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Heart Failure Associate Professor Rob Doughty Dept of Medicine, The University of Auckland & Green Lane Cardiovascular Service, Auckland City Hospital. Acute Heart Failure Chronic heart failure Pharmacotherapy “failed” therapies Device-based therapies Newer therapeutics.

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Heart Failure Associate Professor Rob Doughty Dept of Medicine, The University of Auckland & Green Lane Cardiovascul


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    1. Heart Failure Associate Professor Rob Doughty Dept of Medicine, The University of Auckland & Green Lane Cardiovascular Service, Auckland City Hospital

    2. Acute Heart Failure • Chronic heart failure • Pharmacotherapy • “failed” therapies • Device-based therapies • Newer therapeutics

    3. The Rotterdam Study Bleumink GS et al. Euro Heart J 2004;25:1614-19 • Population-based cohort of 7,983 people age 55 • 30% of individuals age 55 years will develop HF in their remaining life

    4. Hospital Admissions for Heart Failure • Incidence and prevalence data are relatively difficult to obtain • Hospitalisation data are often used as surrogates • Rely on discharge coding • Reasonable reflection of the burden of heart failure • Used for planning healthcare delivery

    5. Aging Population 2021 2001 1986 Source: Statistics NZ

    6. Mortality from Cardiovascular Disease Source: NZ Heart Foundation Technical Report No 82 Jan 2004

    7. Incidence and Prevalence of HF • Incidence & prevalence strongly age related • Incidence • 50’s 2 per 1000, 80’s 40 per 1000 • Prevalence • 2-3%, increasing to 8-10% in elderly populations Levy D et al. NEJM 2002;347:1397

    8. Trends in Hospitalisations for HF Stewart S et al. EHJ 2001;22:209-217

    9. Acute Heart Failure • Definition • Incidence and prevalence • Hospitalisations • Management • Patient characteristics • Aetiology • Treatment

    10. Definition of Heart Failure • Symptoms of heart failure (rest or exercise) • Objective evidence of cardiac dysfunction and in cases where diagnosis remains in doubt • Response to treatment directed at HF ESC HF Guidelines EHJ 2005;26:1115-1140

    11. Definition of Heart Failure Acute heart failure defined as rapid onset of symptoms and signs, secondary to abnormal cardiac function • With or without previous cardiac disease • Systolic or diastolic dysfunction, abnormal rhythm, preload and afterload mismatch • Often life-threatening ESC Acute HF Guidelines EHJ 2005;26:384-416

    12. Several Distinct Clinical Conditions • Acute decompensated HF May be de novo or as decompensated HF Symptoms relatively mild and not 2-4 below • Hypertensive AHF • Pulmonary oedema and severe respiratory distress • Cardiogenic shock • High output HF • Right-sided acute HF Low output syndrome with increased JVP, hepatomegaly and hypotension ESC Acute HF Guidelines EHJ 2005;26:384-416

    13. Patient Characteristics Survey of 11,327 HF cases in Europe • Mean age 71 yrs, 47% women • 65% prior diagnosis of HF • 44% prior admission for HF Presentation • 40% acute dyspnoea • 35% exertional dyspnoea / oedema • 19% acute coronary syndrome • 9% atrial fibrillation Cleland JGF et al. EHJ 2003;24:442-463

    14. Patient Characteristics Admission • 50% general medical wards • 11 days average length of stay Death rates: • 6.9% during index admission • 13.5% at 3 months Cleland JGF et al. EHJ 2003;24:442-463

    15. Aetiology of Heart Failure • Heart failure clinical syndrome with underlying cause • Underlying cause often not focused on • Hypertension & coronary disease commonest causes

    16. Aetiology of Heart Failure Fox KF et al. EHJ 2001;22:228-236

    17. Acute HF: Levosimendan • Levosimendan calcium sensitiser and vasodilator • Previous trials showing efficacy SURVIVE • Levosimendan vs. Dobutamine in patients with acute decompensated HF • 1327 patients • Primary end point: • all cause mortality at 180 days Mebazza A et al. JAMA 2007;297:1883

    18. SURVIVE Trial Mebazza A et al. JAMA 2007;297:1883

    19. Proposed Effects of Nesiritide • Hemodynamic • Vasodilation: • Veins • Arteries • Coronary arteries • Neurohormonal •  Aldosterone •  Endothelin-1 •  Noradrenaline • Renal • Diuresis • Natriuresis BNP • Cardiac • Lusitropic • Anti-remodeling • Anti-fibrotic

    20. Nesiritide • Smaller trials demonstrating short term efficacy • FDA approval in 2001 • Acute decompensated HF • Subsequent meta-analyses suggesting potential adverse effects

    21. Nesiritide Any iv Vasodilator Nesiritide GTN Hauptman PJ, et al. JAMA 2005;296:1877 Data from 491 US hospitals, 385,627 admissions for HF

    22. FUSION II Trial 1 Week 12 All Nesiritide 0.8 All Placebo 0.6 Event Free Survival 0.4 P=0.791 HR (95% CI) 1.03 (0.82, 1.30) 0.2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Weeks Out-patient based treatment, nesiritide 1 or 2 weekly LVEF <40%, Class III/IV HF

    23. Chronic Heart Failure

    24. Neurohormonal Status in Heart Failure • SNS • RAAS • Vasopressin • Endothelin-1 • ?Urotensin II DILATATION • Natriuretic peptides • Nitric oxide • Vasodilatory PGs • Adrenomedullin • Urocortin CONSTRICTION

    25. Neurohormonal Antagonists Annual Mortality (%) 10 5 0 + ACEi + b-blocker Diuretics + Digoxin + ACEi Cleland meta-analysis; Lechat meta-analysis

    26. Secular Trends in Survival For Patients with HF Patients with Reduced LVEF Patients with Preserved LVEF Owan TE, et al. N Engl J Med 2006;355:251-9

    27. Mortality After Hospital Admission for HF Wasywich C. CSANZ 2007

    28. CHARM Trial Programme: Summary CHARM Alternative ACEi intolerant pt Lancet 2003;362:772 ARB suitable alternative to ACEi CHARM Added Candesartan + ACEi Lancet 2003;362:767 Some additive benefit of addition of ARB to ACEi but…..beware adverse effects

    29. Long-Term Effects of Treatment CONSENSUS I Trial 10-year FU 1-year FU

    30. Recent “Failed” Phase III HF Trials ClassDrugTrial TNFEtanercept RENEWAL blockade VasopeptidaseOmapatrilat OVERTURE inhibition EndothelinBosentan ENABLE blockade Packer Circ 2002;106:920 Mann Circ 2004;1091594

    31. “Failed” Drugs in Heart Failure Increase mortality (sudden death) with: • Milrinone • Flosequinan • Ibopamine • Moxonidine • Class I antiarrhythmics

    32. Emerging Drug Therapies in HF • Ranolazine (metabolic agent) • Erythropoietin • HMGcoA reductase inhibitors • Adenosine agonists • AGE cross-link breakers • Immune modulation therapy • Rosuvastatin • Ivabradine (If channel inhibitor) • Eplerenone • Levosimendan • NEP/ECE inhibitors • Vasopressin antagonists • Nesiritide • Copper chelation agents

    33. Vasopressin System V1a receptors V2 receptors Arterial underfilling Hyperosmolality • Baroreceptors • Left atrium • Carotid sinus • Aortic arch Hypothalamus • Supraoptic nucleus • Paraventricular nucleus AVP Collecting duct of kidney Vascular smooth muscle Vasoconstriction Water re-absorption OPC-31260SR121463TolvaptanLixivaptanVP-343FR-161282 OPC-21268Relcovaptan ConivaptanJTV-605CL-3 85004 Adapted from Sanghi et al Eur Heart J 2005

    34. EVEREST Outcome Trial Konstam MA, et al. JAMA 2007;297:1319 • Efficacy of Vasopressin Antagonism in Heart failure Outcome Study with Tolvaptan • Tolvaptan (30mg/d) vs. placebo • 4133 patients with LVEF < 40% • Outcomes: • All-cause mortality • CVS death or hospitalisation for worsening HF • Follow up minimum 60 days, median 9 months

    35. EVEREST Outcome Trial Konstam MA, et al. JAMA 2007;297:1319 All-Cause Mortality CVS Death or Hospitalisation for HF

    36. Anaemia and HF

    37. Erythropoietin in HF • 26 patients, EPO vs. placebo, 6 months • End points: Hb and Peak Vo2 Mancini DM, et al. Circulation 2003;107:294 Haemoglobin VO2

    38. Potential Benefits of EPO • Prevention of apoptosis • Endothelial progenitor cell mobilisation • Induction of angiogenesis/ neovascularisation • Limitation of ischaemia/reperfusion injury

    39. Biventricular Pacing • LBBB common in HF patients • “Dysynchrony” between ventricles • Biventricular pacing (cardiac resynchronisation therapy, CRT) • Pace right and left ventricle (via lead in coronary sinus) • Improved cardiac output in severe HF • Improved quality of life • Improved survival

    40. Implantable Defibrillators • Small implantable devices like pacemakers • Able to deliver small electric shock across the heart to terminate ventricular arrhythmias • Improved survival in patients with chronic heart failure

    41. SCD-HeFT: Amiodarone or ICD in CHF • 2521 patients with HF, NYHA II/III, LVEF <35%, ICD vs. amiodarone vs. placebo • Absolute Risk Reduction at 5yrs = 7.2% G Bardy et al. NEJM 2005;352:225-37

    42. Device-Based Therapy in HF Cardiac resynchronisation therapy • Patients with sinus rhythm, wide QRS on ECG (>120msec), LVEF <35%, moderate to severe symptom Implantable defibrillators • Prophylactic ICD for patients with LVEF<30% and mild to moderate symptoms

    43. HF with Preserved LVEF Inclusion End-Points Duration Drug CHARM CHF, age>70 Mortality 1 yr Candesartan EF>40% Hosp PEP-CHF CHF, age>70 Mortality 2 yrs Perindopril EF>40% Hosp I-PRESERVE CHF, age>60 Mortality 2 yrs Irbesartan EF>45% CVS Hosp TOP CAT CHF Mortality 3 yrs Aldo antag EF>45% Hosp

    44. ACEi in HF with Preserved EF CHARM Preserved CVS Death or HF Hospitalisation PEP-CHF Death or HF Hospitalisation Yusuf S, et al. Lancet 2003;362:777-781 Cleland JGF, et al. EHJ 2006;27:2338

    45. Treatment Heart Failure with Preserved LVEF Disease targeted therapy • Hypertension • BP target levels • Prevent / regress LVH • Atrial fibrillation • Control rate, anticoagulation • Coronary artery disease • Prevention / revascularisation • Diabetes / metabolic syndrome • Other • Anaemia, CRF, arrhythmias (esp. AF)

    46. Diabetes and HF Haas SJ et al. Am Heart J 2003;146:848 Diabetes worse

    47. Diabetes and HF • Specific therapies for patients with diabetes and heart failure • Metformin and improved outcomes in HF (PHANTOM Study) • AGE cross-link breakers in diastolic HF (Alteon) • Copper chelation

    48. Summary • Acute heart failure • Pathophysiology • Aetiology • treament • Chronic heart failure • Established therapies • “Failed” therapies • Device-based therapies • Specific patient subgroups • Disease specific • Patient specific