Leukemia & Lymphoma, October 2014; 55(10): 2368–2374 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.879127
ORIGINAL ARTICLE: RESEARCH
Health resource utilization and cost associated with myeloproliferative neoplasms in a large United States health plan Jyotsna Mehta1, Hongwei Wang1, Jon P. Fryzek2, Sheikh Usman Iqbal1 & Ruben Mesa3 1Oncology-Global Evidence and Value Development, Medical Affairs and Research and Development, Sanofi, Cambridge, MA,
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USA, 2EpidStat Institute, Ann Arbor, MI, USA and 3Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ, USA
Abstract Myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET) may lead to bone marrow fibrosis. Because the disease course of ET and PV are long and the disease course of MF may be fatal, healthcare resource utilization (HRU) associated costs of these neoplasms are especially important to understand. We used a large US health insurance claim database to describe the costs of these diseases. Compared to age–gender matched comparisons without myeloproliferative neoplasms (MPN), all aspects of HRU that we examined, including inpatient, outpatient and emergency room visits and pharmacy, as well as overall healthcare expenditures, were significantly higher in patients with MF, PV and ET (e.g. MF total costs ⴝ $54 168 vs. $10 203; PV ⴝ $14 903 vs. $7913; ET ⴝ $29 553 vs. $8026) than in matched comparisons. In order to reduce the burden of illness associated with these diseases, continued efforts in the development of more efficacious treatments for these disorders are needed. Keywords: Myeloproliferative disorders, health resource utilization
Introduction Primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET) arise from the myeloid lineage in the bone marrow, and are classified based on their chromosomal abnormalities as the three BCR–ABL negative myeloproliferative neoplasms (MPNs) [1]. Most have an activating JAK2 mutation, and inhibition of JAK2 may control the proliferation of hematopoietic cells, leading to the possibility of targeted therapy for these patients [2]. Common disease manifestations of PMF include bone marrow failure, enlarged spleen due to extramedullary hematopoiesis (splenomegaly), debilitating symptoms including fatigue, night sweats, pruritus, early satiety, abdominal pain and discomfort, and marked decrement in patients’ quality of life (QoL) [3]. Decreased survival is a
hallmark of the disease as a result of infections, bleeding and leukemic transformations [4]. Patients with PV and ET suffer from splenomegaly and disease associated symptoms such as pruritus, night sweats, fatigue and bone pain. Both diseases, if progressive despite standard therapies, are associated with an increased risk of thrombosis, bleeding and progression to MF or even acute myeloid leukemia [5]. MPNs are rare diseases. Among five studies in various geographic locations, PMF incidence ranged between 0.3 and 1.5 per 100 000 per year, with most of the studies at the lower end of this range (around 0.4 per 100 000 per year) [6–10]. A study in Olmsted County, Minnesota reported the highest incidence of myelofibrosis (MF) (1.5 per 100 000 per year) [9], probably due to less stringent diagnostic criteria used in the study and the availability of automated platelet counters which would identify asymptomatic cases. PV incidence was lower in four studies using cancer registries (range 0.8–1.1 per 100 000) [6,11–13] than in five large populationbased studies (range 2.0–2.6 per 100 000) [7,8,10,14,15]. This difference may be due to an under-reporting of cases among the cancer registries. The ET incidence range is larger than seen for MF or PV incidence (ET incidence 1.0–2.6 per 100 000 [6–10,14–16]) due to the problems in diagnosing ET. In the recent past, there was not a single clinical or laboratory finding confirming the presence of ET, which means that ET was diagnosed by excluding other MPNs. Most patients with MPNs are older than 60 years at diagnosis. Survival of patients with PMF is much lower than for those with either PV or ET. Most studies have reported a median survival in PMF of just above 3 years [3,13]. In contrast, 80–88% of patients with PV are still alive at 3 years [11,13], and median survival is 7.2–15 years [14,17,18]. Similarly, survival for patients with ET was reported as 81–92% at 3 years, 74% at 5 years, and 61% at 10 years [9,11,13], with median ET survival ranging from 11 to 22.3 years [16,17,19]. PMF treatments are mainly associated with alleviating the symptoms of the disease. In contrast, treatments for PV and
Correspondence: Ruben Mesa, Mayo Clinic Cancer Center, 13400 E. Shea Blvd, Scottsdale, AZ 85259, USA. Tel: ⫹ 1-480-301-8335. Fax: ⫹ 1-480-301-4675. E-mail: [email protected] Received 19 August 2013; revised 2 December 2013; accepted 22 December 2013
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Burden of myeloproliferative neoplasms 2369 ET attempt to control the patient’s blood counts to reduce thrombotic events. In particular, these include phlebotomy to reduce the number of circulating red blood cells, and aspirin, hydroxyurea, anagrelide and interferon to reduce the chance of blood clots [16,20,21]. Because the disease courses of ET and PV are long and the disease course of MF may be fatal, the healthcare resource utilization (HRU) associated costs of these neoplasms is especially important to understand, as healthcare providers and policy makers have increasingly emphasized and evaluated the costs and benefit of medical interventions, especially new therapies, in order to support their reimbursement. These health technology assessments consider economic consequences of treatment failure (or progression) which can be characterized and evaluated with generalizable data on resource use and costs among patients with MPNs. To this end, we used data from one of the largest US health plans in order to characterize current HRU and costs for the treatment of MF, PV and ET.
Materials and methods This was a descriptive observational study of MPNs using data from a large US health insurance claims database. This database can track patients longitudinally over multiple years, and is linked at the patient level by a unique identifier that is consistent across service locations, and time.
Data source This retrospective health insurance claims-based analysis used medical, pharmacy and patient enrollment data from
approximately 45 commercial and Medicare Advantage healthcare plans in the United States. The OptumInsight Impact National Managed Care Database is a fully deidentified Health Insurance Portability and Accountability Act (HIPAA)-compliant data set that includes data covering about 30 million lives per year (8–10% of the US population), representative of an insured population in areas in the USA covered by the plans. Patient demographics (e.g. age and gender), health plan enrollment information, facility revenue codes, place of service, International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnoses and procedures, Healthcare Common Procedure Coding System (HCPCS) and Current Procedural Terminology (CPT) codes, prescription claims data for each patient and associated costs are included in the database. For this analysis, we included patients with continuous enrollment for both medical and pharmacy coverage for 2010.
Patient selection This retrospective descriptive observational study assessed healthcare utilization and costs in patients with MPNs as well as age–gender matched comparisons for medical services provided in 2010. From the national claims database, we selected patients enrolled since 2009 with medical claims for MF (ICD-9 ⫽ 238.76, 289.83), PV (ICD-9 ⫽ 238.4) and ET (ICD-9 ⫽ 238.71) in 2010. Comparisons were free of any of the diseases of interest and were randomly selected to individually age- and gender-match each patient in the MF, PV or ET cohort in a 1:1 ratio (Figure 1).
Figure 1. Subject identification in a large national claims database. MPN, myeloproliferative neoplasms; MF, myelofibrosis; PV, polycythemia vera; ET, essential thrombocythemia.
2370 J. Mehta et al.
Charlson comorbidity index
Polycythemia vera
The Charlson comorbidity index (CCI) score was used in this study to assess patient case mix and overall burden of comorbidity. It contains 17 categories of comorbidity, and each category has an associated weight based on the adjusted risk of mortality. A higher score indicates a more severe comorbidity burden [22–24].
Five thousand seven hundred and fifty-two patients with PV were identified from the healthcare plan in the year 2010, leading to an age adjusted prevalence of 56.5 per 100 000 patients. More patients with PV were men (65%) than women (35%), and the average age was 53 years. Patients with PV had statistically significantly (p ⬍ 0.0001) more comorbidities (mean CCI ⫽ 1.24) than the comparisons (mean CCI ⫽ 0.69) (Table I).
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Analysis methods Simple descriptive statistics (numbers and percentages, means and standard deviations) were used to characterize the MF, PV and ET cohorts as well as their comparisons, their HRU and costs. Differences between the disease cohorts and their age- and gender- matched comparisons were assessed using appropriate tests, including t-tests and χ2 tests. This was an economics study. We defined medical costs as the sum of inpatient costs, outpatient costs and emergency room service costs. Pharmacy costs included injectable and non-injectable chemotherapy, supportive care and other prescription drug costs. For this study, total costs included both medical costs and pharmacy costs. The total cost was the sum of both MPN- and non-MPN-related medical costs.
Results Patient characteristics Myelofibrosis We identified 433 patients with MF from about 12 million enrollees in the healthcare plan with continuous pharmacy and medical coverage (Table I) in the year 2010. This corresponds to an age-adjusted prevalence for MF of 5.4 per 100 000 patients in 2010. The age and sex of the comparisons were similar to those of the patients with MF, reflecting the matching criteria. Fifty percent of the patients were female. The average age was 60 years, with 28% of the patients being 65 or older. Compared with age–gender matched comparisons, patients with MF had statistically significantly (p ⬍ 0.0001) higher comorbidities (mean CCI ⫽ 2.1 vs. 0.9).
Essential thrombocythemia We ascertained 5483 patients with ET (Table I), corresponding to an age adjusted prevalence of 56.1 per 100 000 patients in 2010. Most of the patients with ET were women (67%). The average age of patients with ET was slightly younger (mean age ⫽ 51.1) than that of patients with either MF (mean age ⫽ 60.1) or PV (mean age ⫽ 53.4) patients. Compared with age–gender matched comparison subjects, patients with ET had statistically significantly (p ⬍ 0.0001) more comorbidities (mean CCI 1.43 vs. 0.66).
Healthcare resource utilization Myelofibrosis Thirty-four percent of the MF cohort had an inpatient hospitalization compared to 11% of the comparisons (p ⬍ 0.0001) (Table II). In addition, their mean number of hospital admissions was statistically significantly higher (MF mean admissions ⫽ 0.70 vs. comparisons ⫽ 0.19), and the number of days they were hospitalized during each visit was greater (mean visit days ⫽ 6.64) than for comparisons (mean number of days ⫽ 1.04) (p ⬍ 0.0001). A similar pattern was seen with emergency room visits. The proportion of patients with MF ever using the emergency room (42%) was statistically significantly higher than that for comparisons (25%). Patients with MF also had more physician office visits (57.53 visits vs. 21.55 visits) and ER visits (1.33 visits vs. 0.67 visits) than the comparisons in 2010.
Polycythemia vera Patients with PV were statistically significantly more likely to ever be hospitalized (16%) than matched comparisons
Table I. Characteristics of study populations, 2010. Characteristic Total Female, n (%) Age, mean (SD) Age, n (%) ⬍ 18 18–34 35–44 45–54 55–64 65–74 75⫹ CCI, mean (SD) Insurance type Commercial Medicare Medicaid
Matched Polycythemia Matched Essential Matched Myelofibrosis comparison vera comparison thrombocythemia comparison 433 215 (50%) 60.1 (12.1)
433 215 (50%) 60.1 (12.1)
5752 2027 (35%) 53.4 (13.9)
5752 2027 (35%) 53.4 (13.9)
5483 3685 (67%) 51.1 (16.2)
5483 3685 (67%) 51.1 (16.2)
10 (2%) 33 (8%) 86 (20%) 161 (37%) 82 (19%) 61 (14%) 61 (14%) 2.12 (2.45)*
10 (2%) 33 (8%) 86 (20%) 161 (37%) 82 (19%) 61 (14%) 61 (14%) 0.89 (1.55)
106 (2%) 435 (8%) 736 (13%) 1497 (26%) 2012 (35%) 592 (10%) 374 (7%) 1.24 (1.84)*
106 (2%) 435 (8%) 736 (13%) 1497 (26%) 2012 (35%) 592 (10%) 374 (7%) 0.69 (1.35)
183 (3%) 612 (11%) 853 (16%) 1427 (26%) 1452 (26%) 501 (9%) 455 (8%) 1.43 (2.25)*
183 (3%) 612 (11%) 853 (16%) 1427 (26%) 1452 (26%) 501 (9%) 455 (8%) 0.66 (1.37)
399 (92%) 34 (8%) 0 (0%)
395 (91%) 38 (9%) 0 (0%)
5464 (95%) 265 (5%) 23 (0%)
5479 (95%) 265 (5%) 8 (0%)
5208 (95%) 250 (5%) 25 (0%)
5201 (95%) 264 (5%) 18 (0%)
SD, standard deviation; CCI, Charlson comorbidity index; MPN, myeloproliferative neoplasm. *Statistically significant differences between MPN cohort and matched comparison cohort at p ⬍ 0.0001.
Burden of myeloproliferative neoplasms 2371
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Table II. Healthcare resource utilization by type of service for study populations, 2010.
Hospital inpatient Percent of cohort using Mean number of admissions (SD) Mean length of stay in days (SD) Outpatient claims and services Number of cohort using (%) Mean number of claims (SD) Physician office visit and services Number of cohort using (%) Mean number of visits (SD) Emergency room visits and services Percent of cohort using Mean number of visits (SD) Pharmacy Number of cohort using (%) Mean number of prescriptions (SD)
Myelofibrosis (n ⫽ 433)
Matched comparison (n ⫽ 433)
Polycythemia vera (n ⫽ 5752)
Matched comparison (n ⫽ 5752)
Essential thrombocythemia (n ⫽ 5483)
Matched comparison (n ⫽ 5483)
34%* 0.70 (1.43)* 6.64 (17.05)*
11% 0.19 (0.80) 1.04 (5.09)
16%* 0.27 (0.99)* 1.67 (7.94)*
8% 0.12 (0.47) 0.76 (5.53)
30%* 0.62 (1.49)* 4.97 (16.82)*
9% 0.13 (0.55) 0.91 (6.83)
433 (100.0%) 141.56 (150.94)
432 (99.8%) 40.21 (50.23)
5748 (99.9%) 61.89 (63.71)
5728 (99.6%) 30.76 (38.07)
5481 (100.0%) 78.36 (89.68)
5469 (99.7%) 32.82 (40.63)
428 (98.8%) 57.53 (68.32)*
416 (96.1%) 21.55 (32.58)
5705 (99.2%) 30.65 (31.98)*
5559 (96.6%) 17.58 (24.48)
5444 (99.3%) 36.69 (46.69)*
5344 (97.5%) 18.73 (25.81)
42% 1.33 (3.53)†
25% 0.67 (2.31)
31%* 0.81 (2.65)
22% 0.59 (2.48)
42%* 1.21 (3.20)*
23% 0.60 (2.32)
395 (91.2%) 34.17 (29.21)
373 (86.1%) 22.77 (29.63)
5267 (91.6%) 27.20 (28.42)
4927 (85.7%) 18.11 (22.53)
5053 (92.2%) 28.80 (29.45)
4744 (86.5%) 18.78 (24.45)
SD, standard deviation; MPN, myeloproliferative neoplasm. *Statistically significant differences between MPN cohort and matched comparison cohort at p ⬍ 0.0001. †Statistically significant difference between MPN cohort and matched comparison cohort at p ⫽ 0.001.
(8%) and to use the emergency room (42%) than comparisons (25%) (Table II). Hospital stays of patients with PV were statistically significantly longer (1.67 days vs. 0.76 days), and their hospital admissions (0.27 admissions vs. 0.12 admissions), physician office visits (30.65 visits vs. 17.58 visits) and emergency room visits (0.81 visits vs. 0.59 visits) were more frequent in 2010.
Essential thrombocythemia About 30% of patients with ET used the hospital in 2010, while only 9% of the comparisons used the hospital (p ⬍ 0.0001). Patients with ET were statistically significantly more likely to ever visit the emergency room (42% vs. 23% of the comparisons). Moreover, patients with ET had longer hospital stays (4.97 days vs. 0.91 days for comparisons), visited the physician clinic more frequently (36.69 visits vs. 18.73 visits for comparisons) and sought treatment at the emergency room more often (1.21 visits vs. 0.60 visits for comparisons).
Costs Myelofibrosis
costs (Table III). In fact, inpatient costs were almost 10 times greater for patients with MF ($23 760) than for comparisons ($2291), and outpatient costs were approximately four times greater in patients with MF ($20 928) than in comparisons ($5430).
Polycythemia vera Medical costs ($12 006 vs. $6188) and pharmacy costs ($2897 vs. $1724) were almost two times greater in patients with PV than in comparisons, leading to much higher average annual costs in 2010 for patients with PV ($14 903 vs. $7913). In contrast to patients with MF and ET, outpatient costs for patients with PV ($6806) were greater than inpatient costs ($4670). Although there was a statistically significant difference between patients with PV and comparisons in terms of ER visit costs, these costs only made up a small proportion of the total utilization costs (4% for both patients with PV and comparisons) (Table III).
Essential thrombocythemia
Patients with MF incurred a higher average annual cost in 2010 ($54 168 vs. $10 203) than age- and gender-matched comparisons. These differences were driven by both medical ($45 646 vs. $7987) and pharmacy ($8523 vs. $2216)
Patients with ET incurred about four times greater average annual total utilization costs ($29 553) than age–gender matched comparisons ($8026) (Table III). This was driven by the costs associated with inpatient hospitalizations (mean cost ⫽ $14 567 for patients with ET compared
Table III. Mean and standard deviation healthcare costs in US$ by type of service for study populations, 2010.
Hospital inpatient Outpatient visits and services Emergency room (ER) visits and services Medical (inpatient, outpatient, ER) Pharmacy Total utilization
Myelofibrosis (n ⫽ 433), mean (SD) 23 760* (76 157)* 20 928* (34 007)* 958* (2735)* 45 646* (96 858)* 8523* (17693)* 54 168* (101 569)*
Matched comparison (n ⫽ 433), mean (SD) 2291 (9846) 5430 (18 860) 266 (739)
Polycythemia vera (n ⫽ 5752), mean (SD) 4670* (19 092)* 6806* (14 072)* 529* (1602)*
7987 (21 863) 2216 (4066) 10 203 (23 359)
Matched comparison (n ⫽ 5752), mean (SD)
Matched comparison (n ⫽ 5483), mean (SD)
2019 (11 236) 3863 (11 211) 306 (1651)
Essential thrombocythemia (n ⫽ 5483), mean (SD) 14 567* (49 947)* 10 818* (27 584)* 902* (2593)*
2199 (13 715) 3894 (10 433) 301 (1252)
12 006* (26 679)*
6188 (17 901)
26 287* (63 112)*
6394 (19 546)
2897* (8376)* 14 903* (29 018)*
1724 (4085) 7913 (19 017)
3267* (7715)* 29 553* (65 237)*
1631 (3628) 8026 (20 650)
SD, standard deviation; MPN, myeloproliferative neoplasm. *Statistically significant differences between MPN cohort and matched comparison cohort at p ⬍ 0.0001.
2372 J. Mehta et al. to $2199 for comparisons) and outpatient visits (mean cost ⫽ $10 818 compared to $3894). Mean costs for pharmacy ($3267) and ER visits ($902) were lower than inpatient or outpatient visit costs for patients with ET, but they were still about three times higher than similar costs for the comparisons (mean ER visit costs ⫽ $301 for comparisons and pharmacy ⫽ $1631).
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Hospitalizations Table IV lists the top 20 hospital discharge diagnoses for patients with MF, PV and ET. The top hospital discharge diagnoses for patients with MF included neoplasm of other lymphoid and hematopoietic tissues (4.39%), pneumonia (2.54%) and acute myeloid leukemia (1.85%), for patients with PV they included obstructive chronic bronchitis (0.68%), atrial fibrillation and flutter (0.59%) and pneumonia (0.59%), and for patients with ET the discharge diagnoses included pneumonia (1.55%), osteoarthrosis (1.02%) and septicemia (0.89%).
Discussion To our knowledge, this is one of the first studies to comprehensively evaluate the economic burden of MPN disorders in one of the largest health plans in the USA, and demonstrate that MF, PV and ET contribute to significant healthcare burden. All aspects of HRU that we examined, including inpatient, outpatient and emergency room visits and pharmacy, as well as actual mean costs associated with HRU, are higher in patients with MF, PV and ET compared to age–gender matched comparisons without any of these MPNs. Even though there were fewer patients with MF than with ET or PV, overall total utilization costs were greater for patients with MF than for those with ET or PV. Limited information on the costs associated with MF, PV or ET exists in the literature. One recent abstract reported the costs for 25 145 patients with MPNs in a claims database with about 100 payers across the country [25]. The authors found that mean total costs for patients with MF were
Table IV. Top 20 diagnoses for hospitalization discharges for study populations and percent of each cohort with the diagnosis, 2010. Polycythemia vera (n ⫽ 5752)
Myelofibrosis (n ⫽ 433) 2387 – Other lymphatic and hematopoietic tissues 486 – Pneumonia, organism unspecified
4.39% 2.54%
Essential thrombocythemia (n ⫽ 5483)
4912 – Obstructive chronic bronchitis 4273 – Atrial fibrillation and flutter
0.68%
0.59%
0.59%
2050 – Acute myeloid leukemia
1.85%
0389 – Unspecified septicemia
1.39%
6826 – Cellulitis and abscess of leg, except foot 9968 – Complications of transplanted organ 2859 – Unspecified anemia
1.39%
486 – Pneumonia, organism unspecified 2384 – Neoplasm of uncertain behavior of polycythemia vera 4140 – Coronary atherosclerosis
1.39%
5188 – Other diseases of lung
0.52%
0.92%
6826 – Cellulitis and abscess of leg, except foot 5621 – Diverticula of colon
0.37%
4151 – Pulmonary embolism and infarction 4534 – Venous embolism and thrombosis of deep vessels of lower extremity 5849 – Unspecified acute renal failure 4349 – Unspecified cerebral artery occlusion 7153 – Osteoarthrosis, localized, not specified whether primary or secondary 7865 – Chest pain
0.30%
4280 – Congestive heart failure, unspecified 5990 – Urinary tract infection, site not specified 2841 – Pancytopenia
0.69%
2852 – Anemia of chronic disease
0.69%
2880 – Neutropenia
0.69%
4140 – Coronary atherosclerosis
0.69%
4151 – Pulmonary embolism and infarction 4273 – Atrial fibrillation and flutter
0.69%
4359 – Unspecified transient cerebral ischemia 5119 – Unspecified pleural effusion
0.69%
5589 – Other and unspecified noninfectious gastroenteritis and colitis 7153 – Osteoarthrosis, localized, not specified whether primary or secondary 7806 – Fever and other physiologic disturbances of temperature regulation
0.92% 0.92%
0.69%
0.69%
4280 – Congestive heart failure, unspecified 2963 – Major depressive disorder, recurrent episode 4107 – Acute myocardial infarction, subendocardial infarction
0.54% 0.52%
0.35%
0.30% 0.30% 0.28% 0.28% 0.26% 0.24% 0.23% 0.23%
0.69%
4282 – Systolic heart failure
0.23%
0.69%
0389 – Unspecified septicemia
0.21%
0.69%
185 – Malignant neoplasm of prostate
0.19%
486 – Pneumonia, organism unspecified 7153 – Osteoarthrosis, localized, not specified whether primary or secondary 0389 – Unspecified septicemia
1.55% 1.02%
0.89%
2387 – Other lymphatic and hematopoietic tissues 4140 – Coronary atherosclerosis
0.80%
2873 – Primary thrombocytopenia 9985 – Postoperative infection, not elsewhere classified 5990 – Urinary tract infection, site not specified 2809 – Unspecified iron deficiency anemia 7865 – Chest pain
0.67%
4349 – Unspecified cerebral artery occlusion 6826 – Cellulitis and abscess of leg, except foot 2880 – Neutropenia
0.46%
0.69%
0.64% 0.53% 0.49% 0.49%
0.46% 0.44%
4151 – Pulmonary embolism and infarction 5621 – Diverticula of colon
0.42%
5849 – Unspecified acute renal failure 7159 – Osteoarthrosis, unspecified whether generalized or localized 5609 – Unspecified intestinal obstruction 7806 – Fever and other physiologic disturbances of temperature regulation 4912 – Obstructive chronic bronchitis
0.42%
0.42%
0.42% 0.38% 0.38% 0.36%
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Burden of myeloproliferative neoplasms 2373 $34 690, with most of those costs coming from outpatient services ($18 395). Total costs for patients with MF in this study were somewhat lower than our findings of $54 168 for mean total healthcare costs, mainly due to less inpatient costs reported for patients with MF. Similar to our findings, this study also showed that costs were greatest for patients with MF, followed by patients with ET (mean costs ⫽ $19 672) and PV (mean costs ⫽ $11,927). Karve and colleagues [26] assembled a US-based retrospective cohort of elderly persons identified with a new diagnosis of MPN in 2008 using the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database. Comparisons were selected for each MPN subtype and matched (5:1) on birth year, gender, ethnicity, geography and reason for Medicare eligibility. Costs were adjusted to 2010 US$ and represented amounts reimbursed by Medicare to providers. Mean total costs per patient, driven equally by inpatient and outpatient services, were significantly higher (p ⬍ 0.001) in cases of MPN (ET vs. control: US$11 259 vs. US$8897; PV vs. control: US$13 337 vs. US$8530; MF vs. control: US$20 917 vs. US$7367; MPNNOS vs. control: US$20 174 vs. US$9800). Total healthcare costs during a given year for Medicare enrollees with MPNs were 1.5–3 times higher (depending on subtype) than those of matched comparisons. This contrasted with previously estimated 2–6-fold higher estimated costs for commercially insured patients with MPNs compared with patients without MPNs in our study and the study by Price et al. [25], likely reflecting lower Medicare reimbursement rates, lower coverage of outpatient prescription drugs and increased comorbidity burden in an older population. Further, we were unable to control for differences in education level, income level and other demographic variables that may explain some of the difference between patients with MPNs and the comparisons, because these variables are not available in the claims-based database we used for the analysis. In addition, these differences may also reflect a coverage bias, where some patients may decide against Medicare enrollment. For a stricter definition of MF, PV and ET, we also conducted analyses where we required these patients to have a diagnosis of splenomegaly (ICD-9 ⫽ 789.2) in the same year as their MPN diagnosis and calculated the overall costs. The total costs for the subset of patients with splenomegaly were higher for MF (mean costs ⫽ $74 133), for PV (mean costs ⫽ $34 171) and for ET (mean costs ⫽ $29 553) than for the whole group (see Table III). These additional costs may be due to the treatment of splenomegaly, which may include antibiotics, medications that suppress the immune system, chemotherapy or surgery to remove the spleen. Understanding the breakdown of MPN costs versus non-MPN costs is difficult given the lack of coding specifications on either an MF-related claim or an event that is a sequela of the disease, such as infection or vascular complication. However, we attempted to further understand MF-specific costs by restricting our analysis to those adjudicated medical claims with an MF code associated with the claim, even though we realize that this may be
an underestimation of the true costs for these patients. As pharmacy costs are not associated with an ICD code, this analysis focused only on emergency room, inpatient and outpatient claims. Even with the gross underestimation, on average, 20% ($9176 MF-associated costs/$45 646 all medical costs) of the total costs for patients with MF had costs attributed to MF. Patients with MF have an increased susceptibility to infections [27], so it is not surprising that among the top discharge diagnoses for hospitalization were a number of infectious diseases, including pneumonia, septicemia, cellulitis and abscess of leg, and urinary tract infections. Other discharge diagnoses were related to the disease course, such as anemia, AML and neutropenia [27]. Discharge diagnoses for ET were mainly associated with the disease course, such as infections and thrombocytopenia [27]. It is interesting that 56 patients (1.02%) with ET had a discharge diagnosis of osteoarthrosis. There is no known association between ET and osteoarthrosis. Therefore, the fact that these patients were hospitalized for osteoarthrosis may be due to the long course of ET and the development of other comorbidities (e.g. osteoarthrosis) in these patients not related to ET. While the top discharge codes for PV included infections and coronary events, very few patients had similar discharge diagnoses. In fact, while most patients had a discharge diagnosis associated with obstructive chronic bronchitis, this accounted for only 0.68% of patients with PV. Again, this may be due to the long survival associated with this disease [14,17,18] and the probability of patients with PV developing unrelated comorbidities or diseases. A number of study limitations must be noted. We do not have information on those patients who may have sought treatment elsewhere, which may underestimate our costs. Patients with MPNs in our study were identified through diagnoses in administrative claims, and some of these diagnoses could have been miscoded. Further, a patient had to have a MPN-associated hospitalization, outpatient visit or ER visit in the year 2010 in order to be included in the study. Therefore, some patients and visits may have been misclassified. Not all patients with MPNs seek healthcare on a yearly basis, and therefore some patients without MPNs may be included in the MPN cohort and some patients with MPNs may be in the comparison group. The perspective of our study was that of a third-party payer. Our study did not incorporate out-of-pocket expenses or indirect costs such as productivity loss. All of these impact the economic burden of MPNs. Further, we did not have information on disease duration or severity, which may impact costs. Our study indicates that MPN-associated medical resource utilization and the corresponding expenditures for those services are substantive. In order to reduce the burden of illness associated with these diseases, continued efforts in the development of more efficacious treatments for these disorders are needed.
Acknowledgements This study was funded by Sanofi.
2374 J. Mehta et al. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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References [1] Tefferi A , Thiele J, Orazi A , et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007;110:1092–1097. [2] Levine RL, Pardanani A , Tefferi A , et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 2007;7:673–683. [3] Mesa RA , Schwager S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res 2009;33:1199–1203. [4] Rupoli S, Da Lio L, Sisti S, et al. Primary myelofibrosis: a detailed statistical analysis of the clinicopathological variables influencing survival. Ann Hematol 1994;68:205–212. [5] Scherber R, Dueck AC, Johansson P, et al. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international prospective validation and reliability trial in 402 patients. Blood 2011;118:401–408. [6] Girodon F, Bonicelli G, Schaeffer C, et al. Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: a population-based study. Haematologica 2009;94:865–869. [7] Johansson P, Kutti J, Andreasson B, et al. Trends in the incidence of chronic Philadelphia chromosome negative myeloproliferative disorders in the city of Goteborg, Sweden, during 1983-99. J Intern Med 2004;256:161–165. [8] Kutti J, Ridell B. Epidemiology of the myeloproliferative disorders: essential thrombocythaemia, polycythaemia vera and idiopathic myelofibrosis. Pathol Biol 2001;49:164–166. [9] Mesa RA , Silverstein MN, Jacobsen SJ, et al. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted county study, 1976–1995. Am J Hematol 1999;61:10–15. [10] Ridell B, Carneskog J, Wedel H, et al. Incidence of chronic myeloproliferative disorders in the city of Goteborg, Sweden 1983 - 1992. Eur J Haematol 2001;65:267–271. [11] Phekoo KJ, Richards MA , Moller H, et al. The incidence and outcome of myeloid malignancies in 2,112 adult patients in southeast England. Haematologica 2006;91:1400–1404.
[12] Prochazka AV, Markowe HL. The epidemiology of polycythaemia rubra vera in England and Wales 1968-1982. Br J Cancer 1986;53: 59–64. [13] Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood 2008;112:45–52. [14] Ana BJ, Suman VJ, Sobell JL, et al. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935 - 1989. Am J Hematol 2006;47:89–93. [15] Berglund S, Zettervall O. Incidence of polycythemia vera in a defined population. Eur J Haematol 1992;48:20–26. [16] Jensen MK, de Nully Brown P, Nielsen OJ, et al. Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area. Eur J Haematol 2002;65:132–139. [17] Buhr T, Georgii A , Choritz H. Myelofibrosis in chronic myeloproliferative disorders: incidence among subtypes according to the Hannover Classification. Pathol Res Pract 1993;189:121–132. [18] Policitemia GIS. Polycythemia vera: the natural history of 1213 patients followed for 20 years. Ann Intern Med 1995;123: 656–664. [19] Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med 2004;117:755–761. [20] Myeloproliferative Disorders Research Consortium. What are myeloproliferative disorders. Available from: www.mpd-rc.org/ readarticle.php?article_id⫽1 [21] Zimmerman MP, Mehr SR. Myeloproliferative disorders and myelofibrosis. Am J Manage Care 2012;18:1–3. [22] Hall SF. A user’s guide to selecting a comorbidity index for clinical research. J Clin Epidemiol 2006;59:849–855. [23] Yancik R, Ershler W, Satariano W, et al. Report of the national institute on aging task force on comorbidity. J Gerontol A Biol Sci Med Sci 2007;62:275–280. [24] Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 1987;40:373–383. [25] Price GL, Pohl GM, Xie J, et al. A retrospective observational study of annual healthcare costs for patients with forms of myeloproliferative neoplasms (MPN). Blood 2011;118(Suppl. 1): Abstract 2060. [26] Karve S, Price GL, Davis KL, et al. Health care utilization and associated costs in elderly persons with non-CML myeloproliferative neoplasms: real-world evidence from a United States Medicare population. Blood 2012;120(Suppl. 1): Abstract 4273. [27] The Leukemia & Lymphoma Society. Myeloproliferative neoplasms. Available from: www.lls.org/diseaseinformation/ myeloproliferativediseases/
ORIGINAL ARTICLE: RESEARCH
Health resource utilization and cost associated with myeloproliferative neoplasms in a large United States health plan Jyotsna Mehta1, Hongwei Wang1, Jon P. Fryzek2, Sheikh Usman Iqbal1 & Ruben Mesa3 1Oncology-Global Evidence and Value Development, Medical Affairs and Research and Development, Sanofi, Cambridge, MA,
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USA, 2EpidStat Institute, Ann Arbor, MI, USA and 3Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ, USA
Abstract Myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET) may lead to bone marrow fibrosis. Because the disease course of ET and PV are long and the disease course of MF may be fatal, healthcare resource utilization (HRU) associated costs of these neoplasms are especially important to understand. We used a large US health insurance claim database to describe the costs of these diseases. Compared to age–gender matched comparisons without myeloproliferative neoplasms (MPN), all aspects of HRU that we examined, including inpatient, outpatient and emergency room visits and pharmacy, as well as overall healthcare expenditures, were significantly higher in patients with MF, PV and ET (e.g. MF total costs ⴝ $54 168 vs. $10 203; PV ⴝ $14 903 vs. $7913; ET ⴝ $29 553 vs. $8026) than in matched comparisons. In order to reduce the burden of illness associated with these diseases, continued efforts in the development of more efficacious treatments for these disorders are needed. Keywords: Myeloproliferative disorders, health resource utilization
Introduction Primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET) arise from the myeloid lineage in the bone marrow, and are classified based on their chromosomal abnormalities as the three BCR–ABL negative myeloproliferative neoplasms (MPNs) [1]. Most have an activating JAK2 mutation, and inhibition of JAK2 may control the proliferation of hematopoietic cells, leading to the possibility of targeted therapy for these patients [2]. Common disease manifestations of PMF include bone marrow failure, enlarged spleen due to extramedullary hematopoiesis (splenomegaly), debilitating symptoms including fatigue, night sweats, pruritus, early satiety, abdominal pain and discomfort, and marked decrement in patients’ quality of life (QoL) [3]. Decreased survival is a
hallmark of the disease as a result of infections, bleeding and leukemic transformations [4]. Patients with PV and ET suffer from splenomegaly and disease associated symptoms such as pruritus, night sweats, fatigue and bone pain. Both diseases, if progressive despite standard therapies, are associated with an increased risk of thrombosis, bleeding and progression to MF or even acute myeloid leukemia [5]. MPNs are rare diseases. Among five studies in various geographic locations, PMF incidence ranged between 0.3 and 1.5 per 100 000 per year, with most of the studies at the lower end of this range (around 0.4 per 100 000 per year) [6–10]. A study in Olmsted County, Minnesota reported the highest incidence of myelofibrosis (MF) (1.5 per 100 000 per year) [9], probably due to less stringent diagnostic criteria used in the study and the availability of automated platelet counters which would identify asymptomatic cases. PV incidence was lower in four studies using cancer registries (range 0.8–1.1 per 100 000) [6,11–13] than in five large populationbased studies (range 2.0–2.6 per 100 000) [7,8,10,14,15]. This difference may be due to an under-reporting of cases among the cancer registries. The ET incidence range is larger than seen for MF or PV incidence (ET incidence 1.0–2.6 per 100 000 [6–10,14–16]) due to the problems in diagnosing ET. In the recent past, there was not a single clinical or laboratory finding confirming the presence of ET, which means that ET was diagnosed by excluding other MPNs. Most patients with MPNs are older than 60 years at diagnosis. Survival of patients with PMF is much lower than for those with either PV or ET. Most studies have reported a median survival in PMF of just above 3 years [3,13]. In contrast, 80–88% of patients with PV are still alive at 3 years [11,13], and median survival is 7.2–15 years [14,17,18]. Similarly, survival for patients with ET was reported as 81–92% at 3 years, 74% at 5 years, and 61% at 10 years [9,11,13], with median ET survival ranging from 11 to 22.3 years [16,17,19]. PMF treatments are mainly associated with alleviating the symptoms of the disease. In contrast, treatments for PV and
Correspondence: Ruben Mesa, Mayo Clinic Cancer Center, 13400 E. Shea Blvd, Scottsdale, AZ 85259, USA. Tel: ⫹ 1-480-301-8335. Fax: ⫹ 1-480-301-4675. E-mail: [email protected] Received 19 August 2013; revised 2 December 2013; accepted 22 December 2013
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Burden of myeloproliferative neoplasms 2369 ET attempt to control the patient’s blood counts to reduce thrombotic events. In particular, these include phlebotomy to reduce the number of circulating red blood cells, and aspirin, hydroxyurea, anagrelide and interferon to reduce the chance of blood clots [16,20,21]. Because the disease courses of ET and PV are long and the disease course of MF may be fatal, the healthcare resource utilization (HRU) associated costs of these neoplasms is especially important to understand, as healthcare providers and policy makers have increasingly emphasized and evaluated the costs and benefit of medical interventions, especially new therapies, in order to support their reimbursement. These health technology assessments consider economic consequences of treatment failure (or progression) which can be characterized and evaluated with generalizable data on resource use and costs among patients with MPNs. To this end, we used data from one of the largest US health plans in order to characterize current HRU and costs for the treatment of MF, PV and ET.
Materials and methods This was a descriptive observational study of MPNs using data from a large US health insurance claims database. This database can track patients longitudinally over multiple years, and is linked at the patient level by a unique identifier that is consistent across service locations, and time.
Data source This retrospective health insurance claims-based analysis used medical, pharmacy and patient enrollment data from
approximately 45 commercial and Medicare Advantage healthcare plans in the United States. The OptumInsight Impact National Managed Care Database is a fully deidentified Health Insurance Portability and Accountability Act (HIPAA)-compliant data set that includes data covering about 30 million lives per year (8–10% of the US population), representative of an insured population in areas in the USA covered by the plans. Patient demographics (e.g. age and gender), health plan enrollment information, facility revenue codes, place of service, International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnoses and procedures, Healthcare Common Procedure Coding System (HCPCS) and Current Procedural Terminology (CPT) codes, prescription claims data for each patient and associated costs are included in the database. For this analysis, we included patients with continuous enrollment for both medical and pharmacy coverage for 2010.
Patient selection This retrospective descriptive observational study assessed healthcare utilization and costs in patients with MPNs as well as age–gender matched comparisons for medical services provided in 2010. From the national claims database, we selected patients enrolled since 2009 with medical claims for MF (ICD-9 ⫽ 238.76, 289.83), PV (ICD-9 ⫽ 238.4) and ET (ICD-9 ⫽ 238.71) in 2010. Comparisons were free of any of the diseases of interest and were randomly selected to individually age- and gender-match each patient in the MF, PV or ET cohort in a 1:1 ratio (Figure 1).
Figure 1. Subject identification in a large national claims database. MPN, myeloproliferative neoplasms; MF, myelofibrosis; PV, polycythemia vera; ET, essential thrombocythemia.
2370 J. Mehta et al.
Charlson comorbidity index
Polycythemia vera
The Charlson comorbidity index (CCI) score was used in this study to assess patient case mix and overall burden of comorbidity. It contains 17 categories of comorbidity, and each category has an associated weight based on the adjusted risk of mortality. A higher score indicates a more severe comorbidity burden [22–24].
Five thousand seven hundred and fifty-two patients with PV were identified from the healthcare plan in the year 2010, leading to an age adjusted prevalence of 56.5 per 100 000 patients. More patients with PV were men (65%) than women (35%), and the average age was 53 years. Patients with PV had statistically significantly (p ⬍ 0.0001) more comorbidities (mean CCI ⫽ 1.24) than the comparisons (mean CCI ⫽ 0.69) (Table I).
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Analysis methods Simple descriptive statistics (numbers and percentages, means and standard deviations) were used to characterize the MF, PV and ET cohorts as well as their comparisons, their HRU and costs. Differences between the disease cohorts and their age- and gender- matched comparisons were assessed using appropriate tests, including t-tests and χ2 tests. This was an economics study. We defined medical costs as the sum of inpatient costs, outpatient costs and emergency room service costs. Pharmacy costs included injectable and non-injectable chemotherapy, supportive care and other prescription drug costs. For this study, total costs included both medical costs and pharmacy costs. The total cost was the sum of both MPN- and non-MPN-related medical costs.
Results Patient characteristics Myelofibrosis We identified 433 patients with MF from about 12 million enrollees in the healthcare plan with continuous pharmacy and medical coverage (Table I) in the year 2010. This corresponds to an age-adjusted prevalence for MF of 5.4 per 100 000 patients in 2010. The age and sex of the comparisons were similar to those of the patients with MF, reflecting the matching criteria. Fifty percent of the patients were female. The average age was 60 years, with 28% of the patients being 65 or older. Compared with age–gender matched comparisons, patients with MF had statistically significantly (p ⬍ 0.0001) higher comorbidities (mean CCI ⫽ 2.1 vs. 0.9).
Essential thrombocythemia We ascertained 5483 patients with ET (Table I), corresponding to an age adjusted prevalence of 56.1 per 100 000 patients in 2010. Most of the patients with ET were women (67%). The average age of patients with ET was slightly younger (mean age ⫽ 51.1) than that of patients with either MF (mean age ⫽ 60.1) or PV (mean age ⫽ 53.4) patients. Compared with age–gender matched comparison subjects, patients with ET had statistically significantly (p ⬍ 0.0001) more comorbidities (mean CCI 1.43 vs. 0.66).
Healthcare resource utilization Myelofibrosis Thirty-four percent of the MF cohort had an inpatient hospitalization compared to 11% of the comparisons (p ⬍ 0.0001) (Table II). In addition, their mean number of hospital admissions was statistically significantly higher (MF mean admissions ⫽ 0.70 vs. comparisons ⫽ 0.19), and the number of days they were hospitalized during each visit was greater (mean visit days ⫽ 6.64) than for comparisons (mean number of days ⫽ 1.04) (p ⬍ 0.0001). A similar pattern was seen with emergency room visits. The proportion of patients with MF ever using the emergency room (42%) was statistically significantly higher than that for comparisons (25%). Patients with MF also had more physician office visits (57.53 visits vs. 21.55 visits) and ER visits (1.33 visits vs. 0.67 visits) than the comparisons in 2010.
Polycythemia vera Patients with PV were statistically significantly more likely to ever be hospitalized (16%) than matched comparisons
Table I. Characteristics of study populations, 2010. Characteristic Total Female, n (%) Age, mean (SD) Age, n (%) ⬍ 18 18–34 35–44 45–54 55–64 65–74 75⫹ CCI, mean (SD) Insurance type Commercial Medicare Medicaid
Matched Polycythemia Matched Essential Matched Myelofibrosis comparison vera comparison thrombocythemia comparison 433 215 (50%) 60.1 (12.1)
433 215 (50%) 60.1 (12.1)
5752 2027 (35%) 53.4 (13.9)
5752 2027 (35%) 53.4 (13.9)
5483 3685 (67%) 51.1 (16.2)
5483 3685 (67%) 51.1 (16.2)
10 (2%) 33 (8%) 86 (20%) 161 (37%) 82 (19%) 61 (14%) 61 (14%) 2.12 (2.45)*
10 (2%) 33 (8%) 86 (20%) 161 (37%) 82 (19%) 61 (14%) 61 (14%) 0.89 (1.55)
106 (2%) 435 (8%) 736 (13%) 1497 (26%) 2012 (35%) 592 (10%) 374 (7%) 1.24 (1.84)*
106 (2%) 435 (8%) 736 (13%) 1497 (26%) 2012 (35%) 592 (10%) 374 (7%) 0.69 (1.35)
183 (3%) 612 (11%) 853 (16%) 1427 (26%) 1452 (26%) 501 (9%) 455 (8%) 1.43 (2.25)*
183 (3%) 612 (11%) 853 (16%) 1427 (26%) 1452 (26%) 501 (9%) 455 (8%) 0.66 (1.37)
399 (92%) 34 (8%) 0 (0%)
395 (91%) 38 (9%) 0 (0%)
5464 (95%) 265 (5%) 23 (0%)
5479 (95%) 265 (5%) 8 (0%)
5208 (95%) 250 (5%) 25 (0%)
5201 (95%) 264 (5%) 18 (0%)
SD, standard deviation; CCI, Charlson comorbidity index; MPN, myeloproliferative neoplasm. *Statistically significant differences between MPN cohort and matched comparison cohort at p ⬍ 0.0001.
Burden of myeloproliferative neoplasms 2371
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Table II. Healthcare resource utilization by type of service for study populations, 2010.
Hospital inpatient Percent of cohort using Mean number of admissions (SD) Mean length of stay in days (SD) Outpatient claims and services Number of cohort using (%) Mean number of claims (SD) Physician office visit and services Number of cohort using (%) Mean number of visits (SD) Emergency room visits and services Percent of cohort using Mean number of visits (SD) Pharmacy Number of cohort using (%) Mean number of prescriptions (SD)
Myelofibrosis (n ⫽ 433)
Matched comparison (n ⫽ 433)
Polycythemia vera (n ⫽ 5752)
Matched comparison (n ⫽ 5752)
Essential thrombocythemia (n ⫽ 5483)
Matched comparison (n ⫽ 5483)
34%* 0.70 (1.43)* 6.64 (17.05)*
11% 0.19 (0.80) 1.04 (5.09)
16%* 0.27 (0.99)* 1.67 (7.94)*
8% 0.12 (0.47) 0.76 (5.53)
30%* 0.62 (1.49)* 4.97 (16.82)*
9% 0.13 (0.55) 0.91 (6.83)
433 (100.0%) 141.56 (150.94)
432 (99.8%) 40.21 (50.23)
5748 (99.9%) 61.89 (63.71)
5728 (99.6%) 30.76 (38.07)
5481 (100.0%) 78.36 (89.68)
5469 (99.7%) 32.82 (40.63)
428 (98.8%) 57.53 (68.32)*
416 (96.1%) 21.55 (32.58)
5705 (99.2%) 30.65 (31.98)*
5559 (96.6%) 17.58 (24.48)
5444 (99.3%) 36.69 (46.69)*
5344 (97.5%) 18.73 (25.81)
42% 1.33 (3.53)†
25% 0.67 (2.31)
31%* 0.81 (2.65)
22% 0.59 (2.48)
42%* 1.21 (3.20)*
23% 0.60 (2.32)
395 (91.2%) 34.17 (29.21)
373 (86.1%) 22.77 (29.63)
5267 (91.6%) 27.20 (28.42)
4927 (85.7%) 18.11 (22.53)
5053 (92.2%) 28.80 (29.45)
4744 (86.5%) 18.78 (24.45)
SD, standard deviation; MPN, myeloproliferative neoplasm. *Statistically significant differences between MPN cohort and matched comparison cohort at p ⬍ 0.0001. †Statistically significant difference between MPN cohort and matched comparison cohort at p ⫽ 0.001.
(8%) and to use the emergency room (42%) than comparisons (25%) (Table II). Hospital stays of patients with PV were statistically significantly longer (1.67 days vs. 0.76 days), and their hospital admissions (0.27 admissions vs. 0.12 admissions), physician office visits (30.65 visits vs. 17.58 visits) and emergency room visits (0.81 visits vs. 0.59 visits) were more frequent in 2010.
Essential thrombocythemia About 30% of patients with ET used the hospital in 2010, while only 9% of the comparisons used the hospital (p ⬍ 0.0001). Patients with ET were statistically significantly more likely to ever visit the emergency room (42% vs. 23% of the comparisons). Moreover, patients with ET had longer hospital stays (4.97 days vs. 0.91 days for comparisons), visited the physician clinic more frequently (36.69 visits vs. 18.73 visits for comparisons) and sought treatment at the emergency room more often (1.21 visits vs. 0.60 visits for comparisons).
Costs Myelofibrosis
costs (Table III). In fact, inpatient costs were almost 10 times greater for patients with MF ($23 760) than for comparisons ($2291), and outpatient costs were approximately four times greater in patients with MF ($20 928) than in comparisons ($5430).
Polycythemia vera Medical costs ($12 006 vs. $6188) and pharmacy costs ($2897 vs. $1724) were almost two times greater in patients with PV than in comparisons, leading to much higher average annual costs in 2010 for patients with PV ($14 903 vs. $7913). In contrast to patients with MF and ET, outpatient costs for patients with PV ($6806) were greater than inpatient costs ($4670). Although there was a statistically significant difference between patients with PV and comparisons in terms of ER visit costs, these costs only made up a small proportion of the total utilization costs (4% for both patients with PV and comparisons) (Table III).
Essential thrombocythemia
Patients with MF incurred a higher average annual cost in 2010 ($54 168 vs. $10 203) than age- and gender-matched comparisons. These differences were driven by both medical ($45 646 vs. $7987) and pharmacy ($8523 vs. $2216)
Patients with ET incurred about four times greater average annual total utilization costs ($29 553) than age–gender matched comparisons ($8026) (Table III). This was driven by the costs associated with inpatient hospitalizations (mean cost ⫽ $14 567 for patients with ET compared
Table III. Mean and standard deviation healthcare costs in US$ by type of service for study populations, 2010.
Hospital inpatient Outpatient visits and services Emergency room (ER) visits and services Medical (inpatient, outpatient, ER) Pharmacy Total utilization
Myelofibrosis (n ⫽ 433), mean (SD) 23 760* (76 157)* 20 928* (34 007)* 958* (2735)* 45 646* (96 858)* 8523* (17693)* 54 168* (101 569)*
Matched comparison (n ⫽ 433), mean (SD) 2291 (9846) 5430 (18 860) 266 (739)
Polycythemia vera (n ⫽ 5752), mean (SD) 4670* (19 092)* 6806* (14 072)* 529* (1602)*
7987 (21 863) 2216 (4066) 10 203 (23 359)
Matched comparison (n ⫽ 5752), mean (SD)
Matched comparison (n ⫽ 5483), mean (SD)
2019 (11 236) 3863 (11 211) 306 (1651)
Essential thrombocythemia (n ⫽ 5483), mean (SD) 14 567* (49 947)* 10 818* (27 584)* 902* (2593)*
2199 (13 715) 3894 (10 433) 301 (1252)
12 006* (26 679)*
6188 (17 901)
26 287* (63 112)*
6394 (19 546)
2897* (8376)* 14 903* (29 018)*
1724 (4085) 7913 (19 017)
3267* (7715)* 29 553* (65 237)*
1631 (3628) 8026 (20 650)
SD, standard deviation; MPN, myeloproliferative neoplasm. *Statistically significant differences between MPN cohort and matched comparison cohort at p ⬍ 0.0001.
2372 J. Mehta et al. to $2199 for comparisons) and outpatient visits (mean cost ⫽ $10 818 compared to $3894). Mean costs for pharmacy ($3267) and ER visits ($902) were lower than inpatient or outpatient visit costs for patients with ET, but they were still about three times higher than similar costs for the comparisons (mean ER visit costs ⫽ $301 for comparisons and pharmacy ⫽ $1631).
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Hospitalizations Table IV lists the top 20 hospital discharge diagnoses for patients with MF, PV and ET. The top hospital discharge diagnoses for patients with MF included neoplasm of other lymphoid and hematopoietic tissues (4.39%), pneumonia (2.54%) and acute myeloid leukemia (1.85%), for patients with PV they included obstructive chronic bronchitis (0.68%), atrial fibrillation and flutter (0.59%) and pneumonia (0.59%), and for patients with ET the discharge diagnoses included pneumonia (1.55%), osteoarthrosis (1.02%) and septicemia (0.89%).
Discussion To our knowledge, this is one of the first studies to comprehensively evaluate the economic burden of MPN disorders in one of the largest health plans in the USA, and demonstrate that MF, PV and ET contribute to significant healthcare burden. All aspects of HRU that we examined, including inpatient, outpatient and emergency room visits and pharmacy, as well as actual mean costs associated with HRU, are higher in patients with MF, PV and ET compared to age–gender matched comparisons without any of these MPNs. Even though there were fewer patients with MF than with ET or PV, overall total utilization costs were greater for patients with MF than for those with ET or PV. Limited information on the costs associated with MF, PV or ET exists in the literature. One recent abstract reported the costs for 25 145 patients with MPNs in a claims database with about 100 payers across the country [25]. The authors found that mean total costs for patients with MF were
Table IV. Top 20 diagnoses for hospitalization discharges for study populations and percent of each cohort with the diagnosis, 2010. Polycythemia vera (n ⫽ 5752)
Myelofibrosis (n ⫽ 433) 2387 – Other lymphatic and hematopoietic tissues 486 – Pneumonia, organism unspecified
4.39% 2.54%
Essential thrombocythemia (n ⫽ 5483)
4912 – Obstructive chronic bronchitis 4273 – Atrial fibrillation and flutter
0.68%
0.59%
0.59%
2050 – Acute myeloid leukemia
1.85%
0389 – Unspecified septicemia
1.39%
6826 – Cellulitis and abscess of leg, except foot 9968 – Complications of transplanted organ 2859 – Unspecified anemia
1.39%
486 – Pneumonia, organism unspecified 2384 – Neoplasm of uncertain behavior of polycythemia vera 4140 – Coronary atherosclerosis
1.39%
5188 – Other diseases of lung
0.52%
0.92%
6826 – Cellulitis and abscess of leg, except foot 5621 – Diverticula of colon
0.37%
4151 – Pulmonary embolism and infarction 4534 – Venous embolism and thrombosis of deep vessels of lower extremity 5849 – Unspecified acute renal failure 4349 – Unspecified cerebral artery occlusion 7153 – Osteoarthrosis, localized, not specified whether primary or secondary 7865 – Chest pain
0.30%
4280 – Congestive heart failure, unspecified 5990 – Urinary tract infection, site not specified 2841 – Pancytopenia
0.69%
2852 – Anemia of chronic disease
0.69%
2880 – Neutropenia
0.69%
4140 – Coronary atherosclerosis
0.69%
4151 – Pulmonary embolism and infarction 4273 – Atrial fibrillation and flutter
0.69%
4359 – Unspecified transient cerebral ischemia 5119 – Unspecified pleural effusion
0.69%
5589 – Other and unspecified noninfectious gastroenteritis and colitis 7153 – Osteoarthrosis, localized, not specified whether primary or secondary 7806 – Fever and other physiologic disturbances of temperature regulation
0.92% 0.92%
0.69%
0.69%
4280 – Congestive heart failure, unspecified 2963 – Major depressive disorder, recurrent episode 4107 – Acute myocardial infarction, subendocardial infarction
0.54% 0.52%
0.35%
0.30% 0.30% 0.28% 0.28% 0.26% 0.24% 0.23% 0.23%
0.69%
4282 – Systolic heart failure
0.23%
0.69%
0389 – Unspecified septicemia
0.21%
0.69%
185 – Malignant neoplasm of prostate
0.19%
486 – Pneumonia, organism unspecified 7153 – Osteoarthrosis, localized, not specified whether primary or secondary 0389 – Unspecified septicemia
1.55% 1.02%
0.89%
2387 – Other lymphatic and hematopoietic tissues 4140 – Coronary atherosclerosis
0.80%
2873 – Primary thrombocytopenia 9985 – Postoperative infection, not elsewhere classified 5990 – Urinary tract infection, site not specified 2809 – Unspecified iron deficiency anemia 7865 – Chest pain
0.67%
4349 – Unspecified cerebral artery occlusion 6826 – Cellulitis and abscess of leg, except foot 2880 – Neutropenia
0.46%
0.69%
0.64% 0.53% 0.49% 0.49%
0.46% 0.44%
4151 – Pulmonary embolism and infarction 5621 – Diverticula of colon
0.42%
5849 – Unspecified acute renal failure 7159 – Osteoarthrosis, unspecified whether generalized or localized 5609 – Unspecified intestinal obstruction 7806 – Fever and other physiologic disturbances of temperature regulation 4912 – Obstructive chronic bronchitis
0.42%
0.42%
0.42% 0.38% 0.38% 0.36%
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Burden of myeloproliferative neoplasms 2373 $34 690, with most of those costs coming from outpatient services ($18 395). Total costs for patients with MF in this study were somewhat lower than our findings of $54 168 for mean total healthcare costs, mainly due to less inpatient costs reported for patients with MF. Similar to our findings, this study also showed that costs were greatest for patients with MF, followed by patients with ET (mean costs ⫽ $19 672) and PV (mean costs ⫽ $11,927). Karve and colleagues [26] assembled a US-based retrospective cohort of elderly persons identified with a new diagnosis of MPN in 2008 using the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database. Comparisons were selected for each MPN subtype and matched (5:1) on birth year, gender, ethnicity, geography and reason for Medicare eligibility. Costs were adjusted to 2010 US$ and represented amounts reimbursed by Medicare to providers. Mean total costs per patient, driven equally by inpatient and outpatient services, were significantly higher (p ⬍ 0.001) in cases of MPN (ET vs. control: US$11 259 vs. US$8897; PV vs. control: US$13 337 vs. US$8530; MF vs. control: US$20 917 vs. US$7367; MPNNOS vs. control: US$20 174 vs. US$9800). Total healthcare costs during a given year for Medicare enrollees with MPNs were 1.5–3 times higher (depending on subtype) than those of matched comparisons. This contrasted with previously estimated 2–6-fold higher estimated costs for commercially insured patients with MPNs compared with patients without MPNs in our study and the study by Price et al. [25], likely reflecting lower Medicare reimbursement rates, lower coverage of outpatient prescription drugs and increased comorbidity burden in an older population. Further, we were unable to control for differences in education level, income level and other demographic variables that may explain some of the difference between patients with MPNs and the comparisons, because these variables are not available in the claims-based database we used for the analysis. In addition, these differences may also reflect a coverage bias, where some patients may decide against Medicare enrollment. For a stricter definition of MF, PV and ET, we also conducted analyses where we required these patients to have a diagnosis of splenomegaly (ICD-9 ⫽ 789.2) in the same year as their MPN diagnosis and calculated the overall costs. The total costs for the subset of patients with splenomegaly were higher for MF (mean costs ⫽ $74 133), for PV (mean costs ⫽ $34 171) and for ET (mean costs ⫽ $29 553) than for the whole group (see Table III). These additional costs may be due to the treatment of splenomegaly, which may include antibiotics, medications that suppress the immune system, chemotherapy or surgery to remove the spleen. Understanding the breakdown of MPN costs versus non-MPN costs is difficult given the lack of coding specifications on either an MF-related claim or an event that is a sequela of the disease, such as infection or vascular complication. However, we attempted to further understand MF-specific costs by restricting our analysis to those adjudicated medical claims with an MF code associated with the claim, even though we realize that this may be
an underestimation of the true costs for these patients. As pharmacy costs are not associated with an ICD code, this analysis focused only on emergency room, inpatient and outpatient claims. Even with the gross underestimation, on average, 20% ($9176 MF-associated costs/$45 646 all medical costs) of the total costs for patients with MF had costs attributed to MF. Patients with MF have an increased susceptibility to infections [27], so it is not surprising that among the top discharge diagnoses for hospitalization were a number of infectious diseases, including pneumonia, septicemia, cellulitis and abscess of leg, and urinary tract infections. Other discharge diagnoses were related to the disease course, such as anemia, AML and neutropenia [27]. Discharge diagnoses for ET were mainly associated with the disease course, such as infections and thrombocytopenia [27]. It is interesting that 56 patients (1.02%) with ET had a discharge diagnosis of osteoarthrosis. There is no known association between ET and osteoarthrosis. Therefore, the fact that these patients were hospitalized for osteoarthrosis may be due to the long course of ET and the development of other comorbidities (e.g. osteoarthrosis) in these patients not related to ET. While the top discharge codes for PV included infections and coronary events, very few patients had similar discharge diagnoses. In fact, while most patients had a discharge diagnosis associated with obstructive chronic bronchitis, this accounted for only 0.68% of patients with PV. Again, this may be due to the long survival associated with this disease [14,17,18] and the probability of patients with PV developing unrelated comorbidities or diseases. A number of study limitations must be noted. We do not have information on those patients who may have sought treatment elsewhere, which may underestimate our costs. Patients with MPNs in our study were identified through diagnoses in administrative claims, and some of these diagnoses could have been miscoded. Further, a patient had to have a MPN-associated hospitalization, outpatient visit or ER visit in the year 2010 in order to be included in the study. Therefore, some patients and visits may have been misclassified. Not all patients with MPNs seek healthcare on a yearly basis, and therefore some patients without MPNs may be included in the MPN cohort and some patients with MPNs may be in the comparison group. The perspective of our study was that of a third-party payer. Our study did not incorporate out-of-pocket expenses or indirect costs such as productivity loss. All of these impact the economic burden of MPNs. Further, we did not have information on disease duration or severity, which may impact costs. Our study indicates that MPN-associated medical resource utilization and the corresponding expenditures for those services are substantive. In order to reduce the burden of illness associated with these diseases, continued efforts in the development of more efficacious treatments for these disorders are needed.
Acknowledgements This study was funded by Sanofi.
2374 J. Mehta et al. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
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