11/4/2014

Pharmacist Learning Objectives

Outline the pathophysiology of heart failure
List triggers for decompensated heart failure
Heart Failure Describe current options for treating heart
failure
CTSHP Fall Seminar
Identify how current and future therapy options
Laurajo Ryan, PharmD, MSc, BCPS, can impact the course of disease in heart failure
CDE Devise an appropriate pharmacotherapy
regimen for a patient with heart failure

Pharmacy Technician Objectives A CONDITION IN WHICH BECAUSE OF A

Define heart failure
Describe the epidemiology of heart failure
List triggers for decompensated heart failure
Identify common adverse events associated with
heart failure
CARDIAC ABNORMALITY, THE HEART FAILS TO
PUMP BLOOD AT A RATE THAT MEETS THE
NEEDS OF THE BODY WHILE MAINTAINING LOW
FILLING PRESSURES
A COMPLEX CLINICAL SYNDROME RESULTING
FROM A STRUCTURAL OR FUNCTIONAL CARDIAC
DISORDER THAT IMPAIRS VENTRICULAR FILLING
OR EJECTION

Heart Failure Population Heart Failure Consequences

~5 million patients in the Medicare Impaired cardiac pumping ability
U.S. Most common diagnosis
Numbers rising Most costly diagnosis Cannot keep up with oxygen demand
Aging population Age > 65 Dyspnea & fatigue
MI survival Most common reason for
Mortality hospitalization Decreased exercise tolerance
5 year survival ~50% Age > 75 Fluid retention
Factors affecting prognosis ~10%
Age
Pulmonary congestion
Gender Peripheral edema
LVEF
Renal function
Blood pressure
HF etiology
Drug or device therapy

1
 11/4/2014

Systolic vs. Diastolic Systolic vs. Diastolic

Systolic (HFrEF) Diastolic (HFpEF)
Decreased Pooling of blood in the
Cardiac output venous system
Tissue perfusion Small LV, concentric
Large dilated heart hypertrophy
BP low/normal Women > men
EF Normal or increased EF
S3 gallop S4 gallop
Poor prognosis Treatment not well
established
Prognosis better vs. systolic

Etiology Congestive Heart Failure

Syndrome
Numerous etiologies
Common set of symptoms
Common physiological adaptations
Abnormal ventricular function
Contraction (systole)
Relaxation (diastole)
Neurohormonal regulation
Exacerbate symptoms
Reduce survival

Clinical Presentation Treatment Goals

asymptomatic cardiogenic shock Goals Current standards
Improve quality of life Diuretics
Jugular venous pressure Tachypnea Relieve/reduce symptoms ACE inhibitor or ARB
Heart sounds, murmurs Cough
Prevent, minimize -blocker
Lower extremity edema Hemoptysis
hospitalization spironolactone
Plasma BNP Fatigue
*obesity Nocturia Slow disease progression digoxin
Dyspnea, particularly on Ascites Prolong survival
exertion Abdominal pain
Pulmonary rales, crackles Anorexia
Orthopnea Nausea, bloating
Paroxysmal nocturnal Poor appetite
dyspnea
Early satiety
Exercise intolerance
Mental status changes

2
 11/4/2014

Key advances in the past 10 years of HF

research

PATHOPHYSIOLOGY

Nat Rev Cardiol 2014;127:1038

Pathophysiology PathophysiologyDecreased Perfusion

Cardiac output Cardiac system senses Adaptive responses
= HR X SV decreased perfusion become harmful
systemic vascular Increased cardiac Contribute to disease
resistance (afterload) muscle mass progression
Hypertrophy
Little effect on SV in Changes myocardium
normal ventricle at molecular &
Preload drives CO cellular levels
Major focus for
Large decrease in SV as
therapeutic
afterload rises in HF interventions
Reverse modeling,
decrease mortality,
slow disease
progression

Nat Med 2005:11;828

Compensation
Reaction to decreased pumping capacity
Compensation to maintain CO
Intended to be short term fix for acute reductions
BP or renal perfusion
Persistent decline in CO
Long term activation of compensatory responses
Functional, structural, biochemical, molecular changes
Mechanisms lead to Na+ & H2O retention
PATHOPHYSIOLOGY
preload to CO
COMPENSATORY MECHANISMS Less effect on SV in HF than normal heart

3
 11/4/2014

RAAS Activation Increased AVP

Increases aldosterone
release
Na+ retention
Interstitial cardiac fibrosis
Other target organ
fibrosis, vascular
remodeling, pro-
inflammatory state,
oxidative stress
risk of arrhythmias
Aldosterone antagonists
reduce mortality
Angiotensin II Vasopressin release
Arterial & venous Arterial vasoconstriction
vasoconstriction Venous vasoconstriction
Na+ & water retention Na+ & water retention
Maintains perfusion Initially beneficial
pressure in severe HF
Restores hemodynamic
Stimulates ventricular stability
hypertrophy &
remodeling Eventual cardiac
ACE-inhibitors / ARBs tolerance
prolong survival Decreased vagal tone
Decreased HR variability

Autonomic System Activation Counter-regulatory Hormones

Dysfunctional response to
stressors
heart rate at rest
Contractile stimulation
Increased peripheral vascular
resistance
Arterial vasoconstriction
Venous vasoconstriction
Vasoconstriction
afterload
Attempt to redistribute blood
flow
Coronary & cerebral vessels
Leads to CO
Tachycardia & increased
contractility
Norepinephrine
Abnormal baroreceptor
responses
Decreased cardiac response
Inotropic stimulation
& densensitized 1 receptors
Contributes to exercise
intolerance
Contractile dysfunction
Reduced response to inotropic
agents in acute HF
Metoprolol upregulates the 1
receptors
Hypertrophied myocardial cells
Shortened lifespan
Slower contraction/relaxation
Leads to diastolic failure
Atrial-natriuretic peptide &
brain-natriuretic peptide
Enhance natriuresis & diuresis
Reduce right atrial pressure
systemic vascular resistance
aldosterone secretion
sympathetic activation
systemic resistance
hypertrophy
Vasodilation
Elevated BNP
Marker for increased mortality,
risk of sudden death,
symptoms, hospitalization
BNP assays
BNP or N-terminal pro-BNP
Help with HF diagnosis
Recombinant human BNP
(nesiritide)
Short-term hemodynamic &
symptom improvement
Acute HF
www.cvphysiology.com

HF Exacerbation
Causes
Non-adherance
Na+ & H2O restrictions
Medication
Noncompliance
Inappropriate/inadequate therapy
Medication
Cardiac events
MI/ischemia
CAD
Atrial fibrillation HF EXACERBATION
Anemia
Infection

4
 11/4/2014

HF Management
HF Exacerbation
Control risk
Negative inotropes Cardiotoxic factors
Treatment Follow-up
Antiarrhythmics Ethanol
-blockers Doxorubicin
Calcium channel blockers Daunomycin Alcohol & Disease Aerobic Symptom Patient
smoking treatment exercise treatment education
Verapamil Cyclophosphamide cessation
Diltiazem
Trastuzumab ACEI or ARB Diuretic
Antifungals Imatinib & BB Patient self-
Na+
Itraconazole Treat CAD, care
restriction
Amphetamines myocardial
Terbenafine ischemia Spironolactone if +/- digoxin
Cocaine Phone or
warranted
Methamphetamine electronic
Treat HTN, follow-up
DM, lipids &
thyroid

The
Interventions

DIURETICS

Attridge RL, Miller ML, Moote RD, Ryan L, eds. Internal Medicine: A Guide to Clinical Therapeutics . 1 st ed. New York, NY: McGraw-Hill; 2012

Loop Diuretics Loop Diuretics

Symptomatic treatment Most potent diuretics
of fluid retention Efficacy maintained in
symptoms impaired renal function
hospitalizations Reduced effect with
exercise tolerance dietary Na+
quality of life Electrolyte abnormalities
No evidence of survival
Dosing strategies
Adverse effects
Dose increase
Volume depletion
Addition of thiazide
renal perfusion
Hypokalemia Bolus vs. CI
Hyponatremia

5
 11/4/2014

Thiazide Diuretics
Weak diuretics
alone
Combine with
loop
Improved diuresis
Comparable
effects
Metolazone VASODILATORS
potent
Even with renal
function

ACE Inhibitors Angiotensin Receptor Blockers

Standard of care Adverse events Similar benefit to ACE inhibitors
Improved hemodynamics Cough Theoretical advantage over ACE inhibitors
SVR (afterload) Hypotension Block receptor vs. production
stroke volume CO
Renal insufficiency Well toleratedno cough
pulmonary wedge
Drop in GFR
pressure No effect on bradykinin
Hyperkalemia
Improved functional Less drug interactions
status Angioedema
exercise tolerance Contraindications Not metabolized by cytochrome P-450
symptoms Angioedema Recommended if ACE intolerant
Improved survival Pregnancy Cough
2030% vs. placebo
Angioedema cross reactionuse extreme caution

Nitrates & Hydralazine

Nitrates
Venodilation
preload
Hydralazine
Direct vasodilator
SVR, SV & CO
Combination long-acting nitrate & hydralazine
Add-on to standard therapy in African Americans
43% decrease in all-cause mortality BETA-BLOCKERS
Non-African American patients intolerant of ACE
inhibitor/ARB

6
 11/4/2014

-Blockers
Stable patients with LVEF Initiate low dose
Addon therapy Titrate slowly (over
Improve survival weeks)
Decrease HF progression Adverse effects
Increased ejection fraction particularly with too fast
Improve symptoms titration
Bradycardia
Numerous large clinical trials
support benefit Hypotension
Carvedilol (Coreg) Fatigue
Metoprolol succinate (Toprol Worsening HF
XL ) Continue during ALDOSTERONE ANTAGONISTS
Bisoprolol (Zebeta ) hospitalization unless
Positive effects NOT a class hemodynamically
effect unstable

Aldosterone Antagonists
Aldosterone Spironolactone
Na+ & H2O retention (Aldactone )
Myocardial hypertrophy Gynecomastia
Myocardial fibrosis Eplerenone (Inspra)
Vascular remodeling Selective
Aldosterone blockade mineralocorticoid
receptor blocker
Inhibit Na+ reabsorption
No gynecomastia
Inhibit K+ excretion
Recommended
Improved survival
Pump failure Stage C & D (B with major MISCELLANEOUS AGENTS
Sudden cardiac death risk factors)
Benefit in early disease
not as well established

Digoxin Antiarrhythmic Drugs

Does NOT improve Withdrawal Sudden cardiac death
survival Risk of worsening HF
4050% HF mortality
Improves symptoms ~30% in subsequent 35
months Ventricular tachyarrhythmias
exercise tolerance
Predictors of efficacy Empiric antiarrhythmic therapy
CO
(symptomatic patients)
hospitalization No benefit in HF
S3
Mild positive inotrope Longer duration of HF Pro-arrhythmic
Decreased sympathetic LV dilation
activation Amiodarone (Cordarone, Pacerone)
Sensitizes baroreceptors
LVEF depression
Low dose Destabilizing ventricular tachycardia, fibrillation or
>1.0ng/mL associated
sudden death
with mortality Prevents excessive defibrillator shocks

7
 11/4/2014

Anticoagulation Seven Major Classes of Biomarkers

Thromboembolism is common Contributing to the Biomarker Profile in
Especially with very low EF HF
Should all HF patients be anticoagulated?
Controversial
Absence of atrial fibrillation
Trials have significant overlap

JCHF 2013;1;1

Neprilysin Inhibition

NEW KID ON THE BLOCK

Circulation Heart Failure 2013;6 594

Neprilysin Inhibition PARADIGM-HF

HFrEF
Angiotensin receptorneprilysin inhibitor
LCZ696 vs. enalapril
Methods
Double-blind randomized controlled trial
N = 8442 class II-IV heart failure & EF 40%
Primary outcome
Composite of CV or hospitalization for HF
Results
Trial stopped @ mean f/u 27 months
Primary outcome
LCZ696 = 914 (21.8%) vs. enalapril = 1117 (26.5%)
Hazard ratio 0.80; 95% CI, 0.73 to 0.87; P<0.001
LCZ696 group
> hypotension, non-serious angioedema
< renal impairment, hyperkalemia, cough
Conclusions
LCZ696 superior to enalapril in reducing risk of death & hospitalization for HF

Circulation Heart Failure 2013;6 594 N Engl J Med 2014;371;11

8
 11/4/2014

Non-Pharmacologic Cardiac Stem Cells

Homing mechanism
Migrate to heart after
injection

Cell 2013;154:827

Heart Failure
Common deadly disease
Numerous compensatory mechanisms
HFrEF vs HFpEF
Treatment differences
Current therapies
Up & coming therapies