Marco Metra Cardiologia Università e Spedali Civili di Brescia, Italia

1. 9th International Symposium Heart Failure & Co. Milano, IstitutoClinicoHumanitas Clinical Presentations of Acute Decompensated Heart Failure Marco Metra Cardiologia Università e Spedali Civili di Brescia, Italia

2. The Burden of Acute HF • Most frequent cause of hospitalization for patients aged >65 years • In-hospital stay • Duration, mean: 4 days (US) / 8 days (Europe) • Mortality, 3% to 9% • Follow-up (2-3 months) • Mortality, 9% to 13% • Rehospitalizations, 24% to 30%

3. Definition of Acute Heart Failure(ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008) • Rapid onset or change in the signs and symptoms of HF, resulting in the need for urgent therapy. • May be either • New HF • Worsening of pre-existing chronic HF • Patients may present as a medical emergency (e.g. acute pulmonary edema)

4. Definition of Acute Heart Failure(ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008) • Rapid onset or change in the signs and symptoms of HF, resulting in the need for urgent therapy. • May be either • New HF • Worsening of pre-existing chronic HF • Patients may present as a medical emergency (e.g. acute pulmonary edema)

5. Clinical classification of Acute Heart Failure (ESC guidelines 2008)

6. Factors influencing clinical presentations of AHF • Myocardial ischemia • Blood pressure (peripheral perfusion) • Fluid overload • Kidney dysfunction • Each may or may not be present, with different relative importance, in each patient

7. AHF & myocardial ischaemia • Acute coronary syndromes • Myocardial infarction/unstable angina with large extent of ischemia and ischemic dysfunction • Mechanical complication of acute myocardial infarction • Right ventricular infarction • Chronic coronary artery disease • Ischaemia / necrosis precipitated by AHF • Non-ischaemiccardiomyopathy • Ischaemia / necrosis precipitated by AHF ?

8. AHF & myocardial ischaemia • Acute coronary syndromes • Myocardial infarction/unstable angina with large extent of ischemia and ischemic dysfunction • Mechanical complication of acute myocardial infarction • Right ventricular infarction • Chronic coronary artery disease • Ischaemia / necrosis precipitated by AHF • Non-ischaemiccardiomyopathy • Ischaemia / necrosis precipitated by AHF ?

9. Precipitating factors in AHF: EHFS II % of patients Nieminen et al., Eur Heart J 2006; 27:2725

10. AHF & myocardial ischaemia • Acute coronary syndromes • Myocardial infarction/unstable angina with large extent of ischemia and ischemic dysfunction • Mechanical complication of acute myocardial infarction • Right ventricular infarction • Chronic coronary artery disease • Ischaemia / necrosis precipitated by AHF • Non-ischaemiccardiomyopathy • Ischaemia / necrosis precipitated by AHF ?

11. Prevalence of Detectable (>0.01 pg/ml)Troponin T in patients with AHF with daily blood sampling Metra et al., Eur J Heart Fail. 2007;9:776-86

12. Freedom from Death or CV Hospitalization and cTnT plasma levels in Acute Heart Failure Cardiac mortality or Cardiac mortality CV hospitalizations 1 1 0.8 0.8 0.6 0.6 Fraction of patients Fraction of patients 0.4 0.4 P<0.0001 P<0.01 0.2 0.2 No cTnT detectable No cTnT detectable cTnT detectable cTnT detectable 0 0 0 90 180 270 360 0 90 180 270 360 Days Days Patients at risk Patients at risk: No cTnt 56 55 44 35 33 No cTnt 56 44 30 26 21 cTnT 51 34 21 15 11 cTnt 51 23 11 9 4 Metra et al., Eur J Heart Fail. 2007;9:776-86

13. Prediction of Cardiac Death: CART analysis 107 patients discharged after AHF P<0.0001 NT-proBNP <6078pg/mL n= 76; 1-year survival, 91% NT-proBNP >6078 pg/mL n= 31; 1-year survival, 34% P=0.021 NYHA class III/IV n= 15; 1-year survival, 71% NYHA class I/II n= 61; 1-year survival, 95% P=0.018 cTnT undetectable n= 40; 1-year survival, 100% Metra et al., Eur J Heart Fail. 2007;9:776-86 cTnT detectable n= 21; 1-year survival, 78%

14. Acute HF Hemodynamicabnormalities + neurohorm./ Inflam. activation Inotropic stimulation ↑ Heart rate Low CO / hypotension ↑ LVEDP / ↑ wall stress ↓Coronaryperfusion ↑ myocardial VO2 CAD / hybernating myocardium / ….. Myocardialdamage / necrosis

15. Acute HF + Vasodilators Inotropic stimulation ↑ Heart rate Low CO / hypotension ↑ LVEDP / ↑ wall stress ↓Coronaryperfusion ↑ myocardial VO2 ? CAD / hybernating myocardium / ….. Myocardialdamage / necrosis

16. Nitroprusside and Mortality Patients Presenting With Presumed Acute MI and HF All had a PA Catheter Early: < 9 hrs. Cohn JN, et al. N Engl J Med. 1982; 306:1129.

17. Sodium Nitroprusside for advanced low-output heart failure (n=175, 50% ischemic, 30% prev CABG) Mullens, W. et al. J Am Coll Cardiol 2008;52:200-207

18. Acute HF + Inotropic agents Inotropic stimulation ↑ Heart rate Low CO / hypotension ↑ LVEDP / ↑ wall stress ↓Coronaryperfusion ↑ myocardial VO2 ? CAD / hybernating myocardium / ….. Myocardialdamage / necrosis

19. Predictors of all-cause mortality on multivariate analysis Mullens, W. et al. J Am Coll Cardiol 2008;52:200-207

20. Survival in patients admitted for acute heart failure subdivided on the basis of treatment with inotropic agents No Inotropes No Inotropes Inotropes Inotropes P <0.0001 P=0.025 after adjustment at multivariable analysis P =0.007 P=0.203 after adjustment at multivariable analysis

21. Factors influencing clinical presentations of AHF • Myocardial ischemia • Blood pressure (peripheral perfusion) • Fluid overload • Kidney dysfunction • Each may or may not be present, with different relative importance, in each patient

22. Clinical significance of high blood pressure in AHF • Cause of AHF • Afterload mismatch • Consequence of AHF • ↑neurohormonal activation • ↑cardiac function

23. SBP in AHF Registries • ADHERE, AHJ 2005 • 107 362 patients from 282 hospitals • Mean SBP, 144 mmhg • SBP >140: 50% of pts • OPTIMIZE-HF, JAMA 2006 • 48 612 patients from 259 hospitals • Mean SBP, 143+33 mmhg • SBP >140: 50% of pts • Italian Survey, EHJ 2006 • 2807 patients from 206 cardiology centers • Mean SBP, 141+37 mmhg, 138+36 WHF, 146+36 de novo • SBP >140: 43%; 38% WHF, 49% de novo • EFICA, EJHF 2006 • 599 patients from 60 centers • Mean SBP, 126+39 mmhg; 139 without CS pts

24. Cause of AHF According to SBP: OPTIMIZE-HF Study48 612 patients FROM 259 us HOSPITALS Gheorghiade et al., JAMA 2006; 296:2217

25. Cause of AHF According to SBP: OPTIMIZE-HF Study48 612 patients FROM 259 us HOSPITALS LV Systolic dysfunction LV Ejection fraction 80 80 63 52 60 60 44 35 % of patients 40 40 44.4 LVEF units 40.9 37.8 20 33.3 20 0 0 < 120 120- 140- >161 < 120 120- 140- >161 139 161 139 161 SBP quartiles, mmhg SBP quartiles, mmhg Gheorghiade et al., JAMA 2006; 296:2217

26. ADHERE: Risk Stratification for Inhospital Mortality in theValidation Cohort 32,229 hospitalizations BUN < 43 mg/dLMortality, 2.8% BUN ≥ 43 mg/dLMortality, 8.3% 24,702 hospitalizations 6,697 hospitalizations SBP ≥ 115 mmHg Intermediate risk5.6% mortality SBP< 115 mmHg 15.3% mortality SBP ≥ 115 mmHg Low risk2.3% mortality SBP< 115 mmHg Intermediate risk5.7% mortality 1,862 hospitalizations S-creatinine< 2.75 mg/dL Intermediate risk13.2% mortality S-creatinine≥ 2.75 mg/dL High risk19.8% mortality Fonarow GC, et al. JAMA. 2005;293:572-580.

27. In-Hospital Mortality Rates by Admission Systolic Blood Pressure Deciles (n = 48 567) Gheorghiade, M. et al. JAMA 2006;296:2217-2226.

28. Indipendent Predictors of Outcomes CV death, HF hospitalisation free survival 1.0 0.8 64% Fraction of patients, % 0.6 0.4 P < 0.001 40% SBP at discharge ≥ 110 mmHg (n=304) SBP at discharge < 110 mmHg (n=193) 0.2 0.0 0 60 120 180 240 300 360 Days

29. Factors influencing clinical presentations of AHF • Myocardial ischemia • Blood pressure (peripheral perfusion) • Fluid overload • Kidney dysfunction • Each may or may not be present, with different relative importance, in each patient

31. Hemodynamic Changes Occur Before Clinical Exacerbations in the Patients with CHF Patient # 1 ePAPD RVP Heart Rate Patient # 2 RVP ePAPD HR Adamson et al. JACC 2003; 41:565

32. Patterns of Weight Change Preceding Hospitalization for Heart Failure: cases vs controls. n=268 Chaudhry, … Krumholz. Circulation 2007;116:1549-1554

33. 33% 30 24% 25 16% no change or gain in Body Weight 49% little or no Weight Loss 20 11% 13% 15 7% 10 6% 3% 2% 5 0 (<-20) (-20 to -15) (-15 to -10) (-10 to -5) (-5 to 0) (0 to 5) (5 to 10) (>10) Change in Weight (lbs) Lack of Weight Loss in Large Fraction of Patients Admitted for Acute Heart Failure. ADHERE Registry All Enrolled Discharges from October 2001 to January 2004 Change in weight was assessed in 51,013 patient episodes Discharged Home (including home with additional and/or outpatient care) Enrolled Discharges

34. Freedom from congestion predicts good survival also in patients with advanced HF 146 pts with NYHA IV 4-6 weeks after discharge re-evaluated for congestion 2-year survival (%) 80 High-risk group Criteria: 60 • Orthopnoea •  JVP • Oedema • Weight gain •  baseline diuretics 40 20 3 crit (n=26) 1-2 crit (n=40) 0 crit (n=80) Orth+(n=33) Lucas et al., Am Heart J 2000;140:840

35. Additional weight loss 0.6 kg 0.9 kg No difference in GCS improvement Composite Components(Day 7 or Discharge) Change in Body Weight Change in Global Clinical Status Tolvaptan Placebo P=0.51 P=0.52 20 15 1 P<0.0001 P<0.0001 mm 10 0 n=1007 n=1008 n=1031 n=997 5 -1 n=903 n=910 n=931 n=900 kg 0 -2 Trial A Trial B -3 -4 -5 Trial A Trial B

36. 2061 1532 1137 819 597 385 255 143 55 CV Mortality or HF Hospitalization 1.0 HR 1.04; 95%CI (.95-1.14) 0.9 0.8 0.7 0.6 Proportion Without Event 0.5 0.4 0.3 0.2 TLV 30 mg PLACEBO 0.1 Peto-Peto Wilcoxon Test: P=0.55 0.0 TLV 2072 1562 1146 834 607 396 271 149 58 PLC 0 3 6 9 12 15 18 21 24 Months In Study

37. Weight changes in patients hospitalized with ADHF. Results from ESCAPE (N=433) Mehta et al. . Am J Cardiol 2009; 103:76

38. Lack of association of weight change with subsequent outcomes in patients hospitalised with ADHF. Results from ESCAPE Mehta, Rogers, Hasselblad, Tasissa, Binanay, Califf, O’Connor, on behalf of ESCAPE Trial Investigators . Am J Cardiol 2009; 103:76

39. Comorbidities in AHF • Cardiac • Ischaemia • Valvular disease • Arrhythmias (AF, etc) • Noncardiac • CKD • COPD • Anaemia • Cachexia • Stroke • Etc.

40. Potential impact of kidney dysfunction on outcomes of patienst with AHF • ↑ length of hospitalization • Need of higher furosemide doses • Intolerance to ACEi/ ARBs • ↑ neurohormonal activation & inflammatory activity • Anemia • …

41. Acute HF Low cardiac output Cardiacdamage ↑ venous pressure Hypotension i.v. Furosemide ACEi/ARBs Neurohormonal activation Tubuloglomerular feedback Renal hypoperfusion Kidney dysfunction

42. Independent role of renal blood flow (RBF) and right atrial pressure (RAP) as determinants of Glomerular Filtration Rate in heart failure Multivariable regression analysis for GFR CI, cardiac index; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RBF, renal blood flow. Damman et al. Eur J Heart Fail 2007;9:872-8.

43. Determinants of Glomerular filtration rate in patients with heart failure Damman et al. Clin Res Cardiol 2009; 98:121

44. Urinary neutrophil gelatinase associated lipocalin (NGAL), a marker of tubular damage, and urinary Albumin Excretion (UAE) are increased in patients with chronic heart failure Damman et al., Eur J Heart Fail 10 (2008) 997–1000

45. ADHERE: Risk Stratification for Inhospital Mortality in theValidation Cohort 32,229 hospitalizations BUN < 43 mg/dLMortality, 2.8% BUN ≥ 43 mg/dLMortality, 8.3% 24,702 hospitalizations 6,697 hospitalizations SBP ≥ 115 mmHg Intermediate risk5.6% mortality SBP< 115 mmHg 15.3% mortality SBP ≥ 115 mmHg Low risk2.3% mortality SBP< 115 mmHg Intermediate risk5.7% mortality 1,862 hospitalizations S-creatinine< 2.75 mg/dL Intermediate risk13.2% mortality S-creatinine≥ 2.75 mg/dL High risk19.8% mortality Fonarow GC, et al. JAMA. 2005;293:572-580.

46. Prognostic Significance of Worsening Renal Function in Patients With ADHF P < 0.001 P < 0.001 Δ creatinine < 25% and/or < 0.3 mg/dL Δ creatinine ≥ 25% and ≥ 0.3 mg/dL Δ creatinine < 25% and/or < 0.3 mg/dL Δ creatinine ≥ 25% and ≥ 0.3 mg/dL HF hospitalizations andCV-mortality–free survival CV-mortality–free survival 1.0 86% 1.0 0.8 0.8 55% 0.6 59% 0.6 Patients (%) Patients (%) 0.4 0.4 28% 0.2 0.2 0.0 0.0 0 90 180 270 360 450 540 630 720 0 90 180 270 360 450 540 630 720 Days Days Patients at risk Patients at risk Absolute and percent s-Cr change: Absolute s-Cr change: < 0.3 or 25% 211 143 92 55 36 < 0.3 184 125 79 46 33 ≥ 0.3 & 25% 107 64 36 19 14 ≥ 0.3 134 82 49 27 21 Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.

47. Predictors of Worsening Renal Failure Among 318 Patients Hospitalized for AHFResults of Multivariable Analysis Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.

48. PROTECT Pilot Change in Serum Creatinine 0.35 0.3 Placebo (n = 78) 10 mg (n = 74) 20 mg (n = 75) 0.25 30 mg (n = 74) 0.2 Mean change in serum creatinine (mg/dL) 0.15 0.1 0.05 0 Day 2 Day 3 Day 7 Day 14 −0.05 *Nominal P < 0.05 for dose-related trend at Day 14 Cotter G, et al. J Card Fail. 2008;14:631-640.