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Pharmacologic Considerations for
Reducing Hospital Readmission in
Geriatric Patients with Heart
Failure
Barbara J. Zarowitz, Pharm.D.
Chief Clinical Officer, Vice President of Clinical Services
Omnicare, Inc., and
Adjunct Professor of Pharmacy Practice
College of Pharmacy and Health Sciences
Wayne State University
November 2013
Objectives
 To identify the key pathophysiologic mechanisms operative in patients with
heart failure;
 To differentiate characteristics of heart failure in persons older than 80
years of age compared to younger patients;
 To select strategies of heart failure management recommended in current
evidence-based guideline;
 To identify pharmacokinetic and pharmacodynamics features of older
persons with heart failure;
 To determine important pharmacologic considerations of heart failure
medications in older persons;
 To select the most common reasons for readmission of heart failure
patients to the hospital and strategies to mitigate the risk of
rehospitalization; and
 Using a case-based approach, to select appropriate interventions to
optimize the care of older patients with heart failure.
Heart Failure Clinical Program
© Omnicare, Inc. 2013
2
Disclosures
 Dr. Zarowitz is an employee of Omnicare, Inc., and holds
Omnicare stock
 She has been awarded numerous research grants for
Omnicare Senior Health Outcomes from:









AbbVie
Amgen
Astellas
Avanir
GlaxoSmithKline
Mylan
Optimer
Sanofi-aventis
Savient
Case Presentation
83 year old Caucasian male, Clcr 63 mL/min, dry weight of 160 lb (72.2 kg) who
presented to the nurse practitioner with complaints of shortness of breath and
productive coughing for the last 4 weeks
 BP-90/64, HR-100, RR-20, T98.6
 PMH: NYHA stage IV HF,
glaucoma, coronary artery
disease, hypertension, ocular
strokes
 HPI: hospitalized the
previous year twice for
syncope associated with
heart failure. Cardiac arrest
during one hospitalization
following administration of
ramipril 2.5 mg
 CXR: no infiltrates
 Labs: WBC – wnl
Medication
aspirin EC
clopidogrel
furosemide
metoprolol
mirtazapine
zolpidem
simvastatin
spironolactone
digoxin
Vitamin D3
Vitamin E
latanoprost
furosemide
Dose
81 mg
75 mg
40 mg
50 mg
30 mg
5 mg
40 mg
25 mg
0.0625 mg
1,000 units (2 tabs)
400 units
1 drop each eye
40 mg
40 mg
40 mg (2 tabs)
40 mg (2 tabs)
40 mg (4 tabs)
Frequency
once daily
once daily
once daily
twice daily
at bedtime
at bedtime
at bedtime
once daily
once daily
once daily
once daily
at bedtime
wt ≤ 162 = no dose
wt 163 - 167, 1 tab
wt 168, 2 tabs
wt 169, 2 tabs twice daily
wt 170, 2 tabs twice daily
Heart Failure Pathophysiology
What is Heart Failure?
6
Definition of HF
• Inability of the heart to pump blood to the body
sufficient to meet the body’s demands
• Results from structural or functional cardiac disorder
– Impaired ability of the ventricle to fill with or eject blood
© Omnicare, Inc. 2013
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7
Pathophysiology of Heart Failure
Causal Factors
Myocardial Damage
Myocardial Failure
Cardiac output
 LV end diastolic
pressure
SVR (afterload)
 Blood Volume
(preload)
Compensatory Responses
RAA
SNS
ANF
Vasopressin
Pumping and Filling Problems and Heart
Failure
NORMAL
SYSTOLIC
DYSFUNCTION
DIASTOLIC
DYSFUNCTION
Diastole
(Filling)
The ventricles fill
normally with blood
The enlarged ventricles
fill with blood
The stiff ventricles fill with
less blood than normal
Systole
(Pumping)
The ventricles pump
out ~60% of the blood
© Omnicare, Inc. 2013
The ventricles pump
out less than 40-50%
of the blood
The ventricles pump out
~60% of the blood, but
the amount may be
lower than normal
9
Facts About Heart Failure (HF)
(continued)
 Prevalence of HF in nursing homes (NHs) is ~20%
 HF is the 2nd most preventable cause of emergency department (ED)
visits (19%)
 668,000 ED visits and 1,094,000 hospital discharges in 2009
 Discharges to someplace other than home have tripled in the past decade
 50% of Medicare patients discharged to NHs are rehospitalized
within 6 months
 Characteristics associated with a high risk for rehospitalization with
HF




Higher NYHA stage
Greater functional limitations (ADLs)
Concomitant psychosis
Concomitant renal failure
© Omnicare, Inc. 2013
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Roger VL et al. Heart disease and stroke statistics—2012 update: a report from the American
Heart Association. Circulation. 2012;125:e2–e220.
Hutt E et al. J Am Med Dir Assoc 2011; 12:595-601
10
Facts About Heart Failure (HF)
 In 2008, 1 in 9 death certificates in the U.S. mentioned HF
 An estimated 6.6 million US adults have HF
 60-79 years-old: 9% of men and 5.4% of women
 80+ years-old: 11.5% of men and 11.6% of women
 75% of HF cases had HTN prior to their HF
 Lifetime risk for HF is double for those with BP >160/90 mmHg
compared to <140/90
 More common in the African American population
 More common in men than women
Roger VL et al. Heart disease and stroke statistics—2012 update: a report from the American
Heart Association. Circulation. 2012;125:e2–e220.
11
© Omnicare, Inc. 2013
Heart Failure in the Elderly
 Persons older than 65 years account for 80% of heart failure
hospitalizations
 Prevalence doubles with each decade of life over age 75
 About 6% to 10% over 65 years have heart failure
 88% of newly diagnosed cases occur in patients older than 65
years
 49% are older than 80 years
Features Distinguishing Heart Failure in the Elderly from Heart
Failure Occurring During Middle Age
Middle Age
Elderly
(≥ 65 years)
Prevalence
<1%
≈10%
Gender
M>F
F>M
Etiology
Coronary artery disease
Hypertension
Reduced
Normal
Comorbidities
Few
Multiple
RCTs
Many
Few
Evidence-based
Empiric
Cardiologist
Primary care
LVEF
Therapy
Physician
M=male; F=female; LVEF=left ventricular ejection fraction; RCT=randomized clinical
trial
Adapted from Rich RW. Drug therapy for heart failure in the elderly. Am J Ger Cardiol 2003;12:235-42.
Pharmacokinetic and Pharmacodynamic
Variants in Older Persons with Heart Failure
Absorption
 Increased gastric pH, delayed gastric emptying, reduced
GI blood flow and slowed intestinal transit
 Decreased bioavailability of medications with aciddependent absorption (iron) and slowed absorption of
medications, especially those that are enteric coated
Metabolism
 20 – 30% reduction in liver mass and hepatic blood flow
but hepatocytes remain intact
 CYP isozymes may be decreased but do not necessarily
result in reduced clearance
 first-pass metabolism is reduced with age
Elimination
 Clcr declines progressively with age- 0.75 mL/min/year
14
Underlying Causes of Heart Failure
Coronary Artery
Disease
Cardiovascular disease
Valvular Heart Disease
Infections
Alcohol
Heart
Failure
Hypertension
Radiation
Drugs
Tachycardia
Neuromuscular disease
Connective tissue disease
Nutritional and metabolic
disorders
© Omnicare, Inc. 2013
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Selected Risk Factors for Heart Failure
Unmodifiable
Treatable
Myocardial infarction
Kidney disease
Non-white race
Family history
Male sex
Age
Sleep disordered breathing
Heart disease
Hyperlipidemia
HYPERTENSION
Smoking
Valve disease
Obesity/Diet
Diabetes
Physical inactivity
AFib
Alcohol consumption
Mental stress
Depression
Modifiable
© Omnicare, Inc. 2013
Kenchaiah S et al. Med Clin N Amer 2004:88;1145-72.
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Risk Factors for Heart Failure
Strongly and consistently
associated with HF
Less consistently
associated with HF
Age
Male sex
Hypertension
Electrocardiographic LV
hypertrophy
Myocardial infarction
Diabetes
Valve disease
Overweight/obesity
Excessive alcohol consumption
Smoking
Dyslipidemia
Renal insufficiency
Sleep-disordered breathing
Low physical activity
Low socioeconomic status
Coffee consumption
Dietary sodium intake
Increased heart rate
Impaired pulmonary function
Mental stress and depression
Kenchaiah S et al. Med Clin N Amer 2004:88;1145-72.
Medications That May Exacerbate Heart
Failure
Agents
Antiarrhythmic agents (avoid disopyramide and flecanide;
amiodarone and dofetilide are acceptable, if necessary, for
arrhythmia)
Calcium channel antagonists (diltiazem, verapamil)
Itraconazole
Terbinafine
Alcohol (excessive amounts in predisposed patients)
Doxorubicin
Daunomycin
Cyclophosphamide
Androgens
COX-2 inhibitors
Estrogens
Glucocorticoids
Nonsteroidal anti-inflammatory drugs
Salicylates (high doses)
Sodium-containing drugs (e.g., ticarcillin)
Thiazolidinediones (rosiglitazone, pioglitazone)
Albumin
Blood products
Rationale
Negative inotropic
effects
Cardiotoxic
Sodium and water
retention
Osmotic agents
Signs and Symptoms of Heart Failure
SIGNS
 Tachycardia
 Cachexia and muscle
wasting
 Third heart sound
 Positive hepatojugular reflux
 Bilateral rales
 Peripheral edema
 Laterally displaced apical
pulse
 Elevated jugular venous
distension
 Unexpected weight gain
SYMPTOMS
• Shortness of breath
• Orthopnea
• Paroxysmal nocturnal
dyspnea
• Reduced exercise
tolerance
• Lethargy, fatigue
• Unexplained cough
• Wheeze
• Edema
• Loss of appetite
• Change in urine
production
Congestive Heart Failure
20
The FACES of Heart Failure
• Fatigue
• Activities limited
• Chest congestion
• Edema or ankle swelling
• Shortness of breath
HFSA. Who is the patient with heart failure? 2002. Available at: http://www.hfsa.org/pdf/faces_card.pdf
© Omnicare, Inc. 2013
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21
BNP (B-type natriuretic peptide)
 Released in response to pressure overload
 Should be measured in patients being evaluated for dyspnea in
which the contribution of HF is unknown
 Generally as BNP increases, HF worsens, and as HF is
successfully treated, BNP decreases
 May also be elevated in acute MI, PE, COPD, older age,
female gender and renal impairment
© Omnicare, Inc. 2013
BNP (pg/mL)
Interpretation
<100
Reliably rules out HF
100-399
Possible HF
(~75% of cases are HF)
>400
Suggestive of HF
22
BNP Diagnostic Algorithm
Dyspnea
Physical Examination, Chest XR,
ECG, BNP Level
BNP <100pg/ml
BNP 100-400 pg/ml
BNP >400pg/ml
Baseline LV Dysfunction,
Underlying Cor Pulmonale,
Or Acute Pulmonary Embolism
CHF Very Unlikely
(2%)
Yes
No
Possible
Exacerbation of
CHF (25%)
CHF Likely
(75%)
Adapted from: Tabbibizar R, Maisel A. Curr Opin Cardiol. 2002;17:343.
CHF Very Likely
(95%)
BNP for Diagnosis
BNP Concentration (pg/ml)
BNP concentration for the degree of heart
failure severity
2500
2013 + 266
2000
1500
791 + 165
1000
500
186 + 22
0
Mild
n = 27
Maisel A et al. J Am Coll Cardiol 2001;37(2)379-85.
Moderate
n = 34
Severe
n = 36
Evidence-Based Treatment Guidelines
Yancy CW, et al. 2013 ACCF/AHA Heart Failure Guidelines
http://content.onlinejacc.org
Jessup M, et al. 2009 ACCF/AHA guidelines for the diagnosis and management
of heart failure in adults. Circulation. 2009;119:1977–2016.
25
Heart Failure with Reduced EF
Treatment Approaches for Heart
Failure
27
Goals of Treatment
Survival
Exercise capacity
Quality of life
Morbidity
Progression
of disease
Symptoms
© Omnicare, Inc. 2013
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Approach to Treatment
 Diagnose and Stage HF
 Establish patient-centered goals (e.g., BP)
 Utilize non-pharmacological interventions and
evidence-based medications
 Titrate and maximize doses as tolerated
 Monitor with vigilance
 Dietary considerations
 Changes in signs and symptoms (e.g., weight gain)
 Medication monitoring (e.g., BMP, pulse, etc)
29
© Omnicare, Inc. 2013
Classification of HF
ACC/AHA Heart Failure Stage
A
NYHA Functional Class
At high risk for HF, but without
structural heart disease or
symptoms of HF (e.g., HTN, CAD)
Not applicable
B
Structural heart disease but
without symptoms of HF
I
With cardiac disease but asymptomatic
and without limitations of physical
activity
C
Structural heart disease with prior
or current symptoms of HF
II
Symptomatic with ordinary exertion
resulting in slight limitation of physical
activity (mild HF)
III
Symptomatic with less than ordinary
exertion resulting in marked limitations
of physical activity (moderate HF)
IV
Symptomatic at rest resulting in inability
to carry on any physical activity without
discomfort (severe HF)
D
Refractory HF requiring
specialized interventions
© Omnicare, Inc. 2013
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Medications That May Cause or Exacerbate
HF*
Agents
How they cause/exacerbate HF
Antiarrhythmics† [e.g., Multaq (dronedarone), Rythmol
(propafenone), Tambocor (flecanide)]
Non-dihydropyridine Calcium Channel Blockers [e.g., Calan or
Isoptin (verapamil) or Cardizem (diltiazem)]
Itraconazole or Terbinafine
Negative inotropic effects
(decrease the force of the hearts
contraction)
Alcohol (excessive amounts)
Some chemotherapy treatments (e.g., doxorubicin, daunomycin,
cyclophosphamide)
Cardiotoxic
Androgens or Estrogens
Aspirin (high doses)
NSAIDs (e.g., celecoxib, ibuprofen, meloxicam, naproxen)
Glucocorticoids (e.g., prednisone)
Thiazolidinediones [e.g., pioglitazone, Avandia (rosiglitazone)]
Sodium and water retention
Albumin
Blood products (e.g., transfusion)
Osmotic agents
Avoid or minimize use whenever possible. Monitor closely if must be used.
* - not all inclusive
† - amiodarone or Tikosyn (dofetilide) are acceptable alternatives if necessary for arrhythmias
31
Non-Pharmacological Therapies
 Modifiable risk reduction (e.g., smoking cessation, stress
management)
 Dietary modifications





Low sodium, low saturated fat diet
Limit caffeine intake
Limit alcohol intake
Encourage weight loss if BMI > 25
Closely watch fluid intake
 Encourage physical activity as tolerated
32
© Omnicare, Inc. 2013
Pharmacological Therapies Commonly Used
 ACE Inhibitors (e.g., lisinopril)
 Angiotensin Receptor Blockers [ARBs (e.g.,
losartan, valsartan)
 Beta Blockers (e.g., metoprolol, carvedilol)
 Diuretics
 Digoxin
 Aldosterone Antagonists (e.g.,
spironolactone, eplerenone)
 Hydralazine + Isosorbide
ACCF/AHA Guidelines: “It is recommended that evidence-based therapy for
HF be used in the elderly patient, with individualized consideration of the
elderly patient’s altered ability to metabolize or tolerate standard
medications”
33
© Omnicare, Inc. 2013
Yancy CW, et al. 2013 ACCF/AHA Heart Failure Guidelines
ACE Inhibitors (ACEIs)
(e.g., lisinopril, enalapril)
 Associated with a significant decrease in mortality
 “recommended for all patients with current or prior
symptoms of HF and reduced LVEF, unless
contraindicated”
 Lower blood pressure by causing blood vessels to relax and
expand and by reducing sodium and water retention
 Monitor for:
 Hypotension
 Persistent dry cough (~20%)
 Angioedema (<1%)
 Elevated potassium
 Elevated serum creatinine
Jessup M, et al. 2009 ACCF/AHA Guidelines. Circulation. 2009;119:1977–2016.
Yancy CW, et al. 2013 ACCF/AHA Guidelines. http://content.onlinejacc.org
34
© Omnicare, Inc. 2013
ACE-I: Mechanism of Action
VASOCONSTRICTION
ALDOSTERONE
VASOPRESSIN
SYMPATHETIC
VASODILATATION
PROSTAGLANDINS
Kininogen
tPA
Kallikrein
Angiotensinogen
RENIN
Angiotensin I
A.C.E.
ANGIOTENSIN II
Inhibitor
BRADYKININ
Kininase II
Inactive Fragments
ACE Inhibitors
RISKS
Hypotension
Renal dysfunction
Hyperkalemia
Cough
Angioedema
Neutropenia
* Not an indication for all ACEIs
BENEFITS





Prolonged survival*
Clinical improvement
More stable clinical course
Fewer hospitalizations
Slower disease progression
ACE Inhibitors: Indications and Doses
INDICATION
HF
LV Dysfunction
Initial Dose
Maximum
Dose
captopril (Capoten®)

 (post-MI)
6.25 mg tid
50 mg tid
enalapril (Vasotec®)

 (asymptomatic)
2.5 mg bid
10 – 20 mg
bid
fosinopril (Monopril®)

NA
5 - 10 mg qd
40 mg qd
lisinopril (Prinivil®,
Zestril®)

NA
2.5 - 5 mg qd
20 – 40 mg
bid
quinapril (Accupril®)

NA
10 mg bid
40 mg bid
ramipril (Altace®)

 (post-MI)
1.25 – 2.5mg qd
10 mg qd
trandolapril (Mavik®)

 (post-MI)
1 mg qd
4 mg qd
Agent
ACE = angiotensin-converting enzyme, LV = left ventricular
HF = heart failure, MI = myocardial infarction
ACE Inhibitors, Heart Failure, and Mortality
Reduction
STUDY
ACE-I
CONSENSUS
Enalapril
2.5-40 mg/d
vs. placebo
N=253
Class IV
HF
12
months
6 month mortality ↓ 40%
1 year mortality ↓ 31%
Death from progressive HF ↓ 50%
Enalapril
10 mg bid
vs. placebo
N=2,589
EF < 35%
42
months
3.5 year mortality ↓ 16%
Death or CHF hospitalization ↓26%
CV hospitalization ↓ 10%
Ramipril
2.5-5 mg
bid
N=2,006
HF post MI
30
months
All cause mortality ↓ 17%
Risk of 1st event ↓ 19%
Captopril
12.5-150
mg/d vs.
placebo
N=2,231
EF < 40%
Post MI
42
months
All cause mortality ↓ 19%
CV death ↓ 21%
CHF development ↓ 37%
Recurrent MI ↓ 25%
Mean age 71
SOLVD
Mean age 60
AIRE
Mean age 65
SAVE
Patients
Duration
Results
ATLAS Trial
 Low-dose vs. high dose lisinopril
 2.5 to 5 mg QD or 32.5 to 35 mg qd





N = 3,164
Average age 63.6 years
NYHA II-IV
EF ≤ 30%
High dose group had:
 12% lower risk of death or hospitalization for any reason (P=0.002) for
high
 24% fewer hospitalizations for heart failure (P=0.002)
 Risk of death reduced 8% in the high dose group (P=0.128)
Packer M et al. Circulation 1999;100:2312-8.
CONSENSUS Trial
Probability of death
0.8
Placebo
0.7
0.6
p< 0.001
0.5
p< 0.002
0.4
Enalapril
0.3
0.2
0.1
0
0
1
2
3
4
5
6
7
Months
CONSENSUS. N Engl J Med 1987;316:1429-35.
8
9
10
11
12
SOLVD Trial (Treatment Arm)
0.8
Placebo
Placebo
Percent Survival
0.7
n=1284
p< 0.001
0.6
p = 0.0036
0.5
p< 0.002
0.4
Enalapril
n=1285
Enalapril
0.3
0.2
n = 2589
CHF
- NYHA II-III
- EF < 35
0.1
0
0
6
SOLVD. N Engl J Med 1991;325:293-301.
12
18
24
Months
30
36
42
ACE Inhibitors: Contraindications/
Risk-Benefit Considerations
 Contraindications
 Known bilateral renal artery stenosis
 History of angioedema
 Pregnancy
 Risk-benefit considerations
 Systolic blood pressure < 90 mm Hg
 Serum creatinine > 3 mg/dL
 Serum potassium > 5.5 mEq/mL
Angiotensin Receptor Blockers (ARBs)
(e.g., losartan, valsartan)
 Similar benefit to ACEIs
 “recommended in patients with current or
prior symptoms of HF and reduced LVEF
who are ACE inhibitor-intolerant”
 Routine combined use of ACEI, ARB and
aldosterone antagonist is not recommended
 Monitor for:




43
Hypotension
Angioedema (<1%)
Elevated potassium
Elevated serum creatinine
© Omnicare, Inc. 2013
Yancy CW, et al. 2013 ACCF/AHA Heart Failure Guidelines
Jessup M, et al. 2009 ACCF/AHA guidelines Circulation. 2009;119:1977–2016.
Angiotensin II Receptor
Blockers (ARB): Mechanism of Action
RENIN
Angiotensin I
Angiotensinogen
ACE
Other pathways
ANGIOTENSIN II
AT1
Receptor
Blockers
AT1
Vasoconstriction
RECEPTORS
Proliferative
Action
AT2
Vasodilatation
Antiproliferative
Action
ACC/AHA Guidelines on the Role of ARBs in
HF Therapy
 Several clinical trials with ARBs failed to show mortality
benefit in heart failure
 ARBs should not be considered equivalent or
superior to ACE inhibitors in the treatment of HF
 ARBs should not be used for the treatment of HF in patients who
have had no prior use of an ACE inhibitor
 ARBs should be used in patients with angioedema or an
intractable cough on an ACE-I. ARBs are as likely as ACE-I to
produce hypotension, worsening renal function and hyperkalemia
2013 ACCF/AHA Heart Failure Guidelines . J Am Coll Cardiol. http://content.onlinejacc.org/
Val-HeFT: Comparison of Event Rates
Valsartan
(%)
Placebo
(%)
All-cause mortality
17.3
27.1
0.67
0.017
Morbidity/
mortality
24.9
42.5
0.56
<0.001
Cardiovascular
death
15.7
22.1
0.76
0.074
Sudden death with
resuscitation
0.5
1.1
0.46
0.529
Hospital admission
for HF
13.0
26.5
0.47
<0.001
Event
Maggioni AP et al. J Am Coll Cardiol 2002;40:1414-21.
RR*
p
CHARM Trial
 3 studies in one
 CHARM-Alternative: LVEF ≤ 40% and could not tolerate an ACE
inhibitor
 CHARM-Added: LVEF ≤ 40% who were currently taking an ACE
inhibitor, with or without a beta-blocker
 CHARM-Preserved: LVEF > 40%
 Overall-- showed ARB beneficial in terms of morbidity
and mortality in heart failure
Combination of ACEI and ARB in
Heart Failure Management
Background Therapy
N
ACEI +, Beta Blocker -
3034
ACEI +, Beta Blocker +
1610
ACEI -, Beta Blocker -
228
ACEI -, Beta Blocker +
140
Relative Risk of Death
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
Valsartan Better
Placebo Better
P=0.009
Test for heterogeneity
Cohn JN et al. NEJM 2001;345:1667-75
All-Cause Mortality in the VALIANT Study
All-cause
mortality
(%)
Hazard ratio (95% CI)
compared with
captopril
p
value
19.5
-
-
Valsartan
(n=4909)
19.9
1
(0.90-1.11)
0.98
Combination
(n=4885)
19.3
0.98
(0.89-1.09)
0.73
Group
Captopril
(n=4909)
Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906.
VALIANT: Cardiovascular Death,
Recurrent MI, or Heart Failure Hospitalization
Secondary End Point
CV death, re-MI, or
heart-failure
hospitalization (%)
Hazard ratio
(95% CI)
compared with
captopril
p value
Captopril
(n=4909)
31.9
-
-
Valsartan
(n=4909)
31.1
0.95
(0.88-1.03)
0.20*
Combination
(n=4885)
31.1
0.97
(0.89-1.05)
0.37*
Group
*Not significant
Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906.
VALIANT: Incidence of Adverse Events
Any adverse
event (%)
Any
ADE leading to permanent
study drug discontinuation
(%)
Captopril
28.4
7.7
Valsartan
29.4
5.8*
Combination
34.8*
9.0*
Group
* Significant difference from captopril (p<0.05)
Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906.
Beta-Blockers (BBs)
(bisoprolol, carvedilol, or metoprolol
succinate XL)
 Prevent the speeding up of the damaged heart
 “recommended for all patients with current or prior symptoms of HF and
reduced LVEF, unless contraindicated”
 Start only if patients have stable fluid status and gradually increase the
dose as tolerated
 Titrate no sooner than every 2 weeks
 May initially worsen HF and may need to adjust diuretics to maintain pretreatment weight
 Monitor heart rate and blood pressure
 Typically held if pulse <60 beats per minute
 Monitor for hypoglycemia if diabetic
 May block symptoms of hypoglycemia except sweating
 Carefully assess risk vs. benefit for patients with:
 Reactive airway disease (e.g., asthma)
 COPD
 Peripheral vascular disease
52
2013 ACCF/AHA guidelines. http://content.onlinejacc.org/
Dosages of Beta-Blockers in Heart Failure
Drug
Starting
Dosage
Titration Sequence*
Maximum
Dosage
Bisoprolol
(Zebeta®)
1.25 mg/day Increase to 2.5 mg/day in 2-4 weeks, 10 mg/day
then increase to 5.0 mg/day in 2-4,
weeks, then increase to maximum
Carvedilol
(Coreg®)
3.125 mg
twice daily
Metoprolol 12.5 mg/day
extended
release
(Toprol XL®)
Increase to 6.25 mg bid in 2-4 weeks, 25 mg twice
then increase to 12.5 mg bid in 2-4
daily (50 mg
weeks, then increase to maximum
twice daily if >
85 kg)
Increase to 25 mg/day in 2-4 weeks,
then Increase to 50 mg/day in 2-4
weeks, then increase to 100 mg/day
in 2-4 weeks, then increase to
maximum
200 mg/day
*Doses should only be increased if resident tolerates current dose. Some
residents will not tolerate higher doses or may require slower titration.
ACC/AHA Heart Failure Guidelines, 2001; Farrell MH et al. JAMA 2002;287:890-97.
Diuretics
(furosemide, bumetanide, hydrochlorothiazide,metolazone)
 Reduce fluid volume to decrease workload of the heart
 Loop diuretics (e.g., furosemide) are generally more effective than
thiazide diuretics (e.g., hydrochlorothiazide)
 Thiazides are less effective with declining kidney function





Assess edema and monitor weight frequently
Often requires use/adjustment of potassium supplementation
Monitor electrolytes and kidney function routinely
Monitor for rash/photosensitivity
Combination therapy with a loop and thiazide diuretic may be
necessary in the presence of diuretic resistance
2013 ACCF/AHA guidelines . http://content.onlinejacc.org/
54
Action of Diuretics
Thiazides
Inhibit active exchange of Cl-Na in
the cortical diluting segment of the
ascending loop of Henle
CORTEX
K-sparing
Inhibit reabsorption of Na in distal
convoluted and collecting tubule
MEDULLA
Loop of Henle
Loop Diuretics
Inhibit exchange of Cl-Na-K in thick
segment of the ascending loop of
Henle
Collecting Tubule
Loop Diuretics
 Mechanism of action
 Act on the ascending limb of loop of Henle
 Increase potassium, magnesium and calcium excretion
 More effective than thiazide diuretics
 Adverse reactions
 Electrolyte/metabolic disturbances
 hypokalemia, hypomagnesemia, hyperglycemia, hyperuricemia





Metabolic alkalosis
Azotemia
Hypotension, including orthostasis
Ototoxicity
Other (rash, photosensitivity)
Thiazide Diuretics
 Mechanism of action
 No dose response
 Increase potassium, magnesium and calcium excretion more
than with loop diuretics
 Increase renal vasoconstriction
 Increase uric acid excretion
 Adverse reactions
 Electrolyte/metabolic disturbances
 hypokalemia, hypomagnesemia, hyperglycemia, hyperuricemia




Metabolic alkalosis
Azotemia
Hypotension, including orthostasis
Other (rash, photosensitivity)
Torsemide




Loop diuretic
Consistent absorption
Reduced fatigue
Fewer hospitalizations
 Lower cost of care
Murray MD, Deer MM, Ferguson JA et al. Open-label randomized trial of torsemide compared
with furosemide therapy for patients with heart failure. Am J Med. 2001;111:513-20.
Diuretic Resistance: Causes
 Delayed absorption of the diuretic
 Reduced secretion of the diuretic into the tubular lumen
(its site of action)
 Compensatory retention of sodium after the effective
period of the diuretic
 Hypertrophy and hyperplasia of epithelial cells of the
distal convoluted tubule
Diuretic Resistance: Management
 Rule out non-compliance
 Dose adjustment
 Intravenous bolus injection or continuous infusion of a
loop diuretic
 Combination diuretic therapy
 Metolazone use in combination with loops
 Given 30 minutes prior to loop administration
 Monitor closely for hypokalemia
Digoxin
 Increases the force and velocity of cardiac contraction while also
reducing the heart rate
 “can be beneficial in patients with current or prior symptoms of HF and
reduced LVEF to decrease hospitalizations for HF”
 2012 Updated Beers Criteria list 0.125 mg/day as the maximum
recommended dose
 Monitor pulse prior to giving each dose
 Monitor for signs/symptoms of toxicity (nausea, anorexia, visual
disturbances, electrolyte abnormalities, impaired cognition, weakness,
dizziness, hallucinations, etc)
 Monitor BMP and digoxin concentration routinely
 Serum drug concentration of 0.5-0.8 ng/mL is the recommended therapeutic
range
2013 ACCF/AHA guidelines. http://content.onlinejacc.org/
61
Digoxin
 Inhibits sodium-potassium adenosine triphosphatase
 Promotes calcium influx via sodium-calcium exchange
mechanism
 Results in an increase in the contractile state of the heart
 Stroke volume and cardiac output increase
 Indirect increase in parasympathetic tone
 Results in decrease in heart rate
 Direct and indirect decrease in sympathetic tone
 Secondary to impaired cardiac output
 Indirectly decreases sympathetic vasoconstriction
Digoxin: Mechanism of Action
Digoxin
Na-K ATPase
Na+ K+
K+ Na+
Na-Ca Exchange
Na+
Myofilaments
CONTRACTILITY
Ca++
Ca++
Digoxin: Clinical Use
 Therapy is initiated at dose of 0.125 mg for heart failure
 Lower doses such as every other day
 Some elderly
 Impaired renal function
 Caution in patients with significant sinus or
atrioventricular block
 Not indicated for stabilization of acute decompensated
heart failure
Serum Digoxin Concentrations
 Are lower digoxin concentrations effective?
 Methods
 Data from PROVED and RADIANCE
 Both were randomized, multi-center, double-blind clinical trials
 PROVED – diuretic vs. diuretic + digoxin
 RADIANCE – ACEI+diuretic vs. ACEI+diuretic+digoxin
 Compared digoxin withdrawal vs. continuation for worsening heart
failure
 Serum drug concentration (SDCs) obtained at baseline, 4, 8, and
20 weeks
Adams KF et al. J Am Coll Cardiol 2002;39:946-53.
Risk of Treatment Failure Based on
Randomization SDC Group
Treatment Group
Digoxin concentration
(SDC)
Relative
Risk
95% CI
P Value
< 0.9 ng/ml
0.09
0.01-0.66
0.018
> 0.9-1.2 ng/ml
0.22
0.08-0.61
0.004
> 1.2 ng/ml
0.17
0.06-0.44
<0.001
Relative risk and p values are based on the adjusted Cox proportional hazards analysis.
CI = confidence interval; SDC = serum digoxin concentration
Adams KF et al. J Am Coll Cardiol 2002;39:946-53.
Digoxin: Clinical Trials
 Digitalis Investigation Group (DIG Trial)





6,800 patients with ischemic and non-ischemic cardiomyopathy
Mild to moderate heart failure
Randomized to placebo or digoxin
Digoxin has no effect on mortality
Digoxin was associated with decreased risk of hospitalization (28%
CHF, 6% all cause)
 Digoxin level investigation (post-hoc of DIG Trial)
 SDCs of 1.2 ng/mL and higher may be harmful
 SDCs of ~ 1.0 ng/mL may not provide any clinical benefit vs.
placebo
 SDC of 0.5 to 0.8 ng/mL likely the optimal therapeutic range
The Digitalis Investigation Group. N Engl J Med 1997;336:525-33.
DIG Clinical Trial
50
Percent Mortality
40
Placebo
N=3403
30
20
P=0.8
Digoxin
N=3397
10
n = 6800
NYHA II-III
0
0
12
24
Months
The Digitalis Investigation Group. N Engl J Med 1997;336:525-33.
36
48
Digoxin Concerns in the Elderly
 Narrow therapeutic index
 Age related decrease in renal function
 Results in increased serum digoxin concentrations
 May cause delirium
 Drug-drug interactions
 Affect digoxin bioavailability or excretion
 Increase risk of digoxin toxicity
 Reduced skeletal mass
 Reduced volume of digoxin distribution
Aronow WS. J Am Geriatr Soc 1997;45:1252-8.
Digoxin and Women
Women
digoxin
(%)
Women
Placebo
(%)
p
Absolute diff.
between sexes
(%)*
Death from any
cause
33.1
28.9
0.078
5.8
Death from CV
causes
27.8
24.1
0.098
4.3
Death from
worsening HF
12.4
11.9
0.750
2.8
Hospitalization for
worsening HF
30.2
34.4
0.079
4.7
Outcome
*Absolute difference between the effect of digoxin compared with the effect of placebo
among women vs the same comparative effect in men; p was significant for death from
any cause (p=0.034) and marginally significant for hospitalization for worsening HF
(p=0.053).
Rathore SS et al. N Engl J Med 2002;347:1403-11.
Aldosterone Antagonists (AAs)
(e.g., spironolactone, eplerenone)
 Block aldosterone-induced increases in vasoconstriction
and sodium reabsorption
 “Addition of an aldosterone antagonist is reasonable in selected patients
with moderately severe to severe symptoms of HF and reduced LVEF
who can be carefully monitored for preserved renal function and normal
potassium concentration.”
 SCr should be  2.5 mg/dL for men and  2.0 mg/dL in women
 K+ should be  5.0 mEq/L
 Eplerenone is NOT suggested for those over 75 years of
age due to lack of survival benefit
 Monitor BMP and kidney function routinely
 Minimize concomitant use of potassium supplements,
especially in combination with an ACEI or ARB
 Monitor for endocrine disturbances (e.g., gynecomastia)
2013 ACCF/AHA guidelines http://content.onlinejacc/org
71
Aldosterone Antagonists: Mechanism of
Action
Spironolactone
ALDOSTERONE
Competitive antagonist of the
aldosterone receptor
(myocardium, arterial walls, kidney)
• Retention Na+
• Retention H2O
• Excretion K+
• Excretion
Mg2+
Edema
Collagen
deposition
Fibrosis
Arrhythmias
- myocardium
- vessels
Spironolactone: Indications
 Recent or current symptoms despite ACEI, diuretics,
digoxin, and beta-blockers
 Recommended in advanced heart failure (II-IV), LVEF
of ≤ 35%, in addition to ACEI and diuretics
 Hypokalemia
-ESC HF guidelines 2001
2013 ACCF/AHA guidelines http://content.onlinejacc/org
Background – The RALES Study
 Pts with NYHA Class III & IV HF on ACEI’s and loop
diuretics were randomized to either 25 mg of
spironolactone or placebo (avg dose = 26 mg)
 Spironolactone group had a 30% reduction in risk of
death and 35% reduction in hospitalization for
worsening HF
Pitt B, et al. N Engl J Med 1999;341:709-17.
RALES Trial: Spironolactone
Annual Mortality
Aldactone 18%; Placebo 23%
1.0
Survival
0.9
0.8
Aldactone
0.7
p < 0.0001
0.6
N = 1663
NYHA III-IV
Mean follow-up 2 y
0.5
Placebo
0
RALES. N Engl J Med 1999;341:709
6
12
18
months
24
30
36
RALES Results – patients with HF
Before
RALES
Before
RALES
After
RALES
Early 1994
Early 1999
Late 2001
(per 1000)
(per 1000)
(per 1000)
Spiro Rx’s
34
30
149*
Hyper K+
adms
2.4
4.0
11*
Hyper K+
deaths
0.3
0.7
2.0*
(*p<0.001)
Spironolactone: Contraindications/
Risk-Benefit Considerations
 Contraindications
 Potassium concentration > 5.5 mEq/L
 Risk-benefit considerations
 Concomitant use with potassium supplements
 Life threatening hyperkalemia when used with ACE inhibitors
or ARBs
Eplerenone
 Potassium-sparing diuretic
 Lower affinity than spironolactone for progesterone and
androgen receptors
 Ephesus trial showed statistically significant reduction in
death versus placebo
 More expensive than spironolactone
 Those over 75 years did not respond to treatment
Pitt B et al. N Engl J Med 2003; 348:1309-21.
Pitt B 2003. Circulation 2003;108:1790
Hydralazine/Isosorbide Dinitrate
 Hydralazine is a peripheral arterial vasodilator
 Isosorbide is a peripheral venous vasodilator
 Working together they mimic vasodilating action of ACEIs
 “recommended to improve outcomes for patients self-described as
African-Americans, with moderate-severe symptoms on optimal
therapy with ACE inhibitors, beta blockers, and diuretics.”
 “patients with reduced LVEF who cannot be given an ACE inhibitor
or ARB because of drug intolerance, hypotension, or renal
insufficiency.”
 Monitor closely for hypotension, worsening edema, or
headaches
2013 ACCF/AHA guidelines http://content.onlinejacc/org
79
Inotropic Support
[e.g., Dopamine, Dobutamine, Milrinone
(Primacor®)
 Increase force of cardiac contraction
 May provide symptom improvement but result in overall
increase in mortality
 Central line access required
 Monitor for:





Hypotension
Arrhythmias
Dizziness/Headache
Adequate fluid intake
Peripheral blood perfusion
2013 ACCF/AHA guidelines http://content.onlinejacc/org
80
2013 Guidelines for Inotropic Support
 Until definitive therapy (e.g. coronary revascularization,
mechanical circulatory support (MCS), heart transplantation) or
resolution of the acute precipitating problems.
 Patients with cardiogenic shock should receive temporary
intravenous inotropic support to maintain systemic perfusion and
preserve end-organ performance
 Continuous inotropic support reasonable as “bridge therapy” in
patients with Stage D refractory to medication therapy and
device therapy who are eligible for and awaiting MCS or cardiac
transplantation
 Palliative therapy in stage D despite optimal medication therapy
and device therapy who are not eligible for MCS or
transplantation
 Potentially Harmful – absence of specific indications noted
above
2013 ACCF/AHA guidelines http://content.onlinejacc/org
81
Therapeutic Concerns When Treating HF
82
Therapeutic Concerns with HF in the Elderly
Problem
Suggestions
Hypotension
Start therapies at lower doses
and titrate upward slowly as
tolerated
Hyperkalemia
(with ACEIs, ARBs, AAs)
Avoid concomitant potassium
supplements when possible
Adjust diuretic use
Monitor BMP routinely
Other electrolyte
abnormalities
(e.g., hypokalemia)
Monitor BMP routinely
Monitor fluid status closely
Adjust dietary intake as
necessary
83
© Omnicare, Inc. 2013
Therapeutic Concerns with HF in the Elderly
Problem
Suggestions
Digoxin toxicity
Monitor closely for signs and
symptoms (e.g., nausea, visual
disturbances)
Maintain serum drug
concentration at 0.5-0.8 ng/mL
Monitor kidney function and
electrolytes
Bradycardia
Avoid other drugs that affect heart
fate
Titrate beta blocker dose slowly
Gradually get out of bed/chair
Monitor pulse routinely
© Omnicare, Inc. 2013
84
Actions for Monitoring Heart Failure
 Routine assessment of vital signs (BP, pulse)
 Frequent assessment of weight (e.g., 3 times per week)
 Establish “dry weight”
 Establish threshold for notifying the prescriber (e.g., increase of 3 lbs)
 Monitor for signs of congestion and/or edema
 Increased cough or shortness of breath (especially at night or while
lying down)
 Abdominal or lower extremity swelling
 Monitor for decreased blood perfusion




Cool extremities
Resting tachycardia
Increased confusion
BUN:Cr ratio 20:1 or greater (dehydration)
© Omnicare, Inc. 2013
85
Heart Failure Clinics
 Dedicated clinics to heart failure
 Nurse practitioner trained in heart failure
 Greater access to a clinician
 “Brittle” patients need periodic medication adjustments
 Cheaper
 Reduces repeat hospitalizations
 Reduces morbidity and mortality
87
Ouslander JG, et al. INTERACT® Licensed Materials. http://www.interact2.net/index.aspx
Back to the Case
88
83 year old Caucasian male, Clcr 63 mL/min, dry weight of 160 lb (72.2 kg)
who presented to the nurse practitioner with complaints of shortness of
breath and productive coughing for the last 4 weeks
 BP-90/64, HR-100, RR-20, T98.6
 PMH: NYHA stage IV HF,
glaucoma, coronary artery
disease, hypertension, ocular
strokes
 HPI: hospitalized the
previous year twice for
syncope associated with
heart failure. Cardiac arrest
during one hospitalization
following administration of
ramipril 2.5 mg
 CXR: no infiltrates
 Labs: WBC – wnl
Medication
aspirin EC
clopidogrel
furosemide
metoprolol
mirtazapine
zolpidem
simvastatin
spironolactone
digoxin
Vitamin D3
Vitamin E
latanoprost
furosemide
Dose
81 mg
75 mg
40 mg
50 mg
30 mg
5 mg
40 mg
25 mg
0.0625 mg
1,000 units (2 tabs)
400 units
1 drop each eye
40 mg
40 mg
40 mg (2 tabs)
40 mg (2 tabs)
40 mg (4 tabs)
Frequency
once daily
once daily
once daily
twice daily
at bedtime
at bedtime
at bedtime
once daily
once daily
once daily
once daily
at bedtime
wt ≤ 162 = no dose
wt 163 - 167, 1 tab
wt 168, 2 tabs
wt 169, 2 tabs twice daily
wt 170, 2 tabs twice daily
Response of BP and Weight to
Furosemide Therapy
Zarowitz, BJ, Heart failure management and the war between evidence-based guidelines
and common sense. Geriatr Nurs 2013; 34: 230 – 2.
90
Summary
 HF is associated with a high rate of emergency
department visits, rehospitalizations, and overall
morbidity and mortality
 Vigilance in monitoring for signs and symptoms of HF is
essential
 Evidence-based medications and non-pharmacological
interventions are an important part of improving the care
of HF patients
 Early intervention in exacerbations can reduce
rehospitalizations
© Omnicare, Inc. 2013
91
Questions
Thank you for this opportunity!