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HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF) ALEX ISAACS, PHARMD, BCPS INDIANA PHARMACISTS ALLIANCE ANNUAL CONVENTION SEPTEMBER 18, 2014 THIS.

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Presentation on theme: "HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF) ALEX ISAACS, PHARMD, BCPS INDIANA PHARMACISTS ALLIANCE ANNUAL CONVENTION SEPTEMBER 18, 2014 THIS."— Presentation transcript:

1 HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF) ALEX ISAACS, PHARMD, BCPS INDIANA PHARMACISTS ALLIANCE ANNUAL CONVENTION SEPTEMBER 18, 2014 THIS SPEAKER HAS NO ACTUAL OR POTENTIAL CONFLICTS OF INTEREST IN RELATION TO THIS PRESENTATION

2 OBJECTIVES 1. State the difference between heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) 2. State the difference between the pathophysiology, etiology, and clinical presentation of HFrEF and HFpEF 3. Identify an individualized treatment plan for a patient with HFpEF utilizing current evidence

3 IMPORTANCE  Incidence: 600, ,000 new HF cases annually in US  HFpEF occurs in 40-60% of newly diagnosed HF cases  Healthcare expenditure: $40 billion on HF in 2010  Center for Medicare and Medicaid Services reimbursement  Annual mortality: 5-30% Circulation 2011;123:e Eur J Heart Fail 2013;15:

4 CARDIAC ANATOMY AND PHYSIOLOGY

5 DEFINITION  Heart failure (HF): A clinical syndrome of inadequate oxygen delivery to metabolizing tissues resulting from any cardiac structural or functional impairment of ventricular filling or ejection of blood Eur Heart J 2012;33: Circulation 2013;128:e

6 TYPES OF HEART FAILURE ClassificationEjection Fraction (EF) Heart failure with reduced ejection fraction (HFrEF) Formerly referred to as systolic heart failure < 40% Heart failure with preserved ejection fraction (HFpEF) Formerly referred to as diastolic heart failure > 50% HFpEF borderline41-49% HFpEF improved (patients with a history of HFrEF)> 40% Circulation 2013;128:e

7 CLINICAL PRESENTATION Sign/SymptomHFpEFHFrEF Dyspnea on exertion60%73% Nocturnal dyspnea55%50% Lower extremity edema35%46% Rales72%70% Circulation 2002;105: J Am Coll Cardiol 2007;50: Ann Med 2013;45:37-50.

8 HEART FAILURE SEVERITY NYHA Functional Classification ClassDescription INo limitation of physical activity. Ordinary physical activity does not cause HF symptoms IISlight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF IIIMarked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF IVUnable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest ACCF/AHA HF Staging StageDescription AAt high risk for HF but without structural heart disease or symptoms of HF BStructural heart disease but without signs or symptoms of HF CStructural heart disease with prior or current symptoms of HF DRefractory HF requiring specialized interventions Circulation 2013;128:e

9 RISK FACTORS FOR HF HFpEF Age Gender (females) Hypertension Diabetes Obesity HFrEF Coronary artery disease Family history of heart disease Hypertension Diabetes Obesity J Card Fail 2010;16: Ann Med 2013;45:37-50.

10 HF PATHOPHYSIOLOGY NormalHFrEFHFpEF

11 HFpEF PATHOPHYSIOLOGY Ann Med 2013;45: Cardiol Res Pract 2013; Inflammation Ventricular hypertrophy Neurohormones Impaired cardiac relaxation LV

12 NEUROHORMONES AND HFpEF HFpEF ↓ Cardiac output Activation of sympathetic NS Renin Angiotensin I Vasoconstriction ↑ Heart rate Angiotensin II Aldosterone Na/H 2 O retention ↑ Cardiac filling pressure Cardiac remodeling ↓ Cardiac filling time Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011.

13 NEUROHORMONES AND HFpEF HFpEF ↓ Cardiac output Activation of sympathetic NS Renin Angiotensin I Vasoconstriction ↑ Heart rate Angiotensin II Aldosterone Na/H 2 O retention ↑ Cardiac filling pressure Cardiac remodeling ↓ Cardiac filling time Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011.

14 TREATMENT FOR HFpEF

15 ASSESSMENT QUESTION #1  Which treatments have been shown to decrease mortality in patients with heart failure? A. ACE inhibitors/ARBs B. β- blockers C. Aldosterone antagonists D. All of the above E. None of the above

16 ASSESSMENT QUESTION #1  Which treatments have been shown to decrease mortality in patients with heart failure with preserved ejection fraction? A. ACE inhibitors/ARBs B. β- blockers C. Aldosterone antagonists D. All of the above E. None of the above

17 HFpEF TREATMENT OPTIONS  Non-pharmacologic  Sodium and fluid restriction  Regular exercise  Weight loss  Pharmacologic  Diuretics  ACE inhibitors/ARBs  Aldosterone antagonists  β- blockers  Calcium channel blockers  Digoxin  Statins

18 LOOP DIURETICS  Proposed benefit in HFpEF  Inhibition of sodium/fluid reabsorption results in a reduction in total fluid volume lessening volume overload symptoms  Useful in prevention and management of acute volume overload  Caution: Initiate at low doses as small decreases in volume can impact blood pressure and end-organ perfusion Circulation 2002;105:

19 HONG KONG DIASTOLIC HEART FAILURE STUDY  HFpEF patients (EF > 45%) were randomized to diuretic alone or in combination with an ACE inhibitor or ARB  Slight reduction in LV filling pressures with ACE inhibitor/ARB  QOL scores improved by nearly 50% in each treatment group  Conclusion: No clinical benefit of adding an ACE inhibitor or ARB to diuretic therapy in patients with HFpEF Heart 2008;94:

20 THIAZIDE DIURETICS  Proposed benefits in HFpEF  Inhibition of sodium/fluid reabsorption results in a reduction of blood pressure and left ventricular pressure  Prevention of HFpEF in hypertensive patients  Thiazide diuretics have minimal benefit for the management of volume overload symptoms

21 ALLHAT SUB-ANALYSIS  Chlorthalidone significantly reduced the risk of new-onset HFpEF in high cardiovascular risk patients  ↓ risk by 31% vs. amlodipine  ↓ risk by 47% vs. doxazosin  ↓ risk by 26% vs. lisinopril  Conclusion: Thiazide diuretics are a viable first line therapy for hypertension management to reduce the risk of HFpEF Circulation 2008;118:

22 DIURETICS IN HFpEF  No mortality benefit of diuretics  Loop diuretics useful in relieving HF symptoms  Thiazide diuretics may reduce the risk of HFpEF  Heart failure guidelines  Management of volume overload symptoms  Therapeutic option for control of hypertension Eur Heart J 2012;33: Circulation 2013;128:e

23 RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM (RAAS)  The body’s compensation for reduced cardiac output  However, RAAS neurohormones can contribute to the worsening pathophysiology of HFpEF Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011.

24 RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM (RAAS) HFpEF ↓ Cardiac output Activation of sympathetic NS Renin Angiotensin I ↑ Heart rate Angiotensin II Aldosterone Na/H 2 O retention ↑ Cardiac filling pressure Vasoconstriction Cardiac remodeling ↓ Cardiac filling time ACEI Aldosterone antagonist ARB Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011.

25 RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM (RAAS)  Compensation for reduced cardiac output  However, RAAS neurohormones can contribute to the worsening pathophysiology of HFpEF  Therefore, RAAS targeted for management of HFpEF Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011.

26 ACE INHIBITORS AND ARBs  Proposed benefits in HFpEF  Inhibition of AngII reduces vascular resistance decreasing blood pressure  Prevent cardiac remodeling and myocardial hypertrophy  Manage co-morbidities in HFpEF (diabetes, CAD, CKD)  Efficacy data in HFpEF  Conflicting data with variability in study design  Few large prospective randomized controlled trials Cardiovasc Drugs Ther 2003;17: Eur Heart J 2006;27: Am J Med 2013;126(5):

27 PEP-CHF TRIAL  Perindopril compared to placebo in 850 symptomatic HFpEF patients (EF > 40%)  Non-significant difference in mortality or HF hospitalizations with perindopril (23.6% vs 25.1%)  Perindopril significantly improved symptoms and exercise capacity  Conclusion: ACE inhibitor improved HFpEF symptoms but had no reduction in mortality or HF hospitalizations Eur Heart J 2006;27:

28 CHARM-PRESERVED  Candesartan compared to placebo in 3,023 symptomatic HFpEF patients (EF > 40%)  Significant decrease in HF hospitalizations with ARB (15% vs. 18%)  No difference in mortality (11% for each treatment)  Conclusion: No mortality benefit with use of an ARB in HFpEF but mild impact in preventing HF hospitalization Lancet 2003;362:

29 I-PRESERVE  Symptomatic HFpEF patients (EF > 45%) who were > 60 years were randomized to irbesartan or placebo (N = 4,128)  No difference in composite primary endpoint of death or cardiovascular hospitalization between groups (36% vs. 37%)  Conclusion: No benefit of an ARB in HFpEF N Engl J Med 2008;359:

30 ACE INHIBITORS/ARBs IN HFpEF  No mortality benefit in HFpEF from prospective trials  Utility in HFpEF driven by co-morbidities (diabetes, CAD, CKD)  Heart failure guidelines  First line medication for hypertension management in HFpEF  ARBs may be considered to decrease hospitalization  Use if compelling co-morbidities  Manage co-morbidities in HFpEF (diabetes, CAD, CKD) Eur Heart J 2012;33: Circulation 2013;128:e

31 ALDOSTERONE ANTAGONISTS  Proposed benefits in HFpEF  Inhibit sodium/fluid reabsorption leading to decreased  Prevent cardiac remodeling and myocardial hypertrophy  Efficacy data in HFpEF  Small trials have illustrated improvement in HF symptoms and exercise capacity along with improved left ventricular function Clin Cardiol 2005;28: Congest Heart Fail 2009;15(2): J Am Coll Cardiol 2009;54:

32 TOPCAT  Symptomatic HFpEF patients (EF > 45%) were randomized to spironolactone or placebo (N = 3,445)  No difference in composite outcome of CV death, aborted cardiac arrest, or HF hospitalization (8.6% vs. 20.4%)  Spironolactone did significantly reduce hospitalizations (12% vs. 14%)  Conclusion: Mild benefit of spironolactone in HFpEF N Engl J Med 2014;370(15):

33 ALDOSTERONE ANTAGONISTS IN HFpEF  No mortality benefit in HFpEF  Reductions in HF symptoms and hospitalizations  Heart failure guidelines  No specific recommendations on the use of aldosterone antagonists, but could be adjunctive treatment for hypertension management Eur Heart J 2012;33: Circulation 2013;128:e

34 CHRONOTROPIC MEDICATIONS  β- blockers  Calcium channel blockers  Digoxin

35 HFpEF TARGETS HFpEF ↓ Cardiac output Activation of sympathetic NS Renin Angiotensin I Vasoconstriction ↑ Heart rate Angiotensin II Aldosterone Na/H 2 O retention ↑ Cardiac filling pressure Cardiac remodeling ↓ Cardiac filling time β-blocker Non-DHP CCB Digoxin Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011.

36 β-BLOCKERS  Proposed benefits in HFpEF  Decrease chronotropy  Decrease myocardial oxygen demand  Increase left ventricular filling time  Efficacy data in HFpEF  Small trials have demonstrated improvement of HF symptoms and left ventricular function with one study demonstrating mortality benefit Am J Cardiol 1997;80(2): Eur J Heart Fail 2004;6: J Am Coll Cardiol 2009;53:

37 β-BLOCKER MORTALITY BENEFIT IN HFpEF?  HFpEF patients (EF > 40%) patients with a prior myocardial infarction were randomized to propranolol or placebo (N = 158)  Propranolol significantly reduced mortality (56% vs. 76%)  Considerations: sample size, coronary artery disease, EF cutoff  Conclusion: β -blockers reduce mortality in HFpEF patients with a history of myocardial infarction Am J Cardiol 1997;80(2):207-9.

38 SENIORS HFpEF SUB-ANALYSIS  Compared nebivolol to placebo in patients > 70 years with an EF > 35% (N = 752)  No significant difference for the composite primary endpoint of mortality and HF hospitalization (29% vs. 33%)  Conclusion: No benefit of β -blockers in HFpEF  Authors stated benefit undetermined in HFpEF as the study was not designed to detect a difference J Am Coll Cardiol 2009;53:

39 β-BLOCKERS IN HFpEF  Mortality benefit?  Useful for patients with atrial fibrillation or a history of coronary artery disease  Heart failure guidelines  First line medication for hypertension management in HFpEF  Management of atrial fibrillation Eur Heart J 2012;33: Circulation 2013;128:e

40 CALCIUM CHANNEL BLOCKERS  Non-DHPs: diltiazem, verapamil  Proposed benefits in HFpEF  Decrease chronotropy  Decrease inotropy  Efficacy data in HFpEF  Two studies showed enhanced ventricular relaxation and filling Am J Cardiol 1990;66: Int J Clin Pract 2002;56;57-62.

41 CALCIUM CHANNEL BLOCKERS IN HFpEF  Lack of large randomized controlled trials assessing morbidity and mortality in HFpEF  Useful for rate control in patients with atrial fibrillation  Heart failure guidelines  No specific recommendations on the use of calcium channel blockers, but could be adjunctive treatment for hypertension or atrial fibrillation Eur Heart J 2012;33: Circulation 2013;128:e

42 DIGOXIN  Proposed benefits in HFpEF  Decrease chronotropy  Efficacy data in HFpEF  Conflicting results from post-hoc analyses of DIG study  Heart failure guidelines  No specific recommendations for digoxin in HFpEF, but could be used in patients atrial fibrillation Eur Heart J 2006;27(2): Am J Cardiol 2008;102: Eur Heart J 2012;33: Circulation 2013;128:e

43 STATINS  Proposed benefits in HFpEF  Prevent cardiac remodeling and myocardial hypertrophy  Pleiotropic effects including benefits for endothelial function and inflammation  Efficacy data in HFpEF  Retrospective claims data studies support mortality benefit of statins  Limited prospective trials support potential benefit in HFpEF Circulation 2005;112: Lancet 2008;372: Am J Cardiol 2014;113:

44 STATINS IN HFpEF  Benefit may not be due to protective effects of statins in cardiovascular diseases other than HFpEF  Further prospective randomized controlled trials warranted  Statin use in HFpEF driven by co-morbidities  Heart failure guidelines  No specific recommendations regarding the use of statin therapy Eur Heart J 2012;33: Circulation 2013;128:e

45 HFpEF TARGETS HFpEF ↓ Cardiac output Activation of sympathetic NS Renin Angiotensin I Vasoconstriction ↑ Heart rate Angiotensin II Aldosterone Na/H 2 O retention ↑ Cardiac filling pressure Cardiac remodeling ↓ Cardiac filling time β-blocker Non-DHP CCB Digoxin ACEI ARB Aldosterone antagonist Diuretic Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011.

46 INVESTIGATIONAL THERAPIES IN HFpEF Pharmacotherapy 2011;31(3): JAMA 2013;309(12): Inhibits of cardiac remodeling Improves myocardial relaxation Prevents excessive myocardial cross-linking Sildenafil Ranolazine Alegabrium

47 ASSESSMENT QUESTION #1  Which treatments have been shown to decrease mortality in patients with HFpEF? A. ACE inhibitors/ARBs B. β- blockers C. Aldosterone antagonists D. All of the above E. None of the above

48 MORTALITY BENEFIT HFpEF HFrEF Aldosterone antagonists ACE inhibitors ARBs β-blockers Vasodilators ?

49 ASSESSMENT QUESTION #2  JJ is a 77 year old female who was recently hospitalized for a dyspnea and newly diagnosed with HFpEF. Her past medical history is significant for HTN for which she is being treated with losartan 50 mg PO daily (BP today is 144/88 mmHg). What treatment would you recommend for JJ? A. Furosemide 20 mg PO daily B. Metoprolol tartrate 12.5 mg PO BID C. Amlodipine 2.5 mg PO daily D. Lisinopril 5 mg PO daily

50 TREATMENT RECOMMENDATIONS  With limited prospective efficacy data, lack of consensus treatment recommendations for patients with HFpEF  Guidelines vague on first line recommendations  HFpEF treatment selection is driven by management of symptoms and co-morbid disease states Circulation 2013;128:e Eur Heart J 2012;33:

51 TREATMENT OF HFpEF HFpEF CharacteristicTreatment Recommendations Volume overload symptomsDiuretic HypertensionACE inhibitor, ARB, β-blocker Atrial fibrillation β-blocker, non-DHP CCB, digoxin, amiodarone Diabetes/CKDACE inhibitor, ARB Coronary artery diseaseACE inhibitor or ARB + β-blocker Circulation 2013;128:e Eur Heart J 2012;33:

52 ASSESSMENT QUESTION #3  CL is a 62 year old male with HFpEF, hypertension, COPD, and DM2. Current meds include hydrochlorothiazide 25mg PO daily, diltiazem 180mg PO daily, tiotropium 18mCg inhalation PO daily, insulin glargine 20 units QHS. BP today is 140/92 mmHg and HR is 76 bpm. What treatment (if any) would be best to initiate for this patient? A. Metoprolol succinate 100 mg PO daily B. Alagebrium 420 mg PO daily C. Losartan 25 mg PO daily D. None of the above

53 SUMMARY  Pathophysiology, etiology, and treatment for HFpEF are distinct  Lack of mortality benefit for medications treating HFpEF  Future studies are necessary to determine optimal therapies  Due to lack of strong clinical evidence, treatment guidelines recommend empiric medication selection based on symptoms and co-morbidities

54 HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF) ALEX ISAACS, PHARMD, BCPS INDIANA PHARMACISTS ALLIANCE ANNUAL CONVENTION SEPTEMBER 18, 2014


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