Essentials of CHF

Comorbidities and outcomes in CHF

Anaemia and CHF

Prevalence of anaemia in CHF:1

– varies substantially by grade:

less symptomatic 4–23%

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

Prevalence of Anaemia in CHF: Registry Analyses

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

0 20 40 60Patients (%)

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

ADHERE (n=107,920)

EURO HF (n=11,327)

OPTIMIZE-HF (n=34,059)

Mean age (y) 75 71 73

Women (%) 52 47 52

Prior HF (%) 75 65 87

LVEF <40% 51 46 52

Coronary artery disease (%) 57 68 50

Hypertension (%) 72 53 71

Diabetes (%) 44 27 42

Atrial fibrillation (%) 31 43 31

Renal insufficiency (%) 30 18 NA

Fonarow GC. Am Heart J 2008;155:200−207

Demographics and Concomitant Diseases of Hospitalised Patients with HF in Registries

NA=not available

Cardiovascular Health Study: 5808 subjects, aged >65 years, follow-up: 7.3 years2

Association between Renal Function and CV Outcomes

Fried LF et al. J Am Coll Cardiol 2003;41:1364−1372

1.0

2.0

<1.10 1.10−1.29 1.30−1.49 1.50−1.69 1.70

Serum creatinine mg/dL

Hazard ratio and 95% CI for CVD

Hazard ratio and 95% CI for CHF

48%

92%

Hazard

rati

o

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

20%

40%

60%

GFR<6021%

SOLVD-PNYHA I–II

(n=3673)1

SOLVD-TNYHA II–III(n=2161)1

VALIANT(post AMI, CHF / LVD)

(n=14,527)2

34%

62%

Clinical trials (patients with severe RD excluded)

GFR<6036% GFR

60−75GFR

45−60

GFR<45 GFR

>90

GFR60−90

GFR30−59

GFR<30

ADHERE(acute, decompensated HF)

(n=118,465)3

‘Real life’

Renal Dysfunction – a Frequent Comorbidity in CHF

1. 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

% o

f p

ati

en

ts w

ith

ren

al d

ysfu

ncti

on

GFR, glomerular filtration rate

Ljungman S et al. Drugs 1990;39(Suppl 4):10−21

0

15

20

25

30

35

FF (

%)

0

1.2 1.6 2.0 2.4

Cardiac Index (L/min/m2)

20

40

60

80

GFR

(m

L/m

in/1

.73

m2)

0

100

200

300

400

500

RB

F (

mL/m

in/1

.73

m2)

GFR

FF

RBF

CHF Impairs Renal Function

RBF=renal blood flowFF=filtration fraction

Hillege HL et al. Circulation 2000;102:203−210

RR

(fo

r m

ort

ality

)

1.0

3.0

2.0

GFR

>76 59–76 44–58 <44

1.91

2.85

1.32

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

Renal Dysfunction – A Strong Predictor of Poor Outcome in HF

0 250 500 750 1000 12500.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Days

59−76 mL/min

44−58 mL/min

<44 mL/min

>76 mL/min

Patients (%)

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

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

Prevalence of Anaemia in CHF: Clinical Trials

Anaemia (Hb<12 g/dL) Occurs Early in CHF Progression

Pati

en

ts (

%)

Silverberg DS. J Am Col Cardiol 2000;35:1737–44

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, 2.21)

– 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

Anaemia in CHF Adversely Affects Outcomes (2/2)

O’Meara E et al. Circulation 2006;113:986−94

Patients with anaemia

Patients without anaemia

Mortality

50

100

150

Per

1000 p

ati

en

t-years

CV Non-CV

Reduced LVEF Preserved LVEF

CV Non-CV

Hospital admissions

100

200

400

Per

1000 p

ati

en

t-years

CV Non-CV

Reduced LVEF Preserved LVEF

CV Non-CV

300

CHARM study data

Anaemia was associated with an increased risk of hospitalisation and death, a relationship observed in patients with both reduced and preserved LVEF

Sharma R et al. Eur Heart J 2004;25:1021–8

Non-linear Relationship Between Hb Levels and Mortality in CHF

3.0

2.0

1.5

1.0

0.5

0

2.5RR 0.986p<0.001

RR 1.033p<0.001

Hb (g/dL)

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

ELITE II – RR for death during follow-up (n=3044)

van der Meer P et al. Eur Heart J 2004;25:285–91

Anaemia

Malnutrition

Chronic blood loss

Bone marrow

- Insensitivity to EPO- Cytokines (TNF-)

- Chronic disease- Inflammation

- Use of anticoagulationRenal failure

- Reduced EPO productionMedication

- Use of ACE-inhibitors

Haemodilution

Functional ID - Vitamin B12, folate

Absolute ID

- Chronic blood loss- Malabsorption

Pathophysiology of Anaemia in CHF: Possible Aetiologies

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

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

ESRD, end-stage renal disease

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)

Gilbertson D. J Am Soc Nephrol 2002;13:SA848

2-year mortality (%)

2-year incidence of ESRD (%)

No anaemia, CHF or CKI 7.7 0.1

Anaemia 16.6 0.1

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

Relation of Hb levels to Mortality in Patients Hospitalized With HF (Insight from the OPTIMIZE-HF Registry)

Young JB et al. Am J Cardiol 2008;101:223–230

0.11

0.10

0.09

0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0.10

Pre

dic

ted

pro

bab

ilit

y

of

in-h

osp

ital d

eath

Admission Hb (5–20 g/dL)

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

1,136,201 patients in the 5% Medicare database

– anaemia, CKD and CHF contribute significantly to mortality rates

34.6

CHF andanaemia

Patients with CRAS have a 2-year Mortality Rate of ~46%

0

10

20

30

40

50

7.7

Noanaemia

CHF or CKI

16.1

Anaemia

26.6

CHF

27.3

CKI andanaemia

38.4

CHF andCKI

45.6

Anaemia,CHF and

CKI

2-y

ear

mort

ality

(%

)

Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12

16.4

CKI

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

Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12

2.6

CKI0

2

4

6

5.4

CKI and

anaemia

3.5

CHF and CKI

5.9

Anaemia,CHF and

CKI

2-y

ear

incid

en

ce o

f ES

RD

(%

)

No anaemia,CHF or

CKI

0.1

Anaemia

0.2

CHF

0.2

CHF and anaemia

0.3

The Prognostic Value of Anaemiain Patients with Diastolic Heart Failure

Tehrani F et al. Texas Heart J 2009;36:220–225

0

0

Su

rviv

al d

istr

ibu

tion

fu

ncti

on

(%

)

10

Survival time (months)

0.2

0.6

0.4

0.8

1.0

20 30 40 50 60 70

No anaemia (n=132)

Anaemia (n=162)

Anaemia in Diastolic HF

Felker GM et al. Am Heart J 2006;151:457–462

0.3

0.1

0

0

Su

rviv

al p

rob

ab

ilit

y

1

Years

2 3 4 5 6 7

0.2

0.6

0.4

0.5

0.9

0.7

0.8

1

Anaemia/ISF

No anaemia/PSF

Anaemia/PSF

No anaemia/ISF

KPRR=Kaiser Permanente Renal Registry;HR=hazard ratio

Risk of CV Events and Hospitalisation Increases with Declining Kidney Function

Cohort of 1,120,295 pre-dialysis patients from the KPRR studied for 2.84 years1

1. Go AS et al. N Engl J Med 2004;351:1296–1305

Ag

e-s

tan

dard

ised

rate

of

death

fro

m a

ny c

au

se

(per

100

pers

on

years

)

0.76

≥60

1.08

45–59 30–44 15–29 <15

eGFR (mL/min/1.73 m2)

15

10

5

0

Mortality (N=51,424)

Ag

e-s

tan

dard

ised

rate

of

CV

even

ts

(per

100

pers

on

years

)

2.11

≥60

3.65

45–59 30–44 15–29 <15

eGFR (mL/min/1.73 m2)

40

20

0

CV events (N=138,291)

Hospitalisation (N=554,651)

Ag

e-s

tan

dard

ised

rate

of

hosp

italisati

on

(p

er

100

pers

on

years

)

13.54

≥60

17.22

45–59 30–44 15–29 <15

eGFR (mL/min/1.73 m2)

150

100

50

0

30

1011.29

21.80

36.60

4.76

11.36

14.14

42.26

86.75

144.61

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

1. Shlipak MG et al. J Am Soc Nephrol 2009;20:2625–2630MI, myocardial infarction; PAD, peripheral arterial disease

*defined as cystatin C-based eGFR >3 mL/min/1.73 m2/year

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

Juenger J et al. Heart 2002;87:235–41

CHF: Impact on QoL Compared with Other Diseases

SF-3

6 s

core

* (%

)

n=906 n=502 n=70 n=120 n=205

* General health perceptions

Juenger J et al. Heart 2002;87:235–41

QoL in Relation to NYHA ClassSF-

36 s

core

* (%

)

n=906 n=24 n=98 n=83

* General health perceptions

CHF Patients Willing to Trade Length of Life for Better QoL

Lewis EF et al. J Heart Lung transplant 2001;20:1016–24

Patients are more willing to trade their time for improved QoL when symptoms are poor

Pati

en

ts (

%)

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