Download - Pharmacologic Considerations for Reducing Hospital Readmission in Geriatric Patients with Heart Failure Barbara J. Zarowitz, Pharm.D. Chief Clinical Officer,

Pharmacologic Considerations for Reducing Hospital Readmission in

Geriatric Patients with Heart FailureBarbara J. Zarowitz, Pharm.D.

Chief Clinical Officer, Vice President of Clinical ServicesOmnicare, Inc., and

Adjunct Professor of Pharmacy PracticeCollege 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.

2Heart Failure Clinical Program © Omnicare, Inc. 2013

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, T-98.6

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 Dose Frequencyaspirin EC 81 mg once dailyclopidogrel 75 mg once dailyfurosemide 40 mg once dailymetoprolol 50 mg twice dailymirtazapine 30 mg at bedtimezolpidem 5 mg at bedtimesimvastatin 40 mg at bedtimespironolactone 25 mg once dailydigoxin 0.0625 mg once daily

Vitamin D31,000 units (2 tabs) once daily

Vitamin E 400 units once dailylatanoprost 1 drop each eye at bedtimefurosemide 40 mg wt ≤ 162 = no dose

40 mg wt 163 - 167, 1 tab

40 mg (2 tabs)wt 168, 2 tabs

40 mg (2 tabs)wt 169, 2 tabs twice daily


Heart Failure Pathophysiology

What is Heart Failure?

6

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Definition of HF

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• 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

Pathophysiology of Heart FailureCausal Factors

Myocardial Damage

Myocardial Failure

SVR (afterload)

Blood Volume (preload)

Cardiac output LV end diastolic pressure

Compensatory Responses

RAA SNS ANF

Vasopressin

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Pumping and Filling Problems and Heart Failure

The enlarged ventricles fill with blood

The ventricles fill normally with blood

The stiff ventricles fill with less blood than normal

The ventricles pump out ~60% of the blood

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

NORMALSYSTOLIC

DYSFUNCTIONDIASTOLIC

DYSFUNCTION

Diastole

(Filling)

Systole

(Pumping)


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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

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Roger VL et al. Heart disease and stroke statistics—2012 update: a report from the AmericanHeart Association. Circulation. 2012;125:e2–e220.Hutt E et al. J Am Med Dir Assoc 2011; 12:595-601


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

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Roger VL et al. Heart disease and stroke statistics—2012 update: a report from the AmericanHeart Association. Circulation. 2012;125:e2–e220.


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

Middle AgeElderly

(≥ 65 years)Prevalence <1% ≈10%

Gender M > F F > M

Etiology Coronary artery disease Hypertension

LVEF Reduced Normal

Comorbidities Few Multiple

RCTs Many Few

Therapy Evidence-based Empiric

Physician Cardiologist Primary care

M=male; F=female; LVEF=left ventricular ejection fraction; RCT=randomized clinical trial

Features Distinguishing Heart Failure in the Elderly from Heart Failure Occurring During Middle Age

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 acid-

dependent 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 ageElimination Clcr declines progressively with age- 0.75

mL/min/year14

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Underlying Causes of Heart Failure

Heart Failure

Hypertension Drugs

Infections

Valvular Heart Disease

Cardiovascular disease

Connective tissue disease

Coronary Artery Disease

Alcohol

Tachycardia

Nutritional and metabolic disorders

Neuromuscular disease

Radiation


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Selected Risk Factors for Heart Failure

Unmodifiable

Modifiable

TreatableMyocardial infarction

Kidney disease

Non-white race

Family history

Male sex

Age

Smoking

Obesity/Diet

Physical inactivity

Alcohol consumption

Mental stress

Depression

Sleep disordered breathing

Heart disease

Hyperlipidemia

HYPERTENSION

Valve disease

Diabetes

AFib

Kenchaiah S et al. Med Clin N Amer 2004:88;1145-72. © Omnicare, Inc. 2013

Risk Factors for Heart Failure

Strongly and consistently associated with HF

Less consistently associated with HF

AgeMale sexHypertensionElectrocardiographic LV

hypertrophyMyocardial infarctionDiabetes Valve diseaseOverweight/obesity

Excessive alcohol consumptionSmokingDyslipidemiaRenal insufficiencySleep-disordered breathingLow physical activityLow socioeconomic statusCoffee consumptionDietary sodium intakeIncreased heart rateImpaired pulmonary functionMental stress and depression

Kenchaiah S et al. Med Clin N Amer 2004:88;1145-72.

Medications That May Exacerbate Heart Failure

Agents Rationale

Antiarrhythmic agents (avoid disopyramide and flecanide; amiodarone and dofetilide are acceptable, if necessary, for arrhythmia)

Calcium channel antagonists (diltiazem, verapamil)ItraconazoleTerbinafine

Negative inotropic effects

Alcohol (excessive amounts in predisposed patients)DoxorubicinDaunomycinCyclophosphamide

Cardiotoxic

AndrogensCOX-2 inhibitorsEstrogensGlucocorticoidsNonsteroidal anti-inflammatory drugsSalicylates (high doses)Sodium-containing drugs (e.g., ticarcillin)Thiazolidinediones (rosiglitazone, pioglitazone)

Sodium and waterretention

AlbuminBlood products

Osmotic agents

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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 © Omnicare, Inc. 2013

Congestive Heart Failure

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The FACES of Heart Failure

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• 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


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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

BNP (pg/mL) Interpretation

<100 Reliably rules out HF

100-399 Possible HF(~75% of cases are HF)

>400 Suggestive of HF


BNP Diagnostic AlgorithmDyspnea

Physical Examination, Chest XR, ECG, BNP Level

BNP 100-400 pg/ml

Baseline LV Dysfunction,Underlying Cor Pulmonale,Or Acute Pulmonary Embolism

Yes No

BNP <100pg/ml BNP >400pg/ml

CHF Very Unlikely(2%)

Possible Exacerbation of

CHF (25%)

CHF Likely(75%)

CHF Very Likely(95%)

Adapted from: Tabbibizar R, Maisel A. Curr Opin Cardiol. 2002;17:343.

BNP for Diagnosis

0

500

1000

1500

2000

2500

Mild Moderate Severen = 27 n = 34 n = 36

BN

P C

on

cen

trat

ion

(pg

/ml)

186 + 22

791 + 165

2013 + 266

BNP concentration for the degree of heart failure severity

Maisel A et al. J Am Coll Cardiol 2001;37(2)379-85.

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

http://content.onlinejacc.org/

Heart Failure with Reduced EF

Treatment Approaches for Heart Failure

27

28

Goals of Treatment

Survival

Exercise capacity

Quality of life Morbidity

Progression of disease

Symptoms


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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

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Classification of HF

ACC/AHA Heart Failure Stage NYHA Functional Class

A 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)

D Refractory HF requiring specialized interventions

IV Symptomatic at rest resulting in inability to carry on any physical activity without discomfort (severe HF)


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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

* - not all inclusive † - amiodarone or Tikosyn (dofetilide) are acceptable alternatives if necessary for arrhythmias

Avoid or minimize use whenever possible. Monitor closely if must be used.

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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


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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

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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”

Yancy CW, et al. 2013 ACCF/AHA Heart Failure Guidelines © Omnicare, Inc. 2013

34

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

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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



VASOCONSTRICTION VASODILATATION

Kininogen

Kallikrein

Inactive Fragments

Angiotensinogen

Angiotensin I

RENIN

Kininase IIKininase IIInhibitorInhibitor

ALDOSTERONE

SYMPATHETICVASOPRESSIN

PROSTAGLANDINS

tPA

ANGIOTENSIN IIANGIOTENSIN II

BRADYKININBRADYKININ

ACE-I: Mechanism of Action

A.C.E.A.C.E.

ACE Inhibitors

HypotensionRenal dysfunctionHyperkalemiaCoughAngioedemaNeutropenia

Prolonged survival* Clinical improvement More stable clinical course Fewer hospitalizations Slower disease progression

RISKS BENEFITS

* Not an indication for all ACEIs

ACE Inhibitors: Indications and Doses

INDICATION

Agent 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

ACE = angiotensin-converting enzyme, LV = left ventricular

HF = heart failure, MI = myocardial infarction

ACE Inhibitors, Heart Failure, and Mortality Reduction

STUDY ACE-I Patients Duration Results

CONSENSUSMean age 71

Enalapril2.5-40 mg/d vs. placebo

N=253Class IV HF

12 months

6 month mortality ↓ 40%1 year mortality ↓ 31%Death from progressive HF ↓ 50%

SOLVDMean age 60

Enalapril10 mg bid vs. placebo

N=2,589EF < 35%

42 months

3.5 year mortality ↓ 16%Death or CHF hospitalization ↓26%CV hospitalization ↓ 10%

AIREMean age 65

Ramipril2.5-5 mg bid

N=2,006HF post MI

30 months

All cause mortality ↓ 17%Risk of 1st event ↓ 19%

SAVE Captopril12.5-150 mg/d vs. placebo

N=2,231EF < 40%Post MI

42 months

All cause mortality ↓ 19%CV death ↓ 21%CHF development ↓ 37%Recurrent MI ↓ 25%

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.

PlaceboPlacebo

EnalaprilEnalapril

12111098765

0.1

0.8

0

0.2

0.3

0.7

0.4

0.5

0.6p< 0.001p< 0.001

p< 0.002p< 0.002

43210

CONSENSUS TrialP

roba

bili

ty o

f dea

th

MonthsCONSENSUS. N Engl J Med 1987;316:1429-35.

PlaceboPlacebo

EnalaprilEnalapril

0.1

0.8

0

0.2

0.3

0.7

0.4

0.5

0.6 p< 0.001p< 0.001

p< 0.002p< 0.002

SOLVD Trial (Treatment Arm)

Pe

rce

nt S

urv

ival

Months

SOLVD. N Engl J Med 1991;325:293-301.

p = 0.0036p = 0.0036

Enalapriln=1285Enalapriln=1285

Placebon=1284Placebon=1284

0 6 12 2418 30 36 42

n = 2589

CHF

- NYHA II-III

- EF < 35

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

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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: Hypotension Angioedema (<1%) Elevated potassium Elevated serum creatinine

43

Yancy CW, et al. 2013 ACCF/AHA Heart Failure GuidelinesJessup M, et al. 2009 ACCF/AHA guidelines Circulation. 2009;119:1977–2016.


RENINRENIN

Angiotensinogen Angiotensin I

ANGIOTENSIN II

Angiotensin I

ANGIOTENSIN II

ACEOther pathways

Vasoconstriction Proliferative Action

Vasodilatation Antiproliferative Action

AT1 AT1 AT2AT2

AT1 Receptor Blockers

AT1 Receptor Blockers

RECEPTORSRECEPTORS

Angiotensin II Receptor Blockers (ARB): Mechanism of 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

Event Valsartan

(%) Placebo

(%) RR* p

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

Maggioni AP et al. J Am Coll Cardiol 2002;40:1414-21.

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

Background Therapy

ACEI +, Beta Blocker - 3034

0.2 0.4 0.6 0.8 1.01.2 1.4 1.6 1.8

N

P=0.009Test for heterogeneity

Relative Risk of Death

Valsartan Better Placebo Better

Combination of ACEI and ARB in Heart Failure Management

ACEI +, Beta Blocker + 1610

ACEI -, Beta Blocker - 228

ACEI -, Beta Blocker + 140

Cohn JN et al. NEJM 2001;345:1667-75

All-Cause Mortality in the VALIANT Study

Group

All-cause mortality

(%)

Hazard ratio (95% CI) compared with

captopril p

valueCaptopril (n=4909) 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

Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906.

VALIANT: Cardiovascular Death, Recurrent MI, or Heart Failure

Hospitalization

Group

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*

*Not significantPfeffer MA et al. N Engl J Med 2003; 349:1893-1906.

Secondary End Point

VALIANT: Incidence of Adverse Events

Group 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*

Pfeffer MA et al. N Engl J Med 2003; 349:1893-1906.

* Significant difference from captopril (p<0.05)

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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 pre-treatment 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

2013 ACCF/AHA guidelines. http://content.onlinejacc.org/


Dosages of Beta-Blockers in Heart Failure

DrugStarting Dosage Titration Sequence*

Maximum Dosage

Bisoprolol(Zebeta®)

1.25 mg/day Increase to 2.5 mg/day in 2-4 weeks, then increase to 5.0 mg/day in 2-4, weeks, then increase to maximum

10 mg/day

Carvedilol (Coreg®)

3.125 mg twice daily

Increase to 6.25 mg bid in 2-4 weeks, then increase to 12.5 mg bid in 2-4 weeks, then increase to maximum

25 mg twice daily (50 mg twice daily if > 85 kg)

Metoprolol extended release (Toprol XL®)

12.5 mg/day 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

ACC/AHA Heart Failure Guidelines, 2001; Farrell MH et al. JAMA 2002;287:890-97.

*Doses should only be increased if resident tolerates current dose. Some residents will not tolerate higher doses or may require slower titration.

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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

542013 ACCF/AHA guidelines . http://content.onlinejacc.org/


Action of Diuretics

ThiazidesInhibit active exchange of Cl-

Na in the cortical diluting segment of the ascending

loop of HenleK-sparing

Inhibit reabsorption of Na in distal convoluted and

collecting tubuleLoop Diuretics

Inhibit exchange of Cl-Na-K in thick segment of the

ascending loop of Henle

Collecting Tubule

Loop of Henle

MEDULLA

CORTEX

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

61

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/


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

Na+

K+

K+

Na+

Na+ Ca++

Ca++

Na-K ATPase Na-Ca Exchange

Myofilaments

Digoxin

CONTRACTILITY

Digoxin: Mechanism of Action

-

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 GroupRelative

Risk 95% CI P Value

Digoxin concentration(SDC)

< 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.

50

40

30

20

10

0

480 12 24 36

DIG Clinical Trial

The Digitalis Investigation Group. N Engl J Med 1997;336:525-33.

Months

Pe

rce

nt M

orta

lity

n = 6800

NYHA II-III

P=0.8

PlaceboN=3403

DigoxinN=3397

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

Outcome

Women digoxin

(%)

WomenPlacebo

(%) 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

*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.

71

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

http://content.onlinejacc/org

ALDOSTERONE

• Retention Na+

• Retention H2O

• Excretion K+

• Excretion Mg2+

Collagen deposition

Fibrosis - myocardium - vessels

SpironolactoneSpironolactone

Edema

Arrhythmias

Competitive antagonist of thealdosterone receptor(myocardium, arterial walls, kidney)

Aldosterone Antagonists: Mechanism of Action

· 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

Spironolactone: Indications

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.

Aldactone

Placebo

Surv

ival

1.0

0.9

0.8

0.7

0.6

0.5

0 6 12 18 24 30 36

months

p < 0.0001

Annual MortalityAldactone 18%; Placebo 23%

N = 1663NYHA III-IVMean follow-up 2 y

RALES Trial: Spironolactone

RALES. N Engl J Med 1999;341:709

RALES Results – patients with HF

Before RALES

Before RALES

After RALES

Early 1994 (per 1000)

Early 1999 (per 1000)

Late 2001 (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

79

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

79



80

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 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

81



Therapeutic Concerns When Treating HF

82

83

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 possibleAdjust diuretic useMonitor BMP routinely

Other electrolyte abnormalities(e.g., hypokalemia)

Monitor BMP routinelyMonitor fluid status closelyAdjust dietary intake as necessary


84

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/mLMonitor kidney function and electrolytes

Bradycardia Avoid other drugs that affect heart fateTitrate beta blocker dose slowlyGradually get out of bed/chairMonitor pulse routinely


85

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)


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

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, T-98.6

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 Dose Frequencyaspirin EC 81 mg once dailyclopidogrel 75 mg once dailyfurosemide 40 mg once dailymetoprolol 50 mg twice dailymirtazapine 30 mg at bedtimezolpidem 5 mg at bedtimesimvastatin 40 mg at bedtimespironolactone 25 mg once dailydigoxin 0.0625 mg once daily

Vitamin D31,000 units (2 tabs) once daily

Vitamin E 400 units once dailylatanoprost 1 drop each eye at bedtimefurosemide 40 mg wt ≤ 162 = no dose

40 mg wt 163 - 167, 1 tab

40 mg (2 tabs)wt 168, 2 tabs



Response of BP and Weight to Furosemide Therapy

90Zarowitz, BJ, Heart failure management and the war between evidence-based guidelines and common sense. Geriatr Nurs 2013; 34: 230 – 2.

91

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


Questions

Thank you for this opportunity!