56

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

APPENDIX A. SEARCH STRATEGY

anemia anemia

anaemia 

anemia/

congestive heart 

failure/ coronary heart 

disease/ ischemic 

heart disease

cardiac failure

chf

congestive heart failure

coronary heart disease

ischemic heart disease

heart failure/

coronary disease/

myocardial ischemia/

Erythropoiesisstimulating agents anti-anaemi*

antianaemi*

antianemi*

anti-anemi*

aranesp

darbepoetin

darbepoietin

darbopoetin

epo

epoetin

epogen

epoietin

eprex

Erythopoiesis-stimulating agents

erythropoesis

erythropoetin

erythropoiesis

erythropoietin

ESA

ESAs

hematinics

neorecormon

nesp

procrit

recormon

rheupo

erythropoetin/

Iron - IV or PO ferric

ferrous

iron

iron/

red blood cell 

transfusion

red blood cell transfusion

Erythrocyte Transfusion/

benefits
57

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

harms safe

safety

side-effect*

undesirable effect*

treatment emergent

tolerability

toxicity

adverse adj2 (effect or effects or reaction or reactions or event or events or outcome 

or outcomes)

/adverse effects

/poisoning

/toxicity

/chemically induced

/contraindications

/complications

thromboembolism

thromboembolism/

threshold hemoglobin 

value

threshold hemoglobin value

RCT

 1 randomized controlled trial.pt.

 2 controlled clinical trial.pt.

 3 randomized.ab.

 4 placebo.ab.

 5 drug therapy.fs.

 6 randomly.ab.

 7 trial.ab.

 8 groups.ab

 9 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8

 10 exp animals/ not humans.sh.

 11 9 not 10

[Cochrane’s Highly Sensitive Search Strategy for identifying randomized trials in 

MEDLINE: sensitivity-maximizing version (2008 revision); Ovid format]

human not (not human)

Databases: MEDLINE, Cochrane, EMBASE

ESA Benefits – search strategy

Database(s):Ovid MEDLINE® and Ovid OLDMEDLINE® 1947 to November Week 1 2010, Ovid 

MEDLINE® In-Process & Other Non-Indexed Citations November 11, 2010

# Searches Results

1 anemia.mp. or exp Anemia/ 149879

2 anaemia.mp. 22339

3 1 or 2 157901

4 cardiac failure.mp. or exp Heart Failure/ 77416

5 chf.mp. 8843

6 congestive heart failure.mp. 28353

7 coronary heart disease.mp. or exp Coronary Disease/ 177123

8 ischemic heart disease.mp. or exp Myocardial Ischemia/ 321932

9 4 or 5 or 6 or 7 or 8 407842
58

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

10 3 and 9 2677

11 anti-anaemi*.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 33

12 antianaemi*.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 30

13 antianemi*.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 174

14 anti-anemi*.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 94

15 aranesp.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 83

16 exp Erythropoietin/ or darbepoetin.mp. 18912

17 darbepoietin.mp. 43

18 darbopoetin.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 3

19 epo.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 7585

20 epoetin.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 2037

21 epogen.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 61

22 epoietin.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 51

23 eprex.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 126

24 erythropoesis.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 81

25 erythropoetin.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 164

26 erythropoiesis.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 15771

27 erythropoietin.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 23192

28 ESA.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 1138

29 ESAs.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 475

30 hematinics.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 2350

31 neorecormon.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 31

32 nesp.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 73

33 procrit.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 33

34 recormon.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 30

35 Erythropoiesis-stimulating agent.mp. [mp=title, original title, abstract, name of substance word, 

subject heading word, unique identifier] 152

36 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 

28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 37740
59

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

37 randomized controlled trial.pt. 305853

38 controlled clinical trial.pt. 83372

39 randomized.ab. 218942

40 placebo.ab. 127996

41 drug therapy.fs. 1433066

42 randomly.ab. 161893

43 trial.ab. 227198

44 groups.ab. 1067718

45 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 2717428

46 exp animals/ not humans.sh. 3609973

47 45 not 46 2313774

48 10 and 36 and 47 225

ESA Benefits – search strategy, continued

Database(s):EBM Reviews - Cochrane Central Register of Controlled Trials 4th Quarter 2010

Date searched 11/15/10

# Searches Results

1 anemia.mp. or exp Anemia/ 4561

2 anaemia.mp. 985

3 1 or 2 5004

4 cardiac failure.mp. or exp Heart Failure/ 4150

5 chf.mp. 1152

6 congestive heart failure.mp. 2523

7 coronary heart disease.mp. or exp Coronary Disease/ 9300

8 ischemic heart disease.mp. or exp Myocardial Ischemia/ 17485

9 4 or 5 or 6 or 7 or 8 23230

10 3 and 9 96

11 anti-anaemi*.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 0

12 antianaemi*.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 1

13 antianemi*.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 16

14 anti-anemi*.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 5

15 aranesp.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 25

16 exp Erythropoietin/ or darbepoetin.mp. 1291

17 darbepoietin.mp. 9

18 darbopoetin.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 9

19 epo.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 602

20 epoetin.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 603

21 epogen.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 2

22 epoietin.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 18

23 eprex.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 22

24 erythropoesis.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 5

25 erythropoetin.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 32

26 erythropoiesis.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 449

27 erythropoietin.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 1903

28 ESA.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 51

29 ESAs.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 18

30 hematinics.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 398

31 neorecormon.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 19

32 nesp.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 23
60

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

33 procrit.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 13

34 recormon.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 7

35 Erythropoiesis-stimulating agent.mp. [mp=title, original title, abstract, mesh headings, heading 

words, keyword] 28

36 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 

28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 2764

37 randomized controlled trial.pt. 284694

38 controlled clinical trial.pt. 79466

39 randomized.ab. 147977

40 placebo.ab. 100112

41 randomly.ab. 76867

42 trial.ab. 102732

43 groups.ab. 156434

44 37 or 38 or 39 or 40 or 41 or 42 or 43 419005

45 10 and 36 and 44 33

ESA Benefits – search strategy, continued

Database: EMBASE

Date searched 11/15/10

# Query Results

11 #7 AND #10 105

10 #8 OR #9 346115

9 random$ OR factorial$ OR crossover$ OR cross AND over$ OR ‘cross over$’ OR placebo$ OR 

doubl$ AND adj AND blind$ OR single$ AND adj AND blind$ OR assign$ OR allocat$ OR 

volunteer$ AND [embase]/lim

40406

8 ‘crossover procedure’/exp OR ‘double blind procedure’/exp OR ‘randomized controlled trial’/exp 

OR ‘single blind procedure’/exp

310032

7 #5 AND #6 1015

6 ‘anti anami$’ OR antianaemi$ OR antianemi$ AND o$r AND ‘anti anemi$’ OR ‘aranesp’/exp OR 

‘darbepoetin’/exp OR ‘darbepoietin’/exp OR ‘darbopoetin’/exp OR epo OR ‘epoetin’/exp OR 

‘epogen’/exp OR ‘epoietin’/exp OR ‘eprex’/exp OR ‘erythopoiesis stimulating’ AND agents OR 

erythropoesis OR erythropoetin OR ‘erythropoiesis’/exp OR ‘erythropoietin’/exp OR esa OR esas 

OR ‘hematinics’/exp OR ‘neorecormon’/exp OR ‘nesp’/exp OR ‘procrit’/exp OR ‘recormon’/exp 

OR rheupo AND [embase]/lim

70423

5 #1 AND #4 5587

4 #2 OR #3 376323

3 ‘heart failure’/exp OR ‘coronary artery disease’/exp 352502

2 cardiac AND failure OR chf OR congestive AND ‘heart’/exp AND failure OR coronary AND 

‘heart’/exp AND ‘disease’/exp OR ischemic AND ‘heart’/exp AND ‘disease’/exp AND [embase]/

lim

43081

1 ‘anemia’/exp AND [embase]/lim 141383

ESA harms – search strategy

Database(s):Ovid MEDLINE® and Ovid OLDMEDLINE® 1947 to November Week 1 2010, 

Ovid MEDLINE® In-Process & Other Non-Indexed Citations November 11, 2010

# Searches Results

1 anemia.mp. or exp Anemia/ 149879

2 anaemia.mp. 22339

3 1 or 2 157901
61

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

4 cardiac failure.mp. or exp Heart Failure/ 77416

5 chf.mp. 8843

6 congestive heart failure.mp. 28353

7 coronary heart disease.mp. or exp Coronary Disease/ 177123

8 ischemic heart disease.mp. or exp Myocardial Ischemia/ 321932

9 4 or 5 or 6 or 7 or 8 407842

10 3 and 9 2677

11 anti-anaemi*.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 33

12 antianaemi*.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 30

13 antianemi*.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 174

14 anti-anemi*.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 94

15 aranesp.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 83

16 exp Erythropoietin/ or darbepoetin.mp. 18912

17 darbepoietin.mp. 43

18 darbopoetin.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 3

19 epo.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 7585

20 epoetin.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 2037

21 epogen.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 61

22 epoietin.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 51

23 eprex.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 126

24 erythropoesis.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 81

25 erythropoetin.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 164

26 erythropoiesis.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 15771

27 erythropoietin.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 23192

28 ESA.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 1138

29 ESAs.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 475

30 hematinics.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 2350

31 neorecormon.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 31

32 nesp.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 73

33 procrit.mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier] 33
62

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

34 recormon.mp. [mp=title, original title, abstract, name of substance word, subject heading word, 

unique identifier] 30

35 Erythropoiesis-stimulating agent.mp. [mp=title, original title, abstract, name of substance word, 

subject heading word, unique identifier] 152

36 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 

28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 37740

37 exp Thromboembolism/ or thromboembolism.mp. 47359

38 (adverse effects or poisoning or toxicity or chemically induced or contraindications or 

complications).fs. 2846319

39

(adverse adj2 (effect or effects or reaction or reactions or event or events or outcomes or outcome)).

mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier]

179933

40

(safe or safety or side-effect* or undesirable effect* or treatment emergent or tolerability or toxicity).

mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique 

identifier]

675202

41 37 or 38 or 39 or 40 3311276

42 10 and 36 and 41 280

ESA harms – search strategy, continued

Database(s):EBM Reviews - Cochrane Central Register of Controlled Trials 4th Quarter 2010

Date searched: 11/15/10

# Searches Results

1 anemia.mp. or exp Anemia/c 4561

2 anaemia.mp. 985

3 1 or 2 5004

4 cardiac failure.mp. or exp Heart Failure/ 4150

5 chf.mp. 1152

6 congestive heart failure.mp. 2523

7 coronary heart disease.mp. or exp Coronary Disease/ 9300

8 ischemic heart disease.mp. or exp Myocardial Ischemia/ 17485

9 4 or 5 or 6 or 7 or 8 23230

10 3 and 9 96

11 anti-anaemi*.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 0

12 antianaemi*.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 1

13 antianemi*.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 16

14 anti-anemi*.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 5

15 aranesp.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 25

16 exp Erythropoietin/ or darbepoetin.mp. 1291

17 darbepoietin.mp. 9

18 darbopoetin.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 9

19 epo.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 602

20 epoetin.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 603

21 epogen.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 2

22 epoietin.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 18

23 eprex.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 22

24 erythropoesis.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 5

25 erythropoetin.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 32

26 erythropoiesis.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 449

27 erythropoietin.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 1903
63

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

28 ESA.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 51

29 ESAs.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 18

30 hematinics.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 398

31 neorecormon.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 19

32 nesp.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 23

33 procrit.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 13

34 recormon.mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 7

35 Erythropoiesis-stimulating agent.mp. [mp=title, original title, abstract, mesh headings, heading 

words, keyword] 28

36 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 

or 29 or 30 or 31 or 32 or 33 or 34 or 35 2764

37 exp Thromboembolism/ or thromboembolism.mp. 2067

38 (adverse adj2 (effect or effects or reaction or reactions or event or events or outcomes or outcome)).

mp.

48156

39 (safe or safety or side-effect* or undesirable effect* or treatment emergent or tolerability or toxicity).

mp.

95206

40 37 or 38 or 39 114226

41 10 and 36 and 40 10

ESA harms – search strategy, continued

Database: EMBASE

Date searched: 11/15/10

# Query Results

11 #7 AND #10 412

10 #8 OR #9 1154469

9 safe OR ‘safety’/exp OR ‘side effect$’ OR undesirable AND effect$ OR treatment AND 

emergent OR tolerability OR ‘toxicity’/exp OR (adverse AND adj2 AND (effect OR effects OR 

reaction OR reactions OR event OR events OR outcome OR outcomes)) AND [embase]/lim

432305

8 ‘complication’/exp OR ‘side effect’/exp OR ‘adverse drug reaction’/exp OR ‘drug toxicity’/exp 899447

7 #5 AND #6 1015

6 ‘anti anami$’ OR antianaemi$ OR antianemi$ AND o$r AND ‘anti anemi$’ OR ‘aranesp’/

exp OR ‘darbepoetin’/exp OR ‘darbepoietin’/exp OR ‘darbopoetin’/exp OR epo OR ‘epoetin’/

exp OR ‘epogen’/exp OR ‘epoietin’/exp OR ‘eprex’/exp OR ‘erythopoiesis stimulating’ AND 

agents OR erythropoesis OR erythropoetin OR ‘erythropoiesis’/exp OR ‘erythropoietin’/exp OR 

esa OR esas OR ‘hematinics’/exp OR ‘neorecormon’/exp OR ‘nesp’/exp OR ‘procrit’/exp OR 

‘recormon’/exp OR rheupo AND [embase]/lim

70423

5 #1 AND #4 5587

4 #2 OR #3 376323

3 ‘heart failure’/exp OR ‘coronary artery disease’/exp 352502

2 cardiac AND failure OR chf OR congestive AND ‘heart’/exp AND failure OR coronary AND ‘heart’/

exp AND ‘disease’/exp OR ischemic AND ‘heart’/exp AND ‘disease’/exp AND [embase]/lim

43081

1 ‘anemia’/exp AND [embase]/lim 141383
64

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Iron benefits and harms

Database(s):Ovid MEDLINE® and Ovid OLDMEDLINE® 1947 to November Week 1 2010, 

Ovid MEDLINE® In-Process & Other Non-Indexed Citations November 11, 2010

# Searches Results

1 anemia.mp. or exp Anemia/ 149879

2 anaemia.mp. 22339

3 1 or 2 157901

4 cardiac failure.mp. or exp Heart Failure/ 77416

5 chf.mp. 8843

6 congestive heart failure.mp. 28353

7 coronary heart disease.mp. or exp Coronary Disease/ 177123

8 ischemic heart disease.mp. or exp Myocardial 

Ischemia/ 321932

9 4 or 5 or 6 or 7 or 8 407842

10 3 and 9 2677

11 exp Iron/ or iron.mp. 133944

12 ferric.mp. 18656

13 ferrous.mp. 12391

14 11 or 12 or 13 145012

15 10 and 14 400

Iron benefits and harms – search strategy, continued 

Database(s):EBM Reviews - Cochrane Central Register of Controlled Trials 4th Quarter 2010

Date searched: 11/15/10

# Searches Results

1 anemia.mp. or exp Anemia/ 4561

2 anaemia.mp. 985

3 1 or 2 5004

4 cardiac failure.mp. or exp Heart Failure/ 4150

5 chf.mp. 1152

6 congestive heart failure.mp. 2523

7 coronary heart disease.mp. or exp Coronary Disease/ 9300

8 ischemic heart disease.mp. or exp Myocardial 

Ischemia/ 17485

9 4 or 5 or 6 or 7 or 8 23230

10 3 and 9 96

11 exp Iron/ or iron.mp. 3384

12 ferric.mp. 365

13 ferrous.mp. 604

14 11 or 12 or 13 3566

15 10 and 14 24
65

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

Iron benefits and harms – search strategy, continued 

Database: EMBASE

Date searched: 11/15/10

# Query Results

11 #5 AND #10 593

10 #8 OR #9 112969

9 ferric OR ferrous OR ‘iron’/exp AND [embase]/lim 85359

8 ‘iron’/exp 88060

5 #1 AND #4 5587

4 #2 OR #3 376323

3 ‘heart failure’/exp OR ‘coronary artery disease’/exp 352502

2 cardiac AND failure OR chf OR congestive AND ‘heart’/exp AND failure OR coronary AND ‘heart’/

exp AND ‘disease’/exp OR ischemic AND ‘heart’/exp AND ‘disease’/exp AND [embase]/lim

43081

1 ‘anemia’/exp AND [embase]/lim 141383

RBC transfusion benefits and harms – search strategy

Database(s):Ovid MEDLINE® and Ovid OLDMEDLINE® 1947 to November Week 1 2010, 

Ovid MEDLINE® In-Process & Other Non-Indexed Citations November 11, 2010

Date searched: 11/12/10

# Searches Results

1 anemia.mp. or exp Anemia/ 149879

2 anaemia.mp. 22339

3 1 or 2 157901

4 cardiac failure.mp. or exp Heart Failure/ 77416

5 chf.mp. 8843

6 congestive heart failure.mp. 28353

7 coronary heart disease.mp. or exp Coronary Disease/ 177123

8 ischemic heart disease.mp. or exp Myocardial Ischemia/ 321932

9 4 or 5 or 6 or 7 or 8 407842

10 3 and 9 2677

11 red blood cell transfusion.mp. or exp Erythrocyte Transfusion/ 5368

12 10 and 11 46

RBC transfusion benefits and harms – search strategy continued

Database(s):EBM Reviews - Cochrane Central Register of Controlled Trials 4th Quarter 2010

Date searched: 11/12/10

# Searches Results

1 anemia.mp. or exp Anemia/ 4561

2 anaemia.mp. 985

3 1 or 2 5004

4 cardiac failure.mp. or exp Heart Failure/ 4150

5 chf.mp. 1152

6 congestive heart failure.mp. 2523

7 coronary heart disease.mp. or exp Coronary Disease/ 9300

8 ischemic heart disease.mp. or exp Myocardial Ischemia/ 17485

9 4 or 5 or 6 or 7 or 8 23230

10 3 and 9 96

11 red blood cell transfusion.mp. or exp Erythrocyte Transfusion/ 360

12 10 and 11 6
66

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

RBC transfusion benefits and harms – search strategy continued

Database(s):EMBASE

Date searched: 11/12/10

# Query Results

7 #5 AND #6 205

6 ‘erythrocyte transfusion’/exp 8844

5 #1 AND #4 5587

4 #2 OR #3 376323

3 ‘heart failure’/exp OR ‘coronary artery disease’/exp 352502

2 cardiac AND failure OR chf OR congestive AND ‘heart’/exp AND failure OR coronary AND 

‘heart’/exp AND ‘disease’/exp OR ischemic AND ‘heart’/exp AND ‘disease’/exp AND [embase]/

lim

43081

1 ‘anemia’/exp AND [embase]/lim 141383

Hemoglobin threshold – search strategy

Database(s):Ovid MEDLINE® and Ovid OLDMEDLINE® 1947 to November Week 1 2010, 

Ovid MEDLINE® In-Process & Other Non-Indexed Citations November 11, 2010

# Searches Results

1 (hemoglobin adj3 threshold*).mp. [mp=title, original title, abstract, name of substance word, subject 

heading word, unique identifier] 75

Hemoglobin threshold – search strategy continued

Database: EMBASE

Date searched: 11/12/10

# Query Results

7 #5 AND #6 16

6 threshold AND ‘hemoglobin’/exp AND [embase]/lim 972

5 #1 AND #4 5587

4 #2 OR #3 376323

3 ‘heart failure’/exp OR ‘coronary artery disease’/exp 352502

2 cardiac AND failure OR chf OR congestive AND ‘heart’/exp AND failure OR coronary AND 

‘heart’/exp AND ‘disease’/exp OR ischemic AND ‘heart’/exp AND ‘disease’/exp AND [embase]/

lim

43081

1 ‘anemia’/exp AND [embase]/lim 141383

Hemoglobin threshold – search strategy continued

Database(s):EBM Reviews - Cochrane Central Register of Controlled Trials 4th Quarter 2010

Date searched: 11/12/10

# Searches Results

1 (hemoglobin adj3 threshold*).mp. [mp=title, original title, abstract, mesh headings, heading words, 

keyword] 14
67

Treatment of Anemia in Patients with Heart Disease:

A Systematic Review Evidence-based Synthesis Program

APPENDIX B. INCLUSION/EXCLUSION CRITERIA

1. Is the full text of the article in English? 

Yes...........................................................Proceed to #2

No............................................................... Code X1. STOP

2. Does the study population include adult patients with congestive heart failure or 

coronary heart disease, and anemia or iron deficiency? 

Yes...........................................................Proceed to #3

No........................................... Code X2. Proceed to #8

3. Is the article an intervention study (or a systematic review/meta-analysis of 

intervention studies) comparing the effects of ESAs, iron, or red blood cell 

transfusions with usual care or placebo; or an observational study of the effects of red 

blood cell transfusions?

Yes...........................................................Proceed to #4

No....................................................................Go to #5

4. Does the study report outcomes that include mortality, hospitalization, exercise 

tolerance, cardiovascular events, quality of life, or adverse effects of treatment?

Yes....................................................Code I4. Go to #6

No .................................................. Code X4. Go to #7

5. Is the article an observational study that reports data on the harms of using ESAs or 

iron? 

Yes............................................Code I5. Proceed to #6

No........................................... Code X5. Proceed to #7

6. Does the article describe or analyze the costs of treatment or implementation?

Yes.................................................Add Code C. STOP

No........................................................................STOP

7. Does the article describe or analyze the costs of treatment or implementation?

Yes.................................................Add Code C. STOP

No............................................................Proceed to #8

8. Is the article potentially useful for background, discussion, or reference-mining?

Yes.........................................................Code B. STOP

No........................................................................STOP
68

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

LITY ASSESSMENT TABLES

nt of methodologic characteristics and risk of bias in randomized controlled trials of ESA therapy in patients with CHF or CHD

 

y 

Was allocation 

adequately 

concealed?

Blinding of participants, 

personnel and outcome 

assessors: Was 

knowledge of the allocated 

intervention adequately 

prevented?

Were incomplete 

outcome data 

adequately addressed?

Selective outcome reporting: 

Are reports of the study free 

of suggestion of selective 

outcome reporting?

Other sources of 

bias: Was the study 

apparently free of other 

problems that could put 

it at a high risk of bias?

Summary 

assessment: 

risk of bias (Low, 

Unclear, High)

Unclear No No Unclear No serious baseline 

imbalances. Randomized, 

but very little baseline 

characteristics presented 

though the baseline gender 

imbalance raises concerns 

that groups may not have 

been equal at baseline.

Overall: high risk 

of bias

Unclear Yes - low risk of bias 

for mortality outcome, 

probably low risk of bias for 

hospitalization, MI outcomes.

High risk of bias for physical 

function outcome given that 

blinding of participants and 

outcome assessors is unlikely 

to have occurred

Low risk of bias - data for all 

patients enrolled is reported 

and an intention to treat 

analysis was done

It is unclear why a composite 

outcome was chosen. Functional 

status data were incompletely 

reported (no comparative data, 

only that functional status 

increased with increasing Hct 

levels) –-> high risk of bias for 

functional status outcomes, 

but probably low risk of bias for 

mortality outcome

No serious baseline 

imbalances between groups.

Overall: low risk of 

bias

 

 of 

e 

nt 

h 

rs 

t 

n 

ity 

No No - high risk of bias for 

subjective outcomes

Yes Unclear No serious baseline 

imbalances between groups

Overall: high risk 

of bias

Yes Yes Yes Unclear No serious baseline 

imbalances between groups

Overall: low risk of 

bias

Unclear Yes - though single blind, 

it was placebo controlled 

and evaluation of QOL and 

depression surveys was done 

by blinded personnel

Yes Unclear No serious baseline 

imbalances between groups

Overall: Unclear risk 

of bias
69

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

 

y 

Was allocation 

adequately 

concealed?

Blinding of participants, 

personnel and outcome 

assessors: Was 

knowledge of the allocated 

intervention adequately 

prevented?

Were incomplete 

outcome data 

adequately addressed?

Selective outcome reporting: 

Are reports of the study free 

of suggestion of selective 

outcome reporting?

Other sources of 

bias: Was the study 

apparently free of other 

problems that could put 

it at a high risk of bias?

Summary 

assessment: 

risk of bias (Low, 

Unclear, High)

Unclear Personnel and outcome 

assessors were not blinded

High risk of bias especially for 

QOL outcomes

Yes, though no ITT done, 

only 3 patients did not 

complete treatment

No - high risk of bias - no protocol 

available. The QOL outcome 

is not completely reported - no 

actual values, only that x % 

“improved” and the definition of 

improvement is not provided.

No serious baseline 

imbalances between groups

Overall: high risk 

of bias

Unclear Yes Yes Unclear No serious baseline 

imbalances between groups. 

It is unclear if there is any 

overlap between patients 

in this study and Palazzuoli 

2009 - if so, then possible 

multiple publication bias

Overall: Unclear 

risk of bias, 

but duplicates 

Palazzuoli 2007 

results

Unclear No (for 12 month outcomes) - 

high risk of bias for 12 month 

outcomes such as NYHA 

class. Blinding stopped after 4 

month mark.

No - high risk of bias. 

Not clear that ITT done. 

Nowhere in the results is 

the denominator actually 

reported so it is unclear 

what the final n was used to 

calculate results.

No - no protocol available. The 

study includes 12 month NYHA 

scores as an outcome, but 

there are no objective measures 

of exercise duration which 

one might expect as another 

secondary outcome measure.

No serious baseline 

imbalances between groups.

It is unclear if there is any 

overlap between patients 

in this study and Palazzuoli 

2009 – if so, then possible 

multiple publication bias

Overall: high risk 

of bias. Duplicates 

Palazzuoli 2006 

results with some 

additions.

Unclear Blinding of personnel and 

outcome assessors is unclear 

past the 4 month mark after 

which intervention drug was 

continued, but the control 

group saline injections were 

discontinued. This could create 

high risk of bias for outcomes 

such as NYHA class.

No - high risk of bias. 

No ITT done. 7 of 58 

enrolled patients did not 

make it to f/u and though 

outcomes are briefly and 

incompletely described 

for these patients they are 

not included in analyses. 

Additionally, only 48 of the 

58 pts were included in the 

hospitalization outcome 

and the reasons for the 

discrepant numbers are not 

explained.

No - high risk of bias. No protocol 

available. The incomplete 

reporting of all enrolled patients 

raises suspicion that not all 

outcomes were reported. Further, 

there are signals from within 

paper that this is so (eg - edema 

development was a secondary 

end point but is not reported in 

results). Other secondary end 

points are incompletely described 

(“no significant changes in 

myocardial events was seen”)

No serious baseline 

imbalances between groups.

Overall: high risk 

of bias

Unclear Yes - single blind. Personnel 

not blinded, but outcome 

assessors were 

Yes Unclear No serious baseline 

imbalances between groups. 

It is unclear if there is any 

overlap between patients 

in this study and Parissis 

2009 – if so, then possible 

multiple publication bias

Overall: low risk of 

bias
70

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

 

y 

Was allocation 

adequately 

concealed?

Blinding of participants, 

personnel and outcome 

assessors: Was 

knowledge of the allocated 

intervention adequately 

prevented?

Were incomplete 

outcome data 

adequately addressed?

Selective outcome reporting: 

Are reports of the study free 

of suggestion of selective 

outcome reporting?

Other sources of 

bias: Was the study 

apparently free of other 

problems that could put 

it at a high risk of bias?

Summary 

assessment: 

risk of bias (Low, 

Unclear, High)

Unclear Yes - single blind. Personnel 

not blinded but outcome 

assessors were 

Yes Unclear No serious baseline 

imbalances between groups. 

It is unclear if there is any 

overlap between patients in 

this study and Parissis 2008 

- if so, then possible multiple 

publication bias

Overall: low risk of 

bias

Unclear Yes Yes - 13% attrition, but 

equally balanced between 

two groups

Unclear No serious baseline 

imbalances between groups

Overall: low risk of 

bias

Yes Yes Yes Unclear No serious baseline 

imbalances between groups

Some evidence of spin: 

QOL assessed by three 

measures and improvement 

seen only in one measure, 

not the other two, yet 

conclusions suggest ESA 

improved health related 

quality of life

Overall: low risk of 

bias

No 

“Randomization...

not done in a 

blinded fashion”

No Unclear - Nowhere in the 

results is the denominator 

actually reported so it is 

unclear what the final n was 

used to calculate results.

Unclear No serious baseline 

imbalances between groups

Overall: high risk 

of bias

Yes Yes Yes Unclear No serious baseline 

imbalances between groups

Overall: low risk of 

bias
71

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

ent of methodologic characteristics and risk of bias in randomized controlled trials of RBC transfusion for anemia in

n 

ely 

Was allocation 

adequately 

concealed?

Blinding of participants, 

personnel and outcome 

assessors: Was knowledge 

of the allocated intervention 

adequately prevented?

Were 

incomplete 

outcome data 

adequately 

addressed?

Are reports of 

the study free of 

suggestion of 

selective outcome 

reporting?

Other sources of bias: Was 

the study apparently free of 

other problems that could put 

it at a high risk of bias?

Summary 

assessment: risk of 

bias (Low, Unclear, 

High)

R# 

ment

Unclear, concealment method not described

Study not described as blinded. Yes Yes No serious baseline imbalances 

between groups.

Overall: Unclear risk of bias

on 

d

Yes (sealed envelopes) Study not described as blinded. 

Surgeons and anesthesiologists were 

not blinded.

Yes Yes No serious baseline imbalances 

between groups.

Overall: Low risk of bias

one

h 

Yes: automated 

telephone-response 

system

at a separate research 

institute.

Outcome assessors were blinded; 

blinding was not otherwise specified 

for patients or care personnel.

Yes Yes No serious baseline imbalances 

between groups.

Overall: Low risk of bias

on 

d 

Not described (abstract 

only)

Not described (abstract only) Not described 

(abstract only)

Yes No serious baseline imbalances 

between groups.

Overall: Probably low; study 

is based on the pilot trial 

above (Carson 1998)

on 

d

Yes (opaque envelopes) No: “Blinding of treatment assignment 

was not feasible”

Yes; 6.7% loss to 

follow-up

Yes More smokers in conservative 

group (10% v 33%); more 

diabetes in liberal group (81% v 

54%); P-values not specified.

Overall: Low risk of bias

able) Yes (opaque envelopes) Patient and outcome assessors were 

blinded to group assignment. 

Anesthesiologist and ICU health care 

workers were not blinded.

Yes Yes No serious baseline imbalances 

between groups.

Overall: Low risk of bias

on 

d

Unclear, concealment method not described

Outcome assessors were blinded; 

care personnel were not blinded; 

patient blinding not specified.

Yes Yes No serious baseline imbalances 

between groups.

Overall: Low risk of bias

able) Unclear, concealment 

method not described

Surgeons and anesthesiologists were 

blinded until patient in ICU. Blinding 

of outcome assessor and patient not 

specified.

Yes. No inhospital deaths 

occurred.

Yes No serious baseline imbalances 

between groups.

Overall: Low risk of bias

on 

d

Unclear, concealment method not described

Use of blinding was not stated. Yes Yes No serious baseline imbalances 

between groups.

Overall: Low risk of bias
72

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

ent of methodologic characteristics and risk of bias in observational studies of RBC transfusions for anemia in patients with 

t population

h overall loss 

 follow-up or 

erential loss to 

follow-up?

Outcomes 

prespecified 

and 

defined?

Ascertainment 

techniques 

adequately 

described?

Non-biased and 

adequate 

ascertainment

 methods?

Statistical analysis of potential confounders?

Adequate 

duration of 

follow-up?

Propensity 

matching

Account for 

bleeding

Account for 

timing of 

transfusion

Comments

No Yes Yes Yes Yes No No Multivariate analysis 

did not account for 

some important 

confounders such 

as CHF

30 day and 1 

year

Not reported Yes No. Hospital 

complication registry 

but method of followup not stated

Not reported No No No Confounders not 

reported

Unclear, 30 

day mortality 

reported, but 

graphs show 5-6 

year mortality 

trends.

No Yes Yes Yes Yes Yes No YesNo Yes Yes Yes Yes Yes Yes Yes

No Yes Yes Yes Yes Yes No 1 year

obably No. Lost 

%. Difference in 

between groups 

not reported.

Yes Yes Yes No Yes No 1 year

Not reported Yes Yes Probably yes No Yes No 30 days and 1 

year.

Not reported Yes. No. Probably yes as likely 

is same registry as 

above. But unknown 

based on this abstract.

Abstract only, may be same population as other Maluenda reference 1 year

Not reported Yes No. Probably yes as likely 

is same registry as 

above. But unknown 

based on this abstract.

Abstract only, may be same population as other Maluenda reference 1 year
73

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

h overall loss 

 follow-up or 

erential loss to 

follow-up?

Outcomes 

prespecified 

and 

defined?

Ascertainment 

techniques 

adequately 

described?

Non-biased and 

adequate 

ascertainment

 methods?

Statistical analysis of potential confounders?

Adequate 

duration of 

follow-up?

Propensity 

matching

Account for 

bleeding

Account for 

timing of 

transfusion

Comments

No Yes Yes Yes Yes Yes No Yes

No Yes Mostly yes. NHLBI 

registry. Telephone 

follow-up. But unclear 

why they looked at 

“Hematoma Related 

Transfusion” rather 

than transfusion.

Probably yes. 

Again, didn’t look at 

transfusions, only 

hematoma related 

transfusions.

No No – only 

examined 

transfusions for 

hematoma, but 

not for other 

causes or for 

transfusion 

without bleeding.

No Confounders 

not reported and 

appears a number 

of important 

confounders were 

probably not 

accounted for

1 year

No Yes No, but primary 

outcome was inhospital death.

Yes, probably No Yes No Yes

No Yes Yes Yes No No No Yes

Not reported Yes Yes Unclear if investigators 

doing chart review on 

repeat admissions 

were blinded to 

whether patient had 

transfusion.

Yes No No Yes

No Yes Yes Yes Yes Yes Yes YesNo Yes Yes Yes No Yes No YesNo Yes Yes Yes Yes Yes Yes Also conducted 

sensitivity analyses 

to determine impact 

of “hidden” biases 

and found there 

would have to be 

“enormous” hidden 

biases to account for 

results

Yes

No Yes Yes No, 30 day event rates 

limited to VA hospitals 

only.

No No No Yes
74

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

h overall loss 

 follow-up or 

erential loss to 

follow-up?

Outcomes 

prespecified 

and 

defined?

Ascertainment 

techniques 

adequately 

described?

Non-biased and 

adequate 

ascertainment

 methods?

Statistical analysis of potential confounders?

Adequate 

duration of 

follow-up?

Propensity 

matching

Account for 

bleeding

Account for 

timing of 

transfusion

Comments

robably - primary 

utcome 30 D 

rtality assessed 

sing Medicare 

llment database, 

 proportion with 

plete vital status 

 30 D unclear.

Yes Yes Yes, probably. Yes No Partly – 

conducted 

additional 

analysis 

excluding 

patients who 

died within 

two days of 

admission.

Unclear how 

well transfusion 

administration was 

captured by claims 

data.

Yes

ear - CRUSADE 

nitiative relies on 

ospective chart 

review.

Yes No No - in-hospital 

outcomes only, 

unclear whether postdischarge deaths were 

accounted for.

No No No No

No Yes Yes Yes Yes No No YesNo Yes Yes Yes No No No Yes

Unclear Yes No Unclear No No No Yes 

ear - number of 

nts with complete 0 day survival 

formation not 

reported

Yes Partly Partly - 30 day 

mortality assessed 

through review of 

death certificates and 

phone interviews, but 

not clear they looked 

at death registries

Yes Yes Yes Yes

No Yes Yes Yes Yes Yes Unclear YesNo Yes Yes Yes Yes No No Did not account 

for post-operative 

transfusions.

Yes
75

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

R REVIEW COMMENTS AND RESPONSES

Comment Response

ope, and methods for this review clearly described?

ut a few things in the current iteration of the review: 1) 

n upfront; 2) defining the outcomes upfront; 3) justification of 

vational data. Defining the population – the document refers to 

nd “CHD” but does not drill down and define these. CHF can mptomatic low LVEF or those with symptoms of CHF but 

milarly, CHD can include acute coronary syndrome, PCI, or 

na. I think these clinical entities need to be defined upfront. 

We’ve clarified these definitions in the “study selection” section of Methods. The entities had been defined (fairly broadly) up front, but we agree this was not well-reported in the manuscript. 

ogeneous in their inclusion of these populations, then this 

mentioned. 

We’ve added more detail to the “data abstraction” section of Methods to clarify that we’ve collected and reported the clinical characteristics of study populations. We also added a sentence to the second paragraph of Discussion clarifying that most ESA studies were in patients with systolic heart failure. The applicability of the evidence review findings to various patient populations is also further delineated in the GRADE table, and in the clinical applications section. 

n-anemic patients with iron deficiency if the primary purpose 

nt of anemia? 

Clarified this in “study selection” section. 

s – the document examines several outcomes but no 

d for why they were chosen. 

Clarified that we are defining “health outcome” as those that are patientcentered and apparent to the patient (in contrast to intermediate physiologic outcomes). The list of outcomes was discussed with and approved by the Technical Expert Panel during the topic development phase. 

ational data – on pages 7 and 8, there is a section on Study 

rs to all of the questions posed would result in observational 

y.” This is entirely justified, but there are other ways to evaluate 

 the appropriateness and robustness of the statistical methods. 

nsider including some measure of observational data quality.

We’ve added a table describing the methodologic characteristics of each of the observational studies. We’ve added the quality assessment description to “study quality” section of Methods. 

ho surgery data as large RCT recently completed. The data had not been available, but we will include if enough data available. 

n of bias in our synthesis of the evidence?

 observational studies that are included (see above). Noted and discussed above.

o-ESA than the data supports Noted

ed or unpublished studies that we may have overlooked?

Noted.

l See comment 5 rows below regarding the FOCUS trial. 

Noted.
76

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

Comment Response

al suggestions or comments below. If applicable, please indicate the page and line numbers from the draft report.

erapy doesn’t seem to have a summary of what the overall 

ld be helpful. 

Thanks – yes, an accidental omission – this was added to the beginning of the iron section. 

ongoing trial and likely will not be published for several years. 

 been presented called FOCUS that will be published soon. (see 

g/article/1024017.do for a report of the presented results). 

Thanks for the clarification. The results were amended accordingly. We report the FOCUS results available in an abstract and acknowledge the full document has yet to be published. 

t distinction between the Wu study and the Rao study are that 

 anemia while Rao examined the lowest hct value occurring 

 In addition, patients with active bleeding were excluded from 

We’ve clarified these distinctions in this section of the discussion. 

al Applications should be more prescriptive (see below). It’s 

t what the recommendation is because it is obscured a bit by 

e data.

We’ve stopped short of providing prescriptive recommendations of what should and should not be done intentionally as we’d feel more comfortable developing clinical recommendations in conjunction with our stakeholders/clinical partners. 

umber of paper rejected Thank you – we had accidentally omitted this from the executive summary. 

 the evidence is clear that ESA are associated with harm and 

especially true in diabetic patients

The harm of targeting near-normal hemoglobin, especially in diabetic patients, seems clear after trials like TREAT, but these were not exclusively focused on treatment of anemic heart disease patients. The harms of using ESAs in heart disease populations are not as well elucidated. The language is meant to reflect this uncertainty and the fact that it most closely applies to those with chronic kidney disease. However, we did change the language to be a bit more direct (changed “possibility” to “finding,” and “may be” to “is”. 

it to hemoglobin correction of 10:1 makes no sense – the 

y. 

Thank you – this was a typo – corrected. 

k the case ESA cause harm is proven Please see response to page 2 comment above. 

gly disagree that 6MWT is not influence by blinding – reams 

edicine literature supports placebo effect!

Thank you – yes, we had mis-stated this. Meant to say lack of personnel blinding alone, given that outcome assessors were blinded, shouldn’t carry high risk of bias for these outcomes. Patients were blinded, and control patients received placebo injections. We’ve clarified this in the table. 

to support the notion that longer use of ESA is associated with 

It would be hard to determine this from the studies. The two studies mentioned with long follow-up periods also differed in patient population and treatment from the other smaller, shorter duration ESA trials. The mortality curves in Besarab did begin to separate several months into treatment and continued to diverge 1-2 years into treatment. 

 increased risk of cancer? Was suggested in TRICK study and 

ncology trials...

No, not that was reported in these trials. Of note, many excluded patients with malignancy. 

ment – are the ongoing trials even ethical given what we know 

and bad outcomes with ESA...

Interesting point, but outside the scope of our review. It is a different patient population. 
77

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

Comment Response

d, I have found the discussion in this paper the best 

tanding the complex interplay of transfusions for cardiac 

egies for elective red blood cell transfusion. Welch HG, 

gh LT. Ann Intern Med. 1992 Mar 1;116(5):393-402

Thanks for this suggestion. 

ion of confounder of ACS management and risk of transfusion 

have PCI that did worse with more transfusions??

One of the main confounders would be risk of bleeding associated with management – either procedural or med-related. Not all studies accounted for bleeding, but some did and we’ve added a table clarifying some of the methodologic characteristics of observational transfusion studies, including whether or not they accounted for bleeding complications. 

A recommendation is even more aggressive than stated:

th CKD patients, patients experienced greater risks for death, 

ovascular reactions, and stroke when administered ESAs to 

evel of greater than 11 g/dL.

d a hemoglobin target level, ESA dose, or dosing strategy that 

e risks.

mend:

D, consider starting ESA treatment when the hemoglobin 

dL. This advice does not define how far below 10 g/dL is 

ividual to initiate. This advice also does not recommend that 

a hemoglobin of 10 g/dL or a hemoglobin above 10 g/dL. 

nd use the lowest dose of ESA sufficient to reduce the need for 

ions. Adjust dosing as appropriate.

Agree. We’ve tried to clarify the language further by inserting the phrase “if they are to be used at all”.

 was base on an off the cuff recommendation by a Mayo 

WII (Vox Sang. 2010 Jan;98(1):2-11)

Thank you. We’ve inserted this reference. 

most ACS patients in the USA get PCI should transfusions be 

 hbg > 8-9??

This is a question for policy- and guideline-makers. The data summarized here are still largely of poor quality because it is mostly observational data. 

with the ferritin of 50 is truly iron deficiency and needs some 

ent - also needs a GI work-up – maybe a ferritin of 123 would 

We felt the data was not as strong for patients with ferritin > 100. The Anker study included patients with higher ferritins, but most had ferritin well below 100 and the applicability of the results of this IV iron trial are strongest for patients with low ferritins. 

e trial for ESA for STEMI was distinctly negative - JAMA. 

1863-72. Intravenous erythropoietin in patients with ST

ocardial infarction: REVEAL: a randomized controlled trial.

lloni C, Raman SV, Povsic TJ, Melton L, Barsness GW, 

 Kilaru R, Gruberg L, Hasselblad V, Greenbaum AB, Patel 

Ferrucci L, Longo DL, Lakatta EG, Harrington RA; REVEAL 

troke - Stroke. 2009 Dec;40(12):e647-56

This and 2 other recent trials examined one-time high-dose ESA use in ACS patients but these were not focused on treatment of anemic patients. As such, they fell outside of the scope of our review. Inclusion of the statement alluding to these studies in our discussion is probably confusing and we’ve deleted it. 
78

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

Comment Response

ew. The “emerging themes” concept is great as it does not 

ng in his/her approach to the individual patient.

ke out the high quality studies in fig 3 and 4.

Noted. Thanks. 

 in # of studies rejected.

ight needs the N filled in.

Done.

ce guidelines around this but would not promulgate quality 

Noted.

e, a seemingly transparent, honest assessment of the literature 

nfident in the findings and the interpretations.

Noted.

ight to benefits and harms, or benefits versus harms, the 

ly resolved in this analysis. I’ve no suggestions and in general ached by the authors was reasonable.

Noted.

going study of 80 patients, all (or the vast,vast majority)

d recognized systolic dysfunction. In some CHF series, up ection fractions. . While I can’t think why this would group 

 with treatments for anemia, available studies don’t apply. . In 

aluating arrhythmia patients, a clinical history of CHF was a 

or of outcome than ejection fraction measurements.

Agree. We’ve added statements to the ESA “summary” paragraph in results, the ESA discussion, and the Future studies sections clarifying that this evidence base applies most directly to those with reduced systolic function. 

of very common and potentially important contributors 

g, lung disease, cardiovascular medications, arrhythmias 

illation), others....

We limited the ESA and iron sections to trials only. We examined each trial for important baseline differences, though most were adequately randomized. This is more of an issue for the observational transfusion studies and we have evaluated the methodologic characteristics – including accounting for important confounders – of these studies. 

 performance measures, programs, quality improvement measures, patient care services, or conferences that will be directly affected by this 

.

f blood is high in the VA system as is the use of ESAs. By 

nt, the use of these therapies with limited benefit should be 

fer care for veterans at lower cost.

Noted.

wide implications for multiple areas of care Noted.

ution/system will need to assess its use of ESA’s, iron and 

opulations.

Noted.

commendations on how this report can be revised to more directly address or assist implementation needs.

linical Applications should be more prescriptive. Also the clinical 

ge. I would prefer to see broader categories, or if this is too 

e first column being the clinical situation and the subsequent 

As, Iron, and Blood transfusion. The cells then could have a (+), 

er the evidence supports or refutes use or if there are no data.

We intended the GRADE table to show the level of evidence in various broad clinical categories for each of the interventions.

 part could stand alone as a journal article Noted.

rdiology and hospitalist leaders, but the P&T and blood bank 

.

Noted.