How to define the target population?

Transcription

1 Heart Failure May. Gothenburg, Sweden Mortality or morbidity as target in acute heart failure trials How to define the target population? Marco Metra, Brescia

2 The Burden of Acute HF Acute HF is the most common cause of admission at >65 ys. High mortality In-hospital, 4-9% 6-months post-discharge, 9-15% High rehospitalisation rates 30-45% in the 6 months post-discharge 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 Outcomes of patients 65 years of age, discharged alive to SNF or home after 3-day hospitalization for HF in 2005 and 2006 within the Get With The Guidelines HF Program ( patients from 149 hospitals) Mortality Rehospitalizations 1 year 1 year 53.5% 76.1% 72.2% 29.1% SNF = Skilled Nurse Facility Allen L A et al. Circ Heart Fail 2011;4:

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5 National (England & Wales) Audit Data Deaths post-discharge according to management ward Cleland J G F et al. Heart 2011;97:

6 National (England & Wales) Audit Data Deaths after Discharge accorrding to age This is in addition to in-patient mortality of 5% for those aged <75 years 17% for those aged >75 years Survival time (days) years years years 85 years and over Courtesy of John Cleland

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 Acute Heart Failure: Recommendations and levels of Evidence Group Medication Class recommendation, Level of evidence Diuretics Indication I, B Vasodilators Nitrates Sodium Nitroprusside I, B I, C Morphine Indication IIb, B Inotropics Dopamine IIb, C Dobutamine IIa, C

9 RCT s in AHF not successfull 1. PDE-inhibitors: Milrinone: OPTIME-CHF 2. Endothelin antagonists: Tezosentan: VERITAS 3. Ca-sensitizers: Levosimendan; SURVIVE/REVIVE 4. AVP Antagonists: Tolvaptan; EVEREST 5. Adenosine A1-Receptor Antagonist: Rolofylline; PROTECT 6. Natriuretic Peptides: Nesiritide: ASCEND

10 Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with evidence of myocardial ischaemia with at least one of the following: Symptoms of ischaemia ECG changes indicative of myocardial ischaemia (new ST-T changes or new LBBB) Development of pathological Q-waves in the ECG Imaging evidence of new loss of viable myocardium or new regional WMA

11 Definition of Acute Heart Failure (ESC guidelines, 2008) Rapid onset or change in the signs and symptoms of HF, resulting in the need for urgent therapy No biomarker No ECG No ECHO

12 Flow chart for the diagnosis of heart failure with natriuretic peptides Clinical examination, ECG, Chest X- ray, echocardiography Natriuretic peptides BNP <100 pg/ml NT-proBNP <400 pg/ml BNP pg/ml NT-proBNP pg/ml BNP >400 pg/ml NT-proBNP >2000 pg/ml Chronic HF unlikely Uncertain diagnosis Chronic HF likely ESC guidelines 2008

13 Acute coronary syndromes From Braunwald's Heart Disease, 9th Edition

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15 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, Brutsaert, Dei Cas, Gheorghiade ESC Intensive Acute Cardiac Care textbook

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

17 Fluid overload as the only inclusion criterion for AHF trials: advantages Is the cause of hospitalization for almost every patient Loop diuretics are insufficient The closest to our current practice Give him 5 vials of Lasix!

18 EVEREST: Key Entry Criteria Inclusions Hospitalization for HF <48hrs LVEF 40% Fluid overload; 2 of the following: Jugular venous distention Pitting edema (>1+) Dyspnea Exclusions Recent or planned revascularization or device implant STEMI during hospitalization Systolic BP <90 mm Hg Creat >3.5 mg%; K >5.5 meq/l; Hgb <9 g%

19 kg mm Composite Components (Day 7 or Discharge) Change in Body Weight P< Tolvaptan Additional weight loss 0.6 kg 0.9 kg P< n=997 n=1007 n=1031 n= Change in Global Clinical Status Placebo P=0.51 Trial A P=0.52 n=903 n=910 n=931 n=900 Trial B Trial A Trial B No difference in GCS improvement

20 Physician-assessed Signs and Symptoms (% Patients with Improvement) * * * * Tolvaptan Placebo * * * Day 1 Day 2 Day 3 Day 4 Dyspnea * P< Day 1 Day 2 Day 3 Day 4 Orthopnea * * * * * * Day 1 Day 2 Day 3 Day 4 0 Day 1 Day 2 Day 3 Day 4 24 Fatigue Edema

21 Proportion surviving EVEREST: Tolvaptan in ADHF 1.0 All-cause mortality Tolvaptan Placebo Est. 1-year mortality, 25 vs. 26%; HR Log-rank test: P = 0.76 Peto Peto Wilcoxon Test: P = 0.68 Stratified Peto Peto Wilcoxon Test: P = Months in study Konstam MA, et al. JAMA. 2007;297:

22 ASCEND-HF: KEY Inclusion criteria Hospitalized for ADHF <24 hrs from IV treatment Dyspnea at rest or with minimal activity 1 clinical sign: Respiratory rate 20 breaths per min Rales >1/3 bases 1 objective measure: CXR with pulmonary edema BNP 400 pg/ml or NT-proBNP 1000 pg/ml Prior EF <40% within 12 months PCWP > 20 mmhg

23 % Subjects % Subjects Co-Primary Endpoint: 6 and 24 hour dyspnea 6 Hours 24 Hours P= % 44.5% % P= % Placebo 3371 Nesiritide Placebo 3416 Nesiritide Markedly Better Moderately Better Minimally Better No Change Minimally Worse Moderately Worse Markedly Worse

24 Co-Primary outcome: 30-day all-cause mortality or HF rehospitalization 12 P=0.31 Hazard Ratio 0.93 (95% CI: 0.8,1.08) Placebo 8 Nesiritide % day Death/HF Rehospitalization 30-day Death HF Rehospitalization Risk Diff (95 % CI) -0.7 (-2.1; 0.7) -0.4 (-1.3; 0.5) -0.1 (-1.2; 1.0)

25 DOSE trial: Study Design Acute Heart Failure (1 symptom AND 1 sign) <24 hours after admission 2x2 factorial randomization Low Dose (1 x oral) Q12 IV bolus Low Dose (1 x oral) Continuous infusion High Dose (2.5 x oral) Q12 IV bolus High Dose (2.5 x oral) Continuous infusion 48 hours 1) Change to oral diuretics 2) continue current strategy 3) 50% increase in dose 72 hours Co-primary endpoints 60 days Clinical endpoints

26 Pt Global Assessment by VAS Patient Global Assessment VAS AUC: Low vs. High Intensification Low High Low VAS AUC, mean (SD) = 4171 (1436) High VAS AUC, mean (SD) = 4430 (1401) P = Hours

27 Death, Rehospitalization, or ED Visit Proportion with Death, Rehosp, or ED Visit HR for Continuous vs. Q12 = % CI 0.86, 1.66, p = 0.30 Continuous Days Q12 Proportion with Death, Rehosp, or ED visit HR for High vs. Low = % CI 0.60, 1.16, p = 0.28 High Days Low

28 Fluid overload as the only inclusion criterion for AHF trials: limitations Does not address the cause but only the symptom Has no relation with outcomes Difficult to measure Fluid overload ( body weight) vs. fluid redistribution to the lungs (pulmonary edema) Body weight? Symptoms (dyspnoea)?

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

30 ADHERE: Risk Stratification for Inhospital Mortality in the Validation Cohort 32,229 hospitalizations BUN < 43 mg/dl Mortality, 2.8% BUN 43 mg/dl Mortality, 8.3% 24,702 hospitalizations 6,697 hospitalizations SBP 115 mmhg Low risk 2.3% mortality SBP < 115 mmhg Intermediate risk 5.7% mortality SBP 115 mmhg Intermediate risk 5.6% mortality SBP < 115 mmhg 15.3% mortality 1,862 hospitalizations S-creatinine < 2.75 mg/dl Intermediate risk 13.2% mortality S-creatinine 2.75 mg/dl High risk 19.8% mortality Fonarow GC, et al. JAMA. 2005;293:

31 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:

32 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,

33 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

34 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%

35 PROTECT: Outcomes at Days 14 and 30 by treatment for all subjects and subjects subdivided by baseline s-cr, CrCl, and NYHA class before hospitalization Metra M et al. Eur Heart J 2011;eurheartj.ehr042

36 PROTECT: Outcomes at Days 14 and 30 by treatment for all subjects and subjects subdivided by baseline s-cr, CrCl, and NYHA class before hospitalization Metra M et al. Eur Heart J 2011;eurheartj.ehr042

37 Fraction of patients, % Symptoms relief and short-term outcomes in ADHF Components of the primary end-point in PROTECT Dyspnea relief 51,2 44, 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 Placebo (n=677) Rolofylline (n=1356) Massie et al. N Engl J Med 2010;363:

38 Potential Effects of Aggressive Decongestion During the Treatment of Decompensated HF on Renal Function: Results from ESCAPE trial hemoconcentration defined as 2 of 3 of total Δprotein, Δ albumin, or Δ hematocrit in the highest tertile Testani, J. M. et al. Circulation 2010;122:

39 Survival curves grouped by presence or absence of hemoconcentration after adjustment for baseline characteristics Testani, J. M. et al. Circulation 2010;122:

40 Survival in AHF: Role of Congestion and Worsening Renal Function 100% 90% Survival (%) 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

41 Renal dysfunction as an entry criterion for AHF trials? Appealing with agents affecting renal function Do we have any? Lack of accuracy of serum creatinine as a marker of renal function

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

43 Systolic blood pressure as an inclusion criterion for an AHF trial? Advantages Easy to measure Associated with prognosis Used in guidelines for the choice of treatment Limitations Changes rapidly after admission May be either the cause or a consequence of AHF

44 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

45 Systolic blood pressure (SBP) decrease during the first hours of treatment: tezosentan versus placebo Kaluski, E. et al. J Am Coll Cardiol 2003;41:

46 RELAX-AHF: Inclusion Criteria Admitted for Acute heart failure (all): Dyspnea at rest or with minimal exertion Congestion on chest-x-ray BNP 350 or NT-pro-BNP 1400 pg/ml Baseline BP > 125 mmhg Renal dysfunction (CrCl ml/min) Randomized within 16h of presentation Received at least 40 mg iv Furosemide prior to screening

47 Relaxin as a Preferential Vasodilator: Pre-RELAX-AHF Drug effect on Systolic Blood Pressure over time by baseline SBP Baseline Systolic BP 140 mmhg Baseline Systolic BP > 140 mmhg Teerlink JR, et al. Lancet 2009;373:

48 Sustained Dyspnea Improvement through Day 14 (Visual Analog Scale) Dyspnea (AUC; mm*hr) p=0.11 p=0.15 p=0.16 p=0.06 p=0.05 p= Placebo Placebo Relaxin (mcg/kg/d) Relaxin (mcg/kg/d) Day 5 Day 14

49 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

50 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

51 Effects of iv Vasodilators on Outcomes in ALARM-HF Mebazaa et al. Intensive Care Med (2011) 37:

52 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) ESC 2008 guidelines

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

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

55 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

56 Survival Survival Etiology May influence the Response to Milrinone in Decompensated Heart Failure: OPTIME-CHF Study Ischemic (n= 485) P = 0.01 For interaction Nonischemic (n= 464) Placebo Milrinone Days Days Felker et Al. J Am Coll Cardiol 2003; 41:997

57 Effects of inotropic stimulation on the relationship between subendocardial blood flow and infarct size in anesthetized, open-chest pigs Schulz, Rose, Martin, Brodde, Heusch. Circulation 1993; 88:

58 Temporary conclusions All-comers approach Closer to clinical practice & physicians hopes & pharm companies hopes Selective approach Still lacks of a validation, i.e. a non-neutral trial Which criterion? Which mechanism?