Heart failure (3 of 3): treatment

1. Cardiology – Faculty of Medicine and Surgery UniversityofTurin Heart failure(3 of 3): treatment Giuseppe Biondi Zoccai Division of Cardiology 1, Ospedale San Giovanni Battista “Molinette”, Turin, Italy gbiondizoccai@gmail.com – http://www.metcardio.org

2. Learning goals • Definition • Epidemiology • Pathophysiology • Diagnosis • Prognosis • Management

3. Learning goals • Management: • Prevention • Treatment with “ABCDE”: • Pharmacologic therapy • Non-pharmacologic therapy

4. Learning goals • Management: • Prevention • Treatment with “ABCDE”: • Pharmacologic therapy • Non-pharmacologic therapy

5. Management

6. Learning goals • Management: • Prevention • Treatment with “ABCDE”: • Pharmacologic therapy • Non-pharmacologic therapy

7. Prevention • Addressing all primary causes of cardiac disease eventually leading to HF • Hypertension • Coronary heart disease • Valvular heart disease • Metabolic, toxic, or immunological heart disease

8. Learning goals • Management: • Prevention • Treatment with “ABCDE”: • Pharmacologic therapy • Non-pharmacologic therapy

9. Goals/means of treatment • Prognostic benefits vssymptomatic benefitsvssurrogate benefits • Correction of reversible causes: • Ischemia, valvular disease, thyrotoxicosis and other high output status, shunts, arrhythmias, medications • Palliation for irreversible damage

10. Survival Morbidity Exercise capacity Quality of life Neurohormonal changes Progression of CHF Symptoms Treatment objectives (Cost)

11. Prevention/Control of risk factors • Life style • Treat etiologic cause / aggravating factors • Drug therapy • Personal care. Team work • Revascularization if ischemia causes HF • ICD (Implantable Cardiac Defibrillator) • Ventricular resyncronization • Ventricular assist devices • Heart transplant • Artificial heart • Neoangiogenesis, Gene therapy Treatment strategies All Selected patients

12. Learning goals • Management: • Prevention • Treatment with “ABCDE”: • Pharmacologic therapy • Non-pharmacologic therapy

13. ABCDE approach for HF • A ACE-inhibitors, AII-antagonists, aldosterone-antagonists, anti-arrhythmics, anti- hypertensives, aspirin/anticoagulants • B  beta-blockers • C  cholesterol (statins), cardiac resynchronization (CRT), coronary PTCA/CABG, cardiac restoration, cardiac transplant • D daily weight, diet, diuretics, digoxin, defibrillators, (vaso)dilators • E exercise, (anything) else

14. ABCDE approach for HF • A ACE-inhibitors, AII-antagonists, aldosterone-antagonists, anti-arrhythmics, anti- hypertensives, aspirin/anticoagulants • B  beta-blockers • C  cholesterol (statins), cardiac resynchronization (CRT), coronary PTCA/CABG, cardiac restoration, cardiac transplant • D daily weight, diet, diuretics, digoxin, defibrillators, (vaso)dilators • E exercise, (anything) else

15. Angiotensin Converting Enzyme Inhibitors (ACE-inhibitors) • Block the renin-aldosterone-angiotensin system by inhibiting the conversion of angiotensin I to angiotensin II → ↑vasodilation and ↓Na+ retention • ↓bradykinin degradation ↑its level → ↑PG secretion & NO • Major anti-remodeling effects on myocardium and vessels • Mainstay in HF: they improve cardiac function, symptoms, and survival • Several agents: captopril, enalapril, lisinopril, perindopril, ramipril, zofenopril, … PROGNOSTIC BENEFIT! SYMPTOMATIC BENEFIT!

16. Angiotensin Converting Enzyme Inhibitors (ACE-inhibitors) 30 Asymptomatic ventricular dysfunction post MI Placebo n=1116 Mortality % 20 Captopril n = 2231 3 - 16 days post AMI EF < 40 12.5 - 150 mg / day n=1115 10 SAVE N Engl J Med 1992;327:669 p=0.019 0 0 3 4 1 2 Years

17. Angiotensin Converting Enzyme Inhibitors (ACE-inhibitors)

18. Angiotensin II antagonists • Comparable effect to ACE-inhibitors • Fewer side effects than ACE-inhibitors • Can be used in certain conditions when ACE-inhibitors are contraindicated (angioneurotic edema, cough) • May be combined with ACE-inhibitors, provided BP is ok, to possibly improve survival and definitely reduce hospitalizations • Commonly used agents: candesartan, losartan, valsartan PROGNOSTIC BENEFIT! SYMPTOMATIC BENEFIT!

19. Aldosterone antagonists • Block aldosterone receptors • Can be used in advanced HF, to further inhibit the R-A-A system after complete uptitration of ACE-inhibitors • Check often for risk of hyperkalemia • Available agents: spironolactone, potassium canrenoate, eplerenone PROGNOSTIC BENEFIT! SYMPTOMATIC BENEFIT!

20. 1.0 0.9 0.8 0.7 0.6 0.5 0 6 12 24 30 36 18 Aldosterone antagonists Annual Mortality Aldactone 18%; Placebo 23% Survival N = 1663 NYHA III-IV Mean follow-up 2 y Aldactone p < 0.0001 Placebo months RALES NEJM 1999;341:709

21. Antiarrhythmics • Most common cause of sudden cardiac death in HF is ventricular tachyarrhythmia • Antiarrhythmic drugs may suppress PVC but may induce VT or VF!!! • Only amiodaronehas a reasonably safe profile in HF, but landmark SCD-HeFT Study has demonstrated no impact of amiodarone on prognosis • Remember the many toxic effects of amiodarone: • lung, thyroid, eye, liver SYMPTOMATIC BENEFIT!

22. Aspirin/oral anticoagulants • Aspirin is recommended in all patients with coronary heart disease, diabetes or any other established form of atherosclerotic disease, unless contraindicated by bleeding diathesis • Oral anticoagulants are recommended in patients with paroxysmal/permanent atrial fibrillation, or those with previous embolic events (eg in LV dysfunction) despite aspirin treatment PROGNOSTIC BENEFIT!

23. ABCDE approach for HF • A ACE-inhibitors, AII-antagonists, aldosterone-antagonists, anti-arrhythmics, anti- hypertensives, aspirin/anticoagulants • B  beta-blockers • C  cholesterol (statins), cardiac resynchronization (CRT), coronary PTCA/CABG, cardiac restoration, cardiac transplant • D daily weight, diet, diuretics, digoxin, defibrillators, (vaso)dilators • E exercise, (anything) else

24. Beta-blockers • Traditionally were contraindicated in HF • Now another mainstay in HF: • improved LV function and symptoms • Improved survival • The only contraindication is severe and truly decompensated HF • Agents approved for HF: bisoprolol, metoprolol, carvedilol PROGNOSTIC BENEFIT! SYMPTOMATIC BENEFIT!

25. Beta-blockers 100 90 80 Survival % Carvedilol 70 p=0.00014 35% RR N = 2289 III-IV NYHA 60 Placebo 50 0 4 8 12 16 20 24 28 COPERNICUS NEJM 2001;344:1651 Months

26. The best beta-blocker? Probably carvedilol

27. Use of best beta-blocker invarious settings

28. ABCDE approach for HF • A ACE-inhibitors, AII-antagonists, aldosterone-antagonists, anti-arrhythmics, anti- hypertensives, aspirin/anticoagulants • B  beta-blockers • C  cholesterol (statins), cardiac resynchronization (CRT), coronary PTCA/CABG, cardiac restoration, cardiac transplant • D daily weight, diet, diuretics, digoxin, defibrillators, (vaso)dilators • E exercise, (anything) else

29. ABCDE approach for HF • A ACE-inhibitors, AII-antagonists, aldosterone-antagonists, anti-arrhythmics, anti- hypertensives, aspirin/anticoagulants • B  beta-blockers • C  cholesterol (statins), cardiac resynchronization (CRT), coronary PTCA/CABG, cardiac restoration, cardiac transplant • D daily weight, diet, diuretics, digoxin, defibrillators, (vaso)dilators • E exercise, (anything) else

30. Diuretics • The most effective symptomatic relief • Usually short-term IV therapy followed by long-term PO therapy • Thiazides: • HCTZ, chlorthalidone • Loop diuretics: • Furosemide, torasemide, bumetanide, etacrynic acid • Mixed agents: • Metolazone, nesiritide SYMPTOMATIC BENEFIT!

31. Diuretics

32. Digitalis glycosides (digoxin, digitoxin) • Their role has declined in recent years (s/p DIG Study) • Digitals does not affect mortality in CHF patients but causes significant: • Reduction in hospitalization • Reduction in symptoms of HF • Actions: • Positive inotropic effect • Arrhythmogenic effect • Vagotonic effect USEFUL IN CASE OF CHF & AF! SYMPTOMATIC BENEFIT!

33. Digitalis glycosides (digoxin, digitoxin) • Digoxin levels should be 1.0 – 2.0 ng/dL, but narrow & variable therapeutic window(check serum!) • Toxicity - non cardiac manifestations: • Anorexia, nausea, vomiting, headache, xanthopsia sotoma, disorientation • Toxicity - cardiac manifestations: • Sinus bradycardia and arrest, A/V block (usually 2nd degree), atrial tachycardia with A/V block, development of junctional rhythm in patients with AF, PVC, VT/ VF (bi-directional VT)

34. Daily doses of digoxin

35. (vaso) Dilators: nitrates & hydralazine • Reduction of afterload by arteriolar vasodilatation (hydralazin) ↓LVEDP, O2 consumption, myocardial perfusion, stroke volume and CO • Reduction of preload by venous dilation (nitrates) ↓venous return  ↓load on both ventricles • Usually maximum benefit achieved by using both agents, but currently approved (in US) only for African Americans • Other drugs (eg nesiritide) have still very limited clinical role PROGNOSTIC BENEFIT! SYMPTOMATIC BENEFIT!

36. (vaso) Dilators: nitrates & hydralazine A-HeFT Trial NEJM 2004;351:2049

37. ABCDE approach for HF • A ACE-inhibitors, AII-antagonists, aldosterone-antagonists, anti-arrhythmics, anti- hypertensives, aspirin/anticoagulants • B  beta-blockers • C  cholesterol (statins), cardiac resynchronization (CRT), coronary PTCA/CABG, cardiac restoration, cardiac transplant • D daily weight, diet, diuretics, digoxin, defibrillators, (vaso)dilators • E exercise, (anything) else

38. Positive inotropic agents • Improve myocardial contractility (β adrenergic agonists, dopaminergic agents, phosphodiesterase inhibitors, calcium-channel sensitizers): dopamine, dobutamine, milrinone, amrinone, levosimendan • Most studies showed ↑ long-term mortality with inotropic agents • Yet beneficial at short-term use for peripheral hypoperfusion +/- pulmonary edema refractory to diuretics and vasodilators • Only use them is in acute conditions such as cardiogenic shock, as bridge to another lasting intervention (eg transplant) or cardiac injury should be temporary SYMPTOMATIC BENEFIT!

39. Positive inotropic agents

40. Learning goals • Management: • Prevention • Treatment with “ABCDE”: • Pharmacologic therapy • Non-pharmacologic therapy

41. Diet • Salt restriction • Fluid restriction • Low fat diet in patients at risk or with coronary artery disease • Plus daily weight and, if needed, monitoring of urine output (to tailor therapy) SYMPTOMATIC BENEFIT!

42. Exercise training ExTraMATCH Meta-analysis N=801 BMJ 2004;328:189 PROGNOSTIC BENEFIT! SYMPTOMATIC BENEFIT!

43. Non-invasiveventilatoryassistance • CPAP and NIPPV in cardiogenic pulmonary edema reduce the need for tracheal intubation and mechanical ventilation • Moreover, they reduce mortality in acutely decompensated patients • However, there are logistic and compliance issues inherent to these treatment means, especially as long-term regimens PROGNOSTIC BENEFIT! SYMPTOMATIC BENEFIT!

44. Non-invasiveventilatoryassistance Masip et al meta-analysis N=783 JAMA 2004;294:3124

45. Implantable cardioverter debribillators (ICD) • Patients with EF≤35% and CHF → benefit from ICD (primary prevention) • Patients with history of sustained VT or SCD → benefit from ICD (secondary prevention) • Patients with history of non-sustained VT and EF between 30-40% → electrophysiological testing ± ICD (primary prevention) PROGNOSTIC BENEFIT!

46. Implantable cardioverter debribillators (ICD) DEFINITE Trial NEJM 2004;350:2151

47. Amiodarone vs ICD – SCD-HeFT SCD-HeFT Trial NEJM 2005;352:225

48. Cardiacresynchronizationtherapy (CRT) PROGNOSTIC BENEFIT! SYMPTOMATIC BENEFIT!

49. Cardiacresynchronizationtherapy (CRT)

50. CRT improves cardiac function (6 Months) LVEF Avg. Change (Absolute %) MR Jet Area Avg. Change (cm2) Not Reported  Control CRT Data sources: MIRACLE: Circulation 2003;107:1985-1990 MIRACLE ICD:JAMA 2003;289:2685-2694 Contak CD: J Am Coll Cardiol 2003;2003;42:1454-1459