1. Comorbidities and outcomes in CHF
Essentials of CHF
Comorbidities and outcomes in CHF 1

2. Anaemia and CHF Prevalence of anaemia in CHF:1
varies substantially by grade:
less symptomatic –23%
higher severity grade: 30–61%
Incidence of anaemia in CHF:
SOLVD:2 1 year: 9.6%
Val-HeFT:3 1 year: 16.9%
COMET:4 1 year: 14.2%  5 year: 27.5%
1. Tang YD et al. Circulation 2006;113:2454–61; 2. Ishani A et al. J Am Coll Cardiol 2005;45:391–9;
3. Anand IS et al. Circulation 2005;112:1121–7; 4. Komajda M et al. Eur Heart J 2006;27:1440–6

3. Prevalence of Anaemia in CHF: Registry Analyses
Patients (%)
EHFS-I (Hb <12 g/dL)1
EHFS-II (Hb <12 g/dL)2
ADHERE (Hb <12 g/dL)3
In-CHF (Hb <12 d/dLm, <11 w)4
Horwich (Hb <12.3 g/dL)5
Silverberg (Hb <12 g/dL)6
McClellan (Hct <35%)7
Golden (Hct <35%)8
Alberta (ICD-9 codes)9
1. Cleland JG et al. Eur Heart J 2003;24:442–63; 2. Komajda M et al. Eur Heart J 2003;24:464–74; 3. Adams KF et al. Am Heart J 2005;149:
209–16; 4. Maggioni AP et al. J Card Fail 2005;11:91–8; 5. Horwich TB et al. J Am Coll Cardiol 2002;39:1780–6; 6. Silverberg DS et al. J Am Coll Cardiol 2000;35:1737–44; 7. McClellan W et al. Curr Med Res Opin 2004;20:1501–10; 8. van Tellingen A et al. Neth J Med 2001;59:270–9; 9. Ezekowitz JA et al. Circulation 2003;107:223–5

4. Demographics and Concomitant Diseases of Hospitalised Patients with HF in Registries
ADHERE (n=107,920)
EURO HF (n=11,327)
OPTIMIZE-HF (n=34,059)
Mean age (y) 75 71 73
Women (%) 52 47
Prior HF (%) 65 87
LVEF <40% 51 46
Coronary artery disease (%) 57 68 50
Hypertension (%) 72 53
Diabetes (%) 44 27 42
Atrial fibrillation (%) 31 43
Renal insufficiency (%) 30 18 NA
NA=not available
Fonarow GC. Am Heart J 2008;155:200−207 4

5. Association between Renal Function and CV Outcomes
Cardiovascular Health Study: 5808 subjects, aged >65 years, follow-up: 7.3 years2
 92%
2.0
 48%
Hazard ratio
1.0
Hazard ratio and 95% CI for CVD
Hazard ratio and 95% CI for CHF
<1.10
1.10−1.29
1.30−1.49
1.50−1.69
1.70
Serum creatinine mg/dL
Fried LF et al. J Am Coll Cardiol 2003;41:1364−1372 5

6. CV Risk: Influences on Renal Dysfunction
Excess comorbidities
Underuse of cardioprotective therapies
Excess toxicities of therapies
Abnormal CV biology
 RAAS and SNS, proinflammatory activation, oxidative stress, LVH, impaired myocyte contractility)
McCullough PA. J Am Coll Cardiol 2003;41:725−728 6

7. Renal Dysfunction – a Frequent Comorbidity in CHF
Clinical trials (patients with severe RD excluded)
‘Real life’
60%
62%
GFR 30−59
40%
% of patients with renal dysfunction
GFR
<60
36%
34%
GFR 60−75
GFR 60−90
20%
GFR
<60
21%
GFR 45−60
GFR <30
GFR <45
GFR >90
SOLVD-P NYHA I–II (n=3673)1
SOLVD-T NYHA II–III
(n=2161)1
VALIANT
(post AMI, CHF / LVD)
(n=14,527)2
ADHERE
(acute, decompensated HF)
(n=118,465)3
Dries DL et al. J Am Coll Cardiol 2000;35:681−689
2. Anavekar NS et al. N Engl J Med 2004;351:1285−1295
3. Heywood JT et al. J Card Fail 2007;13:422−430
GFR, glomerular filtration rate 7

8. CHF Impairs Renal Function
500 35
RBF
400 30
300 25 FF 80
FF (%)
RBF (mL/min/1.73 m2)
GFR (mL/min/1.73 m2)
200 60
GFR 20 40
100 15 20
1.2
1.6
2.0
2.4
Cardiac Index (L/min/m2)
RBF=renal blood flow
FF=filtration fraction
Ljungman S et al. Drugs 1990;39(Suppl 4):10−21 8

9. Renal Dysfunction – A Strong Predictor of Poor Outcome in HF
250
500
750
1000
1250
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Proportion Survival
Days
59−76 mL/min
44−58 mL/min
<44 mL/min
>76 mL/min
1708 CHF patients (NYHA III–IV) from PRIME II Trial
GFR was the most predictive of survival at multivariate analysis
GFR <60 mL/min, 2.1 risk of mortality
Surpassed LVEF, NYHA class, hypotension concomitant medications, diabetes mellitus, tachycardia
RR (for mortality)
1.0
3.0
2.0
GFR
>76
59–76
44–58
<44
1.91
2.85
1.32
Hillege HL et al. Circulation 2000;102:203−210 9

10. Prevalence of Anaemia in CHF: Clinical Trials
ValHeFT (Hb <12 g.dL m 11 w)1,2
ELITE-II (Hb <12.5 g/dL)3
Renaissance (Hb <12 g/dL)4
COMET men (Hb <13 g/dL)5
COMET women (Hb <12 g/dL)5
CHARM (Hb <12 g/dLw, 13 m)6
Patients (%)
1.Cohn JN et al. N Engl J Med 2001;345:1667–75; 2. Anand IS et al. Circulation 2005;112:1121–7; 3. Sharma R et al. Eur Heart J 2004;25:1021–8; 4. Anand I et al. Circulation 2004;110:149–54; 5. Komajda M et al. Eur Heart J 2006;27:1440–6; 6. O’Meara E et al. Circulation 2006;113:986−94 10

11. Anaemia (Hb<12 g/dL) Occurs Early in CHF Progression
Patients (%)
Silverberg DS. J Am Col Cardiol 2000;35:1737–44

12. Anaemia in CHF Adversely Affects Outcomes (1/2)
Anaemia is an independent risk factor for mortality
in a meta-analysis of 34 studies involving a total of 153,180 patients with HF, 37% were anaemic
minimum 6-month mortality rates
46.8% among patients with anaemia
29.5% among patients without anaemia
OR for increased death in the anaemic group: 1.96 (95% CI: 1.74, )
anaemia was an independent risk factor for mortality
hazard ratio adjusted for anaemia: 1.46 (95% CI: 1.26, 1.69)
Groenveld HF et al. J Am Coll Cardiol 2008;52:818–27 12 12

13. Anaemia in CHF Adversely Affects Outcomes (2/2)
CHARM study data
Patients with anaemia
Patients without anaemia
Hospital admissions
100
200
400
Per 1000 patient-years CV
Non-CV
Reduced LVEF
Preserved LVEF
300
Mortality 50
100
150
Per 1000 patient-years CV
Non-CV
Reduced LVEF
Preserved LVEF
Anaemia was associated with an increased risk of hospitalisation and death,
a relationship observed in patients with both reduced and preserved LVEF
O’Meara E et al. Circulation 2006;113:986−94 13 13

14. Non-linear Relationship Between Hb Levels and Mortality in CHF
ELITE II – RR for death during follow-up (n=3044)
3.0
2.0
1.5
1.0
0.5
2.5
RR 0.986
p<0.001
RR 1.033
p<0.001
11.5–12.4
10.5–11.4
8.0–10.4
12.5–13.4
13.5–14.4
14.5–15.4
15.5–16.4
16.5–17.4
17.5–20.0
Low
High
Hb (g/dL)
Sharma R et al. Eur Heart J 2004;25:1021–8

15. Pathophysiology of Anaemia in CHF: Possible Aetiologies
Malnutrition
Chronic blood loss
Bone marrow
- Insensitivity to EPO
- Cytokines (TNF-)
Chronic disease
Inflammation
- Use of anticoagulation
Renal failure
- Reduced EPO production
Medication
- Use of ACE-inhibitors
Haemodilution
Functional ID
- Vitamin B12, folate
Absolute ID
- Malabsorption
van der Meer P et al. Eur Heart J 2004;25:285–91

16. Anaemia, CHF and CKD have an Additive Effect on Mortality
Anaemia can increase disease progression, hospitalisation, morbidity, and mortality, in patients with CHF1–3 and with CKD4–8
There is an additive effect of each of anaemia, CKD and CHF affecting mortality risk6,9,10 and progression to ESRD9,10
ESRD, end-stage renal disease
1. Vasu S et al. Clin Cardiol 2005;28:454–458; 2. He WS & Wang LX. Congest Heart Fail 2009;15:123–130; 3. Lindenfeld J. Am Heart J 2005;149:391–401; 4. Xia H et al. J Am Soc Nephrol 1999;10:1309–1316; 5. Levin A et al. Nephrol Dial Transplant 2003;18(suppl 4):358:393–394;6. Herzog CA et al. J Card Fail 2004;10:467–472; 7. Ma JZ et al. J Am Soc Nephrol 1999,10:610–619; 8. Thorp M et al. Nephrology 2009;14:240–246; 9. Efstratiadis G et al. Hippokratia 2008;12:11–16; 10. Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12

17. CRAS – an Ominous Coexistence
2-year mortality and incidence of ESRD in a 5% sample of Medicare patients from the USA (1.1 million patients)
2-year mortality (%)
2-year incidence of ESRD (%)
No anaemia, CHF or CKI
7.7
0.1
Anaemia
16.6
CHF
26.1
0.2
CHF and anaemia
34.6
0.3
CKI
16.4
2.6
CKI and anaemia
27.3
5.4
CHF and CKI
38.4
3.5
CHF, CKI and anaemia
45.6
5.9
Note: the additive effect of anaemia, CHF and CKI on the mortality rate and on the incidence of ESRD
Gilbertson D. J Am Soc Nephrol 2002;13:SA848 17 17

18. Predicted probability of in-hospital death
Relation of Hb levels to Mortality in Patients Hospitalized With HF (Insight from the OPTIMIZE-HF Registry)
0.11
0.10
0.09
0.08
0.07
Predicted probability of in-hospital death
0.06
0.05
0.04
0.03
0.02
0.01
0.10 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Admission Hb (5–20 g/dL)
Young JB et al. Am J Cardiol 2008;101:223–230 18

19. Patients with CRAS have a 2-year Mortality Rate of ~46%
1,136,201 patients in the 5% Medicare database
anaemia, CKD and CHF contribute significantly to mortality rates 50
45.6
Anaemia, CHF and CKI 40
38.4
CHF and CKI
34.6
CHF and anaemia 30
2-year mortality (%)
27.3
CKI and anaemia
26.6
CHF 20
16.1
Anaemia
16.4
CKI 10
7.7
No anaemia CHF or CKI
Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12 19

20. Patients with CRAS have a 2-year ESRD Incidence Rate of ~6%
1,136,201 patients in the 5% Medicare database
anaemia, CKD and CHF contribute significantly to the incidence of ESRD
2.6
CKI 2 4 6
5.4
CKI and anaemia
3.5
CHF and CKI
5.9
Anaemia, CHF and CKI
2-year incidence of ESRD (%)
No anaemia, CHF or CKI
0.1
Anaemia
0.2
CHF
CHF and anaemia
0.3
Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12 20

21. Survival distribution function (%) Survival time (months)
The Prognostic Value of Anaemia in Patients with Diastolic Heart Failure
1.0
0.8
No anaemia (n=132)
0.6
Survival distribution function (%)
Anaemia (n=162)
0.4
0.2 10 20 30 40 50 60 70
Survival time (months)
Tehrani F et al. Texas Heart J 2009;36:220–225 21

22. Anaemia in Diastolic HF1
No anaemia/PSF
0.9
No anaemia/ISF
0.8
0.7
0.6
Survival probability
0.5
0.4
Anaemia/ISF
Anaemia/PSF
0.3
0.2
0.1 1 2 3 4 5 6 7
Years
Felker GM et al. Am Heart J 2006;151:457–462 22

23. Risk of CV Events and Hospitalisation Increases with Declining Kidney Function
Mortality (N=51,424)
Cohort of 1,120, pre-dialysis patients from the KPRR studied for 2.84 years1
14.14 15
11.36 10
Age-standardised rate of death from any cause (per 100 person years)
4.76 5
0.76
1.08
≥60
45–59
30–44
15–29
<15
eGFR (mL/min/1.73 m2)
Hospitalisation (N=554,651)
CV events (N=138,291)
144.61 40
36.60
150 30
21.80
100
86.75
Age-standardised rate of CV events (per 100 person years)
Age-standardised rate of hospitalisation (per 100 person years) 20
11.29
42.26 50 10
3.65
13.54
17.22
2.11
≥60
45–59
30–44
15–29
<15
≥60
45–59
30–44
15–29
<15
eGFR (mL/min/1.73 m2)
eGFR (mL/min/1.73 m2)
KPRR=Kaiser Permanente Renal Registry;HR=hazard ratio
1. Go AS et al. N Engl J Med 2004;351:1296–1305

24. Rapid Declines in Kidney Function
Rapid Declines in Kidney Function* are Associated with Greater Incidence of CV Events
Cohort of 4378 patients aged ≥65 years recruited from Medicare eligibility lists1
Incidence of CV events was significantly higher in patients with rapid declines in kidney function (p<0.001)1
Rapid declines in kidney function were independently associated with higher risk for heart failure, MI and PAD but not stroke
*defined as cystatin C-based eGFR >3 mL/min/1.73 m2/year
MI, myocardial infarction; PAD, peripheral arterial disease
1. Shlipak MG et al. J Am Soc Nephrol 2009;20:2625–2630 24

25. CV Morbidity and Mortality Increase with Worsening Kidney Function
CKD progression leads to a requirement for dialysis and/or kidney transplantation1
However, most patients with CKD die prematurely of CVD2
CV morbidity and mortality increases with decreasing kidney function3–5
1. Zhang Q-L & Rothenbacher D. BMC Public Health 2008;8:117; 2. Besarab A et al. N Engl J Med 1998;339:584–590; 3. Go AS et al. N Engl J Med 2004;351:1296–1305; 4. Shlipak MG et al. JAMA 2005;293:1737–1745; 5. Keith DS et al. Arch Intern Med 2004;164:659–663 25

26. CHF: Impact on QoL Compared with Other Diseases
SF-36 score* (%)
n= n= n= n= n=205
* General health perceptions
Juenger J et al. Heart 2002;87:235–41

27. QoL in Relation to NYHA Class
SF-36 score* (%)
n= n= n= n=83
* General health perceptions
Juenger J et al. Heart 2002;87:235–41

28. CHF Patients Willing to Trade Length of Life for Better QoL
Patients are more willing to trade their time for improved QoL when symptoms are poor
Patients (%)
Lewis EF et al. J Heart Lung transplant 2001;20:1016–24

29. QoL as a CHF Management Target?
CHF reduces QoL at least as much as other chronic medical conditions (e.g., diabetes, arthritis, chronic lung disease)
Treatment in CHF focuses on symptomatic improvement preventing the transition of asymptomatic cardiac dysfunction to symptomatic CHF, modulating the progression of CHF and reducing mortality
Despite some recent evidence of improved prognosis after first hospitalisation for heart failure, pharmacological treatment does not impressively improve the high morbidity and mortality rates associated with CHF
Thus QoL is a worthwhile target for patients with CHF