitations. Because this was an observational study, we could not conclude that nonadherence or poor persistence with gout medications resulted in high sUA levels, poor clinical outcomes, and high health care costs. However, this relationship warrants further consideration and prospective investigation. Additional limitations of this study were inherent in inclusion criteria of a diagnosis of gout and/or pharmacy claim for a gout medication with at least 2 sUA tests. Despite some advantages of using the mean of 2 sUA levels, it was possible that the time periods observed to obtain the second reading might have been different between cohorts. However, we found that there were no statistically significant differences in the time from first sUA to second sUA testing among cohorts (P ⫽ 0.065). Only patients with at least 2 sUA levels were included in the analysis, resulting in a sample size smaller than anticipated compared with all gout patients. Particularly, the number of patients with low sUA levels (sUA ⬍6.0 mg/dL) was much smaller than the other 2 cohorts, which introduced increased statistical variance. This might also indicate that sUA was typically not being managed to clinical standards, as well. Previous studies showed that ⬍20% of patients had relevant sUA results in the datasets.8,9,14 The incomplete laboratory results might limit the generalizability of the study results for all gout patients. Moreover, when estimating gout-related pharmacy costs, we included only allopurinol, colchicine, febuxostat, probenecid, and probenecid/colchicine fixed-dose combination. NSAIDs and corticosteroids, common medications used in gout, were not included in the gout-specific medication category, because these medications could be used for diseases other than gout and/or obtained over the counter. This might underestimate the gout-related pharmacy costs. Another limitation was that although the final cost analysis was adjusted for comorbidities, intrinsic disease severity differences might still influence the results. For instance, unmeasured confounding variables such as body mass index, alcohol consumption, and family history1 not captured in administrative claims might be related to the outcomes. Finally, the study population was derived from a single health care institution and might not be representative of all gout patients.
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CONCLUSIONS This retrospective study showed that high sUA levels (ⱖ9 mg/dL) were associated with increased utilization and costs in gout patients. Nonadherence to gout medications occurred in the majority of the study population. Higher sUA levels were associated with lower medication adherence and lower persistence for patients newly starting gout medication therapy.
ACKNOWLEDGMENTS The authors wish to thank the medical informatics team at Scott & White Health Plan Prescription Services Division who provided the claims and laboratory data. Dr. Park was involved in all aspects of the analysis and writing of the article. Dr. Rascati served as the principal investigator from the proposal development stage to completion and was responsible for obtaining study funding and study design. Dr. Prasla was involved from proposal development and provided the data and feedback on the analysis and the article. Dr. McBayne reviewed all the work and provided input throughout the process. All authors had full access to the data, vouch for the veracity and completeness of the data and the data analysis, and take responsibility for its integrity. The article was written in its entirety by the authors.
CONFLICTS OF INTEREST This study was funded by Takeda Pharmaceuticals America, Inc., Deerfield, Illinois. Drs. Park and Rascati (The University of Texas at Austin) received a research grant from Takeda Pharmaceuticals America, Inc. Dr. Prasla is an employee of Scott & White Health Plan, Health Economics and Outcomes Research, Temple, Texas. Dr. McBayne is an employee of Takeda Pharmaceuticals America, Inc.
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Address correspondence to: Karen L. Rascati, PhD, Eckerd/Turley Centennial Professor of Pharmacy, The University of Texas College of Pharmacy, 2409 University Avenue PHR 3.209 Austin, Texas. E-mail: krascati@ mail.utexas.edu.
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