Heart failure with preserved ejection fraction ( HF p EF )

$Page 1: Heart failure with preserved ejection fraction ( HF p EF )$
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 USHFpEF 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.

www.wallpaperstone.com

CARDIAC ANATOMY AND PHYSIOLOGY

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 bloodEur 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

ClassificationClas

sDescription

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 StagingStag

eDescription

A At high risk for HF but without structural heart disease or symptoms of HF

B Structural heart disease but without signs orsymptoms of HF

C Structural heart disease with prior or currentsymptoms of HF

D Refractory HF requiring specialized interventions

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;16:475-539.Ann Med 2013;45:37-50.

www.biomerieux-diagnostics.com

HF PATHOPHYSIOLOGY

Normal HFrEF HFpEF

HFpEF PATHOPHYSIOLOGY

Ann Med 2013;45:37-50.Cardiol Res Pract 2013;824135.

Inflammation

Ventricular hypertrophy

Neurohormones

Impaired cardiac relaxation

LV

NEUROHORMONES AND HFpEF

HFpEF

↓ Cardiac output

Activation of sympathetic

NSRenin

Angiotensin I Vasoconstricti

on ↑ Heart rate

Angiotensin II

AldosteroneNa/H2O

retention

↑ Cardiac filling pressure

Cardiac remodeling

↓ Cardiac filling time

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


Which treatments have been shown to decrease mortality in patients with heart failure with preserved ejection fraction?


B. β-blockers


D. All of the above


HFpEF TREATMENT OPTIONS

Non-pharmacologicSodium and fluid

restriction Regular exercise Weight loss

PharmacologicDiuretics ACE inhibitors/ARBsAldosterone antagonistsβ-blockersCalcium channel blockers DigoxinStatins

Circulation 2002;105:1503-8.

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

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

Circulation 2008;118:2259-67.

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

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



HFpEF

↓ Cardiac output


NSRenin

Angiotensin I ↑ Heart rate

Angiotensin II

AldosteroneNa/H2O

retention


Vasoconstriction

Cardiac remodeling


ACEI

Aldosterone antagonist

ARB



Compensation for reduced cardiac output

However, RAAS neurohormones can contribute to the worsening pathophysiology of HFpEF

Therefore, RAAS targeted for management of HFpEF


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 HFpEFConflicting 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 HFpEFN 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

HFpEFARBs may be considered to decrease hospitalization Use if compelling co-morbidities

Manage co-morbidities in HFpEF (diabetes, CAD, CKD)


ALDOSTERONE ANTAGONISTS

Proposed benefits in HFpEF Inhibit sodium/fluid reabsorption leading to decreased Prevent cardiac remodeling and myocardial hypertrophy

Efficacy data in HFpEFSmall 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 guidelinesNo specific recommendations on the use of aldosterone

antagonists, but could be adjunctive treatment for hypertension management


CHRONOTROPIC MEDICATIONS

β-blockers

Calcium channel blockers

Digoxin

HFpEF TARGETS

HFpEF

↓ Cardiac output


NSRenin


on ↑ Heart rate

Angiotensin II

AldosteroneNa/H2O

retention


Cardiac remodeling


β-blockerNon-DHP CCBDigoxin


β-BLOCKERS

Proposed benefits in HFpEFDecrease chronotropy

Decrease myocardial oxygen demand Increase left ventricular filling time

Efficacy data in HFpEFSmall 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 HFpEFAuthors 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 guidelinesFirst line medication for hypertension management in

HFpEFManagement of atrial fibrillation


CALCIUM CHANNEL BLOCKERS

Non-DHPs: diltiazem, verapamil

Proposed benefits in HFpEFDecrease chronotropyDecrease inotropy

Efficacy data in HFpEFTwo 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.


DIGOXIN

Proposed benefits in HFpEFDecrease chronotropy

Efficacy data in HFpEFConflicting 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.


STATINS

Proposed benefits in HFpEFPrevent cardiac remodeling and myocardial hypertrophyPleiotropic effects including benefits for endothelial

function and inflammation

Efficacy data in HFpEFRetrospective 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 HFpEFFurther prospective randomized controlled trials

warranted

Statin use in HFpEF driven by co-morbidities

Heart failure guidelinesNo specific recommendations regarding the use of statin

therapy Eur Heart J 2012;33:1787-1847.Circulation 2013;128:e240-327.

HFpEF TARGETS

HFpEF

↓ Cardiac output


NSRenin


on ↑ Heart rate

Angiotensin II

AldosteroneNa/H2O

retention


Cardiac remodeling


β-blockerNon-DHP CCBDigoxin

ACEI

ARB

Aldosterone antagonist DiureticAdapted from Goodman & Gilman's The Pharmacological Basis of Therapeutics

2011.

INVESTIGATIONAL THERAPIES IN HFpEF

Pharmacotherapy 2011;31(3):312-31.JAMA 2013;309(12):1268-77.

Inhibits of cardiac remodeling

Improves myocardial relaxation

Prevents excessive myocardial cross-linking

Sildenafil

Ranolazine

Alegabrium


Which treatments have been shown to decrease mortality in patients with HFpEF?


B. β-blockers


D. All of the above


MORTALITY BENEFIT

HFpEF HFrEF

Aldosterone antagonists

ACE inhibitors

ARBs

β-blockers

Vasodilators?


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 Treatment Recommendations Volume overload symptoms

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


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

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Heart failure with preserved ejection fraction ( HF p EF )