Raising expectations for Acute Heart Failure: What does the future bring to us?

Transcription

1 Raising expectations for Acute Heart Failure: What does the future bring to us? Piotr Ponikowski, MD, PhD, FESC Medical University, Centre for Heart Disease Clinical Military Hospital Wroclaw, Poland

2 Speaker disclaimer Receiving honoraria for lectures and membership of the advisory boards from Novartis, Johnson & Johnson, Bayer, Cardiorentis, Amgen, Servier, Coridea, Vifor 2

3 Outline Management of Acute Heart Failure Syndromes 1. Hurdles and disappointments in the everyday clinical practice 2. Outlook for the (nearest) future a. new approach: profiling and strategizing care b. can early, short-term intervention affect long-term outcomes? c. optimize peri-discharge management to improve the outcomes

4 Episode of HF worsening (regardless of being admitted to hospital or treated ambulatory) carries very high risk MADIT-CRT population: NYHA class I-II, optimally managed Annual mortality rate: Free of a primary HF event: 1.5 / 100 pt-yrs Outpatient HF event: 15.9 / 100 pt-yrs Inpatient HF event: 18.5 / 100 pt-yrs Skali H et al. Eur J Heart Fail 2014;16:560-5

5 Acute Heart Failure: landscape at the beginning of the 21 st century EURObservational Research Program: The Heart Failure Pilot Survey All-cause death or HF hospitalization 1892 pts with acute HF& 3226 pts with chronic HF 1-year all cause mortality: acute HF 16.8% chronic HF 6.8% Acute HF: 35.1% Cardiologist s summary: broadly speaking, the pharmacological armamentarium for AHFS loop diuretics, vasodilators and inotropes is largely unchanged from 1970s Felker GM et al., Circ Heart Fail 2010;3: Chronic HF: 17.2% It s hard to make predictions, particularly about the future. Days from enrolment Niels Bohr or Yogi Berra or Albert Einstein or Mark Twain A. Maggioni ESC 2011

6 Management of acute heart failure: why so difficult? Clinical Factors: Underlying causes: multifactorial, precipitating factor often not identified Clinical presentation: spectrum of various conditions, heterogeneous pathophysiology, different risk of subsequent complications Natural course complicated by worsening clinical status Cardiovascular and non-cardiovascular comorbidities Pathophysiological targets: uncertain End-points selection: not standardized

7 Initial, short-term therapies (hours-days) Target Traditional therapeutic approach Effects on long-term outcome Alleviate congestion i.v. diuretics? May be detrimental Reduce LV filling pressure Hypoperfusion Poor cardiac performance i.v. nitrates? i.v. inotropes Detrimental Dissociation between symptomatic improvement, clinical stabilisation & favourable long-term outcome Modified from Pang PS et al. Eur Heart J 2010;31:784-93

8 RECENT AHFS TRIALS Study Patients Primary End Point Natriuretic Peptide (Nesiritide) VMAC 489 PCWP 3 h and Dyspnoea 3 h PRECEDENT ASCEND HF Vasopressin Antagonists (Tolvaptan) Arrhythmias Change in dyspnoea at 6 and 24h HF hospitalization and death at 30 days ACTIV HF 319 Body wt 24 h and Worse HF 60 d EVEREST 3433 SERCA agonist & Na/K ATPase inhibitor (Istaroxime) Short term: Body wt + GCA at 7 days Long term: Mortality and Re-hospitalization HORIZON-HF 120 PCWP Changes from baseline Selective adenosine A 1 -receptor antagonist (Rolofylline) PROTECT 2033 Changes in dyspnoea Death or readmission through day 7 Courtesy of M. Metra

9 Outline Management of Acute Heart Failure Syndromes 1. Hurdles and disappointments in the everyday clinical practice 2. Outlook for the (nearest) future a. new approach: profiling and strategizing care b. can early, short-term intervention affect long-term outcomes? c. optimize peri-discharge management to improve the outcomes

10 Profiling and strategizing care in AHF Appropriate timing of each intervention Phases of AHF management Initial (ED/ICU/CCU) In-hospital Discharge Clinical tasks: Defining goals of treatment Characterizing patient clinical profile Strategizing care Monitoring effects of treatment

11 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 Initial phase in ED/ICU/CCU Profiling and strategizing care Clinical profile is fundamental for decision-making in AHF Strategy: identify and treat life-threatening conditions

12 Profiling AHF patients at the early stage: different therapies for different clinical profiles Hemodynamic profiles: Therapeutic consequences Warm & Dry Warm & Wet A dry-out B Cold & Dry L Cold & Wet C warm-up & dry-out Filippatos G et al, Heart Fail Rev 2007 ;12:87-90 Adapted from Stevenson LW, Eur J Heart Failure 2005;7:323

13 Profiling AHF patients at the peri-discharge phase: consequences for the management Clinical profile may affect management strategy in-hospital HF worsening HF aetiology cardiovascular and non-cardiovascular co-morbidities Immediate (ED/ICU/CCU) candidate for device therapy identification of high-risk patients Intermediate (in-hospital) Phases in the AHF management Pre-discharge management and long-term planning Modified from ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012

14 Improvement of heart failure Variability in the clinical course of AHF: steady improvement vs. worsening Effects of new therapy: prevention of WHF ~10 30% of patients develop WHF Intensification of treatment rescue therapy death WHF = worsening heart failure Time (days)

15 RELAX-AHF: Worsening of Heart Failure RELAX-AHF Cumulative proportion of worsening heart failure to Day 5 (%) *p<0.001 through Day 5 Kaplan-Meier estimate for time to WHF (%) **HR 0.7 (0.51, 0.96); p=0.024 n= Worsening Heart Failure (WHF) - worsening signs and/or symptoms of HF that required an intensification of IV therapy for heart failure or mechanical ventilatory or circulatory support. *p value by Wilcoxon test **p value by log rank test for Serelaxin vs. Placebo; HR estimate by Cox model, HR<1.0 favors Serelaxin Teerlink J. LBCT Presentation, AHA 2012

16 Why do we need to focus on in-hospital Worsening of Heart Failure? Represents meaningful change in clinical status leading to intensification / change of therapy Is associated with markers of end-organ damage and short- and long-term prognosis In-hospital worsening heart failure End-organ damage Outcomes (short & long-term) Adapted from M. Packer

17 Outline Management of Acute Heart Failure Syndromes 1. Hurdles and disappointments in the everyday clinical practice 2. Outlook for the (nearest) future a. new approach: profiling and strategizing care b. can early, short-term intervention affect long-term outcomes? c. optimize peri-discharge management to improve the outcomes

18 Need for paradigm shifting in acute heart failure: short-term intervention improving long-term outcomes Targeted-approach = characterizing patient clinical profile different pathophysiologies & therapies for different clinical profiles (?) An ideal drug / intervention What is needed? symptomatic improvement, end-organ protection, improvement in neurohumoral and proinflammtory profile Appropriate timing = early administration of therapy the earlier the better (?) prevention of tissue damage; phase of severe symptoms; early clinical stabilization & chance to introduce disease-modifying therapies

19 Fast and slow mechanisms of circulatory congestion Precipitant (minor) Sympathetic activation Renal and dietary mechanisms Mobilization of venous reservoir Sodium and water retention Fast Effective circulatory volume Slow Congestion Fallick et al. Circ Heart Failure 2011;4:669 75

20 Linking short-term intervention with long-term benefit: An ideal drug / intervention Targeting different pathophysiological mechanisms MORTALITY

21 Survival probability Need for paradigm shifting in acute heart failure: short-term intervention with favourable long-term effects Risk for All-Cause Mortality in Pre-RELAX-AHF, RELAX-AHF, and Combined Pre-RELAX-AHF: placebo Pre-RELAX-AHF: serelaxin RELAX-AHF: placebo RELAX-AHF: serelaxin Combined: placebo Combined: serelaxin Study Pre-RELAX-AHF: p=0.16 RELAX-AHF: p=0.020 Combined: p= Metra et al. JACC 2013;61:

22 Adverse Effects Benefits Effects of serelaxin versus current therapies Benefits Diuretics Nitrates Inotropes Serelaxin Dyspnea? Congestion? Worsening HF?? Length of Stay? Mortality? Troponin Hypotension Low High (Low) Low Tachycardia No Yes Yes No Myocardial Ischemia/ Necrosis No No Yes No Renal Dysfunction Yes No No No Neutral effect Positive effect Negative effect

23 New AHF (phase 3) Trials With Mortality EPs -2 N >6,000 BP 125 mmhg Treatment start within 16 hrs from hosp presentation Primary EP: CV death during 180 days N >2,150 4,000 BP >115 mmhg Treatment start within 12 hrs from hosp presentation Primary EP: CV deaths until end of trial and Clinical Composite at 48 h

24 Summary of the pharmacological effects of ularitide Hemodynamic (vasodilation) veins arteries Carstens. Clin Sci 1997;92: Bestle. Am J Physiol 1999;276:R Pro Arg Ser Ala Leu Arg Gly Arg Flüge. Regul Pept Thr Arg Gly Met Bronchodilation Ser Phe Asp NH 1995;59: Ser Cys Arg Arg Tyr Ser Phe S IIe Cys Gly Asn Gly Ala Leu Gly Ser Gin Neurohumoral RAAldosterone Endothelin Carstens. Clin Sci 1997;92: Bestle. Am J Physiol 1999;276: R Renal diuresis natriuresis Carstens. Clin Sci 1997;92: Bestle. Am J Physiol 1999;276:R684 95

25 Outline Management of Acute Heart Failure Syndromes 1. Hurdles and disappointments in the everyday clinical practice 2. Outlook for the (nearest) future a. new approach: profiling and strategizing care b. can early, short-term intervention affect long-term outcomes? c. optimize peri-discharge management to improve the outcomes

26 Goals of Treatment in Acute Heart Failure Treat symptoms Restore oxygenation Improve organ perfusion & haemodynamics Limit cardiac/renal damage Prevent thrombo-embolism Minimize ICU length of stay Immediate (ED/ICU/CCU) Maintain patient stabilisation with optimised treatment Initiate, up-titrate, optimize disease-modifying pharmacological therapy Identify aetiology and relevant co-morbidities Consider device therapy in appropriate patients Identify high-risk patients and evaluate fluid status Enrol in disease management programme, educate, initiate appropriate lifestyle adjustments Intermediate (in-hospital) Phases in the AHF management Pre-discharge management and long-term planning Modified from ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012

27 All-Cause Mortality by Beta-Blocker Use at Baseline and Discharge 1.0 Probability of survival Yes / Yes No / Yes No / No Yes / No Baseline Discharge Days since start of study drug infusion M. Boehm et al. Crit Care Medicine 2011

28 Number Courtesy J. McMurray PARADIGM-HF: cause/mode of death All causes CV causes Sudden Worsening HF Enalapril LCZ696 HR p = 0.84 <

29 PARADIGM-HF: Hospitalization for heart failure (%) Enalapril Proportion of patients HR 0.79 (0.71, 0.89) p < LCZ696 Number of admissions* RR 0.77 (0.67, 0.89) p = Courtesy J. McMurray Patients hospitalized Hospitalizations *Includes repeat episodes

30 Iron deficiency is common and predicts poor outcome in patients hospitalized for AHF Cumulative survival 100% 93% (81-100%) 85% (75-95%) χ 2 =29.45, p< % (47-71%) Iron deficiency (both low hepcidin and high stfr) (1) Isolated high stfr (2) Isolated low hepcidin (3) Preserved iron status (4) Follow-up (months) Jankowska EA et al. Eur Heart J 2014 (in press)

31 Influence of time from discharge and length of hospital stay on risk of death after discharge from a hospitalization for HF most vulnerable period Solomon S D et al. Circulation. 2007;116:

32 broadly speaking, the pharmacological armamentarium for AHFS loop diuretics, vasodilators and inotropes is largely unchanged from 1970s Felker GM et al., Circ Heart Fail 2010;3: Sunrise or sunset? The results of the new trials will entirely change this perspective (?)