Anemia has long been regarded as a biomarker for disease activity in both Crohn's disease (CD) and ulcerative colitis (UC).1,2 Historically, hemoglobin and hematocrit were the only laboratory parameters that were included in inflammatory bowel diseases (IBD) activity scores.1,2 However, anemia itself is associated with hospitalization, mortality, and a reduction in quality of life not only in IBD but also in various other disease states.3 In addition, anemic patients create higher health care costs.4 Therefore, anemia has evolved as an independent treatment target within a variety of medical conditions, including patient blood management, renal failure, and chronic heart failure.5–7
In IBD, both systemic inflammatory activity and iron deficiency are the most common causes of anemia.8 The term “anemia of chronic disease” has been replaced by “anemia of inflammation,”9 which is a consequence of various mechanisms including iron sequestration from the circulation into macrophages of the spleen and other sites, inhibition of erythropoietin production, and alterations of erythropoiesis in the bone marrow.10 In addition, iron deficiency in IBD results from intestinal bleeding and inhibition of iron absorption due to induction of hepcidin production.11,12 In fact, IBD is a paradigm for a disease state associated with multifactorial anemia that frequently leads to iron supplementation or blood transfusion.8
For the patient, anemia is a source of significant morbidity. It is a common trigger for hospitalization or prolongations of days in hospital.13 It is associated with reduced ability to work, including cognitive and physical performance, and a decrease in general quality of life.14,15 Chronic fatigue has been related to anemia in IBD.16 Even more important, iron deficiency itself (without anemia) has been related to chronic fatigue and various symptoms of depression including difficulty to sleep or to perform regular daily activities, all of which are responsive to iron replacement therapy.17,18 As iron deficiency and anemia have such an enormous impact on quality of life, they have become independent treatment targets in IBD, which is best reflected by the development of specific guidelines.19,20
Although guidelines exist for the care of anemia among patients with IBD, gaps remain in how anemia is addressed in clinical practice. As seen across many other disease states, guideline development and publication alone has limited ability to influence practice change.21–24 The goals of this study were to identify current practices and provider perceptions of anemia and to develop a clinical care pathway for screening, management, and follow-up of anemia among patients with IBD.
A pathway development committee was formed including gastroenterologists (J.K.H., C.A.S., G.M.), subject matter experts in anemia (C.G., N.Z.D.), and the Crohn's and Colitis Foundation of America (CCFA) (S.A.W., O.G.E., R.O.). A cognitive task analysis was performed through (1) collection of preliminary knowledge of anemia management in IBD, (2) identification of knowledge representations for anemia care by subject experts, (3) elicitation of focused knowledge of anemia management from subject experts, (4) analysis and verification of data, and (5) formatting results for use in a care pathway.25 Preliminary knowledge elicitation occurred via focus groups of clinical providers of patients with IBD, and the anemia care pathway committee convened a series of meetings to develop the care pathway.
Collection of Preliminary Knowledge of Anemia Management in IBD
To understand general perceptions of the approach to anemia among providers for patients with IBD, a series of focus groups were conducted. The Survey Research Institute at Cornell University facilitated 3 focus groups with health care providers, one each in Atlanta, GA; Houston, TX; and Minneapolis, MN. Participants were recruited by the local CCFA Chapter Medical Advisory Committees and were composed of providers who care for patients with IBD, including gastroenterologists, surgeons, and mid-level providers. Participants completed a prefocus group questionnaire, which included questions about anemia testing and management details on recent patients with IBD. Focus groups were audio recorded and transcribed. The Survey Research Institute identified domains and themes based on review of the focus group transcripts. The focus groups received IRB exemption from Cornell University.
Identification of Knowledge Representations for Anemia Care of Subject Experts
A summary of the domains and themes in provider awareness and their perceptions of anemia among patients with IBD from the focus groups were distributed to anemia care pathway committee members for review before the first meeting. Described practice patterns and perceptions of anemia by providers were used to create a learning hierarchy of skills required to recognize, manage, and treat patients with IBD and iron deficiency. The learning hierarchy of skills was contextualized by the subject experts on the committee to develop flow charts of clinical approaches to patients with IBD and anemia.
Elicitation of Focused Knowledge of Anemia Management from Subject Experts
Case-based scenarios using flow charts of clinical approaches of anemia care were discussed with the subject experts and modified in an iterative fashion based on how clinical decisions should be made at each step of care, specifically incorporation of available information, acquisition of additional clinical information, or referral to other clinical providers. Cases with varying degrees of anemia, iron parameters, and clinical presentations were presented to the subject experts to elicit management decisions, including laboratory cutoff values, identification of patients for interventions including iron therapy, route of administration of iron therapy, means of follow-up, and management of refractory anemia.
Analysis of Data
Preliminary flow charts and concept mapping were reviewed in an iterative fashion with the committee to ensure accurate representations. In cases of disagreement regarding cutoff values or decision branch-points, further literature review was performed and presented to the committee until consensus was obtained. A literature review of current guidelines for anemia care in the general population and in IBD care specifically was performed to identify standard cutoff values and management recommendations for the development of the care pathway.
Formatting of Results for Anemia Care Pathway Implementation
Case-based discussion regarding implementation of the care pathway was examined as a committee. Potential barriers to the clinical use of the care pathway were considered based on results of the provider focus groups. Implementation of the care pathway was reviewed by committee members to determine how laboratory and clinical data required for decision making will be collected and incorporated into the care pathway, including the integration of laboratory and patient-reported data. Variations in practice patterns were also considered in barriers to implementation.
A total of 23 health care providers participated in the focus groups (12 men and 11 women), including 16 gastroenterologists, 1 colorectal surgeon, and 6 mid-level providers. Reponses from the participants were categorized into 3 domains: (1) recognition of anemia, (2) treatment of anemia, and (3) follow-up of anemia (Table 1).
Recognition of Anemia
Four themes were observed in the recognition of anemia: (1) lack of standardized screening for anemia, (2) uncertainty in defining iron deficiency among patients with IBD, (3) lack of awareness of non-anemic iron deficiency, and (4) perception of anemia management as being secondarily important to IBD disease activity management.
Participants provided a wide range of estimated prevalence of anemia among their patients with IBD, ranging from 15% to 70%. All participants acknowledged the negative impact of anemia on patient's quality of life. The participants depended heavily on laboratory tests for the diagnosis of anemia in patients with IBD; however, no standard practice was described as to when or how frequently screening should be performed or how to assess contributing factors to anemia.
The participants provided varying ranges of what lower threshold of hemoglobin should trigger an intervention, and none cited the World Health Organization (WHO) guidelines on the interpretation of hemoglobin to diagnose anemia. Many participants depended on abnormal laboratory notifications to identify out-of-range thresholds of hemoglobin. Only one provider specifically mentioned the role of history taking in making a diagnosis of anemia and none described screening tools for symptoms of anemia, such as fatigue. Furthermore, participants gave varying responses to the definition of iron deficiency among patients with IBD (Table 2). Further evaluation for causes of anemia in a given patient was described by participants only on a case-by-case basis primarily through evaluations of inflammation (fecal calprotectin, colonoscopy, capsule endoscopy, or enterography). There was disagreement on the reliability of ferritin to diagnose iron deficiency in patients with active IBD, with several participants commenting on ferritin as an acute phase reactant and therefore not a reliable marker among patients with IBD to diagnose iron deficiency as the etiology for anemia. Evaluation for causes of anemia other than iron deficiency was reported primarily among patients with CD (for B12 deficiency) or those on thiopurine therapy potentially experiencing myelosuppression. Iron, vitamin B12, and folate were not routinely monitored in the absence of anemia.
There were varying responses to what participants felt was the prevalence of iron deficiency in the absence of anemia, ranging from 10% to 40%, although some participants stated they do not evaluate for iron deficiency in the absence of anemia.
Participants expressed concerns that anemia was perceived both by participants and by patients as a secondary problem to IBD activity. All participants perceived IBD activity as being directly related to anemia in the patients' examples provided, as stated by one participant, “Therefore treating and controlling IBD plays a significant, if not the most important, role in the treatment of anemia long-term.” Many participants suggested that anemia is not the primary concern for their patients with IBD who first worry about their active IBD symptoms and management, although no provider specifically attributed symptoms of fatigue to anemia.
Treatment of Anemia
Three themes were identified from within the domain of treatment of anemia: (1) variations in hemoglobin thresholds for treatment for anemia, (2) variations in selecting patients for oral or IV iron, and (3) lack of comfort and familiarity with prescribing IV iron.
Participants provided varying hemoglobin thresholds for when to intervene for anemia, with some participants recommending intervention below 11.5 g/dL with or without symptoms, and others waiting for hemoglobin levels below 10 g/dL with symptoms. When recommending treatment, the majority of participants recommended oral iron repletion unless patients have active IBD due to concerns of exacerbation of gastrointestinal symptoms associated with oral iron. Participants instead would wait until IBD symptoms improved before initiating oral iron. Participants also described general cutoff thresholds for route of iron administration based on hemoglobin level, with greater than 10 g/dL defined as “mild” anemia with recommendation of oral iron, 8 to 10 g/dL as moderate anemia with recommendation of IV iron, and “severe anemia” at less than 8 g/dL with a recommendation for blood transfusions. Some participants stated that they would not specifically recommend therapy with low hemoglobin in the absence of symptoms, particularly if the anemia was chronic.
Participants described several barriers to treating iron deficiency anemia, including access and safety (Table 3). Most participants agreed that adherence to oral iron is a major problem in successfully treating their patients with IBD and anemia due to gastrointestinal side effects of oral iron therapy. Some participants expressed concern regarding infusion reactions and anaphylaxis associated with parenteral iron and therefore lacked comfort in prescribing parenteral iron. Several participants noted the cost of parenteral iron treatment can be prohibitive to some patients with concerns regarding insurance coverage of specific parenteral iron formulations. Participants also noted patients may have fear of needles or infusions and decline parenteral iron therapy. Although most of the barriers described were regarding parenteral iron, several participants reported a strong preference for parenteral iron because of fewer gastrointestinal side effects.
Follow-up of Anemia
Participants reported a wide range of follow-up intervals and stated that decisions were made on a case-by-case basis, ranging from every few weeks to every few months. All participants stated the goal of treatment was correction of the hemoglobin and/or ferritin levels. Most participants believed that iron repletion therapy is only necessary for short-term treatment and most patients can stop iron supplementation once iron stores were replete. Participants did not describe using patient-reported symptoms to assess resolution of anemia. In patients with anemia who did not improve or could not tolerate oral iron therapy, either parenteral iron or referral to a hematologist was recommended.
Development of the Anemia Care Pathway
Based on findings from the focus groups and from interviews with the subject content experts, a learning hierarchy of skills required to recognize, manage, and treat patients with IBD and iron deficiency or anemia was developed (Table 4).
Given the variations in definitions of both anemia and iron deficiency, the anemia care pathway committee recommended screening for anemia using the WHO definitions of anemia based on gender (Hb <12 g/dL in women, Hb <13 g/dL in men)3 (Fig. 1). Fatigue and clinical bleeding were also recognized as patient-reported symptoms related to anemia, and therefore, screening for fatigue and GI bleeding symptoms are recommended. To screen for fatigue, validated patient-reported outcome scales were considered, such as the PROMIS Fatigue scales.26 The committee also recommended screening for non-anemic iron deficiency using universal ferritin screening, given the association between iron deficiency and fatigue in non-IBD populations, although the committee recognized the paucity of data regarding the clinical impact of non-anemic iron deficiency specifically among patients with IBD.27,28
The focus group findings revealed wide variations in provider definitions of iron deficiency using noninvasive assessments. The committee recommended classifying patients by likelihood of response to iron therapy as follows: (1) inadequate iron stores: ferritin <100 ng/mL or transferrin saturation <20%, (2) iron overload: ferritin >800 ng/mL, or (3) adequate iron stores (ferritin ≥100 ng/mL and transferrin saturation ≥20%).13,19,20
Both the literature review and recommendations from the subject experts were consistent that parenteral iron should be recommended in patients with active IBD with inadequate iron stores due to concerns regarding oral iron absorption (CD) and tolerance (UC and CD) in the setting of active inflammation, and potential exacerbation of gastrointestinal symptoms with oral iron. Among patients with inadequate iron stores, evaluation of IBD activity should therefore be assessed. The committee recommended that patients with endoscopic, radiographic, or noninvasive (erythrocyte sedimentation rate, C- reactive protein, calprotectin) evidence of inflammation should be classified as having active IBD and therefore be considered for parenteral iron over oral iron therapy.
In patients with inadequate iron stores, iron therapy is recommended. In patients with inactive IBD, oral iron therapy is recommended, with 30 to 100 mg/d of elemental iron. In patients with active IBD, parenteral iron is recommended (Table 5). Patient scenarios of both CD and UC were discussed, with concerns regarding absorption of iron as a concern, primarily in CD, and tolerance of oral iron for both CD and UC in the setting of active IBD. Treatment of anemia should not be delayed for treatment of active IBD symptoms and can be provided concurrently with IBD therapy. Referral to a hematologist may be considered if the provider lacks familiarity with parenteral iron administration or access to parenteral iron formulations. For patients with iron overload, defined as ferritin >800 ng/mL, referral to a hematologist is recommended. For patients with adequate iron stores, assessment for other causes of anemia is recommended, including medications (thiopurines, sulfasalazine, methotrexate, tumor necrosis factor antagonists) and vitamin B12 and folate deficiency. If the etiology of anemia is not identified, referral to a hematologist should be considered.
Assessment to response to iron therapy should be performed 4 weeks after iron therapy has been initiated. An increase of hemoglobin by at least 2 g/dL from baseline should be achieved by 4 weeks. If improvement has not been achieved, consider either change from oral to parenteral iron therapy or consider referral to a hematologist. If hemoglobin has responded to therapy at 4 weeks, then hemoglobin should be reassessed every 4 weeks until anemia has resolved (Hb ≥12 g/dL in women, Hb ≥13 g/dL in men). At each clinical assessment, the patient should also be reassessed for symptoms of fatigue. If fatigue persists, consider evaluation of non-anemic causes of fatigue. If fatigue has resolved, then the clinician should continue active screening for anemia with hemoglobin, ferritin, and symptoms of fatigue at routine clinical appointments.
Significant variations occur in provider perceptions of anemia among patients with IBD. Despite guidelines for anemia, provider perceptions and approaches to anemia vary greatly. This study identified significant variations in the perception and practices in anemia care among gastroenterologists and other providers who manage patients with IBD, including wide variations in defining anemia, selection of when and how to treat anemia, and appropriate means of follow-up for anemia.
Clinical care pathways are evidence-based health care tools to guide and standardize care. There are numerous definitions of clinical care pathways, which can generally be characterized by 5 criteria: (1) multidisciplinary development, (2) use of guidelines or evidence to translate care into local processes; (3) detailing the steps in a course of treatment or care, (4) use of timeframes or criteria-based progression, and (5) aim of standardizing care for a specific clinical problem of health care in a specific population.29 There is a paucity of data regarding processes of clinical care pathway development as well. For this study, we used an informal cognitive task analysis using interview and observation techniques to understand the knowledge necessary and decision processes used by providers and subject matter experts in the care of patients with IBD and anemia.25
Specifically regarding anemia in IBD, guidelines have reviewed the literature and provided recommendations, upon which this current clinical pathway is based.19,20 Clinical practice guidelines have existed for many years, yet their recommendations, in many instances, have not been translated into clinical practice. Failure of published guidelines to change clinical practice has been demonstrated across medical specialties, including diabetes, congestive heart failure, cirrhosis, and IBD.21–24,30 Therefore, the use of clinical care pathways that incorporate guideline recommendations and clinical context (and barriers) may facilitate integration into clinical practice. Care pathways have been used in hospital and postoperative settings, showing improvements in discharge outcomes and reductions in cost.31–33
Providers perceived that anemia is directly related to IBD activity, and therefore prioritized IBD disease management over anemia treatment. Providers reported that they expected anemia to resolve once IBD was adequately treated, a perception which may unnecessarily delay treatment of anemia and negatively impact patient's quality of life. Providers also described reluctance to use oral iron therapy in patients with active IBD due to the concern of exacerbating gastrointestinal symptoms related to oral iron side effects. Some providers also seem to have a reluctance to use parenteral iron due to safety concerns. Consistent with current anemia guidelines for patients with IBD, the clinical care pathway recommends the screening and treatment for anemia in patients with IBD regardless of disease activity but recommends the use of parenteral iron over oral iron among patients with evidence of active IBD.
One key step in the CCFA anemia care pathway is the recognition of anemia, particularly among patients who would benefit from iron therapy. We observed wide variations from providers in the definition of anemia and the definition of iron deficiency. Patients with active IBD may have elevations in ferritin as an acute phase reactant and providers lacked familiarity with how to use ferritin to define iron deficiency. Therefore, to simplify the identification of patients whose anemia may respond to iron therapy, we chose to use the terminology of “adequate” or “inadequate” iron stores rather than iron deficiency, based on cutoff levels from previously published guidelines (guideline refs).
This study has specific limitations. Focus group participants were recruited by local CCFA chapters and therefore may be biased by CCFA professional members with increased awareness of IBD-specific issues regarding anemia. However, despite this potential bias, we identified several barriers and gaps in anemia care. Care pathways will require local implementation and validation across various practice settings. However, the process of clinical care pathway development was specifically designed to anticipate barriers based on focus groups and descriptions from the gastroenterologists and anemia context experts included in the committee.
In conclusion, we identified domains of how providers perceive and manage patients with IBD and anemia, and developed a care pathway to align clinical practices with guideline recommendations. Further implementation testing and validation of the care pathway will be required.
J. K. Hou has received research funding from Redhill Biosciences, Coronado Biosciences, Celgene, Pfizer Inc. J. K. Hou serves on the speaker bureau for Abbvie and UCB pharmaceuticals. C. Gasche: Advisory Board/Consultant/Speaker's Bureau: AstraZeneca Austria, Ferring Int., Falk Pharma, Fresenius Medical Care, Insightra Inc., Pharmacosmos A/S, Renapharma Sweden, Shire Inc., Vifor Int. Grant/Research Support: AESKA Austria, AOP Orphan Pharmaceuticals, Biogena Naturstoffe GmbH, Byk Österreich Pharma, DNAX Research Institute, Falk Foundation, Ferring Int., Giuliani Pharma, Janssen & Cilag Austria, Pentax, Schering-Plough Inc., Shire Inc., Vifor International. C. A. Siegel: consultant for Abbvie, Amgen, Lilly, Janssen, Sandoz, Pfizer, Prometheus, Takeda, and UCB; speaker for CME activities for American Regent, Abbvie, Janssen, Pfizer, Takeda; grant support from Abbvie, Janssen, Pfizer, and Takeda. G. Y. Melmed: consultant for Abbvie, Celgene, Covance, Genentech, Janssen, Luitpold, Takeda, Pfizer, Samsung Bioepis, and UCB, and has received research funding from Pfizer, Prometheus Labs, and Shire Pharmaceuticals. The remaining authors have no conflict of interest to disclose.
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