Evidence‐based Synthesis Pro

(ESP)

Treatment of Anemia in Patients wit

Disease

A Systematic Review of the Eviden

Devan Kansagara MD, MCR

David Kagen MD

Edward Dyer MD

Cyberseminar 4/16/12
Evidence‐based Synthesis Pro

(ESP)

Acknowledgements

Co‐Authors/Collaborators Expert Panel/Revie

o Honora Englander MD o Sunil Rao MD

o Michele Freeman MPH o Tom Delougho Rose Relevo MLIS, MS o Nick Fitterma

o Barry Massie 

o Inderjit Inderjit Anano Jack McAnult
Evidence‐based Synthesis Pro

(ESP)

Disclosure

This report is based on research research conducted conducted by the Evidence Evidence‐based 

Program (ESP) Center located at the Portland VA Medical Center fu

Department of Veterans Affairs, Veterans Health Administration, Of

Research Research and Development Development, Quality Quality Enhancement Enhancement Research Research Initiat

Initiat

findings and conclusions in this document are those of the author(s

responsible for its contents; the findings and conclusions do not ne

represent represent the views of the Department Department of Veterans Veterans Affairs Affairs or the U

government. Therefore, no statement in this article should be cons

official position of the Department of Veterans Affairs. No investiga

affiliations affiliations or financial financial involvement (e.g., employment, consultanci

ltanci

stock ownership or options, expert testimony, grants or patents rec

pending, or royalties) that conflict with material presented in the re
Evidence‐based Synthesis Pro

(ESP)

VA E id v ence‐based Synthesis (ESP)

Program Overview

• Sponsored by VA Office of Research & Development, Quality 

Research Initiative (QUERI).

• Established Established to provide provide timely and accurate accurate syntheses/reviews syntheses/reviews 

topics identified by VA clinicians, managers and policy‐maker

work to improve the health and healthcare of Veterans.

• Builds on staff and expertise already in place at the Evidence‐

Practice Centers (EPC) designated by AHRQ. Four of these EP

ESP Centers:

o Durham VA Medical Center; VA Greater Los Angeles Healt

System; Portland VA Medical Center; and Minneapolis VA 

Center.
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(ESP)

• Provides evidence syntheses on important clinical practice to

to Veterans, and these reports help:

o develop cli i l n ca poli i c es i f n ormed by evidence,o the implementation of effective services to improve 

outcomes and to support VA clinical practice guidelin

performance measures, and

o guide the direction for future research to address gap

knowledge.

• Broad topic nomination process – e.g. VACO, VISNs, field – fa

ESP Coordinating Center (Portland) through online process:

http://www.hsrd.research.va.gov/publications/esp/TopicNomin
;

Evidence‐based Synthesis Pro

(ESP)

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and VISN) provides oversight and guides program direction.

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• External Peer Reviewers & Policy Partners

o Reviews Reviews and comments comments on draft report

• Final reports posted on VA HSR&D website and disseminated 

through the VA.

http://www.hsrd.research.va.gov/publications/esp/reports
Outline

• Poll• Anemia in heart disease disease• Summarize systematic review of anem

treatment efficacy

– Methods– Results: ESAs, iron, transfusions

• Implications• Questions
–

Poll Question Question 1

• How would you describe your primary

responsibility?

– 1) Researcher– 2) Clinician, mainly outpatient– 3) Clinician, mainly inpatient

– 4) Clinician, subspecialty

– 5) Administration
–

–

Poll question question 2

• Do you believe erythropoeisis stimulati

agents (eg EPO) should be used to tre

anemia in patients with congestive hea

f il a ure?

– 1) Yes– 2) No– 3) Unsure
–

Poll question question 3

• Have you used iron supplementation t

sy p m tomatic patients with heart failu

– 1) yes

2) no, but I have seen it used at my insti

insti

– 3) no– 4) unsure
Poll question question 4

• A 68 yo male is hospitalized after sustaining a hip fra

is awaiting awaiting surgery surgery. He has hip pain but is otherwise otherwise

asymptomatic. He has a history of MI 1 year ago. I w

transfuse him if hemoglobin were less than:

– 1) 10 g/dL

– 2) 9 g/dL– 3) 8 g/dL– 4) 7 g/dL
Poll question 5

• A 60 yo male was admitted with unstab

angina and underwent successful stent

placement today. He is not bleeding, b

Hgb is slightly slightly lower at 9 g/dL today. W

you transfuse him?

– 1) Yes

– 2) Only if he had symptoms

– 3) No

– 4) Unsure
Prevalence of anemia in he

disease

• 10‐20% of coronary heart disease pat

• One‐third of congestive congestive heart failure failure p

p

• Iron deficiency with or without anemi

very common
Anemia is associated with 

outcomes in CHF

• 2% increase in 1 yr mortality for each 1% low

hematocrit

K

• In stable CHF patients, development of new a

frequent frequent and associated associated with increasing increasing risk 

and hospitalization

• The mechanism for poor outcomes may be u

to underlying CHD and myocardial ischemia

F lk e 
Anemia and CHD

• Lower hemoglobin associated with hig

mortality risk after STEMI and NSTEM

• Anemia can decrease myocardial oxyg

delivery distal to a stenosis, and incre

myocardial oxygen demand
Anand, I. S. J Am Coll Cardiol 2008;52:501-511 

Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply. 
Potential treatments

• Erythropoiesis‐stimulating agents (ESA

• Iron

• Red Blood Cell Transfusions
‐

Cochrane Cochrane review ESAs in C

“This review shows that ESAs improves anaemia, exe

tolerance, quality of life and reduces symptoms in he

failure patients with a mild anaemia. ESAs may also 

hospital admission and improve survival. There was 

increase in major side effects in those receiving ESA 

compared compared to control control over the 2‐12 month study peri

Ngo K et al, Cochrane Database Sy
Variation Variation in transfusion transfusion pra

pra

• “10/30” rule – dogma originating in 194

• RBC transfusions transfusions have remained remained at pea

throughout last decade

• Survey studies suggest hi hg er th h ld reshold

in CHD patients

• Cohort studies suggest triggers range 8

g/dL
Key Questions

In patients with CHF or CHD,• Key Question 1. What are the health outcome ben

harms of treating treating anemia with erythropoiesis erythropoiesis‐stim

stim

agents (ESAs)?

• Key Question #2. What are the health outcome be

and harms of using iron to treat iron deficiency wi

without anemia?

• Key Question #3. What are the health outcome be

and harms of treating anemia with red blood celltransfusions?
Study selection

• Patients: Adult patients with

– CHF (with or without reduced systolic function) – CHD (acute coronary syndrome, post‐acute coro

syndrome, history of MI or angina), and anemia 

deficiency

• Interventions:

– ESAs with or without without iron: These include include erythr

erythr

and darbepoeitin

– Iron: Intravenous or oral

– Red blood cell transfusion

• Comparator: Usual care, placebo
Study Selection

• Outcomes:

– Mortality (all‐cause and disease specific)– hospitalization ( ll a ‐cause and disease‐spe

– exercise tolerance or duration (any metri

commonly NYHA class, 6‐mi t nu e walk t 

es 

– quality of life,

– cardiovascular events (myocardial infarct

failure exacerbation, need for revasculari

– Harms (HTN, VTE, cerebrovascular event
Study selection

• Transfusions – included observational s

– Except cardiac surgery
Search

• MEDLINE and Cochrane• 1947‐Nov 2010• ClinicalTrials.gov• Directly contacted drug companies
Literature Flow – Anemia and CHF

Title

A Systematic Systematic Review of the Evidenc

Evidenc

Name, Degree

Title

Center

Name of VA Medical Center

Date
Literature Literature flow, continued continued

Title

A Systematic Systematic Review of the Evidenc

Evidenc

Name, Degree

Title

Center

Name of VA Medical Center

Date
Erythropoiesis Erythropoiesis stimulating stimulating agent
Erythropoiesis stimulating agent

• 16 RCTs

– 11 trials enrolled patients with CHF

• Mean LVEF < 35%

• Most patients had comorbid CHD

• Mean GFR of CKD 3 or worse in most studies

– 2 trials enrolled equal numbers CHD and CHF– 1 trial focused on CHD only

– 2 trials analyzed a CHF or CHD subgroup from larg

CKD patients
Change in NYHA scores in CHF patients: m

difference comparing ESA to control gro
Change in NYHA scores in CHF patients – studies w

of bias, excluding excluding studies studies with duplicate duplicate patient patient po

po

mean difference comparing ESA to contro

Title

A Systematic Systematic Review of the Evidenc

Evidenc

Name, Degree

Title

Center

Name of VA Medical Center

Date
All‐cause mortality in patients with CHF o

studies with low risk of bias: ESA vs. co

Title

A Systematic Systematic Review of the Evidenc

Evidenc

Name, Degree

Title

Center

Name of VA Medical Center

Date
Hypertension events in patients with CHF 

ESA vs. control

Title

A Systematic Systematic Review of the Evidenc

Evidenc

Name, Degree

Title

Center

Name of VA Medical Center

Date
ESAs in patients with CKD and heart

disease

Harms results dominated by 2 large studipatients patients with CKD and heart disease disease

Studies by size N TREAT CHD b TREAT, CHD subgroup; Pf ffe er 2009 2636 Besarab 1998, 2008 1233 CHOIR CHF subgroup; CHOIR, CHF subgroup; Szczech 2010 375 STAMINA-HeFT; Ghali 2008 319 Van-Veldhuisen 2007 165 Other studies 23-65 
Erythropoiesis‐stimulating agents:

Pfeffer 2009, subgroup of TREAT

TREAT: multicenter, international RCT

D b ar epoietin vs Placebo in anemic diabetic CKDTargeted Hgb: 13 g/dL vs >9.0 g/dLEvent d ir ven, 29 months, n=4 044 ,No difference in primary endpoint of CV eventsbut exami d ne a previously d fi e ned subgroup:

Cardiovascular disease, n=2,636

of which 50% had CHF

Pfeffer MA et al, AJKD 2009;54
Erythropoiesis‐stimulating agents:

Pfeffer 2009, subgroup of TREAT

TREAT: subgroup with cardiovascular dise

CHF 50%, mean GFR 34, mean Hgb 

g/dL

Mortality Risk of cardiovascular cardiovascular event Risk of cerebrovascular event RR Risk of VTE RR 

Pfeffer MA et al, AJKD 2009;54

*
Erythropoiesis‐stimulating agents:

Besarab 1998, 2008

Multicenter, USA, RCT (unblinded)

Comparative dose st du y: Epoeitin 1‐3 /x weekPatients on hemodialysis with either CHD or CHFTargeted H tc : 42% (n=618) vs 30% (n=615)Most patients also received IV iron

Primary endpoint: event‐free survival

Halted early due to mortality

Besarab A et al, NEJM 2008;35
Erythropoiesis‐stimulating agents:

Besarab 1998, 2008

Primary endpoint: event‐free survival

H l a ted early (median 14 month )s

Mortality RR Risk of cardiovascular cardiovascular event Risk of VTE RR 

Besarab A et al, NEJM 2008;35
Iron
Analysis of the benefits and harms o

therapy in CHF or CHD

Only 3 RCTs.Dominated by 1 large trial.

Studies of iron N FAIR-HF, Anker 2009 459 FERRIC-HF, Okonko 2008 35 Tobili 2007 40 
Iron therapy in CHF:

FAIR‐HF, Anker 2009

FAIR‐HF: multicenter, international, RCT.

24 weeks: all wi ht CHFIV iron weekly (n=304) vs Placebo (n=155)1st study with ferric‐carboxymaltoseNote: Mean Hgb 11.9 g/dL!

~50% were not anemicMean f iti err n 55, Transferrin S t%a 17

Note: 80% NYHA class III, remainder class II

Anker SD et al, NEJM 2009;361:2
Iron therapy in CHF:

FAIR‐HF, Anker 2009

Results:

Similar Similar outcomes outcomes for anemic and noanemic patients

Improvement in NHYA by 1 OR 2.40

Improvement in PGA OR 2.51

6‐MWT (meters) 313 vs 27QOL: KCCQ score 66 vs 59QOL: EQ‐5D score 63 vs 57

All values significant at p<

Anker SD et al, NEJM 2009;36
Transfusions
–

–

Transfusion Literature Se

• 9 controlled trials

– 2 in medical medical populations populations– 4 in cardiac surgery– 3 in non‐cardiac surgery

• 24 observational cohort studies

– 21 in medical populations

3 in non‐cardiac cardiac surgery surgery
TRICC Trial

• Hebert PC et al – NEJM 1999

– Multicenter (all in Canada) RCT (unblinded), 6

– 838 ICU pts, all w/ hgb ≤9 g/dL within 72 hrs o

admission, all considered euvolemic

– Intervention:

• Restrictive strategy – transfuse at hgb <7, 1 unit at 

goal h bg 7‐9 g/dL

• Liberal strategy – transfuse at hgb <10, 1 unit at a 

hgb 10‐12 g/dL

Hebert PC et al, NEJM 1999; 340: 409‐417.
TRICC Trial – Outcomes

Hebert PC et al, NEJM 1999; 340: 409‐417.
TRICC Trial ‐ Outcomes Outcomes

Outcome30d mortalityHospital mortalityMODS, adjustedCardiac eventsPulmonary compsInfectious compsLOS, ICU (d)LOS, hospital (d)

R18.7%

22.2%

10.7

13.2%

25.4%

10.0%

11.034.8

L

23.3%

28.1%

11.8

21.0%

29.0%

11.9%

11.535.5

RRR 20

RRR 21

NS

NS

NS

NS

NS

NS

Hebert PC et al, NEJM 1999; 340: 409‐417.
TRICC Trial – Outcomes

• Subgroup analyses – younger and less 

Hebert PC et al, NEJM 1999; 340: 409‐417.
Conclusions

• A restrictive transfusion policy (goal hgb >7 

safe in critically ill pts, including those being

mechanically ventilated

• Withholding transfused RBCs may actually 

beneficial, particularly in younger and less c

pts
That still leaves the question of cardiov

disease...

• TRICC trial – subgroup analysis

– 357 pts w/ 1o or 2o admitting diagnosis of C

• Over 85% mechanically ventilated, >50% w/ PA • Average APACHE II score 23

Hebert et al, Crit Care Med 2001; 29: 227‐234.
TRICC Trial – CVD Subgroup Subgroup Outcom

Outcom

Hebert et al, Crit Care Med 2001; 29: 227‐234.
TRICC Trial

• Cardiovascular disease patientsOutcome R L30d mortality 23% 23% NS

Hospital mortality 26% 27% NS

MODS, adjusted 11.1 11.9 

LOS, ICU (d) 9.2 11.3 NSLOS, hospital (d) 33.0 35.1 

Hebert et al, Crit Care Med 2001; 29: 227‐234.
TRICC Trial

IHD Subgroup Outcomes

Also looked at 257 pts w/ ischemic heart disease

Hebert et al, Crit Care Med 2001; 29: 227‐234.
Ou co e

TRICC Trial

• Ischemic heart disease patientsOutcome R L

30d mortality 26% 21% p=0.38

Hospital Hospital mortality mortality 29% 27% NSMODS, adjusted 11.8 11.6 LOS, ICU (d) 9 3. 10 4. NSLOS, hospital (d) 28.8 30.6 Also no significant difference in rate of new MI (datHebert et al, Crit Care Med 2001; 29: 227‐234.
TRICC summary

• A restrictive strategy (goal hgb >7) appear

pts w/ underlying CV diseases as well

– Caveat: more difficult to draw conclusions giv

sample size, post‐hoc subgroup analysis

• Question remains about the particular su

pts w/ ischemic heart disease
Is there any other data available to g

decision

‐making in ischemic heart dise
CRIT trial – Cooper 2011

• M lti u center (US) RCT from 2003‐2009• 45 pts admitted w/ acute MI

– 40% had STEMI, 56% received PCI

– All w/ hct ≤30%, no major bleeding

• Intervention:

– Conservative strategy – transfuse at hct <24, 

time, w/ goal hct 24‐27

– Liberal strategy – transfuse at hct <30, 1 unit 

w/ goal hgb 30‐33

Cooper HA et al, Am J Cardiol 2011; 108: 1108.
CRIT trial – Cooper 2011

Outcome R LMortality, in‐hospital 8% 5% NSDeath/MI/CHF, in‐hospital 13% 38% CHF, in‐hospital 8% 38% Mortality, 30 d 8% 5% NSDeath/MI/CHF h/MI/CHF, 30 d 20% 60% p=0 02 .Also no significant difference in recurrent ischemia 

LOS (hospital or CCU)

Cooper HA et al, Am J Cardiol 2011; 108: 1108.
Meta‐Analysis – 30 d Mort

Transfusion in Medical Popul
Perioperative Transfusion

in CV Disease

• FOCUS trial – hip fracture repair

– Multicenter RCT in US and Canada 2004‐2009

– 2016 pts ≥ 50 yrs old undergoing hip fracture rep

• Known CVD (IHD hx, consistent ECG, CHF, PVD, CVA/TI• RFs (HTN, DM, d li ys pidemia, smoking, Cr ≥ 2.0)

– Intervention

• Liberal Liberal strategy strategy – transfuse transfuse at hgb <10, 1 unit at a time• Restrictive strategy – transfuse 1 unit at a time upon d

signs/sx of anemia (cardiac CP, CHF, tachycardia/hypot

unresponsive to IVF) or at discretion of MD if hgb <8

Carson JL et al, NEJM 2011; 365: 2453.
FOCUS trial

Outcome R L ODeath/can Death/can’t walk 10 ft, 60 d 34.7% 35.2% 1 01 . (0.84‐Mortality, 60 d 6.6% 7.6% 1.17 (0.75‐1.83)Death/MI/UA, in‐hospital 5.2% 4.3% 0.82 (0.48‐MI, in‐hospital 3.8% 2.3% 0.60 (0.30‐1.19)CHF, in‐hospital 3.5% 2.7% 0.77 (0.39‐1.50)Also no significant difference in CVA/TIA, pna, wound infe

need for repeat operation, ICU transfer, LOS, ADL/IADL 

Carson JL et al, NEJM 2011; 365: 2453.
FOCUS trial

Carson JL et al, NEJM 2011; 365: 2453.
Meta‐Analysis – 30 d Morta

Transfusion in Surgical Popula
Meta‐Analysis – All Populati

Title

A Systematic Systematic Review of the Evidenc

Evidenc

Name, Degree

Title

Center

Name of VA Medical Center

Date
Observational Studies of Transfusio

IHD

• PCI setting – 9 studies, ~2000‐39,000 pts

– Transfusion Transfusion associated associated with higher mortality mortality in 

difference in 9th)

• Finding was consistent in both bleeding and 

bleeding transfused cohorts
Observational Studies of Transfusio

IHD

• ACS/AMI populations – 12 studies

– Outcomes Outcomes w/ transfusion ansfusion at any hgb/hct hgb/hct level (

(

reported in 9 studies

• Higher mortality in 8 of 9 studies (no differe

last one)
Observational Observational Studies Studies of Transfusion Transfusion 

• ACS/AMI populations – 12 studies

– Outcomes Outcomes w/ transfusion ansfusion at hct <24‐25% ‐ repo

repo

studies

• Improved survival in 2 studies

• Mixed result in 1: Better survival in STEMI b

NSTE‐ACS

• No difference in mortality in 3 (2 showed a t

towards fewer deaths in transfused pts)
Observational Observational Studies Studies of Transfusion Transfusion 

• ACS/AMI populations – 12 studies

o Outcomes Outcomes w/ transfusion ansfusion at hct >30% ‐ reporte

reporte

studies

• Higher mortality in 4• Mixed result in 2:

o Mortality higher in NSTE‐ACS, but lower wit

in STEMI at hgb <12 g/dL (neutral (neutral at hgb >12

o No difference in mortality at hct 30‐36% but 

mortality above hct 36% in 1
Observational Observational Studies Studies of Transfusion Transfusion 

• ACS/AMI populations – 12 studies

o Outcomes w/ transfusion at hct 25‐30% ‐ re

st di u es

• Improved survival in 1

• Mixed in 1 (improved survival w/ STEMI, worse w

ACS)

• Neutral in 1• Increased mortality in 1• One additional study found higher mortality am

patients transfused at nadir hgb >8 g/dL (did no

h bg 8‐10 and >10 g/dL)
–

Observational Observational Studies Studies of Transfusi

Transfusi

• CHF populations – 2 studies

Higher mortality mortality w/ transfusion transfusion in 1

– Lower mortality in the other
Summary

Observational Studies

• No benefit/possible harm with transfusion at hgb >

(possible exception: STEMI)

• Mixed results but no clear benefit from transfusion 

down to 8‐9 g/dL in NSTE‐ACS

• Consistent evidence of increased mortality with tra

the unselected PCI population, at a mean nadir hg

• Higher incidence of death seen with transfusion in 

of hemorrhage but may be higher still in non‐bleed

patients

• No studies in stable CAD, and conflicting results se

decompensated CHF
Summary: ESA

• ESAs

– No consistent, good‐quality evidence for 

outcomes

– Potential Potential for serious serious harms, including including th

th

and mortality, especially in patients with 

kidney disease
Review design matters matters

• Our review differs from others in severa

– Conducted additional analyses evaluating 

of study quality on results

– Included studies of patients with advance

disease if heart disease subgroup data rep

– Included both CHF and CHD (though most 

were CHF)
Implications: ESA

• Routine use of ESAs in patients with C

probably not warranted at this time

• For patients with comorbid chronic kid

disease disease, consider consider FDA recs that, if use

Hgb should be at least < 10 g/dL
Summary: Iron

• Iron

– Most information from one large RCT– Improvement in short‐term exercise tole

QOL

• Most applicable to patients with NYHA III CH

ferritin < 100

– Long‐term effects and effects on mortali

events unknown
Implications: Iron

• Intravenous iron may be a promising

adjunctive therapy in patients with

symptomatic CHF and low ferritin, but 

study is needed
vidence is stron er in sur ical tions

Summary: Transfusions

• Transfusions

– More liberal transfusion protocols ( gg tri e

10g/dL) do not improve outcomes compmore conservative protocols ( gg tri er hgb 

g/dL)

• Evidence is stronger in surgical populations popula• Does not apply to actively symptomatic/uns

patients
AABB Guidelines

• The AABB suggests adhering to a restri i ct ve strategy in hospita

patients with preexisting cardiovascular disease and considerin

transfusion for patients with symptoms or a hemoglobin level 

less (Grade: weak recommendation; moderate‐quality evidenc

• The AABB cannot recommend for or against a liberal or restrict

transfusion transfusion threshold threshold for hospitalized, hospitalized, hemodynamically hemodynamically stable 

with the acute coronary syndrome (Grade: uncertain recommevery low‐quality evidence).

• The AABB suggests th t a transfusion d ii ec s ons be i fl n uenced by 

as well as hemoglobin concentration (Grade: weak recommenquality evidence).

Carson J et al, Ann Int M
Future studies

• RED‐HF

– Target of 2600 pts symptomatic symptomatic CHF and r

r

LVEF

– Results Results ≈ 2014– Darbepoetin titrated to hgb ≥ 13 g/dL

• Still need long‐term outcomes for iron,

transfusion transfusion trials in ACS patients, patients, ESA t

with less aggressive Hgb targets
Evidence‐based Synthesis Pro

(ESP)

Questions?

If you have further questions,

feel free to contact:

Devan Kansagara, MD, MCR

kansagar@ohsu.edu

The full report and cyberseminar presentation is available on the E

http://www.hsrd.research.va.gov/publications/esp/