Impact of Treatment of Iron Deficiency Anemia in Inflammatory Bowel Disease: Considerations in Managed Care

Supplements and Featured Publications, Evolving Evidence-Based Treatment Guidelines for Iron Deficiency Anemia in Inflammatory Bowel Disease: Considerations in Managed Care, Volume 27, Issue 11

Abstract

Inflammatory bowel disease (IBD) is commonly associated with iron deficiency anemia (IDA), with a multifactorial pathophysiology. Diagnosis of both IDA and IBD places patients at risk for poor quality of life, as well as increased hospitalization and healthcare utilization. Treatment of IDA involves iron repletion with either oral or intravenous iron products. When selecting therapy, the total expenses of care must be considered, including direct and indirect costs, as well as patient clinical outcomes.

Am J Manag Care. 2021;27(suppl 11):S219-S223. https://doi.org/10.37765/ajmc.2021.88715

Introduction

Iron deficiency anemia (IDA) is one of the most documented extraintestinal manifestations and clinical complications relating to inflammatory bowel disease (IBD), occurring in 17% to 76% of patients with IBD.1 IDA is largely due to iron depletion from acute or chronic blood loss or from decreased iron absorption secondary to poor diet, inflammation, or surgery.1 Factors associated with an increased prevalence of anemia in this population include a greater number of IBD-related outpatient visits, younger age, being a woman, as well as a diagnosis of Crohn disease (CD).2 Anemia is associated with a more severe disease course, poor quality of life (QOL), frequent hospitalizations, longer hospital stays, and overall increased healthcare burden.3 Therefore, appropriate diagnosis and management of IDA related to IBD is crucial.

Direct Healthcare Costs

IBD is one of the costliest chronic diseases, with substantial direct and indirect costs in the United States.3 An estimated 1 million people in the United States have IBD, with direct medical costs calculated to exceed $6 billion in 2004.4 The major contributors to costs include hospitalizations, surgery, ambulatory costs, and pharmaceuticals. Healthcare costs are expected to continue increasing as the prevalence of IBD is expected to grow exponentially due to advances in diagnostics and screenings, in conjunction with low disease mortality.4 Additionally, patients with IBD may have extraintestinal manifestations, including hematologic or renal adverse effects.5,6 Anemia is one of the most common complications, and patients with IBD have a higher incidence and duration of anemia compared with those without, which may impact the cost of care.7

Data from the Crohn’s and Colitis Foundation’s Cost of Inflammatory Bowel Disease Care Initiative have shown that in this patient population, the cost of care is driven by patient comorbidities and disease severity. Patients with IBD incurred greater than 3-fold direct healthcare costs when compared with non-IBD controls ($22,987 vs $6956 per member per year paid claims) and had more than twice the out-of-pocket costs ($2213 compared with $979 per year).8 This study found the presence of concomitant anemia was associated with higher use of healthcare resources, mainly due to hospitalizations. After adjusting for other factors, patients with anemia had 8% higher costs when compared with patients without anemia, with a cost ratio of 1.081 (P <.001).8

A 2015 study aimed to investigate the use patterns of emergency department visits of patients with IBD in relation to hospitalizations and surgical rates. This cross-sectional analysis used the Nationwide Emergency Department Sample to evaluate adult patients with IBD as a primary diagnosis during emergency department visits and found that 20% of patients had concomitant anemia. Anemia was found to be one of the most significant factors associated with hospitalization (OR, 7.54), with about an 8-fold higher risk of hospitalization compared with those patients with IBD without anemia.9 This finding indicates the potential need to proactively treat anemia in an effort to reduce inpatient hospitalization.

The impact of anemia severity on healthcare use has also been assessed. In a retrospective chart review of adult patients between 2014 and 2018, health resource use and cost were assessed in patients with IBD. The records of 1763 patients with IBD were included, 966 of which (55%) had CD, 799 (44%) had ulcerative colitis (UC), and 18 (1%) had unspecified IBD. Of these patients, 951 (54%) had concomitant anemia. Patients with anemia had significantly higher direct healthcare costs, a greater number of hospitalizations, an increase in hospital length of stay, and more frequent emergency department, and both gastrointestinal and primary care physician, visits than those with IBD without anemia. Total mean costs for patients with IBD and anemia were estimated to be $19,627 compared with $7976 for those without anemia (P <.0001). In addition, the severity of anemia was directly correlated to higher healthcare costs, as shown in Table 1. Patients with severe anemia had an increased number of hospitalizations (mean [SD] severe anemia 2.2 [2.8] vs moderate anemia 1.3 [2.34] vs mild anemia 0.7 [1]; P = .0001) in addition to increased inpatient length of stay, averaging 2.8 days longer for patients with severe anemia compared with those with mild (95% CI, 2.28-3.48; P <.0001) and moderate anemia (95% CI, 1.28-1.82; P <.0001). Surprisingly, patients who were treated with either oral or intravenous (IV) iron did not have lower overall healthcare use or costs when compared with those who did not receive iron therapy (Table 2).3 Although treatment may not be associated with decreased cost or healthcare use, the authors suggest that treating symptoms of IBD, including anemia, early in the disease may have an impact on prevention of severe disease, and that additional analysis may be needed due to the acuity of the patients studied.

Indirect Healthcare Costs

Absenteeism, Presenteeism

Indirect healthcare costs include lost labor earnings due to absence from paid work (absenteeism), reduced productivity at work (presenteeism), and reduced opportunities for unpaid activities (loss of leisure).10 A large systematic review aimed to evaluate the economic burden of UC, specifically related to indirect costs. Although hard to estimate, the study concluded average indirect costs accounted for 35% of total UC healthcare costs.10 Additionally, a retrospective analysis assessed lost workdays due to IBD, finding that those with IBD missed more workdays than those without (13.4 missed days vs 9.9; P = .004), with indirect costs accounting for $249 million per year in the United States.11

Zand and colleagues prospectively evaluated presenteeism and potential work limitations in patients with IBD, assessing work-related productivity, patient QOL, and overall disease activity. In this study, absenteeism was calculated based on the number of work hours missed due to disease based on the percentage of hours worked per week. Presenteeism and work activity impairment were assessed using questionnaires completed by patients during clinic visits.In 440 patients assessed, presenteeism was significantly higher in those with IBD compared with controls (62.9% vs 27.3%; P = .004), with no significant difference in absenteeism. A total of 98.9% of patients with active disease had a high incidence activity impairment. Even after disease remission was obtained, patients continued to experience presenteeism. Additionally, these patients had increased indirect costs compared with controls: $17,766 vs $9179 per year (P <.03), as well as a decrease in productivity suggesting long-term effects of IDA.12

A cross-sectional study was conducted as part of the ongoing web-based WORK-IBD study to evaluate the impact of indirect costs of IBD, mainly focusing on predictors of work productivity loss, fatigue, and reduced health-related QOL (HRQOL).13 The study included 510 patients with IBD who were employed. Study participants were given multiple surveys including Work Productivity and Activity Impairment, Multidimensional Fatigue Inventory, and Short Inflammatory Bowel Disease Questionnaire. Investigators found that disease activity and disease burden led to loss of work productivity in approximately half of study participants. Fatigue was found to be the most important reason for productivity loss, accounting for 56% of absenteeism and 70% of presenteeism. Although fatigue in IBD may be multifactorial, anemia is a likely contributor. Tight disease control to manage anemia and related fatigue have been recommended to reduce disease burden and contributing indirect costs.13

Impact of Iron Repletion on Health-Related Quality of Life

IDA has been shown to have negative consequences on patient HRQOL in patients with IBD. Treatment of IDA with either oral or IV iron is recommended as first-line treatment.14 Although easily accessible and low in cost, many patients are not able to tolerate oral iron therapy or may not have an adequate response; therapy selection is often guided by patient specifics, including degree of iron deficiency, patient tolerability, and access for drug administration.15,16

In a study by LaVallee and colleagues, investigators assessed the likelihood that patients with chronic diseases, including IBD, would receive full planned iron replacement dosing, and also achieve a normalized hemoglobin. Over 46,000 patients with IDA were enrolled in the study, with 1167 patients with IBD. In the IBD cohort, 201 (29.3%) received ferric carboxymaltose (FCM), 129 (31.8%) received ferric maltol (FM), and 837 (44.6%) received sodium ferric gluconate, iron dextran, or iron sucrose (IS). Although outcomes were not reported specifically for the IBD subgroup, across the entire cohort, 53.9% of patients had normalized hemoglobin within 1 year of treatment initiation with parenteral iron, and those patients who received FCM specifically were more likely to have normalized hemoglobin compared with those receiving FM or another parenteral iron preparation (average OR [AOR], 1.88; P <.001 compared with FM; AOR, 1.4; P = .004 compared with other iron products). Those receiving FCM were more likely to receive full iron replacement doses as well (AOR, 5.1; P <.001 compared with FM; AOR, 3.71; P <.0001 compared with other iron products). Additionally, those patients receiving FCM also had a decreased number of outpatient clinic visits compared with those receiving other iron formulations (5.9 vs 9.2 visits; P ≤.001 compared with FM; 5.7 vs 11.8 visits; P ≤.001 compared with other iron products). The investigators concluded that the choice of parenteral iron products impacts clinical outcomes, and also may decrease outpatient clinic visits.17

In a phase 3, double-blind, placebo-controlled trial of patients with IBD whose oral iron replacement treatment failed, results showed a statistically significant and clinically meaningful improvement in outcomes when patients were treated with IV ferumoxytol; 81.1% of patients responded to IV iron replacement, compared with 5.5% of those treated with placebo (P <.0001). Additionally, an improvement in the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-Fatigue) score was improved at week 5 in the treatment arm compared with placebo (P <.0001).18 To explore the durability of this outcome, a subgroup analysis was conducted over a 6-month period of the trial to evaluate the impact of patient-reported outcomes following one dose of ferumoxytol. Results remained favorable; the FACIT-Fatigue scores were increased from baseline to week 5 of the study, with improvement seen over the 6-month period.15

A Swiss study aimed to evaluate the cost-effectiveness for FCM versus iron isomaltoside 1000 (IIM), IS, and oral iron therapy. The study developed a health economic model to assess the additional cost per additional responder defined as normalization or increase in hemoglobin of at least 2 grams/dL. Results of the study found that response rates were 81% with FCM, 74% with IIM, 75% with IS, and 69% with oral iron therapy. FCM was determined to be the most cost-effective treatment. The FCM and IIM formulations used in the study required the same number of infusions; however, due to the lower dose of FCM and thus the lower cost, FCM was found to be less costly. Compared with IS, FCM required fewer infusions and, therefore, was associated with cost savings; however, the precise economic impact in the United States has not been elucidated.19

Impact of Undertreatment of Iron Deficiency Anemia

IDA appears to have a high prevalence and affects overall QOL, although the condition is unfortunately undertreated.20 The European Crohn’s and Colitis Organisation recommend annual screening for IDA in patients with IBD. Reasons for undertreatment of IDA are multifactorial, including underscreening for anemia and misconceptions regarding iron products.21,22 Undertreatment may present missed opportunities for improvements in QOL. Additionally, as anemia is a symptom of more severe disease, earlier treatment may play a factor in reducing disease severity.3

One study aimed to evaluate the prevalence of IDA in a cohort at time of first diagnosis of IBD and early in disease course. Factors evaluated included iron treatment frequency, route of iron administration, and effectiveness of subsequent treatments. Hemoglobin levels of 279 patients (183 with CD, 90 with UC, and 6 with indeterminate colitis) were evaluated. Laboratory data further identified the type of anemia present in 70% of patients. At the time of first diagnosis of IBD, IDA was also diagnosed in 26 of the 68 patients with anemia (38.2%; 20 with CD, 4 with UC, and 2 with indeterminate colitis). Only 9 of these patients (34.6%) received iron replacement therapy at the time of diagnosis. At 1 year, 27 patients had concomitant IDA, and 20 (71.4%) received iron replacement therapy. Of the entire cohort with a diagnosis of IDA throughout the study treatment period, 38 (54.3%) did not receive any iron replacement therapy. Additionally, the majority of patients that did receive treatment were administered oral iron products (61; 82.4%), and many patients continued to have IDA despite treatment at 1 year (55.5%). The authors concluded there were inconsistencies in not only diagnosing IDA, but also in managing IDA therapies. This study highlighted potential undertreatment of IDA, and the potential to impact patient outcomes if IDA is managed.23

In recognition of the gap of undertreatment and underscreening of IBD and IDA, in 2016 the Anemia Care Pathway (ACP) was developed by the Crohn’s and Colitis Foundation to address the inconsistencies seen in clinical practice. Specifically, an explicit algorithm detailing steps to treat IDA, treatment thresholds, and specific time frames for laboratory monitoring was developed. One study aimed to implement the ACP in a managed care setting and identify where improvements in practice habits were seen, as well as barriers to care. The ACP was implemented from July 2016 to June 2017 and retrospectively studied. Results were compared with other providers in the same center not using the ACP. Out of the 640 IBD encounters evaluated in the ACP clinic, patients received iron therapy in 30% of encounters at baseline. Three months after implementation of the ACP, the percentage of patients with anemia prescribed iron therapy rose to a median of 80%. The incidence of anemia decreased from 48% to 25%. There was no improvement seen in the actual screening for iron deficiency, and no shifts in practice were seen in the non-ACP clinics despite awareness of the ACP and other guidelines. The investigators concluded that although screening rates for IDA did not improve, the ACP did appear to reduce missed opportunities for iron therapy by about half, which resulted in an overall decrease of anemia. Barriers identified by the investigators included the lack of a formal system to track patients including those with an incomplete screening, who screened positive for anemia, or who needed iron infusions. Additionally, laboratory tests were typically ordered after the point-of-care visit, meaning that if a suboptimal hemoglobin level was found, follow-up for additional screening and laboratories were delayed until the next scheduled visit, as many patients did not return to the clinic solely for follow-up laboratories.22 This study provides a framework for areas of improvement, specifically for patient follow-up.

Conclusions

In conclusion, IDA is one of the most common clinical complications of IBD. IDA has shown to increase direct healthcare costs by contributing to increased hospital admissions, increased hospital lengths of stay, and increased pharmacy costs. The severity of anemia seems to be directly correlated to use of healthcare resources. Although the indirect healthcare use impact such as absenteeism and presenteeism has been studied less, fatigue is likely a contributing factor for missed time at work and reduced productivity. Treatment with IV or oral therapy has shown a positive impact on patient HRQOL. Although there are clinical practice guidelines for the management of IDA associated with IBD with iron replacement, IDA may be undertreated. Treatment of IBD-related IDA may improve patient outcomes, mitigate healthcare expenses, and improve patient QOL.

Author affiliation: Jeenal Patel, PharmD, BCGP, is associate director, Formulary Design and Strategy, Oscar Health, Lakeland, FL.

Funding source: This activity is supported by an educational grant from American Regent.

Author disclosure: Dr Patel has no relevant financial relationships with commercial interests to disclose.

Authorship information: Analysis and interpretation of data,drafting of the manuscript, and critical revision of the manuscript for important intellectual content.

Address correspondence to: jbpatel06@gmail.com

Medical writing and editorial support provided by: Jenna Wood, PharmD

References

1. Akpınar H, Çetiner M, Keshav S, Örmeci N, Törüner M. Diagnosis and treatment of iron deficiency anemia in patients with inflammatory bowel disease and gastrointestinal bleeding: iron deficiency anemia working group consensus report. Turkish J Gastroenterol. 2017;28(2):81-87. doi: 10.5152/tjg.2017.17593

2. Akhuemonkhan E, Parian A, Miller K, Hanauer S, Hutfless S. Prevalence and screening for anemia in mild to moderate Crohn’s disease and ulcerative colitis in the United States, 2010-2014. BMJ Open Gastroenterol. 2017;4(1):e000155. doi: 10.1136/bmjgast-2017-000155.

3. Blaney H, Vu P, Mathew A, et al. Anemia severity associated with increased healthcare utilization and costs in inflammatory bowel disease. Dig Dis Sci. Published online September 5, 2020. doi: 10.1007/s10620-020-06590-y

4. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 2015;12(12):720-727. doi: 10.1038/nrgastro.2015.150

5. Calvo P, Pablo L. Managing IBD outside the gut: ocular manifestations. Dig Dis. 2013;31(2):229-232. doi: 10.1159/000353375

6. Jimenez KM, Gasche C. Management of iron deficiency anaemia in inflammatory bowel disease. Acta Haematol. 2019;142(1):30-36. doi: 10.1159/00049672

7. Patel D, Yang YX, Trivedi C, et al. Incidence, duration, and management of anemia: a nationwide comparison between IBD and non-IBD populations. Inflamm Bowel Dis. 2020;26(6):934-940. doi: 10.1093/ibd/izz206

8. Park KT, Ehrlich OG, Allen JI, et al. The cost of inflammatory bowel disease: an initiative from the Crohn’s & Colitis Foundation. Inflamm Bowel Dis. 2020;26(1):1-10. doi: 10.1093/ibd/izz104. Erratum in: Inflamm Bowel Dis. 2020;26(7):1118. doi: 10.1093/ibd/izaa081

9. Gajendran M, Umapathy C, Loganathan P, Hashash JG, Koutroubakis IE, Binion DG. Analysis of hospital-based emergency department visits for inflammatory bowel disease in the USA. Dig Dis Sci. 2016;61(2):389-399. doi: 10.1007/s10620-015-3895-2

10. Constantin J, Atanasov P, Wirth D, Borsi A. Indirect costs associated with ulcerative colitis: a systematic literature review of real-world data. BMC Gastroenterol. 2019;19(1):179. https://doi.org/10.1186/s12876-019-1095-9

11. Gunnarsson C, Chen J, Rizzo JA, Ladapo JA, Naim A, Lofland JH. The employee absenteeism costs of inflammatory bowel disease: evidence from US National Survey Data. J Occup Environ Med. 2013;55(4):393-401. doi: 10.1097/JOM.0b013e31827cba48

12. Zand A, van Deen WK, Inserra EK, et al. Presenteeism in inflammatory bowel diseases: a hidden problem with significant economic impact. Inflamm Bowel Dis. 2015;21(7):1623-1630. doi: 10.1097/MIB.0000000000000399

13. Van Gennep S, Evers SW, Rietdijk S, et al. High disease burden drives indirect costs in employed inflammatory bowel disease patients: the WORK-IBD study. Inflamm Bowel Dis. 2021;27(3):352-363.doi: 10.1093/ibd/izaa082

14. Jimenez K, Gasche C, Auerbach M. On both sides of the ocean. Blood Transfus. 2016;14(2):197-198. doi: 10.2450/2016.0304-15

15. Barish C, Dahl NV, Jiang J, Strauss WE. P074 sustained improvements in fatigue and quality of life in patients with IBD and iron deficiency anemia following a single course of ferumoxytol: results of a 6-month extension study. Inflamm Bowel Dis. 2019;25(suppl 1):S35-S36. https://doi.org/10.1093/ibd/izy393.081

16. Gómez-Ramírez S, Brilli E, Tarantino G, Muñoz M. Sucrosomial iron: a new generation iron for improving oral supplementation. Pharmaceuticals (Basel). 2018;11(4):97. doi: 10.3390/ph11040097

17. LaVallee C, Cronin P, Bansal I, Kwong WJ, Boccia RV. Effectiveness of parenteral iron therapy in the real-world setting: a retrospective analysis. J Clin Haematol. 2020;1(1):16-25.

18. Vadhan-Raj S, Strauss W, Ford D, et al. Efficacy and safety of IV ferumoxytol for adults with iron deficiency anemia previously unresponsive to or unable to tolerate oral iron. Am J Hematol. 2014;89(1):7-12. doi: 10.1002/ajh.23582

19. Aksan A, Schoepfer A, Juillerat P, et al. Iron formulations for the treatment of iron deficiency anemia in patients with inflammatory bowel disease: a cost-effectiveness analysis in Switzerland. Adv Ther. 2021;38(1):660-677. doi: 10.1007/s12325-020-01553-1

20. Stein J, Dignass AU. Management of iron deficiency anemia in inflammatory bowel disease - a practical approach. Ann Gastroenterol. 2013;26(2):104-113.

21. Blaney H, Mathew A, Snelling R, et al. 2905 Adherence to the Crohn’s and Colitis Foundation’s IBD anemia care pathway: treatment of iron deficiency anemia in IBD. Am J Gastroenterol. 2019;114:p S1588. doi: 10.14309/01.ajg.0000601152.05329.4a

22. Qureshi T, Nguyen TP, Wang R, Willis D, Shah R, Hou JK. Improving anemia in inflammatory bowel disease: impact of the anemia care pathway. Dig Dis Sci. 2019;64(8):2124-2131. doi: 10.1007/s10620-019-05559-w

23. Ott C, Liebold A, Takses A, Strauch UG, Obermeier F. High prevalence but insufficient treatment of iron-deficiency anemia in patients with inflammatory bowel disease: results of a population-based cohort. Gastroenterol Res Pract. 2012;2012:595970. doi: 10.1155/2012/595970