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

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 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Anaemia in Diastolic HF 1 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

Risk of CV Events and Hospitalisation Increases with Declining Kidney Function Mortality (N=51,424) Cohort of 1,120,295 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

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

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

CHF: Impact on QoL Compared with Other Diseases SF-36 score* (%) 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 Class SF-36 score* (%) n=906 n=24 n=98 n=83 * General health perceptions Juenger J et al. Heart 2002;87:235–41

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

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