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Heart failure with preserved ejection fraction ( HF p EF )

Heart failure with preserved ejection fraction ( HF p EF ). 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. objectives.

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Heart failure with preserved ejection fraction ( HF p EF )

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

  3. Importance • Incidence: 600,000-700,000 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:e18-209. Eur J Heart Fail 2013;15:604-13.

  4. cardiac anatomy and physiology www.wallpaperstone.com

  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;33:1787-1847. Circulation 2013;128:e240-327.

  6. Types of Heart failure Circulation 2013;128:e240-327.

  7. Clinical presentation Circulation 2002;105:1387-93. J Am CollCardiol 2007;50:768-77. Ann Med 2013;45:37-50.

  8. Heart failure severity NYHA Functional Classification ACCF/AHA HF Staging Circulation 2013;128:e240-327.

  9. Risk factors for HF J Card Fail 2010;16:475-539. Ann Med 2013;45:37-50.

  10. HF pathophysiology Normal HFrEF HFpEF www.biomerieux-diagnostics.com

  11. HFpEF pathophysiology Ventricular hypertrophy Inflammation Neurohormones LV Impaired cardiac relaxation Ann Med 2013;45:37-50. Cardiol Res Pract 2013;824135.

  12. Neurohormones and HFpEF HFpEF Activation of sympathetic NS ↓ Cardiac output Renin ↑ Heart rate Vasoconstriction Angiotensin I ↓ Cardiac filling time Angiotensin II Cardiac remodeling Aldosterone ↑ Cardiac filling pressure Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011. Na/H2O retention

  13. Treatment for HFpEF

  14. Assessment Question #1 • Which treatments have been shown to decrease mortality in patients with heart failure? • ACE inhibitors/ARBs • β-blockers • Aldosterone antagonists • All of the above • None of the above

  15. Assessment Question #1 • Which treatments have been shown to decrease mortality in patients with heart failure with preserved ejection fraction? • ACE inhibitors/ARBs • β-blockers • Aldosterone antagonists • All of the above • None of the above

  16. 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

  17. 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;105:1503-8.

  18. 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;94:573-80.

  19. 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

  20. 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;118:2259-67.

  21. 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;33:1787-1847. Circulation 2013;128:e240-327.

  22. 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.

  23. Renin-angiotensin aldosterone System (RAAS) HFpEF Activation of sympathetic NS ↓ Cardiac output Renin ↑ Heart rate Vasoconstriction Angiotensin I ACEI ARB ↓ Cardiac filling time Angiotensin II Cardiac remodeling Aldosterone ↑ Cardiac filling pressure Aldosterone antagonist Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011. Na/H2O retention

  24. 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.

  25. 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;17:133-9. Eur Heart J 2006;27:2338-45. Am J Med 2013;126(5):401-10.

  26. 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;27:2338-45.

  27. 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;362:777-81.

  28. 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;359:2456-67.

  29. 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;33:1787-1847. Circulation 2013;128:e240-327.

  30. 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 ClinCardiol 2005;28:484-7. Congest Heart Fail 2009;15(2):68-74. J Am CollCardiol 2009;54:1674-82.

  31. 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):1383-92.

  32. 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;33:1787-1847. Circulation 2013;128:e240-327.

  33. Chronotropic medications • β-blockers • Calcium channel blockers • Digoxin

  34. HFpEF Targets HFpEF β-blocker Non-DHP CCB Digoxin Activation of sympathetic NS ↓ Cardiac output Renin ↑ Heart rate Vasoconstriction Angiotensin I ↓ Cardiac filling time Angiotensin II Cardiac remodeling Aldosterone ↑ Cardiac filling pressure Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011. Na/H2O retention

  35. 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):207-9. Eur J Heart Fail 2004;6:453-61. J Am CollCardiol 2009;53:2150-8.

  36. 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.

  37. 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 CollCardiol 2009;53:2150-8.

  38. 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;33:1787-1847. Circulation 2013;128:e240-327.

  39. 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;66:981-86. Int J ClinPract 2002;56;57-62.

  40. 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;33:1787-1847. Circulation 2013;128:e240-327.

  41. 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):178-86. Am J Cardiol 2008;102:1681-6. Eur Heart J 2012;33:1787-1847. Circulation 2013;128:e240-327.

  42. 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;112:357-63. Lancet 2008;372:1231-9. Am J Cardiol 2014;113:1198-1204.

  43. 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;33:1787-1847. Circulation 2013;128:e240-327.

  44. HFpEF Targets HFpEF β-blocker Non-DHP CCB Digoxin Activation of sympathetic NS ↓ Cardiac output Renin ↑ Heart rate Vasoconstriction Angiotensin I ACEI ARB ↓ Cardiac filling time Angiotensin II Cardiac remodeling Aldosterone ↑ Cardiac filling pressure Aldosterone antagonist Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011. Na/H2O retention Diuretic

  45. Investigational therapies in HFpEF Sildenafil Ranolazine Alegabrium Pharmacotherapy 2011;31(3):312-31. JAMA 2013;309(12):1268-77.

  46. Assessment Question #1 • Which treatments have been shown to decrease mortality in patients with HFpEF? • ACE inhibitors/ARBs • β-blockers • Aldosterone antagonists • All of the above • None of the above

  47. Mortality benefit ?

  48. 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? • Furosemide 20 mg PO daily • Metoprolol tartrate 12.5 mg PO BID • Amlodipine 2.5 mg PO daily • Lisinopril 5 mg PO daily

  49. 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:e240-327. Eur Heart J 2012;33:1787-1847

  50. Treatment of HFpEF Circulation 2013;128:e240-327. Eur Heart J 2012;33:1787-1847

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