Therapy of HFrEF Student Handout Fall 2024 PDF

Hannah Marie Ferrari, PharmD, BCACP Fall 2024 **About this handout:** This handout is a guide to understanding the pathophysiology of and therapy of Heart Failure with Reduced Ejection Fraction (HFrEF). For our purposes this semester, this handout should be used to prepare for your TBL session on...

Hannah Marie Ferrari, PharmD, BCACP Fall 2024 **About this handout:** This handout is a guide to understanding the pathophysiology of and therapy of Heart Failure with Reduced Ejection Fraction (HFrEF). For our purposes this semester, this handout should be used to prepare for your TBL session on 11/18/24. Prior to that, you will have an introductory lecture on 11/11/24. Therapy of HF with Preserved EF will be covered in lecture on 11/18/24. The focus of our case-based session on 11/18/24 will be treatment of Heart Failure with Reduced Ejection Fraction (treatment section begins on p.12). **Learning Objectives:** 1. Define heart failure (HF); heart failure with reduced ejection fraction (HFrEF). 2. Explain the difference between right sided and left sided heart failure. 3. Compare and contrast left ventricular dysfunction, left ventricular hypertrophy, cardiomyopathy, cardiomegaly and right heart failure. 4. Describe acute heart failure. 5. List the risk factors for developing heart failure. 6. Describe the causes and precipitating events of heart failure. 7. Identify drugs that may exacerbate HF and explain the mechanism. 8. Describe the pathophysiology of heart failure. 9. Summarize the compensatory mechanisms seen in heart failure and their long-term effects. 10. Identify the signs and symptoms of HF. 11. Given a patient history, place the patient in the appropriate NYHA functional class and AHA stage. 12. Describe the incidence of mortality and causes of death associated with HF. 13. Define the management goals of heart failure. 14. Identify the national evidence-based guidelines that define standards for the treatment of HFrEF. 15. Educate a patient regarding the importance of self-care and non-pharmacologic measures to control symptoms of HF. 16. Describe the role in therapy, expected benefit, contraindications, major drug interactions, clinical use (dosing), monitoring (efficacy and toxicity), management of adverse effects, and patient counseling for the medications used in the treatment of HFrEF.\ a. Diuretics\ b. ACE inhibitors\ c. Angiotensin Receptor Blockers\ d. Aldosterone antagonist\ e. Neprilysin inhibitor / ARB\ f. Beta blockers\ f. Digoxin\ g. Hydralazine / Nitrates\ h. Ivabradine i\. Sodium Glucose Cotransporter 2 (SGLT2) inhibitors j\. Soluble guanylyl cyclase stimulators 17. Given a patient with HF with reduced ejection fraction, design a monitoring plan and determine the appropriateness of drug therapy. Supplemental Readings Ng TH, Yeung SL. Heart Failure. In: Chisholm-Burns MA, Schwinghammer TL, Malone PM, Kolesar JM, Bookstaver P, Lee KC. eds. *Pharmacotherapy Principles & Practice, 6e*. McGraw Hill; 2022. **Treatment Guidelines for Heart Failure with Reduced EF** Maddox, T, Januzzi, J, Allen, L. et al. 2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. *JACC*. 2024 Apr, 83 (15) 1444--1488. https://doi.org/10.1016/j.jacc.2023.12.024 Heidenreich P, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. *J Am Coll Cardiol.* 2022 May, 79 (17) e263--e421. https://doi.org/10.1016/j.jacc.2021.12.012 PATHOPHYSIOLOGY OF HEART FAILURE I. Heart Failure A. Pathophysiologic state in which there is a mismatch in myocardial oxygen supply and demand from the body. This can result from impaired ejection of blood to systemic circulation ("systolic heart failure" or heart failure with reduced ejection fraction) or impaired ventricular filling ("diastolic heart failure" or heart failure with preserved ejection fraction). B. Clinical syndrome characterized by a limitation of exercise tolerance due to dyspnea or fatigue and congestion of the pulmonary and/or systemic circulation. Symptoms are all related to hypoperfusion or congestion. C. Epidemiology: 1. Affects nearly 7 million in the U.S.A. and 56 million world-wide. 2. Nearly 960,000 new cases in the U.S.A. per year. 3. Most common medical discharge diagnosis for patients over 65, prevalence increases with age: Increasing incidence because of aging population and improved survival of MI's. 4. Estimated medical expenditures \> \$39.2 billion/year -- medication costs account for the largest out of pocket expenses for patients. 5. 5-year mortality for all patients hospitalized for HF: Approximately 50%. 6. Stage D heart failure: 6-12 month life expectancy. 7. Causes of death: a. Most common cause is sudden cardiac death (40%) b. Progressive heart failure and other causes 8. Readmission after a HF hospitalization: 30-60% within 6 months D. Although a number of medications decrease mortality -- mortality rates remain high. Some basic review: II. Classifications of HF by LVEF HFrEF -- HF with reduced ejection fraction LVEF ≤ 40% -------------------------------------------- --------------------------------------------------------------- HFimpEF -- HF with improved EF Previous LVEF ≤ 40% and a follow up measurement of LVEF \>40% HFmrEF -- HF with mildly reduced EF LVEF 41-49% HFpEF -- HF with preserved EF LVEF ≥ 50% III. Other definitions: IV. Causes of HF -- typically categorized as ischemic or nonischemic in nature. Preserved and reduced EF heart failure share some common etiologies. +-----------------------------------+-----------------------------------+ | **Ischemic cardiomyopathy** | **Nonischemic cardiomyopathy** | | | | | Results from damage to the | Any causes of decreased heart | | myocardium due to lack of blood | function not related to impaired | | supply to the muscle | blood flow | +===================================+===================================+ | - **Coronary artery disease** | - **Hypertension** | | | | | - **Myocardial infarction** | - Pulmonary hypertension | | | | | | - **Valvular disease** | | | | | | - Infections (bacterial, viral, | | | parasitic) | | | | | | - Uncontrolled thyroid disease | | | | | | - Toxins (alcohol, | | | anthracyclines, cocaine, | | | amphetamines) | | | | | | - Pregnancy-related heart | | | disease | | | | | | - Renal failure | | | | | | - Congenital heart disease | | | | | | - Arrhythmias | +-----------------------------------+-----------------------------------+ V. Risk factors for developing HFrEF or HFpEF E. Aging (seen in \> 50% of patients \> 70 years old) F. Hypertension, particularly long-standing, poorly treated hypertension G. Diabetes H. CAD/previous MI I. Obesity J. Family history of cardiomyopathy K. Use of cardiotoxins: Doxorubicin, trastuzamab, amphetamines (cocaine/methamphetamine), alcohol -- particularly in HFrEF VI\. Pathophysiology of HF - primary disturbance in myocardial contractility (concentrating on systolic heart failure) A. Ejection fraction - percent of blood entering the ventricle during diastole that is expelled during systole (normal EF is \> 50%) B. Cardiac output (CO) = heart rate (HR) X stroke volume (SV) = L/min C. HR is controlled primarily by the sympathetic and parasympathetic NS D. SV is dependent on contractility, preload, and afterload 1. Contractility (inotropic state of the heart) is decreased by poorly functioning muscle fibers. Enhanced primarily by sympathetic NS activity. This is the primary dysfunction and leads to the symptoms of inadequate perfusion. 2. Preload - describes force acting from venous side of circulation to affect tension on wall of ventricle during diastole a. Increase in preload / blood volume leads to increased pressure and wall tension in the left ventricle b. Frank-Starling curve - stroke volume vs left ventricular end diastolic volume c. Causes of increased preload: venous constriction, increased venous blood volume, malfunctioning mitral or aortic valve, impaired myocardial contractility 3. Afterload - forces acting on arterial side of circulation to produce tension in the ventricle as myocardial contraction (systole) occurs. d. Causes of increased afterload: increased systemic vascular resistance, narrowing of the aortic valve VII. Compensatory Mechanisms: Neurohormonal Activation in congestive heart failure (CHF) - the body senses decreased perfusion and tries to increase cardiac output. A. Neurohormonal activation leads to ↑preload (fluid retention) and ↑ afterload (peripheral resistance), ↑ heart rate, ventricular remodeling 1. Sympathetic nervous system (SNS)- ↑ levels of plasma norepinephrine a. ↑ peripheral vasoconstriction (afterload) b. ↑ sodium retention by kidney (preload) -- by stimulating renin release c. ↑ heart rate -- this is most likely to lead to increases in cardiac output, but also adds additional work to the heart long term. High heart rate is related to increased risk of death. d. ↑ inotropic support to heart; but, may induce ventricular arrhythmias and be toxic to the myocardium. When the myocardium is damaged, it may not be able to increase contractility with stimulation by the SNS 2. Renin-angiotensin-aldosterone system - stimulated by the SNS as well as hypoperfusion of the kidneys. e. Angiotensin II causes peripheral vasoconstriction (afterload), impaired water clearance (preload) and stimulation of thirst centers. f. Aldosterone stimulates sodium and water retention to enhance preload g. Ventricular remodeling -- similar to what is seen post MI and with long standing hypertension, may help short term, but long term -- leads to worsening myocardial function. 3. Many other neurohormonal factors are activated in heart failure, causing both vasodilation and vasoconstriction. (including vasopressin and endothelin) 4. Natriuretic Peptides -- helps to combat some of the adverse consequences of SNS and RAAS activation. See image below for their positive effects in HF (i.e. vasorelaxation, diuresis) h. High ventricular filling pressure stimulate the release of natriuretic peptides (remember that high ventricular filling pressures = increased preload = increased volume) i. There are multiple "types" of natriuretic peptides: ANP - atrial natriuretic peptide also called A-type; BNP - B-type natriuretic peptide; C-type and D-type have now been identified as well j. Increased levels of BNP are associated with increased HF symptoms (diagnostic) Figure : From Novartis **Summary of the Pathophysiology of HF** VIII. Precipitating factors of HF -- can aggravate both HFpEF and HFrEF. B. Lack of adherence (with low sodium diet and medications) C. Uncontrolled hypertension D. Arrhythmias -- especially atrial fibrillation E. Systemic / pulmonary infection F. Pulmonary embolus G. Fluid overload (worsening renal function) H. Myocardial ischemia / infarction I. Endocrine disorders (diabetes, hypothyroidism, hyperthyroidism) J. Drugs that aggravate symptoms: +-----------------------------------+-----------------------------------+ | Negative inotropic effect | Sodium and water retention | | | | | (Only aggravates HFrEF) | (Aggravates both preserved and | | | reduced EF) | +===================================+===================================+ | Antiarrhythmics | Thiazolidinediones | | | (rosiglitazone, pioglitazone) | | Beta-blockers | | | | Glucocorticoids, Androgens, | | Calcium channel blockers | | | | Estrogens | | | | | | NSAID's / Salicylates / COX-2 | | | Inhibitors | | | | | | Sodium-containing drugs | +-----------------------------------+-----------------------------------+ IX. Signs and symptoms of CHF -- related to the pathophysiology of the disease. K. Symptoms of inadequate perfusion 5. Fatigability, weakness, lethargy 6. Exercise intolerance 7. Altered mental status 8. Daytime oliguria 9. Tachypnea 10. Shortness of breath -- may be result of inadequate perfusion OR congestion L. Symptoms of congestion 11. DOE - dyspnea on exertion 12. Orthopnea (shortness of breath when lying flat) -- described by the number of pillows someone uses to sleep / PND (paroxysmal nocturnal dyspnea) 13. Cough 14. Nocturia 15. Edema 16. GI symptoms - anorexia, nausea, bloating, constipation, emesis M. Signs of CHF 17. Weight gain 18. Rales, pulmonary edema 19. S~3~ - hallmark in moderate - severe heart failure 20. Resting sinus tachycardia 21. Peripheral edema 22. Jugular venous distension 23. Congestive hepatomegaly, ascites 24. Hepatojugular reflux 25. Hypotension 26. Cool extremities 27. Worsening renal function 28. Cyanosis of the fingers/toes N. Laboratory markers 29. BNP -- Brain natriuretic peptide(elevated \> 100 pg/ml in CHF) 30. NT-proBNP (elevated \> 300 pg/ml in CHF) 31. Troponin -- needed to rule out acute myocardial injury 32. Dilutional hyponatremia (low serum Na+) 33. ↓ potassium and magnesium 34. Elevated liver enzymes with hepatic congestion 35. ↑ in sCr and BUN O. Chest X-Ray -- will show enlarged heart, pulmonary edema, pleural effusions in CHF P. Measuring Ejection Fraction 36. Echocardiogram ()\ Most common test to determine the function of the myocardium and the valves. k. Determines ejection fraction l. Identifies valve dysfunction m. Documents impairment of relaxation, filling, diastolic compliance or diastolic stiffness of the left ventricle demonstrate further diastolic dysfunction 37. Cardiac catheterization -- Ventriculogram X. Classification of CHF by symptoms - New York Heart Association Functional Class (NYHA - FC) Q. Class I : No limitations in physical activity R. Class II : Slight limitation of physical activity, ordinary activity results in symptoms. S. Class III: Marked limitation of physical activity, less than ordinary activity results in symptoms. T. Class IV: Inability to carry on any physical activity without discomfort. Patient has symptoms at rest. XI. ACC/AHA Practice Guidelines Staging of Heart Failure +-----------------------------------+-----------------------------------+ | **STAGE A: At Risk for Heart | **At risk for developing HF** but | | Failure** | without current or prior symptoms | | | of HF or structural heart disease | +===================================+===================================+ | **STAGE B: Pre-Heart Failure** | **No current or prior symptoms of | | | HF** but evidence of at least one | | | of the following: | | | | | | - Structural heart disease | | | | | | - Abnormal cardiac function | | | | | | - Elevated natriuretic peptide | | | or cardiac troponin levels | +-----------------------------------+-----------------------------------+ | **STAGE C: Heart Failure** | **Current or prior symptoms of | | | HF** caused by structural or | | | functional cardiac abnormality | +-----------------------------------+-----------------------------------+ | **STAGE D: Advanced Heart | **Severe symptoms of HF at rest, | | Failure** | recurrent hospitalizations | | | despite max GDMT**, refractory or | | | intolerant to GDMT, requiring | | | advance therapies (transplant, | | | mechanical circulatory support, | | | or palliative care) | +-----------------------------------+-----------------------------------+ Adapted from *Gibson GT, Blumer V, Mentz RJ, Lala A* [THERAPY OF HEART FAILURE] **About this section:** This section of the handout goes over the treatment for Heart Failure with Reduced Ejection Fraction (HFrEF). The key points for use of each drug class are provided. For most of the drug classes, the sections in Pharmacotherapy: A Pathophysiologic Approach 11^th^ ed (found in AccessPharmacy from the WSU library) are listed. You may read these specific sections along with this handout to provide complete understanding and perspective for the use of each drug class. If you read the sections referred to and focus on one drug class at a time, you will develop a deep understanding of the clinical use of each agent. Also, please be familiar with any drugs/doses shaded in gray in the tables. **NOTE:** Please refer to cardiac drug table (in course Canvas site) for contraindications and adverse effects unless otherwise noted in the handout. - GDMT: Guideline-directed medical therapy, representing treatment options supported for use by clinical practice guidelines - Optimal therapy: Treatment provided at either the target or the highest-tolerated dose for a given patient - Target dose: Doses targeted in clinical trials I. Goals of heart failure therapy A. Slow disease progression B. Prolong survival C. Prevent rehospitalizations D. Minimize Symptoms and maximize quality of life Treatment will begin with aggressive control of the underlying cause(s) and risk factors, i.e. hypertension, CAD, diabetes, obesity, valve repair II. Patient Self Care and Education E. Medication Taking - adherence F. Symptom Monitoring\ 1 -- Daily weights: Call provider if weight increases 3 lbs in a day or 5 lbs in a week G. Diet -- H. Exercise -- start with supervised exercise programs (i.e. cardiac rehab) for safety. I. Smoking cessation J. Infection prevention---RSV vaccine (if [\>]60 years old), updated pneumonia vaccine, annual flu vaccine, handwashing K. Avoid use of NSAIDs or Nutritional Supplements -- ask patients about use at every encounter. (Omega 3 fatty acids may be reasonable to take) L. Encourage patients to use apps for self-monitoring: healthstorylines.com **[Pharmacologic Treatment of Heart Failure with Reduced Ejection Fraction (HFrEF) ]** A. Diuretics B. **Vasoactive RAAS inhibitors** - **Angiotensin Receptor Antagonist/ Neprilysin inhibitor (ARNI)** - **ACE Inhibitors (ACEi)** - **Angiotensin Receptor Antagonists/Blockers (ARB)** C. **Aldosterone Antagonists (Mineralocorticoid Receptor Antagonists -- MRAs)** D. **Beta Blockers (BBs)** E. Digoxin F. Nitrate/hydralazine G. Ivabridine (Corlanor) -- *I*~f~ current inhibitor H. **Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors** I. Soluble Guanylyl Cyclase Stimulators **\*\*Bolded agents indicate components of GDMT** **Treatment Summaries by Stage or Type of HF** **Treatment of Stage A and B HF focuses on the management of underlying disease states that can contribute to progression of HF (hypertension, diabetes, coronary artery disease, etc.). These are reviewed in other lectures and modules. The focus of this handout is the treatment of Stage C HF.** Treatment Summary for Stage C and D HF:  **\ ** **Diuretics** A. Mechanism of action B. Role in therapy -- 1. Indicated in all patients with signs and symptoms of fluid overload (fluid retention) 2. Loop diuretics given intravenously as acute therapy for respiratory distress due to pulmonary edema C. Expected benefit -- 3. **Symptomatic relief** (patients feel better), relieve congestion, prevent worsening of symptoms D. Contraindications -- see drug table for the course E. Major drug interactions - 4. Other medications that promote diuresis -- monitor fluid status, renal function, electrolytes (Na+, K+, Mg++) 5. Antihypertensive agents -- monitor BP (can cause hypotension) F. Drug initiation, titration, and target doses -- **Thiazide Diuretics** -- to be used for **mild** sodium retention ------------------------------------------------------------------------------------------------- ---------------------------------- -------------------------- **Drug** **Initial oral dose** **Max total daily dose** Metolazone 2.5 mg daily 20mg Hydrochlorothiazide 25mg daily or twice daily 200mg Chlorthalidone 12.5 to 25 mg daily 100mg **Loop diuretics** - **most potent diuretic**, used for **moderate to severe** sodium retention **Drug** **Initial oral dose** **Max total daily dose** Furosemide 20-40 mg daily or twice daily 400 mg Torsemide 10-20 mg daily 100 mg Bumetanide 0.5 -- 1 mg daily or twice daily 10mg G. Loop diuretics -- 6. Most potent diuresis, therefore used most frequently in HF. 7. Need to provide adequate dose of the loop diuretic to reach the diuretic threshold -- the point at which urinary excretion of Na^+^ (diuresis) occurs 8. The dose is titrated to effect of diuresis. The lowest effective dose is the desired dose. 9. ***In patients with renal dysfunction, higher doses may be required*** H. Thiazide diuretics -- 10. Less potent diuresis effect than loop diuretics. Potentially larger antihypertensive effect, therefore sometimes considered for use in patients requiring mild diuresis and antihypertensive effect. This is not a common scenario. 11. Loss of effect at CrCl \< 30 ml/min 12. Metolazone (2.5-5.0 mg daily) - retains its activity at markedly reduced renal function and is often used in combination with loop diuretics for synergistic effect. Use of hydrochlorothiazide and chlorthalidone are alternative options to metolazone. I. Diuretic Resistance -- 13. Causes 1. 2. a. **Distal tubular hypertrophy** -- Chronic administration of loop diuretics can lead to hypertrophy of the distal segment of the nephron. With this, most of the sodium that is prevented from being reabsorbed in the ascending limb of Henle by loop diuretic is now being reabsorbed in the distal segment. 3. b. NSAIDs -- increase solute reabsorption at loop of Henle and may decrease renal blood flow and GFR. c. Probenecid -- decreases proximal tubular secretion of thiazides and loop diuretics d. IV antibiotics with high sodium loads 4. e. With decompensated HF, absorption may be altered due to GI congestion and delayed gastric emptying 14. Management 5. 6. 7. 8. 9. f. g. 10. J. Monitoring 15. Efficacy: monitored by evaluating fluid status, in relation to the patient's initial presentation of fluid overload (i.e. daily weight, edema, shortness of breath) **Fluid status** **Description in relation to diuretic use** ------------------------------------ ----------------------------------------------------------------- Euvolemia The goal of therapy; Occurs with appropriate doses of diuretics Fluid retention Occurs with inappropriately low doses of diuretics Volume contraction and dehydration Occurs with inappropriately high doses of diuretics 16. Side effect monitoring and management a. Dehydration 11. Monitor: elevation in BUN/Scr, decrease in BP, urine output (look for anuria, oliguria, BUN/Scr \>20:1 or azotemia) 12. Management: h. Dehydration with clinical evidence fluid overload (pulmonary or peripheral congestion): Decrease dose or frequency of loop diuretic i. Dehydration without fluid overload: Discontinue diuretic use b. Hypotension (with dehydration) 13. Orthostatic hypotension -- largely associated with dehydration 14. Monitor blood pressure, orthostatics, BUN/Scr, and clinical signs of dehydration 15. Management: decrease dose or discontinue diuretic if no signs of fluid overload or if and/or patient is hypotensive; provide fluids if patient volume depleted c. Electrolyte imbalances: hypokalemia and hypomagnesemia with both loop and thiazide diuretics 16. Monitor electrolytes 17. Management: replace electrolytes as needed (K, Mg) d. Glucose elevations (typically occurs with use of thiazide diuretics; has clinical importance in patients with diabetes) 18. Monitor: blood glucose 19. Management: alter antidiabetic therapy (i.e. insulin) to allow for better glucose control e. Uric acid elevations (typically with thiazide diuretics; clinical importance in patients with gout) 20. Monitor: serum uric acid 21. Management: ensure appropriate gout treatment initiated and discontinue agent if causing gout flare f. Ototoxicity 22. Monitor: hearing changes, tinnitus, ringing in ears 23. Management: avoid rapid, high dose intravenous infusions of loop diuretics; (avoid IV furosemide dose rate of \>4mg/min) K. Patient counseling 17. Medication adherence 18. Importance of measuring daily weights; Call MD if weight increases 3lbs. in a day or 5 lbs. in a week 19. Salt restriction \Treatment of Chronic Heart Failure\>Diuretics **\ ** **The next 3 sections will cover the Vasoactive RAAS Inhibitor agents (ACE Inhibitors, ARBs, and ARNI -- in this order).** **Angiotensin Converting Enzyme Inhibitors (ACEIs)** A. Mechanism of action 1. Decrease neurohormonal activation by blocking conversion of angiotensin I (AT1) to angiotensin II (AT2), thereby allowing for inhibition of vasoconstriction and cardiac remodeling 2. The breakdown of bradykinin is also reduced, thereby allowing for arterial and venous dilation, decrease in preload and afterload, and decreased myocardial workload 3. Promote favorable effects on cardiac hemodynamics (↓ systemic vascular resistance, pulmonary arterial pressure, pulmonary artery wedge pressure, ↑ cardiac output and stroke volume) B. Role in therapy: Second line therapy for patients with contraindications, intolerant to, or unable to access (due to cost or insurance coverage) an ARNI. C. Expected benefit 4. Decrease mortality 5. Reduce hospitalizations 6. Improve clinical symptom and exercise tolerance 7. Improve NYHA functional class 8. Improve LV size and function 9. Improved quality of life D. Contraindications --Any history of angioedema, Pregnancy/lactation, Potassium \>5.5 meq/dL, Bilateral renal artery stenosis, E. Use with CAUTION if Scr \>2.5 mg/dl, Changing renal function (\>0.5 increase in 2 weeks), Severe aortic stenosis F. Major drug interactions 10. Other drugs that increase K+ (i.e. K+ sparing diuretics, K+ supplements) 11. NSAIDs 12. Other drugs that can cause renal toxicity -- monitor renal function 13. Other antihypertensives -- only a concern if patient has symptomatic hypotension G. Drug Initiation and Target -- Goal is to achieve target dose if blood pressure allows. ACE Inhibitor Initial Daily Dose Maximum/Target Dose -------------------------------- -------------------- --------------------- Enalapril (Vasotec) 2.5 mg bid 10 - 20 mg bid Lisinopril (Prinivil, Zestril) 2.5- 5 mg daily 20 -- 40 mg daily Quinapril (Accupril) 5 mg bid 20 bid Ramipril (Altace) 1.25-2.5 mg daily 10 mg daily Trandolapril (Mavik) 1 mg daily 4 mg daily Fosinopril (Monopril) 5 -- 10 mg daily 40 mg daily Benazapril (Lotensin) 10 mg daily 40 mg daily Perindopril (Aceon) 2 mg daily 8 -- 16 mg daily Captopril (Capoten) 6.25-12.5 mg tid 50 mg tid H. Monitoring 14. Efficacy a. Clinical symptoms and exercise tolerance b. NYHA functional class c. Hospitalizations/ED visits for HF exacerbations 15. Side effect monitoring and management d. Symptomatic hypotension: Monitor blood pressure; alter dosage as needed to prevent symptomatic hypotension with or without syncope. Provide fluids if patient is volume depleted. e. Hyperkalemia: Monitor potassium (K+) 1. Check at baseline, then 2 weeks after initiation, and after dose titration 2. Consider discontinuation or decreasing dose f. Renal function -- BUN, SCr 3. Check at baseline, then 2-4 weeks after initiation, and after dose titration 4. If patient presents with increased SCr, check volume status. If patient is volume depleted, should correct with fluids because dehydration increases the risk of renal dysfunction from an ACE inhibitor. g. Other adverse effects: dry cough, angioedema 5. Can occur at any time during course of therapy 6. Counsel patient at initiation and instruct them to report any adverse effects 7. If cough is intolerable (i.e. it interrupts sleep, the patient does not want to continue), can try ARB agent in place of the ACE-inhibitor 8. Angioedema: Can be life-threatening. Higher incidence in Black/African American population. In HF, ARBs can be considered as an alternative to ACE-inhibitors in patients who have developed angioedema with ACE-inhibitor, angioedema has been reported infrequently with ARBs. I. Patient Counseling 16. As with all BP-lowering medications, patients can develop symptomatic hypotension h. Can manifest as dizziness and lightheadedness i. Usually occurs within initiation or increasing doses, but can develop at any time 17. Angioedema -- Know signs and symptoms (facial/lip swelling, airway swelling) -- should contact medical care immediately if these symptoms occur because it may become a medical emergency ACE inhibitor reading: Pharmacotherapy: Principles and Practice -- Chapter 7: Heart Failure\>Treatment of Chronic Heart Failure\>Neurohormonal Blocking Agents\>ANGIOTENSIN-CONVERTING ENZYME INHIBITORS **Angiotensin II receptor Antagonists/blockers (ARBs)** A. Mechanism of action 1. Selectively block the effects of angiotensin II on the AT1 receptor, which subsequently blocks vasoconstriction and release of aldosterone. Lack the effect on bradykinin that ACE-inhibitors display. 2. Selective blockade of AT1 and not AT2, which allows for the effects of AT2 stimulation to persist -- vasodilation and inhibition of cardiac remodeling 3. Considered to have similarly hemodynamic and neurohormonal effects as ACE inhibitors. However, the clinical trial experience with ACE inhibitors exceeds that of ARBs. B. Role in therapy: Same as ACE inhibitor in those patients who cannot tolerate an ACEi or use of ARNI is not feasible C. Expected benefit 4. Same mortality, hospitalization, hemodynamic, and neurohormonal benefits as ACE inhibitors D. Contraindications -- Same as ACE inhibitor; can use cautiously in patients with advanced CKD and/or ESRD (with or without dialysis) E. Major drug interactions and management -- same as ACE inhibitors F. Drug initiation / Titration / Targets **Drug** **Initial dose** **Maximum Dose** ----------------------- ------------------ ------------------ Candesartan (Atacand) 4- 8 mg daily 32 mg daily Valsartan 20-40 mg bid 160 mg bid Losartan (Cozaar) 25-50 mg daily 50-150 mg daily G. Monitoring 5. Efficacy: same as ACE-inhibitors 6. Side effect monitoring and management a. See ACE inhibitor section, same as above, except ARBs do not have the propensity to cause dry cough and angioedema to the extent that ACE-inhibitors do H. Patient Counseling 7. Same as above, except dry cough is not a typical side effect. ARB readings: Pharmacotherapy: Principles and Practice -- Chapter 7: Heart Failure\>Treatment of Chronic Heart Failure\>Neurohormonal Blocking Agents\>ANGIOTENSIN RECEPTOR BLOCKERS **Neprilysin Inhibitor/ARB** combination -- only one agent available, a combination product of Sacubitril/Valsartan. Sacubitril is the neprilysin inhibitor and valsartan is the ARB. Prior to it becoming available in 2015, its name was LCZ696 (see image below). Trade name is Entresto™. A. Mechanism of action of Sacubitril 1. Neprilysin inhibitor: Sacubitril inhibits neprilysin, a natural enzyme that catalyzes the breakdown of natriuretic peptides (ANP, BNP, CNP), and other vasodilating peptides, including bradykinin, substance P, endothelin-1, and angiotensin II à see figure on page 8 for normal role of natriuretic peptides 2. Increased levels of ANP and BNP lead to more binding on natriuretic peptide receptors, which leads to a generation of cGMP, ultimately enhancing diuresis, natriuresis, and myocardial relaxation, and reducing myocardial hypertrophy 3. ANP and BNP also inhibit renin and aldosterone secretion B. Mechanism of action of valsartan: same as above in ARB section. Inhibiting angiotensin II is essential because neprilysin breaks down angiotensin II. So, a neprilysin INHIBITOR will INCREASE angiotensin II levels. This is undesirable in HF. Thus, the ARB is an essential component of this combination.  C. Role in therapy 4. Class 1 Recommendation in HFrEF and NYHA Class II-IV symptoms 5. In patients with chronic symptomatic HFrEF who tolerate ACEi or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality 6. ARNI can be started without previously having taken an ACEi or ARB D. Expected benefit 7. Decreased CV death and HF hospitalizations (compared to enalapril in PARADIGM-HF) 8. Improve diastolic function, LV function, quality of life, and burden of arrhythmias E. Contraindications -- See drug table; same as those listed for ARBs F. Major drug interactions -- Same as ACE-inhibitors and ARBs G. Drug dosing - U.S. labeling +-----------------------+-----------------------+-----------------------+ | Population | Initial dose | Titration to target | | | | dose | +=======================+=======================+=======================+ | Previously taking | After 36-hr | In 2-4 weeks, double | | moderate to high | washout\*: | dose to target of | | doses of ACE-i/ARB: | | sacubitril | | | Sacubitril | 97mg/valsartan 103mg | | enalapril \>10mg/day | 49mg/valsartan 51mg | bid | | or equivalent | bid | | | | | | | -or- | | | | | | | | valsartan \>160mg/day | | | | or equivalent | | | +-----------------------+-----------------------+-----------------------+ | Previously taking low | After 36-hr | Double dose every 2-4 | | doses of ACE-i/ARB: | washout\*: | weeks until reach | | | | target of | | enalapril *≤*10mg or | Sacubitril | 97mg/valsartan 103mg | | equivalent, -or- | 24mg/valsartan 26mg | bid | | | bid | | | valsartan *≤160mg | | | | valsartan or | | | | equivalent* | | | +-----------------------+-----------------------+-----------------------+ | Patients not | Sacubitril | Double dose every 2-4 | | currently taking an | 24mg/valsartan 26mg | weeks until reach | | ACE inhibitor or ARB | bid | target of | | | | 97mg/valsartan 103mg | | | | bid | +-----------------------+-----------------------+-----------------------+ | eGFR \Treatment of Chronic Heart Failure\>Neurohormonal Blocking Agents\>Sacubitril/Valsartan **Aldosterone Antagonists (Mineralocorticoid Receptor Antagonists -- MRAs)** A. Mechanism of action 1. Inhibit aldosterone, a key neurohormone involved in promoting detrimental effects in HF. Aldosterone levels are increased in HF. 2. Eplerenone exhibits selectivity for the mineralocorticoid receptor B. Role in therapy 3. Recommended for patients with chronic, symptomatic HF C. Expected benefit 4. Decrease morbidity and mortality when added to therapy of patient with NYHA Class II - IV HF 5. Improvement in NYHA functional class 6. Decrease in hospitalizations 7. Benefit likely due to the neurohormonal effect and potassium sparing rather than the diuretic/antihypertensive effect D. Contraindications -- see cardiac drug table for full list Contraindicated if K+ is [≥]{.math.inline}5.0 mEq/L, or if Scr is [≥]{.math.inline}2.5 mg/dl in men; or Scr [≥]{.math.inline}2.0 in women E. Major drug interactions 8. Other medications causing an elevation in potassium -- monitor 9. Medications that cause renal toxicity -- monitor F. Drug initiation and maintenance dose (per ACC/AHA guidelines) +-----------------------+-----------------------+-----------------------+ | | Initiation | Maintenance dose | +=======================+=======================+=======================+ | Eplerenone (Inspra) | eGFR ≥50ml/min: 25mg | eGFR ≥50 ml/min: 50mg | | | daily | daily | | | | | | | eGFR 30-49 ml/min: | eGFR 30-49 ml/min: | | | 25mg once every other | 25mg daily | | | day | | +-----------------------+-----------------------+-----------------------+ | Spironolactone | eGFR ≥50 ml/min: 12.5 | eGFR ≥50 ml/min: 25mg | | (Aldactone) | -- 25mg daily | daily or bid | | | | | | | eGFR 30-49 ml/min: | eGFR 30-49 ml/min: | | | 12.5mg once daily or | 12.5- 25mg daily | | | every other day | | +-----------------------+-----------------------+-----------------------+ G. Monitoring 10. Efficacy a. Clinical signs/symptoms of HF b. Hospitalizations and ED visits for HF exacerbation c. NYHA functional class 11. Side effects 1. Hyperkalemia -- monitor K+ 2. Hypertriglyceridemia with eplerenone 3. Nausea, vomiting 4. Gynecomastia and impotence with spironolactone à can use eplerenone in patients with these ADEs 5. Menstrual changes H. Patient Counseling - Review possible side effects with patients Aldosterone Antagonist: Pharmacotherapy: Principles and Practice -- Chapter 7: Heart Failure\>Treatment of Chronic Heart Failure\>Neurohormonal Blocking Agents\>Mineralocorticoid Receptor Antagonists (MRAs) **Beta Blockers** A. Mechanism of action 1. Blockade of the B-adrenergic receptors, therefore competitively blocking the effects of the sympathetic nervous system 2. The benefit of the sympathetic blocking effects have been shown to far outweigh the negative inotropic effects that B-blockers provide 3. Chronic use also provides positive benefit on ventricular size and shape B. Role in therapy 4. Every patient with HFrEF with current or previous symptoms should receive an evidence-based beta blocker (listed in table below) unless contraindicated. C. Expected benefit 5. Reduction in hospitalizations 6. Reduction in mortality 7. Improvement in EF D. Contraindications: Bradycardia, 2nd or 3rd degree heart block, cardiogenic shock, severe reactive airway disease, decompensated HF, pulmonary edema E. Major drug interactions 8. Other drugs that cause hypotension or bradycardia 9. Carvedilol and metoprolol are major substrates of CYP2D6 -- potential for increased/decreased effects if concomitantly taken with agents also acting on this enzyme -- monitor BP and HR F. Drug Dosing and Titration 10. Dose should be initiated at the lowest dose and increased every 2 weeks with careful monitoring. The goal should be to attain the maximum (or target) dose if tolerated. 11. Early in therapy, if patient decompensates, increase the diuretic dose or decrease the beta blockers dose **Drug** **Initial dose** **Maximum/target dose** **Titration** --------------------------- --------------------- ----------------------------------- ----------------------------------------------------------------- Bisoprolol 1.25 mg daily 10 mg daily Double dose every 2 weeks to get to target dose (if tolerated). Carvedilol 3.125-6.25 mg bid 25 mg bid (or 50 bid if \> 85 kg) Metoprolol succinate (XL) 12.5 -- 25 mg daily 200 mg daily G. Monitoring 12. Efficacy a. Hospitalizations for HF b. Ejection fraction 13. Side effects c. Symptomatic hypotension -- monitor BP; alter dose as needed to avoid d. Bradycardia, heart block -- monitor HR at baseline and after each dose titration; monitor ECG if suspected; decrease dose as needed to avoid e. Worsening HF symptoms (edema, SOB, fatigue) f. Fatigue -- usually after initiation and titration of dose g. Depression h. Sexual dysfunction i. Masking of hypoglycemic signs and symptoms (except sweating) -- especially important for patients with diabetes on glucose-lowering agents H. Patient Counseling 14. Review potential side effects with patient. Patients should understand that they may initially feel worse because of the negative inotropic effects. However, quality of life and symptoms are improved at 3 months of therapy. Beta Blocker readings: Pharmacotherapy: Principles and Practice -- Chapter 7: Heart Failure\>Treatment of Chronic Heart Failure\>Neurohormonal Blocking Agents\>β-ADRENERGIC ANTAGONISTS **Direct Acting Vasodilators - Combination of hydralazine and nitrates** A. Mechanism of action 1. ↓ cardiac workload by ↓ afterload (hydralazine\--arterial dilator) and preload (nitrates\--venodilators) B. Expected Benefits 2. This [combination] (not agents alone) decreases mortality compared to placebo, but does not increase mortality when compared to an ACE inhibitor C. Role in therapy 3. Class 1 recommendation for patients who self-identify as Black/African American with NYHA class III-IV HFrEF who are receiving optimal medical therapy (i.e. maximum tolerated beta blocker and ACEi/ARB/ARNI) , this combination is recommended to improve symptoms and reduce morbidity and mortality a. Frequently used as an add-on for additional hypertension control despite max-dose GDMT in this population 4. Patients who cannot tolerate ACE inhibitors/ARBS/Neprilysin inhibitors because of drug intolerance (particularly because of renal dysfunction) D. Hydralazine - arterial dilator 5. Initial dose in CHF: 25 mg tid 6. Target dose: 75 mg tid 7. Adverse effects: Hypotension, reflex tachycardia, systemic lupus erythematosus-like syndrome, nausea, sodium and water retention, headache E. Nitrates -- venodilator 8. Data in CHF is with isosorbide dinitrate (Isordil) 9. Initial dose in CHF: 10-20 mg tid 10. Target oral dose: 40 mg tid 11. Duration of action: 4-6 hours 12. Adverse effects: headache, hypotension, flushing, nausea F. Combination Product: Bidil (starting dose: hydralazine 37.5 mg, isosorbide dinitrate 20 mg tid; target dose hydralazine 75 mg, isosorbide dinitrate 40 mg tid) -- significantly more expensive that taking the 2 generic drugs separately therefore not frequently used G. Clinical Pearls 13. This combination can be very difficult for patients to adhere to because of the number of pills required. Patients should be part of the decision making for this combination because of that difficulty. 14. A nitrate free period does not need to be provided. It was not done in the clinical trials and the hydralazine may (theoretically) decrease nitrate tolerance -- note that this is a vastly different indication for nitrates than coronary artery disease. Hydralazine and Isosorbide Dinitrate readings: Pharmacotherapy: Principles and Practice -- Chapter 7: Heart Failure\>Treatment of Chronic Heart Failure\>Neurohormonal Blocking Agents\>HYDRALAZINE AND ISOSORBIDE DINITRATE **Digoxin - oldest drug used for treatment of heart failure** A. Inhibits the NaK-ATPase pump to produce a positive inotropic effects B. Major effect probably neurohormonal mediator to decrease sympathetic outflow and suppress the renin secretion from the kidneys. C. Place in therapy is controversial (not a mainstay of HFrEF treatment anymore) 1. Class 2b recommendation: In patients with symptomatic HFrEF despite GDMT, or those who cannot tolerate GDMT, digoxin might be considered to decrease HF hospitalizations 2. Has not been shown to influence survival 3. Causes reduced symptoms in some patients (increased exercise tolerance). Beneficial effects may be seen in patients with low ejection fraction, left ventricular dilatation, or a third heart sound. 4. Drug with narrow therapeutic index and high risk of toxicity. 5. Use is well accepted in patients with atrial fibrillation. D. Dosage 0.125-0.25 mg/day, depending on age and renal function. Most common dose 0.25 mg/day. If patient has Cr Cl \< 30 ml/min, should automatically give 0.125 mg daily E. Monitoring digoxin serum concentration (goal level \< 1.2 ng/ml) 6. Suspect toxicity 7. Patient on an interacting drug 8. Not seeing any benefit and wonder if patient is adherent 9. Change in renal function F. Drug interactions - many drugs interact with digoxin (will learn more about this in pharmacokinetics). Automatic reductions in the digoxin dose should be made if patients are started on the following medications: amiodarone, verapamil, carvedilol. G. Adverse effects related to toxic serum concentrations: Nausea, vomiting, confusion, disorientation, agitation, vision abnormalities, hyperkalemia, cardiac arrhythmias. Digoxin readings: Pharmacotherapy: Principles and Practice -- Chapter 7: Heart Failure\>Treatment of Chronic Heart Failure\>Neurohormonal Blocking Agents\>Digoxin **Ivabradine (Corlanor®) - *I*~f~ current inhibitor** A. Mechanism of action 1. Selective inhibitor of the *I*~f~ current on the sinoatrial node 2. Prolongs diastolic depolarization which slows firing in the sinoatrial node, and ultimately reduces heart rate B. Role in therapy 3. Class 2a recommendation for use in patients with NYHA class II-III HFrEF, in sinus rhythm with resting HR 70 bpm or more, and already taking GDMT including **beta blocker at maximally tolerated dose** C. Expected benefit 4. Reduction in hospitalization due to HF. D. Contraindications E. Major drug interactions 5. Other agents with that can cause bradycardia -- monitor HR, ECG 6. Strong CYP3A4 inhibitors -- Ivabradine is a major substrate; concomitant use is contraindicated F. Drug initiation and titration 7. Initial dose: 5mg BID or 2.5mg BID if patient with history of conduction defects or who may experience hemodynamic compromise due to bradycardia 8. After 2 weeks, adjust dose based on resting HR. Dose is adjusted to achieve target heart rate, not target dose. a. HR \>60 bpm: increase by 2.5mg BID b. HR 50-60 bpm (target resting HR): maintain dose c. HR \