1 - Therapeutics Of Chronic Heart Failure Spring 2019.docx

Therapeutics of Heart Failure A. Tatachar, 2019

Therapeutics of Chronic Heart Failure Spring 2019 Amulya Tatachar, PharmD, BCACP Learning Objectives 1. Justify the role of therapies used in chronic HF management, including pharmacologic effects, place in therapy, and impact on outcomes. 2. Recall initial and target dosing of heart failure medications based on most recently revised guidelines by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) and literature supporting these recommendations. 3. Discuss causes and management of diuretic resistance. 4. Discuss the efficacy, safety, and patient education relevant to each therapy used in management of HF. 5. Discuss outcomes of the following landmark trials: PARADIGM-HF, ATLAS, MERIT-HF, RALES, EMPHASIS-HF, and SHIFT. 6. Identify and discuss medications not recommended in heart failure patients. 7. Provide evidence-based, patient-centered recommendations to optimize efficacy and tolerability of treatment regimens in patients with HF. I.

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Desired Outcomes a. Improve patient’s quality of life b. Relieve or reduce symptoms c. Prevent or minimize hospitalizations for exacerbations of HF d. Slow progression of disease e. Prolong survival Guidelines a. 2013 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for the Management of Heart Failure b. Numerous large, randomized, double-blinded, multi-center trials guide treatment options in HF c. No randomized trials conducted in HFpEF (based primarily on clinical investigations in relatively small groups of patients, clinical experience, and concepts based on pathophysiology of disease) ACE-Inhibitors a. Pharmacologic effect i. Lowers blood pressure (BP) – decreases afterload ii. Decreases production of angiotensin II – decreases preload and afterload 1. Slows progression of heart failure 2. Reduces ventricular remodeling 3. Lowers aldosterone levels – decreases preload iii. Increases accumulation of bradykinin (decrease preload and afterload) iv. No direct effect on heart rate or contractility b. Place in Therapy i. All patients unless contraindicated c. Impact on Outcomes i. Improves survival ii. Reduces rate of hospitalizations iii. Slows progression of HF iv. Reduce rate of reinfarction d. Agent selection (refer to 2013 ACC/AHA Guidelines Table 15. Drugs Commonly Used For Stage C HFrEF) i. Captopril (Capoten®) 6.25 mg TID – 50 mg TID 1. Shorter acting

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2. Easy to titrate (typically used in hospital settings for titration) 3. Poor compliance (TID dosing) 4. Goal dose: 50 mg TID ii. Enalapril (Vasotec®) 2.5 mg BID – 10 to 20 mg BID 1. Goal dose: at least 10 mg BID, preferred: 20 mg BID iii. Lisinopril (Prinivil®, Zestril®) 2.5 QD – 40 mg QD 1. Starting dose: 2.5 or 5 mg QD 2. Goal/max dose: 20 to 40 mg QD iv. Ramipril (Altace®) 1.25 mg QD – 10 mg QD 1. Goal dose: 10 mg QD 2. Available strengths: 1.25, 2.5, 5, 10 mg tablets v. Dose Titration 1. Start low and titrate appropriately to predetermined target proven to be beneficial in clinical trials (unless doses are not tolerated) e. Adverse Effects i. Angioedema (potentially fatal) ii. Hyperkalemia iii. Cough iv. Renal dysfunction v. Hypotension (dizziness, syncope, lightheadedness) vi. Rash vii. Taste disturbance f. Contraindications i. Serum creatinine > 3.0 g/dL ii. History of angioedema or hyperkalemia iii. Bilateral renal stenosis iv. Severe aortic stenosis v. Pregnancy vi. Labile BP and hypotension (increases risk of cardiogenic shock) g. Monitoring i. Safety 1. Baseline – BUN, SCr, potassium, BP 2. Follow-up (within 1-2 weeks from initiation or dose adjustment) – BUN, SCr, potassium, BP ii. Efficacy 1. Symptoms 2. Imaging h. Evidence i. Numerous placebo-controlled trials involving over 7,000 patients with reduced LVEF documented favorable effects of ACE-I on symptoms, NYHA functional classification, clinical status, hospitalizations, exercise tolerance, quality of life ii. Compared to placebo, fewer treatment failures, hospitalizations, and increases in diuretic dosages iii. Improve survival by 20-30% vs. placebo and benefits maintained throughout therapy iv. ATLAS trial – patients randomized to high-dose lisinopril (32.5-35 mg/day) had significantly lower risk of all-cause death or all-cause hospitalization, than patients randomized to lower dose lisinopril (2.5-5 mg/day). All-cause mortality was similar between the high- and low-dose groups v. Benefits independent of etiology of HF (ischemic vs. non-ischemic) and observed in patients with mild, moderate, or severe symptoms Angiotensin Receptor Blockers (ARBs) a. Introduction i. ACE escape 2

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1. Angiotensin II can be formed in other tissues (e.g., heart) through non-ACE-dependent pathways 2. Increasing circulating angiotensin II and aldosterone with chronic administration of ACE-Inhibitors ii. ARB blocks angiotensin II receptors  attenuates deleterious effects of angiotensin II on ventricular remodeling iii. Less bradykinin  less risk of cough and angioedema iv. Overall: similar clinical benefits with potentially fewer side effects Pharmacologic effects i. Lowers BP – decreases afterload ii. Blocks effects of angiotensin II on angiotensin receptor subtype 1 (AR1) (e.g., vasoconstriction, NE and aldosterone release) iii. Less accumulation of bradykinin iv. No direct effect on heart rate or contractility Place in Therapy i. Patients unable to tolerate ACE-I inhibitors (e.g., uncontrollable cough) 1. Patients who have hyperkalemia, hypotension, renal failure, or angioedema with ACE-I may exhibit similar side effects with ARBs ii. Controversy combining with ACE-I 1. Adding an ARB may be recommended for patients with HF who remain symptomatic despite optimal treatment with ACE-I and beta blockers (unless contraindications are present) and in whom an mineralocorticoid antagonist (MRA) s not indicated or not tolerated 2. Val-HeFT and CHARM-added trial did not show significant benefits but combination therapy was associated with higher risk of hyperkalemia and increases in SCr 3. OVERALL: evidence discourages use of combination therapy (no additional benefits, increased/additive side effects) Impact on Outcomes i. Improves survival ii. Reduces hospitalization iii. Slows progression of HF Agent selection (refer to 2013 ACC/AHA Guidelines Table 15. Drugs Commonly Used For Stage C HFrEF) –three ARBs approved for HF treatment i. Valsartan (Diovan®) 1. Starting dose: 40 mg BID 2. Goal dose: 160 mg BID (titrate every 2 weeks as tolerated to achieve goal dose) 3. Available: 40, 80, 160, and 320 mg tablets ii. Candesartan (Atacand®) 1. Starting dose: 4 or 8 mg QD 2. Goal dose: 32 mg QD 3. Available: 4, 8, 16, 32 mg tablets iii. Losartan (Cozaar®) 25 mg QD – 150 mg QD 1. Goal dose: 50- 150 mg QD Adverse effects i. Similar to ACE-I but may have different frequency ii. Lower incidence of cough Monitoring i. Baseline: BP, renal function, potassium ii. Follow-up (1-2 weeks after initiation or dose adjustment): BP, renal function, potassium Evidence

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i. CHARM (Candesartan in Heart Failure; Assessment of Reduction in Mortality and Morbidity) ii. HEAAL (Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan) iii. VALIANT, ON-TARGET, and Val-HeFT trials - no benefit of combination of ACE-I + ARB Beta-blockers a. Pharmacologic effects i. Slows heart rate 1. Decreases work load on heart 2. Increases ventricular filling which improves cardiac output ii. Decreases force of contraction of the heart in short term (during titration) – improves ventricular contractility in the long term (e.g., 3 months) iii. Lowers BP iv. Anti-arrhythmic properties v. Blocks effects of NE (NE causes tachycardia, vasoconstriction) b. Place in Therapy i. All stable patients unless contraindicated c. Impact on Outcomes i. Improves survival ii. Reduces hospitalization iii. Slows progression of HF (“reverse remodeling”) d. Agent selection (refer to 2013 ACC/AHA Guidelines Table 15. Drugs Commonly Used For Stage C HFrEF) i. Carvedilol (Coreg® & Coreg CR®) 1. Non-selective beta-blocker with alpha-antagonist and antioxidant properties (does not have intrinsic sympathomimetic properties) 2. Metabolized by CYP450 enzymes (mainly CYP2D6) 3. Carvedilol immediate release a. Starting dose: 3.125 mg BID b. Goal dose i. < 85 kg: 25 mg BID ii. > 85 kg: 50 mg BID c. Available: 3.125, 6.25, 12.5, and 25 mg tablets 4. Carvedilol controlled release a. Starting dose: 10 mg QD b. Goal dose: 80 mg QD c. Available: 10, 20, 40, 80 mg tablets d. Do not administer with alcohol (including alcohol-based elixirs) within 2 hours of Coreg CR® 5. Both formulations should be taken with food ii. Extended release Metoprolol succinate (Toprol XL®) 1. Starting dose: 12.5 mg QD 2. Goal dose: 200 mg QD 3. Available: 25, 50, 100, 200 mg 4. Tablets are scored and can be cut (not crushed or chewed) 5. Do not use immediate release metoprolol tartrate (Lopressor®) because not shown to be beneficial in heart failure iii. Bisoprolol (off-label use): 1.25 QD – 10 mg QD iv. Dose Titration 1. Start at lowest dose – lower dose decreases risk of worsening heart failure 2. Slowly titrate to goal dose 3. Can increase dose every 2 weeks if no evidence of clinically significant worsening HF and vitals stable

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4. Assess HR, blood pressure, and clinical status after each titration e. Contraindications/precautions i. Decompensated heart failure 1. Can worsen heart failure if not started and titrated appropriately 2. Slows HR and decreases force of contraction ii. Bradycardia (HR < 60 bpm) iii. Hypotension iv. Sick sinus syndrome v. 2nd or 3rd degree AV block vi. Pulmonary disease (selective vs. non-selective) vii. Hemodynamic instability viii. Fluid overloaded f. Monitoring (within 1 – 2 weeks within initiation, dose adjustments, and periodically once stabilized on a dose) i. Symptoms may worsen initially – should be mild to continue betablockers ii. HR, BP, heart failure symptoms iii. Fatigue (very common) iv. Depression (very common) g. Drug Interactions i. Additive effects with other drugs that reduce HR (e.g., digoxin, verapamil, diltiazem) ii. Additive effects with other drugs that reduce BP h. Pearls i. Beta-blocker still should be given even if symptoms are mild or wellcontrolled with diuretic and ACE-I ii. ACE-I doses does not have to be optimized (e.g., at target dose) to start beta-blocker (addition of beta-blocker likely to be of greater benefit than increase of ACE-I dose) iii. Recommended in asymptomatic patients with reduced LVEF (Stage B) to decrease risk of progression of HF iv. Carvedilol – good therapy for treatment of HTN and HF v. Metoprolol XL – good therapy for treatment of post-MI or atrial fibrillation (AF) and HF vi. More mortality benefit with beta-blockers compared to ACE-I; therefore, important to reach goal/target or max tolerated doses of beta-blocker i. Patient Education i. Important to educate patients that dose titration may be a long, gradual process to achieve target dose ii. Therapy may be delayed if HF symptoms worsen during initiation period iii. Educate patients on the benefit of long-term BB therapy and necessity to continue treatment once symptoms stabilize j. Evidence i. Been studied in over 20,000 patients with systolic heart failure in placebo-controlled trials ii. MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure) – largest beta-blocker mortality trial iii. CIBIS II (Cardiac Insufficiency Bisoprolol Study II) iv. COPERNICUS (Carvedilol, Prospective, Randomized, Cumulative Survival) Diuretics a. Pharmacologic properties i. Decreases volume overload – decreases preload ii. Mildly lowers blood pressure iii. May mildly increase heart rate 5

Therapeutics of Heart Failure A. Tatachar, 2019 iv. No direct effect on ventricular contractility b. Place in Therapy i. Symptoms of volume overload (e.g., pulmonary edema, bilateral pitting edema, weight gain, increased nocturia) c. Impact on Outcomes i. Improve symptoms ii. Improve exercise intolerance iii. Improve quality of life iv. Not shown to improve survival d. Agent selection (dosing may vary; at clinical discretion) (refer to 2013 ACC/AHA Guidelines Table 14. Oral Diuretics Recommended for Use in the Treatment of Chronic HF) i. Furosemide (Lasix®) 1. Least expensive 2. Initial dose: 20 to 40 mg QD or BID 3. Max total daily dose: 600 mg 4. Available: 20, 40, 80 mg tablets ii. Bumetanide (Bumex®) 1. Initial dose: 0.5 to 1.0 mg QD or BID 2. Max total daily dose: 10 mg 3. Available: 0.5, 1, 2 mg iii. Torsemide (Demadex®) 1. Initial dose: 10 to 20 mg QD 2. Max total daily dose: 200 mg 3. Available: 5, 10, 20, 100 mg tablets e. Thiazide-like (refer to 2013 ACC/AHA Guidelines Table 14. Oral Diuretics Recommended for Use in the Treatment of Chronic HF) i. Metolazone (Zaroxolyn®) 2.5 – 10 mg 30 min before loop diuretic ii. Initial dose: 2.5 mg once plus loop diuretic iii. Max daily dose: 10 mg (rarely used this high) iv. Available: 2.5, 5, 10 mg tablets f. Monitoring i. Renal function (BUN, SCr) ii. Electrolytes (K, Mg, Na, Ca) 1. Goal potassium > 4.0 mEq/L a. Hypokalemia – strong independent predictor of mortality in heart failure b. RAAS and sympathetic nervous system induces hypokalemia plus diuretic medications c. ACE-I and aldosterone antagonists mortality benefit is partly due to increased serum potassium and ventricular arrhythmia reduction iii. BP iv. Fluid status 1. Daily morning weights 2. Counseling point: patients who gain 1 lb/day for several consecutive days or 3-5 lbs in a week – contact healthcare provider for instructions (may need to increase diuresis dose temporarily) g. Pearls i. Do not use as monotherapy ii. Use lowest effective dose iii. Bioavailability differs among agents (bioavailability of bumetanide and torsemide 80-100% and furosemide exhibits marked intrapatient and interpatient variability from 10-100%, average 50%) 1. Oral furosemide dose approximately double that of IV dose 6

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a. Furosemide IV to PO conversion – 1:2 (e.g., 20 mg IV = 40 mg PO) 2. IV and oral doses same for torsemide and bumetanide a. Torsemide and Bumetanide IV to PO conversion – 1:1 (i.e., 20 mg IV = 20 mg PO) 3. Furosemide 40 mg (PO) = Bumetanide 1 mg = Torsemide 10 or 20 mg iv. Onset 15-60 minutes; peak effect within 30-90 minutes v. Co-administration of furosemide and bumetanide with food decreases bioavailability, whereas food has no effect on bioavailability of torsemide vi. Reduce dose when patient not volume overloaded h. Diuretic resistance i. Causes 1. Advanced heart failure 2. Renal dysfunction 3. NSAIDs, thiazolidinediones (TZDs) 4. Hyponatremia 5. Hypotension ii. Lifestyle – diet (e.g., fast foods) iii. Metolazone 1. Inhibits sodium reabsorption at cortical diluting segment of nephron when sodium absorption blocked at ascending loop of Henle 2. Creates synergistic diuresis – can be profound (must monitor closely) 3. Preferred to thiazide diuretics – longer duration, does not reduce GFR 4. Not typically used daily due major electrolyte deficiencies Aldosterone antagonist a. Pharmacologic effects i. Mildly lowers BP ii. Inhibit cardiac extracellular matrix and collagen deposition (attenuating cardiac fibrosis, ventricular remodeling) iii. No direct effect on heart rate or contractility iv. Weak diuretic (especially at low doses in HF; not used as a diuretic in HF) v. Potassium sparing (mortality benefit partly due to increased serum potassium) b. Place in Therapy i. NYHA class II to IV HF and who have LVEF < 35% on standard therapy 1. NYHA class II HF should have history of prior cardiovascular hospitalization or elevated plasma natriuretic peptide levels 2. On standard therapy (e.g., ACE-I, beta-blockers) – does not have to be optimal doses of ACE-I/ARB and beta blockers before MRA initiation ii. Following an acute MI in patient who have LVEF < 40% who develop symptoms of HF or who have history of diabetes mellitus, unless contraindicated iii. Eplerenone – consider in patients after acute myocardial infarction (MI) with clinical HF symptoms and LVEF < 40% iv. Do NOT use in patients using ACE-I + ARB concurrently v. No clear guidelines for those who fall outside of the populations studied in clinical trials (mentioned above) c. Impact on Outcomes i. Improves survival ii. Slows progression of HF 7

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iii. Improves symptoms iv. Reduces hospitalizations d. Agent selection i. Spironolactone (Aldactone®) 1. Non-selective aldosterone antagonist 2. Starting dose: 12.5 to 25 mg QD 3. Titrate to 50 mg QD if no AE with progression HF 4. Available: 25, 50, 100 mg tablets ii. Eplerenone (Inspra®) 1. Selective aldosterone antagonist (lower incidence of gynecomastia than spironolactone) 2. Starting dose: 25 mg QD 3. Goal dose: 50 mg QD iii. Renal dose adjustments – refer to 2013 ACC/AHA Heart Failure Guideline: Table 16. Drug Dosing for Aldosterone Receptor Antagonists e. Contraindications i. Spironolactone 1. Anuria 2. CrCl < 10 mL/min 3. Hyperkalemia 4. K + supplements and K+ sparing diuretics ii. Eplerenone 1. CrCl < 30 mL/min all patients 2. CrCl < 50 mL/min in patients with elevated SCr (>1.8 mg/dL in women or 2.0 mg/dL in men) 3. Type 2 diabetes with microalbuminuria iii. Both: Concurrently with ACE-I + ARB (hyperkalemia risk) f. Adverse effects i. Gynecomastia (higher incidence with spironolactone) ii. Hyperkalemia (refer to 2013 ACC/AHA Heart Failure Guideline: Table 17. Strategies to Minimize the Risk of Hyperkalemia in Patients Treated With Aldosterone Antagonists for recommended strategies for reducing risk for hyperkalemia with aldosterone antagonists) iii. Hyponatremia g. Monitoring i. Baseline: renal function, potassium ii. Follow-up: renal function, potassium (3-7 days after initiation, dose adjustment and periodically when stabilized) h. Evidence i. RALES (Randomized Aldactone Evaluation Study) – reduction in allcause mortality, reduced risk of hospitalizations ii. EMPHASIS-HF (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms) iii. EPHESUS (Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction) Digoxin (Lanoxin®, Digitek®, Lanoxicaps®) a. Pharmacologic effects i. Slows HR (increases AV nodal refractoriness) - negative chronotrope (good for atrial fibrillation) ii. Increases ventricular force of contraction – positive inotrope (good for heart failure) b. Place in Therapy i. Systolic heart failure (primarily) – increases contractility ii. Concomitant atrial fibrillation (AF) with HFrEF – negative chronotrope iii. Optimized on ACE-I, beta-blocker, and aldosterone antagonists with symptoms 8

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Impact on Outcomes i. Reduces hospitalizations ii. Improves symptoms iii. Improves exercise tolerance iv. Does not improve survival d. Pearls i. Dosing 1. Most patients will need 0.125 mg – 0.25 mg QD 2. Elderly patients (> 70 years), patients with renal dysfunction, low lean body mass, or patients with interacting drugs (e.g., amiodarone) – 0.125 mg QD or QOD 3. Loading doses of digoxin generally not needed in chronic HF ii. Narrow therapeutic range 1. Monitor digoxin blood levels (goal: 0.5-0.9 ng/mL) 2. Concentration ≥ 2.5 ng/mL, ~50% will experience digoxin toxicity 3. Blood levels may be different in various disease states 4. Not necessary to monitor routinely unless suspected digoxin toxicity, worsening renal function, interacting drug, or other conditions that may affect blood levels iii. Toxicity 1. Causes: hypokalemia, hypomagnesemia, and hypercalcemia 2. Treatment - DigiFab® e. Pharmacokinetics i. 2-compartment model (distributes rapidly into small volume of distribution, then distributes into larger areas like myocardium) ii. Long distribution phase of 8-12 hours iii. Good, rapid oral absorption (dependent on formulation; typically 70-80% bioavailability) iv. Obtain digoxin levels after digoxin has distributed to myocardium (6 – 12 hours after oral dose, 4 hours after IV dose) v. Primarily renally eliminated (~75%) vi. Low protein binding (~25%) vii. Elimination half-life ~ 30-40 hours (prolonged in elderly, patients with heart failure, patients with renal dysfunction) f. Adverse effects i. Bradycardia ii. Heart block iii. Arrhythmias (combination of potassium abnormalities + digoxin  arrhythmia) iv. Visual disturbances (e.g., halos, green + yellow appearance) v. Fatigue, weakness vi. Confusion, psychosis vii. Potassium abnormalities (low or high) g. Drug Interactions i. Pharmacokinetic 1. Digoxin – substrate p-glycoprotein (energy-dependent drugefflux pump) a. Inhibitors of p-glycoprotein: amiodarone, diltiazem, verapamil, propafenone ii. Pharmacodynamic 1. Drugs affecting HR (e.g., verapamil, diltiazem, beta-blockers, amiodarone, anti-arrhythmics drug) 2. Drugs affecting potassium levels (e.g., diuretics, ACE-I, aldosterone antagonists) a. Digoxin becomes more toxic if potassium levels are low or high (increases risk of fatal arrhythmias) 9

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iii. Miscellaneous 1. Antacids – decreases digoxin absorption (administer separately) 2. Licorice – interferes with digoxin assay h. Monitoring (within 1-2 weeks of initiation) i. HR ii. Symptoms iii. Potassium iv. Renal function v. Digoxin levels (2 weeks from initiation, dose adjustments, and at least annually) i. Evidence i. DIG (Digitalis Investigation Group) ii. PROVED (Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure) iii. RADIANCE (Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors) Hydralazine/isosorbide combination a. Pharmacologic effects i. Nitrate – venodilator  reduce preload ii. Hydralazine – arterial dilator  reduce afterload b. Place in Therapy i. Combination of hydralazine and issorbide dinitrate (ISDN) recommended for African Americans with HFrEF who remain symptomatic despite concomitant optimal use of ACE-I, BB, (and aldosterone antagonist) ii. Current or prior symptomatic HFrEF who cannot be given ACE-I or ARB because of drug intolerance, hypotension, renal insufficiency, unless contraindicated c. Impact on Outcomes (African American population) i. Reduces mortality ii. Reduces hospitalizations iii. Improves quality of life iv. Potentially slows progression of HF d. Agent selection i. Bidil® - combination of hydralazine 37.5 mg and isosorbide dinitrate 20 mg 1. Starting dose: 1 tablet TID 2. Max dose: 2 tablets TID ii. Hydralazine 75 mg TID and isosorbide dinitrate (ISDN) 1. Start low and titrate to goal doses 2. Initial: Hydralazine 25 to 50 mg TID or QID and ISDN 20 to 30 mg TID or QID 3. Max dose: Hydralazine 300 mg QD divided doses and ISDN 120 mg daily in divided doses 4. Available a. Hydralazine: 10, 25, 50, 100 mg tabs (not scored; difficult to cut) b. ISDN – 20, 40 mg tabs (many available strengths) iii. Dosing 1. Repeated administration of nitrates result in diminished relaxation of smooth muscle in blood vessels, tolerance, and unwanted side effects (e.g., hypotension, headache) 2. Tolerance develops quickly but wears off after a brief nitrate-free interval (10-12 hours for short-acting and 15 to 17 hours for sustained release) in 24-hour period, maintaining effectiveness of treatment 3. Maintain nitrate-free interval 10

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4. Example: Administer sustained release at 8AM and 2PM for twice daily regimen. e. Adverse effects i. Hypotension ii. Headache f. Monitoring i. Adverse effects (hypotension, headache) ii. BP iii. HR g. Evidence i. A-HeFT (African-American Heart Failure Trial) Ivabradine (Corlanor) a. Mechanism of action i. Blocks hyperpolarization-activated cyclic nucleotide-gated (HCN) channel in the sinoatrial node, responsible for the If current ii. Delays diastolic hyperpolarization b. Pharmacologic effects i. Reduces heart rate at rest and during exercise in patients in sinus rhythm ii. Maintains myocardial contractility and atrioventricular conduction c. Place in therapy i. Stable, symptomatic chronic HF with all of the below: 1. EF ≤ 35% 2. In sinus rhythm with resting heart rate ≥ 70 beats per minute 3. Either on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use 4. On standard therapy (beta-blocker, ACE-I or ARB, MRA) 5. Persistent symptoms (NYHA Class II-IV) d. Impact on Outcomes i. Reduces hospitalizations e. Dose i. Initial dose: 5 mg twice daily (2.5 mg twice daily in patients with history of conduction defects or who may experience hemodynamic compromise due to bradycardia) ii. Max dose: 7.5 mg twice daily iii. Titration: After 2 weeks, adjust dose to achieve resting heart rate between 50 and 60 beats per minute. Thereafter, adjust dose as needed based on resting heart rate and tolerability. iv. Take with meals v. Dose adjustments 1. HR > 60 bpm: Increased dose by 2.5 mg twice daily (max: 7.5 mg BID) 2. HR 50 – 60 bpm: Maintain dose 3. HR < 50 bpm or signs and symptoms of bradycardia: decrease dose by 2.5 mg BID; if current dose is 2.5 mg BID, discontinue therapy f. Contraindications i. Acute decompensated heart failure ii. Severe liver impairment iii. Blood pressure < 90/50 mm Hg iv. Resting heart rate < 60 bpm v. Heart rate solely maintained by pacemaker vi. Sick sinus syndrome vii. Sinoatrial block viii. Third degree atrioventricular block ix. Strong inhibitors of CYP3A4 11

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g. Adverse effects i. Bradycardia ii. Hypertension iii. Atrial fibrillation iv. Luminous visual phenomena h. Pregnancy i. Fetal harm may occur ii. Effective contraception is recommended in women of reproductive potential i. Evidence i. SHIFT Study 1. Randomized, double-blind, placebo-controlled, parallel-group study with symptomatic heart failure and LVEF of <35%, in sinus rhythm, HR ≥ 70 bpm, admitted to hospital for heart failure within the previous year, and on stable background treatment, including beta-blocker if tolerated 2. Patients randomly assigned ivabradine titrated to 7.5 mg twice daily vs. placebo 3. 56% patients on beta-blockers treated with at least 50% target doses defined by European Society of Cardiology Guidelines, 26% were at target dose, and11% did not receive beta-blocker due to intolerability or contraindications 4. Low use of devices 5. Cardiovascular deaths or hospital admissions for worsening heart failure occurred in 29% in placebo vs. 24% in ivabradine group (p<0.0001) a. 18% relative risk reduction for cardiovascular death and hospital admission (p < 0.0001) b. Mainly driven by hospital admissions for worsening heart failure (26% relative risk reduction; p< 0.0001) c. All-cause hospital admissions significantly reduced (11% reduction; p = 0.003) d. Cardiovascular death not significantly reduced in ivabradine group 6. Safety: more bradycardia vs. placebo (p<0.0001) 7. Average15 bpm reduction in HR on top of optimal therapy 8. Improved score on health-related quality of life via Kansas Cardiomyopathy Questionnaire (KCCQ) Sacubitril/Valsartan (Entresto) a. Mechanism of action i. Sacubitril: Prodrug that inhibits neprilysin (neutral endopeptidase) through active metabolite LBQ657, leading to increased levels of peptides, including natriuretic peptides 1. Does not degrade biologically inert NT-proBNP, but degrades BNP, C-type natriuretic peptide, and ANP 2. Neprilysin breaks down angiotensin; therefore, require dualacting compound that inhibits both neprilysn and block generation of angiotensin ii. Valsartan: Produces direct antagonism of angiotensin II (AT2) receptors. Displaces angiotensin II from AT1 receptor; antagonizes AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic response b. Pharmacologic effects i. Vasodilation 1. Decrease sympathetic tone 2. Decreases aldosterone levels 12

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3. Decreases fibrosis 4. Decreases hypertrophy 5. Decreases blood pressure ii. Natriuresis/Diuresis Place in therapy i. NYHA Class II-IV with reduced ejection fraction used in place of ACEI or ARB Impact on Outcomes i. Reduces cardiovascular death ii. Reduces hospitalizations Dosing i. Film-coated tablets (sacubitril-valsartan): 24/26 mg, 49/51 mg, 97/103 mg ii. Initial dose: 49/51 mg twice daily 1. Double dose after 2-4 weeks to target maintenance dose of 97/103 mg twice daily, as tolerated by patient iii. Reduce starting dose to 24/26 mg twice daily for patients for: 1. Not currently taking ACEI or ARB or previously taking a low dose of these agents 2. Severe renal impairment 3. Moderate hepatic impairment 4. Double dose every 2-4 weeks to target maintenance dose of 97/103 mg twice daily, as tolerated by patient Contraindications i. Hypersensitivity ii. History of angioedema related to previous ACE-I or ARB therapy iii. Concomitant use with ACE-I iv. Concomitant use with aliskiren in patients with diabetes Adverse effects i. Hypotension ii. Hyperkalemia iii. Cough iv. Renal impairment v. Angioedema Drug Interactions i. ACE-I or ARB ii. Do not use with aliskiren in patients with diabetes - poor outcomes Potassium-sparing diuretics – elevated potassium iii. NSAIDs – renal impairment iv. Lithium – increased risk of lithium toxicity Special populations i. Lactation – breastfeeding or drug should be discontinued ii. Severe hepatic impairment – do not use Monitoring i. Baseline and periodic serum potassium ii. Renal function iii. BP Patient education i. Pregnancy: advise female patients of childbearing age about consequences of exposure to sacubitril-valsartan ii. Angioedema iii. Need 36 hour wash-out period if switching from or to an ACE-I Evidence i. PARADIGM-HF: designed to replace current use of ACEIs and ARBs as the cornerstone of therapy in HFrEF

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1. 7,980 patients with class II-IV heart failure randomized to enalapril 10 mg BID or sacubitril/valsartan 200 mg BID for 21-43 months 2. Reduction in primary outcome, composite of death from CV causes or a first hospitalization for worsening heart failure (p = 0.0000004) (21.8% vs. 26.5%) 3. Reduction in all-cause mortality (13.3% vs. 16.5%) (p < 0.001) 4. No interaction seen between NYHA class and effect on death from CV causes 5. Less cough, lesser incidence of increase in SCr above 2.5 mg/dL in intervention group 6. Study prematurely stopped because prespecified interim analysis showed lower CV mortality in patients randomized to sacubitril-valsartan ii. PARAMOUNT: parallels PARADIGM for HFpEF 1. Randomized, parallel-group, double-blinded in 13 counties on background treatment and ACE-I and ARB discontinued 24 hours prior to randomization 2. Patients with NYHA Class II-III heart failure, LVEF > 45%, NTproBNP > 400 pg/mL randomized to either sacubitril-valsartan 200 mg BID vs. valsartan 160 mg BID x 36 weeks 3. Primary endpoint: reduction in NT pro-BNP from baseline at 12 weeks (p = 0.005) 4. 23% greater reduction in elevated baseline levels of NT pro-BNP vs. valsartan 5. Greater improvements in left atrial size and NYHA class independent of BP reduction 6. Need to translate this finding into improve outcomes 7. Hypothesis-generating trial that provided rationale for larger outcomes trial, PARAGON-HF iii. PARAGON-HF: comparing vs. valsartan 160 mg BID 1. 4300 patients with symptomatic HF with HFpEF in 37 countries 2. On-going trial Anticoagulation a. Controversial topic b. Typically use anticoagulants in heart failure plus an indication (e.g., atrial fibrillation, deep vein thrombosis/pulmonary embolism, mechanical valve replacement) c. Routine use of aspirin (ASA) not recommended in heart failure, unless indicated for a condition independent of heart failure Calcium Channel Blockers a. Pharmacologic effects i. Vasodilator ii. Slows heart rate – verapamil, diltiazem iii. Decreases contractility – verapamil, diltiazem b. Patient population – not recommended in routine treatment for patients with HFrEF c. Agent selection i. Dihydropyridines (extended release nifedipine, felodipine, amlodipine) 1. Benefit not established in systolic heart failure 2. Adverse effects - peripheral edema a. Not related to fluid (does not cause fluid overload) b. Will interfere with accurate assessment of fluid status ii. Non-dihydropyridine (diltiazem, verapamil) 1. Systolic heart failure – can worsen (avoid diltiazem, verapamil) 2. Diastolic heart failure – unclear (not adequately studied) 14

Therapeutics of Heart Failure A. Tatachar, 2019 XIV.

XV.

XVI.

Dangerous medications in heart failure a. NSAIDs and COX-2 Inhibitors – hypervolemia/fluid retention i. Inhibits vasodilatory prostaglandins  vasoconstriction (increase afterload) ii. Inhibition of prostaglandins (specially, renal prostaglandins)  fluid retention 1. Reduces renal blood flow  may contribute to “diuretic resistance” 2. Prostaglandins in distal tubules responsible for sodium and water homeostasis – inhibition leads to sodium and water reabsorption (clinically significant in heart failure vs. healthy patients) 3. Leads to symptomatic fluid overload b. Metformin i. Possible reduced clearance of lactic acid in heart failure + possible reduced clearance of lactic acid with metformin use  additive risk of lactic acidosis (increased lactic acid concentrations) ii. Lactic acidosis  50% mortality c. Thiazolidinediones (TZD; pioglitazone, rosiglitazone) – hypervolemia/fluid retention i. Caution – NYHA Class I, II ii. Contraindication – NYHA Class III, IV d. Non-dihydropyridine calcium channel blockers (verapamil, diltiazem) – worsening of HF (weakens ventricular contraction) e. TNF-alpha antagonist (etanercept, infliximab, adalimunab) i. Used in immunologic mediated rheumatic disease (e.g., rheumatoid arthritis) ii. May increase mortality & hospitalizations (Phase II trial of infliximab in patients with HF) iii. 47 new cases of heart failure with 3-4 months after initiation of TNFalpha antagonist (Ann Intern Med 2003; 138:807-811) f. Serotonin agonists – “triptans” i. Indicated for migraines ii. Vasoconstriction  increase afterload Non-pharmacologic Interventions a. Devices – reduce death (reduces sudden cardiac death and improve overall cardiovascular function) i. Implantable cardiac defibrillators (ICD) ii. Pacemakers iii. Cardiac Resynchronization Therapy b. Lifestyle modifications i. Low salt-diet (no more than 2 grams/day) 1. Conflicting evidence regarding salt intake but below points are what is usually followed in clinical practice 2. Suggest salt substitute (caution: may cause excess potassium intake) 3. Offenders: canned soup/vegetables/meals, potato chips, processed meats, taco seasoning, soy sauce, fast food ii. Restriction of fluid intake (2 liters/day) (fluid includes: water, clear liquids, milk, ice cream, yogurt, jello, pudding, soups) iii. Avoid alcohol iv. Supervised exercise (cardiac rehab) Treatment based on ACCF/AHA Stages a. Stage A (do not have structural disease or HF symptoms but are at high risk for developing HF because of presence of risk factors) i. Risk factor identification and modification (prevent development of structural heart disease and subsequent HF) 15

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1. Risk factors: HTN, dyslipidemia, diabetes, obesity, metabolic syndrome, smoking, coronary artery disease 2. Effective control of both systolic and diastolic BPs reduce risk of developing HF by 50% 3. Diabetic control minimizes risk of end-organ damage ii. ACE-I or ARBs recommended for HF preventions in patients with vascular risk factors b. Stage B (structural disease, but do not have HF symptoms) i. Includes left ventricular hypertrophy, recent or remote MI, valvular disease, reduced LVEF (< 40%) ii. ACE-I or ARBs + beta-blockers (if indicated, e.g., MI regardless of LVEF or reduced LVEF with no symptoms) c. Stage C (structural heart disease and previous or current HF symptoms) i. ACE-I or ARB and beta-blocker – standard therapy for all patients unless contraindicated ii. Loop diuretics for all volume overloaded iii. Persistently symptomatic African Americans, NYHA class III-IV on standard therapy – add hydralazine-nitrates iv. NYHA class II-IV, add aldosterone antagonist if remains symptomatic despite standard therapy v. Non-pharmacologic – ICD, cardiac resynchronization therapy d. Stage D (refractory symptoms at rest despite maximal medical therapy) i. Most advanced form of HF ii. Therapies include mechanical circulatory support, continuous IV positive inotropic therapy, and cardiac transplantation in addition to standard treatments in Stages A to C iii. Management of fluid status is challenging (may need combination of loop + thiazide, mechanical methods of fluid removal) iv. Less tolerant to ACE-I (hypotension, worsening renal insufficiency) due high levels of neurohormonal activation to maintain circulatory homeostasis v. End-of-life care discussion should begin Evidence-Based Pharmacotherapy for HFpEF (Refer to 2013 ACCF/AHA Heart Failure Guideline Table 21. Recommendations for Treatment of HFpEF for entire recommendations) a. No completed randomized trials studying HFpEF b. Future study – PARAGON (currently an ongoing clinical trial)

Recommendations Systolic and diastolic blood pressure should be controlled according to published clinical practice guidelines Diuretics should be used for relief of symptoms due to volume overload Use of beta-blocking agents, ACE-I, and ARBs for hypertension in HFpEF ARBs might be considered to decrease hospitalizations in HFpEF Nutritional supplementation* is not recommended in HFpEF

Recommendation Grade B C C C C

*Coenzyme 10, carnitine, taurine, antioxidants, etc. Strength of recommendations: A, randomized controlled clinical trials; B, cohort and case control studies based on observations from observational studies or registries, post hoc, subgroup, and metaanalysis; C, expert opinion, epidemiologic findings from observational studies, and safety findings from large-scale use. XVIII.

Summary Points

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a. Chronic treatment in HF should include: appropriate doses of ACE-I and betablocker unless patients have contraindications b. Symptomatic fluid overload are treated with loop diuretics (do not give loop diuretics as monotherapy) c. Patients with advanced heart failure (NYHA II - IV) should be given aldosterone antagonist unless patient has contraindications (CrCl < 30 mL/min; K > 5.0 mEq/L) d. Digoxin should be reserved for patients with systolic heart failure on the above treatments (ACE-I, beta-blockers, diuretics, spironolactone [?], and remains symptomatic unless patient has contraindications) e. Black patients should be appropriately up-titrated ACE-I and beta-blockers. Once on stable doses of ACE-I and beta-blockers, black patients should be started on Bidil or hydralazine/isosorbide dinitrate combination f. Educate patients on the medications and lifestyle modifications (e.g., low sodium diet) i. Most common cause of decompensated heart failure – medication nonadherence ii. 2nd most common cause of decompensated heart failure – dietary nonadherence g. Closely monitor all medications for safety and effectiveness (before and during treatment) i. Laboratory monitoring (potassium, SCr, BUN, magnesium, calcium, uric acid) ii. Blood pressure iii. Heart rate (resting heart rate: 55-60 beats per minute) iv. Fluid overload symptoms 1. Shortness of breath 2. Nocturia 3. Weight gain a. Daily weights b. Undressed c. Same time, same scale d. Log book 4. Orthopnea (number of pillows) 5. Paroxysmal nocturnal dyspnea (PND) 6. Cough 7. Lower extremity edema 8. Anorexia 9. Ascites h. Medication reconciliation - look for dangerous medications (e.g., NSAIDs, COX-2 inhibitors, TZD) Potential therapies in HF a. Regenerative medicine b. Stem-cell study: PreSERVE-AMI c. Spinal cord stimulation to modify sympathetic tone – study: Defeat-HF d. Injection of hydrogel into left ventricular myocardium – study: AUGMENT HF

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