Anemia and Cardiovascular Disease: The Good, The Bad, The Ugly

1
Anemia and Cardiovascular Disease The Good,
The Bad, The Ugly

• Scott D. Solomon, MD
• Director, Noninvasive Cardiology
• Brigham and Womens Hospital
• Associate Professor of Medicine
• Harvard Medical School

2
Disclosures

• Dr. Solomon receives research grant support from
  Amgen, Alteon, Novartis, Genzyme, Genentech,
  Guidant, Medtronic, Kai, National Cancer
  Institute, National Institute for Diabetes,
  Digestive and Kidney Diseases, National Heart
  Lung and Blood Institute

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CV Death, MI, HF, RSD, or Strokeby Renal Function
0.6
1.7 0.4 (154.5)
0.5
1.3 0.2 (118.2)
0.4
Probability of Event
0.3
1.1 0.1 (100.0)
0.9 0.1(81.8)
0.2
0.1
0
Months
0
6
12
18
24
30
36

45 1644 1029 894 776 469 220 40
4559.9 3218 2365 2143 1953 1177 646 148
6074.9 4105 3314 3106 2893 1900 973 233
³ 75 5560 4719 4472 4200 2804 1593 438
5
Cardiovascular Events
eGFR (mL/min/1.73m2)
CV Death Reinfarction CHF Stroke RSD Composite
6
Spectrum of Risk (CV events)
lt 45n 1644
4559.9n 3218
6074.9n 4105
³ 75n 5560
14
12
10
8
Adjusted (70) Hazard Ratio
6
4
2
p lt 0.0001
0
eGFR (mL/min/1.73m2)
Anavekar NS et al NEJM 2004 3511285
7
VALIANT CKD

• Mean eGFR in VALIANT
• 67
• of patients with eGFR lt 60
• 33
• Total of patients going on to ESRD 14

/14,703 lt 0.1
8
Anemia and CV Risk
9
World Health Organization (WHO) Anemia
Definition1
Frequency
Hemoglobin (g/dL)
1. World Health Organization. Geneva,
Switzerland 2001. 2. Dallman et al. In Iron
Nutrition in Health and Disease. London, UK John
Libbey Co 199665-74.
10
Based on WHO Definition, 9 of Adults Have
Anemia ARIC Study
ARIC Study1 PopulationAges 45 to 64 N 15,792
Anemic
All
9
Women
Men
91
95
87
5
13
Anemia definition2Men Hgb lt13 g/dLWomen
Hgb lt12 g/dL

• The Atherosclerosis Risk in Communities (ARIC)
  study enrolled subjects in 4 US communities
  Forsyth County, NC Jackson, Miss Minneapolis,
  Minn and Washington County, Md.
• 1. Sarnak et al. J Am Coll Cardiol.
  20024027-33. 2. World Health Organization.
  Geneva, Switzerland 2001.

11
Causes of Anemia in CVD

• Normally, bone marrow generates 200 billion new
  cells per day to match the cells lost or removed
  from circulation.
• The expected compensatory response to anemia is a
  heightened rate of erythropoiesis.
• Failure to demonstrate a compensatory response
  signifies slowed or defective erythropoiesis.
• Most common cause of defective erythropoiesis in
  CAD population is chronic kidney disease (even
  mild CKD).

12
Anemia and Increased Cardiovascular Disease ARIC
Study
Women (P.04)(Hgb lt12 g/dL)
1.0
0.98
0.96
0.94
0.92
Proportion of Patients Free of Cardiovascular
Disease
0.90
0.88
Men (P.04)(Hgb lt13 g/dL)
Nonanemic Women
0.86
Anemic Women
N14,410Fully adjusted N13,883
0.84
Nonanemic Men
0.82
Anemic Men
0.80
0
500
1000
1500
2000
2500
3000
Time From Baseline (days)
Patients with hemoglobin levels. Sarnak et al. J
Am Coll Cardiol. 20024027-33.
13
Anemia and CV Death in ACS
Sabatine et al. Circulation 2005
14
Acute MI Higher Hematocrit is Associated with
Lower Risk of Death
3.16
Odds Ratio
Mortality at 1 year
1.94
1.35
1.0
Hematocrit
Langston, Kid Int 2003, 641398-1405 Retrospective
cohort of 709 Medicare patients admitted to
community hospitals for acute MI Odds Ratio
Adjusted for age, sex, race, kidney function and
cardiovascular co-morbidities 4 decrease in one
year risk of death per 1 increase in hematocrit
15
ESRD - USRDS Higher Hematocrit is Associated
with Fewer Hospital Days
Li Collins, Kid Int 2004, 65626-633 50,579
incident HD patients in the US between Jan 98
Dec 1999 Follow-up 2.5 yrs (hospitalization) and
3.0 yrs (mortality) Unadjusted data
16
Anemia, Diabetes and CKD Have Similar Impact on
Mortality
Collins, AJ. Adv Stud in Med. 20033(3C)S14-S17.
17
Anemia and CKD are Risk Factors for Mortality
Retrospective analysis of 6,635 patients SOLVD
database
Al-Ahmad A, et al. J Am Coll Cardiol.
200138(4)955-962.
18
Hazard Ratio for 3-yr Mortality
eGFR (ml/min/1.78 m²)
Hematocrit ()
Gurm et al. Am J Cardiol 20049430-4.
19
Dual Antiplatelet Agents Increase Risk of GI
Bleeding in Cardiac Patients
Risk ratio
Study
Weight
(95 CI)
2.92 (1.96,4.36)
MATCH
40.5
1.78 (1.25,2.54)
CURE
59.5
2.24 (1.72,2.92)
Overall (95 CI)
In VALIANT, dual antiplatelet agent use was
associated with an 85 increased adjusted risk of
GI bleeding (each 10 points of reduced eGFR
increased GI bleeding risk by 20)
.229503
1
4.35725
20
ANEMIA IN HF
21
Anemia In Patients With Heart Failure
Hb hemoglobin Hct hematocrit HF heart
failure

• The prevalence of anemia in heart failure
  patients is approximately
• 30 for Inpatients
• 20 for Outpatients

22
The Prevalence of Anemia and The Severity Of
Heart Failure
70
60
60
56
52
50
44
40
40
Patients
30
29
29
30
21
20
19
20
14
13
12
11
8
10
6
4
2
2
0
I (n158)
II (n467)
III (n340)
IV (n25)
NYHA Class
Hblt10g/dL (n32)
Hblt11g/dL (n97)
Hblt11.5g/dL (n165)
Hblt12.0g/dL (n244)
Hblt12.5g/dL (n337)
Source STAMINA Registry 45 General
Cardiologist sites, n673, 12 Academic sites
(incl. HF Specialists), n337
23
Heart Failure Higher Hematocrit is Associated
with Lower Risk of Death
McClellan, JASN 2002, 131928-36 Retrospective
cohort of 655 Medicare patients admitted to
community hospitals for heart failure Adjusted
for age, sex, race, kidney function and
cardiovascular co-morbidities 2.4 decrease in
one year risk of death per 1 increase in
hematocrit
24
The Etiology of Anemia in Heart Failure is Likely
Multifactorial
Bone marrow dysfunction Abnormal iron homeostasis
(uptake, release, utilization) Intravascular
fluid imbalance (hemodilution) EPO deficiency or
resistance
25
Causes of Anemia in HF
1Chatterjee et al. Eur J Heart Fail.
20002393-398. 2Silverberg et al. J Am Coll
Cardiol. 200035(7)1737-44. 3Volpe et al. Am J
Cardiol. 199474468-473. 4Androne et al.
Circulation. 2003107226-229.
26
Pathophysiology of Anemia in CHF
? Inflammation Exercise
Anemia
?
Tissue Hypoxia
CHF
Apoptosis?
RemodelingLVH cell death
Peripheralvasodilation
? LV Mass
? Blood pressure
? LV diameter
? Plasma volume Edema
Activation of SNS
? Diuretics
? Renal blood flow
Increased Retention
? Renin AngiotensinAldosterone ADH
Adapted from Okonko Anker. J Cardiac Failure.
200410(suppl)S5-S9.
27
Patients with Anemia Have Worse Heart
FailureVal-HeFT Database
Baseline Variables
No Anemia
Anemia
P-value
(n 3857)
(n 1145)
Age 65 yrs
6211
66 11
lt0.001
NYHA III-IV
36
45
lt0.001
History of PND
8
11
lt0.001
SBP (mmHg, meanSD)
124.218
122.618
lt0.001
Edema ()
23
38
lt0.001
GFR (ml/min/1.73m2)
6015
52 17
lt0.001
MLHFQ score (meanSD)
3123
3524
lt0.001
Background therapy,
Diuretics
84
91
lt0.001
Digoxin
66
70
0.02
Serum Albumin (g/L, meanSD)
4.20.3
4.00.4
lt0.001
CRP (pg/mL, meanSD)
5.78.9
8.912.9
lt0.001
BNP (pg/mL, meanSD)
162210
242276
lt0.001
LVEF (meanSD)
277
267
0.21
LVIDd/BSA cm/m2 (meanSD)
3.60.5
3.70.5
0.09
Anand et al 2005, Circulation 1121121-1127
28
Anemia is Associated with Increased Risk for
Hospitalization in Heart Failure Patients
1Alexander M, et al. Am Heart J.
1999137919-927 2Polanczyk CA, et al. J Card
Failure. 20017289-298 3Felker GM, et al. Am J
Cardiol. 200392625-628 4Kosiborod M, et al. Am
J Med. 2003114112-119 5Anker SD, et al. J Am
Coll Cardiol. 200443(suppl A)Abstract 842-2
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Anemia and Mortality In Heart Failure Patients
RENAISSANCE
NYHA Class II to IV LVEFlt30 N912 P0.0172
Log-rank test 1-year mortality was 28 in
anemic subjects (Hblt12 g/dL) vs. 16 in
non-anemic subjects 1Anand et. al.,
Circulation. 2004110149-154
31
Anemia and Mortality In Heart Failure Patients
PRAISE
PRAISE Study1
1.7
NYHA Class IIIb or IV LVEFlt30 N1,130
1.6
1.52
1.5
For patients in the lowest quintile of Hct
(lt37.6), each 1 decrease in Hct was associated
with an 11 higher risk of death (Plt0.01)
1.4
Adjusted Hazard Ratio for Death
1.3
1.18
1.2
1.12
1.10
1.1
1.0
n229
n224
n229
n223
0.9
lt37.6
37.6-40.6
40.7-43.0
43.1-46.0
gt46.0
Hematocrit ()
Adjusted for age, gender, diabetes, smoking,
heart failure etiology, EF, NYHA Class, systolic
BP, WBC count serum creatinine
1Mozaffarian et al. J Am Coll Cardiol.
2003411933-1939
32
Severity Of Anemia and the Risk For Death Or
Heart Failure Hospitalization
COPERNICUS Study1
N2,286 LVEFlt25 severe HF with dyspnea or
fatigue at rest or on minimal exertion
1Anker SD, et al. J Am Coll Cardiol.
200443(suppl A)Abstract 842-2
33
Worsening of Hb from Baseline to 12 Months was
Associated with Increased Mortality in Val-HeFT
P 0.024
P 0.31
P 0.32
13.2
Percent Mortality
9.9
9.8
8.5
Q1
Q2
Q3
Q4
lt - 0.8
gt - 0.8 to lt -0.1
gt - 0.1 to lt 0.5
0.5
Quartile change in Hgb, g/dL
- 1.66
- 0.47
0.15
1.11
Mean change in Hgb, g/dL
14.24
13.92
13.71
13.30
Mean BL Hgb, g/dL
Mean 12 month Hgb, g/dL
12.58
13.44
13.86
14.40
950
991
937
1028
Number of patients
Anand et al 2005, Circulation 1121121-1127
34
CHARM Programme
3 component trials comparing candesartan to
placebo in patients with symptomatic heart failure
CHARM Added
CHARMPreserved
CHARMAlternative
n2028 LVEF 40ACE inhibitor intolerant
n2548 LVEF 40ACE inhibitor treated
n3025 LVEF gt40ACE inhibitor treated/not
treated
Primary outcome for each trial CV death or CHF
hospitalisation
Primary outcome for Overall Programme All-cause
death
35
Relevant exclusions

• Serum creatinine 265 µmol/l (3 mg/dl)
• Known bilateral RAS
• Haemoglobin/anaemia NOT specifically mentioned

36
Baseline characteristics
Alternative Added Preserved Overall n2028 n25
48 n3023 n7599
Mean age (years) 67 64 67 66 Women
() 32 21 40 32 NYHA class () II 48 24 60 45 II
I 49 73 38 52 IV 3 3 2 3Mean
LVEF 30 28 54 39 Medical history () myocardial
infarction 61 56 44 53 diabetes 27 30 28 28
hypertension 50 48 64 55 atrial
fibrillation 25 26 29 27
37
Median eGFR and Haemoglobin quintiles
Hgb 15.7
Hgb 14.4
Hgb 13.6
Hgb 12.8
Median eGFR (ml/min/1.73m2)
Hgb 11.3
OMeara et al. CHARM Investigators. Circulation
2006
38
CHARM anemia independent of GFR
OMeara et al. CHARM Investigators. Circulation
2006
39
Relationship between haemoglobin and ECG
LVHCHARM-Overall
OMeara et al. CHARM Investigators. Circulation
2006
40
Relationship between haemoglobin and radiological
cardiomegaly CHARM-Overall
OMeara et al. CHARM Investigators. Circulation
2006
41
Hemoglobin and Mortality
Hgb 11.3
Hgb 12.8
Hgb 13.6
Hgb 15.7
Hgb 14.4
OMeara et al. CHARM Investigators. Circulation
2006
42
Rationale for Anemia Correction
43
Potential Benefits of Treating Anemia in CVD

• Improved oxygen delivery
• Improved exercise tolerance
• Attenuate adverse remodeling
• Improved QoL
• Antiapoptotic?
• Decrease in hosp./death?

Adapted from Felker and OConnor J Am Coll
Cardiol. 200444959-966.
44
Erythropoietin Receptors are Present on Adult
Cardiac Myocytes
50 ?m
50 ?m
EPOR protein in adult rat heart sections using
immuno- histochemistry
EPOR protein in isolated adult rat cardiac
myocytes visualized by fluorescence microscopy
Wright et al. 2004. FASEB.
45
EPO Administered at time of LADLigation Reduces
Myocyte Apoptosis
Tramontano et al. Biochem Biophys Res Commun.
2003308990-994.
46
Effect of EPO on Cardiac Function in Rats Post-MI
LVEDP (mmHg)
N-terminal ANP plasma levels (pmol/L)
p lt0.05 vs MI p lt0.01 vs MI p lt0.01 vs
sham
Van der Meer P, et al. JACC 2005
47
Clinical Trials of Anemia Correction with
Erythropoeitin
48
Studies Evaluating The Effect Of Treatment Of
Anemia With Recombinant Human Erythropoietin
(rHuEPO) In Heart Failure Patients
1J Am Coll Cardiol. 200035(7)1737-1744 2J Am
Coll Cardiol. 200137(7)1775-1780 3Nephrol Dial
Transplant. 200318141-146 4Circulation.
2003107294-299 5Kidney Blood Press Res.
20052841-47
49
Congestive Heart Failure (CHF) and CKDClinical
Benefit of Anemia Correction
126 Anemic Patients With Resistant CHF
Statistical difference following anemia
correction p lt 0.05 NYHA New York Heart
Association
Silverberg DS, et al. Peritoneal Dial Int.
200121(suppl 3)S236-S240.
50
Effect of Treatment Of Anemia With rHuEPO On
Exercise Duration And 6-Minute Walk
Mean Change in Exercise Duration
Mean Change in 6-Minute Walk Distance
6-Minute Walk Distance (feet)
Exercise Duration (seconds)
Plt0.004
PNS
Plt0.05
Randomized, placebo-controlled, single-blinded
study N23 (n8 for placebo group, n15 for EPO
group)
Mancini et al. Circulation. 2003107294-299.
51
As Well As Peak VO2 And Quality Of Life In Heart
Failure Patients
Mean Change in Peak VO2
Mean Change in MLHFQ Score
Peak VO2 (mL/kg/min)
MLHFQ (points)
PlaceboGroup
rHuEPOGroup
PlaceboGroup
rHuEPOGroup
Plt0.05
Plt0.04
PNS
(P not available)
Randomized, placebo-controlled, single-blinded
study N23 (n8 for placebo group, n15 for EPO
group)
Mancini et al. Circulation. 2003107294-299.
52
Pooled Analysis of HF Anemia Trials
Abraham W. ESC 2006
53
Pooled Analysis of HF Anemia Trials
Abraham W. ESC 2006
54
Potential Benefits and Risks of Treating Anemia
in HF

• Potential Benefits
• Improved oxygen delivery
• Improved exercise tolerance
• Attenuate adverse remodeling
• Improved QoL
• Antiapoptotic?
• Decrease in hosp./death?

• Potential Risks
• Increased thrombosis
• Platelet activation
• Hypertension
• Endothelial activation

Adapted from Felker and OConnor J Am Coll
Cardiol. 200444959-966.
55
Recent Oncology Publications Raised Concern
Regarding VTE Risk in EPO-Treated Patients
The Lancet Oncology 20034459-460.
56
Treatment of Anemia with Erythropoietin
Stimulating Agents (ESAs) What We Know

• Dialysis CKD

Improvements Hb Reduces Transfusion
/- Quality of Life /- CV Outcomes
no
3 RCTs
57
Normal Hematocrit Dialysis Trial
Hb 13
N618
Hb 10
N615
Besarab et al,New Engl J Med 1998
58
Normal Hematocrit Dialysis Trial
N618

• No benefit higher Hct (Hb)
• More vascular access problems

Death or MI
N615
RR 1.3 (95 CI 0.9 to 1.9)
Besarab et al,New Engl J Med 1998
59
Current NKF/ KDOQI Guidelines for Anemia
Correction

• In patients with CKD, Hb should be 11.0 g/dL or
  greater (MODERATELY STRONG RECOMMENDATION)
• Observational data that patients with lower Hb do
  worse
• Assocation between anemia and LVH
• Improvement in QOL with anemia correction to
  11-12 g/dL
• In the opinion of the Work Group, there is
  insufficient evidence to recommend routinely
  maintaining Hb levels at 13.0 g/dL or greater in
  ESA-treated patients.

60
3 RCTs Designed to Address Whether Anemia
Correction in CKD May Improve CV Morbidity and
Mortality

• CREATE (Cardiovascular risk Reduction by Early
  Anemia Treatment with Epoetin beta) - Completed
• Determine the impact of early vs late anemia
  correction on mortality and cardiovascular
  morbidity in patients with CKD
• CHOIR (Correction of Hemoglobin and Outcomes In
  Renal insufficiency) Terminated Early
• Determine the impact of degree of anemia
  correction on mortality and cardiovascular
  morbidity in patients with CKD
• TREAT (Trial to Reduce Cardiovascular Events with
  Aranesp? Therapy) - Enrolling
• Determine the impact of anemia therapy (yes/no)
  on mortality and cardiovascular morbidity in
  patients with CKD and type 2 diabetes

61
Pooled Efficacy ResultsHemoglobin Response in
Studies 170 and 171
Hemoglobin Concentrations (Mean ? SE) Over Time
Darbepoetin alfa
Placebo
For subjects in study 170 who stayed on study
longer than 27 weeks, the Hb concentration
remained stable throughout the study
62
General Design Differences
Treatment starts when Hb lt10.5 g/dL
63
Key Inclusion Criteria and Baseline
Characteristics
a Study population sample w/ available data b
Abstracts, 2004 ASN, St. Louis, MO c MacDougall
et al. NDT 200318suppl 2ii13-ii16 d
www.theKidney.org
TREAT, CHOIR mL/min/1.73m2 CREATE mL/min
64
European Best Practice Guideline 4 Comments
Regarding Initiation of rHuEPO

• "There is widespread agreement that symptoms
  usually begin when the Hb is lt11 g/dL."
• "There is abundant evidence, including data from
  randomized studies, that quality of life, CV
  morbidity, exercise capacity, endocrine, immune
  and sexual function, and hospitalization rates,
  are all improved in pre-dialysis patients if the
  Hb is increased from lower levels to gt10-11
  g/dL."
• "Prospective data suggesting mortality can be
  diminished by increasing the Hb concentration
  are, as yet, lacking."

Nephrol Dial Transpl 199914(Suppl 5)11-13.
65
Study Endpoints
66
CREATE Study design
Primary study objectives To investigate the
effects of early epoetin beta treatment to normal
target haemoglobin (Hb) values compared to
partial anaemia correction on cardiovascular (CV)
events
600 patients from gt20 countries
Hg 11-12.5 eGFR 15-35
Randomisation
High target Hb(1315 g/dl)
Standard target Hb (10.511.5 g/dl)
Group 2
Group 1
67
Primary endpointTime to first CV events (105
events)
Events 58 vs 47 HR1.22 (0.831.79) Log rank
test p0.20
68
Cardiovascular Risk Reduction by Early Anemia
Treatment with Epoetin beta (CREATE)
a www.theKidney.org
69
Correction of Hemoglobin and Outcomes in Renal
Insufficiency (CHOIR)
1432 Patients Randomized
715 Group A (Hb 135 g/L)
717 Group B (Hb 113 g/L)
279 Early Withdrawal without experiencing primary
endpoint
271 Early Withdrawal without experiencing primary
endpoint
DSMB Stopped Study May 2005 for Futility (not a
stopping rule) Results Released April 2006 at NKF
meeting
Singh A et al. NEJM 2006
70
Kaplan-Meier Plot of the Time to the Primary
Composite Event between Randomization and
Termination ITT Population
Hazard ratio 1.337 (1.025, 1.743) P 0.0312
Hazard ratio 1.337 (1.025, 1.743) P 0.0312
101 107
0 3
715 717
587 594
55 44
457 499
270 293
At risk
Singh A et al. NEJM 2006
71
Components of the Primary Endpoint
CHF Hospitalization (where RRT did not occur)
Death
p 0.0674
p 0.0727
Hazard ratio 1.483 (0.969, 2.268)
Hazard ratio 1.409 (0.967, 2.054)
Myocardial Infarction
Stroke
p 0.9803
p 0.7836
Hazard ratio 1.010 (0.454, 2.249)
Hazard ratio 0.915 (0.484, 1.729)
Singh A et al. NEJM 2006
72
CHOIR Outcomes Mortality and CV Morbidity
Time for KM curves to separate 6-8 months
Singh A et al. NEJM 2006
73
CHOIR Results
Primary Composite Endpoint
Death
CHF Hospitalization
Myocardial Infarction
Stroke
0 1
2
135 g/L target better
113 g/L target better
Singh A et al. NEJM 2006
74
Cause of Death in CHOIR
75
Metaanalysis Mortality
Lancet 2007
76
Metaanalysis MI
Lancet 2007
77
TREAT Trial to Reduce Cardiovascular Events with
Aranesp? (Darbepoetin alfa) Therapy
Hypothesis Treatment of anemia with darbopoetin
alfa reduces the risk of mortality and nonfatal
cardiovascular events in patients with CKD and
type 2 diabetes
Darbopoetin alfa Group (Target Hemoglobin 13 g/dL)
N 2000

• Study Population
• Hemoglobin ?11 g/dL
• GFR 20-60 mL/min
• Type 2 DM

Design randomized (11), double blind,
controlled
Control Group
N 2000
Event-driven
Event-driven 1200 patients
78
TREAT almost 2x greater overall exposure to
study drug than CHOIR
CHOIR vs. TREAT Subject Exposure
Based on 01-Mar-2007 Oracle Clinical
Database Crude estimate 1432 patients x (16
months / 12 months/year) 1900 patient-years
79
NEJM 2007
Lancet February 2007
80
Unanswered Question in Anemia Rx

• What Targets?
• Which Patients?

81
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82
Anemia is a readily identifiable surrogate
associated with high rates of adverse clinical
outcomes. Because ESP can raise hematocrit, it is
imperative to definitively determine the risk
benefit ratios of these available therapies. To
accept a benefit based on the existing data may
be exposing patients to an expensive therapy that
is either ineffective or may even contribute to
adverse outcome. On the other hand, to accept
harm based on existing data may deny patients the
ability to improve their prognosis as well as
quality of life.
Rev Cardiovasc Med 2005
83
RED-HF Trial Hypothesis and Study Design
Hypothesis Treatment of anemia with darbepoetin
alfa in subjects with symptomatic left
ventricular systolic dysfunction and anemia
decreases the risk of all-cause mortality or
hospital admission for worsening HF
Darbepoetin alfa group (target Hb 13.0, not to
exceed 14.5 g/dL)
N 1700

• Study Population
• Hb 9 to 12 g/dL
• LVEF lt 35
• NYHA Class II to IV

11 randomization
Placebo group
N 1700
Young JB, et al J Cardiac Failure 2006(Suppl
1)6S77.
84
Randomized Controlled Trials Play A Critical Role
in Advancing Patient Care Through Guidelines
Clinical Trials
Drug Discovery
Guidelines
Patient Outcomes
Quality Indicators
Caregiver Performance
Califf, R et al JACC 200240(11)1895-1901
85
Monthly Hemoglobin (Hb) of US Dialysis Patients
Hb gt13.0
15
Hb 12.0-lt13.0
Hb10.0-lt11.0
Hb 9.0-lt10.0
Hb 11.0-lt12.0
43
22
Hb lt9.0
Hb level 11 g/dL a CMS Performance Measure
Steinbrook, Lancet 20063682191.
86
Randomized Controlled Trials Have Driven the
Evolution of Guidelines in Cardiology ACC/AHA
Guidelines for Management of Acute MI Beta
Blockade

• 1990 Beta blockers are first recommend for
  targeted patients (reflex tachycardia, systolic
  hypertension, persistent angina, no signs of
  heart failure)1
• 1996 Guidelines include 'non ST MI' patients in
  the highest level recommendation2
• 1999 Patients with 'moderate LV failure' are
  moved from the class III (potentially harmful) to
  the class IIb (potentially useful) level
  recommendation3
• 2001 Beta blockers are a highest-level
  recommendation for all post-MI patients4

1 Gunnar RM, et al. Circulation
199082(2)664-707 2 Ryan TJ, et al. Circulation
199694(9)2341-2350 3 Ryan TJ, et al.
Circulation 1999100(9)1016-30 4 Smith CC, et
al. Circulation 2001104(13)1577-9
ACC American College of Cardiology AHA
American Heart Association MI myocardial
infarction LV left ventricular
87
Negative Results From Randomized Controlled
Trials Evolve The Practice of Medicine

• Secondary prevention of cardiovascular disease
  with estrogens1
• Prophylaxis against ventricular dysrhythmia in
  the peri-myocardial infarction setting with
  lidocaine2
• Prophylaxis against pre-eclampsia with calcium
  supplementation3

1 Hulley S, et al. JAMA 1998280(7)605-613. 2
Sadowski ZP, et al. American Heart Journal
1999137(5)792-798. 3 Levine RJ, et al. NEJM
1997337(2)69-76.
88
Patients who are deficient in X do not
necessarily benefit from repleting X

• Hormone Replacement Therapy
• Reduced Estrogen associated with increased risk
  of
• Heart Disease
• Bone Loss
• Observational Suggested Benefits of HRT
• Randomized Trials suggested harm with HRT
• Thyroid Replacement
• Just enough good
• Too much - bad

89
Beneficial Impact on HRQOL Does Not Always
Extrapolate to Other Health Outcomes
Improvement in Exercise duration1
Heart failure symptoms1
RR 1.43 plt0.05
HRQOL health-related quality of life
Decreased survival2
1 Packer M, et al. JACC 1993 22(1)65-72. 2
Packer M, et al. (abstract) Circulation
199388(Suppl)I-301. 2 Van Veldhuisen DJ, et
al. International Journal of Cardiology
200180(1)19-27.
90
Anemia Management Guidelines State that
Additional Data Are Needed

• National Kidney Foundation1
• "Additional studies are needed to clarify the
  relationship between Hgb/Hct and outcomes in CKD
  patients, particularly those with heart disease."
• European Best Practice Guidelines
• "Prospective data suggesting mortality can be
  diminished by increasing the Hb concentration
  are, as yet, lacking."2
• "no prospective data have yet shown an
  improvement in survival in any single group of
  patients treated with erythropoiesis-stimulating
  agents."3

1 Am J Kid Dis 20011(Suppl 1)S182-S238. 2
Nephrol Dial Transpl 199914(Suppl 5)11-13. 3
Nephrol Dial Transplant 200419(Suppl 2)ii6-ii15.
91
Conclusions

• Anemia is a risk factor for adverse outcome in
  patients with CKD and CVD
• Correction of anemia with ESPs may offer benefits
  to some patients in some clinical circumstances,
  although degree of correction is hotly debated
• Nevertheless, the potential for harm has been
  demonstrated with anemia correction in the CKD
  population
• We should be cautious until we have results from
  ongoing major clinical trials in anemia
  correction to reduce CV risk

92
I was hoping Id be in the active therapy group?
Well, I was hoping Id be in the placebo group?
The definition of equipoise
93
Trials of Anemia Targets in CKD

• CHOIR study
• 1432 subjects recruited, diabetic and nondiabetic
  CKD patients
• Epoetin-alfa
• 130 centers, US only
• Hb 13.5 g/dL vs 11.3 g/dL
• Study stopped by Data and Safety and Monitoring
  Board
• CREATE study
• Approximately 603 subjects
• Epoetin-beta
• 100 centers. 22 countries
• Study reported data at European Renal
  Association/European Dialysis and Transplant
  Association conference
• TREAT study
• 4000 subjects with CKD and type 2 diabetes
• Darbepoietin
• 700 centers, 26 countries
• Placebo-controlled with rescue arm Hb 9.0 g/dL
  vs 13.0 g/dL
• Enrollment under way

CHOIR American Correction of Hemoglobin and
Outcomes in Renal Insufficiency CREATE
Cardiovascular Risk Reduction by Early Anemia
Treatment With Epoetin-beta TREAT Trial to
Reduce Cardiovascular Events with Aranesp
Therapy.
94
CHOIR Study Design

• Open label, Randomized Controlled Trial
• 130 sites randomized 1432 subjects in US
• 3 years duration
• Median f/u 16 months
• Study population
• Hb lt 11 g/dl
• Age ? 18
• Steady-state GFR ? 15 ml/min and ? 50 ml/min
• Primary Endpoint Composite event
• Death
• Myocardial infarction
• Stroke
• CHF hospitalization (excluding RRT)

Singh et al In press
95
Baseline Characteristics
Singh et al In press
96
Hemoglobin and Epoetin alfa over Time
Singh et al In press
97
CHOIR QOL

• 3 instruments
• LASA
• KDQ
• SF-36
• Limitations
• Open label
• Subjective

98
CHOIR QOL LASA
Longitudinal Analysis High vs.
Low Difference P value Energy
Level 0.0798 0.350 Ability in
DL 0.1356 0.233 Overall QOL -0.001 0.991
99
CHOIR KDQ Fatigue
Longitudinal Analysis High Gp Low Gp
Difference P value Estimate 0.0275 0.0248
0.0027 0.527 SD 0.0031 0.00
3
100
CHOIR QOL Vitality
Longitudinal Analysis High Gp Low Gp
Difference P value Estimate 0.3778 0.3527
0.0251 0.701 SD 0.0468 0.04
55
101
TREAT Trial to Reduce Cardiovascular Events with
Aranesp? (Darbepoetin alfa) Therapy
Hypothesis Treatment of anemia with Aranesp?
reduces the risk of mortality and nonfatal
cardiovascular events in patients with CKD and
type 2 diabetes
Event-driven
Event-driven 1200 patients
102
RED-HF Trial Hypothesis and Study Design
Hypothesis Treatment of anemia with darbepoetin
alfa in subjects with symptomatic left
ventricular systolic dysfunction and anemia
decreases the risk of all-cause mortality or
hospital admission for worsening HF
Darbepoetin alfa group (target Hb 13.0, not to
exceed 14.5 g/dL)
N 1700

• Study Population
• Hb 9 to 12 g/dL
• LVEF lt 35
• NYHA Class II to IV

11 randomization
Placebo group
N 1700
Young JB, et al J Cardiac Failure 2006(Suppl
1)6S77.
103
FDA Black Box Warning March 9 2007

• WARNINGS Erythropoiesis-Stimulating Agents
• Use the lowest dose of ESA that will gradually
  increase the hemoglobin concentration to the
  lowest level sufficient to avoid the need for red
  blood cell transfusion (see DOSAGE AND
  ADMINISTRATION).
• ESAs increased the risk for death and for serious
  cardiovascular events when administered to target
  a hemoglobin of greater than 12 g/dL (see
  WARNINGS Increased Mortality, Serious
  Cardiovascular and Thromboembolic Events).
• Cancer Patients Use of ESAs
• Shortened overall survival and increased deaths
  attributed to disease progression at 4 months in
  patients with metastatic breast cancer receiving
  chemotherapy when administered to target a
  hemoglobin of greater than 12 g/dL,
• Increased the risk of death when administered to
  target a hemoglobin of 12 g/dL in patients with
  active malignant disease receiving neither
  chemotherapy nor radiation therapy. ESAs are not
  indicated in this population.