Iron Deficiency Anemia — Bridging the Knowledge and Practice Gap Aryeh Shander, Lawrence T. Goodnough, Mazyar Javidroozi, Michael Auerbach, Jeffrey Carson, William B. Ershler, Mary Ghiglione, John Glaspy, Indu Lew PII: DOI: Reference:
S0887-7963(14)00046-7 doi: 10.1016/j.tmrv.2014.05.001 YTMRV 50400
To appear in:
Transfusion Medicine Reviews
Received date: Revised date: Accepted date:
15 November 2013 24 April 2014 9 May 2014
Please cite this article as: Shander Aryeh, Goodnough Lawrence T., Javidroozi Mazyar, Auerbach Michael, Carson Jeffrey, Ershler William B., Ghiglione Mary, Glaspy John, Lew Indu, Iron Deficiency Anemia — Bridging the Knowledge and Practice Gap, Transfusion Medicine Reviews (2014), doi: 10.1016/j.tmrv.2014.05.001
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Iron Deficiency Anemia — Bridging the Knowledge and Practice Gap
T
Aryeh Shander, MD, FCCM, FCCP;1* Lawrence T. Goodnough, MD;2 Mazyar Javidroozi MD,
RI P
PhD;3 Michael Auerbach, MD;4 Jeffrey Carson, MD;5 William B. Ershler, MD;6 Mary Ghiglione
SC
RN, BSN, MSN, MHA;7 John Glaspy, MD;8 Indu Lew, PharmD9
1) Clinical Professor of Anesthesiology, Medicine and Surgery, Mount Sinai School of Medicine, New York, NY and Chief, Department of Anesthesiology, Critical Care Medicine, Pain Management and
NU
Hyperbaric Medicine, Englewood Hospital and Medical Center, Englewood, NJ; 2) Professor of Pathology and Medicine, Director of Transfusion Service, Stanford University Medical Center, Stanford,
MA
CA; 3) Scientist, Department of Anesthesiology, Critical Care Medicine, and Hyperbaric Medicine, Englewood Hospital and Medical Center, Englewood, NJ; 4) Clinical Professor of Medicine, Division of Hematology and Oncology, Georgetown University School of Medicine, Washington, DC; 5) Professor
ED
of Medicine, Robert Wood Johnson Medical School; Chief, Division of Internal Medicine, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ;
PT
6) Department of Hematology/Oncology, Scientific Director, Institute for Advanced Studies in Aging, Falls Church, VA; 7) National Director of Blood Management, aLab Services, San Diego, CA; 8)
CE
Professor of Medicine, UCLA School of Medicine, Director, JCCC Women’s Cancer Research Program, Los Angeles, CA; 8) Vice President, Corporate Pharmacy, Education and Research, Barnabas Health,
AC
South Plainfield, NJ
* Corresponding Author: Aryeh Shander, MD Department of Anesthesiology, Critical Care and Hyperbaric Medicine, Englewood Hospital and Medical Center, 350 Engle Street, Englewood, NJ 07631, USA Tel: +1-201-894-3238 Fax: +1-201-894-0585 E-mail: [email protected]
1
ACCEPTED MANUSCRIPT ABSTRACT
T
Despite its high prevalence, anemia often does not receive proper clinical attention and its detection,
RI P
evaluation, and management of iron deficiency anemia and iron-restricted erythropoiesis can possibly be an unmet medical need. A multidisciplinary panel of clinicians with expertise in anemia management
SC
convened and reviewed recent published data on prevalence, etiology, and health implications of anemia as well as current therapeutic options and available guidelines on management of anemia across various
NU
patient populations, and made recommendations on the detection, diagnostic approach and management
MA
of anemia. The available evidence confirms that the prevalence of anemia is high across all populations, especially in hospitalized patients. Anemia is associated with worse clinical outcomes including longer length of hospital stay, diminished quality of life and increased risk of morbidity and mortality, and it is a
ED
modifiable risk factor of allogeneic blood transfusion with its own inherent risks. Iron deficiency is
PT
usually present in anemic patients. An algorithm for detection and management of anemia was discussed which incorporated iron study (with primary emphasis on transferrin saturation), serum creatinine and
CE
GFR and vitamin B12 and folic acid measurements. Management strategies included iron therapy (oral or
AC
intravenous), erythropoiesis stimulating agents and referral as needed.
Keywords: Anemia; Anemia, Iron-Deficiency; iron; Blood Transfusion; Hemoglobin.
2
ACCEPTED MANUSCRIPT Introduction Anemia management and its relationship to improved patient outcomes are gaining recognition in
T
the health care community [1,2]. Iron deficiency anemia (IDA) occurs across all populations and is
RI P
associated with diminished quality of life, physical and cognitive performance and unfavorable clinical outcomes [3]. In addition, presence of anemia greatly increases the likelihood of allogeneic blood
SC
transfusions in hospitalized patients, and is associated adverse events and outcomes related to blood transfusions [3]. Hospital-acquired anemia can develop in 3 out of every 4 hospital admissions, and it is
NU
associated with increased resource utilization and mortality [4].
MA
While data (some discussed here) indicate the high prevalence of the condition across many patient populations, the data on how widely and successfully the anemia is managed by the clinicians is succinct, and the available studies are often indicative of limited treatment of anemia [5,6]. This suggests
ED
that the detection, evaluation, and management of iron deficiency anemia and iron-restricted
PT
erythropoiesis (formerly known as functional iron deficiency) is unmet medical needs [7,8]. Practice guidelines for management of anemia is a step toward providing the needed information and closing the
CE
gap between physician knowledge and practice. The Society for Advancement of Blood Management (SABM) and Network for Advancement of Transfusion Alternatives (NATA) have developed guidelines
AC
for detection, evaluation and management of anemia in patients scheduled for elective orthopedic surgery [9,10], but new guidelines for other populations are lacking. Awaiting much needed future works on formulating formal practice guidelines, a multidisciplinary panel of clinicians with expertise in anemia management convened to review the existing evidence on prevalence and significance of anemia across patient populations, discuss clinical strategies for management of anemia and identify areas in need of future research.
Methods The project was planned to feature a narrative overview of the evidence followed by unstructured discussions of an expert panel. For the purpose of the panel discussion and given its widespread 3
ACCEPTED MANUSCRIPT acceptance, the World Health Organization (WHO) definition of anemia (Table 1) [11] was used unless otherwise indicated. The Panel was organized by the Society for the Advancement of Blood Management
T
(SABM; http://www.sabm.org), using a modified RAND Delphi method as previously described [12]. In
RI P
this method, candidates were selected based on their expertise in various aspects of the subject (as indicated by their publication records, academic positions, prior membership in expert/advisory boards,
SC
etc) by SABM leadership and the final eight panelists were determined by their willingness to participate in the study. All the panelists are listed as authors of this manuscript with the exception of the third author
NU
(MJ) who was not a panelist and was primarily responsible for literature search and synthesis. The
MA
meeting took place on May 31st, 2012 in Santa Monica, CA. During the meeting, panelists reviewed and addressed recent published data on prevalence, etiology, and health implications of anemia as well as current therapeutic options and available guidelines on management of anemia across various patient
ED
populations.
PT
Articles indexed in PubMed were searched using the following primary Medical Subject Heading (MeSH) search term: "Anemia, Iron-Deficiency"[Mesh] OR ("Anemia"[Mesh] AND ("Chronic
CE
Disease"[Mesh] OR "Inflammation"[Mesh] OR "Aged"[Mesh] OR "Neoplasms"[Mesh] OR "Kidney Diseases"[Mesh] OR "Heart Diseases"[Mesh] OR "Outpatients"[Mesh] OR "Pregnancy"[Mesh] OR
AC
"Lung Diseases"[Mesh] OR "Cerebrovascular Disorders"[Mesh] OR "Cardiac Surgical Procedures"[Mesh] OR "Organ Transplantation"[Mesh] OR "Critical Illness"[Mesh] OR "Orthopedics"[Mesh])). . Given the narrative nature of the review and available resources, the literature search was not intended to be all-inclusive and focused on the most recent primary research manuscripts as well as review and practice guidelines published from 2010 to 2012. Additional studies and publications were included and reviewed as suggested by the panelists. The panelists made recommendations on the detection, diagnostic approach and management of anemia with emphasis on populations that are deemed at significant risk of anemia and its consequences. A summary of the discussions made by the panelists on significance of anemia and management strategies is provided here.
4
ACCEPTED MANUSCRIPT Results Current Status of Anemia Across Populations
T
Summary of data on prevalence of anemia in various patient populations and the reported
RI P
consequences of anemia is provided in Table 2. This data was reviewed and discussed by the panelists.
SC
Panel Discussions Significance of Anemia
NU
The prevalence of anemia is high across all reviewed populations, especially in hospitalized
MA
patients and emphasized anemia is associated with worse clinical outcomes including longer length of hospital stay, reduced survival, diminished quality of life and increased risk of morbidity and mortality. Anemia is a modifiable risk factor of allogeneic blood transfusion with its own inherent risks. Anemia can
ED
also be a warning sign for underlying serious diseases (e.g. colorectal cancer) [3]. Anemia can be
PT
acquired or exacerbated during hospital stay, and the issue of hospital-acquired/exacerbated anemia is often ignored, under-attended, and underappreciated and can lead to worse outcomes. Lastly, effective
CE
treatment modalities for anemia that can greatly help improve health and clinical outcomes are available.
AC
Common Causes of Anemia
Despite various etiologies, most anemic patients (with the exception of those with hemolytic anemia) usually have some component of iron deficiency which responds to iron administration. In a study of 47 consecutive anemic patients with chronic kidney disease with no other underlying cause for anemia, Gotloib et al detected iron deficiency in 46 patients using bone marrow aspiration, with most responding well to intravenous iron with no need for ESAs [13]. Among the elderly, the etiology is attributed to iron (and folate/B12) deficiency in about one-third and chronic inflammation or renal disease in another one-third. The etiology in the remaining is often indiscernible [14]. Unexplained anemia of the elderly (UAE, which may also be called "anemia of aging") can sometimes be attributed to reduced response to endogenous erythropoietin. Evidence suggests 5
ACCEPTED MANUSCRIPT increased levels of erythropoietin may predict who will go on to develop erythropoietin-resistant anemia later during life [15]. Not surprisingly, these "erythropoietin-resistant" patients are expected to
T
demonstrate limited response to exogenous ESAs which poses additional treatment challenges and may
RI P
result in worse clinical outcomes [16]. This is not necessarily the case for many other elderly patients, in whom blunted erythropoietin levels characterize UAE whereby endogenous erythropoietin levels remain
SC
inappropriately low for the observed mild or moderate anemia. Accordingly, the use of low dose exogenous ESAs has been considered one viable approach to the management of UAE and preliminary
NU
reports have been encouraging [17-21].
MA
Among iatrogenic causes of anemia, drug-related anemia should be underscored with a growing list of commonly used medications being implicated (Table 3) [22]. Data on blood loss due to excessive
ED
diagnostic phlebotomy in hospitalized patients has also been a (preventable) cause of concern [23].
PT
Algorithm for Detection, Evaluation and Management of Anemia A number of practice guidelines for management of anemia are available, namely the guidelines
CE
developed by Pasricha et al [24] in Australia and the revisions of SABM and NATA guidelines from 2005 to 2011 [9,10]. Hb measurement should be included as part of surgical pre-admission testing as early as
AC
30 days prior to admission, using simple and readily available methods (laboratory CBC, bed-side Hemocue® Hb System [AB Leo Diagnostics, Helsingborg, Sweden], or other non-invasive point-of-care methods [Total Hb or SpHb, Masimo, Irvine, CA]). Given their widespread acceptance, the WHO criteria can be used to make the diagnosis of anemia (Table 1) [11]. Once anemia is detected, presence of iron deficiency (absolute or functional) should be assessed. In "traditional" approaches to evaluating anemia, the mean corpuscular volume (MCV) has typically been used as a starting index [25], followed by biochemical analysis. For example, in microcytic anemia, if transferrin saturation is
S0887-7963(14)00046-7 doi: 10.1016/j.tmrv.2014.05.001 YTMRV 50400
To appear in:
Transfusion Medicine Reviews
Received date: Revised date: Accepted date:
15 November 2013 24 April 2014 9 May 2014
Please cite this article as: Shander Aryeh, Goodnough Lawrence T., Javidroozi Mazyar, Auerbach Michael, Carson Jeffrey, Ershler William B., Ghiglione Mary, Glaspy John, Lew Indu, Iron Deficiency Anemia — Bridging the Knowledge and Practice Gap, Transfusion Medicine Reviews (2014), doi: 10.1016/j.tmrv.2014.05.001
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Iron Deficiency Anemia — Bridging the Knowledge and Practice Gap
T
Aryeh Shander, MD, FCCM, FCCP;1* Lawrence T. Goodnough, MD;2 Mazyar Javidroozi MD,
RI P
PhD;3 Michael Auerbach, MD;4 Jeffrey Carson, MD;5 William B. Ershler, MD;6 Mary Ghiglione
SC
RN, BSN, MSN, MHA;7 John Glaspy, MD;8 Indu Lew, PharmD9
1) Clinical Professor of Anesthesiology, Medicine and Surgery, Mount Sinai School of Medicine, New York, NY and Chief, Department of Anesthesiology, Critical Care Medicine, Pain Management and
NU
Hyperbaric Medicine, Englewood Hospital and Medical Center, Englewood, NJ; 2) Professor of Pathology and Medicine, Director of Transfusion Service, Stanford University Medical Center, Stanford,
MA
CA; 3) Scientist, Department of Anesthesiology, Critical Care Medicine, and Hyperbaric Medicine, Englewood Hospital and Medical Center, Englewood, NJ; 4) Clinical Professor of Medicine, Division of Hematology and Oncology, Georgetown University School of Medicine, Washington, DC; 5) Professor
ED
of Medicine, Robert Wood Johnson Medical School; Chief, Division of Internal Medicine, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ;
PT
6) Department of Hematology/Oncology, Scientific Director, Institute for Advanced Studies in Aging, Falls Church, VA; 7) National Director of Blood Management, aLab Services, San Diego, CA; 8)
CE
Professor of Medicine, UCLA School of Medicine, Director, JCCC Women’s Cancer Research Program, Los Angeles, CA; 8) Vice President, Corporate Pharmacy, Education and Research, Barnabas Health,
AC
South Plainfield, NJ
* Corresponding Author: Aryeh Shander, MD Department of Anesthesiology, Critical Care and Hyperbaric Medicine, Englewood Hospital and Medical Center, 350 Engle Street, Englewood, NJ 07631, USA Tel: +1-201-894-3238 Fax: +1-201-894-0585 E-mail: [email protected]
1
ACCEPTED MANUSCRIPT ABSTRACT
T
Despite its high prevalence, anemia often does not receive proper clinical attention and its detection,
RI P
evaluation, and management of iron deficiency anemia and iron-restricted erythropoiesis can possibly be an unmet medical need. A multidisciplinary panel of clinicians with expertise in anemia management
SC
convened and reviewed recent published data on prevalence, etiology, and health implications of anemia as well as current therapeutic options and available guidelines on management of anemia across various
NU
patient populations, and made recommendations on the detection, diagnostic approach and management
MA
of anemia. The available evidence confirms that the prevalence of anemia is high across all populations, especially in hospitalized patients. Anemia is associated with worse clinical outcomes including longer length of hospital stay, diminished quality of life and increased risk of morbidity and mortality, and it is a
ED
modifiable risk factor of allogeneic blood transfusion with its own inherent risks. Iron deficiency is
PT
usually present in anemic patients. An algorithm for detection and management of anemia was discussed which incorporated iron study (with primary emphasis on transferrin saturation), serum creatinine and
CE
GFR and vitamin B12 and folic acid measurements. Management strategies included iron therapy (oral or
AC
intravenous), erythropoiesis stimulating agents and referral as needed.
Keywords: Anemia; Anemia, Iron-Deficiency; iron; Blood Transfusion; Hemoglobin.
2
ACCEPTED MANUSCRIPT Introduction Anemia management and its relationship to improved patient outcomes are gaining recognition in
T
the health care community [1,2]. Iron deficiency anemia (IDA) occurs across all populations and is
RI P
associated with diminished quality of life, physical and cognitive performance and unfavorable clinical outcomes [3]. In addition, presence of anemia greatly increases the likelihood of allogeneic blood
SC
transfusions in hospitalized patients, and is associated adverse events and outcomes related to blood transfusions [3]. Hospital-acquired anemia can develop in 3 out of every 4 hospital admissions, and it is
NU
associated with increased resource utilization and mortality [4].
MA
While data (some discussed here) indicate the high prevalence of the condition across many patient populations, the data on how widely and successfully the anemia is managed by the clinicians is succinct, and the available studies are often indicative of limited treatment of anemia [5,6]. This suggests
ED
that the detection, evaluation, and management of iron deficiency anemia and iron-restricted
PT
erythropoiesis (formerly known as functional iron deficiency) is unmet medical needs [7,8]. Practice guidelines for management of anemia is a step toward providing the needed information and closing the
CE
gap between physician knowledge and practice. The Society for Advancement of Blood Management (SABM) and Network for Advancement of Transfusion Alternatives (NATA) have developed guidelines
AC
for detection, evaluation and management of anemia in patients scheduled for elective orthopedic surgery [9,10], but new guidelines for other populations are lacking. Awaiting much needed future works on formulating formal practice guidelines, a multidisciplinary panel of clinicians with expertise in anemia management convened to review the existing evidence on prevalence and significance of anemia across patient populations, discuss clinical strategies for management of anemia and identify areas in need of future research.
Methods The project was planned to feature a narrative overview of the evidence followed by unstructured discussions of an expert panel. For the purpose of the panel discussion and given its widespread 3
ACCEPTED MANUSCRIPT acceptance, the World Health Organization (WHO) definition of anemia (Table 1) [11] was used unless otherwise indicated. The Panel was organized by the Society for the Advancement of Blood Management
T
(SABM; http://www.sabm.org), using a modified RAND Delphi method as previously described [12]. In
RI P
this method, candidates were selected based on their expertise in various aspects of the subject (as indicated by their publication records, academic positions, prior membership in expert/advisory boards,
SC
etc) by SABM leadership and the final eight panelists were determined by their willingness to participate in the study. All the panelists are listed as authors of this manuscript with the exception of the third author
NU
(MJ) who was not a panelist and was primarily responsible for literature search and synthesis. The
MA
meeting took place on May 31st, 2012 in Santa Monica, CA. During the meeting, panelists reviewed and addressed recent published data on prevalence, etiology, and health implications of anemia as well as current therapeutic options and available guidelines on management of anemia across various patient
ED
populations.
PT
Articles indexed in PubMed were searched using the following primary Medical Subject Heading (MeSH) search term: "Anemia, Iron-Deficiency"[Mesh] OR ("Anemia"[Mesh] AND ("Chronic
CE
Disease"[Mesh] OR "Inflammation"[Mesh] OR "Aged"[Mesh] OR "Neoplasms"[Mesh] OR "Kidney Diseases"[Mesh] OR "Heart Diseases"[Mesh] OR "Outpatients"[Mesh] OR "Pregnancy"[Mesh] OR
AC
"Lung Diseases"[Mesh] OR "Cerebrovascular Disorders"[Mesh] OR "Cardiac Surgical Procedures"[Mesh] OR "Organ Transplantation"[Mesh] OR "Critical Illness"[Mesh] OR "Orthopedics"[Mesh])). . Given the narrative nature of the review and available resources, the literature search was not intended to be all-inclusive and focused on the most recent primary research manuscripts as well as review and practice guidelines published from 2010 to 2012. Additional studies and publications were included and reviewed as suggested by the panelists. The panelists made recommendations on the detection, diagnostic approach and management of anemia with emphasis on populations that are deemed at significant risk of anemia and its consequences. A summary of the discussions made by the panelists on significance of anemia and management strategies is provided here.
4
ACCEPTED MANUSCRIPT Results Current Status of Anemia Across Populations
T
Summary of data on prevalence of anemia in various patient populations and the reported
RI P
consequences of anemia is provided in Table 2. This data was reviewed and discussed by the panelists.
SC
Panel Discussions Significance of Anemia
NU
The prevalence of anemia is high across all reviewed populations, especially in hospitalized
MA
patients and emphasized anemia is associated with worse clinical outcomes including longer length of hospital stay, reduced survival, diminished quality of life and increased risk of morbidity and mortality. Anemia is a modifiable risk factor of allogeneic blood transfusion with its own inherent risks. Anemia can
ED
also be a warning sign for underlying serious diseases (e.g. colorectal cancer) [3]. Anemia can be
PT
acquired or exacerbated during hospital stay, and the issue of hospital-acquired/exacerbated anemia is often ignored, under-attended, and underappreciated and can lead to worse outcomes. Lastly, effective
CE
treatment modalities for anemia that can greatly help improve health and clinical outcomes are available.
AC
Common Causes of Anemia
Despite various etiologies, most anemic patients (with the exception of those with hemolytic anemia) usually have some component of iron deficiency which responds to iron administration. In a study of 47 consecutive anemic patients with chronic kidney disease with no other underlying cause for anemia, Gotloib et al detected iron deficiency in 46 patients using bone marrow aspiration, with most responding well to intravenous iron with no need for ESAs [13]. Among the elderly, the etiology is attributed to iron (and folate/B12) deficiency in about one-third and chronic inflammation or renal disease in another one-third. The etiology in the remaining is often indiscernible [14]. Unexplained anemia of the elderly (UAE, which may also be called "anemia of aging") can sometimes be attributed to reduced response to endogenous erythropoietin. Evidence suggests 5
ACCEPTED MANUSCRIPT increased levels of erythropoietin may predict who will go on to develop erythropoietin-resistant anemia later during life [15]. Not surprisingly, these "erythropoietin-resistant" patients are expected to
T
demonstrate limited response to exogenous ESAs which poses additional treatment challenges and may
RI P
result in worse clinical outcomes [16]. This is not necessarily the case for many other elderly patients, in whom blunted erythropoietin levels characterize UAE whereby endogenous erythropoietin levels remain
SC
inappropriately low for the observed mild or moderate anemia. Accordingly, the use of low dose exogenous ESAs has been considered one viable approach to the management of UAE and preliminary
NU
reports have been encouraging [17-21].
MA
Among iatrogenic causes of anemia, drug-related anemia should be underscored with a growing list of commonly used medications being implicated (Table 3) [22]. Data on blood loss due to excessive
ED
diagnostic phlebotomy in hospitalized patients has also been a (preventable) cause of concern [23].
PT
Algorithm for Detection, Evaluation and Management of Anemia A number of practice guidelines for management of anemia are available, namely the guidelines
CE
developed by Pasricha et al [24] in Australia and the revisions of SABM and NATA guidelines from 2005 to 2011 [9,10]. Hb measurement should be included as part of surgical pre-admission testing as early as
AC
30 days prior to admission, using simple and readily available methods (laboratory CBC, bed-side Hemocue® Hb System [AB Leo Diagnostics, Helsingborg, Sweden], or other non-invasive point-of-care methods [Total Hb or SpHb, Masimo, Irvine, CA]). Given their widespread acceptance, the WHO criteria can be used to make the diagnosis of anemia (Table 1) [11]. Once anemia is detected, presence of iron deficiency (absolute or functional) should be assessed. In "traditional" approaches to evaluating anemia, the mean corpuscular volume (MCV) has typically been used as a starting index [25], followed by biochemical analysis. For example, in microcytic anemia, if transferrin saturation is
