Controversial issues in heart failure. Can we change the outcome of patients with acute heart failure?

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1 Controversial issues in heart failure Can we change the outcome of patients with acute heart failure? Marco Metra, MD, FESC Associateprofessor of Cardiology. University of Brescia

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% Data from: Cleland et al. Eur Heart J. 2003;24:442; Gheorghiade et al. Circulation. 2005;112:3958. Rudiger A et al., Eur J Heart Fail 2005; 7:662; Adams et al., Am Heart J. 2005;149:209; O'Connor et al. J Card Fail. 2005;11:200; Tavazzi L et al., Eur Heart J 2006; 27:1207; Zannad et al., Eur J Heart Fail 2006; 8;697; Nieminen M et al. Eur Heart J 2006; 27, 2725; Fonarow et al. J Am Coll Cardiol 2005;45:345A.

3 One-year survival in AHF patients discharged alive: comparison between clinical classes. Harjola V... Tavazzi Eur J Heart Fail 2010;12:

4 tachycardia coronary perfusion pressure Myocardial ischemia MVO 2 Pathophysiologic mechanisms in acute heart failure LV afterload CO / LVEDP Cardiac dysfunction systolic diastolic End-organ hypoperfusion venous pressure Neurohormonal activation RAA SNS - ADH Inflammatory activation Diuretic use Diuretic resistance Renal dysfunction Na-H 2 O retention Congestion Fluid redistribution to the lungs Lung congestion LV wall stress LV preload Metra et al.. ESC Intensive Acute Cardiac Care textbook

5 tachycardia coronary perfusion pressure Myocardial ischemia MVO 2 Pathophysiologic mechanisms in acute heart failure LV afterload CO / LVEDP Cardiac dysfunction systolic diastolic End-organ hypoperfusion venous pressure Neurohormonal activation RAA SNS - ADH Inflammatory activation Diuretic use Diuretic resistance Renal dysfunction Na-H 2 O retention Congestion Fluid redistribution to the lungs Lung congestion LV wall stress LV preload Metra et al.. ESC Intensive Acute Cardiac Care textbook

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7 Changes in symptoms (dyspnoea) in the URGENT Trial Change in dyspnoea in the first 6 hours of treatment Change in dyspnoea from sitting to lying supine Mebazaa et al. Eur Heart J Apr;31(7): Hogg KJ, McMurray JJ. Eur Heart J Apr;31(7):771-2.

8 Freedom from congestion predicts good survival also in patients with advanced HF 146 pts with NYHA IV 4-6 weeks after discharge reevaluated for congestion Criteria: 1. Orthopnoea 2. JVP 3. Oedema 4. Weight gain 5. baseline diuretics year survival (%) 0 crit (n=80) 1-2 crit (n=40) High-risk group 3 crit (n=26) Orth+ (n=33) Lucas et al., Am Heart J 2000;140:840

9 Fraction of patients Fraction of patients Prognostic value of NT-ProBNP at discharge in patients hospitalised for AHF 1 Cardiac mortality 1 Cardiac mortality or CV Hospitalizations Patients at risk NT-ProBNP: P< Discharge NT-ProBNP <6078 Discharge NT-ProBNP > Days Patients at risk NT-prBNP: P< Discharge NT-ProBNP <3275 Discharge NT-ProBNP >3275 < < > > Days Metra et al. Eur J Heart Fail. 2007;9:

10 NT-ProBNp ignoto Ospedalizzazione IC acuta / No SCA Misurazione NT-ProBNP ore pre-dimissione & alla dimissione Randomizzazione 1:1 NT-ProBNP <3000 pg/ml NT-ProBNp noto NT-proBNP in the Optimization of Treatment in Acute Heart Failure (BOT- AcuteHF) Trial NT-ProBNP >3000 pg/ml F-Up clinico Rivalutazione terapia: dose diuretici / ACEi / Dig/ARB/AA/IDN /Terapia i.v. Rivalutazione NT- ProBNP Dimissione F-Up clinico NT-ProBNP >25% or <3000 pg/ml

11 Survival probability, % Effects of Nt-proBNP guided therapy on survivavl after an AHF hospitalisation All-cause mortality 100% 80% 60% 40% P = % 0% Nt-pro-BNP guided Control Days of follow-up

12 Weight changes in patients hospitalized with ADHF. Results from ESCAPE (N=433) 40% 25% Mehta et al.. Am J Cardiol 2009; 103:76

13 Large RCTs in ADHF Trial Agent Pts No. Effects on symptoms Effects on outcomes VMAC, 2002 Nesiritide 489 Yes vs 3 h n.s. OPTIME-CHF, 2002 Milrinone 951 No No, AEs VERITAS, 2007 Tezosentan 1448 No No EVEREST, 2007 Tolvaptan 4133 Mild No REVIVE-II, 2009 Levosim. 600 Mild No, AEs PROTECT* Rolofylline 2033 Mild No * All these changes corresponded to a 6 to 12% difference in the proportion of patients with dyspnea improvement VMAC PC JAMA 2002; 287:1531; Cuffe et al. JAMA 2002; 287:1541; McMurray et al., JAMA 2007;298:2009; Gheorghiade et al. JAMA 2007; 297:1332; de Lissovoy et al. Eur J Health Econ 2009;; Massie et al. to be submitted

14 Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema Gray A et al. N Engl J Med 2008;359:

15 Large RCTs in ADHF Trial Agent Pts No. Effects on symptoms Effects on outcomes VMAC, 2002 Nesiritide 489 Yes vs 3 h n.s. OPTIME-CHF, 2002 Milrinone 951 No No, AEs Drug s efficacy Drug s cardiovascular safety VERITAS, 2007 Tezosentan 1448 No No EVEREST, 2007 Tolvaptan 4133 Mild No REVIVE-II, 2009 Levosim. 600 Mild No, AEs PROTECT* Rolofylline 2033 Mild No * All these changes corresponded to a 6 to 12% difference in the proportion of patients with dyspnea improvement VMAC PC JAMA 2002; 287:1531; Cuffe et al. JAMA 2002; 287:1541; McMurray et al., JAMA 2007;298:2009; Gheorghiade et al. JAMA 2007; 297:1332; de Lissovoy et al. Eur J Health Econ 2009;; Massie et al. to be submitted

16 PROTECT STUDY DESIGN Screening AHF & fluid overload, need of iv loop diuretic CrCl, ml/min Treatment phase Rolofylline 30 mg IV Placebo IV Follow-up All cause mortality CV/Renal hosp All cause mortality Days Randomisation Rolofylline to placebo, 2:1 Kidney Function

17 Fraction of patients, % Symptoms relief and short-term outcomes in ADHF Components of the primary end-point in PROTECT Dyspnea relief 60 51, , Placebo (n=677) Rolofylline (n=1356) Death day 7 2,1 1,7 HF Rehosp day 7 0,6 0,4 WHF day 7 9,7 9,1 WRF, day ,1 12,7 PROTECT EC, PC & investigators. Presented at ESC 2009

18 Cumulative Risk Time to Death or CV or Renal Rehospitalization - Day Hazard Ratio (95% CI) = 0.98 (0.83, 1.17) P-value = Placebo Rolofylline 30 mg Study Day Study Day No. of patients at risk Placebo (N=677) Rolofylline (N=1356) Death: Placebo 9.5% vs rolofylline 8.9% Re-hospitalization: Placebo 25.6% vs rolofylline 25.7%

19 Effects of rolofylline on short-term outcomes Metra et al. Submitted to Eur Heart J

20 Effects of rolofylline on short-term outcomes Short Term Outcome By Baseline Creatinine (Median) 14 Days 30 Days In-hospital All Cause Mortality 14 Days 30 Days In-hospital HF Mortality Baseline Creatinine 14 Days 30 Days In-hospital >= 1.5 mg/dl < 1.5 mg/dl 14 Days 30 Days In-hospital CV Mortality All Cause Mortality 14 Days 30 Days In-hospital HF Mortality 14 Days 30 Days In-hospital CV Mortality Hazard Ratio (95% C.I.) Favors Rolofylline Favors Placebo Metra et al. Submitted to Eur Heart J

21 tachycardia coronary perfusion pressure MVO 2 Myocardial ischemia LV afterload CO / LVEDP Cardiac dysfunction systolic diastolic End-organ hypoperfusion venous pressure Neurohormonal activation RAA SNS - ADH Inflammatory activation Diuretic use Diuretic resistance Renal dysfunction Na-H 2 O retention Congestion Fluid redistribution to the lungs Lung congestion LV wall stress LV preload Metra et al. ESC Intensive Acute Cardiac Care textbook

22 Acute HF treatment strategy according to SBP Oxygen /NIV, loop diuretic + vasodilator Clinical evaluation SBP >100 mmhg SBP mmhg SBP <90 mmhg Vasodilator (NTG, nitroprusside, nesiritide), levosimendan Vasodilator and/or inotrope (dobutamine, PDEI, levosimendan) Consider preload correction with fluids or inotrope (dopamine) Good response stabilize & initiate oral diuretics, ACEI/ARB, β-blocker Poor response inotrope, vasopressor, mechanical support, consider PAC ESC 2008 guidelines

23 Significance of SBP in AHFS Index of cardiac function & peripheral perfusion Indication for the choice of treatment Cause of end-organ damage

24 Predicted value of VAS AUC change Increased symptom-improvement with the novel vasodilator, relaxin, in AHF patients with elevated BP. Results from Pre-Relax-AHF Placebo Relaxin 30 mcg/kg/m Systolic blood pressure, mmhg Teerlink et al. Eur Heart J 2009 ; 30 ( Abstract Supplement ), 164

25 Sustained Dyspnea Improvement through Day 14 (Visual Analog Scale) Teerlink, Metra, Felker et al. Lancet 2009;373:1429.

26 RELAX-AHF: Cardiovascular Deaths to Day Relaxin 30 mcg/kg/d (p<0.05) Relaxin 10 mcg/kg/d Relaxin 100 mcg/kg/d Relaxin 250 mcg/kg/d Placebo Days Teerlink, Metra, Felker et al. Lancet 2009;373:1429.

27 Prediction of CV death or HF/RF rehospitalisations at 60 days: Multivariable regression model Age per years Systolic BP per mmhg BUN per mg/dl Creatinine increase >0.3 mg/dl at day 5 BNP>500 or NTproBNP >2000 pg/ml Sodium per 3.93 meq/l Dyspnea AUC at 5 days per mm*h WHF vs none Relaxin 10 & 30 mcg vs Placebo Relaxin 100 & 250 mcg vs Placebo Metra et al. Presented at HFA 2009 LBCTs Hazard ratios and 95% CIs

28 Predictors of WRFin Pre-RELAX AHF: Role of SBP 234 AHF patients (SBP 125mmHg) from the Pre-RELAX-AHF study 1,0 1,0 Probability of persistent WRF 0,8 0,6 0,4 0,2 0,0 Probability of persistent WRF 0,8 0,6 0,4 0,2 0, Baseline SBP (mmhg) change in SBP (mmhg) Persistent WRF was associated >5 times higher day 60 (p<0.001) mortality Adjusted for potential confounders, a higher baseline SBP (p<0.001) and a greater SBP drop <48 hours of admission (p=0.008) were the strongest predictors of persistent WRF Voors et al, Eur Heart J 2009 ; 30 ( Abstract Supplement ), 1020

29 tachycardia coronary perfusion pressure MVO 2 Myocardial ischemia LV afterload CO / LVEDP Cardiac dysfunction systolic diastolic End-organ hypoperfusion venous pressure Neurohormonal activation RAA SNS - ADH Inflammatory activation Diuretic use Diuretic resistance Renal dysfunction Na-H 2 O retention Congestion Fluid redistribution to the lungs Lung congestion LV wall stress LV preload Metra et al. ESC Intensive Acute Cardiac Care textbook

30 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-ischaemic cardiomyopathy Ischaemia / necrosis precipitated by AHF?

31 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-ischaemic cardiomyopathy Ischaemia / necrosis precipitated by AHF?

32 Prevalence of Detectable (>0.01 pg/ml)troponin T in patients with AHF with daily blood sampling Coronary artery disease Idiopathic dilated cardiomyopathy 46% 26% 28% 60% 26% 14% TnT (1 sample) TnT (>1 sample) No TnT TnT (1 sample) No TnT TnT (>1 sample) Metra et al., Eur J Heart Fail. 2007;9:776-86

33 Fraction of patients Freedom from Death or CV Hospitalization and ctnt plasma levels in Acute Heart Failure Fraction of patients 1 Cardiac mortality Cardiac mortality or CV hospitalizations P< No ctnt detectable ctnt detectable Days P<0.01 No ctnt detectable ctnt detectable Patients at risk Patients at risk: No ctnt No ctnt ctnt ctnt Metra et al., Eur J Heart Fail. 2007;9: Days

34 Significato del rilascio di tropinina durnate l ospedalizzazione per IC acuta: Incidenza di morti o riospedalizzazioni Non Rilascio TnT (n=141) p= Rilascio TnT (n=39) Giorni

35 tachycardia coronary perfusion pressure MVO 2 Myocardial ischemia LV afterload CO / LVEDP Cardiac dysfunction systolic diastolic End-organ hypoperfusion venous pressure Neurohormonal activation RAA SNS - ADH Inflammatory activation Diuretic use Diuretic resistance Renal dysfunction Na-H 2 O retention Congestion Fluid redistribution to the lungs Lung congestion LV wall stress LV preload Metra et al. ESC Intensive Acute Cardiac Care textbook

36 Worsening Renal Function and outcome Study Odds ratio (95% CI) Inhospital patients Krumholz (2000), n= ( 1.10, 1.82) Smith (2003), n= ( 1.00, 2.98) Akhter (2004), n= ( 1.66, 4.13) Cowie (2006), n= ( 0.96, 3.05) Owan (2006), n= ( 1.30, 1.71) Subtotal 1.61 ( 1.35, 1.93) Outhospital patients De Silva (2005), n=1216 Jose (2006), n=1854 Khan (2006), n=6535 Subtotal Overall 1.44 ( 0.98, 2.09) 1.46 ( 1.06, 2.02) 1.79 ( 1.59, 2.02) 1.69 ( 1.48, 1.94) 1.62 ( 1.45, 1.82) lower risk for WRF higher risk for WRF Damman et al. J Card Fail 2007

37 Patients (%) Patients (%) Prognostic Significance of Worsening Renal Function in Patients With ADHF 1.0 HF hospitalizations and CV-mortality free survival 1.0 CV-mortality free survival 86% % % P < Patients at risk Absolute and percent s-cr change: 28% Δ creatinine < 25% and/or < 0.3 mg/dl Δ creatinine 25% and 0.3 mg/dl Days P < Patients at risk Absolute s-cr change: Δ creatinine < 25% and/or < 0.3 mg/dl Δ creatinine 25% and 0.3 mg/dl < 0.3 or 25% < & 25% Days Metra M, Dei Cas Eur J Heart Fail. 2008;10:

38 Adenosine type 1 receptor antagonists initial trials Agent Author, year Model/ patients Effects BG-9719 Lucas, JCP 2001 Pacing HF model PWP, CrCl, una BG-9719 BG-9719 BG-9928 Rolofylline (KW-3902) Rolofylline (KW-3902) Jackson, JPET 2001 Gottlieb, Circulation 2002 Greenberg, JACC 2007 Givertz, JACC 2007 Dittrich, JCF 2007 CMP model diuresis, RBF, GFR 63 CHF patients diuresis, una, inhibition furosemideinduced GFR 50 CHF patients una, BW, =GFR CHF patients Rolofylline Cotter, JCF hospitalised AHF patients diuresis, GFR, s-creat, Fur dose, sustained at 7 days 32 CHF patients 32% GFR, 45% RBF symptoms, BW, s-creat,

39 Fraction of patients, % Symptoms relief and short-term outcomes in ADHF Components of the primary end-point in PROTECT Dyspnea relief 60 51, , Placebo (n=677) Rolofylline (n=1356) Death day 7 2,1 1,7 HF Rehosp day 7 0,6 0,4 WHF day 7 9,7 9,1 WRF, day ,1 12,7 PROTECT EC, PC & investigators. Presented at ESC 2009

40 Percent of Patients Secondary Endpoint: Persistent Renal Impairment* Odds ratio (95% CI) vs Pbo: 1.11 (0.85, 1.46); p = Placebo Ro 30 mg *Persistent renal impairment SCr >0.3 mg/dl at both Day 7 and Day 14 or initiation of hemofiltration or dialysis through Day 7, or death by Day 7

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42 Damman, K. et al. J Am Coll Cardiol 2009;53: Curvilinear Relationship Between CVP and egfr According to Different Cardiac Index Values Cardiac index >3.2 L/min/m L/min/m 2 <2.5 L/min/m 2 Central venous pressure, mmhg

43 Survival in AHFS: Role of Congestion and Worsening Renal Function Survival (%) 100% 90% 80% 70% 60% 50% No Congestion / No WRF (n=267) No Congestion / WRF (n=178) Congestion & WRF (n=183) Congestion / No WRF (n= 101) Days

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45 Clinical significance of high blood pressure in AHF Cause of AHF Afterload mismatch Consequence of AHF neurohormonal activation cardiac function

46 SBP in AHF Registries ADHERE, AHJ patients from 282 hospitals Mean SBP, 144 mmhg SBP >140: 50% of pts OPTIMIZE-HF, JAMA patients from 259 hospitals Mean SBP, mmhg SBP >140: 50% of pts Italian Survey, EHJ patients from 206 cardiology centers Mean SBP, mmhg, WHF, de novo SBP >140: 43%; 38% WHF, 49% de novo EFICA, EJHF patients from 60 centers Mean SBP, mmhg; 139 without CS pts

47 % of patients % of patients Cause of AHF According to SBP: OPTIMIZE-HF Study patients FROM 259 us HOSPITALS Hypertensive Ischemic < >161 0 < >161 SBP quartiles, mmhg SBP quartiles, mmhg Gheorghiade et al., JAMA 2006; 296:2217

48 % of patients LVEF units Cause of AHF According to SBP: OPTIMIZE-HF Study patients FROM 259 us HOSPITALS LV Systolic dysfunction < >161 SBP quartiles, mmhg LV Ejection fraction < > SBP quartiles, mmhg Gheorghiade et al., JAMA 2006; 296:2217

49 % of patients % of patients Cause of AHF According to SBP: OPTIMIZE-HF Study patients FROM 259 us HOSPITALS In-hospital mortality Postdischarge mortality ,2 3,6 < , ,7 > ,4 < , >161 SBP quartiles, mmhg SBP quartiles, mmhg Gheorghiade et al., JAMA 2006; 296:2217

50 % of patients Cause of AHF According to SBP: OPTIMIZE-HF Study patients FROM 259 us HOSPITALS d rehospitalisations ,6 29,9 30,3 27,6 < >161 SBP quartiles, mmhg Gheorghiade et al., JAMA 2006; 296:2217

51 Clinical signs & ECHO in the management of AHFS AHF with SBP < 100 mmhg Assess volume status: signs of dehydration ECHO: Treatable cause ECHO: LV systolic dysfunction Yes Yes Yes Fluid administration Coronary angiography, PCI, surgery, etc. Inoropic agent ECHO: persistent intracardiac pressure IVC congestion Yes diuretic dose / trial of vasodilator

52 Risk of Worsening Renal Function With Nesiritide in Patients With ADHF Nesiritide 0.03 μg/kg/min vs. non inotrope-based controls Risk ratio (95% CI) Nesiritide 0.03 μg/kg/min vs. all controls; nesiritide μg/kg/min vs. non inotrope-based controls Nesiritide μg/kg/min vs. non inotrope-based controls Nesiritide μg/kg/min vs. all controls Nesiritide 0.06 μg/kg/min vs. non inotrope-based controls Nesiritide 0.06 μg/kg/min vs. all controls Nesiritide better Nesiritide worse Sackner-Bernstein JD, et al. Circulation. 2005;111:

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

54 Dyspnea score Weight loss (kg) Serum creatinine change (mg/dl) Ultrafiltration vs. IV Diuretics in Patients Hospitalized for ADHF 1 efficacy endpoints 1 safety end points 6 Ultrafiltration arm 5 P = Standard care arm 4 m = 5.0, 3 CI ± kg (n = 83) Ultrafiltration m = 6.4, m = 6.1, CI ± 0.11 CI ± 0.15 (n = 80) (n = 83) P = 0.35 Ultrafiltration m = 3.1, CI ± 0.75 kg (n = 84) Standard care Standard care 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 P > 0.05 at all times UF n = SC n = Costanzo MR, et al. J Am Coll Cardiol. 2007;49:

55 Patients free from rehospitalization (%) Freedom From Heart Failure Rehospitalization in UNLOAD Ultrafiltration arm (16 events) Standard care arm (28 events) P = Days Number of patients at risk Ultrafiltration Standard care Costanzo MR, et al. J Am Coll Cardiol. 2007;49:

56 Predicted probability of freedom from death and death or heart failure (HF) rehospitalization across levels of sodium after adjusting for important covariates Gheorghiade, M. et al. Arch Intern Med 2007;167:

57 Hyponatraemia in ADHF Prognostic marker Peripheral hypoperfusion / Kidney dysfunction Neurohormonal activation (RAA, NE) Poor prognosis Treatment problem: loop diuretics Intolerance to neurohormonal antagonists Resistance to loop diuretics Exacerbation of hyponatremia free water clearance further s[na] Cause of symptoms & poor prognosis (?)

58 Symptoms of Hyponatremia s[na + ] mmol/l Normal Lethargy, Apathy Confusion Muscle Cramps Agitation Anorexia and nausea Hallucinations Seizures Coma Depressed reflexes Pseudobulbar palsy Hypothermia Death Depend on Severity Onset (acute vs chronic - < or >48 hours) Susceptibility Age (young and old) CNS insult Respiratory reserve Female gender and hormonal milieu Volume status

59 Vasopressin antagonists Antagonist Conivaptan Tolvaptan Lixivaptan Sitavaptan Mozavaptan Receptors V 1 /V 2 V 2 V 2 V 2 V 1 /V 2 V 1 /V 2 selectivity 10:1 29:1 100:1 112:1 10:1 Route Iv, oral Oral Oral Oral Iv, oral Half-life, hs Indications HypoNa, ADHF HypoNa, ADHF, PKD HypoNa, ADHF with hypona HypoNa, ADHF, cirrhosis SIADH Modified from Finley, Konstam, Udelson. Circulation 2008;118:

60 Schrier RW et al. N Engl J Med 2006;355:

61 EVEREST: Secondary Endpoints at Day 1 Δ in BW (kg) Trial A Trial B Tolvaptan Placebo Tolvaptan Placebo ± 1.8 ± 1.8 ± 2.0 ± 1.9 Both trials P<0.001 Difference 0.7 kg 0.9 kg Δ in Dyspnea (% of pts with baseline dyspnea) 80 Improved worsened Tolvaptan Placebo Tolvaptan Placebo (n=894) (n=915) (n=941) (n=914) Both trials P<0.001 Markedly better Moderately better Minimally better Worse Gheorghiade et al. JAMA 2007;297: