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.
1

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

EXECUTIVE SUMMARY

BACKGROUND

Anemia is very common in congestive heart failure (CHF) and coronary heart disease (CHD) 

patients. Anemia in CHF and CHD patients is associated with poorer outcomes, including an 

increased risk of hospitalization, decreased exercise capacity, and poor quality of life. Despite 

the association with poorer outcomes, it is unclear whether treating anemia or iron deficiency 

will improve outcomes. Anemia treatment strategies in heart failure and CHD patients include 

erythropoiesis-stimulating agents (ESAs) and red blood cell transfusions. Iron replacement 

in iron deficient patients with or without anemia has also been investigated. The objective of 

this evidence review is to evaluate the balance of benefit and harms of these treatments. We 

conducted a systematic review to address the following key questions:

In patients with CHF or CHD,

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

METHODS

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

published from 1947 to November 2010, and 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 and by contacting pharmaceutical 

companies directly. Reviewers trained in the critical analysis of literature assessed for relevance the 

abstracts of citations identified from literatures searches. Full-text articles of potentially relevant 

abstracts were retrieved for further review. We assessed the internal validity of each study using 

the Cochrane Risk of Bias tool. We assessed the overall quality of the body of evidence for each 

outcome by considering the consistency, coherence, and applicability across studies, as well as the 

internal validity of individual studies, using a method developed by the Grades of Recommendation, 

Assessment, Development, and Evaluation (GRADE) Working Group. We performed meta-analyses 

of the effects of ESAs on health outcomes and we conducted additional analyses according to study 

quality, and according to baseline and change in hemoglobin. We qualitatively reviewed the much 

smaller number of trials evaluating iron and blood transfusion effects.

RESULTS

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. 
2

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

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

reviewed. Of the full-text articles, we rejected 266 that did not meet our inclusion criteria.

ESAs

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

disease. Most of these studies included patients with CHF and reduced systolic function. Though 

the group of studies as a whole showed ESA use may improve exercise tolerance, this benefit 

diminished substantially when we included only trials with low risk of bias. 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.

Iron

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 

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.

Blood Transfusions

Nine controlled trials have compared outcomes with the use of a restrictive versus more liberal 

strategy of red blood cell transfusion among patients with heart disease. In each, conservative 

use of blood products, guided by a transfusion trigger of hemoglobin 7-9 g/dL, was found to 

be as safe as transfusion to a higher hemoglobin threshold (most often 10 g/dL). However, 

the large majority of these studies were quite small, substantially underpowered for detecting 

important differences in clinical outcomes, and most were conducted in the perioperative setting. 

Nevertheless, the consistency of the results in the perioperative setting suggests conservative use 

of transfusion should be the default strategy.

Twenty-one additional observational studies have examined transfusion 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; 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.
3

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

DISCUSSION/CONCLUSION

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 erythropoiesis-stimulating agents or blood transfusions improves 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. The application of the evidence to different patient subsets is described in the 

main report and is summarized in the following table. 

EXECUTIVE SUMMARY TABLE

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.
4

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Treatment Outcome Effect* GRADE 

Classification† Comment

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.

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.
5

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Treatment Outcome Effect* GRADE 

Classification† Comment

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.

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.