Systolic Heart Failure: Medical Therapy Laura Wexler MD, FAHA, FACC Adj. Professor of Medicine/Cardiology University of Cincinnati College of Medicine Department of Veterans Affairs Medical Center

Goals of therapy Treatment of acute exacerbation – Diuretics are the main stay of therapy Aims of long-term therapy Prolong survival Decrease morbidity Improve quality of life / functional status Improve cardiac function Prevent re-hospitalization

New York Heart Association Functional Classification of Heart Failure I. Symptoms only at levels that would limit normal people. II. Slight limitation: fatigue, dyspnea with normal exertion: eg., 2 flights III. Marked limitation: comfortable at rest but minor activity causes symptoms: eg., walking on level ground. IV. Symptoms at rest: unable to carry out any activity without discomfort Prognosis (1 y mortality) NYHA Class II: 5-10% NYHA Class IV: 50%

Stages of CHF Stage A: High risk for HF, but no structural heart disease or symptoms. Stage B: Heart disease with asymptomatic LV dysfunction. Stage C: Current or history of prior symptomatic CHF Stage D: Advanced heart disease and severe or refractory symptoms.

Stages in the development of HF and recommended therapy by stage. Stages in the development of HF and recommended therapy by stage. ACEI indicates angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin-receptor blocker; CAD, coronary artery disease; CRT, cardiac resynchronization therapy; DM, diabetes mellitus; EF, ejection fraction; GDMT, guideline-directed medical therapy; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HRQOL, health-related quality of life; HTN, hypertension; ICD, implantable cardioverter-defibrillator; LV, left ventricular; LVH, left ventricular hypertrophy; MCS, mechanical circulatory support; and MI, myocardial infarction. Adapted from Hunt et al.38 Clyde W. Yancy et al. Circulation. 2013;128:e240-e327 myamericanheart.com Copyright © American Heart Association, Inc. All rights reserved.

Compensatory Mechanisms in CHF: Neurohormonal activation Renin-angiotensin-aldosterone system Vasopressin (ADH) Sympathetic nervous system

How do these effects “compensate” for the effects of CHF? Salt and water retention (preload) recruits “Starling effect” to preserve CO. Increased sympathetic nervous system activity increases HR and contractility to maintain CO. Increased systemic vascular resistance in peripheral beds shunts perfusion to more critical vascular beds in brain, heart, and kidney.

BUT...deleterious effects of “compensatory mechanisms”… Increased pre-load creates volume overload, leads to pulmonary congestion. Increased SNS activation Tachycardia: increases MVO2, limits diastolic filling. Vasoconstriction increases afterload… impairs ejection fraction, increases MVO2 Chronic sympathetic stimulation leads to beta receptor dysregulation

ACE INHIBITORS Decrease mortality by about 17% Reduce hospitalization by ~ 30%. Benefits seen in patients with mild, moderate and severe CHF. May improve EF. Cough is a common side effect (up to 20%); angioedema is less common (<1%). Contraindications: If pregnant or plan to become pregnant Bilateral renal artery stenosis Hyperkalemia (K > 5.5) Renal insufficiency (Sr. Cr > 3) Yancy CW, Jessup M, Bozkurt B. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239.

ACEi initiation and maintenance No differences among the available ACE inhibitors Initiate at low doses and gradually increase dose in 1-2 week intervals Monitor renal function in 1-2 weeks after initiation or increase in dose and periodically thereafter Avoid hypovolemia (excessive diuretic use) Uptitrate to doses shown to reduce CV events in clinical trials (dose NOT determined by symptoms) Watch for: Hypotension (first dose response) Worsening renal function (up to 30% increase in creatinine from base line is acceptable) Cough, hyperkalemia, angioedema (can occur at any time). Yancy CW, Jessup M, Bozkurt B. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239.

ACEi commonly used in HFrEF ACE inhibitor Initial daily dose Maximum dose Mean dose achieved in clinical trials Captopril 6.25 mg 3 times 50 mg 3 times 122.7 mg/day Enalapril 2.5 mg twice 10 to 20 mg twice 16.6 mg/day Lisinopril 2.5 to m mg once 20 to 40 mg once 32.5 to 35 mg/day Ramipril 1.25 to 2.5 mg once 10 mg once Fosinopril 5 to 10 mg once 40 mg once Yancy CW, Jessup M, Bozkurt B. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239.

ANGIOTENSIN RECEPTOR BLOCKERS Primarily used in patients with ACEi intolerance related to cough. Reduced mortality or HF hospitalizations by 17% in ACEi intolerant patients (CHARM Alternative) over a mean follow up of 34 months. Have similar effects as ACEi on renal function, blood pressure and potassium. Patients intolerant of ACEi due to angioedema can be tried on ARBs as risk of recurrent angioedema is low….but should be instituted with careful monitoring. 3 patients out of 39 ACEi intolerant patients b/o angioedema developed angioedema with Candesartan in CHARM Alternative trial and only one had to stop Candesartan. No angioedema occurred in patients intolerant of ACEi b/o other reasons) Yancy CW, Jessup M, Bozkurt B. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239.

Beta Adrenergic receptor blockers Reduce risk of death (34%) Reduce hospitalizations (41%) May improve EF. Usually do NOT improve symptoms initially. Beta blockers with proven mortality benefit in HFrEF Carvedilol Bisoprolol Sustained release metoprolol succinate (Toprol XL) Not a class effect (unlike ACEi) Bucindolol lacked uniform effectiveness across different populations Short acting Metoprolol tartrate was less effective Nebivolol did not reduce mortality In new onset heart failure DO NOT initiate beta-blockers until the patient is euvolemic or near euvolemic Though there was a modest effect on combined end point of all-cause mortality or cardiovascular hospitalizations; however the population included Yancy CW, Jessup M, Bozkurt B. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239.

Beta Blockers: Initiation and Maintenance General considerations Should be initiated in all patients with HFrEF, unless contraindicated or unable to tolerate. Reactive airway disease or bradycardia are not contraindications. Initiate at low doses Initiation & Titration Up-titrate gradually, generally no sooner than at 2 week intervals Uptitrate to doses shown to be effective in clinical trials (carvedilol 25-50bid, metoprolol succinate 200 QD.) Aim to achieve target dose in 8-12 weeks Maintain at maximum tolerated dose If symptoms worsen or other side effects appear Adjust dose of diuretic or concomitant vasoactive med Continue titration to target after symptoms return to baseline If up-titration continues to be difficult Prolong titration interval Reduce target dose Consider referral to a HF specialist NOTE THAT SPECIFIC LANGUAGE OF RECOMMENDATIONS SHOULD BE CONSULTED.

Beta blockers Beta blockers should be continued in most patients experiencing a symptomatic exacerbation of HF unless they develop cardiogenic shock, refractory volume overload, or symptomatic bradycardia. Avoid abrupt withdrawal In new onset heart failure DO NOT initiate beta-blockers until the patient is euvolemic or near euvolemic. In patients taking a low dose of an ACE inhibitor, the addition of a beta blocker produces a greater improvement in symptoms and reduction in the risk of death than does an increase in the dose of the ACE inhibitor, even to the target doses used in clinical trials Usually diuretics are needed to maintain sodium and fluid balance and prevent the exacerbation of fluid retention that can accompany the initiation of beta-blocker therapy Yancy CW, Jessup M, Bozkurt B. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239.

Aldosterone receptor antagonists 30% reduction in all-cause mortality 35% reduction in HF hospitalizations Recommended in patients with NYHA Class II-IV HF who have LVEF < 35% following acute MI who have LVEF < 40% and develop HF symptoms or have DM Initiation and maintenance: Spironolactone 12.5 to 25 mg daily (GFR > 50) or 12.5 mg once daily or every other day (GFR 30-49) Eplerenone 25 mg daily (GFR > 50) or 25 mg every other day (GFR 30-49) Can be increased to maintenance dose after 4 weeks if K+ is consistently < 5 mEq/L DO NOT initiate in patients with any of the following Serum K+ > 5 mEq/L Serum creatinine > 2.5 mg/dL (men) or 2.0 mg/dL (women) eGFR < 30 mL/min/1.73 m2 3 patients out of 39 ACEi intolerant patients b/o angioedema developed angioedema with Candesartan in CHARM Alternative trial and only one had to stop Candesartan. No angioedema occurred in patients intolerant of ACEi b/o other reasons) Yancy CW, Jessup M, Bozkurt B. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239.

Hydralazine + Nitrates Fixed dose combination of hydralazine + Isosorbide dinitrate showed incremental benefit when added to standard therapy including ACEi + BB for patients self-described as African Americans with NYHA class III–IV HFrEF receiving optimal therapy with ACE inhibitors (Class I, LOE: A) 43% mortality reduction compared to placebo(A-HeFT trial) The combination of hydralazine and isosorbide dinitrate is best alternative in patients who are intolerant of ACE inhibitor or ARB because of hypotension, hyperkalemia or renal insufficiency. Titration: START LOW, aim for clinical trial doses: 200 mg/day hydralazine, 60 mg/day isosorbide. Hydralazine is short acting and can be uptitrated fairly quickly. Hypotension is main limitation. Yancy CW, Jessup M, Bozkurt B. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239.

Digoxin for HFrEF Digoxin can be beneficial in patients with HFrEF to decrease hospitalizations for HF1 Has no survival benefit1,2 Increased mortality in women3,4 Useful for rate control in patients with acute or chronic systolic heart failure and atrial fibrillation in whom beta-blockers are contraindicated/limited. 1. Yancy CW, Jessup M, Bozkurt B. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239. 2. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525-534 3. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347:1403-1411 4. Adams KF Jr, Patterson JH, Gattis WA, O'Connor CM, Lee CR, Schwartz TA, Gheorghiade M . Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis. JACC, Volume 46, Issue 3, 2 August 2005, Pages 497-504

Ivabradine: Slows HR in NSR without lowering BP TWO NEW DRUGS: Ivabradine: Slows HR in NSR without lowering BP Sacubitril/valsartan: ARB plus naprolysin inhibitor : ARNI (EntrestoR) 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America

IVABRADINE Reduces sinus rate WITHOUT reducing blood pressure. Improved composite outcome, primarily re-hospitalization rate. Indication: HFrEF with EF</= 35% Class II-IV CHF on optimal therapy including max. tolerated beta blocker Persistent resting heart rate in NSR >70 bpm .

Sacubitril/valsartan (Entresto) In patients with mild-to moderate HFrEF (elevated BNP or recent hospitalization), reduced hospitalizations and mortality compared with enalapril in doses known to improve outcomes in previous landmark clinical trials. Has been approved for patients with symptomatic HFrEF and is intended to be substituted for ACE inhibitors or ARBs. Use of an ARNI is associated with hypotension and a low-frequency incidence of angioedema. Must withdraw ACE-I 36 hours prior to initiating ARNI.

Primary prevention ICD Prophylactic ICD placement: Patients with LVEF ≤35% and mild to moderate HF symptoms (NYHA Class II-III) whether or not they have ever had significant ventricular ectopy or SCD. Decision should be made ideally after 3-6 mos. of optimal medical therapy. Decision must include consideration of functional status, age, prognosis based on severity of underlying HF and comorbid conditions…..as well as patient preference. Recent data suggests ICD primarily effective in patients with ischemic HFrEF…watch for changes in recommendations for patients with non-ischemic HFrEF. Before placement, LV function should be re-assessed, ideally after 3-6 months of optimal medical therapy. Adapted from:

Device Therapy: Cardiac resynchronization therapy (CRT / CRT-D) Indicated in pts with EF < 35% and QRS > 120ms and symptoms despite optimal medical therapy. Can improve quality of life and decrease hospitalizations and mortality Yancy CW, Jessup M, Bozkurt B. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239.

DO NOT FORGET! -Exercise - Cardiac rehab -Diagnosis and treatment of depression -Diagnosis and treatment* of sleep apnea (30-70% prevalence in HFrEF). *OSA: CPAP Central sleep apnea: Best treatment not yet defined. Provide nocturnal O2 for patients who desaturate at night.