Evidence-based Synthesis Program Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program 

Treatment of Anemia 

in Patients with Heart Disease:

A Systematic Review

Department of Veterans Affairs

Health Services Research & Development Service

October 2011

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) Center

Portland VA Medical Center

Portland, OR

Devan Kansagara, M.D., M.C.R., Director

Investigators:

Principal Investigator: 

Devan Kansagara, M.D., M.C.R.

Co-Investigators: 

Edward Dyer, M.D.

Honora Englander, M.D.

David Kagen, M.D.

Research Associate:

Michele Freeman, M.P.H.
i

Treatment of Anemia in Patients with Heart Disease: 

A Systematic Review Evidence-based Synthesis Program

PREFACE

Health Services Research & Development Service’s (HSR&D’s) Evidence-based Synthesis 

Program (ESP) was established to provide timely and accurate syntheses of targeted healthcare 

topics of particular importance to Veterans Affairs (VA) managers and policymakers, as they 

work to improve the health and healthcare of Veterans. The ESP disseminates these reports 

throughout VA.

HSR&D provides funding for four ESP Centers and each Center has an active VA affiliation. The 

ESP Centers generate evidence syntheses on important clinical practice topics, and these reports 

help:

• develop clinical policies informed by evidence,

• guide the implementation of effective services to improve patient outcomes and to 

support VA clinical practice guidelines and performance measures, and 

• set the direction for future research to address gaps in clinical knowledge.

In 2009, the ESP Coordinating Center was created to expand the capacity of HSR&D Central 

Office and the four ESP sites by developing and maintaining program processes. In addition, 

the Center established a Steering Committee comprised of HSR&D field-based investigators, 

VA Patient Care Services, Office of Quality and Performance, and Veterans Integrated Service 

Networks (VISN) Clinical Management Officers. The Steering Committee provides program 

oversight, guides strategic planning, coordinates dissemination activities, and develops 

collaborations with VA leadership to identify new ESP topics of importance to Veterans and the 

VA healthcare system.

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP 

Coordinating Center Program Manager, at nicole.floyd@va.gov.

Recommended citation: Kansagara D, Dyer EAW, Englander H, Freeman M, Kagen D, 

Treatment of Anemia in Patients with Heart Disease: A Systematic Review. VA-ESP Project #05-

225; 2011.

This report is based on research conducted by the Evidence-based Synthesis Program 

(ESP) Center located at the Portland VA Medical Center, Portland OR funded by the 

Department of Veterans Affairs, Veterans Health Administration, Office of Research 

and Development, Health Services Research and Development. The findings and 

conclusions in this document are those of the author(s) who are responsible for its 

contents; the findings and conclusions do not necessarily represent the views of 

the Department of Veterans Affairs or the United States government. Therefore, no 

statement in this article should be construed as an official position of the Department 

of Veterans Affairs. No investigators have any affiliations or financial involvement (e.g., 

employment, consultancies, honoraria, stock ownership or options, expert testimony, 

grants or patents received or pending, or royalties) that conflict with material presented 

in the report.
ii

Treatment of Anemia in Patients with Heart Disease: 

A Systematic Review Evidence-based Synthesis Program

TABLE OF CONTENTS

EXECUTIVE SUMMARY

Background.................................................................................................................................................... 1

Methods......................................................................................................................................................... 1

Results ........................................................................................................................................................... 1

Discussion/Conclusion .................................................................................................................................. 3

Executive Summary Table............................................................................................................................. 3

INTRODUCTION............................................................................................................................................... 6

METHODS

Topic Development........................................................................................................................................ 7

Search Strategy.............................................................................................................................................. 9

Study Selection.............................................................................................................................................. 9

Data Abstraction .......................................................................................................................................... 10

Study Quality............................................................................................................................................... 10

Rating the Body of Evidence....................................................................................................................... 11

Data Synthesis............................................................................................................................................. 11

Peer Review................................................................................................................................................. 12

RESULTS

Literature Flow ............................................................................................................................................ 13

Key Question #1. In patients with CHF or CHD, what are the health outcome benefits and harms of 

treating anemia with ESAs?.................................................................................................... 14

Key Question #2. In patients with CHF or CHD, what are the health outcome benefits and harms 

of using iron to treat iron deficiency with or without anemia? ............................................... 25

Key Question #3. In patients with CHF or CHD, what are the health outcome benefits and harms 

of treating anemia with red blood cell transfusions? .............................................................. 29

SUMMARY AND DISCUSSION ................................................................................................................ 40

Clinical Applications................................................................................................................................... 43

Limitations................................................................................................................................................... 45

Future Studies.............................................................................................................................................. 45

Conclusions ................................................................................................................................................. 45

REFERENCES ................................................................................................................................................... 49
iii

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

TABLES

Table 1. Characteristics of randomized controlled trials of ESA Therapy in Patients with CHF 

or CHD.................................................................................................................................... 15

Table 2. Characteristics of randomized controlled trials of Iron Therapy in Patients with CHF 

or CHD.................................................................................................................................... 28

Table 3. Randomized controlled trials of red blood cell transfusion for anemia in patients with 

CHD or CHF, stratified by patient setting............................................................................... 34

Table 4. Transfusion Studies................................................................................................................. 35

Table 5. Summary of the Evidence for the Effects of ESAs, Iron, and Blood Transfusions by 

Patient Population and Outcomes........................................................................................... 46

FIGURES

Figure 1. Analytic Framework.................................................................................................................. 8

Figure 2. Literature Flow – Anemia and CHF........................................................................................ 13

Figure 3. Change in NYHA Scores in CHF Patients: Mean Difference Comparing ESA to 

Control Group ......................................................................................................................... 18

Figure 4. Change in NYHA Scores in CHF Patients – Studies with Low Risk of Bias, and 

Excluding Studies with Duplicate Patient Populations: Mean Difference Comparing 

ESA to Control Group............................................................................................................. 19

Figure 5. Change in Six-Minute Walk Distance (Meters) In CHF Patients: Mean Difference 

Comparing ESA to Control Group.......................................................................................... 19

Figure 6. All-Cause Mortality in Patients with CHF or CHD – Studies with Low Risk of Bias: 

ESA vs. Control....................................................................................................................... 21

Figure 7. Risk of One or More Hospitalizations in Patients with CHF or CHD – Studies with 

Low Risk of Bias: ESA vs. Control ....................................................................................... 22

Figure 8. Cardiovascular Events in Patients with CHF or CHD: ESA vs. Control............................... 22

Figure 9. Cerebrovascular Events in Patients with CHF or CHD: ESA vs. Control............................. 23

Figure 10. Hypertension Events in Patients with CHF or CHD: ESA vs. Control.................................. 24

APPENDIX A. Search Strategy................................................................................................................ 56

APPENDIX B. Inclusion/Exclusion Criteria...................................................................................... 67

APPENDIX C. Quality Assessment Tables

Table 1. Assessment of methodologic characteristics and risk of bias in randomized controlled 

trials of ESA therapy in patients with CHF or CHD............................................................... 68

Table 2. Assessment of methodologic characteristics and risk of bias in randomized controlled 

trials of RBC transfusion for anemia in patients with CHF or CHD ...................................... 71

Table 3. Assessment of methodologic characteristics and risk of bias in observational studies of 

RBC transfusions for anemia in patients with CHD/CHF, stratified by patient population.... 72

APPENDIX D. Peer Review Comments and Responses.................................................................... 75
6

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

EVIDENCE REPORT

INTRODUCTION

Anemia is very common in patients with heart disease: about one-third of congestive heart failure 

(CHF) patients and 10 to 20 percent of coronary heart disease (CHD) patients are anemic, though 

prevalence estimates vary according to the definition used and illness burden in the population 

being studied.1-3 The etiology of anemia in heart disease remains incompletely understood, 

though there are a number of factors that likely contribute including: comorbid chronic kidney 

disease, blunted erythropoietin production, hemodilution, aspirin-induced gastrointestinal blood 

loss, the use of renin-angiotensin-aldosterone system (RAAS) blockers, cytokine-mediated 

inflammation (anemia of chronic disease), and gut malabsorption with consequent nutritional 

deficiency. Iron deficiency is also common. Cytokine mediated sequestration of iron in the 

reticuloendothelial system may contribute to a functional iron deficiency, while an absolute 

deficiency can result from decreased oral iron absorption associated with cytokine induced 

hepcidin synthesis.4

Anemia is associated with poor outcomes in patients with heart disease, but it is unclear whether 

anemia directly and independently contributes to these poor outcomes, or whether it simply 

reflects more severe underlying illness and comorbidities.5-7 Strategies to correct anemia and/

or iron deficiency have included erythropoiesis-stimulating agents, iron supplementation, and 

red blood cell transfusions. The purpose of this systematic review is to summarize the health 

outcome effects of each of these treatment strategies in adult medicine patients with heart 

disease.
7

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

METHODS

TOPIC DEVELOPMENT

The review was commissioned by the Department of Veterans Affairs’ Evidence-based Synthesis 

Program. We conferred with VA and non-VA experts to select the patients and subgroups, 

interventions, outcomes, and setting addressed in the review. We addressed the following key 

questions in our review of the literature:

In patients with CHF or CHD,

Key Question 1. What are the health outcome benefits and harms of treating anemia with 

erythropoiesis-stimulating agents (ESAs)?

Key Question #2. What are the health outcome benefits and harms of using iron to treat iron 

deficiency with or without anemia?

Key Question #3. What are the health outcome benefits and harms of treating anemia with red 

blood cell transfusions?

The criteria for patient population, treatment and comparator interventions, outcomes of interest, 

and patient care setting are outlined below: 

Patients: Adult patients with symptomatic CHF (with or without reduced systolic function) or 

CHD (acute coronary syndrome, post-acute coronary syndrome, history of MI or angina, ) and 

anemia or iron deficiency. 

Interventions:

•	ESAs with or without iron: These include erythropoietin and darbepoeitin

•	Iron: Intravenous or oral

•	Red blood cell transfusion

Comparator: Usual care, placebo

Outcomes: Mortality (all-cause and disease specific), hospitalization (all-cause and diseasespecific), exercise tolerance or duration (any metric, most commonly NYHA class, 6-minute 

walk test), quality of life, cardiovascular events (myocardial infarction, heart failure 

exacerbation, need for revascularization)

Setting: Inpatient or outpatient

Figure 1 illustrates the analytic framework that guided our review and synthesis.
8

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Figure 1. Analytic Framework

Patients with CHF and/or CHD

AND

Anemia and/or Iron Deficiency

Treatment harms

•	 Cerebrovascular events

•	 Hypertension

•	 Venous thrombosis

•	 Other

Treatment interventions

A. Erythropoiesis-stimulating agents

B. Iron (oral or intravenous)

C. Red blood cell transfusions

Final health outcomes

•	 Activity tolerance

•	 Cardiovascular events

•	 Hospitalizations

•	 Mortality

•	 Quality of life

Intermediate outcomes

•	 Change in hemoglobin

•	 Change in glomerular filtration rate

•	 Ejection fraction

•	 Oxygen consumption
9

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

SEARCH STRATEGY

We conducted a search in Medline® and the Cochrane database of systematic reviews of literature 

published from 1947 to November 2010. Appendix A provides the search strategy in detail. We 

obtained additional articles from systematic reviews, reference lists of pertinent studies, reviews, 

editorials, and by consulting experts. We also searched for information about unpublished studies 

on ClinicalTrials.gov. All citations were imported into an electronic database (EndNote X1).

STUDY SELECTION

Three reviewers assessed for relevance the abstracts of citations identified from literature 

searches. Two reviewers independently assessed for inclusion full-text articles of potentially 

relevant abstracts based on the eligibility criteria shown in Appendix B. Disagreements were 

resolved through a consensus process.

Eligible articles had English-language abstracts and provided primary data relevant to the key 

questions. We included studies of anemic patients (hemoglobin < 13 g/dL in men, < 12 g/dL 

in women) with symptomatic CHF (with or without reduced systolic function), CHD (acute 

coronary syndrome, post-acute coronary syndrome, history of MI or angina), or both. Further 

eligibility criteria varied depending on the question of interest, as described below.

To evaluate the efficacy of ESAs, we considered prospective, controlled clinical trials of ESAs 

compared either to placebo or to less intensive ESA use in patients with anemia and heart 

disease. In evaluating the efficacy of iron, we included studies with mixed populations of anemic 

and non-anemic patients, but then described how treatment effects might differ for anemic 

and non-anemic patients. We did include studies of broader patient populations as long as they 

separately reported outcomes data for the subpopulation of patients with heart disease.

Included studies had to report at least one prespecified patient-centered health outcome which 

we defined as clinically important outcomes apparent to the patient (Appendix B). We excluded 

studies reporting only intermediate physiologic outcomes such as change in ejection fraction or 

oxygen delivery metrics.

Based on an initial exploratory search of red blood cell transfusions in patients with heart disease, 

we recognized there was a dearth of controlled clinical trial data and that current recommendations 

for blood transfusion use in heart disease patients are largely based on interpretation of 

observational studies. Therefore, to better understand the evidence currently guiding clinical 

practice, we included observational studies as well as controlled clinical trials that reported at least 

one of the above listed health outcomes. Given the complex technique of cardiac surgery, involving 

induction of hypothermia, cardioplegia, and establishment of an extracorporeal circuit, we felt 

that the potential confounding factors were too vast to permit use of observational data to guide 

decision-making. Therefore, for this population, we elected to consider controlled trials only.

To evaluate the harms of ESAs, iron, and blood transfusion, we collected adverse events data 

from all the included trials, and we specifically gathered data on the following events from 

each trial: hypertension, venous thromboembolic events (including deep venous thrombosis, 

pulmonary embolism, and vascular access thrombosis), and ischemic cerebrovascular events.
10

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

DATA ABSTRACTION

From each study, we abstracted the following: study design, objectives, setting, population 

characteristics (including sex, age, left ventricular ejection fraction, baseline NYHA class, 

definition of CHD), subject eligibility and exclusion criteria, number of subjects, years of 

enrollment, duration of follow-up, the study and comparator interventions (including route 

and dosage), important co-interventions (i.e., iron administration in ESA studies), baseline 

hemoglobin, change in hemoglobin, health outcomes, and adverse events. 

STUDY QUALITY

Two reviewers independently assessed the quality of each trial using a tool developed by the 

Cochrane Collaboration.8 Disagreements were resolved through discussion. This tool asks the 

following questions about the methodologic characteristics of each study to guide assessment of 

the risk of bias:

•	 Was the allocation sequence adequately generated?

•	 Was allocation adequately concealed?

•	 Blinding of participants, personnel and outcome assessors: Was knowledge of the 

allocated intervention adequately prevented during the study?

•	 Were incomplete outcome data adequately addressed?

•	 Are reports of the study free of suggestion of selective outcome reporting?

•	 Was the study apparently free of other problems that could put it at a high risk of bias? 

(We assessed whether or not there were extreme baseline differences between groups.)

Each study was then given an overall summary assessment of either low, high, or unclear risk of 

bias. The risk of bias within a given study can vary according to outcome. For instance, the risk 

of bias associated with lack of blinding might be low for mortality outcomes, but high for more 

subjective outcomes such as quality of life or symptom scores. 

Though there is no widely accepted standard for quality assessment of observational studies, 

we used the following questions to guide a comparison of observational study methodologic 

characteristics:

1. Was the selection of patients for inclusion unbiased? (Was any group of patients systematically excluded?)

2. Was there important differential loss to follow-up or overall high loss to follow-up? (Numbers should be given for each group.)

3. Were the events investigated specified and defined?

4. Was there a clear description of the techniques used to identify the events?

5. Was there unbiased and accurate ascertainment of events (that is, by independent ascertainers 

using a validated ascertainment technique)?

6. Were potential confounding variables and risk factors identified and examined using acceptable statistical techniques?

7. Was the duration of follow-up reasonable for investigated events?

Within question 6, we specifically assessed whether each study: 1) conducted an analysis 

adjusting for patient propensity to receive a blood transfusion, 2) accounted for bleeding 
11

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

complications – whether procedurally related or not – in the study population, and 3) accounted 

for the timing of transfusion given the potential for issues such as survival bias in which patients 

who died could not have received a transfusion. 

We do not report an overall summary assessment for observational studies because there are no 

validated criteria for doing so and all would be poorly valid in determining the health outcome 

effects of blood transfusions. 

Appendix C provides the details of our quality assessment of trials and observational studies. 

RATING THE BODY OF EVIDENCE

We assessed the overall quality of evidence for outcomes using a method developed by the 

GRADE Working Group.9 The GRADE method considers the consistency, coherence, and 

applicability of a body of evidence, as well as the internal validity of individual studies, to 

classify the grade of evidence across outcomes as follows: 

•	 High = Further research is very unlikely to change our confidence on the estimate of 

effect.

•	 Moderate = Further research is likely to have an important impact on our confidence in 

the estimate of effect and may change the estimate.

•	 Low = Further research is very likely to have an important impact on our confidence in 

the estimate of effect and is likely to change the estimate.

•	 Very Low = Any estimate of effect is very uncertain.

DATA SYNTHESIS

We performed meta-analyses of ESA trials for each of the following outcomes: mean 

difference in the change of NYHA class, exercise duration during the six-minute walk test, 

all-cause mortality, hospitalizations, cardiovascular events, hypertension events, and ischemic 

cerebrovascular events. We abstracted the number of events and total subjects from each 

treatment arm, and obtained a pooled estimate of relative risk (RR) using a random effects 

model.10 We did not meta-analyze quality of life outcomes because we felt a quantitative 

summary estimate of effect would be less meaningful than a descriptive approach given the 

variety of assessment tools used. 

In order to determine the influence study quality may have had on summary results, we ran 

analyses for all outcomes excluding those studies with high or unclear risk of bias. To determine 

whether the effects of ESAs were modified by anemia characteristics, we conducted analyses 

according to baseline hemoglobin and mean change in hemoglobin in the intervention group, 

using 11g/dL and 2 g/dL, respectively, as the cutpoints based on distribution of values among 

included studies. If only the hematocrit was reported, we used a conversion of 3:1 to approximate 

the hemoglobin value. 

Statistical heterogeneity was assessed by Cochran’s Q test and I2

 statistic.8 Because of the small 

number of trials that could be combined, we did not perform assessments for publication bias.11 

All analyses were performed using Stata 10.0 (StataCorp, College Station, TX, 2007).
12

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Because there were only three trials examining the effects of iron therapy, with one large 

trial dominating results, we decided to only qualitatively synthesize these results. We also 

qualitatively synthesized the mostly observational blood transfusion literature. 

PEER REVIEW

A draft version of this report was sent to the technical expert panel and additional peer reviewers. 

The comments and suggestions we received from reviewers and our responses in revising the 

report are provided in Appendix D. 
13

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

RESULTS

LITERATURE FLOW

We reviewed 1,546 titles and abstracts from the electronic search, and identified an additional 83 

from reviewing reference lists, and performing manual searches for recently published studies, 

and unpublished or ongoing studies. 

After applying inclusion/exclusion criteria at the abstract level, 320 full-text articles were 

reviewed, as shown in Figure 2. Of the full-text articles, we rejected 266 that did not meet our 

inclusion criteria.

Figure 2. Literature Flow – Anemia and CHF

2444 Citations identified from 

electronicdatabase searches

1026 from MEDLINE®

1329 from EMBASE

89 from Cochrane library 

83 Citations identified from reference lists of 

review articles, and manual searches for recent, 

unpublished or ongoing studies

1546 Citations screened for title and 

abstract review 

898 Duplicate citations excluded

1629 Potentially relevant citations 

identified for further review

Total excluded articles = 266

Non-English language = 2

Study population not in scope = 14 

Studied outcomes not in scope = 8

Study design or article type out of scope = 58

Retrieved for background, discussion, methods or 

other contextual purposes = 179

Duplicate publication of same study = 5

1309 Citations excluded due to lack

of relevance in title or abstract

320 Potentially relevant articles identified for further review

54 articles of 52 primary studies in patients with anemia and CHF/CHD

35 articles on RBC transfusion

9 RCTs

24 observational studies in 26 publications

16 RCTs of

ESAs

3RCTs of 

iron
14

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

KEY QUESTION #1. In patients with CHF or CHD, what are the health 

outcome benefits and harms of treating anemia with ESAs?

Summary

Sixteen randomized, controlled trials evaluated the impact of ESAs in patients with heart disease 

(Table 1).12-27 We excluded one study28 whose patient population was included in a subsequent 

publication.21, 28 Eleven trials enrolled patients with CHF, and in the 10 trials reporting systolic 

function, the mean ejection fraction was ≤ 35%. Most patients had comorbid CHD. Two trials 

included roughly even proportions of patients with CHD and CHF,14, 26 and only one trial focused 

exclusively on patients with CHD.27 The most commonly reported health outcomes were exercise 

tolerance measures such as NYHA (nine trials), and exercise duration as measured by the sixminute walk test (five trials) or the Naughton protocol (two trials). Nine trials reported mortality 

and seven trials reported hospitalizations. Two trials were primarily designed to assess the 

comparative effects of ESAs titrated to high or low hemoglobin targets in anemic patients with 

chronic kidney disease, but included a large proportion of patients with heart disease for whom 

adequate subgroup data are reported.13, 14

Overall, we found little good quality evidence that ESA use consistently improves health 

outcomes. Some studies found ESA use improved exercise tolerance and duration, but this body 

of evidence is limited by inconsistency of findings and important methodologic weaknesses. The 

potential benefits of ESA use seen in some studies may be further tempered by the finding that 

ESA use is associated with serious harms such as mortality and vascular thrombosis, especially 

in patients with comorbid chronic kidney disease.

Methodologic Considerations

We characterized the quality of each of the included studies according to the impact 

methodologic flaws could have on an outcome of interest. For example, flaws such as the lack 

of patient and/or outcome assessor blinding could lead to biased results for subjective outcomes 

such as exercise tolerance. Five trials contained serious methodologic flaws which could have 

biased key findings,12, 15, 21, 24, 25 and unclear reporting made it difficult to assess the risk of bias in 

one trial.17 Additionally, there was some evidence for multiple publication bias: in two cases we 

found multiple publications reporting results for apparently overlapping populations.16, 18, 21, 28 The 

methodologic characteristics of each study are detailed in Appendix C, Table 1. 
15

 with Heart Disease: A Systematic Review Evidence-based Synthesis Program

domized controlled trials of ESA therapy in patients with CHF or CHD

:

y; 

Clinical subgroup

(CHF/CAD);

Mean LVEF %;

% on RAAS 

blockers

(T v C)

Baseline 

kidney 

function, 

GFR or 

Serum Cr

(T v C)

Intervention

(Drug, Dose)

v Control

Baseline 

measures of 

iron stores

(T v C)

Iron in Tx 

group

Iron in 

Control 

group

Baseline 

Hgb

(T v C)

Mean 

change in 

Hgb

(T v C)

Funding 

source

h CHF

 

Advanced CHF + CRI: 

LVEF: 34.5 v 34.6

NYHA III: 66.7 v 81.6

NYHA IV: 33.3 v 18.4

Ischemic etiology: 66.7 

v 55.3

ACEI/ARB: 70.4 v 76.3

Aldo antag: 74.1 v 60.5

GFR: 48.1 v 

50.3

Epoeitin 4000u IV weekly, 

adjusted to target Hgb 12.5-

14.5

+ iron sucrose IV 200mg 

weekly x 5-6 wks to target 

ferritin>400, then q 4-6 wks.

Control group was not given a 

placebo.

ferritin: 220.7 v 

140.7

TSAT%: 23.2 v 

19.9

Y N 10.9 v 10.9 1.7 v 0.4 NR

LVEF: 35 v 36.

NYHA I: 1 v 2

NYHA II: 38 v 32

NYHA III: 59 v 62

NYHA IV: 2 v 3

RAAS blockers: 90 v 90

GFR: 47.2 v 

47.5

Darbepoeitin alfa 0.75mcg/

kg sc q 2 wks titrated to target 

Hgb ~ 14

vs. “matching placebo”

ferritin: 121 v 124

TSAT%: 23.5 v 

23.5

Y, daily 

elemental oral 

iron

Y, daily 

elemental oral 

iron

11.5 v 11.3 Median Hgb 

change at 27 

weeks: 1.8 

v 0.3

 53 weeks: 2.1 

v 0.5

Amgen

LVEF: 2 v 8

NYHA II: 38 v 45

NYHA III: 62 v 55

Ischemic CM: 62 v 60

ACEI: 71 v 65

ARB: 19 v 20

Aldo antag: 57 v 55

Cr: 1.7 v 1.7 Darbepoeitin alfa 1.5 mcg/kg 

sc q 20 days titrated to target 

Hgb ~ 14 vs. 0.9% saline

ferritin: 144 v 159

Iron: 45 v 59

Y, oral iron 250 

mg BID

Y, oral iron 250 

mg BID

10.9 v 11.4 1.6 v -0.9 none

NYHA 3-4

LVEF: 24 v 21

h/o CAD: 53.3 v 50

RAAS blockers not 

different between both 

groups; most were on 

RAAS blockers (NOS)

Cr: 1.6 v 1.6 Epoetin 5000 sc TIW - titrated 

up to 10,000 TIW if Hgb did 

not increase 1 g/dL

vs. saline

NR Y, oral iron 325 

mg daily

N 10.9 v 11.0 3.3 v 0.6

(T increased 

from 11 to 14.3 

and C 10.9 to 

11.5)

NIH

 

LFEF: 30 v 31

NYHA III: 69 v 68

NYHA IV: 30.8 v 32

Mean NYHA: 3.4 v 3.6

ACEI: 69 v 64

ARB: 19 v 28

GFR: 43 v 45 Beta erythropoeitin 6000 IU 

sc twice weekly to goal Hgb 

12-12.5 vs. saline

NR Y, oral iron 

gluconate 300 

mg daily

Y, oral iron 

gluconate 300 

mg daily

10.4 +/- 0.6 

v 10.6 +/- 

0.7

2.0 v -0.1 none
16

 with Heart Disease: A Systematic Review Evidence-based Synthesis Program

:

y; 

Clinical subgroup

(CHF/CAD);

Mean LVEF %;

% on RAAS 

blockers

(T v C)

Baseline 

kidney 

function, 

GFR or 

Serum Cr

(T v C)

Intervention

(Drug, Dose)

v Control

Baseline 

measures of 

iron stores

(T v C)

Iron in Tx 

group

Iron in 

Control 

group

Baseline 

Hgb

(T v C)

Mean 

change in 

Hgb

(T v C)

Funding 

source

d

LVEF 30.1 vs 30.8

RAAS blockers NR

Cr: 2.3 vs 2.4 Epoetin 6000 sc BIW

vs. saline placebo for first four 

months

NR FeGluconate 

300 mg QD

FeGluconate 

300 mg QD

9.6 v 9.3 Final Hgb:

12.4 v 10.4

NR

LVEF: 26 v 28

NYHA II: 19 v 27

NYHA III: 81 v 73

Ischemic related: 90 v 82

ACEI: 71 v 73

ARB 19 v 18

Aldo antag: 57 v 55

Cr: 1.7 v 1.8 Darbepoeitin alfa 1.5mcg/kg 

sc q 20 days

vs. 0.9% saline

ferritin: 153 +/- 119 

v 170 +/- 135.

Y, oral iron 

sulfate 125 mg 

BID

Y, oral iron 

sulfate 125 mg 

BID

11.0 v 11.4 Final Hgb: 

12.8 v 11.8

NR

LVEF: 28 v 27

NYHA II: 53.3 v 60

NYHA III: 46.7 v 40

Ischemic: 86.7 v 73.3

ACEI: 93.3 v 86.7

ARB: 6.7 v 2/15

Cr: 1.6 v 1.5 Darbepoeitin alfa 1.5 mcg/kg 

q 20 days

vs. 0.9% saline

ferritin: 133 +/- 126 

v 127 +/- 112.

Y, oral iron 

sulfate 125 mg 

BID

Y, oral iron 

sulfate 125 mg 

BID

11.2 v 11.5 1.6 v 0.4 none

 

NYHA I: 0 v 5

NYHA II: 58 v 36

NYHA III: 42 v 59

Ischemic: 84 v 86

RAAS blockers NR

GFR: 59 v 52 Darbepoeitin alfa 0.75mcg/

kg sc q 2 wks, titrated to Hgb 

13-15

vs. placebo “in identical singledose vials”

median ferritin 

(25th and 75th): 

71 (46, 143) v 161 

(83, 256).

TSAT%: 25.3 (SD 

6.6) v 34.6 (SD 12.8).

N, not 

specified

N, not 

specified

11.8 v 11.6 2.4 v 0.9 Amgen

.2

LVEF: 30.8 v 28.4 

Mean NYHA: 3.8 v 3.5 

Ischemic: 69 v 62.5

ACEI: 87.5 v 87.5

ARB: 6.6 v 12.5

Cr: 1.7 v 1.4 Erythropoeitin 4000 IU sc 

weekly adjusted to goal Hgb 

12.5

Control not reported.

ferritin: 221 (SD 

165) v 264 (SD 

162), NS.

TSAT%: 25.1 (SD 

12.9) v 22.5 (SD 

16.7), NS.

Y, IV ferric 

sucrose 200 

mg q 2 weeks

N 10.3 v 10.9 2.6 v -0.1 none

 

LVEF: 29 v 27

NYHA I: 3 v 2

NYHA II: 36 v 44

NYHA III: 59 v 53

NYHA IV: 2 v 2

Ischemic: 69 v 64

ACEI: 77 v 75

ARB: 18 v 20

ACE/ARB: 94 v 91

GFR: 56.5 v 

53.5

Darbepoeitin alpha 0.75 mcg/

kg sc q 2 wks OR 50 mcg 

(fixed dose)

vs. identical placebo provided 

by Amgen

ferritin: 198 (SD 

232) v 200 (SD 

224).

TSAT%: 26 (SD 9) 

v 25 (SD 8).

Y, 200 mg oral 

iron daily

Y, 200 mg oral 

iron daily

11.5 v 11.4 1.87 (0.75 

mcg/kg) v 0.07 

Amgen
17

 with Heart Disease: A Systematic Review Evidence-based Synthesis Program

:

y; 

Clinical subgroup

(CHF/CAD);

Mean LVEF %;

% on RAAS 

blockers

(T v C)

Baseline 

kidney 

function, 

GFR or 

Serum Cr

(T v C)

Intervention

(Drug, Dose)

v Control

Baseline 

measures of 

iron stores

(T v C)

Iron in Tx 

group

Iron in 

Control 

group

Baseline 

Hgb

(T v C)

Mean 

change in 

Hgb

(T v C)

Funding 

source

th CAD

.2

CAD (at least one episode 

of angina or dysrhythmia 

in last year)

RAAS blockers NR

All pts ESRD 

on HD

Epoeitin IV 25 IU/kg post 

each HD

Control not reported.

NR NR NR NR in both 

groups

8.1 to 8.97 in 

Tx group

NR

th CHF or CAD

CHF (44 v 47) or CHD

LVEF NR

RAAS blockers: no 

significant difference 

between groups (NOS)

All pts ESRD 

on HD

Epoetin IV or SQ to target Hct 

42 ±3

vs. Epoetin IV or SQ to target 

Hct 30 ± 3

ferritin: 334 v 403 

(p = 0.002)

TSAT%: 26.8 v 

26.3 

IV iron dextran 

in 526/618 pts

IV iron dextran 

in 464/615 pts

Hct: 30.5 v 

30.5

Change in 

Hct: approx 10 

v 0%

Amgen

bgroup of patients with CKD

d 

CVD: 67.9

CHF: 50.2

PAD: 31.8

RAAS blockers: 77.7

GFR: 34 Darbepoeitin alpha titrated to 

high (13.0 g/dL) vs. low (9.0 g/

dL) Hgb target

TSAT%: 23

ferritin: 134

N N 10.4 For overall 

cohort 

(n=4,044)

Median 

achieved Hgb 

12.5 (change 

of 2.1)

v 10.6 (change 

of 0.1)

Amgen

5 

CHF GFR: 26.9 v 

26.0

Epoeitin alpha

titrated to high (13.5 g/dL) vs. 

low (11.3 g/dL) Hgb target 

ferritin (Hgb 13.5 

group vs Hgb 11.3 

group): 159.5 v 

193.5, p=0.050.

TSAT%: 22.1 v 

24.1, p=0.043.

Hgb 13.5: 

10.0 

Hgb 11.3: 

10.0

CHOIR 

funded 

by Ortho 

Biotech 

and 

Johnson & 

Johnson. 

This 

secondary 

analysis by 

NIH.
18

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Exercise Tolerance and Duration

Overall, though there is some data that ESAs may improve exercise tolerance, the body of 

evidence is limited by inconsistent results and the methodologic weaknesses of some studies. 

Pooled results from nine trials reporting change in NYHA scores were highly heterogeneous 

and found a decline in NYHA scores in ESA-treated patients while control patients generally 

maintained stable scores or worsened (mean difference in NYHA scores treatment vs. control, 

-0.77, 95% CI -1.21 to -0.32, I2

=96.0%, Figure 3). However, this improvement was significantly 

attenuated when we limited the analysis to the four methodologically stronger trials (mean 

difference in NYHA scores -0.15; 95% CI -0.36 to 0.06; I2=62.1%, Figure 4). The largest of these 

trials randomized 319 patients to twice-monthly darbepoietin or saline placebo, and measured 

exercise duration, tolerance and quality of life outcomes at 27 weeks.19 The authors found 

darbepoietin had no effect on any of the outcomes despite raising hemoglobin by 1.8 g/dL on 

average. 

Figure 3. Change in NYHA scores in CHF patients: mean difference comparing ESA to control 

group

Overall (I

2 = 96.0%, p = 0.000)

Ponikowski 200723

Parissis 200818

Study

Parissis 200916

Comin-Colet 200912

Ghali 200819

Palazzuoli 200721

Van Veldhuisen 200722

Silverberg 200125

Palazzuoli 200915

-0.77 (-1.21, -0.32)

-0.02 (-0.48, 0.44)

-1.20 (-1.58, -0.82)

-0.80 (-1.31, -0.29)

-1.50 (-1.76, -1.24)

-0.06 (-0.17, 0.05)

-0.70 (-0.98, -0.42)

-0.07 (-0.27, 0.13)

-2.00 (-2.42, -1.58)

-0.61 (-0.97, -0.25)

2601

19, -.11 (.769)

21, -.7 (.458)

15, -.667 (.612)

27, -1.3 (.557)

162, -.19 (.509)

26, -.6 (.557)

110, -.3 (.629)

16, -1.6 (.608)

26, -.63 (.7)

2575

(SD); Control

22, -.09 (.727)

11, .5 (.557)

N, mean

15, .133 (.794)

38, .2 (.458)

157, -.13 (.501)

25, .1 (.458)

55, -.23 (.593)

16, .4 (.608)

25, -.02 (.624)

-0.77 (-1.21, -0.32)

WMD (95% CI)

-0.02 (-0.48, 0.44)

-1.20 (-1.58, -0.82)

-0.80 (-1.31, -0.29)

-1.50 (-1.76, -1.24)

-0.06 (-0.17, 0.05)

-0.70 (-0.98, -0.42)

-0.07 (-0.27, 0.13)

-2.00 (-2.42, -1.58)

-0.61 (-0.97, -0.25)

2601

(SD); Treatment

19, -.11 (.769)

21, -.7 (.458)

N, mean

15, -.667 (.612)

27, -1.3 (.557)

162, -.19 (.509)

26, -.6 (.557)

110, -.3 (.629)

16, -1.6 (.608)

26, -.63 (.7)

←Favors Treatment Favors Control→

-2.5 -2 -1.5 -1 -.5 0 .5
19

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Figure 4. Change in NYHA scores in CHF patients – studies with low risk of bias, and excluding 

studies with duplicate patient populations: mean difference comparing ESA to control group

Overall (I

2 = 62.1%, p = 0.048)

Parissis 200916

Study

Van Veldhuisen 200722

Ponikowski 200723

Ghali 200819

-0.15 (-0.36, 0.06)

-0.80 (-1.31, -0.29)

-0.07 (-0.27, 0.13)

-0.02 (-0.48, 0.44)

-0.06 (-0.17, 0.05)

2601

15, -.667 (.612)

110, -.3 (.629)

19, -.11 (.769)

162, -.19 (.509)

2575

15, .133 (.794)

N, mean

55, -.23 (.593)

22, -.09 (.727)

157, -.13 (.501)

(SD); Control

-0.15 (-0.36, 0.06)

-0.80 (-1.31, -0.29)

-0.07 (-0.27, 0.13)

-0.02 (-0.48, 0.44)

-0.06 (-0.17, 0.05)

WMD (95% CI)

2601

15, -.667 (.612)

N, mean

110, -.3 (.629)

19, -.11 (.769)

162, -.19 (.509)

(SD); Treatment

←Favors Treatment Favors Control →

-2.5 -2 -1.5 -1 -.5 0 .5

Six trials reported exercise distance or duration. Four of these trials reported the mean change 

in six-minute walk distance and found ESA use was associated with a marginally significant 

increase in distance walked, though results were quite different among the trials (mean change 

in meters walked: 74.4; 95% CI -0.16 to 149.0; I2=88.7%) (Figure 5). Two trials reported change 

in exercise treadmill time using the Naughton protocol; the larger trial found no improvement 

associated with ESA use,19 while a smaller trial found ESA use was associated with a small 

increase in exercise duration.28 Exclusion of poorer quality studies did not alter results 

substantially, but such analyses are limited by the very small number of studies. 

Figure 5. Change in six-minute walk distance (meters) in CHF patients: mean difference comparing 

ESA to control group

Overall (I

2 = 88.7%, p = 0.000)

Van Veldhuisen 200722

Parissis 200816

Kourea 200817

Mancini 200324

Study

74.42 (-0.16, 148.99)

22.80 (-1.94, 47.54)

WMD (95% CI)

116.00 (47.35, 184.65)

146.00 (101.33, 190.67)

5.51 (-85.03, 96.05)

2601

110, 34.2 (76.6)

21, 69 (97.3)

21, 106 (66)

15, 43 (81.5)

N, mean

2575

55, 11.4 (76.4)

(SD); Control

11, -47 (92.4)

20, -40 (79)

8, 37.5 (116)

N, mean

74.42 (-0.16, 148.99)

22.80 (-1.94, 47.54)

WMD (95% CI)

116.00 (47.35, 184.65)

146.00 (101.33, 190.67)

5.51 (-85.03, 96.05)

2601

110, 34.2 (76.6)

(SD); Treatment

21, 69 (97.3)

21, 106 (66)

15, 43 (81.5)

Treatment

-100 -50 0 50 100 150 200
20

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Quality of Life

Five trials reported quality of life measures as a primary or secondary outcome,17, 19, 22-24 but 

analysis was limited by the variety of and inconsistency among specific instruments used. Most 

trials used several different methods for evaluating quality of life. Four trials evaluated change 

in the Patient Global Assessment scale.19, 22-24 In two of these studies, a significantly greater 

proportion of treatment patients reported improvement than controls, but one of these studies 

had several important methodologic flaws, including lack of blinding, that could bias these 

subjective results.24 The other trial found no improvement in two simultaneously measured 

QOL instruments including the Minnesota Living with Heart Failure Questionnaire (MLHFQ) 

and the Kansas City Cardiomyopathy Questionnaire (KCCQ).23 Four trials reported MLHFQ 

scores,19, 22-24 but only one trial with high risk of bias showed a significant improvement in scores 

associated with treatment.24 Kourea et al. found treatment was associated with improvement in 

the Duke Activity Status Index (DASI), Beck Depression Inventory (BDI) and Zung Self-rating 

Depression Scale (SDS).17

The KCCQ measures quality of life in multiple domains which can be combined into summary 

scores to facilitate interpretation. Three trials reported different types of KCCQ summary 

scores without defining which domains were used in each summation.17, 22, 23 One trial reported a 

significant difference between groups in mean change from baseline of a KCCQ “total symptom 

score”: 8.2 v 1.5, p=0.027.22 Another trial noted significant improvements in a KCCQ “functional 

score” (21 +/- 19 v 2 +/- 11, p=0.004), as well as a KCCQ “summary” score (20 +/- 20 v 6 +/- 

14, p=0.04).17
21

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Mortality

Nine trials reporting at least one death in the treatment or control group found ESA use was 

associated with a marginally significant increased mortality risk (RR 1.11; 95% CI 0.99 – 1.24; 

I2

=0.0%). An analysis of the six trials with low risk of bias found very similar results (Figure 6). 

These findings are largely driven by two large trials with extended follow-up and very high event 

rates. Indeed, a sensitivity analysis without these two trials showed ESAs had a neutral effect on 

mortality (RR 0.79, 95% CI 0.51 – 1.22; I2

=0.0%). One of the trials compared aggressive (goal 

hematocrit 42%) to less aggressive (goal hematocrit 30%) epoietin titration in patients with endstage renal disease and heart failure and/or ischemic heart disease.26 After a prolonged follow-up 

of 29 months, the authors found a 20 percent increase in the risk of all-cause mortality, and most 

of the events were of cardiovascular origin. Another large trial compared darbepoietin to placebo 

in patients with type 2 diabetes and chronic kidney disease. A prespecified analysis of the large 

subgroup with comorbid heart disease showed a non-significant increased risk of death in the 

treatment group after a similarly long follow-up period.14, 29 

Figure 6. All-cause mortality in patients with CHF or CHD – studies with low risk of bias: ESA vs. 

control

Overall (I

2 = 22.7%, p = 0.263)

Van Veldhuisen 200722

Ghali 200819

Parissis 200916

Ponikowski 200723

Pfeffer 200914

Besarab 1998,

26 Besarab 200820

Study

1.12 (1.00, 1.26)

6.56 (0.38, 114.34)

0.59 (0.29, 1.21)

0.20 (0.01, 3.85)

1.16 (0.08, 17.28)

1.10 (0.93, 1.29)

1.20 (1.01, 1.42)

429/1573

6/110

11/162

0/15

1/19

203/633

208/634

403/1594

0/55

18/157

2/15

Control

1/22

209/714

173/631

Events,

1.12 (1.00, 1.26)

6.56 (0.38, 114.34)

0.59 (0.29, 1.21)

0.20 (0.01, 3.85)

RR (95% CI)

1.16 (0.08, 17.28)

1.10 (0.93, 1.29)

1.20 (1.01, 1.42)

429/1573

6/110

11/162

0/15

Treatment

1/19

203/633

208/634

Events,

←Favors Treatment Favors Control→

.00875 1 114
22

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Hospitalizations

Six trials found ESA treatment was associated with a reduction in hospitalizations (RR 0.70, 95% 

CI 0.57 – 0.87; I2

=37.7%), but, again, this benefit largely disappeared when we included only the 

higher quality trials (Figure 7).

Figure 7. Risk of one or more hospitalizations in patients with CHF or CHD – studies with low risk 

of bias: ESA vs. Control

Overall (I2 = 0.0%, p = 0.841)

Ghali 200819

Besarab 199826 and 200820

Ponikowski 2007 23

Study

0.85 (0.67, 1.08)

0.74 (0.44, 1.26)

0.88 (0.67, 1.17)

0.77 (0.14, 4.14)

NR

NR

80/618

2/19

NR

NR

90/615

Control

3/22

Events,

RR (95% CI) Treatment

2/19

Events,

.144 1 6.96 ←Favors Treatment Favors Control→

Cardiovascular Events

ESAs had a neutral effect on the occurrence of cardiovascular events across seven trials (RR 0.96, 

95% CI 0.85 – 1.08; I2=41.5%, Figure 8). The only trial showing a benefit focused on CHD patients, 

and had many significant methodologic weaknesses which threaten the validity of the results.27

Figure 8. Cardiovascular events in patients with CHF or CHD: ESA vs. control

Overall (I2 = 41.5%, p = 0.115)

Besarab 1998,26 Besarab 200820

Van Veldhuisen 200722

Ponikowski 200723

Study

Palazzuoli 200721

Pfeffer 200914

Bellinghieri 199427

Szczech 201013

0.96 (0.85, 1.08)

1.24 (0.65, 2.38)

0.79 (0.37, 1.71)

0.39 (0.04, 3.41)

0.48 (0.17, 1.40)

1.02 (0.87, 1.20)

0.26 (0.09, 0.72)

0.91 (0.74, 1.12)

329/1638

20/634

14/108

1/19

4/26

197/633

4/26

89/192

352/1640

16/631

9/55

Control

3/22

Events,

8/25

217/714

6/10

93/183

0.96 (0.85, 1.08)

1.24 (0.65, 2.38)

0.79 (0.37, 1.71)

RR (95% CI)

0.39 (0.04, 3.41)

0.48 (0.17, 1.40)

1.02 (0.87, 1.20)

0.26 (0.09, 0.72)

0.91 (0.74, 1.12)

329/1638

20/634

14/108

Treatment

1/19

Events,

4/26

197/633

4/26

89/192

.0437 1 22.9

Favors Treatment Favors Control
23

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Cerebrovascular Events

There were very few cerebrovascular events among the four trials reporting this outcome (Figure 

9). There was an increased risk of stroke associated with ESA use in the TREAT trial among 

patients with diabetes and chronic kidney disease (RR 1.92, 95% CI 1.38 – 2.68),30 but these data 

are not reported separately for the large subgroup of heart disease patients.

Figure 9. Cerebrovascular events in patients with CHF or CHD: ESA vs. control

Overall (I2 = 15.9%, p = 0.305)

Kourea 200817

Parissis 200818

Ponikowski 200723

Ghali 200819

Study

1.03 (0.39, 2.71)

0.32 (0.01, 7.38)

0.18 (0.01, 4.13)

(Excluded)

1.70 (0.51, 5.68)

7/223

0/21

0/21

0/19

7/162

6/210

Control

1/20

1/11

0/22

4/157

Events,

1.03 (0.39, 2.71)

RR (95% CI)

0.32 (0.01, 7.38)

0.18 (0.01, 4.13)

(Excluded)

1.70 (0.51, 5.68)

7/223

Treatment

0/21

0/21

0/19

7/162

Events,

←Favors Treatment Favors Control→

.00801 1 125
24

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Other Harms

Combined results from seven trials suggest ESA use may be associated with excess risk of 

hypertension (RR 1.11, 95% CI 1.00 – 1.24; I2

= 0.0%), though the findings are again dominated 

by one large trial.14 The finding of excess risk became non-significant when we excluded this trial 

(RR 1.25, 95 % CI 0.65 – 2.38; I2=0.0%). Reported hypertension events in the other trials were 

rare, but the quality of adverse event reporting was unclear and the definitions used varied widely 

(Figure 10). 

Figure 10. Hypertension events in patients with CHF or CHD: ESA vs. control

Overall (I

2

 = 0.0%, p = 0.947)

Pfeffer 200914

Kourea 200817

Parissis 200818

Parissis 200916

Ghali 200819

Van Veldhuisen 200722

Ponikowski 200723

Study

1.11 (1.00, 1.24)

1.11 (0.99, 1.24)

0.95 (0.06, 14.22)

1.64 (0.07, 37.15)

3.00 (0.13, 68.26)

1.26 (0.57, 2.79)

0.51 (0.07, 3.52)

3.45 (0.15, 80.03)

510/2350

491/2004

1/21

1/21

1/15

13/162

2/108

1/19

459/2299

446/2019

Control

1/20

0/11

0/15

10/157

2/55

0/22

Events,

1.11 (1.00, 1.24)

1.11 (0.99, 1.24)

RR (95% CI)

0.95 (0.06, 14.22)

1.64 (0.07, 37.15)

3.00 (0.13, 68.26)

1.26 (0.57, 2.79)

0.51 (0.07, 3.52)

3.45 (0.15, 80.03)

510/2350

491/2004

Treatment

1/21

1/21

1/15

13/162

2/108

1/19

Events,

Favors Treatment Favors Control

.0125 1 80

One large trial in end-stage renal disease patients found an increase in the risk of thrombosis – 

mainly of vascular access sites – associated with aggressive epoietin titration (RR 1.37, 95% CI 

1.17 – 1.61).26 The risk of venous thromboembolism was similarly increased in another trial of 

patients with chronic kidney disease and diabetes (RR 1.80, 95% CI 1.08 – 2.98), though data 

for the cardiac disease subgroup were not reported separately.14 On the other hand, only two 

other studies reported the occurrence of venous thromboembolic events with no difference seen 

between groups.19, 22

Hemoglobin Target

We were not able to determine how anemia severity and hemoglobin change influenced 

outcomes in the placebo-controlled trials. Almost all the small trials comparing ESAs to placebo 

in heart failure patients included patients with moderate anemia and a mean baseline hemoglobin 

within the narrow 10 – 12 g/dL range. In all cases, ESA use was associated with a significant 

increase in hemoglobin (mean increase range 1.6 – 2.8 g/dL). In order to better understand the 

influence of baseline hemoglobin and change in hemoglobin on outcomes, we conducted the two 

following sensitivity analyses for all outcomes and found no substantive difference in results: 
25

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

1) exclusion of studies in which the mean baseline hemoglobin < 11 g/dL; and 2) exclusion 

of studies in which the mean increase in hemoglobin associated with ESA use was < 2 g/dL. 

However, the utility of such subgroup analysis is limited by the relatively small number of trials, 

and also by concurrent characteristics which could influence results. For instance, exclusion of 

studies with mean baseline hemoglobin < 11 g/dL examining change in NYHA scores left only 

the poorer quality studies. Furthermore, there may not have been enough variation in mean 

baseline hemoglobin and change in hemoglobin across studies given the relatively small sample 

of trials. 

The best evidence evaluating the influence of hemoglobin targets comes from the three trials 

(or subgroups of trials) of patients with comorbid chronic kidney and heart disease, in which 

ESAs titrated to normal or near-normal targets were compared to ESAs titrated to lower targets 

(hemoglobin 9 – 11.3 g/dL).13, 14, 20 None of the trials found a benefit from aggressive ESA use 

and, in fact, two of the trials found a significant increase in venous thromboembolic risk and a 

near-significant increase in mortality.14, 20

No trials in heart disease patients have evaluated the effects of more moderate hemoglobin 

targets (e.g. hemoglobin 10 – 12 g/dL) compared to lower targets. 

In Progress Trials

Two trials of ESAs in heart failure are ongoing. The Reduction of Events with Darbepoetin 

alfa in Heart Failure (RED-HF) study is an international, multicenter, randomized and placebocontrolled trial.31 The intent is to recruit ~2600 optimally treated patients with low ejection 

fraction (~40%) and symptomatic CHF with a Hgb concentration 9.0 – 12.0 g/dL. Patients will 

be administered darbepoetin every two weeks, titrated to a goal Hgb of >= 13.0 g/dL, with oral 

iron repletion as needed. The primary outcome is time to death from any cause or first hospital 

admission for worsening CHF. The secondary outcomes include mean change in KCCQ scores at 

six months. Started in June 2006, this event-driven, industry-sponsored trial is estimated to finish 

in 2014.

Also expected are results from the Anemia in Heart Failure With a Preserved Ejection 

Fraction trial.32 This randomized, placebo-controlled trial is examining the effects of weekly 

erythropoietin, also titrated to a target hemoglobin of 13 g/dL, in 80 patients with anemia and 

heart failure and a preserved ejection fraction. They will evaluate the primary outcomes of left 

ventricular end diastolic volume atsix months, as well as secondary outcomes of peak oxygen 

consumption, six-minute walk duration, KCCQ scores, hospitalization, and others. Started in 

July 2007, it is anticipated to be completed by March 2012. 

Key Question #2. In patients with CHF or CHD, what are the health 

outcome benefits and harms of using iron to treat iron deficiency with 

or without anemia?

Summary

Two small and one large, well-conducted multicenter trials show that IV iron can improve shortterm exercise tolerance and quality of life in patients with symptomatic systolic heart failure and 
26

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

iron deficiency, with or without anemia. The impact on distal health outcomes such as mortality 

and cardiovascular events remains undertested, as do the long-term effects of such treatment. The 

evidence supporting symptomatic benefit most closely applies to patients with NYHA III heart 

failure and evidence of low iron stores. 

Details 

We included three trials of IV iron in patients with iron deficiency. Results are largely dominated 

by one recent trial that studied the effect of iron infusion on patients with iron deficiency with or 

without anemia.33

The FAIR-HF (Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure) 

trial is a randomized, double-blind, multicenter trial that evaluated the efficacy of intravenousiron infusion on symptoms and submaximal exercise capacity in a cohort of patients with chronic 

mild or moderate heart failure due to left ventricular systolic dysfunction. The study enrolled 

459 stable outpatients with NYHA class II or III heart failure, low ejection fraction, and iron 

deficiency as defined by a ferritin < 100 μg/dL or between 100 – 299 μg/dL if the transferrin 

saturation was < 20 percent. Pre-specified primary endpoints included self-reported Patient 

Global Assessment and NYHA functional class after 24 weeks of therapy. Secondary endpoints 

included distance walked in six minutes and health-related quality of life. Patients receiving IV 

iron received 200 mg infusion of ferric carboxymaltose with repeat dosing until iron repletion 

was achieved (correction phase) and then every four weeks during the maintenance phase, which 

started at week eight or week twelve, depending on the required iron-repletion dose. Control 

patients received an IV saline placebo with the same dosing schedule. 

Patient characteristics, which were well-matched between the two groups at baseline, are 

detailed in Table 2. Most patients had NYHA Class III symptoms and moderate to severe systolic 

dysfunction. Only half the patients were anemic (HHgb ≤ 12g/dL), but most had ferritin levels < 

100.

Patients in the treatment group were more likely to report they were much or moderately 

improved on the Patient Global Assessment compared with control patients (50 v 28%, OR 2.51; 

95% CI 1.75 – 3.61). Iron treated patients also showed improvement in NYHA functional class 

(OR for improvement by one class, 2.40; 95% CI 1.55 – 3.71). Improvements in Patient Global 

Assessment and NYHA scores were observed in both prespecified subgroups of patients with 

and without anemia (Hgb ≤ 12g/dL). Significant improvements were also seen in secondary 

endpoints, including an increased distance on the six-minute walk test (313 meters compared 

with 277 meters) and quality of life assessments (EQ5-D, where higher score is better, of 63 vs. 

57).

The FAIR-HF trial was large and well-conducted, but there are several limitations of note. It 

relied on subjective primary endpoints, though the strong study design should minimize the risk 

of biased results. The size of the study and relatively short follow-up period limit its ability to 

examine intervention effects on more distal health outcomes such as mortality. Finally, there 

were too few patients with NYHA class II heart failure to meaningfully apply results to this 

group of patients.
27

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

We also included two smaller trials of iron therapy. The first randomized 40 patients with 

iron deficiency, anemia, chronic heart failure and chronic kidney disease to receive 200 mg of 

intravenous iron sucrose or saline weekly for five weeks.34 Investigators found that after six 

months, participants who received iron sucrose had significant improvement in MLHFQ score, 

decreased levels of N-terminal pro-brain natriuretic peptide (117.5 +/- 87.4 pg/ml vs. 450.9 

+/-248.8 pg/ml, p<0.01) and C-reactive protein (2.3 +/- 0.8 mg/l vs. 6.5 +/-3.7 mg/l, p <0.01), 

an increase in left ventricular ejection fraction percentage (35.7 +/- 4.7 vs. 28.8 +/- 2.4), and 

distance on the six-minute walk test.

The FERRIC-HF (Ferric Iron Sucrose in Heart Failure) trial randomized 35 patients and 

measured the effect of 200 mg of intravenous iron sucrose compared with placebo on exercise 

tolerance and QOL.35 The lack of blinding contributes to a high risk of bias given the subjective 

nature of the functional status and QOL outcomes. Also, substantially more patients in the 

intervention group dropped out of the study (16 v 9%). 
28

 with Heart Disease: A Systematic Review Evidence-based Synthesis Program

domized controlled trials of iron therapy in patients with CHF or CHD

haracteristics of patient population, T v C Results, N(%), T v C Quality assessment

304 v 155

male: 47.6 v 45.2white: 99.7 v 100

an age: 67.8 v 67.4an LEVF%: 31.9 v 33.0

NYHA II: 17.4 v 18.7NYHA III: 82.6 v 81.3RAAS blockers: 92.4 v 91.0

seline GFR: 63.8 v 64.8seline ferritin: 52.5 v 60.1seline TSAT%: 17.7 v 16.7 seline Hgb: 11.9 v 11.9 

Mean change in HHgb: 1.1 v 0.6Mortality: 5 (3.4) v 4 (5.5)Cardiac events: 46 events in 38 pts (27.6%) v 49 events in 33 pts (50.2%), p=0.01First cardiovascular hospitalization: HR 0.53 (95% CI 0.25-1.09, p 0.08)Functional status/activity tolerance:NYHA, OR for improvement by 1 class: 2.40 (95% CI 1.55-3.71)Patient global assessment, OR for improvement: 2.51 (95% CI 1.75-3.61) 

6 minute walk (meters): 313 v 277 Quality of life outcomes: 

Kansas City Cardiomyopathy Questionnaire Score: 66 v 59EQ-5D Score: 63 v 57Adverse events: GI event: 29 events in 24 pts (16.9%) v 7 events in 5 pts (6.9%), p=0.06Respiratory event: 9 events in 9 pts (6.2%) v 13 events in 10 pts (14.2%), p=0.06

Overall: low risk of biasFunding source:Vifor Pharma

24 v 11

male: 71 v 73

white: 88 v 91

an age: 64 v 62

CAD: 79 v 73

EF%: 30 v 29

AAS blockers: 96 v 91

seline Cr: 1.23 v 1.17 (mg/dL)seline ferritin: 62 v 88 

seline TSAT%: 20 v 21seline Hgb: 12.6 v 12.2

Mean change in Hgb: 0.5 v 0.4Mortality: 1/24 (4.2%) v 0Hospitalizations: 3/24 (12%) v 3/11 (27%)Functional status/activity tolerance:NYHA: 2.1 v 2.6Mean change NYHA -0.4 v 0.2, p = 0.007Mean change exercise duration (s): 45 v -15 Patient global assessment: 1.5 v -0.2, p = 0.002Mean change MLHFQ: -10 v 3, p = 0.07Adverse events: abdominal pain -2/24 (8%) v 0TIA - 1/24 (4%) v 0

Overall: unclear risk of biasFunding source:Vifor International

20 v 20

male: NRwhite: NR

an age: 76 v 74

CAD: 60 v 55

an LVEF%: 31.3 v 30.8

RAAS blockers: 95 v 100

seline GFR: 39.8 v 37.7seline ferritin: 73.0 v 70.6seline TSAT%: 20 v 20seline Hgb: 10.3 v 10.2

Mean change in Hgb: +1.5 v -0.4Mean change in CrCl: +5.1 v -6.0, p<0.01Hospitalizations: 0/20 v 5/20 (20%), p<0.01Functional status/activity tolerance:MLHFQ score: 41 v 59, p<0.01Mean change in MLHFQ score: -19 v -66 minute walk (meters): 240.1 v 184.5 , p<0.01

Overall: low risk of bias.
29

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

KEY QUESTION #3. In patients with CHF or CHD, what are the health 

outcome benefits and harms of treating anemia with red blood cell 

transfusions? 

Summary

We found 35 studies that examine the association between red blood cell transfusion and clinical 

outcomes in patients with CHD or CHF. Ten of these studies evaluated transfusion use in the 

perioperative period; the remaining reports, all but one published since 2001, focused on the nonsurgical population. Three of these studies were subgroup analyses of the same registry;36-38 thus, 

in the end, we found 23 unique studies of the potential benefits and harms of transfusion outside 

of the perioperative period in patients with ischemic heart disease and/or CHF. 

Outside of the surgical setting, red blood cell transfusion has been evaluated as a treatment for 

anemia in heart disease in two controlled trials: one found no difference in survival from more 

aggressive transfusion above a threshold hemoglobin 10 g/dL,39 while the other found a higher 

incidence of heart failure in patients transfused to that level, without a difference in survival.40

Twenty-one additional observational studies have been conducted in patients undergoing 

percutaneous coronary intervention (PCI) or admitted with acute coronary syndrome, myocardial 

infarction, or decompensated heart failure. Inconsistency of findings and methodological 

weaknesses complicate the interpretation of results, but several themes emerge: 1) the evidence 

strongly suggests that transfusion has no benefit and may be harmful in patients with heart 

disease and hemoglobin >10 g/dL, with the possible exception of those with ST-elevation 

myocardial infarction; 2) outcomes do not appear to improve with transfusion in non-STelevation ACS patients with hemoglobin levels down to the 8 – 9 g/dL range; 3) transfusion 

is consistently associated with higher mortality risk in the unselected PCI population, across 

multiple studies with mean nadir hemoglobin of 8 – 9 g/dL; and 4) the elevated risk in the PCI 

population is seen in patients with anemia related or unrelated to bleeding but may be higher in 

the non-bleeding anemic population. There is no evidence to guide decision-making in the stable 

coronary disease population, and the two studies in decompensated heart failure have conflicting 

results.

The literature evaluating the use of perioperative transfusion in patients with heart disease is 

concentrated primarily on the cardiac surgery population but does include several studies in 

vascular and orthopedic surgery and one in the general non-cardiac surgery population. Seven 

perioperative randomized controlled trials have been conducted, and each found no difference 

in survival or cardiovascular complications between patients transfused to a higher versus 

lower target hemoglobin. In the observational cohorts, transfusion did not appear to offer any 

protection; and in one study in the vascular surgery setting, mortality and myocardial infarction 

rates were higher overall in the transfused group, a harm in subgroup analysis limited to those 

transfused at a hemoglobin ≥ 9 g/dL.41
30

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Non-operative Setting

Randomized Controlled Trials

Only 2 of the 23 studies in nonsurgical populations were randomized controlled trials (Table 

3).39, 40 The TRICC trial, published in 1999, remains the only large controlled trial of transfusion 

strategies in hospitalized patients.42 This landmark study randomized 838 euvolemic, nonbleeding, critically ill patients with hemoglobin < 9 g/dL to one of two transfusion thresholds: 

hemoglobin of 7 g/dL (restrictive transfusion strategy) or 10 g/dL (liberal strategy). They found 

no significant difference between the two groups in mortality in the hospital or at 30 days, or in 

other clinical outcomes including cardiac events, pulmonary or infectious complications, organ 

dysfunction scores, and length of stay. Importantly, the trend suggested the potential for higher 

mortality and more cardiac events in patients treated to the higher hemoglobin level. In the 

subgroups of patients younger than 55 years of age or with APACHE II scores of 20 or lower, the 

mortality rate was statistically significantly higher in the liberally transfused group. 

In 2001, the TRICC authors published a post-hoc subgroup analysis focusing on patients with 

cardiovascular disease in general and ischemic heart disease in particular.39 Once again, there 

were no significant differences in any clinical outcome. However, the trend toward improved 

survival with a restrictive transfusion strategy disappeared in the general cardiovascular disease 

population, and in the ischemic heart disease subgroup, there was a higher mortality rate in the 

restrictive group, though the difference was nonsignificant (30 day mortality 21.1% versus 26.1% 

with liberal and restrictive strategies, respectively; p=0.38). Like the TRICC trial population 

overall, the ischemic heart disease subgroup was severely ill with multiple comorbidities (mean 

APACHE II scores of 23, 87% requiring mechanical ventilation). 

Cooper et al. performed a pilot trial (CRIT) designed to evaluate conservative versus liberal 

transfusion strategies specifically in patients with acute myocardial infarction.40 They randomized 

45 patients with hematocrit under 30 percent to a transfusion trigger of 24 percent (conservative 

strategy), with a target hematocrit 24 – 27 percent, or a trigger of 30 percent (liberal strategy), 

with a target of 30 – 33 percent. They found a higher rate of the primary endpoint, a composite of 

in-hospital death, recurrent MI, or new/worsening heart failure, in the liberally transfused group 

compared to the conservative group (38% versus 13%; p=0.046). The difference was explained 

entirely by a higher incidence of new or worsening CHF. 

An additional study, the Myocardial Ischemia and Transfusion trial, began two years ago and is 

now collecting final outcomes data.43 This multicenter, randomized, controlled trial aimed to enroll 

200 anemic patients hospitalized with acute coronary syndrome, including both STEMI and NSTEACS, or stable CAD undergoing cardiac catheterization during the index hospitalization. Like the 

TRICC and CRIT trials, patients were assigned to a restrictive (< 8 g/dL) or liberal (< 10 g/dL) 

transfusion threshold and were observed for clinical outcomes including mortality, myocardial 

ischemia, stroke, heart failure, infectious complications, and readmission. 

Observational Studies

Given the sparse and the inconsistent data from the trial literature, clinical decision-making 

appears largely guided by an imperfect body of evidence characterized by conflicting 
31

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

observational data. We reviewed these observational studies, in part to clarify their utility in 

guiding transfusion treatment decisions (Table 4).

Because of the observational nature of these studies, the decision to transfuse patients was based on 

clinical judgment which, in turn, would be naturally influenced by severity of illness, symptoms, 

and observation of bleeding. All the included observational studies suffer from the possibility 

of residual confounding and are all, therefore, of lower quality than the evidence provided by 

randomized controlled trials. However, there were methodologic differences amongst observational 

studies. For instance, some accounted for bleeding and conducted propensity to transfuse 

adjustments, while others did not. These factors are summarized in Appendix C, Table 3. 

Percutaneous Coronary Intervention

Nine observational studies looked exclusively at populations undergoing percutaneous coronary 

intervention; six included all indications,36-38, 44-48 and three examined PCI solely in the setting of 

acute MI.49-51

In those studies that recorded it, 1.8 – 6.7 percent of unselected patients undergoing PCI received 

PRBC transfusion; rates were higher in those studies for which anemia was an inclusion 

criterion. A substantial proportion of patients who received transfusions did so because of major 

bleeding (22 – 100%), and median nadir hematocrit prior to transfusion ranged across studies 

from 24 to 30 percent. After adjustment for potential confounding factors in multivariable 

analyses, transfusion was associated with worse survival in all studies but one;36-38 it found no 

significant relationship between transfusion exposure and death or MI, both in cohorts with 

hematocrit < 27 percent and 24 – 30 percent. The association between transfusion and increased 

mortality appeared stronger in non-bleeding patients,44, 51 but was also noted in several studies 

that examined patients with major bleeding.44-46

Acute Coronary Syndrome/Myocardial Infarction

Twelve observational studies evaluated transfusion in the setting of acute coronary syndrome or 

myocardial infarction; four included only patients with non-ST-elevation ACS,52-55 two included 

patients exclusively with ST-elevation MI,50, 56 and six examined mixed ST/non-ST elevation ACS 

populations. Of these, three included predominately STEMI patients,51, 57, 58 two had a majority 

NSTE-ACS population,59, 60 and one did not record the breakdown.49 PCI rates ranged from 10 to 

100 percent and transfusion rates from 4 to 30 percent across cohorts. Nadir hematocrit among 

patients who were transfused averaged from 25 to 29 percent in those studies that recorded it. 

Eight of the ACS/AMI studies did find an association between transfusion and higher risk of death, 

including the three studies that focused exclusively on AMI patients undergoing PCI;49-51 three 

involving patients with high-risk non-ST-elevation ACS,52-54 and two examining patients primarily 

with ST-elevation myocardial infarction.56, 58 One additional study found no relationship between 

transfusion status and in-hospital mortality in a mixed ST/non-ST-elevation ACS population, 

regardless of whether the transfusion was bleeding-related or for non-specific anemia.60

Six studies examined whether mortality risk varies according to hemoglobin level, but they had 

varied results and used different thresholds for their stratified analyses, making it difficult to 

draw firm conclusions.52, 54, 55, 57-59
32

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Wu et al. examined a cohort of nearly 79,000 Medicare beneficiaries 65 years of age or older 

who were hospitalized with confirmed acute MI and were not actively bleeding.59 They found a 

consistent association between transfusion and improved survival in patients with hematocrit values 

on admission of 30 percent or less, stronger in each successively lower hematocrit category. This 

benefit was lost in patients with hematocrit above 33 percent, and risk of death at 30 days was 

statistically significantly higher with transfusion once hematocrit rose above 36 percent. 

Meanwhile, Rao et al. analyzed 24,112 patients who had been enrolled in three large 

international ACS trials (GUSTO IIB, PURSUIT, PARAGON B).52 They found that receipt of 

transfusion predicted increased risk of death and death/MI at 30 days. After stratifying results by 

nadir hematocrit, they noted no association between transfusion exposure and mortality with a 

hematocrit of 25 percent or below, but they found a highly increased probability of death at 30 

days with transfusion at a nadir hematocrit of 30 percent or higher.

Sabatine et al. performed a post-hoc meta-analysis of 16 prior TIMI cardiac trials, finding that 

transfusion appeared to confer a protective effect in terms of cardiovascular mortality in patients 

with STEMI and admission hemoglobin less than 12 g/dL.57 Meanwhile, there was a nonsignificant trend towards worse outcomes in STEMI with transfusion at hemoglobin level greater 

than 12 g/dL; and in the NSTE-ACS population, they noted an association between transfusion and 

higher risk for a combined mortality and cardiovascular event endpoint at all hemoglobin levels. 

Of the three remaining studies that performed stratified analyses, transfusion was found to be of 

potential benefit in acute MI patients with nadir hemoglobin 8 g/dL or less,58 and nonsignificant 

trends toward improved outcomes were noted in NSTE-ACS patients with hemoglobin at 

presentation less than 9 g/dL,54 and NSTE-ACS patients with hematocrit 24 percent or less.55

In each case, transfusion at hemoglobin or hematocrit levels higher than these thresholds was 

associated with increased mortality. 

Heart Failure

Two observational studies evaluated patients with acute decompensated heart failure,61, 62 with 

conflicting results. Garty et al. evaluated 2,335 patients admitted for acute decompensated heart 

failure to public hospitals in Israel.61 They found that transfusion appeared to confer lower 

risk of death at 30 days, with trends toward benefit in-hospital, at one year and at four years. 

Meanwhile, Kao et al. noted higher adjusted in-hospital mortality with transfusion in a large 

cohort of patients hospitalized for heart failure in California.62 This association was noted in both 

anemic and non-anemic patients but was much stronger in the non-anemic cohort. 

Perioperative Setting

Cardiac Surgery

There were four randomized controlled trials of which two enrolled fewer than 40 patients 

total and were designed to evaluate primarily hemodynamic and lab parameters, while two 

were larger, enrolling 400 to 500 patients with primary clinical endpoints (Table 3). All 

were consistent in finding no difference in survival or cardiovascular complications with a 

conservative compared to a liberal transfusion strategy.63-66
33

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Non-cardiac Surgery

Six studies, including three controlled trials and three observational studies, have reported 

outcomes based on transfusion status in patients with heart disease undergoing non-cardiac 

surgery. In the three controlled trials, performed in hip fracture and vascular surgery populations, 

there was no apparent benefit or harm from a more versus less aggressive transfusion strategy 

(Table 3).67-69 By far, the largest of these studies, the FOCUS trial that enrolled over 2,000 

patients undergoing hip fracture surgery, has only reported results in abstract form, with full 

publication expected in the very near future. The authors report no difference in mortality and 

functional status outcomes between the liberal and conservative transfusion groups. In the 

observational cohorts, transfusion did not appear to offer any protection, and in one study in the 

vascular surgery setting, mortality and myocardial infarction rates were higher overall in the 

transfused group, a harm in subgroup analysis limited to those transfused at a hemoglobin ≥ 9 g/

dL (Table 3).41, 68, 70
34

 with Heart Disease: A Systematic Review Evidence-based Synthesis Program

d trials of red blood cell transfusion for anemia in patients with CHD or CHF, stratified by patient setting

N

Intervention

Transfusion Rate 

(%) Rate of 

Major 

Bleeding 

(%)

Mean Achieved 

Hgb/Hct

Outcome

%

HR/OR adj or

P value

Liberal 

Hgb/Hct 

trigger

Restrictive 

Hgb/Hct 

trigger

Liberal Restric- tive Liberal Restric- tive Liberal Restric- tive

CI)

45 Hct 30 Hct 24 100 54 0 

(exclusion 

criterion)

Hct 30.6 Hct 27.9 mortality, in-hospital

death/MI/CHF, in-hospital

CHF, in-hospital

mortality, 30 d

death/MI/CHF, 30 d

5

3838

5

60

8

13

88

20

p=1.0

p=0.046

p=0.03

p=1.0

p=0.02

dx

RCT

se 

357 (44.8% 

restrictive)

257 (43.2% 

restrictive)

Hgb 10 Hgb 7 100

(full 

study)

67

(full study)

0 

(exclusion 

criterion)

Hgb 10.3 Hgb 8.5 mortality, 30 d

mortality, 60 dmortality, 30 dmortality, 60 d

22.826.921.124.5

22.526.226.128.8

0.79 (0.45-1.43)

p=0.9

p=0.38p=0.48

F)

6

99 Hgb 10 Hgb 9 NR NR NR Hgb 11.0 Hgb 9.8 mortality, 30 d

MI, 30 d

cardiac events, 48 hrs

84

16

82

16

p>0.6

for all

0 

7

84 Hgb 10 Hgb 8 100 45 NR Hgb 10.7 Hgb 9.7 mortality, 60 d

death/immobility, 60 d

4.8

45.2

11.9

39.0

NSNS

wn 

3-

2016 Hgb 10 Hgb 8 100 NR NR Hgb 9.2 Hgb 7.9 mortality, 60 d

death/immobility, 60 d

readmissions

falls

fatigue

7.6

35

6.5

35

1.19 (0.76-1.86)1.03 (0.85-1.23)

NSNSNS

428 Hgb 9 Hgb 8 64 60 NR NR NR mortality, in-hospital

MI, in-hospital

2.70.5

1.4

0

p=0.32

NS

10

502 Hct 30 Hct 24 78 47 NR Hct 31.8 Hct 28.4 mortality, 30 d

death/shock/ARDS/

dialysis, 30 d

cardiac complications

5

1021

6

11

24

p=0.93p=0.85p=0.27

R

39 Hct 32 Hct 25 100 80 NR Hct 31.3 Hct 28.4 mortality, in-hospital

MI/CVA/CHF, in-hospital

0

11.1

05

NSNS

NR

27 Hgb 12 

(plus 

plasma for 

volume)

Hgb 7 

(plus 

crystalloid for 

volume)

NR NR NR Hgb 12.1 Hgb 8.9 mortality, 72 hrs

MI, 72 hrs

00

00

NSNS
35

 with Heart Disease: A Systematic Review Evidence-based Synthesis Program

 of red blood cell transfusion for anemia in patients with CHD/CHF

on Design Number

Transfusion 

Rate (%)

Rate of Major 

Bleeding (%)

Mean/Median 

Nadir Hct, 

Transfused 

Cohort (%) Outcome

Crude %

HR/OR adj

Transfused

Not 

Transfused

% ACS, 

umbia, 

Observational 

cohort, registry

Propensity score 

matched cohort

38872

914

2.5

50

NR NR mortality, 30 d

mortality, 1 yr

mortality, 30 d

propensity matched

mortality, 1 yr

propensity matched

12.622.9

7.7

19.3

1.33.2

2

5.7

4.01 (3.08-5.22)3.58 (2.94-4.36)

3.9 (1.89-8.0)

3.38 (2.22-5.14)

% urgent/

 NR)

005

Observational 

cohort, 

administrative 

database

17901 6.7 4.8 (overall)

38 (transfused cohort)

NR mortality, 30 d

1-2 units

≥3 units

mortality, 1 yr 24.6 13

8.9 (6.3-12.6)

18.1 (13.7-24.0)

STEMI 

BS),1997-

Observational 

cohort, registry

Propensity score 

matched cohort

4623

1196

22.3 NR Hgb 10.0 

(overall) 

transfused 

cohort NR but 

87.8% Hgb <10

mortality, in-hospital

MACE, in-hospital

stroke/TIA

mortality, in-hospital, 

propensity matched

stroke/TIA,

propensity matched

14.5220.81

2.42

12.71

2.01

3.015.130.847.362.01

2.02 (1.47-2.79)

, 2004-

Observational 

cohort, post-hoc 

analysis of APEXAMI trial

5532 3.9 81.7 (transfused 

cohort)

Hgb 8.7 mortality, 90 d

CV death, 90 d

MI, 90 d

CHF, 90 d

CVA, 90 d

26

16.7

7.8

15.2

4.9

4.13.52.64.4

1

2.16 (1.20-3.88)

/STEMI 

2002

Observational 

case-control, 

registry

146 txfused 

pts, 292 

controls

NR 100 24 mortality, in hospital

mortality, 1 yr

11

26

3.1

10.3

p=0.0008

2.42 (1.32-4.46)

% AMI, 

na)

-2000

Observational 

cohort, registry

10974 5.4 5.4 (overall)

41.8 (transfused 

cohort)

24.7 mortality, in-hospital

major bleeding

no bleeding

mortality, 1 yr

major bleeding

no bleeding

9.2

10.610.328.422.736.8

0.65.10.45.4

13.6

5

2.0 (1.1-3.2)1.9 (1.4-2.5)

/STEMI 

CI

3-2007

Observational 

cohort, registry

379 53.5 NR 24.1 death/MI, 1 yr 26.6 17.2 1.1 (0.7-1.6)
36

 with Heart Disease: A Systematic Review Evidence-based Synthesis Program

on Design Number

Transfusion 

Rate (%)

Rate of Major 

Bleeding (%)

Mean/Median 

Nadir Hct, 

Transfused 

Cohort (%) Outcome

Crude %

HR/OR adj

Transfused

Not 

Transfused

/STEMI 

CI

3-2007

shock

bleeding

Observational 

cohort, registry

625202

60

30.2 9.6 (overall)

22.8 (transfused 

cohort)

100 (transfused 

cohort)

26.5 death/MI, 30 d

mortality, 30 d

death/MI, 1 yr

mortality, 1 yr

death/MI, 30 d

death/MI, 1 yr

death/MI, 30 d

death/MI, 1 yr

15.815.328.627.5

14

27.9

7.16.9

19.618.5

11.8

17.6

1.4 (0.8-2.5)1.4 (0.9-2.0)1.3 (0.6-2.8)0.9 (0.5-1.9)

NSNS

/STEMI 

major 

3-2007

Observational 

cohort, registry

3738 1.6 100 (transfused 

cohort)

NR death/MI, 1 yr 16.4 3.7 1.93 (0.81-4.17)

MI)

, 1997-

sion for 

bleed

Observational 

cohort, posthoc analysis of 

CADILLAC trial

2082

33 major 

bleeding

49 no bleed

4 40.2 (transfused 

cohort)

29.9 (53.7% Hct 

>30)

28.5 (bleeding)

\

30.4 (no evident 

bleeding)

mortality, 30 d

mortality, 1 yr

MACE, 1 yr

mortality, 30 d

mortality, 1 yr

mortality, 30 d

mortality, 1 yr

13.423.9

41

6.1

19

18.429.3

3.4

16.6

4.71 (1.97-11.26)

3.16 (1.66-6.03)

% urgent/

EMI rate 

9, 2001-

Observational 

cohort, registry

6656 1.8 1.8 (overall)

100 (transfused 

cohort)

NR mortality, in-hospital

mortality, 1 yr

9.9

18.8

1.24.7

3.59 (1.66-7.77)1.65 (1.01-2.70)

% PCI)

-2006

Observational 

case-control

103 txfused 

pts, 185 

controls

NA 42 (transfused cohort) 26.2 mortality, in-hospital

non-specific anemia

overt bleeding

19.4 10.8 1.8 (0.6-5.1)

0.9 (0.3-2.4)

2.7 (0.7-10.0)
37

 with Heart Disease: A Systematic Review Evidence-based Synthesis Program

on Design Number

Transfusion 

Rate (%)

Rate of Major 

Bleeding (%)

Mean/Median 

Nadir Hct, 

Transfused 

Cohort (%) Outcome

Crude %

HR/OR adj

Transfused

Not 

Transfused

2% PCI)

2005

Observational 

cohort, registry 

(CRUSADE)

44242 10.4 (0.9%-

79.2% lowesthighest 

quartile)

11.9 (overall; not given 

for transfused cohort)

25.7 mortality, in-hospital

Hct ≤ 24

Hct 24.1-27Hct 27.1-30

Hct >30

death/MI, in-hospital

Hct ≤ 24

Hct 24.1-27Hct 27.1-30

Hct >30

CHF, in-hospital

Hct ≤ 24

Hct 24.1-27Hct 27.1-30

Hct >30

11.8

9.37.3

12.215.913.110.618.217.419.116.417.9

15

9.16.12.6

17.412.5

8.3

4

9.4

12.8

11.5

5.3

0.67 (0.45-1.02)1.01 (0.79-1.30)1.18 (0.92-1.50)3.47 (2.30-5.23)

8% PCI, 

000-2006

Observational 

cohort, registry

2358 8.1 NR Hgb 8.8 mortality, 6 mo, all

Hgb ≤ 8

Hgb > 8

death/MI/CHF, 

6 mo, all

Hgb ≤ 8

Hgb > 8

28.141.1

11.7

19.6

1.9 (p=0.001)

0.13 (CI 0.03-0.65)

2.2 (CI 1.5-3.3)

1.4 (p=0.05)

0.24 (CI 0.07-0.75)

1.6 (CI 1.1-2.2)

 NR)

, 1994-

Observational 

cohort, post-hoc 

meta-analysis of 

3 RCTs (GUSTO 

IIB, PURSUIT, 

PARAGON B)

24112 10 NR (tracked bleeding 

and adjusted for but 

didn’t report)

29 mortality, 30 d

Hct 20Hct 25Hct 30Hct 35

death/MI, 30 d

8

29.2

3.1

10

3.94 (3.26-4.75)1.59 (0.95-2.66)1.13 (0.70-1.82)

168.6 (7.5-3797.7)

291.6 (10.3-8273.8)

2.92 (2.55-3.35)

4.8% 

enter 

001

Observational 

cohort, post-hoc 

meta-analysis of 

16 TIMI trials

39922 3.9 (overall)

4.6 (STEMI)

2.7 (NSTEACS)

80 (transfused cohort) NR CV mortality, 30d, 

STEMI 

Hgb < 12

Hgb ≥ 12

MACE, 30 d, NSTE-ACS

0.42 (CI 0.20-0.89)

1.42 (CI0.94-2.17)

1.54 (CI 1.14-2.09)

I)

, 1994-

Observational 

cohort, posthoc analysis of 

GUSTO IIB trial

Propensity score 

matched cohort

3575

316

8.6 97 (transfused cohort)

0.6 (non-transfused)

25.1 mortality, 30 d

MI, 30 d

mortality, 6 mo

MI, 6 mo

mortality , 1 yr

mortality, 30 d,

propensity matched

mortality, 6 mo,

propensity matched

mortality, 1 yr,

propensity matched

13.719.721.8

5.56.98.7

3.89 (2.66-5.68)

3.44, p<0.001

3.63 (2.67-4.95)

2.69, p<0.001

3.03 (2.25-4.08)5.44 (3.21-9.22)4.81 (3.00-7.71)3.10 (2.18-4.40)
38

 with Heart Disease: A Systematic Review Evidence-based Synthesis Program

on Design Number

Transfusion 

Rate (%)

Rate of Major 

Bleeding (%)

Mean/Median 

Nadir Hct, 

Transfused 

Cohort (%) Outcome

Crude %

HR/OR adj

Transfused

Not 

Transfused

PCI rate 

dl

-2005

Observational 

cohort, registry

370 29.7 NR NR mortality, 30 d

death/MI, 30 d

recurrent MI, 30 d

26.433.6

7.3

11.2

14.2

3.5

2.57 (1.41-4.69)

% cath, 

1995

Observational 

cohort, 

administrative 

database

78974 4.7 0 (exclusion criterion) NR mortality, 30 d

admission Hct 5-25

Hct 24.1-27Hct 27.1-30Hct 30.1-33Hct 33.1-36Hct 36.1-39

Hct >39

0.22 (0.11-0.45)

0.48 (0.34-0.69)0.60 (0.47-0.76)0.69 (0.53-0.89)1.13 (0.89-1.44)1.38 (1.05-1.80)1.46 (1.18-1.81)

 rate NR)

2004

Observational 

cohort, registry 

(CRUSADE)

85111 (overall), 

74,271 nonCABG

14.9 (overall), 

10.3 (nonCABG)

NR 26 mortality, in-hospital

death/MI, in-hospital

11.5

13.4

3.85.8

1.67 (1.48-1.88)1.44 (1.30-1.60)

nosis

003

Observational 

cohort, survey

Propensity score 

matched cohort

2335

206

7.1 NR Hgb 8.7 mortality, in-hospital

mortality, 30 d

mortality, 1 yr

mortality, 4 yrs

mortality, in hospital,

propensity matched

mortality, 30 d,

propensity matched

mortality, 1 yr,

propensity matched

mortality, 4 yrs

propensity matched

10.8

11

39.669.5

8.79.7

38.872.8

5.28.5

28.559.514.618.442.776.7

0.48 (0.21-1.11)

0.29 (0.13-0.64)0.74 (0.50-1.09)0.86 (0.64-1.14)

nosis

0-2006

Observational 

cohort, 

administrative 

database

596456

`

6.2 NR NR; 27.1% had 

ICD-9 dx of 

anemia

mortality, in-hospital

anemic

non-anemic

8.377.09

17.46

3.964.433.81

3.8 (3.5-4.1)1.7 (1.6-1.8)

scular 

anada, 

Observational 

cohort

1365 24.2 NR Hgb 10.7 mortality, ICU

Hgb < 9.5

Hgb < 9.5 + APACHE >20 

+ txfusion ≤6 units

1-3 units4-6 units

7-10 units

>10 units

28.831.234.3

17.527.4

55

0.61 (0.37-1.00)0.49 (0.23-1.03)0.96 (0.39-2.45)0.64 (0.24-1.69)
39

 with Heart Disease: A Systematic Review Evidence-based Synthesis Program

on Design Number

Transfusion 

Rate (%)

Rate of Major 

Bleeding (%)

Mean/Median 

Nadir Hct, 

Transfused 

Cohort (%) Outcome

Crude %

HR/OR adj

Transfused

Not 

Transfused

ective (hx 

2.0%)

e NR

Observational 

cohort

359 26.5 8.6 Hgb 9.2 mortality, 30 d

Hgb 7-9

Hgb ≥ 9

MI, 30 d

death/MI, 30 d

Hgb 7-9

Hgb ≥ 9

mortality, 16.3 mo

MI, 16.3 mo

death/MI, 16.3 mo

16.821.127.4

1.56.87.2

5.38 (1.45-20.0)0.64 (0.13-3.18)

18.70 (3.12-112.1)

2.23 (0.98-5.09)3.07 (1.43-6.59)0.83 (0.26-2.60)

4.53 (1.69-12.12)

4.02 (2.24-7.87)2.02 (1.15-3.57)2.67 (1.71-4.18)

disease 

1993

Observational 

cohort 

3783 42% (overall); 

NR for CV 

disease pts

NR mortality, 30 d

Hgb 7-7.9Hgb 8-9.9

Hgb ≥ 10

1.07 (0.75-1.52)

NSNSNS

mergent,

30%

Observational 

cohort, National Surgical Quality 

Improvement 

Program registry

10,100 

(overall); 

cardiac disease 

subgroup NR

21.4 (overall) NR Baseline Hct 

27.1

mortality, 30 d NS
40

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

SUMMARY AND DISCUSSION

Anemia commonly complicates heart disease. Despite its association with poor outcomes and a 

biologically plausible argument supporting anemia correction, we found little evidence that use 

of ESAs or blood transfusions improve health outcomes in patients with heart disease. A limited 

evidence base consisting mainly of one trial suggests correction of iron deficiency in patients 

with symptomatic heart failure improves exercise tolerance and quality of life. 

By far, the largest number of trials has examined ESAs in patients with heart failure, and 

most of these included patients with systolic heart failure. Though a grouped analysis of these 

mainly small, single-center studies shows some initial promise that ESAs may improve exercise 

tolerance, the evidence base is limited by inconsistent findings across trials, with some finding 

benefit and others finding no effect. There are a number of possible reasons for the discrepant 

results including differences in patient populations, treatment dosing and formulation, and 

outcomes examined. For example, the largest of the trials19 enrolled slightly older patients and 

achieved a slightly smaller hemoglobin improvement with ESA use than did other trials finding 

a benefit. However, our analyses suggest that the clearest contributor to the discrepant findings 

was the quality of the individual studies themselves, with the poorer quality studies generally 

supporting a greater benefit from ESAs and the more rigorous trials finding a neutral effect.

Our review differs from a similar recent review of ESAs72 for three main reasons: 1) we evaluated 

studies in both heart failure and CHD patients, though most studies focused on heart failure; 2) we 

conducted additional analyses investigating the impact of study quality on the overall results; and 

3) we included studies of patients with advanced kidney disease if there were separately reported 

data for the subgroup of patients with comorbid heart disease. We felt the latter difference was 

justifiable because kidney disease is common among patients with heart disease, and we felt these 

data were important in understanding the potential benefits and harms in this population. 

Though there were few excess harms reported in the smaller ESA trials of heart failure patients, 

the excess risk associated with ESAs in CKD populations73 and cancer populations74 is of 

concern. Moreover, our own analysis suggests the potential for serious harms associated with 

aggressive ESA use among the large proportion of patients with heart disease and comorbid 

CKD. On the other hand, these data may not apply to patients with symptomatic heart failure and 

reduced systolic function, and they do not elucidate the role of less aggressive ESA use, leaving 

us with very limited evidence with which to truly evaluate the balance of benefits and harms 

of ESAs in patients with heart disease. While the large RED-HF trial should more definitively 

establish the balance of benefits and harms of ESA use in patients with heart failure, the current 

uncertainty of benefit and the possibility of significant harms suggest widespread use of ESAs in 

patients with heart disease may be premature. For patients with comorbid chronic kidney disease, 

the recent cautious FDA recommendations seem reasonable, as they acknowledge the uncertainty 

of the role of ESA use and suggest that, if they are to be used at all, patients should have Hgb of 

at least < 10 g/dL.75

There is good evidence from one methodologically sound, large multicenter trial that intravenous 

iron carboxymaltose improves exercise tolerance, quality of life, and exercise duration in patients 

with chronic, stable systolic heart failure.33 These results are most applicable to iron deficient 

patients with NYHA class III heart failure; relatively few patients with milder degrees of heart 
41

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

failure were included. It also may be premature to apply these results to patients with more subtle 

evidence of relative iron deficiency. Biologic plausibility and test of concept studies suggest iron 

replacement could play a role in improving symptoms of heart failure even when, theoretically, 

iron stores are adequate because symptoms may be related to a functional misuse of iron rather 

than absolute deficiency.4

 Nevertheless, though the criteria used to define iron deficiency were 

fairly broad, most patients enrolled in the FAIR HF trial had evidence of more advanced iron 

deficiency and limited iron stores. Finally, though these results are encouraging and have the 

potential to influence treatment of heart failure, the long-term health and cost implications of this 

are uncertain, and harms have not been more widely assessed.

Despite a paucity of data to support this contention, for decades, many physicians adhered to 

the “10/30 rule,” transfusing patients with hemoglobin under 10 g/dL and hematocrit under 30 

percent for perceived safety reasons.76 In recent years, the recognition of immunomodulatory 

effects from leukocyte contamination and changes in RBCs with storage that impair oxygen 

exchange have led to increased scrutiny of RBC transfusion practice, culminating in the TRICC 

trial. After its publication, there was widespread adoption of more restrictive transfusion 

standards. However, because oxygen extraction is already maximized in the coronary circulation, 

concern has remained that patients with fixed coronary stenoses, who cannot increase blood flow 

to enhance oxygen delivery, will be more susceptible to ischemia in the setting of anemia and, 

therefore, should generally be transfused to a higher target than the general population. Often, 

this continues to be a hemoglobin of 10 g/dL. 

In the perioperative literature, accumulating evidence from randomized controlled trials supports 

use of a conservative hemoglobin trigger no higher than 8 g/dL among heart disease patients 

in the intra- and postoperative setting. The results of the FOCUS trial, by far the largest study 

to investigate transfusion use in heart disease with over 2,000 enrolled patients, have thus far 

been released only in abstract form, but it found no difference in mortality, ability to walk across 

a room unaided, falls, or readmissions with transfusion at a threshold of 8 versus 10 g/dL.69

While they have some methodological weaknesses, four randomized controlled trials in cardiac 

surgery, one additional study in hip fracture, and one trial in vascular surgery all were consistent 

in finding no difference in mortality or other health outcomes with more restrictive use of 

transfusion.63-68 No similar trial has been conducted in the general surgery population. 

The data from observational studies in the perioperative setting are congruent with the results 

from randomized controlled trials. In non-cardiac surgery cohorts, transfusion did not appear to 

offer any protection.41, 68, 70 We chose to exclude cardiac surgery observational cohorts from our 

review; nevertheless, in 13 out of 14 such studies aggregated in two prior reviews, the primary 

results suggested increased risk of adverse clinical events, and the fourteenth was neutral.77, 78

No definitive conclusions about best transfusion practice in heart disease outside of the 

perioperative setting can be drawn from the evidence from randomized controlled trials. The 

TRICC subgroup analysis found no significant difference in survival between restrictive and 

liberal transfusion groups, but mortality was slightly lower in the liberally transfused group, a 

trend opposite of that noted in the overall population or any other studied subgroup.39 In any 

case, it is difficult to extrapolate from this critically ill population, where the mean APACHE 

II score was 23, most patients were mechanically ventilated, and many had noncardiac 

primary diagnoses. Meanwhile, the CRIT trial suggests that transfusion leads to heart failure 
42

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

exacerbations in ACS patients but was too small to properly evaluate for any effect on survival or 

recurrent myocardial ischemia.40 Results from the in-progress MINT trial may shed some light, 

but it is also small and designed only as a pilot, with the plan for a large scale follow-up trial.

Despite the limitations inherent to their design, several themes emerged in our review of the 

observational data that can potentially help to guide practice: 1) the evidence strongly suggests 

that transfusion has no benefit and may be harmful in patients with heart disease and hemoglobin 

> 10 g/dL; 2) outcomes do not appear to improve with transfusion in non-ST-elevation ACS 

patients with hemoglobin levels down to the 8 – 9 g/dL range; 3) transfusion is consistently 

associated with higher mortality risk in the unselected PCI population, across multiple studies 

with mean nadir hemoglobins of 8 – 9 g/dL; and 4) the elevated risk in the PCI population is seen 

in patients with anemia related or unrelated to bleeding but may be higher in the non-bleeding 

anemic population. There is no evidence to guide decision-making in the stable coronary disease 

population, and the two studies in decompensated heart failure have conflicting results.

One of the larger questions remains: at what hemoglobin threshold does transfusion become 

protective in ACS patients (i.e., the risks of anemia exceed the hazards of transfusion)? Wu et al. 

found that transfused AMI patients had lower adjusted mortality than nontransfused patients at 

any hemoglobin level under 10-11 g/dL,59 and Sabatine et al. noted that STEMI patients appeared 

to have lower cardiovascular mortality if they received PRBCs at a hemoglobin below a 

threshold of 12 g/dL.57 In contrast, Sabatine found increased risk of major adverse cardiac events 

in NSTE-ACS patients who received transfusion at any hemoglobin level; and Rao et al. found 

no benefit to transfusion in NSTE-ACS down to hemoglobin of ~7 g/dL, and a substantially 

increased risk of death with transfusion above hemoglobin of 10 g/dL.52 One other study found 

a significantly reduced risk of death at six months in AMI patients transfused at hemoglobin 

< 8 g/dL,58 and two noted non-significant trends toward improved survival in NSTE-ACS 

with transfusion at a hemoglobin below 8 – 9 g/dL.54, 55 All three studies found higher adjusted 

mortality in patients transfused above the 8 – 9 g/dL hemoglobin threshold.

Why might the identified hemoglobin thresholds differ across studies? In particular, can we 

explain the outlier findings by Wu and Sabatine that transfusion may be beneficial above a 

hemoglobin of 10 g/dL? The patients in the Wu study were generally older than in other trials, 

with potentially greater comorbidities (having not been screened for a clinical trial), and had 

lower rates of exposure to red blood cells. In contrast to many of the other studies, the Wu study 

relied on claims data with limited granularity. For example, the study grouped patients according 

to baseline anemia and did not examine how the development of anemia during hospitalization 

or the timing of transfusion affected outcomes. Though they excluded patients with major 

bleeding, it is almost certain that mean hemoglobin fell over the course of hospitalization; thus, 

their results, stratified by admission hemoglobin, would seem to overestimate any potential nadir 

hemoglobin threshold below which transfusion may be beneficial. Wu also excluded patients 

who underwent CABG, and fewer patients in the Wu study had PCI or reperfusion therapy. In 

theory, revascularized/reperfused patients may be more tolerant of severe anemia than their 

conservatively managed counterparts, since they can increase myocardial oxygen delivery 

through augmentation of blood flow without the need for PRBCs. 

The Sabatine study results suggest that STEMI patients, who suffer abrupt and complete 

occlusion of a coronary artery, may have a lower tolerance for anemia than NSTE-ACS patients 
43

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

and thus benefit more from transfusion, even to a hemoglobin of 12 g/dL. However, like Wu et 

al., they used admission hemoglobin in their study, so their results likely inflate the threshold 

hemoglobin nadir. Moreover, several other studies that included STEMI patients primarily 

or exclusively did not find any evidence of benefit from transfusion.50, 51, 56, 58 PCI rates were 

generally higher in these studies, however, which again might explain the difference.

As noted, aside from inconsistency of results, the major limitation of this body of observational 

studies is selection bias, namely, confounding by indication.79 In other words, because of the 

observational nature of these studies, the decision to transfuse patients was based on clinical 

judgment which, in turn, would be naturally influenced by severity of illness, symptoms, and 

observation of bleeding. Indeed, the studies show that the groups who were transfused more 

aggressively were more severely ill. Additionally, bleeding rates did vary substantially across 

studies but were inconsistently reported; one might reasonably expect that the risk-benefit 

balance of red blood cell transfusion would change in the setting of bleeding compared to stable 

blood volume. Despite, in some cases, the very careful propensity adjustment, the possibility of 

residual confounding remains and renders this a fairly tenuous evidence base. 

Perhaps in part because of the conflicting results, there is continued widespread variation in RBC 

transfusion practices, highlighting the need for more definitive guidance from large controlled 

clinical trials examining the comparative benefits of liberal and conservative transfusion 

strategies in patients with heart disease. Of note, the CRIT trial could not enroll their goal of 92 

patients in over six years of active recruitment; it is not clear why there were difficulties with 

recruitment, but this raises concerns about the feasibility of a large scale trial. There is increasing 

evidence as well that freshly collected units may be safer and more effective than PRBCs stored 

for longer periods;45, 80 future studies should also look specifically at the comparative benefits/

risks of transfusion of fresh RBCs in the heart disease population. 

CLINICAL APPLICATIONS

Clinicians encounter anemia in many different types of patients with heart disease, and may need 

to understand how the overall evidence base for anemia treatment pertains to the patient in front 

of them. Here we summarize how the data presented previously might apply to different common 

clinical scenarios:

1. Outpatient with stable NYHA class III congestive heart failure, ferritin of 50 μg/dL and a 

Hgb of 10g/dL

Intravenous iron supplementation could be considered to improve symptoms, but there 

is no consistent good-quality evidence at this time to support the use of ESAs or blood 

transfusions in this patient. The use of iron could even be considered if this patient had a 

normal hemoglobin. Of note, the data supporting IV iron comes largely from one trial, albeit 

a well-conducted one, that reported only short-term quality of life and exercise tolerance 

outcomes.33 Furthermore, the use of IV iron would be unsupported if this patient had milder 

heart failure symptoms or if the ferritin were normal given that there were few such patients 

included in the trial. Though a number of trials have examined the use of ESAs for patients 

similar to this, they do not convincingly show a consistent benefit and there may be important 

harms, especially if this patient had advanced kidney disease. A larger ongoing trial of 
44

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

ESA use should better clarify their role in this type of patient. There are no trials of blood 

transfusions applicable to this patient. 

2. Outpatient with stable NYHA class III congestive heart failure, end stage renal disease on 

hemodialysis, and Hgb 9 g/dL

The decision to use ESAs would be based largely on this patient’s comorbid kidney disease 

rather than the heart disease itself. The once common practice of using ESAs to raise 

hemoglobin in patients with advanced chronic kidney disease has been undermined by recent 

large-scale trials, and new FDA recommendations suggest use of ESAs only for patients 

with Hgb < 10 g/dL, and with as low a dose necessary to obviate blood transfusion. Three 

of these trials included substantial proportions of heart disease patients and found no benefit 

and possible serious harms from ESAs titrated to normal or near-normal hemoglobin.13, 26, 30

The benefit of titrating ESAs to lower hemoglobin targets in patients with heart disease and 

advanced kidney disease remains unexplored. There are no studies of iron supplementation or 

blood transfusion that would apply to this patient.

3. Hospitalized patient with decompensated heart failure and Hgb 9 g/dL

There is no data to guide the use of ESAs or iron in this patient. It is noteworthy that 

nearly all of the ESA and iron trials reviewed would have excluded patients like this 

with decompensated disease. Two observational studies of blood transfusions in patients 

hospitalized with CHF found conflicting results and do not convincingly support routine 

transfusion of patients like this, though the evidence base is very limited.

4. Patient with acute coronary syndrome and Hgb 9 g/dL

There is very little good direct evidence to guide whether or not to administer blood 

transfusions in this patient. One older trial of critically ill patients with cardiovascular disease 

found that patients transfused more aggressively (Hgb threshold 10 g/dL) did no better than 

those transfused less aggressively (threshold 7 g/dL). A small recent trial suggested a more 

aggressive strategy may actually be harmful in patients with acute coronary syndrome. Many 

observational studies in patients with ACS have found conflicting results, though the majority 

of them suggest increased harms associated with transfusions certainly above Hgb 10g/dL 

and in some cases, above Hgb > 8 g/dL, especially in patients who have undergone PCI. 

No trials have evaluated iron in patients with ACS.

5. Outpatient with chronic stable angina and Hgb 8 g/dL

There is no good evidence that directly applies to this patient. However, a large study of 

patients with ESRD and heart disease, many of whom had a history of angina, showed 

ESAs titrated to a normal hemoglobin did not reduce the incidence of angina requiring 

hospitalization and was associated with increased thrombotic events and higher mortality.26

Though patients in this study also received IV iron, there are no studies of IV iron alone in 

patients with chronic stable angina, nor are there studies examining blood transfusions. 

6. Patient admitted with a hip fracture awaiting surgery who has known, stable CHD and 

anemia with a Hgb of 9 g/dL
45

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

There is no evidence that transfusing such patients above a hemoglobin of 8 g/dL improves 

outcomes. Data from one large randomized controlled trial and a smaller pilot study found no 

benefit of transfusing patients to a target hemoglobin of 10 g/dL compared to 8 g/dL. There is 

no data which addresses the use of ESAs or iron in such patients. 

LIMITATIONS

Because our review was focused on patient-centered health outcomes, we did not include 

physiologic surrogates of exercise tolerance such as Vo2 max. In excluding such outcomes, we 

could have missed evidence of benefit on proximal outcomes. The largest ESA trials by far are 

those of patients with advanced renal disease and comorbid heart disease. We felt it important to 

include these studies given the large proportion of heart disease patients with comorbid chronic 

kidney disease and the potential harms these studies underscore. However, we acknowledge 

the limited applicability of these results to many patients with heart failure. The inclusion of 

observational studies in our review of the efficacy of blood transfusions may risk overstating the 

depth of the evidence base when, in fact, there is little trial data to guide practice and the risk of 

bias in the observational studies is likely too high to make them a reliable source of evidence to 

guide decision-making. Nevertheless, we felt the inclusion of such studies would allow greater 

transparency of the types of studies that are, de facto, currently guiding practice.

FUTURE STUDIES

Ongoing studies such as RED-HF should be able to more clearly define whether or not there 

is a role for ESAs in the treatment of anemic heart failure patients. If the study results are 

positive, there may be a need for future studies comparing the relative benefits of ESAs and iron 

in heart failure patients. Given that most ESA studies were conducted in patients with systolic 

dysfunction but a large proportion of CHF patients have preserved systolic function, future 

studies should clarify the role of ESAs in patients with preserved systolic function. There should 

be more studies of anemic patients with ischemic heart disease. Future studies should better 

clarify the influence of chronic kidney disease on the effectiveness of various anemia treatments. 

Rather than the very high hemoglobin targets trials to date have examined in patients with 

advanced kidney disease, future studies may consider the value of more moderate hemoglobin 

targets given the remaining uncertainty for patients with moderate anemia. There is a pressing 

need for more trials examining the role of blood transfusions; treatment of patients with stable 

or decompensated heart failure, as well as patients with stable, asymptomatic or actively 

symptomatic ischemic heart disease, remains uncertain. 

CONCLUSIONS

Anemia is common in patients with heart disease, but the evidence base to date does not 

convincingly support a role for ESAs for anemia correction. Iron treatment may help ameliorate 

symptoms over the short-term in patients with symptomatic heart failure. The role of blood 

transfusions remains understudied and unclear. Table 5 summarizes the evidence on the 

effectiveness of these therapies according to patient population and outcome.
46

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Table 5. Summary of the Evidence for the Effects of ESAs, Iron and Blood Transfusions for Anemia, by Patient Population and Outcome

Treatment Outcome Effect* GRADE 

Classification† Comment

Stable CHF, and no worse than stage 3 CKD

ESAs Exercise tolerance and 

duration

(~) Moderate Inconsistent results and methodologic 

weaknesses in some studies limit the 

evidence base. Overall, studies with low risk 

of bias found no significant effect. 

Quality of life (~) Low Infrequent reporting, inconsistent results, 

the variety of instruments used, and 

methodologic weaknesses in some studies 

greatly limit the evidence base. 

Mortality (~) Low Based on mainly small, single center trials 

with limited power and low event rates. 

Hospitalizations (~) Low Inconsistent results and methodologic 

weaknesses in some studies limit the 

evidence base. The two studies with low risk 

of bias found no significant effect. 

Harms including 

hypertension, 

cerebrovascular and 

thrombotic events

(~) Low Based on mainly small, single-center trials 

with low event rates. 

Iron Exercise tolerance and 

duration

(+) Moderate/High One well-conducted large multicenter trial 

and two smaller trials found benefit. 

Quality of life (+) Moderate/High One well-conducted large multicenter trial 

and two smaller trials found benefit. 

Mortality (~)/(+) Low The one large trial showed a trend towards 

benefit, but was, like the two smaller trials, 

not powered for this outcome.

Cardiovascular events (+) Moderate One large multicenter trial found benefit, but 

follow-up was relatively short. 

Serious harms (~) Moderate Based on one large and two small trials. 

Blood 

transfusions

All outcomes (0) No evidence.

Stable CHF, and stage 4 or 5 CKD

ESAs Exercise tolerance and 

duration

(0) No evidence. Trials including subgroups of 

CHF patients did not report this outcome 

separately.

Quality of life (~) Low One large trial of heart disease patients 

including large subgroup of CHF patients, 

but subgroup specific data not available. 

Mortality (–) Moderate Based on two large trials including large 

numbers with CHF; in one trial the increased 

risk of mortality was not significant; type and 

severity of CHF not reported. 

Cardiovascular events (~) High Based on three large trials including large 

numbers with CHF; type and severity of CHF 

not reported.

Venous thrombosis (–) Moderate Based on two large trials including large 

numbers with CHF; type and severity of 

CHF not reported; effects of more moderate 

hemoglobin targets not tested.
47

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Treatment Outcome Effect* GRADE 

Classification† Comment

Hypertension, 

cerebrovascular events

(–) Low Based on one large trial including large 

numbers with CHF, but CHF subgroup data 

not separately reported for this outcome.

Iron All outcomes (0) No evidence.

Blood 

transfusions

All outcomes (0) No evidence.

Decompensated CHF

ESAs All outcomes (0) No evidence.

Iron All outcomes (0) No evidence.

Blood 

transfusions

Mortality (–) Very low Two observational studies found conflicting 

results – one showed harm, one a possible 

benefit.

Stable CHD

ESAs Mortality (–) Low One large trial of heart disease patients 

including large subgroup of CHD patients, 

but subgroup specific data not available. 

Patients with ESRD, unclear application to 

other populations.

Quality of life (~) Low One large trial of heart disease patients 

including large subgroup of CHD patients, 

but subgroup specific data not available. 

Patients with ESRD, unclear application to 

other populations. 

Venous thrombosis (–) Low One large trial of heart disease patients 

including large subgroup of CHD patients, 

but subgroup specific data not available. 

Patients with ESRD, unclear application to 

other populations.

All other outcomes (0) No evidence.

Iron All outcomes (0) No evidence.

Blood 

transfusions

All outcomes (0) No evidence.

Acute coronary syndrome

ESAs All outcomes (0) No evidence.

Iron All outcomes (0) No evidence.

Blood 

transfusions

Mortality (~) Moderate Two RCTs, one with limited applicability 

to non ICU population, showed no benefit 

from transfusing above Hgb > 10 g/dL. 

Observational studies in PCI patients 

consistently showed no benefit and possible 

harm. 

Cardiovascular events (~) Low Two RCTs found conflicting results: one 

found harm, a larger trial found no effect. 

Observational studies did not commonly 

report this as a separate outcome.

Non-cardiac surgery

ESAs All outcomes (0) No evidence.

Iron All outcomes (0) No evidence.
48

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Treatment Outcome Effect* GRADE 

Classification† Comment

Blood 

transfusions

Mortality (~) Low One large RCT, but reported only in abstract 

form and only applicable to hip fracture 

patients.

Cardiac surgery

ESAs All outcomes (0) No evidence.

Iron All outcomes (0) No evidence.

Blood 

transfusions

Mortality (~) Moderate Two large and two small RCTs with some 

methodologic weaknesses.

GRADE = Grades of Recommendation, Assessment, Development, and Evaluation; ICU = intensive care unit; RCT = 

randomized controlled trial.

*Effect: (+) benefit; (–) harm; (~) mixed findings/no effect; (0) no evidence.

† GRADE classification: high = further research is very unlikely to change our confidence on the estimate of effect; 

moderate = further research is likely to have an important impact on our confidence in the estimate of effect and may 

change the estimate; low = further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very low = any estimate of effect is very uncertain.
49

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

REFERENCES

1. Boyd CM, Leff B, Wolff JL, et al. Informing clinical practice guideline development and 

implementation: prevalence of coexisting conditions among adults with coronary heart 

disease. Journal of the American Geriatrics Society. May 2011;59(5):797-805.

2. Felker GM, Adams KF, Jr., Gattis WA, O’Connor CM. Anemia as a risk factor and 

therapeutic target in heart failure. Journal of the American College of Cardiology. Sep 1 

2004;44(5):959-966.

3. Malyszko J, Bachorzewska-Gajewska H, Levin-Iaina N, et al. Prevalence of chronic 

kidney disease and anemia in patients with coronary artery disease with normal serum 

creatinine undergoing percutaneous coronary interventions: relation to New York Heart 

Association class. Israel Medical Association Journal: Imaj. Aug 2010;12(8):489-493.

4. Gonzalez-Costello J, Comin-Colet J. Iron deficiency and anaemia in heart failure: 

understanding the FAIR-HF trial. European Journal of Heart Failure. Nov 

2010;12(11):1159-1162.

5. Komajda M, Anker SD, Charlesworth A, et al. The impact of new onset anaemia on 

morbidity and mortality in chronic heart failure: results from COMET. European Heart 

Journal. Jun 2006;27(12):1440-1446.

6. Kosiborod M, Smith GL, Radford MJ, Foody JM, Krumholz HM. The prognostic 

importance of anemia in patients with heart failure. American Journal of Medicine. Feb 1 

2003;114(2):112-119.

7. Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous erythropoietin 

and intravenous iron for the treatment of the anemia of severe, resistant congestive 

heart failure improves cardiac and renal function and functional cardiac class, and 

markedly reduces hospitalizations. Journal of the American College of Cardiology. Jun 

2000;35(7):1737-1744.

8. Higgins JPT, Altman DG, editors. Chapter 8: Assessing risk of bias in included studies. 

In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of 

Interventions. 2008;Version 5.0.1. The Cochrane Collaboration, 2008. Availablefrom 

www.cochrane-handbook.org.

9. Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of 

recommendations. BMJ. Jun 19 2004;328(7454):1490.

10. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. Sep 

1986;7(3):177-188.

11. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a 

simple, graphical test. BMJ. Sep 13 1997;315(7109):629-634.
50

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

12. Comin-Colet J, Ruiz S, Cladellas M, Rizzo M, Torres A, Bruguera J. A pilot evaluation 

of the long-term effect of combined therapy with intravenous iron sucrose and 

erythropoietin in elderly patients with advanced chronic heart failure and cardio-renal 

anemia syndrome: influence on neurohormonal activation and clinical outcomes. Journal 

of Cardiac Failure. Nov 2009;15(9):727-735.

13. Szczech LA, Barnhart HX, Sapp S, et al. A secondary analysis of the CHOIR trial shows 

that comorbid conditions differentially affect outcomes during anemia treatment. Kidney 

International. Feb 2010;77(3):239-246.

14. Pfeffer MA, Burdmann EA, Chen C-Y, et al. Baseline characteristics in the Trial to 

Reduce Cardiovascular Events With Aranesp Therapy (TREAT). American Journal of 

Kidney Diseases. Jul 2009;54(1):59-69.

15. Palazzuoli A, Silverberg DS, Calabr, et al. Beta-erythropoietin effects on ventricular 

remodeling, left and right systolic function, pulmonary pressure, and hospitalizations in 

patients affected with heart failure and anemia. Journal of Cardiovascular Pharmacology. 

Jun 2009;53(6):462-467.

16. Parissis JT, Kourea K, Andreadou I, et al. Effects of Darbepoetin Alfa on plasma 

mediators of oxidative and nitrosative stress in anemic patients with chronic heart 

failure secondary to ischemic or idiopathic dilated cardiomyopathy. American Journal of 

Cardiology. Apr 15 2009;103(8):1134-1138.

17. Kourea K, Parissis JT, Farmakis D, et al. Effects of darbepoetin-alpha on quality of life 

and emotional stress in anemic patients with chronic heart failure. European Journal of 

Cardiovascular Prevention & Rehabilitation. Jun 2008;15(3):365-369.

18. Parissis JT, Kourea K, Panou F, et al. Effects of darbepoetin alpha on right and left 

ventricular systolic and diastolic function in anemic patients with chronic heart failure 

secondary to ischemic or idiopathic dilated cardiomyopathy. American Heart Journal. 

Apr 2008;155(4):751.e751-757.

19. Ghali JK, Anand IS, Abraham WT, et al. Randomized double-blind trial of darbepoetin 

alfa in patients with symptomatic heart failure and anemia. Circulation. Jan 29 

2008;117(4):526-535.

20. Besarab A, Goodkin DA, Nissenson AR, Normal Hematocrit Cardiac Trial A. The normal 

hematocrit study--follow-up. New England Journal of Medicine. Jan 24 2008;358(4):433-434.

21. Palazzuoli A, Silverberg DS, Iovine F, et al. Effects of beta-erythropoietin treatment 

on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels 

in patients with the cardiorenal anemia syndrome. American Heart Journal. Oct 

2007;154(4):645.e649-615.

22. van Veldhuisen DJ, Dickstein K, Cohen-Solal A, et al. Randomized, double-blind, placebocontrolled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients 

with heart failure and anaemia. European Heart Journal. Sep 2007;28(18):2208-2216.
51

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

23. Ponikowski P, Anker SD, Szachniewicz J, et al. Effect of darbepoetin alfa on exercise 

tolerance in anemic patients with symptomatic chronic heart failure: a randomized, 

double-blind, placebo-controlled trial. Journal of the American College of Cardiology. 

Feb 20 2007;49(7):753-762.

24. Mancini DM, Kunavarapu C. Effect of erythropoietin on exercise capacity in anemic patients 

with advanced heart failure. Kidney International - Supplement. Nov 2003(87):S48-52.

25. Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia 

in severe, resistant congestive heart failure using subcutaneous erythropoietin and 

intravenous iron: a randomized controlled study. Journal of the American College of 

Cardiology. Jun 1 2001;37(7):1775-1780.

26. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low 

hematocrit values in patients with cardiac disease who are receiving hemodialysis and 

epoetin. New England Journal of Medicine. Aug 27 1998;339(9):584-590.

27. Bellinghieri G, Savica V, De Gregorio C, De Gregorio G. Use of erythropoietin in 

ischemic and arrhythmic cardiopathy of hemodialyzed patients. Contributions to 

Nephrology. 1994;106:135-137.

28. Palazzuoli A, Silverberg D, Iovine F, et al. Erythropoietin improves anemia exercise 

tolerance and renal function and reduces B-type natriuretic peptide and hospitalization in 

patients with heart failure and anemia. American Heart Journal. Dec 2006;152(6):1096.

e1099-1015.

29. Desai A, Lewis E, Solomon S, McMurray JJV, Pfeffer M. Impact of erythropoiesisstimulating agents on morbidity and mortality in patients with heart failure: An updated, 

post-TREAT meta-analysis. European Journal of Heart Failure. 2010;12(9):936-942.

30. Pfeffer MA, Burdmann EA, Chen C-Y, et al. A trial of darbepoetin alfa in type 2 

diabetes and chronic kidney disease. New England Journal of Medicine. Nov 19 

2009;361(21):2019-2032.

31. Amgen. RED-HFTM Trial - Reduction of Events With Darbepoetin Alfa in Heart Failure 

Trial. ClinicalTrials.gov identifier: NCT00358215. Ongoing study.

32. Maurer MS. Anemia in Heart Failure With a Preserved Ejection Fraction (HFPEF). 

ClinicalTrials.gov Identifier: NCT00286182. Ongoing study.

33. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients 

with heart failure and iron deficiency. New England Journal of Medicine. Dec 17 

2009;361(25):2436-2448.

34. Toblli JE, Lombra, x00F, a A, Duarte P, Di Gennaro F. Intravenous iron reduces NTpro-brain natriuretic peptide in anemic patients with chronic heart failure and renal 

insufficiency. Journal of the American College of Cardiology. Oct 23 2007;50(17):1657-

1665.
52

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

35. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on 

exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart 

failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. 

Journal of the American College of Cardiology. Jan 15 2008;51(2):103-112.

36. Maluenda G, Lemesle G, Ben-Dor I, et al. Value of blood transfusion in patients with 

a blood hematocrit of 24% to 30% after percutaneous coronary intervention. American 

Journal of Cardiology. Oct 15 2009;104(8):1069-1073.

37. Maluenda G, Lemesle G, Syed A, et al. Does transfusion for major bleeding after 

percutaneous coronary intervention impact clinical outcome in patients admitted with 

normal Hematocrit? Journal of the American College of Cardiology. 2009;53(10):A72.

38. Maluenda G, Lemesle G, Syed A, et al. Should patients who develop anemia (hematocrit 

(less-than or equal to) 27%) after percutaneous coronary intervention be transfused? 

Journal of the American College of Cardiology. 2009;53(10):A84.

39. Hebert PC, Yetisir E, Martin C, et al. Is a low transfusion threshold safe in critically ill 

patients with cardiovascular diseases? Critical Care Medicine. Feb 2001;29(2):227-234.

40. Cooper HA, Rao SV, Greenberg MD, et al. Conservative Versus Liberal Red Cell 

Transfusion in Acute Myocardial Infarction (the CRIT Randomized Pilot Study). The 

American journal of cardiology. 2011.

41. Bursi F, Barbieri A, Politi L, et al. Perioperative red blood cell transfusion and outcome 

in stable patients after elective major vascular surgery. European Journal of Vascular & 

Endovascular Surgery. Mar 2009;37(3):311-318.

42. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical 

trial of transfusion requirements in critical care. Transfusion Requirements in Critical 

Care Investigators, Canadian Critical Care Trials Group. New England Journal of 

Medicine. Feb 11 1999;340(6):409-417.

43. Carson JL. Myocardial Ischemia and Transfusion (MINT). ClinicalTrials.gov identifier: 

NCT01167582. Ongoing study.

44. Kinnaird TD, Stabile E, Mintz GS, et al. Incidence, predictors, and prognostic 

implications of bleeding and blood transfusion following percutaneous coronary 

interventions. American Journal of Cardiology. Oct 15 2003;92(8):930-935.

45. Kim P, Dixon S, Eisenbrey AB, O’Malley B, Boura J, O’Neill W. Impact of acute blood 

loss anemia and red blood cell transfusion on mortality after percutaneous coronary 

intervention. Clinical Cardiology. Oct 2007;30(10 Suppl 2):II35-43.

46. Yatskar L, Selzer F, Feit F, et al. Access site hematoma requiring blood transfusion 

predicts mortality in patients undergoing percutaneous coronary intervention: data from 

the National Heart, Lung, and Blood Institute Dynamic Registry. Catheter Cardiovasc 

Interv. Jun 1 2007;69(7):961-966.
53

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

47. Doyle BJ, Ting HH, Bell MR, et al. Major femoral bleeding complications after 

percutaneous coronary intervention: incidence, predictors, and impact on long-term 

survival among 17,901 patients treated at the Mayo Clinic from 1994 to 2005. Jacc: 

Cardiovascular Interventions. Apr 2008;1(2):202-209.

48. Chase AJ, Fretz EB, Warburton WP, et al. Association of the arterial access site at 

angioplasty with transfusion and mortality: the M.O.R.T.A.L study (Mortality benefit 

Of Reduced Transfusion after percutaneous coronary intervention via the Arm or Leg). 

Heart. Aug 2008;94(8):1019-1025.

49. Jani SM, Smith DE, Share D, et al. Blood transfusion and in-hospital outcomes in anemic 

patients with myocardial infarction undergoing percutaneous coronary intervention. 

Clinical Cardiology. Oct 2007;30(10 Suppl 2):II49-56.

50. Jolicoeur EM, O’Neill WW, Hellkamp A, et al. Transfusion and mortality in patients with 

ST-segment elevation myocardial infarction treated with primary percutaneous coronary 

intervention. European Heart Journal. Nov 2009;30(21):2575-2583.

51. Nikolsky E, Mehran R, Sadeghi HM, et al. Prognostic impact of blood transfusion after 

primary angioplasty for acute myocardial infarction: analysis from the CADILLAC 

(Controlled Abciximab and Device Investigation to Lower Late Angioplasty 

Complications) Trial. Jacc: Cardiovascular Interventions. Jul 2009;2(7):624-632.

52. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical 

outcomes in patients with acute coronary syndromes. Journal of the American Medical 

Association. 2004;292(13):1555-1562.

53. Yang X, Alexander KP, Chen AY, et al. The implications of blood transfusions for patients 

with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE 

National Quality Improvement Initiative. Journal of the American College of Cardiology. 

Oct 18 2005;46(8):1490-1495.

54. Singla I, Zahid M, Good CB, Macioce A, Sonel AF. Impact of blood transfusions in 

patients presenting with anemia and suspected acute coronary syndrome. American 

Journal of Cardiology. Apr 15 2007;99(8):1119-1121.

55. Alexander KP, Chen AY, Wang TY, et al. Transfusion practice and outcomes in nonST-segment elevation acute coronary syndromes. American Heart Journal. Jun 

2008;155(6):1047-1053.

56. Shishehbor MH, Madhwal S, Rajagopal V, et al. Impact of blood transfusion on shortand long-term mortality in patients with ST-segment elevation myocardial infarction. 

Jacc: Cardiovascular Interventions. Jan 2009;2(1):46-53.

57. Sabatine MS, Morrow DA, Giugliano RP, et al. Association of hemoglobin levels with 

clinical outcomes in acute coronary syndromes. Circulation. Apr 26 2005;111(16):2042-

2049.
54

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

58. Aronson D, Dann EJ, Bonstein L, et al. Impact of red blood cell transfusion on clinical 

outcomes in patients with acute myocardial infarction. American Journal of Cardiology. 

Jul 15 2008;102(2):115-119.

59. Wu WC, Rathore SS, Wang Y, Radford MJ, Krumholz HM. Blood transfusion in 

elderly patients with acute myocardial infarction. New England Journal of Medicine. 

2001;345(17):1230-1236.

60. Aggarwal C, Panza JA, Cooper HA, Aggarwal C, Panza JA, Cooper HA. Does the 

relation between red blood cell transfusion and mortality vary according to transfusion 

indication? A case-control study among patients with acute coronary syndromes. Coron 

Artery Dis. May 2011;22(3):194-198.

61. Garty M, Cohen E, Zuchenko A, et al. Blood transfusion for acute decompensated heart 

failure--friend or foe? American Heart Journal. Oct 2009;158(4):653-658.

62. Kao DP, Kreso E, Fonarow GC, et al. Characteristics and outcomes among heart failure 

patients with anemia and renal insufficiency with and without blood transfusions (public 

discharge data from California 2000-2006). American Journal of Cardiology. Jan 

2011;107(1):69-73.

63. Weisel RD, Charlesworth DC, Mickleborough LL, et al. Limitations of blood 

conservation. Journal of Thoracic & Cardiovascular Surgery. Jul 1984;88(1):26-38.

64. Johnson RG, Thurer RL, Kruskall MS, et al. Comparison of two transfusion strategies 

after elective operations for myocardial revascularization. Journal of Thoracic & 

Cardiovascular Surgery. Aug 1992;104(2):307-314.

65. Bracey AW, Radovancevic R, Riggs SA, et al. Lowering the hemoglobin threshold for 

transfusion in coronary artery bypass procedures: effect on patient outcome. Transfusion. 

Oct 1999;39(10):1070-1077.

66. Hajjar LA, Vincent JL, Galas FR, et al. Transfusion requirements after cardiac surgery: 

the TRACS randomized controlled trial. JAMA. Oct 13 2010;304(14):1559-1567.

67. Bush RL, Pevec WC, Holcroft JW. A prospective, randomized trial limiting perioperative 

red blood cell transfusions in vascular patients. American Journal of Surgery. Aug 

1997;174(2):143-148.

68. Carson JL, Terrin ML, Barton FB, et al. A pilot randomized trial comparing symptomatic 

vs. hemoglobin-level-driven red blood cell transfusions following hip fracture. 

Transfusion. Jun 1998;38(6):522-529.

69. Carson JL, Terrin ML, Magaziner J, Sanders D, Cook DR, Hildebrand K. Transfusion 

trigger trial for functional outcomes in cardiovascular patients undergoing surgical hip 

fracture repair (FOCUS): The principal results. Blood. 2009;114(22).
55

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

70. Glance LG, Dick AW, Mukamel DB, et al. Association between intraoperative blood 

transfusion and mortality and morbidity in patients undergoing noncardiac surgery. 

Anesthesiology. Feb 2011;114(2):283-292.

71. Hebert PC, Wells G, Tweeddale M, et al. Does transfusion practice affect mortality in 

critically ill patients? Transfusion Requirements in Critical Care (TRICC) Investigators 

and the Canadian Critical Care Trials Group. Am J Respir Crit Care Med. May 

1997;155(5):1618-1623.

72. Ngo K, Kotecha D, Walters JA, et al. Erythropoiesis-stimulating agents for anaemia 

in chronic heart failure patients. Cochrane Database of Systematic Reviews. 

2010(1):CD007613.

73. Palmer SC, Navaneethan SD, Craig JC, et al. Meta-analysis: erythropoiesis-stimulating 

agents in patients with chronic kidney disease. Annals of Internal Medicine. Jul 6 

2010;153(1):23-33.

74. Agency for Healthcare Research and Quality. Comparative Effectiveness of Epoetin and 

Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment - Update 

DRAFT. AHRQ Comparative Effectiveness Review. In progress.

75. U.S. Food and Drug Administration. FDA Drug Safety Communication: Modified dosing 

recommendations to improve the safe use of Erythropoiesis-Stimulating Agents (ESAs) 

in chronic kidney disease Accessed 7/29/2011 at http://www.fda.gov/Drugs/DrugSafety/

ucm259639.htm#.TjNK6A-AqfM.email.

76. Wang JK, Klein HG. Red blood cell transfusion in the treatment and management of 

anaemia: the search for the elusive transfusion trigger. Vox Sanguinis. Jan 2010;98(1):2-11.

77. Gerber DR. Transfusion of packed red blood cells in patients with ischemic heart disease. 

Critical Care Medicine. Apr 2008;36(4):1068-1074.

78. Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a 

systematic review of the literature. Critical Care Medicine. Sep 2008;36(9):2667-2674.

79. Norris S, Atkins D, Bruening W, et al. Selecting observational studies for comparing 

medical interventions. In: Agency for Healthcare Research and Quality. Methods Guide 

for Comparative Effectiveness Reviews. Rockville, MD. Available at: http://www.

effectivehealthcare.ahrq.gov/ehc/products/196/454/MethodsGuideNorris_06042010.pdf

2010.

80. Robinson SD, Janssen C, Fretz EB, et al. Red blood cell storage duration and mortality in 

patients undergoing percutaneous coronary intervention. American Heart Journal. May 

2010;159(5):876-881.

81. Carson JL, Duff A, Berlin JA, et al. Perioperative blood transfusion and postoperative 

mortality. JAMA. Jan 21 1998;279(3):199-205.