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## Complete Summary

#### GUIDELINE TITLE

Identification, diagnosis, and management of anemia in adult ambulatory
patients treated by primary care physicians: evidence-based and
consensus recommendations.

#### BIBLIOGRAPHIC SOURCE(S)

Dubois RW, Goodnough LT, Ershler WB, Van Winkle L, Nissenson AR.
Identification, diagnosis, and management of anemia in adult ambulatory
patients treated by primary care physicians: evidence-based and
consensus recommendations. Curr Med Res Opin 2006 Feb;22(2):385-95. \[56
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16466611)

#### GUIDELINE STATUS

This is the current release of the guideline.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [July 31, 2008, Erythropoiesis Stimulating Agents
    (ESAs)](http://www.fda.gov/medwatch/safety/2008/safety08.htm#ESA2):
    Amgen and the U.S. Food and Drug Administration (FDA) informed
    healthcare professionals of modifications to certain sections of the
    Boxed Warnings, Indications and Usage, and Dosage and Administration
    sections of prescribing information for Erythropoiesis Stimulating
    Agents (ESAs). The changes clarify the FDA-approved conditions for
    use of ESAs in patients with cancer and revise directions for dosing
    to state the hemoglobin level at which treatment with an ESA should
    be initiated.

-   [November 8, 2007 and January 3, 2008 Update, Erythropoiesis
    Stimulating Agents
    (ESAs)](http://www.fda.gov/medwatch/safety/2007/safety07.htm#ESA2):
    The U.S. Food and Drug Administration (FDA) notified healthcare
    professionals of revised boxed warnings and other safety-related
    product labeling changes for erythropoiesis-stimulating agents
    (ESAs) stating serious adverse events, such as tumor growth and
    shortened survival in patients with advanced cancer and chronic
    kidney failure.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Anemia (excluding anemia related to nutritional deficiencies,
cancer/chemotherapy, or chronic renal failure)

#### GUIDELINE CATEGORY

Diagnosis\
Management\
Risk Assessment\
Screening

#### CLINICAL SPECIALTY

Family Practice\
Geriatrics\
Internal Medicine\
Obstetrics and Gynecology\
Preventive Medicine\
Rheumatology

#### INTENDED USERS

Advanced Practice Nurses\
Health Care Providers\
Physician Assistants\
Physicians

#### GUIDELINE OBJECTIVE(S)

Provide evidence based and consensus recommendations for the
identification, diagnosis, and management of ambulatory patients with
anemia not related to nutritional deficiencies, cancer/chemotherapy, or
chronic renal failure

#### TARGET POPULATION

Adult ambulatory patients treated by primary care physicians who have or
may have anemia not related to nutritional deficiencies,
cancer/chemotherapy, or chronic renal failure

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Screening/Risk Assessment**

1.  Routine complete blood count at time of office visit in select
    populations

2.  Assessment of risk based on age, presence or absence of
    cardiovascular disease or symptoms, presence or absence of anemia
    symptoms, and hemoglobin levels

**Diagnosis**

1.  Stool for occult blood

2.  Additional optional tests, such as reticulocyte count, iron, total
    iron binding capacity, folate, B12, ferritin, creatinine, or chest
    x-ray

**Note**: Guideline developers considered but recommended against
referral to a gastroenterologist or hematologist for initial diagnostic
work-up

**Management**

1.  No intervention (observation only)

2.  Referral

3.  Trial of empiric iron therapy

4.  Transfusion

5.  Erythropoietic growth factors (epoetin alfa, epoetin beta, or
    darbepoetin)

#### MAJOR OUTCOMES CONSIDERED

Among patients with anemia, what impact does treatment have on:

-   Mortality

-   Morbidity

-   Quality of life and functioning

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Guideline developers conducted a search of the literature using the
PubMed database, from 1990 through 2003. The search terms and strategies
were developed in conjunction with clinical experts in anemia and
included, but were not limited to, \'anemia\', \'therapy\', \'quality of
life\', \'mortality\', \'survival\', \'prevalence\', \'disease
progression\',\' outcome assessment\', \'treatment outcome\',
\'referral\', \'consultation\', \'diagnostic tests\', \'etiology\',
epidemiology\', and \'mass screening\'. Additional articles were
identified from among the reference lists of papers selected for review.
Panelists reviewed the reference lists and recommended additional
relevant references.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Expert Consensus

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not applicable

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Clinicians or epidemiologists trained in health services research
extracted all the data from the studies to create evidence tables. These
tables underwent subsequent review by two physicians with training in
health services research. The nine-member expert panel also reviewed the
evidence synthesis for completeness and accuracy.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

Guideline developers used a validated evidence-based but not
evidence-constrained consensus process (the RAND/UCLA Appropriateness
Method) to develop recommendations for the identification, diagnosis,
and management of patients with anemia in an ambulatory environment.

The panelists received the literature review and an initial set of
scenarios by mail. They were requested to carefully study the synthesis
of the literature and to rate each scenario using a scale of 1 to 9 (1 =
extremely inappropriate, 5 = uncertain, 9 = extremely appropriate).
\'Appropriateness\' was defined as the expected health benefits of the
therapy exceeding its expected negative health consequences by a
sufficiently wide margin to justify prescribing the therapy.

After having accomplished this task independently, the results of the
initial rating were compiled. Finally, the group was convened for a
2-day meeting. During the meeting, the panelists reviewed the summarized
first-round ratings, revised the structure of the clinical scenarios,
ensured that all panelists were working from the same definition of key
terms, and discussed reasons for the degree of agreement or disagreement
in the ratings from the first round. Panelists then independently and
confidentially re-rated all indications.

The final rating was the median score of the nine panelists. Guideline
developers considered that indications were \'appropriate\' for median
ratings between 7 and 9 (without disagreement), \'inappropriate\' for
median ratings between 1 and 3 (without disagreement), and \'uncertain\'
for median ratings between 4 and 6 or if panelists disagreed. The
consensus method did not force agreement. Guideline developers defined
disagreement as occurring when at least two panelists rated the
indication \'appropriate\' and at least two rated the indication
\'inappropriate\', regardless of the median rating.

*Clinical Scenarios*

Guideline developers attempted to create a comprehensive list of all
possible clinical scenarios for the identification, diagnosis, and
management of anemic patients in an ambulatory setting. Preliminary
scenarios were constructed by the authors, and subsequently underwent a
two-round review process by the expert panel. Patients with cancer- or
chemotherapy-related anemia, or chronic kidney disease related anemia,
were excluded from consideration. Scenarios pertained to three clinical
situations described in the original guideline document.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**The RAND/UCLA Appropriateness Method**

**Appropriate**: Median ratings between 7 and 9 (without disagreement)

**Uncertain**: Median ratings between 4 and 6 or if panelists disagreed
(when two panelists rated the indication \"appropriate\" and at least
two rates the indication as \"inappropriate)

**Inappropriate**: Median ratings between 1 and 3 (without disagreement)

Rating Scale of Appropriateness\* (1 to 9)

1 = extremely inappropriate

5 = uncertain

9 = extremely appropriate

\*\'Appropriateness\' was defined as the expected health benefits of the
therapy exceeding its expected negative health consequences by a
sufficiently wide margin to justify prescribing the therapy.

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not stated

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

The levels of recommendation (Appropriate, Uncertain, Inappropriate) are
defined at the end of the \"Major Recommendations\" field.

***Identification***

The panel rated it \'appropriate\' to perform a routine complete blood
count (CBC) at the time of an office visit in patients with an
underlying chronic condition (e.g., rheumatoid arthritis, congestive
heart failure) who had not received a CBC in the past year. In patients
without an underlying chronic condition, it was rated \'appropriate\' to
perform a CBC if a CBC had not been done in the past 5 years for all
women, men aged 50 and older, or those with anemia symptoms (Table 1).

***Table 1**. Appropriateness of a Routine Complete Blood Count at the
Time of an Office Visit*

  ---------------------------------------------------------------------------------
  **Comorbidity**   **Interval**   **Population**                   **Consensus**
  ----------------- -------------- -------------------------------- ---------------
  No chronic        Every 5 years  Men aged 18 to 49 without anemia Uncertain
  comorbidity                      symptoms                         

                                   All women                        

                                   Men aged 50 and older            Appropriate

                                   Men with anemia symptoms         

  Chronic           Yearly         All                              Appropriate
  comorbidity                                                       
  ---------------------------------------------------------------------------------

***Diagnosis***

In women aged 18 to 49 with a hemoglobin (Hb) \> 12 g/dL, the panel
rated it \'inappropriate\' to perform any diagnosis and \'appropriate\'
to just observe. The corresponding threshold for men or women aged 50
and older was a hemoglobin of \> 13 g/dL (Table 2).

***Table 2**. Appropriateness of a Diagnosis Given Patient
Characteristics*

  -------------------------------------------------------------------------------------------------------------------------
  **Population**       **Hb level (g/dL)**  **No intervention **Perform basic **Empiric       **Refer for GI  **Refer for
                                            (just observe)**  diagnosis**     iron**          diagnosis**     Hematologic
                                                                                                              work-up**
  -------------------- -------------------- ----------------- --------------- --------------- --------------- -------------
  Women 18 to 39 years [\<]{.underline}12   Inappropriate\*   Appropriate     Uncertain       Inappropriate   
  old                                                                                                         

                       \>12                 Appropriate       Inappropriate                                   

  Women aged 40 to 49  [\<]{.underline}12   Inappropriate\*   Appropriate     Inappropriate                   
  years old                                                                                                   

                       \>12                 Appropriate       Inappropriate                                   

  Women aged           [\<]{.underline}13   Inappropriate     Appropriate                                     
  [\>]{.underline}50                                                                                          
  (or post-menopausal                                                                                         
  and 18 to 49) years                                                                                         
  old or any man                                                                                              

                       \>13                 Appropriate       Inappropriate                                   
  -------------------------------------------------------------------------------------------------------------------------

\*Uncertain is Hb 11-12 g/dL and no comorbid chronic disease

GI= gastrointestinal

A diagnosis was rated \'appropriate\' in women aged 18 to 50 with
hemoglobin [\<]{.underline}12 g/dL (or [\<]{.underline}13 g/dL in men or
post-menopausal women). When an evaluation was indicated, the panel
rated the performance of a basic evaluation \'appropriate\' (e.g., test
stool for occult blood and obtain routine labs or chest x-ray). However,
referral to a gastroenterologist or hematologist for a work-up was rated
\'inappropriate\' (Table 2). The use of an empiric trial of iron therapy
in the absence of a diagnostic workup was rated \'inappropriate\' in all
situations except for women aged 18 to 39.

***Management***

With respect to management, the panel rated it \'appropriate\' to just
observe and \'inappropriate\' to transfuse or give erythropoietic growth
factors in patients with a hemoglobin of [\>]{.underline}11 g/dL and no
anemia symptoms or underlying cardiovascular disease (Table 3).

***Table 3**. Appropriateness of anemia management options given patient
characteristics (non-nutritional anemia)*

  ------------------------------------------------------------------------------------------------------
  **Hb       **Cardiovascular   **Anemia     **Age**   **Management                      
  (g/dL)**   disease**          symptoms**             options**                         
  ---------- ------------------ ------------ --------- --------------- ----------------- ---------------
                                                       **Observe**     **Transfuse**     **Epo/darbo**

  \<8.0                                                Inappropriate   Appropriate\*     Appropriate

  8 to 9.4   --                 --           18 to 69  Uncertain       Uncertain         Appropriate+

             --                 --           70 or     Inappropriate   Appropriate       
                                             older                                       

             Either CVD or                                             Appropriate++     Appropriate
             symptoms                                                                    

  9.5 to     --                 --                     Uncertain       Inappropriate     Uncertain
  10.9                                                                                   

             --                 \+                     Inappropriate   Uncertain         Appropriate

             \+                 --           18 to 49                  Inappropriate     Uncertain

             \+                 \+                                     Appropriate       

             --                 --                     Uncertain       Inappropriate\$   Uncertain

             --                 \+                     Inappropriate   Uncertain         Appropriate

             \+                 --           50 or                                       
                                             older                                       

             \+                 \+                                     Appropriate       

  11 to      --                 --                     Appropriate     Inappropriate     Inappropriate
  11.9\*\*                                                                               

             --                 \+                     Uncertain                         Uncertain

             \+                 --                     Appropriate                       Inappropriate

             \+                 \+                     Uncertain                         Uncertain

  12 or                                                Appropriate     Inappropriate     
  greater                                                                                
  +++                                                                                    
  ------------------------------------------------------------------------------------------------------

\*Uncertain if age 18 to 49, no CVD, and no anemia symptoms

+Uncertain if age 18 to 49

++Uncertain if no anemia symptoms

\$Uncertain if age [\>]{.underline}70 years

\*\*11 to 12.9 if age [\>]{.underline}70 years

+++ [\>]{.underline}13 if age [\>]{.underline}70 years

CVD = cardiovascular disease; epo = epoetin; darbo = darbepoetin

For patients with hemoglobin of 9.5 to 10.9 g/dL, it was rated
\'inappropriate\' to just observe the patient if the patient had anemia
symptoms or cardiovascular disease. If the patient had anemia symptoms,
the use of erythropoietic growth factors was rated \'appropriate\' (or
\'uncertain\' if no anemia symptoms were present). The use of blood
transfusion was rated \'inappropriate\' if the patient had no anemia
symptoms, \'uncertain\' in the presence of just anemia symptoms, and
\'appropriate\' if the patient had anemia symptoms and underlying
cardiovascular disease.

In patients with hemoglobin \< 9.5 g/dL, it was rated \'inappropriate\'
to just observe (unless the patient had no symptoms, no cardiovascular
disease, and was younger than age 70 in which case it was rated
\'uncertain\'). The use of an erythropoietic growth factor was rated
\'appropriate\'. Transfusion was considered appropriate in patients aged
70 and older and in those presenting with either anemia symptoms or
underlying cardiovascular disease.

In patients with hemoglobin \< 8 g/dL, the use of either transfusion or
erythropoietic growth factor was rated \'appropriate\' and observation
was rated \'inappropriate\'.

**[Definitions]{.underline}**:

**Rating Scheme for Strength of Recommendations**

**Appropriate**: Median ratings between 7 and 9 (without disagreement)

**Uncertain**: Median ratings between 4 and 6 or if panelists disagreed
(when two panelists rated the indication \'appropriate\' and at least
two rates the indication as \'inappropriate\')

**Inappropriate**: Median ratings between 1 and 3 (without disagreement)

Rating Scale of Appropriateness\* (1 to 9)

1 = extremely inappropriate

5 = uncertain

9 = extremely appropriate

\*\'Appropriateness\' was defined as the expected health benefits of the
therapy exceeding its expected negative health consequences by a
sufficiently wide margin to justify prescribing the therapy.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of evidence supporting the recommendations is not specifically
stated.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Appropriate identification, diagnosis, and management of anemia to
improve outcomes in ambulatory patients with anemia (specifically,
anemia not related to nutritional deficiencies, cancer/chemotherapy, or
chronic renal failure)

#### POTENTIAL HARMS

Risks associated with diagnostic tests including venipuncture and
colonoscopy

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

This recommendation does not address the issue of population
identification or when patients should visit a physician to have an
anemia assessment performed. Rather, this recommendation addresses the
somewhat narrower issue of whether to obtain a routine complete blood
count (CBC) when the patient had already sought medical care.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better\
Living with Illness\
Staying Healthy

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Dubois RW, Goodnough LT, Ershler WB, Van Winkle L, Nissenson AR.
Identification, diagnosis, and management of anemia in adult ambulatory
patients treated by primary care physicians: evidence-based and
consensus recommendations. Curr Med Res Opin 2006 Feb;22(2):385-95. \[56
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16466611)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2006 Feb

#### GUIDELINE DEVELOPER(S)

National Anemia Action Council - Private Nonprofit Research Organization

#### SOURCE(S) OF FUNDING

National Anemia Action Council

#### GUIDELINE COMMITTEE

Panel of Experts

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Authors*: Robert W. Dubois, Cerner Health Insights, Beverly Hills, CA,
USA; L. Tim Goodnough, Stanford University, Dept. of Pathology and
Medicine, Stanford, CA, USA; William B. Ershler, Institute for Advanced
Studies in Aging and Geriatric Medicine, Washington, DC, USA; Lloyd Van
Winkle, Medina Valley Family Practice, Castroville, TX, USA; Allen R.
Nissenson, David Geffen School of Medicine at UCLA, Division of
Nephrology, Los Angeles, CA, USA

*Panel Members*: Kirkwood Adams, Jr., MD, Associate Professor of
Medicine and Radiology, Director, Heart Failure Program, University of
North Carolina, Chapel Hill, NC; Alan M. Adelman, MD, MS, Professor and
Vice Chair for Academic Affairs and Research, Department of Family and
Community Medicine, Pennsylvania State University College of Medicine,
Hershey, PA; Steven Deutsch, MD, Medical Director, Cedars-Sinai Medical
Care Foundation, Beverly Hills, CA; William B. Ershler, MD, Director,
Institute for Advanced Studies in Aging and Geriatric Medicine, Clinical
Professor of Medicine, The George Washington University College of
Medicine, Washington, DC; L. Tim Goodnough, MD, Professor of Medicine
and Pathology, Washington University Medical Center, Division of
Laboratory Medicine, St. Louis, MO; Michael Hattwick, MD, Medical
Director, Northern Virginia Healthcare, Annandale, VA; John Ingard, MD,
Chief of Internal Medicine, Harvard Vanguard Medical Associates, Natick,
MA; Allen R. Nissenson, MD, Professor of Medicine, University of
California at Los Angeles School of Medicine, Division of Nephrology;
Lloyd Van Winkle, MD, Clinical Associate Professor of Medicine,
Department of Family Practice, University of Texas Health Science
Center, San Antonio, TX

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

National Anemia Action Council (NAAC) has received unrestricted
educational grants from Amgen, Inc.

Robert W. Dubois is Senior Vice President of Cerner Health Insights,
which provided consulting services to Amgen, Inc. Kirkwood F. Adams is a
member of NAAC and has received grants and research support from Amgen
Inc. William Ershler is a member of NAAC. Allen Nissenson is President
of NAAC. L. Tim Goodnough was Vice President of NAAC at the time the
guidelines were developed, and has received honoraria for teaching and
speaking from the following companies: Amgen, Watson, and American
Regent.

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available to subscribers in Portable Document Format
(PDF) from the [Current Medical Research and Opinion Web
site](http://libra.publisher.ingentaconnect.com/content/libra/cmro/2006/00000022/00000002/art00017).

Print copies: Available from Robert W. Dubois, MD, PhD, Senior Vice
President, Cerner Health Insights, 9100 Wilshire Blvd, Suite 655 East
Tower, Beverly Hills, CA 90212; Phone: +1-310-598-4563; Fax:
+1-816-936-1963; Email: <rdubois@cerner.com>

#### AVAILABILITY OF COMPANION DOCUMENTS

None available

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on January 15, 2007. The
information was verified by the guideline developer on February 5, 2007.
This summary was updated by ECRI Institute on July 9, 2007, following
the FDA advisory on erythropoiesis stimulating agents. This summary was
updated by ECRI Institute on March 21, 2008 following the FDA advisory
on Erythropoiesis Stimulating Agents. This summary was updated by ECRI
Institute on August 15, 2008 following the U.S. Food and Drug
Administration advisory on Erythropoiesis Stimulating Agents (ESAs).

#### COPYRIGHT STATEMENT

This material is for personal use only and any commercial distribution
is strictly prohibited.

### DISCLAIMER

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Date Modified: 11/3/2008