Heart Failure Pharmacotherapy An Update

Transcription

1 Heart Failure Pharmacotherapy An Update Kenneth Mishler, PharmD, MBA Objectives Review the epidemiology of heart failure (HF) Review evidence based guidelines for the use of mediations used to treat HF Review new therapies Review evidence based guidelines to reduce HF related emergency department visits, hospitalizations and rehospitalizations Heart Failure Facts 5.7 million adults in the US are living with HF One in nine deaths in 2009 included heart failure as a contributing cause About half of people who develop heart failure die within 5 years of diagnosis Heart failure costs the nation an estimated $30.7 billion each year. This total includes the cost of health care services, medications and missed days of work. 1

2 HF Deaths by Geography Characteristics of HF Hospitalizations Over 1 million hospitalizations occur each year in the US Over 500,000 emergency department visits annually Heart failure accounts for 25% of all cardiovascular related admissions. 20% are for new onset HF 80% represent readmissions Approximately 20% of all HF discharges are readmitted within the first 30 days. The five most common reasons for readmissions are 1) exacerbation of HF, 2) renal disease, 3) pneumonia, 4) cardiac arrhythmia, 5) sepsis. Desai AS. The three phase terrain of heart failure readmissions. Cir Heart Fail. 2012;5: Centers for Medicare & Medicaid Services. Readmissions Reduction Program. Available at: Fee for Service Payment/AcuteinpatientPPS/Readmissions Reduction Program.html. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics 2015 update: a report from the American Heart Association. Circulation. 2015;131:e Classification of Heart Failure 2

3 Definition of Heart Failure Citations for HF Guidelines 2013 ACCF / AHA Guidelines for Management of Heart Failure. Developed in Collaboration With the American Academy of Family Physicians, American College of Chest Physicians, Heart Rhythm Society, and International Society for Heart and Lung Transplantation 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guidelines for the Management of Heart Failure 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. Circulation;2017:135 (24) Classification of Recommendations & Levels of Evidence 3

4 Treatment of HF Stages A to D Stage A At high risk for HF but without structural heart disease or symptoms or HF NYHA Functional Classification None Circle of Life (and Death) of HF Cardiac Output Post MI, heart disease, tobacco use, etc. Afterload Vasoconstriction Systemic vascular resistance Goals of Therapy Improve the patients quality of life by reducing symptoms Prolong survival Alter the natural course of the disease Reduce hospital and emergency department admissions 4

5 Stage A Hypertension and lipid disorders should be controlled in accordance with contemporary guidelines to lower the risk of heart failure. Class I, Level A Other conditions that may lead to or contribute to HF, such as obesity, diabetes mellitus, tobacco use and known cardiotoxic agents, should be controlled or avoided. Class I, Level C Treatment of HF Stages A to D Stage B Structural heart disease but without signs or symptoms of HF. NYHA Functional Classification I No limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF. Recommendations for Prevention & Treatment of Stage B HF COR=Class (strength) of Recommendation; LOE Level of Evidence 5

6 Role of Endogenous Angiotensin II Renin/Aldosterone/Angiotensin System (RAAS) Renal Perfusion Renin Vasodilatory Prostaglandins Histamine Angiotensinogen Angiotensinogen 1 Bradykinin Angiotensin Converting Enzyme (ACE) Angiotensin II Inactive Kinins Angiotensin II Receptor potent peripheral vasoconstriction Afterload and Heart Failure Afterload and Heart Failure 6

7 Treatment of HF Stages A to D Stage C Structural heart disease with prior or current symptoms of HF. NYHA Functional Classification I No limitations of physician activity, ordinary physical activity does not cause symptoms II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms. III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms Pharmacological Therapy for Management of Stage C HFrEF HFrED= HF with reduced Ejection Fraction GDMT= Goal Directed Medication Therapy Diuretics Drug Initial Daily Dose(s) Maximum Doses(s) Mean Doses Achieved in Clinical Trials Thiazide Diuretics Hydrochlorothiazide (HCTZ) 25mg twice 100mg daily ** Thiazide-like Diuretics Metolazone (Zaroxolyn ) 2.5mg twice 20mg ** Loop Diuretics Furosemide (Lasix ) 20mg-40mg daily 600mg Sliding scale Bumetanide (Bumex ) 0.5mg 1mg 10mg Sliding scale Indapamide (Lozol ) 2.5mg 5mg COR=I ; LOE = 3 Reduce pre load and after load on the heart by decreasing total blood volume Some benefits to combination therapy (thiazide + loop) Primary side effect: electrolyte imbalance HYPOKALEMIA, hypomagnesemia, hypochloremia, azotemia ( BUN) Might be ameliorated by use with ACEI, ARB, K + sparing diuretic 7

8 Drugs Commonly Used for HFrEF Stage C HF with reduced Ejection Fraction Role of Endogenous Angiotensin II Renin/Aldosterone/Angiotensin System (RAAS) Renal Perfusion Renin Vasodilatory Prostaglandins Histamine Angiotensinogen Angiotensinogen 1 Bradykinin Angiotensin Converting Enzyme (ACE) Angiotensin II Inactive Kinins Angiotensin II Receptor potent peripheral vasoconstriction Angiotensin Converting Enzyme Inhibitors (ACEI) * pril drugs Peripheral vasodilator Reduce blood pressure REDUCE AFTERLOAD ON HEART Adverse effects Hypotension, dizziness, lightheadedness, syncope Cautious use in renal dysfunction Hyperkalemia, worsen renal function ACEI Cough Inhibition of breakdown of Bradykinin Continued dry, non productive cough Associated with ALL ACEI Angioedema Hives Swelling of face, lips, eyes, soft tissue 8

9 Angiotensin II Receptor Blockers * sartan drugs Reduce the vasoconstrictor effect by blocking the receptor where angiotensin II engages Angiotensin converting enzyme is still active Bradykinin does not build up Very low incidence of cough Very low incidence of angioedena Cautious use in renal dysfunction Hyperkalemia Role of Endogenous Angiotensin II Renin/Aldosterone/Angiotensin System (RAAS) Renal Perfusion Renin Vasodilatory Prostaglandins Histamine Angiotensinogen Angiotensinogen 1 Bradykinin Angiotensin Converting Enzyme (ACE) Angiotensin II Inactive Kinins ARB Angiotensin II Receptor potent peripheral vasoconstriction Renin Aldosterone System Mineralocorticoid receptor blocker/aldosterone Antagonists Indicated in more advanced NYHA class III and IV, LVEF 35% and less Aldosterone stimulates the retention of salt (and therefore water), causes myocardial hypertrophy and potassium excretion. In HF there is increased levels of aldosterone due to: Stimulation by angiotensin II Decreased clearance due to liver congestion Spironolactone and eplerenone counter act these effects Also may decrease collagen synthesis that promotes organ fibrosis 30% reduction in mortality in patients on ACEI 9

10 Renin Aldosterone System Mineralocorticoid receptor blocker/aldosterone Antagonists Creatinine should be <2.5 mg/dl in men or <2.0 mg/dl in women (estimated GFR of > 30ml/min/1.73m 2 )before starting therapy. Serum potassium should be < 5 meq/l before starting therapy Adverse effects Hyperkalemia (Once referred to as Potassium Sparing Diuretics ) Gynecomastia and breast pain in men (10%), leading to a high discontinuation rate. Rate no difference than placebo with eplerenone Role of Endogenous Angiotensin II Renin/Aldosterone/Angiotensin System (RAAS) Renal Perfusion Renin Vasodilatory Prostaglandins Histamine Angiotensinogen Angiotensinogen 1 Bradykinin Angiotensin Converting Enzyme (ACE) Angiotensin II Inactive Kinins ARB Angiotensin II Receptor potent peripheral vasoconstriction Pharmacological Therapy for Management of Stage C HFrEF (cont.) 10

11 Drugs Commonly Used for HFrEF Stage C Heart Failure (cont.) Beta Blockers * olol drugs Once considered contraindicated, or at least counterintuitive, in HF At higher doses decreased cardiac output, decreased EF, through adrenergic blockade (blocking epinephrine/adrenalin effect). Reversal of epinephrine mediated reduction in left ventricular compliance. Ventricular relaxation, increased stroke volume and increased glucose utilization. Reduced oxygen consumption Attenuation of the direct toxic effects on heart fiber (lactic acid) Reduces the myocardium remodeling that occurs over time Increased intracellular calcium in damaged heart fibers Normalizes beta receptors in myocardial tissue Beta Blockers (cont.) Careful use (not necessarily contraindicated) in bronchospastic disease (asthma) and diabetes Start doses low and increase carefully Do not stop therapy abruptly. 11

12 Hydralazine + Long Acting Isosorbide First drugs proven to decrease morbidity and mortality in HF Use of potent peripheral vasodilators to reduce afterload on the heart. Addition to ACEI and beta blocker therapy in African Americans. Alternative in patients that are TRULY intolerant to ACEIs and ARBs Adverse Effects Primarily hypotension, dizziness Headaches Drugs Commonly Used for HFrEF Stage C Heart Failure (cont.) Drugs Commonly Used for HFrEF Stage C Heart Failure (cont.) 12

13 Medical Therapy for Stage C HFrEF: Magnitude of Benefit Demonstrated in Randomized Controlled Trials Treatment of HF Stages A to D Stage D Refractory HF requiring specialized interventions NYHA Functional Classification I Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest. New Agent 13

14 Neprilysin Inhibitors Natriuretic Peptide System Counter regulates the detrimental effects of the renin/aldosterone/angiotensin system (RAAS). Has a positive effect on the autonomic (epinephrine) system in HF Reduces sodium and water retention and vasoconstriction that results from the activation of RAAS B type natriuretic peptides (BNP) Promotes natriuresis and vasodilation Past efforts to improve outcomes in HF by infusing recombinant human BNP (Nesiritide ) showed initial promise but failed to improve symptoms and decrease hospital stays. Pathways blocked by ACE inhibitors, angiotensin receptor blockers and neprilysin inhibitors. Pardeep S Jhund, and John J V McMurray Heart doi: /heartjnl Copyright BMJ Publishing Group Ltd & British Cardiovascular Society. All rights reserved. Sacubitril/Valsartan (Entresto ) Sacubitril inhibits neprilysin Increasing endogenous BNP and CMP Inhibiting the RAAS Peripheral vasodilation Valsartan blocks the Angiotensin II receptor PARADIGM HF Trial (McMurray JV, et.al. NEJM 371;11: ) Double blind, comparative trial Sacubitril/valsartan 200mg BID vs. enalapril 20mg BID Sacubitril 97mg + valsartan 103mg = 200mg Primary outcome composite of cardiovascular death or hospitalization for HF. Trial was designed to detect mortality. 14

15 Sacubitril/Valsartan (Entresto ) Results of PARADIGM HF Trial Trial stopped early 27 months because of overwhelming benefit Primary outcome (dealth+hospitalization) Sacubitril/valsartan 21.8% versus 26.5% in the enalapril arm (P<0.001) Cardiovascular death Sacubitril/valsartan 17.0% versus 19.8% in the enalapril arm (P<0.001) Risk of hospitalization Sacubitril/valsartan had a 21.0% lower risk of hospitalization versus enalapril (P<0.001) Controversy around the dose maximum dose of valsartan vs. low dose of enalpril No medication run in period eliminated 20% of the applicants. Were the worst (and most applicable) patients eliminated from the trial? Early termination of what was designed to be a long term trial. Sacubitril/Valsartan (Entresto ) Dosing Sacubitril/valsartan, a neprilysin inhibitor and angiotensin II receptor blocker is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure patients NYHA Class II IV. Initiate therapy sacubitril 49mg/valsartan 50mg (100mg) BID Double the dose after 2 4 weeks, sacubitril 97mg/valsartan 103mg (200mg) Reduced starting dose to sacubitril 24mg/valsartan 26mg (50mg) In patients not taking or taking a low dose of an ACEI or ARB Patients with severe renal failure Patients with moderate liver failure Double the dose to maximally tolerated. Contraindications History of angioedema with ACEI or ARB Hospital Discharge (Reducing Hospital Readmission) 15

16 Hospital Discharge (Reducing Hospital Readmission) Heart Failure Society of America Recommended Elements of HF Disease Management Programs Comprehensive education and counseling individualized to the patient and patient s caregiver Promotion of self care behaviors including potentially selftitration of diuretic dosing (with family member/healthcare provider assistance). Emphasis on behavioral strategies to ensure adequate adherence to instructions Adequate follow up after hospital discharge or clinical instability (preferably within the first 7 days after event) Optimization of oral therapy, especially evidence based therapy Adequate access to healthcare providers Early attention to signs and symptoms of fluid overload and instructions on how to react Assistance with financial and social concerns QUESTIONS? 16