Congestive Heart Failure/Treatment

1. Congestive Heart Failure/Treatment Yeditepe Üniversite Hastanesi Kardiyoloji ABD 2014-2015

2. TREATMENT STRATEGY*

3. Treatment Objectives* • Survival • Morbidity • Exercise capacity • Quality of life • Neurohormonal changes • Progression of CHF • Symptoms

4. Treatment • 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 All Selected patients

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8. ESSENTIALS of HF TREATMENT * • An ACE inhibitor is recommended, in addition to a beta-blocker, for all patients with an EF ≤40% to reduce the risk of HF hospitalization and the risk of premature death. • A beta-blocker is recommended, in addition to an ACE inhibitor (or ARB if ACE inhibitor not tolerated), for all patients with an EF ≤40% to reduce the risk of HF • hospitalization and the risk of premature death. • An MRA is recommended for all patients with persisting symptoms (NYHA class II–IV) and an EF ≤35%, despite treatment with an ACE inhibitor (or an ARB if an ACE inhibitor is not tolerated) and a beta-blocker, to reduce the risk of HF hospitalization and the risk of premature death.

10. Diuretics* The effects of diuretics on mortality and morbidity have not been studied in patients with HF, unlike ACE inhibitors, betablockers, and MRAs (and other treatments). However, diuretics relieve dyspnoea and oedema and are recommended for this reason in patients with signs and symptoms of congestion, irrespective of EF. Loop diuretics produce a more intense and shorter diuresis than thiazides, which cause a more gentle and prolonged diuresis. Thiazides may be less effective in patients with reduced kidney function. Loop diuretics are usually preferred to thiazides in HF-REF although they act synergistically and the combination may be used (usually on a temporary basis) to treat resistant oedema. The aim of using diuretics is to achieve and maintain euvolaemia (the patient’s ‘dry weight’) with the lowest achievable dose. This means that the dose must be adjusted, particularly after restoration of dry body weight, to avoid the risk of dehydration leading to hypotension and renal dysfunction. Essential to control symptomssecondary to fluidretention

11. Diuretics Thiazides Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle Cortex K-sparing Inhibit reabsorption of Na in the distal convoluted and collecting tubule Loop diuretics Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle Medulla Loop of Henle Collecting tubule

12. Diuretics. Indications • 1. Symptomatic HF, with fluid retention • Edema • Dyspnea • Lung Rales • Jugular distension • Hepatomegaly • Pulmonary edema (Xray)

13. Loop Diuretics / Thiazides. Practical Use • Start with variable dose. Titrate to achieve dry weight • Monitor serum K+ at “frequent intervals” • Reduce dose when fluid retention is controlled • Teach the patient when, how to change dose • Combine to overcome “resistance” • Do not use alone

14. Loop diuretics. Dose (mg) Initial Maximum Bumetanide 0.5 to 1.0mg/12-24h 10mg /day Furosemide 20 to 40mg/12-24h 400mg /day Torsemide 10 to 20mg/12-24h 200mg /day

15. Thiazides, Loop Diuretics. Adverse Effects • K+, Mg+ (15 - 60%) (sudden death ???) • Na+ • Stimulation of neurohormonal activity • Hyperuricemia (15 - 40%) • Hypotension. Ototoxicity. Gastrointestinal. Alkalosis. Metabolic

16. ACE-i. Mechanism of Action VASOCONSTRICTION VASODILATATION ALDOSTERONE PROSTAGLANDINS VASOPRESSIN tPA Kininogen SYMPATHETIC Kallikrein Angiotensinogen RENIN BRADYKININ Angiotensin I A.C.E. Kininase II Inhibitor ANGIOTENSIN II Inactive Fragments

17. ACE-I. Clinical Effects* • Improve symptoms • Reduce remodelling / progression • Reduce hospitalization • Improve survival

18. Mortality Reduction with ACE-i Study ACE-i Clinical Seting CONSENSUS Enalapril CHF SOLVD treatment Enalapril CHF AIRE Ramipril CHF Vheft-II Enalapril CHF TRACE Trandolapril CHF / LVD SAVE Captopril LVD SMILE Zofenopril High risk HOPE Ramipril High risk

19. ACE-i. Indications Symptomatic heart failure Asymptomatic ventricular dysfunction - LVEF < 35 - 40 % Selected high risk subgroups (CAD+HT, DM+HT with LVH)

20. ACE-i Practical Use* • Start with very low dose • Increase dose if well tolerated • Renal function & serum K+ after 1-2 w • Avoid fluid retention / hypovolemia (diuretic use) • Dose NOT determined by symptoms • Combine to overcome “resistance”

21. ACE-i Dose (mg) Initial Maximum Captopril 6.25 / 8h 50 / 8h Enalapril 2.5 / 12 h 10 to 20 / 12h Fosinopril 5 to 10 / day 40 / day Lisinopril 2.5 to 5.0 / day 20 to 40 / day Quinapril 10 / 12 h 40 / 12 h Ramipril 1.25 to 2.5 / day 10 / day

22. ACE-I. Adverse Effects* • Hypotension (1st dose effect) • Worsening renal function • Hyperkalemia • Cough • Angioedema • Rash, ageusia, neutropenia, …

23. ACE-I. Contraindications* • Intolerance (angioedema, anuric renal fail.) • Bilateral renal artery stenosis • Pregnancy • Renal insufficiency (creatinine > 3 mg/dl) • Hyperkalemia (> 5,5 mmol/l) • Severe hypotension

24. ß-Adrenergic BlockersMechanism of action* • Density of ß1 receptors • Inhibit cardiotoxicity of catecholamines • Neurohormonal activation • HR • Antiischemic • Antihypertensive • Antiarrhythmic • Antioxidant, Antiproliferative

25. ß-Adrenergic BlockersClinical Effects* • Improve symptoms (only long term) • Reduce remodelling / progression • Reduce hospitalization • Reduce sudden death • Improve survival

26. ß-Adrenergic BlockersIndications* • Symptomatic heart failure • Asymptomatic ventricular dysfunction • LVEF < 35 - 40 % • After AMI

27. ß-Adrenergic Blockers When to start* • Patient stable • No physical evidence of fluid retention • No need for i.v. inotropic drugs • Start ACE-I / diuretic first • No contraindications • In hospital or not

28. ß-Adrenergic Blockers Dose (mg) Initial Target Bisoprolol 1.25 / 24h 10 / 24h Carvedilol 3.125 / 12h 25 / 12h Metoprolol tartrate 6.25 / 12h 75 / 12h Metoprolol succinnate 12,5-25 / 24h 200 / 24h Nebivolol • Start Low, Increase Slowly • Increase the dose every 2 - 4 weeks

29. ß-Adrenergic Blockers Adverse Effects* • Hypotension • Fluid retention / worsening heart failure • Fatigue • Bradycardia / heart block • Review treatment (+/-diuretics, other drugs) • Reduce dose • Consider cardiac pacing • Discontinue beta blocker only in severe cases

30. ß-Adrenergic Blockers Contraindications* • Asthma (reactive airway disease) • AV block (unless pacemaker) • Symptomatic hypotension / Bradycardia • Diabetes is NOT a contraindication • Progressive severe PAD (relative)

31. Digitalis - Na-K ATPase Na-Ca Exchange Na+ K+ Na+ Ca++ Ca++ Myofilaments K+ Na+ CONTRACTILITY

32. - Plasma Noradrenaline - Peripheral nervous system activity - RAAS activity - Vagal tone - Normalizes arterial baroreceptors Digitalis. Mechanism of Action Blocks Na+ / K+ ATPase => Ca+ + • Inotropic effect • Natriuresis • Neurohormonal control

33. DigitalisClinical Effects* • Improve symptoms • Modest reduction in hospitalization • Does not improve survival In patients with symptomatic HF and AF, digoxin may be used to slow a rapid ventricular rate, although other treatments are preferred Digoxin may also be used in patients in sinus rhythm with symptomatic HF and an LVEF ≤40% Digoxin can cause atrial and ventricular arrhythmias, particularly in the context of hypokalaemia, and serial monitoring of serum electrolytes and renal function is mandatory

34. Digitalis. Indications* • When no adequate response to ACE-i + diuretics + beta-blockers, in combination with ACE-i + diuretics if persisting symptoms • AF, to slow AV conduction • Dose 0.125 to 0.250 mg / day

35. Digoxin. Contraindications* • Digoxin toxicity • Advanced A-V block without pacemaker • Bradycardia or sick sinus without PM • PVC’s and VT • Marked hypokalemia • W-P-W with atrial fibrillation

36. Aldosterone Inhibitors ALDOSTERONE Spironolactone - Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) • Retention Na+ • Retention H2O • Excretion K+ • Excretion Mg2+ • Collagen • deposition • Fibrosis • - myocardium • - vessels Edema Arrhythmias

37. Mineralocorticoid/aldosterone receptor antagonists * Spironolactoneandeplerenoneblockreceptorsthatbindaldosterone andothercorticosteroids, andarebestcharacterized as MRAs.

38. Spironolactone. Practical use * • Do not use if hyperkalemia, renal insuf. • Monitor serum K+ at “frequent intervals” • Start ACE-i first • Start with 25 mg / 24h • If K+ >5.5 mmol/L, reduce to 25 mg / 48h • If K+ is low or stable consider 50 mg / day • New studies in progress

39. Other Drugs. (only in selectedpatients)* • Inotropics: refractory HF • Nitrates: ischemia, angina, pulmonary congestion • ARB: Contraindications to ACE-i • Antiarrhythmics: (only amiodarone) H risk arrhyth. • Anticoagulants: High risk of embolysm • Ca channel blockers: (only amlodipine) ischemia

40. Angiotensin II Receptor Blockers (ARB) RENIN Angiotensin IANGIOTENSIN II Angiotensinogen ACE Other pathways AT1 Receptor Blockers RECEPTORS AT1 AT2 Vasoconstriction Proliferative Action Vasodilatation Antiproliferative Action

41. Angiotensin II Receptor Blockers (ARB) • Candesartan, Eprosartan, Irbesartan Losartan, Telmisartan, Valsartan • Efficacy not equal / superior to ACE-I • Not indicated with beta blockers • Indicated in patients intolerant to ACE-I AHA / ACC HF guidelines 2001 ESC HF guidelines 2001

42. Vasodilators Venous Vasodilatation VENOUS Nitrates Molsidomine MIXED Calcium antagonistsa-adrenergic Blockers ACE-I, ARBs K+ channel activators Nitroprusside ARTERIAL Minoxidil Hydralazine Arterial Vasodilatation

43. • Cardiac output• Blood pressure NITRATESHEMODYNAMIC EFFECTS 1- VENOUS VASODILATATION Preload2- Coronary vasodilatation Myocardialperfusion 3- Arterial vasodilatation Afterload 4- Others Pulmonary congestionVentricular sizeVent. Wall stressMVO2

44. Nitrates. Clinical Use • CHF with myocardial ischemia • Orthopnea and paroxysmal nocturnal dyspnea • In acute CHF and pulmonary edema:NTG sl / iv • Nitrates + Hydralazine in intolerance to ACE-I (hypotension, renal insufficiency)

45. IVABRADIN* • Ivabradine is a drug that inhibits the If channel in the sinus node. Its only known pharmacological effect is to slow the heart rate in patients in sinus rhythm (it does not slow the ventricular rate in AF). • Should be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤35%, a heart rate remaining ≥70 b.p.m., and persisting symptoms (NYHA class II–IV) despite treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose below that), ACE inhibitor (or ARB), and an MRA (or ARB)

46. Positive Inotropes • Digitalis • Sympathomimetics • Catecholamines • B-adrenergic agonists • Phosphodiesterase inhibitors • Amrinone, Milrinone, Enoximone • Calcium sensitizers • Levosimendan, Pimobendan

47. Positive Inotropic Therapy* • May increase mortality Exception: Digoxin, Levosimendan • Use only in refractory CHF • NOT for use as chronic therapy

48. Drugs to Avoid (may increase symptoms, mortality) • Inotropes, long term / intermittent • Antiarrhythmics (except amiodarone) • Calcium antagonists (except amlodipine) • Non-steroidal antiinflammatory drugs (NSAIDS) • Tricyclic antidepressants • Corticosteroids • Lithium ESC HF guidelines 2001

50. NEW DRUGS (ongoing research) 1.New neurohormonal modulators 2. New inotropics 3. Gene therapy 4. Myocyte transplant and mitosis 5. Neoangiogenesis / Growth factors