HFrEF : ANSWERS YOU NEVER GET TO QUESTIONS YOU ALWAYS ASK

1. BART COX, M.D., FACC DIRECTOR, ADVANCED HEART FAILURE PROGRAM ASSOCIATE PROFESSOR OF MEDICINE UNIVERSITY OF NEW MEXICO SCHOOL OF MEDICINE HFrEF: ANSWERS YOU NEVER GET TO QUESTIONS YOU ALWAYS ASK

2. DISCLOSURES • NONE

3. WHAT IS THE DEFINITION OF HEART FAILURE?

4. HEART FAILURE (HF) • A complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood

5. HEART FAILURE WITH REDUCED EJECTION FRACTION (HFrEF) HF with LVEF < 40%

6. HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF) HF with LVEF > 50%

7. HEART FAILURE WITH PRESERVED EJECTION FRACTION, BORDERLINE HF with LVEF 41-49%

8. HEART FAILURE WITH PRESERVED EJECTION FRACTION, IMPROVED • HFpEF + LVEF previously < 40% that is now > 40%

9. NEW YORK HEART ASSOCIATION FUNCTIONAL CLASS • NYHA I: Ordinary physical activity does not cause symptoms of HF • NYHA II: Ordinary physical activity results in symptoms of HF • NYHA III: Less than ordinary physical activity results in symptoms of HF • NYHA IV: Unable to carry on any physical activity without HF symptoms, or symptoms of HF at rest

10. ACCF/AHA STAGES OF HEART FAILURE • A: High risk for HF but without structural heart disease or HF symptoms (e.g., DM, metabolic syndrome, CAD, obesity, hypertension, history of familial CM, or use of cardiotoxin) • B: Structural heart disease but without history of HF signs or symptoms (e.g., asymptomatic valve disease, LVH, reduced LVEF, MI) • C: Structural heart disease + prior / current HF symptoms or signs • D: Advanced HF: Refractory HF requiring specialized interventions (e.g., transplant, MCS, etc)

11. ASYMPTOMATIC LV DYSFUNCTION • LVEF < 40% with NO history of signs and symptoms of HF • If there is ANY history of signs and symptoms of HF, this is NOT asymptomatic LV dysfunction. Must call it HF +NYHA class • NYHA I: no symptoms currently with ordinary activity • NYHA II: symptoms of HF with ordinary activity • NYHA III: symptoms of HF with less than ordinary activity • NYHA IV: symptoms of HF with any activity or at rest

12. ACUTE DECOMPENSATED HEART FAILURE (ADHF) • Also called “Acute Heart Failure Syndromes” • Poor prognosis: mortality 1 year post discharge can be as high as 30% • Subgroups include entities such as HF + Acute Coronary Syndromes, shock, acutely worsening right HF, postoperative HF decompensation, and accelerated hypertension with acutely decompensated HF • Definition: Rapid or gradual development of HF signs and symptoms requiring urgent therapy

13. WHAT IS THE ROLE OF ACE INHIBOITORS?

14. ACEI: THE EVIDENCE • CONSENSUS (Enalapril v. placebo) • SOLVD (Enalapril v. placebo) • SAVE (Captopril v. placebo) • POST MI TRIALS • AIRE • TRACE • ISIS IV • GISSI 3 • CHINESE CAPTOPRIL TRIAL

15. ACE INHIBITORS (ACEI): 2013 ACCF/AHA GUIDELINES • CLASS I • ACE inhibitors are recommended in patients with HFrEF and current or prior symptoms, unless contraindicated, to reduce morbidity and mortality (Level of Evidence A)

16. ACEI: THE ANSWER • Use in all patients with LVEF <40% (both Asymptomatic LV Dysfunction and HFrEF of any NYHA class) • Start with low dose and uptitrate slowly (i.e., every two weeks) after evaluating K, renal function, and orthostasis • Uptitrate to the optimally tolerated dose, with the goal dose same as the dose used in trials

17. WHAT IS THE ROLE OF ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)?

18. ARBs: THE EVIDENCE • Val-HeFT (Valsartan v. placebo) • VALIANT (Valsartan v. Valsartan + Captopril v. Captopril in post MI patients LVEF <35-40% • HEAAL (high dose losartan v. low dose losartan) • CHARM ADDED (Candesartan v. placebo) • CHARM ALTERNATIVE (Candesartan v. placebo)

19. ARBs: 2013 ACCF/AHA GUIDELINES • CLASS I • ARBs are recommended in patients with HFrEF with current or prior symptoms who are ACEI intolerant, unless contraindicated, to reduce morbidity and mortality (Level of Evidence A)

20. ARBs: 2013 ACCF/AHA GUIDELINES • CLASS IIa • ARBs are reasonable to reduce morbidity and mortality a alternatives to ACEI as first-line therapy for patients with HFrEF, especially for patients already taking ARBs for other indications, unless contraindicated (Level of Evidence A)

21. ARBS: 2013 ACCF/AHA GUIDELINES • CLASS IIb • Addition of an ARB may be considered in persistently symptomatic patients with HFrEF who are already being treated with an ACEI and a beta blocker in whom an aldosterone antagonist is not indicated or tolerated (Level of Evidence A)

22. ARBs: 2013 ACCF/AHA GUIDELINES • CLASS III: HARM • Routine combined use of an ACEI, ARB, and aldosterone antagonist is potentially harmful for patients with HFrEF (Level of Evidence C)

23. ARBs: THE ANSWER • It is recommended to use ARBs in ACEI-intolerant patients (due to cough and PERHAPS angioedema) with NYHA I-IV HFrEF • ARBs are reasonable as alternatives to ACEI as first-line therapy in HFrEF • Only 3 ARBs have been studied in HFrEF (Valsartan, Losartan, and Candesartan) • Uptitrate to the doses used in the trials • If ACEI is contraindicated due to hyperkalemia or renal insufficiency, use nitrate-hydralazine combination. DO NOT USE ARB IN THIS SETTING.

24. WHAT IS THE ROLE OF BETA BLOCKERS?

25. BETA BLOCKERS: THE EVIDENCE • U.S. CARVEDILOL HEART FAILURE STUDY • CAPRICORN (Carvedilol v. placebo) • COPERNICUS (Carvedilol v. placebo) • COMET (Carvedilol v. Metoprolol Tartrate) • CIBIS II (Bisoprolol v. placebo) • MERIT-HF (Metoprolol Succinate CR/XL v. placebo) • SENIORS (Nebivolol v. placebo)

26. BETA BLOCKERS: 2013 ACCF/AHA GUIDELINES • CLASS I • Use of 1 of the 3 beta blockers proven to reduce mortality (i.e., bisoprolol, carvedilol, and sustained-release metoprolol succinate) is recommended for all patients with current or prior symptoms of HFrEf, unless contraindicated, to reduce morbidity and mortality (Level of Evidence A)

27. BETA BLOCKERS: THE ANSWER • Use in all patients with LVEF <40% (both HFrEF and asymptomatic LV dysfunction all NYHA classes • Use only evidence-based beta blockers. Not all beta blockers are alike • Start at low dose and uptitrate slowly (i.e., every two weeks) after evaluating for bradycardia, AV block, hypotension, congestion, and fatigue • Uptitrate to the doses used in the trials. DO NOT STOP UPTITRATING JUST BECAUSE THEY ARE ASYMPTOMATIC!

28. WHAT IS THE ROLE OF DIURETICS?

29. DIURETICS: 2013 ACCF/AHA GUIDELINES • CLASS I • Diuretics are recommended in patients with HFrEf who have evidence of fluid retention, unless contraindicated, to improve symptoms (Level of Evidence C)

30. DIURETICS: THE EVIDENCE • DOSE • Low dose infusion v. low dose intermittent bolus v. high dose infusion v. high dose intermittent bolus in patients with Acute Decompensated Heart Failure

31. DIURETICS: THE ANSWER • Use for symptomatic relief of systemic or pulmonary congestion • Diurese until dry and at the correct rate, then institute maintenance dose • Best strategy for maintenance diuretic is to prescribe a weight-based diuretic dose • Must combine diuretic with a low Na diet • Monitor electrolytes, renal function, and orthostatic symptoms and signs closely

32. WHAT IS THE ROLE OF ALDOSTERONE ANTAGONISTS?

33. ALDOSTERONE ANTAGONISTS: THE EVIDENCE • RALES • Spironolactone v. placebo • EPHESUS • Eplerenone v. placebo • EMPHASIS-HF • Eplerenone v. placebo

34. ALDOSTERONE ANTAGONISTS: 2013 ACCF/AHA GUIDELINES • CLASS I • Aldosterone receptor antagonists (or mineralocorticoid receptor antagonists) are recommended in patients with NYHA class II-IV and who have LVEF of <35%, unless contraindicated, to reduce morbidity and mortality (Level of Evidence A) • Patients with NYHA II should have a history of prior cardiovascular hospitalization or elevated plasma natiuretic peptide levels to be considered for aldosteronereceptro antagonists.

35. ALDOSTERONE ANTAGONISTS: 2013 ACCF/AHA GUIDELINES • CLASS I • Creatinine should be <2.5 mg/dL in men or <2.0 mg/dL in women (or estimated GFR > 30 mL/min/1.73 sq. meters), and potassium should be < 5.0 mEq/L. • Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely followed thereafter to minimize risk of hyprekalemia and renal insufficiency

36. ALDOSTERONE ANTAGONISTS: 2013 ACCF/AHA GUIDELINES • CLASS I • Aldosterone receptor antagonists are recommended to reduce morbidity and mortality following an acute MI in patients who have LVEF of <40% who develop symptoms of HF or who have a history of DM, unless contraindicated (Level of Evidence B)

37. ALDOSTERONE ANTAGONISTS: 2013 ACCF/AHA GUIDELINES • CLASS III • Inappropriate use of aldosterone receptor antgonists is potentially harmful because of life-threatening hyperkalemia or renal insufficiency when serum creatinine is > 2.5 mg/dL in men or> 2.0 mg/dL in women (or estimated glomerular filtration rate < 30 mL/min/1.73 sq. meters) (Level of Evidence B)

38. ALDOSTERONE ANTAGONISTS: THE ANSWER • Use to reduce mortality and morbidity in NYHA II-IV HFrEF + LVEF <35% + already on ACEI (or ARB) and evidence beta blocker • Start in NYHA II HFrEF only if BNP is elevated or previous CV hospitalization • Use post-MI beginning day 3-14 x 1 year (at least) to reduce mortality and morbidity in patients with LVEF<40% + symptoms of HF or presence of DM • Remember the contraindications to aldosterone antagonists, and DO NOT COMBINE ACE + ARB+ ALDOSTERONE ANTAGONIST • Once initiated, check K and renal function 3 and 7 days later, q 1 month x3, then q 3 months thereafter. Restart the cycle with any change of dose of ACEI (or ARB), diuretic, or aldosteroneantanonist

39. WHAT IS THE ROLE OF NITRATE-HYDRALAZINE COMBINATION?

40. NITRATE-HYDRALAZINE COMBINATION: THE EVIDENCE • V-HeFT • ISDN/hydralazine v. prazosin v. placebo • A-HeFT • ISDN/Hydralazine v. placebo

41. NITRATE-HYDRALAZINE: 2013 ACCF/AHA GUIDELINES • CLASS I • The combination of hydralazine and isosorbide dinatrate is recommended to reduce morbidity and mortality for patients self-described as African Americans with NYHA class III-IV HFrEF receiving optimal therapy with ACEI and beta blockers, unless contraindicated (Level of Evidence A)

42. NITRATE-HYDRALAZINE: 2013 ACCF/AHA GUIDELINES • CLASS IIa • A combination of hydralazine and isosorbide dinatrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACEI or ARB because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated (Level of Evidence B)

43. NITRATE-HYDRALAZINE COMBINATION: THE ANSWER • Use the combination to reduce mortality and morbidity in African Americans + HFrEF +NYHA III-IV +already on optimum therapy with evidence-based beta blockers, ACEI (or ARB), and aldosterone antagonist • Use the combination to reduce mortality and morbidity in HFrEF + contraindication to ACEI or ARB (due to hypotension, renal insufficiency, or drug intolerance)

44. WHAT IS THE ROLE OF DIGOXIN?

45. DIGOXIN: THE EVIDENCE • DIGITALIS INVESTIGATION GROUP (DIG) TRIAL • DIGOXIN WITHDRAWAL TRIALS • RADIANCE • PROVED

46. DIGOXIN: 2013 ACCF/AHA GUIDELINES • CLASS IIa • Digoxin can be beneficial in patients with HFrEF, unless contraindicated, to decrease hospitalizations for HF (IIa, Level of Evidence B)

47. DIGOXIN: ANSWER • Digoxin is indicated for HFrEF patients already treated with ACEI (or ARB), evidence based beta blockers, aldosterone antagonist, diuretic, and persistent NYHA II-IV symptoms to reduce rehospitalization • If the patient with HFrEF is stable on digoxin with an appropriate level, do not discontinue • Keep the digoxin level between 0.5-0.9

48. WHAT IS THE ROLE OF ANTICOAGULANTS?

49. ANTICOAGULATION: THE EVIDENCE • WATCH • Warfarin v. aspirin v. clopidogrel • WARCEF • Warfarin v. asppirin

50. ANTICOAGULATION: 2013 ACCF/AHA GUIDELINES • CLASS I • Patients with chronic HF with permanent/ persistent/ paroxysmal AF and an additional risk factor for cardioembolic stroke (history of hypertension, DM, previous stroke or TIA, or > 75 years of age) should receive chronic anticoagulant therapy (Level of Evidence A)