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Recent updates in acute heart failure management Piotr Ponikowski, MD, PhD, FESC Medical University, Centre for Heart Disease Clinical Military Hospital Wroclaw, Poland Management of Acute Heart Failure Syndromes 1. Challenges in everyday clinical practice guidelines & reality 2. Results (disappointing) of the recent trials 3. Outlook for the future different approach needed ? 1 Acute Heart Failure: landscape at the beginning of the 21st century Cardiologist’s summary: EURObservational Research Program: The Heart Failure Pilot Survey „broadly speaking, the pharmacological All-cause death or HF hospitalization armamentarium for AHFS – loop diuretics, 1892 pts with acute HF& 3226 pts with chronic HF vasodilators and inotropes – is largely Acute HF: 35.1% 1-year all cause mortality: unchanged from 1970s…” acute HF – 16.8% Felker GM et al., Circ Heart Fail 2010;3:314-25 chronic HF – 6.8% Chronic HF: 17.2% Cardiologist’s question: Why all successful phase II studies are followed by failures in phase III trials ? Do we need shift in a „AHF paradigm” ? Days from enrolment A. Maggioni ESC 2011 Acute Heart Failure Syndromes: Clinical challenges Incidence Mortality: pre-hospital in-hospital 60-90 days Targets of therapy Clinical trials results Guidelines (level of evidence) AHFS ACS ~ 1.000.000/y ~ 1.000.000/y ? 3 – 6% 10% high 3 – 4% 2% Unclear Clearly defined Minimal / no benefit / harmful Beneficial A/B – minimal mostly C A/B – mostly Modified from Weintraub NL et al., Circulation 2010 2 Hospitalization for HF: why so important ? Cardiac Function & CHF severity Risk of death increases substantially with each subsequent HF hospitalization Hypothesis: With each hospitalization, there is myocardial and/or renal damage leading to further progression of the disease Setoguchi S et al. Am Heart J 2007 Hospitalization Hospitalization Hospitalization Gheorghiade M et al. Am J Cardiol. 2005; 96 (6A) Time HF hospitalization: a. independent predictor of poor outcome; b. major contributor to impaired QoL; c. responsible for majority of HF-related costs Hospitalization for HF: why so important ? Divergent trends in survival and readmission for HF Analysis in 50 125 patients with HF hospitalization from 2002 to 2006 in the VA Health Care System 1.2 Increase 30-day HF rehospitalization 1.4 1.0 0.8 0.6 Decrease Adjusted odds ratio for outcomes 1.6 0.4 30-day mortality 0.2 0.0 2002 2003 2004 2005 2006 Heidenreich PA et al. J Am Coll Cardiol. 2010;56(5):362-8. 3 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 Cardiovascular and non-cardiovascular comorbidities Pathophysiological targets: uncertain End-points selection: not standardized ADHERE: precipitating factors for hospitalisations Fonarow, G. C. et al. Arch Intern Med 2008;168:847-854. 4 Acute Heart Failure: clinical classification ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 Demographics and concomitant diseases of hospitalized 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 52 Prior HF (%) 75 65 87 LVEF <40% 51 46 52 Coronary artery disease (%) 57 68 50 Hypertension (%) 72 53 71 Diabetes (%) 44 27 42 Atrial fibrillation (%) 31 43 31 Renal insufficiency (%) 30 18 NA Fonarow GC. Am Heart J 2008;155:200−207 Other non-CV comorbidities: anaemia (20-40%), iron deficiency (30-50%), COPD (20-50%) 5 Management of Acute Heart Failure Syndromes 1. Challenges in everyday clinical practice guidelines & reality 2. Results (disappointing) of the recent trials 3. Outlook for the future different approach needed ? Heart Failure ESC guidelines: two decades of history Committee for Practice Guidelines Document Reviewers 26 authors 6 Goals of treatment in each phase of AHF management Immediate: • Treat life-threatening conditions • Confirm AHF diagnosis • Restore oxygenation • Improve organ perfusion & haemodynamics • Treat symptoms • Limit cardiac/renal damage • Prevent thrombo-embolism • Minimize ICU length of stay Intermediate: • Stabilise patient and optimise treatment strategy • Initiate and up-titrate diseasemodifying pharmacological therapy • Consider device therapy in appropriate patients • Identify aetiology and relevant co-morbidities Initial (ED/ICU/CCU) In-hospital Pre-discharge and long-term management: • Plan follow-up strategy • Plan to up-titrate/optimize disease-modifying drugs • Assess for appropriate device therapy • Prevent early readmission • Enrol in disease management programme, educate, initiate lifestyle adjustments • Improve symptoms, QoL and survival Consecutive phases of AHF management Discharge ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 Pang PS et al. Eur Heart J 2010;31:784-93 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 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 7 Initial phase in ED/ICU/CCU: profiling and strategizing care CLINICAL PROFILES Low perfusion at rest ? NO (eg. narrow PP, cool extremities, hypotension) YES NO YES Congestion at rest ? (eg. orthopnea, elevated JVP, pulmonary rales, S3, oedema) ESC Guidelines for the Diagnosis and Treatmentof Acute and Chronic Heart Failure 2008 ACCF/AHA Guidleline for the Management of Heart Failure 2013 8 Initial phase in ED/ICU/CCU: profiling and strategizing care Hemodynamic profiles: therapeutic implications • diuretics • ultrafiltration „dry-out” Warm & Wet Warm & Dry Vasodilators • nitroglycerin • nesiritide B A Cold & Dry Cold & Wet L C • nitroprusside Adapted from Stevenson LW, Eur J Heart Failure 2005;7:323 Fluid retention or redistribution ? Interventions to Relieve Congestion Sodium & fluid restriction Diuretics* Vasodilators Ultrafiltration / dialysis • BNP (nesiritide) • Vasopressin antagonists ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 9 Low-dose dopamine or low-dose nesiritide for AHF patients with renal dysfunction: ROSE trial Conclusion: in AHF patients with renal dysfunction neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. Chen HH et al. JAMA 2013 Fluid redistribution Fluid accumulation Gheorghiade M et al.; Am J Cardiol 2005;96[suppl]:11G–17G ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 10 Initial phase in ED/ICU/CCU: profiling and strategizing care Hemodynamic profiles: therapeutic implications Patients with hypotension, hypoperfusion or shock „warm-up” & „dry-out” Warm & Dry Warm & Wet A B Cold & Dry Cold & Wet L C Inotropes • dobutamine • dopamine • levosimendan • nitroprusside Adapted from Stevenson LW, Eur J Heart Failure 2005;7:323 Limitations of Inotropic Agents Tachyarrhythmias ↑ ventricular arrhythmias ↑ ventricular rate in atrial fibrillation Myocardial ischemia → progression of LV dysfunction? Hypotension / coronary hypoperfusion ↑ myocardial VO2 (contractility & HR) Mechanisms ↑ cytoplasmic Ca2+ Myocardial efficiency (work/VO2)? Vasodilation /hypotension Courtesy M.Metra 11 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 Algorithm for management of acute pulmonary oedema/congestion ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 12 Goals of treatment in each phase of AHF management Immediate: • Treat life-threatening conditions • Confirm AHF diagnosis • Restore oxygenation • Improve organ perfusion & haemodynamics • Treat symptoms • Limit cardiac/renal damage • Prevent thrombo-embolism • Minimize ICU length of stay Initial (ED/ICU/CCU) Intermediate: • Stabilise patient and optimise treatment strategy • Initiate and up-titrate diseasemodifying pharmacological therapy • Consider device therapy in appropriate patients • Identify aetiology and relevant co-morbidities In-hospital Pre-discharge and long-term management: • Plan follow-up strategy • Plan to up-titrate/optimize disease-modifying drugs • Assess for appropriate device therapy • Prevent early readmission • Enrol in disease management programme, educate, initiate lifestyle adjustments • Improve symptoms, QoL and survival Consecutive phases of AHF management Discharge ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 Pang PS et al. Eur Heart J 2010;31:784-93 AHF: management after stabilization ACE inhibitor/angiotensin receptor blocker In patients with reduced EF not already receiving an ACE inhibitor(or ARB), this treatment should be started as soon as possible, blood pressure and renal function permitting*. Beta-blocker In patients with reduced EF not already receiving a beta-blocker, this treatment should be started as soon as possible after stabilization, blood pressure and heart rate permitting*. Beta-blocker treatment may be continued in many patients during an episode of decompensation Mineralocorticoid receptor antagonist In patients with reduced EF not already receiving an MRA, this treatment should be started as soon as possible, renal function and potassium permitting*. As the dose of MRA used to treat HF has a minimal effect on blood pressure, even relatively hypotensive patients may be started on this therapy during admission. * - The dose of ACEi/ARB, beta-blockers, MRA should be up-titrated as far as possible before discharge, and a plan made to complete dose uptitration after discharge. ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 13 Regional differences in the management of AHF ALARM-HF: Data from 4953 pts with AHF treated in 9 countries; Oct 2006 – Mar 2007 Treatment strategies among participating countries Follath F, et al. Intensive Care Med (2011) 37:619–626 Management of Acute Heart Failure Syndromes 1. Everyday clinical practice guidelines & reality 2. Results (disappointing) of the recent trials 3. Outlook for the future different approach needed ? 14 RECENT AHFS TRIALS Study Patients Primary End Point Natriuretic Peptide (Nesiritide) VMAC 489 PCWP 3 h and Dyspnoea 3 h PRECEDENT 255 Arrhythmias ASCEND HF 7147 Change in dyspnoea at 6 and 24h HF hospitalization and death at 30 days Vasopressin Antagonists (Tolvaptan) ACTIV HF 319 Body wt 24 h and Worse HF 60 d EVEREST 3433 Short term: Body wt + GCA at 7 days Long term: Mortality and Re-hospitalization SERCA agonist & Na/K ATPase inhibitor (Istaroxime) HORIZON-HF 120 PCWP Changes from baseline Selective adenosine A1-receptor antagonist (Rolofylline) PROTECT 2033 Changes in dyspnoea Death or readmission through day 7 Courtesy of M. Metra RECENT AHFS TRIALS Study Patients Primary End Point Endothelin Antagonist (Tezosentan) RITZ-1 675 Dyspnea 6 h RITZ-2 292 Change in CI 6 h VERITAS 1800 Dyspnea 24 h and Worsen HF 7 d Calcium Sensitizer (Levosimendan) LIDO 203 Change CI 24 h and PCWP 24 h CASINO 299 Mortality 30 d and Mortality 180 d REVIVE II 600 Composite global assess. at 6 h, 24 h 5 d SURVIVE 800 Mortality 180 d Phosphodiesterase Inhibitor (Milrinone) OPTIME-CHF 951 Days Hospitalized within 60 d Courtesy of M. Metra 15 Ideal properties for AHF therapy Pang PS et al. Eur Heart J 2010;31:784-93 Novel therapies for AHF Pang PS et al. Eur Heart J 2010;31:784 It´s hard to make predictions, particularly about the future…. Niels Bohr or Yogi Berra or Albert Einstein or Mark Twain 16 Cinaciguat in patients with AHF Phase IIb, placebo-controlled study, 139 AHF patients, PCWP ≥18 mmHg, EF <40% Erdmann E et al. Eur Heart J 2013;34:57–67 Hemodynamic effcts of stresscopin in HF patients Double-blind, placebo-controlled study with 62 HF pts with EF ≤ 35% & CI ≤ 2.5 L/min/m2 Conclusion. Stresscopin has demonstrated an ability to safely increase CI and reduce SVR without significantly affecting HR and SBP, making it potentially unique and advantageous compared with currently available inotropes. Further studies (also in AHF setting) are needed Gheorghiade M et al. Eur J Heart Fail 2013;15:679–689 17 A Phase 2 Study of Intravenous Omecamtiv Mecarbil, A Novel Cardiac Myosin Activator, In Patients With Acute Heart Failure John R. Teerlink, G. Michael Felker, John J. V. McMurray, Piotr Ponikowski, Marco Metra, Gerasimos S. Filippatos, Kenneth Dickstein, Justin A. Ezekowitz, John G. Cleland, Jae B. Kim, Lei Lei, Beat Knusel, Andrew A. Wolff, Fady I. Malik and Scott M. Wasserman on behalf of the ATOMIC-AHF Investigators and Patients Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator Mechanochemical Cycle of Myosin Omecamtiv mecarbil increases the entry rate of myosin into the tightly-bound, force-producing state with actin “More hands pulling on the rope” Increases duration of systole Increases stroke volume No increase in myocyte calcium Force production No change in dP/dtmax No increase in MVO2 Malik FI, et al. Science 2011; 331:1439-43. 18 Summary Efficacy OM did not meet the 1° endpoint of dyspnoea relief Appeared to improve dyspnoea in Cohort 3 Trends towards reduction of worsening HF Safety Overall SAE profile and tolerability similar to placebo Increase in troponin; no clear relationship to OM concentration Numerical imbalance in MIs in Cohort 3 No evidence of pro-arrhythmia Pharmacology PK similar to healthy volunteers and stable HF patients Systolic ejection time significantly increased consistent with MOA No measured adverse effect on heart rate or blood pressure Management of Acute Heart Failure Syndromes 1. Everyday clinical practice guidelines & reality 2. Results (disappointing) of the recent trials 3. Outlook for the future different approach needed ? 19 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 i.v. nitrates ? Potentially favourable Hypoperfusion i.v. inotropes Detrimental Poor cardiac performance Dissociation between symptomatic improvement, clinical stabilisation & favourable long-term outcome Modified from Pang PS et al. Eur Heart J 2010;31:784-93 Lessons from ACS trials: short-term intervention can result in long-term benefit ISIS-2 follow-up % pts STK Control/placebo 15 10 GISSl ISIS-2 5 21-day mortality 5-week vascular mortality Baignet C et al. BMJ 1998;316:1337-43 % pts PCI 15 Thrombolysis 10 5 Death Death & re-MI In-hospital Death Death & re-MI 6-month Grines CL et al. NEJM 1993;328:673-9 20 Need for paradigm shifting in acute heart failure: short-term intervention and long-term goals (?) What is needed ? Targeted-approach = characterizing patient’ clinical profile different pathophysiologies & therapies for different clinical profiles (?) An ideal drug / intervention 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 Pre-RELAX-AHF and RELAX-AHF: clinical trials testing the efficacy of serelaxin in AHF Timeline: Day 1 Day 5 Day 3 Day 14 Day 60 Treatment (within 16h of symptoms) 48h i.v. Primary EP1 Primary EP2 ∆ Dyspnea Safety ∆ Worsening HF (%) Safety Creatinine changes HE LoS (days) Secondary EP1 Days alive out of hospital Secondary EP2 CV mortality or re-hospitalization for HF or renal failure Outcome CV Mortality (%) Hospital admission Day 180 „the earlier the better” Early Relief (Likert) 6, 12, 24 h Sustained Effect (VAS AUC) 0-100 mm; 0, 6, 12, 24h, D2-D5 Hospital discharge Day 60 analysis Follow-up Teerlink et al. Lancet 2009;373:1429–39; Clinicaltrials.gov 2009 (NCT00520806) 21 1° Endpoint: Dyspnea Relief (VAS AUC) Change from baseline (mm) 19.4% increase in AUC with serelaxin from baseline through day 5 (Mean difference of 448 mm-hr) Placebo Serelaxin AUC with placebo, 2308 ± 3082 AUC with serelaxin, 2756 ± 2588 *P=0.0075 6 12 hrs Days RELAX-AHF Teerlink J. LBCT Presentation, AHA 2012 RELAX-AHF: Worsening of Heart Failure Cumulative proportion of worsening heart failure to Day 5 (%) *p<0.001 through Day 5 n= 11 3 16 4 31 10 44 17 57 25 64 36 69 37 Kaplan-Meier estimate for time to WHF (%) **HR 0.7 (0.51, 0.96); p=0.024 573 570 573 570 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 RELAX-AHF 22 Changes from baseline in biomarkers related to organ damage in the RELAX-AHF study hs-cTnT ≥20% increase at day 2 %pts placebo serelaxin Cystatin C ≥0.3 mg/l increase at day 2 Creatinine ≥0.3 mg/dl increase at day 2 20 AST ≥20%l increase at day 2 10 Cardiac damage Renal damage Liver damage RELAX-AHF Metra M et al. JACC 2013;61:196-206 CV Death through Day 180 K-M estimate CV death (ITT) (%) 14 Number of Events, n (%) 12 HR 0.63 (0.41, 0.96); p=0.028 Placebo (N=580) 10 55 (9.5%) NNT = 29 8 6 35 (6.0%) Serelaxin (N=581) 4 2 0 0 14 30 60 90 120 150 180 Days 580 567 559 547 535 523 514 444 Placebo 581 573 563 555 546 542 536 463 Serelaxin Teerlink J. LBCT Presentation, AHA 2012 RELAX-AHF 23 All-cause Death through Day 180 K-M estimate for All-cause Death ITT (%) 14 Number of Events, n (KM%) 12 65 (11.3%) Placebo (N=580) HR 0.63 (CI 0.43, 0.93); p=0.020 10 NNT = 25 8 42 (7.3%) 6 Serelaxin (N=581) 4 2 0 0 14 30 60 90 120 180 Days 150 580 567 559 547 535 523 514 444 Placebo 581 573 563 555 546 542 536 463 Serelaxin RELAX-AHF Teerlink J. LBCT Presentation, AHA 2012 Short-term relief, long-term goals – the cardiologist’s perspective on a novel therapeutic approach to acute heart failure „broadly speaking, the pharmacological armamentarium for AHFS – loop diuretics, vasodilators and inotropes – is largely unchanged from 1970s…” Will it be changed after RELAX ? Sunrise or sunset ? 24 25