http://orcid.org/0000-0002-5405-2215
Abstract
Introduction: Primary immune thrombocytopenia (ITP), an autoimmune disorder characterized by low platelet count, can lead to serious bleeding events. Little is known about the current epidemiology of ITP in the US, and even less is known about the current healthcare burden of ITP, especially in the 12-month period following ITP diagnosis.
Method: We used a retrospective cohort design and data from two US private healthcare claims databases (2010–2016) to identify persons with evidence of newly diagnosed ITP. We weighted estimates of the annual incidence of ITP by age and sex to reflect the US population, and summarized healthcare utilization and expenditures (2016 US$) during the first 12 months after ITP diagnosis (“follow-up period”).
Results: Annual incidence of ITP in the US was 6.1 per 100,000 persons, higher among females versus males (6.7 vs. 5.5), and highest among children aged 0–4 years (8.1) and adults aged ≥65 years (13.7). Patients with ITP averaged 0.33 (95% CI: 0.32–0.35) hospitalizations and 15.3 (15.1–15.6) ambulatory encounters during the follow-up period; mean total healthcare expenditures during this period were $21,290 (20,502–22,031). Hospitalizations were more common during the first 3 months following diagnosis, and were twice as frequent among children versus adults; expenditures for ambulatory encounters were substantially higher for adults versus children aged 0–4 years.
Conclusions: Our findings suggest that nearly 20,000 children and adults are newly diagnosed with ITP each year in the US, substantially higher than previously reported. Among patients requiring formal medical care, the economic burden during the first 12 months following diagnosis is high, with estimated US expenditures totaling over $400 million.
Introduction
Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count (<100,000/µL) due to increased platelet destruction and suboptimal platelet productionCitation1. The disorder can be diagnosed in the absence of any other initiating or underlying cause of the thrombocytopenia, and should not be confused with secondary thrombocytopenias—including those associated with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections—for which treatment and outcomes can be very differentCitation1. ITP is quite rare, with previous incidence estimates ranging from 2.5 to 3.9 per 100,000 persons of all ages in Sweden and the United KingdomCitation2.
In adults, ITP normally has a sudden onset and follows an extended course, while in children, disease onset often follows a viral infection or immunization, with approximately 80% recovering spontaneously within 6 months of onset, 5% recovering within 6–12 months of onset, and 15% requiring extended managementCitation1,Citation3–5. According to practice guidelines, ITP can be classified into three groups based on duration of disease: newly diagnosed (0–<3 months), persistent (≥3–<12 months), and chronic (≥12 months)Citation1,Citation6–8. Patients with ITP often have no symptoms or minimal bruising, although some experience serious bleeding—such as skin, mucosal, gastrointestinal, or intracranial—the risk of which increases with ageCitation1,Citation9,Citation10.
The decision to treat depends on a number of cofactors, including age, platelet count, and conditions/drugs predisposing to bleedingCitation1,Citation7. Given the nature of pediatric ITP, observation alone is recommended as initial management for children who do not experience severe bleeding, followed by treatment as necessaryCitation1,Citation7. For adults, treatment may be recommended immediately following diagnosis, depending on platelet count and other patient cofactors, and consists of raising platelet levels to a safe rangeCitation1,Citation8,Citation11,Citation12. Standard frontline therapy for children and adults with ITP includes corticosteroids; alternative therapies include immunoglobulin therapy, Rho(D) immune globulin (RhD-Ig), and/or platelet transfusionCitation1,Citation7,Citation8. Second-line therapies include thrombopoietin receptor agonists (eltrombopag and romiplostim), rituximab, and splenectomyCitation1,Citation7,Citation8,Citation13,Citation14.
Evidence on the epidemiology of ITP in the US is limited to a single point estimate that was reported in the discussion section of a retrospective chart review of children aged <18 years with ITP who were treated at a single hospital from 1993 to 2003Citation15. Moreover, surprisingly little data exist on the clinical consequences and economic costs of ITP in US clinical practice, especially during the newly diagnosed and persistent phases. This study was undertaken to estimate the annual incidence of ITP among persons of all ages in the US, and to evaluate healthcare utilization and expenditures for ITP during the 12-month period following diagnosis in US clinical practice.
Methods
A detailed description of study methods—including the data sources and algorithms/codes employed to identify the study population as well as study variables—may be found in the Online Supplement. A brief description follows.
Study design and data sources
We employed a retrospective cohort design and data from two large integrated US private healthcare claims databases spanning January 1, 2010 through December 31, 2016. We pooled patient-level claims data from the two databases for analyses. The two study databases—IBM MarketScan Commercial and Medicare Databases (‘MarketScan Database’), and IQVIA Real-World Data Adjudicated Claims (PharMetrics Plus) (‘PharMetrics Plus Database’)—comprise claims for reimbursement that were submitted by healthcare providers (e.g. hospitals, physicians, clinics, outpatient pharmacies) to health plans for medical and pharmacy services rendered to their members. Collectively, the two study databases include healthcare claims information from demographically and geographically diverse populations totaling >30 million persons annually who are enrolled in a large number of private US health plans.
Source and study populations
The source population comprised all persons who had comprehensive health benefits for at least one day during the period beginning on January 1, 2012 and ending on December 31, 2015. From the source population, all patients who had evidence of ITP between January 1, 2012 and December 31, 2015 were identified based on ≥1 hospitalization with a diagnosis code for ITP or ≥2 ambulatory (non-lab) encounters with a diagnosis code for ITP separated by ≥30 days. The ‘date of initial ITP diagnosis’ was defined as the date of the first such encounter. Because ITP is a diagnosis of exclusion, and thus patients may be designated as having another type of thrombocytopenia before a formal diagnosis of ITP is established, the date of initial ITP diagnosis was redefined for those with a diagnosis of another type of thrombocytopenia during the prior 12-month period based on the earliest such evidence.
Patients who were designated as having ITP were stratified by calendar year based on their date of initial ITP diagnosis. Within each year-specific subset, patients were designated as having newly diagnosed ITP if they: were continuously eligible for health benefits for at least 2 years prior to the date of initial ITP diagnosis (except for children aged <2 years on date of diagnosis, for whom the eligibility criterion was adjusted accordingly); did not have evidence of ITP or any other thrombocytopenia from January 1, 2010 through December 31, 2011; did not have evidence of another type of thrombocytopenia more than 12 months prior to their initial diagnosis of ITP; and did not have evidence of causes of secondary thrombocytopenia or other selected conditions at any time on/before the date of their initial ITP diagnosis.
Study outcomes
Annual incidence of ITP was calculated on an age- and sex-specific basis within each calendar year from 2012 to 2015 by dividing the total number of patients with newly diagnosed ITP in each subgroup by the corresponding total number of persons from the source population who were continuously eligible for comprehensive health benefits during that year as well as the prior calendar year (i.e., a continuous 24-month period). Healthcare utilization and expenditures for ITP were ascertained from the date of initial diagnosis through the end of the 12-month follow-up period, and included hospital admissions, ambulatory encounters, and outpatient pharmacotherapy. Expenditures were expressed in 2016 US$, and were based on amounts paid by health plans and patients for services rendered by providers.
Statistical analyses
Annual incidence of ITP was calculated by age and sex in each calendar year from 2012 to 2015, and year-specific values were weighted by the size of the corresponding source population to yield estimates of annual incidence based on all available data. Annual rates of ITP incidence in the US—overall and by sex—were projected using age- and sex-specific incidence rates from analyses of the study databases and population weights from the US Census. Incidence estimates were expressed as rates per 100,000 persons.
Numbers and expenditures for ITP-related admissions, ambulatory encounters, and outpatient pharmacotherapy during the 12-month period following diagnosis (“follow-up period”) were summarized using means, frequencies, and corresponding 95% confidence intervals (CIs); 95% CIs were calculated using techniques of non-parametric bootstrapping. With this technique, repeated samples with replacement were drawn from the study population (1,000 samples in total, each with 11,028 patients) and values (i.e. means, percentages) for the measures of interest were calculated for each sample; 95% CIs were then constructed based on the empirical distribution of the sample-specific means and percentages. Measures of disease burden were reported per patient and per admission/encounter, as appropriate, on an overall basis (i.e. for the entire study sample), by segment of the follow-up period (months 0–<3 [newly diagnosed phase] vs. months ≥3–<12 [persistent phase]), and by age. Encounters and expenditures were characterized based on all ITP-related diagnosis and procedure codes noted on the corresponding claims (thus, if a single claim included multiple qualifying diagnoses and/or procedures, each one was reported separately). Measures of disease burden were adjusted for differential follow-up during each of the respective phases; patients who dis-enrolled from their health plan prior to the beginning of the persistent phase (and thus their healthcare encounters and expenditures during this period were unobserved) were excluded from calculations of disease burden for the persistent period.
Results
Among the approximately 120 million persons in the source population, 41,344 persons had evidence of ITP between January 2012 and December 2015, and among this subset, 11,028 met all remaining inclusion/exclusion criteria and thus qualified for inclusion in the study population (). Mean (SD) age of patients with ITP was 43 (25) years; 22% were aged 0–17 years, 60% were aged 18–64 years, and 18% were aged ≥65 years (). The majority of patients (57%) were female, and use of ITP-related pharmacotherapy during the 12-month period prior to the date of initial ITP diagnosis was <1% (except for glucocorticosteroids [8%]).
Table 1. Selection of patients for inclusion in the study population.
Table 2. Characteristics of patients with ITP in study population.
Overall age/sex-standardized annual incidence of ITP in the US was estimated to be 6.1 cases per 100,000 persons, and was estimated to be higher for females (6.7 per 100,000) versus males (5.5 per 100,000) (, Online Supplement – Table). Incidence rates were highest among children aged 0–4 years (8.1 per 100,000) and adults aged ≥65 years (13.7 per 100,000), and were lower among those aged 5–17 years (3.6 per 100,000), 18–49 years (4.3 per 100,000), and 50–64 years (5.9 per 100,000) (). Annual ITP incidence rates were roughly comparable across calendar years (i.e. 2012–2015) ranging from 5.7 to 6.4 per 100,000 persons, 5.0–5.6 per 100,000 males, and 6.3–7.0 per 100,000 females.
Figure 1. Annual incidence of ITP in the US, overall and by sex. Abbreviation. ITP, primary immune thrombocytopenia.
Figure 2. Annual incidence of ITP in the US, by age and sex. Abbreviation. ITP, primary immune thrombocytopenia.
During the follow-up period, patients averaged 0.33 (95% CI: 0.32–0.35) ITP-related hospitalizations and 15.3 (15.1–15.6) ITP-related ambulatory encounters, and corresponding mean expenditures per patient were $7,802 (7,332–8,282) and $12,978 (12,425–13,543); including outpatient pharmacotherapy, mean total healthcare expenditures were $21,290 (20,502–22,031) (). During the first 3 months following diagnosis compared with the next 9 months, ITP-related hospital admissions were more common (0.28 [0.27–0.30] vs. 0.05 [0.04–0.06]) and expenditures were higher ($6,338 [5,952–6,745] vs. $1,464 [1,188–1,776]), while mean ITP-related ambulatory encounters (7.6 [7.4–7.7] vs. 7.8 [7.6–8.0]) and expenditures ($6,202 [5,873–6,526] vs. $6,776 [6,332–7,196]) were comparable between periods. Total ITP-related expenditures averaged $12,626 (12,059–13,185) during the first 3 months, versus $8,664 (8,067–9,233) during the next 9 months.
Table 3. ITP-related encounters and expenditures during 1-year follow-up period, overall and for newly diagnosed phase (0–<3 months) and persistent phase (≥3–<12 months).
ITP-related hospitalizations (mean [95% CI]) were twice as common among children (0–4 years: 0.59 [0.55–0.64]; 5–17 years: 0.51 [0.47–0.55]) than adults (18–49 years: 0.27 [0.26–0.29]; 50–64 years: 0.27 [0.25–0.29; ≥65 years: 0.29 [0.27–0.32]) (). Hospital length of stay and expenditures per admission increased with age (e.g. two-fold higher among persons aged ≥65 years vs. children aged 0–4 years), and thus, on balance, expenditures for ITP-related hospitalizations per patient were roughly comparable across age groups. While mean numbers of ambulatory care encounters were largely similar across age groups (range, 13.8–18.0 per patient), mean costs of such encounters were lowest among the youngest age group ($4,321 [3,816–4,892] vs. $11,822 [10,588–13,059] to $15,467 [14,314–16,886] across other age groups). Overall mean (95% CI) ITP-related expenditures during the follow-up period totaled $12,278 (11,229–13,367) among children aged 0–4 years, and ranged from $20,741 (19,400–22,126) to $24,572 (22,838–26,437) among older children and adults.
Table 4. ITP-related encounters and expenditures during one-year follow-up period, by age.
Discussion
Using data on 120 million demographically and geographically diverse persons from two US private healthcare claims databases, we undertook a study to estimate the annual incidence of ITP in US clinical practice, and to evaluate healthcare utilization and expenditures for ITP during the 12-month period following diagnosis. The findings of this study suggest that the overall annual incidence of ITP in the US is 6.1 per 100,000 persons, higher than previously believed based on available evidence. In a review of 13 published studies, incidence estimates were reported to range from 2.5 to 3.9 per 100,000 persons of all ages, and subsequent studies based on non-US populations reported findings within this rangeCitation2,Citation16–19. While generally higher than previous findings, estimates of ITP incidence in this study were—consistent with prior research—highest among young children (8.1 per 100,000) and the elderly (13.7 per 100,000), and higher among females versus males (6.7 vs. 5.5 per 100,000)Citation17,Citation18,Citation20.
The findings of this study also suggest that expenditures for ITP-related care during the first 12 months following diagnosis are substantial (mean, $21,290), especially among older children and adults who are more likely to require extended disease management, and that over 50% of expenditures accrue during the first 3 months following diagnosis. While other studies have utilized various data sources to characterize the cost of hospitalizations for ITP in the US, our study is the first to estimate levels of healthcare utilization and expenditures during the 12-month period after first ITP diagnosis in US clinical practiceCitation9,Citation21–23. Extrapolating from our estimates of disease incidence and disease burden to the US population, the findings of this study suggest that nearly 20,000 children and adults are newly diagnosed with ITP each year in the US, and that among patients requiring formal medical care, US expenditures for ITP-related healthcare during the 12-month period following ITP diagnosis totals over $400 million.
A few limitations of our study deserve mention. Most notably, a validated (and sufficiently sensitive/specific) algorithm for identifying ITP in healthcare claims data is—to the best of our knowledge—not available from published literature. We therefore employed an operational algorithm for ITP that we believe is clinically reasonable and consistent with approaches used in other retrospective evaluationsCitation24–26. We note, however, that our algorithm has not been formally validated against a ‘gold-standard’ and thus its accuracy is unknown. Patients who had ITP but did not meet our minimum case-ascertainment criteria (e.g. they had only one ambulatory encounter with a diagnosis code for ITP during the period of interest) were not considered, which would downwardly bias our estimates of disease incidence and—if such patients had milder disease—upwardly bias estimates of healthcare utilization and expenditures. On the other hand, patients who did not have ITP but had such diagnoses recorded—for example, as a rule-out or in the process of diagnosing the specific type of thrombocytopenia—may inflate somewhat our estimates of disease incidence, although we believe the impact of any such bias to be minimal. It was assumed that all patients with ITP who did not have evidence of thrombocytopenia during the 2-year period prior to the date of initial ITP diagnosis were newly diagnosed in the corresponding year; while believed to be reasonable, the veracity of this assumption is unknown. Because of this 2-year requirement, we also limited attention in the source population to those who had 2 years of continuous enrollment when defining the denominator population for calculating disease incidence.
Our operational algorithm for identifying ITP-related healthcare utilization and expenditures employed diagnosis and procedure codes believed to be associated with the condition of interest. To the extent ITP diagnosis codes appeared on encounters for other reasons (e.g. to document the presence of a condition but for which treatment was not provided during that encounter), we may have over-estimated disease burden. We note, however, that inpatient encounters were limited to those with a corresponding diagnosis in the principal position (indicating the reason for admission as determined at the time of discharge) and outpatient encounters typically include only one or two diagnosis codes, increasing the probability that services provided were related to the recorded codes. The study databases do not include comprehensive information on date of death (a competing risk), and thus annualized levels of ITP-related encounters/expenditures may have been overestimated somewhat. In addition, because the study databases do not include information on the use of drugs in hospital, it was not possible to characterize ITP-related pharmacotherapy associated with inpatient encounters. Finally, we note that our study employed data from convenience—albeit large—samples of persons enrolled in private health insurance programs in the US. Persons with such insurance may differ systematically—in terms of their health status and/or healthcare experience—from those with public health insurance (e.g. Medicare, Medicaid) and those without health insurance in the US, as well as from persons in other countries with different population demographics or health systems. Accordingly, caution should be used in generalizing the results of this study to other populations and settings.
In summary, the findings of this study suggest that approximately 20,000 children and adults are diagnosed with ITP in US clinical practice each year, and thus that ITP incidence may be substantially higher than previously estimated, especially among the adult population. Study findings also suggest that the burden of ITP is high—exceeding $20,000 per patient—during the initial 12-month period following diagnosis, with US expenditures totaling over $400 million during this period, and is especially high during the first 3 months following diagnosis. Additional research evaluating the epidemiology and economic burden of ITP in other countries, across subgroups defined on important characteristics (e.g. race), and using more recent data is needed.
Transparency statement
Declaration of funding
Funding for this research was provided by Amgen Inc. to Policy Analysis Inc. (PAI).
Declaration of financial/other relationships
Aaron Grossman, Ahuva Hanau, Derek Weycker, and Hongsheng Wu are employed by PAI. Mark Bensink, David Chandler, Mark Hatfield, and Anjali Sharma are employed by, and own stock in, Amgen Inc. Michael Tarantino is an advisory board consultant for Amgen, Genentech, Grifols, Novo Nordisk, and Shire; is a clinical trial PI for Amgen; has a research grant from Grifols; is a speaker for Grifols, Novo Nordisk, and Shire; reviews grants for Pfizer; has an investigator initiated study with Novo Nordisk, and is the PI for program grants for HRSA and CDC.
JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
Authorship was designated based on the guidelines promulgated by the International Committee of Medical Journal Editors (2004). All persons who meet criteria for authorship are listed as authors on the title page. The contribution of each of these persons to this study is as follows: (1) conception and design (Chandler, Hatfield, Weycker), acquisition of data (Chandler, Hatfield, Weycker), analysis or interpretation of data (all authors); and (2) preparation of manuscript (Grossman, Hanau, Weycker), critical review of manuscript (Bensink, Chandler, Hatfield, Sharma, Tarantino, Wu). The study sponsor reviewed the study research plan and study manuscript; data management, processing, and analyses were conducted by PAI, and all final analytic decisions were made by study investigators. All authors have read and approved the final version of the manuscript.
Supplemental Material Tables
Download MS Excel (477 KB)Supplemental Material: Methods and Appendices
Download MS Word (318.5 KB)Acknowledgements
None reported.
Data availability statement
There are restrictions on data sharing, as the study employed extracts comprising healthcare claims from the Truven Health Analytics MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Databases and the IQVIA Real-World Data Adjudicated Claims PharMetrics Plus Database. The data are proprietary, provided by third-party vendors, and the authors do not have permission to disseminate these data without approval of the vendors.
References
- Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168–186.
- Terrell DR, Beebe LA, Vesely SK, et al. The incidence of immune thrombocytopenic purpura in children and adults: a critical review of published reports. Am J Hematol. 2010;85(3):174–180.
- Provan D, Newland AC. Current management of primary immune thrombocytopenia. Adv Ther. 2015;32(10):875–887.
- Terrell DR, Beebe LA, Neas BR, et al. Prevalence of primary immune thrombocytopenia in Oklahoma. Am J Hematol. 2012;87(9):848–852.
- Kuhne T, Buchanan GR, Zimmerman S, et al. A prospective comparative study of 2540 infants and children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) from the intercontinental childhood ITP study group. J Pediatr. 2003;143(5):605–608.
- Warrier R, Chauhan A. Management of immune thrombocytopenic purpura: an update. Ochsner J. 2012;12(3):221–227.
- Neunert CE. Current management of immune thrombocytopenia. Hematology. 2013;2013(1):276–282.
- Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190–4207.
- Tarantino MD, Danese M, Klaassen RJ, et al. Hospitalizations in pediatric patients with immune thrombocytopenia in the United States. Platelets. 2016;27(5):472–478.
- Chalmers S, Tarantino MD. Romiplostim as a treatment for immune thrombocytopenia: a review. J Blood Med. 2015;6:37–44.
- Cines DB, McMillan R. Management of adult idiopathic thrombocytopenic purpura. Annu Rev Med. 2005;56:425–442.
- Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386–2393.
- Nplate [package insert]. Thousand Oaks (CA): Amgen Inc.; 2017.
- Promacta [package insert]. East Hanover (NJ): Novartis AG; 2017.
- Watts RG. Idiopathic thrombocytopenic purpura: a 10-year natural history study at the Childrens Hospital of Alabama. Clin Pediatr (Phila). 2004;43(8):691–702.
- Wu SR, Kuo HC, Huang WC, et al. Incidence, clinical characteristics, and associated diseases in patients with immune thrombocytopenia: a nationwide population-based study in Taiwan. Thromb Res. 2018;164:90–95. Apr
- Moulis G, Palmaro A, Montastruc JL, et al. Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France. Blood. 2014;124(22):3308–3315.
- Schoonen WM, Kucera G, Coalson J, et al. Epidemiology of immune thrombocytopenic purpura in the General Practice Research Database. Br J Haematol. 2009;145(2):235–244.
- Koylu A, Pamuk GE, Uyanik MS, et al. Immune thrombocytopenia: epidemiological and clinical features of 216 patients in northwestern Turkey. Ann Hematol. 2015;94(3):459–466.
- Frederiksen H, Schmidt K. The Incidence of idiopathic thrombocytopenic purpura in adults increases with age. Blood. 1999;94(3):909–913.
- Kime C, Klima J, Rose MJ, et al. Patterns of inpatient care for newly diagnosed immune thrombocytopenia in US children’s hospitals. Pediatrics. 2013;131(5):880–885.
- Danese MD, Lindquist K, Gleeson M, et al. Cost and mortality associated with hospitalizations in patients with immune thrombocytopenic purpura. Am J Hematol. 2009;84(10):631–635.
- An R, Wang PP. Length of stay, hospitalization cost, and in-hospital mortality in US adult inpatients with immune thrombocytopenic purpura, 2006-2012. VHRM. 2017;13:15–21.
- Mezaache S, Derumeaux H, Ferraro P, et al. Validation of an algorithm identifying incident primary immune thrombocytopenia in the French national health insurance database. Eur J Haematol. 2017;99(4):344–349.
- Segal JB, Powe NR. Prevalence of immune thrombocytopenia: analyses of administrative data. J Thromb Haemost. 2006;4(11):2377–2383.
- Segal JB, Powe NR. Accuracy of identification of patients with immune thrombocytopenic purpura through administrative records: a data validation study. Am J Hematol. 2004;75(1):12–17.