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
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
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.
CARDIAC ANATOMY AND PHYSIOLOGY
www.wallpaperstone.com
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.
TYPES OF HEART FAILURE
Classification
Ejection 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 borderline
41-49%
HFpEF improved (patients with a history of HFrEF)
> 40%
Circulation 2013;128:e240-327.
CLINICAL PRESENTATION
Sign/Symptom
HFpEF
HFrEF
Dyspnea on exertion
60%
73%
Nocturnal dyspnea
55%
50%
Lower extremity edema
35%
46%
Rales
72%
70%
Circulation 2002;105:1387-93.
J Am Coll Cardiol 2007;50:768-77.
Ann Med 2013;45:37-50.
HEART FAILURE SEVERITY
NYHA Functional Classification
Class Description
I
No limitation of physical activity. Ordinary
physical activity does not cause HF symptoms
II
Slight limitation of physical activity. Comfortable
at rest, but ordinary physical activity results in
symptoms of HF
III
Marked limitation of physical activity.
Comfortable at rest, but less than ordinary
activity causes symptoms of HF
IV
Unable to carry on any physical activity without
symptoms of HF, or symptoms of HF at rest
ACCF/AHA HF Staging
Stage Description
A
At high risk for HF but without structural
heart disease or symptoms of HF
B
Structural heart disease but without signs or
symptoms of HF
C
Structural heart disease with prior or current
symptoms of HF
D
Refractory HF requiring specialized
interventions
Circulation 2013;128:e240-327.
RISK FACTORS FOR HF
HFpEF
HFrEF
Age
Coronary artery disease
Gender (females)
Family history of heart disease
Hypertension
Hypertension
Diabetes
Diabetes
Obesity
Obesity
J Card Fail 2010;16:475-539.
Ann Med 2013;45:37-50.
HF PATHOPHYSIOLOGY
Normal
HFrEF
HFpEF
www.biomerieux-diagnostics.com
HFpEF PATHOPHYSIOLOGY
Ventricular hypertrophy
Inflammation
LV
Neurohormones
Impaired cardiac relaxation
Ann Med 2013;45:37-50.
Cardiol Res Pract 2013;824135.
NEUROHORMONES AND HFpEF
HFpEF
Activation of
sympathetic NS
↑ Heart rate
↓ Cardiac output
Vasoconstriction
↓ Cardiac filling
time
↑ Cardiac filling
pressure
Renin
Angiotensin I
Cardiac
remodeling
Angiotensin II
Aldosterone
Na/H2O retention
Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011.
TREATMENT FOR HFpEF
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
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
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
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.
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.
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
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.
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.
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.
RENIN-ANGIOTENSIN ALDOSTERONE SYSTEM (RAAS)
HFpEF
Activation of
sympathetic NS
↑ Heart rate
↓ Cardiac output
Vasoconstriction
↓ Cardiac filling
time
↑ Cardiac filling
pressure
Renin
Angiotensin I
ACEI
Cardiac
remodeling
Angiotensin II
Aldosterone
Na/H2O retention
Aldosterone antagonist
Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011.
ARB
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.
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.
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.
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.
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.
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
Eur Heart J 2012;33:1787-1847.
Circulation 2013;128:e240-327.
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;28:484-7.
Congest Heart Fail 2009;15(2):68-74.
J Am Coll Cardiol 2009;54:1674-82.
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.
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.
CHRONOTROPIC MEDICATIONS
 β-blockers
 Calcium channel blockers
 Digoxin
HFpEF TARGETS
β-blocker
Non-DHP CCB
Digoxin
HFpEF
Activation of
sympathetic NS
↑ Heart rate
↓ Cardiac output
Vasoconstriction
↓ Cardiac filling
time
↑ Cardiac filling
pressure
Renin
Angiotensin I
Cardiac
remodeling
Angiotensin II
Aldosterone
Na/H2O retention
Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011.
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 Coll Cardiol 2009;53:2150-8.
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.
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;53:2150-8.
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.
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 Clin Pract 2002;56;57-62.
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.
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.
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.
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.
HFpEF TARGETS
β-blocker
Non-DHP CCB
Digoxin
HFpEF
Activation of
sympathetic NS
↑ Heart rate
↓ Cardiac output
Vasoconstriction
Angiotensin I
ACEI
↓ Cardiac filling
time
↑ Cardiac filling
pressure
Renin
Cardiac
remodeling
Angiotensin II
Aldosterone
Na/H2O retention
Aldosterone antagonist
Diuretic
Adapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics 2011.
ARB
INVESTIGATIONAL THERAPIES IN HFpEF
Sildenafil
Ranolazine
Inhibits of cardiac remodeling
Improves myocardial relaxation
Alegabrium Prevents excessive myocardial cross-linking
Pharmacotherapy 2011;31(3):312-31.
JAMA 2013;309(12):1268-77.
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
MORTALITY BENEFIT
HFpEF
HFrEF
Aldosterone antagonists
ACE inhibitors
ARBs
β-blockers
Vasodilators
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
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
TREATMENT OF HFpEF
HFpEF Characteristic
Volume overload symptoms
Treatment Recommendations
Diuretic
Hypertension
ACE inhibitor, ARB, β-blocker
Atrial fibrillation
β-blocker, non-DHP CCB, digoxin, amiodarone
Diabetes/CKD
ACE inhibitor, ARB
Coronary artery disease
ACE inhibitor or ARB + β-blocker
Circulation 2013;128:e240-327.
Eur Heart J 2012;33:1787-1847
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
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
HEART FAILURE WITH PRESERVED
EJECTION FRACTION (HFpEF)
ALEX ISAACS, PHARMD, BCPS
INDIANA PHARMACISTS ALLIANCE ANNUAL CONVENTION
SEPTEMBER 18, 2014