Pharmacological Treatment of Heart Failure in the Elderlys3.amazonaws.com/zanran_storage/ filePharmacological Treatment of Heart Failure in the Elderly ASCP Annual Meeting and Exhibition

Pharmacological Treatment ofHeart Failure in the Elderly

ASCP Annual Meeting and Exhibition – November 11th 2010

Spencer A. Morris, Pharm.D., BCPSSoutheastern Continuing MedicalEducation Consultants, LLCGeorgetown, South Carolina

Heart failure is very common in the elderly and is the

most common Medicare diagnosis-related group. Heart failure

patients require an extensive medication regimen to maintain

symptom and disease control and are predisposed to drug

interactions and medication-related adverse effects. Long-term

care pharmacists can expand and enhance their role in the

management of heart failure patients through a thorough

understanding of this chronic medical condition and the

appropriate medications used to treat it.

ABSTRACT

Southeastern Continuing Medical EducationConsultants, LLC, DOES NOT have any financialrelationships with any manufacturers of anycommercial pharmaceutical products and does notaccept any pharmaceutical industry funding forplanning or organization of its programs, ashonoraria for its speakers, or in any otherapplicable manner, nor does it plan to in the future.

Commercial Support Disclosure Policy:

Educational Objectives

1) Recognize which forms of heart failure affectpredominantly the elderly and genderdifferences in heart failure type and prevalence

2) Identify differences in systolic and diastolic heartfailure in terms of pathophysiology andapproach to treatment

3) Identify the appropriate dose and importantsafety considerations for medications commonlyutilized in older patients with heart failure

Educational Objectives

4) Interpret historical and recent clinical trialfindings and their impact on heart failuretreatment recommendations for geriatricpatients

5) Identify medications which may exacerbateand/or precipitate heart failure.

Self-Assessment Questions:

1) Which of the following are appropriate ways toclassify/categorize heart failure?

A. Systolic vs. Diastolic heart failure

B. New York Heart Association Functional Classes

C. ACC/AHA Heart Failure Staging System

D. All of the above


2) What are the five major classes of medicationsused to treat heart failure patients?

1) __________________________________

2) __________________________________

3) __________________________________

4) __________________________________

5) __________________________________


3) Can you name at least one important patientsafety consideration associated with each typeof heart failure medication?____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________


4) Which of the following represents a therapeuticdigoxin level according to the best availableevidence?A. 2.0 nanograms/mLB. 1.5 nanograms/mLC. 1.0 nanograms/mLD. 0.5 nanograms/mL

5) What is an acceptable rise in serum creatinine,as a percentage from baseline, in a geriatricpatient started on an ACE-blocking drug?______

Part I.Background and OperationalDefinitions, New ClinicalTrial Information

Defining Heart Failure:

! ACC/AHA Definition:" A complex clinical syndrome that can result fromany structural or functional cardiac disorder thatimpairs the ability of the ventricles to fill with or ejectblood.

# Because not all patients have volume overload atthe time of initial or subsequent evaluation, theterm “heart failure” is preferred over the olderterm “congestive heart failure”

Defining Heart Failure:

! “ The situation when the heart is incapable of maintaining acardiac output adequate to accommodate metabolicrequirements and the venous return.” - Eugene Braunwald

! Acute cardiopulmonary edema vs. progressive disease

! End result of a variety of diseases

! “Because of the complexity of its many causes andpathophysiological origins, heart failure may escape aunifying definition.” - Prevention of Heart Failure. AHA ScientificStatement. Circulation 2008;117:2544-2565

! Over 5 million heart failure patients in the US! Over 550,000 new cases diagnosed each year! Over 1 million heart failure hospitalizations annuallywith half the patients readmitted within 6 months# Most common Medicare hospital discharge diagnosis

! Mortality rates remain high! The economic burden of heart failure continues togrow and more Medicare dollars are spent for thediagnosis and treatment of heart failure than for anyother diagnosis.

Heart Failure:Heart Failure:Scope of the ProblemScope of the Problem

Evolution of Heart FailureCellular Ventricular Ventricular

Risk Factors Pathopysiology Remodeling Dysfunction

AgingHypertensionDyslipidemiaDiabetesObesityToxinsGenes

HypertrophyInfaractionAcceleratedApoptosis

Fibrosis

LVHDilatationBoth

Systolic FailureDiastolic FailureBoth

Stage A Stage B StagesC and D

“pre-HF”Structural heart diseasewithout symptoms

SymptomaticHeart Failure

ACC/AHA Stages of Heart Failure

Established and Hypothesized Risk Factors for Heart Failure

ACC/AHA Classification of HF

$ Marked symptoms at rest despitemaximal medical therapy (e.g., those whoare recurrently hospitalized or cannot besafely discharged from the hospital withoutspecialized interventions)

Refractoryend-stage HF

! Known structural heart disease! Shortness of breath and fatigue! Reduced exercise tolerance

Symptomatic HF

! Previous MI! LV systolic dysfunction! Asymptomatic valvular disease

Asymptomatic HF

! HTN! CAD! DM! Family history of cardiomyopathy

High risk fordeveloping HF

Patient DescriptionHeart Failure Stages

A

B

C

D

New York Heart AssociationFunctional Classes

I. No limitations to physical activityOrdinary activity does not cause undue fatigue

II. Slight limitation of physical activitySymptoms develop with ordinary activity

III. Marked limitation of physical activityComfortable at rest but symptoms develop withless than ordinary activity

IV. Unable to carry out physical activitySymptoms present at rest

NYHA Functional Classes Heart Failure Stages

CLASS I - patients with no limitation ofactivities; they suffer no symptoms fromordinary physical activity

CLASS II - patients with slight, mildlimitation of activity; they are comfortablewith rest or with mild exertion

CLASS III - patients with markedlimitation of activity; they are comfortableonly at rest.

CLASS IV - patients who should be atcomplete rest, confined to bed or chair; anyphysical activity brings on discomfort andsymptoms occur at rest.

STAGE A – high risk for HF; nounderlying strucutural disease

STAGE D refractory heart failure

Relationship of the NYHA Functional Classes tothe ACC/AHA Heart Failure Staging System:

NO CORRELATION

STAGE C - Structural heartdisease with past or currentsymptoms of heart failure

STAGE B – structural disease byasymptomatic

Pathophysiologic Differentiationof Symptoms and Progression

!What produces symptoms?Hemodynamic abnormalities, such as changes incardiac function and peripheral hemodynamics

!What contributes to progression?Neurohormonal abnormalities, such as activationof the renin-angiotensin-aldosterone system(RAAS) and the sympathetic nervous system(SNS)

ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult.J Am Coll Cardiol. 2001;38:2101-2113.

Neurohormonal Activation in HF

Myocardial injury Initial fall in LV performance

Activation of RAS and SNS

Peripheral vasoconstrictionHemodynamic alterations

Heart failure symptomsMorbidity and mortality

Myocardial toxicity

Remodeling andprogressiveworsening ofLV function

The geometry of the heart muscle actuallychanges through “remodeling” followingmyocardial injury

Anatomically Normal heart Dilated heart

REMODELING

What type of Heart Failure are wedealing with?

• Diastolic heart failure follows a different natural historyfrom classic, symptomatic systolic dysfunction

• Data from the Framingham Heart Study indicate that fewerthan half of study patients who developed heart failure hada history of antecedent MI

• Several community-based studies indicate " to one-half ofHF patients have preserved LV function

MI

LVH

HTN

SystolicDysfunction

DiastolicDysfunction

HF

SmokingDyslipidemia

ObesityDiabetes

Normal LVstructure and

function LV remodelingSubclinical

LV dysfunction

Clinicalheartfailure

Years Years / months

Relationship between hypertension and progression toovert HF via the increasing incidence of MI and LVH

From “Demographics and concomitant disorders in heart failure” Lancet 2003;362:14758.

Systolic versus Diastolic?

Systolic Dysfunction• decreased pump function

• Cardiomegaly, eccentric leftventricle hypertrophy

• if enlarged left atrium andatrial fibrillation, lose atrialkick, decreased LV filling…

• etiology:• AMI• idiopathic dilated CM

Diastolic Dysfunction• decreased relaxation andcompliance of left ventricleimpairs ventricular filling

• concentric left ventricularhypertrophy

• normal “pump” function

• etiology:• systemic hypertension• hypertrophic CM

Demographics inSystolic and

Diastolic Failure

Diastolic HF(Hypertrophied Heart)

• More common in geriatrics

• More common in females

• Preserved or normal LVEF( > 40% to 50% )

• More commonly associatedwith systemic HTN; may existalone w/out SHF

Systolic HF(Dilated Heart)

• All ages affected

• Both sexes affected

• Depressed LVEF,(approx 40% or <)

• Commonly associatedwith previous MI; existsconcurrently with DHF

Adapted from: Medical Progress: Heart Failure. NEJM 2003; 348: 2007-2018.

Co-morbiditiesassociated withSystolic andDiastolic Failure:

HTN ++ +++DM ++ +++Previous MI +++ +Obesity + +++COPD 0 ++Sleep apnea ++ ++Longterm dialysis 0 ++A. fib (usually persistent) (usually paroxysmal)

Systolic Heart Failure Diastolic Heart Failure

Adapted from: Medical Progress: Heart Failure. NEJM 2003; 348: 2007-2018.

Physical Exam Findings

! Peripheral Edema/ Ascites! S3 or S4! Murmur! Cardiomegaly! Laterally displaced PMI(point of maximal impulse)

! Elevated jugularvenous pressures

! Elevated pulmonarycapillary wedgepressures

! Hepatic engorgement! Rales/ Crackles

SYMPTOMS – it is not possible todifferentiate the two forms of HF throughsymptomatology; the sx are the same

! Fatigue! Shortness of Breath (SOB)! Dyspnea on Exertion (DOE)! Weight Gain! Edema/ Ascites! Orthopnea/ PND (Paroxysmal Nocturnal Dyspnea)! Nocturia! Cough

Emergency department visits or hospitalizations(Meta-analysis of RCTs)

9Digoxin

One death over two years in patients with NYHAclass IV failure (RALES)

One death over 16 months for patients with post-MIheart failure diagnosis (EPHESUS)

9

44

Spironolactone

Eplerenone

One death over one year Meta-analysis

One hospitalization over one year of RCTs

23

13Beta blockers

One death over one year in patients with NYHAclass III and IV failure (CONSENSUS)

One death over one year in patients with NYHAclass I or II failure (Meta-analysis of RCTs)

6

100ACE inhibitors

OUTCOMES PREVENTEDNNTDRUG or

DRUG CLASS

The Evidence Base for Systolic Heart Failure

Evidence for using ACE-blockingdrugs for Diastolic Heart Failure:

36–compositeof CV death,hospitaladmission, MIor CVA over 3years

42 – forrecurrentadmissions forHF over 3Years

54%

N = 3023

60% NYHA Class II

38% NYHA Class III

2% NYHA Class IV

Candesartanadded tostandardHF therapyin patientswith LVEF> 40%

CHARM-Preserved

NumberNeeded toTreat

AverageLVEF ofstudy

participants

RepresentativePatient

Population

Backgroundand

ContextTrial

I-PRESERVE: Irbesartan in patientswith heart failure and preserved ejectionfraction. N Engl J Med 2008;359:2456-67.

! The renin angiotensin system (RAS) has a centralposition in vascular and myocardial remodeling thoughtto be involved in HF-PEF.

! Previous trials with RAS inhibitors in HF-PEF have notprovided overall favorable results although encouragingsignals were noted.

! There is currently no evidence-based treatment toimprove patient outcomes.

I-PRESERVE: Objectives

! To determine whether treatment with the angiotensinreceptor blocker irbesartan reduces mortality and morbidityin patientswith HF-PEF.

! To better define the characteristics, natural history, andunderlying mechanism of heart failure in this population.

Age "60 yearsCurrent HF symptoms

LVEF "0.45

NYHA Class III/IV

# Echo (LVH, LAE)# ECG (LVH, LBBB)# CXR congestion

I-PRESERVE: Entry Criteria

NYHA class II - IV#HF hosp. $6 months

Key Exclusions: SBP >160 mm Hg; prior EF <40%; ACS or stroke ! 3m,hypertrophic or restrictive CM, pericardial or valvular disease, significantpulmonary disease, creatinine >2.5, Hb <11

www.clinicaltrialresults.org

E. EUROPE 36%E. EUROPE 36%

LATIN AMERICA 17%LATIN AMERICA 17%

N. AMERICA 9%N. AMERICA 9%

293 enrolling sites in 25 countries

I-PRESERVE Subject Accrual by Region/CountryAll Randomized Subjects (N=4128)

Canada (3%)U.S.A (6%)

Argentina (9%)Brazil (4%)Mexico (4%)

CZ Republic (2%)Hungary (2%)Poland (7%)Russia (25%)

W. EUROPE 35%W. EUROPE 35%

Belgium (4%)Denmark (<1%)France (6%)Germany (6%)Greece (<1%)Italy (<1%)Netherlands (5%)Norway (<1%)Portugal (<1%)Spain (9%)Sweden (1%)Switzerland (<1%)UK and Ireland (2%)

AFRICA 1%AFRICA 1%

South Africa

AUSTRALIAAUSTRALIA

1%1%


Placebo

Forced titration MaintenanceEnrollmentSingle-blind2 weeks

W 2 W 4 W 8 M 6 M 10 M 14 to endEvery 4 months

75 mg 150 mg 300 mg

Follow-up continued until 1,440 primary endpoints occurred

N=4,128

I-PRESERVE: Study Design

Irbesartan

R

Only 1/3 pts couldenter on an ACEI

Randomized, double-blind, placebo controlled trial


I-PRESERVE: Outcomes• Primary endpoint: All cause mortality andprotocol-specified CV hospitalizations (for heartfailure, MI, unstable angina, stroke, ventricular oratrial arrhythmia).

• Secondary endpoints:– All cause mortality– CV death– HF death or HF hospitalization– CV death, MI or stroke– QoL (Minnesota)– Change in BNP levels


I-PRESERVE: Baseline Treatments

3230Lipid lowering

5958Antiplatelet

4039Calcium channel blocker

5958Beta-blocker

1413Digoxin

2625ACE-inhibitor

1515Spironolactone8284

Treatment (%)

Diuretic

Irbesartan(N = 2067)

Placebo(N = 2061)

38%39%

27%28%

Total % exposed during the study

72% 72%


I-PRESERVE: Primary EndpointDeath or protocol specified CV hospitalization

Months from Randomization

Cum

ulativeIncidenceof

PrimaryEvents(%)

40 -

0 -

10 -

20 -

30 -

0 6 12 18 24 36 4230 48 6054

2067 1929 1812 1730 1640 1513 12911569 1088 4978162061 1921 1808 1715 1618 1466 12461539 1051 446776

No. at RiskIrbesartanPlacebo

HR (95% CI) = 0.95 (0.86-1.05)Log-rank p=0.35 Placebo

Irbesartan


I-PRESERVE: Conclusions

! In I-PRESERVE, enrolled patients experiencedsubstantial mortality and cardiovascular morbidity.

! Irbesartan did not reduce the primary endpoint of deathand protocol-specified CV hospitalizations, nor did itsignificantly benefit prespecified secondary endpoints.

! The results are consistent with the two previous trials inpatients with HF-PEF that did not demonstrate a positiveeffect (re: CHARM-Preserved, PEP-CHF)

! For this large group of patients constituting half of allheart failure patients, there continues to be no specificevidence-based therapy.

! TOPCAT is a multi-center, international, randomized, double blindplacebo-controlled trial

! Patients will be recruited internationally from over 200 clinical centersin the US, Canada, Russia, Republic of Georgia, Argentina, andBrazil

! Patients will be randomized to spironolactone or placebo (standardtherapy)

! ENDPOINTS" The primary endpoint is a composite of cardiovascular mortality,aborted cardiac arrest or hospitalization for the management ofheart failure.

" Secondary endpoints include all-cause mortality, new onset ofdiabetes mellitus or atrial fibrillation, and quality of life.

www.topcatstudy.com

! TRIAL DESIGN" The trial duration is 4.25 years, with 2.0 years for subjectenrollment and an additional 2.25 years of follow-up, allowing foran average subject follow-up of 3.0 years.

" The trial will have 90% power to detect a relative reduction of 20%in the primary endpoint.

! ELIGIBILITY" Male or female age 50 years or older" Heart failure with preserved systolic function (determined bysigns and symptoms in conjunction with prior hospitaladmission and/or brain natriuretic peptide (BNP) level)

" Left ventricular ejection fraction > 45% (per local reading)" Controlled systolic blood pressure (SBP)" Serum potassium < 5.0 mmol/L.

www.topcatstudy.com

! Clinical Context" With the null results from I-PRESERVE, TOPCAT isevaluating the last possible treatment option for HFwith preserved EF through inhibition of the RAAS

" No preliminary results/findings are available at thistime; however, recruitment is ongoing. Study willconclude in 2012.

" TOPCAT results are very likely to determine futuredirections of research and optimal treatment for thiscondition.% Personal communication: Sonja McKinlay, PhD, Co-PrimaryInvestigator, New England Research Institutes, May 6th 2009

www.topcatstudy.com

Part II.

Pharmacologic Therapy

What are the Standard HFDrug Regimens?

Systolic Dysfunction! ACE-Inhibitors (or ARBs)! Diuretics! Digoxin! Beta-blockers! Aldosterone Antagonists

! Nitrates! Hydralazine! Felodipine/Amlodipine! Statins???

Diastolic Dysfunction! Negative Inotropes(beta-blockers, diltiazem,verapamil)

! ACE-Inhibitors/ARBs???! Diuretics! Aldosterone Antagonists???

Drug Class Mechanism of Action

Diuretics % preloadAldosterone Antagonists blunt neurohormonal toneDigoxin & inotropeACEI & ARBs blunt neurohormonal tone,

% preload and afterloadNitrates % preloadVasodilators % preload & afterloadBetablockers blunt neurohormonal tone,

' chronotropesNonDHP CCBs ' chronotropesDHP CCBs % afterload/vasodilators

The Mechanics of HF drugs:

! ACE-Inhibitors prevent conversion of Angiotensin I toAngiotensin II

! ARBs block Angiotensin II at receptor site

! Result: vasodilation/decreased SVR

! Result: Na & H20 excretion, K& absorption (check K &

levels!)

! Decrease preload and afterload

! Decrease BP by 10-20% from baseline

ACE-Inhibitors/ARBs –Pharmacologic Actions:

Recommendations for the use ofACE-Is & ARBs in Heart Failure:

# ACE-Is remain first-line therapy for the Tx of systolic heartfailure

# Reserve ARBs for those patients refractory to ACE-Is:# Intolerable cough# Angioedema

# The addition of ARBs to ACE-Is based on the results ofrecent hypertension trials ( ONTARGET) lead to more D/Cof therapy, ( HYPERkalemia and worsening of renalfunction

# Do NOT use combined ACE-I/ARB therapy for HF!

!1 receptor blockade onthe myocardium:

• %’s heart rate

• %’s BP

• %’s myocardial contractility

Beta-Blockers: Mechanism(s) of Action

!-blockade also indirectly % plasma renin levels

!2-blockadein theperiphery:

• (’s systemicvascular resistancedue to unopposed)-stimulation

• contracts vascularsmooth muscle andbronchial airways

Initiation and Maintenance of !-Blockersin Systolic Heart Failure:

• Start LOW and go SLOW:

• If patient experiences orthostasis upon initiation of the !-blocker, don’t give up, half the dose of ACE-I and diureticsand re-challenge

• ( dose in gradual increments if lower doses have been welltolerated

• Planned increments in the dose should be delayed until anyside effects observed with lower doses have disappeared

• With this approach, 85% of the patients in the clinical trialsreached target doses

Adaptation of the ACC/AHA Guidelines forInitiation and Maintenance of Beta-Blockers inSystolic Heart Failure

NYHAClass IIINOYES200mg daily12.5mg daily

Metoprolol Succinate(Toprol XL®)Extended- Release

NYHAClass III &

IVYESNO

25mg bid;50mg bid forpatients >85kg

3.125mg bidCarvedilol (Coreg®)

- - - - - - -NOYES75mgBID

6.25mg BIDMetoprolol Tartrate(Lopressor®)

NYHAClass II& III

NOYES10mg daily1.25mg dailyBisoprolol(Zebeta®)

Initial Target

HF PopStudied

)-blockingproperties?

*1Selective ?

Heart Failure Tx Doses*-Blocker

* Positive findings with these three agents SHOULD NOT be considered a class effect

Do beta-blockers have beneficialeffects in Diastolic Heart Failure?

! Yes !!!" Slow the heart rate (negative chronotropic agent) toallow LV filling

!NOT beta-blockers with ISA (intrinsicsympathomimetic activity):" Pindolol (Visken®)" Acebutalol (Sectral®)These agents will mildly increase the restingheart rate.

Evidence supporting diuretics inHeart Failure?

! Should NOT be used asmonotherapy

! Should be prescribed on an“as-needed” basis unlessshown to definitively requiredaily diuresis.

! Diuretics may perpetuate the “vicious cycle” ofneurohormonal activation in HF" stimulate renin release" increase peripheral vascular resistance" decrease cardiac output

Diurectic evidence in systolic &diastolic HF?

! Systolic:" symptomatically reduce preload and pulmonarycongestion

" diuretics should never be used alone !!!

!Diastolic:" deplete intravascular volume and impair diastolic filling(patients with diastolic dysfunction need elevated fillingpressure to maintain adequate stroke volume)

" use cautiously - excessive diuresis increases symptoms

Problems with diuretic use?

! Volume depletion impairing renal perfusion:" BUN/ Scr increases indicating contraction hypovolemia" Should decrease diuretic dose, even if pedal edema andpulmonary congestion present

" Do not mistake this for ACE-I induced renal dysfunction!

REALITY: Some patients with HF will never be able tocompletely resolve their edema (as it would lead to excessiveintravascular volume depletion and progressive renalimpairment).

" FIND A BALANCE between edema and BUN/SrCr elevations.

Problems with diuretic use?

!Electrolyte imbalances:" HYPOkalemia

" HYPOmagnesemia

" HYPOnatremia

" HYPERuricemia

" Rarely, alkalosis

Digoxin

!Cardiac Glycosides used for > 200 years! Isn’t using digoxin a given?

" Digoxin has inotropic activities (inhibits Na/K pump)and neurohormonal effects (improve LV fillingpressures and cardiac output)

!Who? Patients with systolic dysfunction" an S3 gallop" an enlarged heart" NOT appropriate in diastolic dysfunction…..

DIG Trial

! The DIG trial studied the effect of initiating digoxintherapy on mortality and hospitalizations in 6800patients over 37 months.

! Mean ejection fraction = 28%! NYHA Class I 13%

II 54%III 30%IV 2%

! Digoxin dosage 0.25 mg once daily! Digoxin level 0.86 ng/mL

DIG Results

Digoxin Placebo P value NNT

Mortality 34.8% 35.1% NS HF 11.6% 13.2% NS Other CV 15% 13% 0.04 50

Hospitalizations 64.3% 67.1% 0.006 35HF 26.8% 34.7% <0.001 13Susp. Toxicity 2.0% 0.9% <0.001 90

New Perspectives on Digoxin

!Renalysis of the DIG trial evaluated safety andefficacy of digoxin at varying serumconcentrations" < 1 mcg/mL reduced mortality

" > 1 mcg/mL increased mortality

! “Dig-lite” is best% optimized serum concentration 0.5 - 0.8 ng/mL

All-Cause Mortality Rates by SerumDigoxin Concentration Groups

(from JAMA 2003; 289: 871-878)

The figure presents the crude all-cause mortality rate with 95% confidence intervals and the risk-adjusted rate for patientsassigned to digoxin according to their serum digoxin concentration. The mortality rate in patients assigned to placebo ispresented for comparison. The risk-adjusted mortality rate was estimated using fractional polynomial modeling.

Digoxin

! Pharmacokinetics and dosing:

! Digoxin is NOT lipophilic; distributes intolean body tissue" i.e. geriatric patients are inherentlymore sensitive to digoxin’s pharmacodynamicand toxic effects

! Typically cited digoxin reference range is0.8 to 2.0 nanograms/mL

“Dig-Lite” is Best for SystolicHeart Failure:

! Target serum concentration 0.5 - 0.8 mcg/mL! Start at the lowest possible dosage

" 0.125 mg/day" titration to 0.25 mg/day may not be necessary

! Avoid in patients with normal LV function! Benefits are greatest in patients with severe SHF(enlarged heart, 3rd heart sound)

! The level of recommendation for use of digoxin has beenchanged from a Class I recommendation to a Class IIarecommmendation (re: reasonable to prescribe vs.should be routinely prescribed)

Digoxin use in Diastolic HeartFailure:

N/A – nostatisticaldifferencesbetween groupsin rates ofhospitalizationor mortality over3 years

Not Reported

N =988

NYHAClassification not

specified

Digoxin +ACE-Is &diuretics inpatients withLVEF > 45%

DIGAncillaryTrial

NumberNeeded toTreat

AverageLVEF ofstudy

participants

RepresentativePatient

PopulationBackgroundand ContextTrial

Suggested Algorithm for Managing HF symptoms with Digoxin

Patient presents with active HF

Diastolic HF – EF > 45%& inotropic therapy is NOTbeneficial

Systolic HF – EF < 45%

Determine HF severity – ACC/AHA Staging System

Stages A and B Stages C and D

Maximize risk factor reductionConsider empiric, low-dose digoxin for patients withpersistent symptoms on ACE-I, *-Blockers, diuretics +

Serum digoxin conc. = 0.5 to 1.0ng/mLSerum digoxin conc. > 1.0ng/mL

Current therapy at current dose & monitorEvaluate for causes of ( level

Avoid loading doses; max daily dose should usually be 0.125mg daily or EVERY OTHER DAY; use0.0625mg once daily in severe renal insufficiency.

+

Excerpted from: Morris SA, Hatcher H, Reddy DK. Am Fam Physician; 74: 613-8.

Guidelines to Minimize the Risk ofHyperkalemia in Patients treatedwith Aldosterone Antagonists

1) Considered impaired renal function before prescribing& Risk of HYPERkalemia increases significantly when Serum

Creatinine > 1.6mg/dL& Elderly patients, low muscle mass; calculate CrCL& Avoid use if calculated Creatinine Clearance < 30mL/min.

2) DO NOT administer if baseline K& > 5.0 mEq/Liter3) Use an initial dose of 12.5mg spironolactone or 25mg

eplerenone (max dose 50mg/day both)4) Risk of HYPERkalemia is increased with concomitant use

of higher dose ACE-Is (e.g. captopril > 75mg/day orenalapril or lisinopril > 10mg/day)

Guidelines to Minimize the Risk ofHyperkalemia in Patients treatedwith Aldosterone Antagonists

5) NSAIDs and COX-II Inhibitors should be avoidedif possible

6) Potassium supplements should be D/C orreduced.

7) Close monitoring of serum K& is required;potassium levels and renal function should bechecked in 3 days and at 1 week after startingtherapy, then at least monthly , 1st three months

8) Diarrhea or other causes of dehydration shouldbe addresses emergently

Clinical Trial underway to determine roleof aldosterone antagonists in treatmentof Diastolic Heart Failure (TOPCAT)

Spironolactone in NYHA Class III & IVpatientsEplerenone for improved survival in HFpatients with AMI

& Inotropic therapy is NOT warranted;use only for refractory tachyarrhythmias& hospitalizations

Digoxin in patients with Stage C & D HF;low doses for persistent Sx andrecurrent hospitalizations

!-Blockers to % HR and improve LVfilling; can dose more aggressively

May need to use rate lowering CCBs insevere COPD

!-Blockers - to % all-cause mortality

Diuretics should be dosed cautiously toavoid excessive preload reduction

Intermittent diuretics for symptoms

ACE-Is or ARBs to % hospitalizationsACE-Is – to % all-cause mortalitySystolic HF Treatment Diastolic HF Treatment

Patient Case: Heart Failurecomplicated by Type 2 Diabetes(Adapted from JAMA 2006;295:1935-1940)

!MJ is a 68 yo Korean womanwith a history of:" previous MI" NYHA Class II HF" Type 2 Diabetes Mellitus" Urinary frequency &incontinence

! Social history:" Widowed, lives in ALF" Independent in ADL" Makes own healthcare decisionsbut requires assistance with finances,meds and transportation

! MJ’s problem list:' HTN' CHD/CAD' Type 2 DM' Hypercholesterolemia' Osteopenia' Chronic constipation' Diabetic Peripheral Neuropathy' Bilateral LEE (lower extremityedema)

' Social Anxiety (fears having anotherMI and losing her independence;embarrassed by urinary symptoms)

! Labs/Objective Info:

' BP" 148/88mmHg (sitting)" 154/92 mmHg (standing)

' Hgb A1C = 10%' TC = 225mg/dL' LDL = 130mg/dL' HDL = 45mg/dL' SrCr = 1.2mg/dL' Microalbumin = 100mg/L


! MJ’s medication list and associated diagnoses:" EC-Aspirin 325mg daily (CHD/CAD)" Enalapril 5mg once daily (CHD/CAD)" Furosemide 20mg once daily (LEE)" Atorvastatin 20mg at bedtime (Hypercholesterolemia)" Verapamil ER 240mg once daily (CHD/CAD/angina)" Insulin Glargine 20 units subcutaneously at bedtime (T2DM)" Neutral Protamine Lispro 75/25 Insulin 16 units subcutaneouslywith breakfast and 12 units with dinner (T2DM)

" Pioglitazone 30mg once daily (T2DM)" Caltrate-D 600 one tablet twice daily (% BMD)" Pregabalin 75mg twice daily (DPN)


! Patient’s pre-dinner blood glucose levels range from180 to 240mg/dL

! Patient walks every afternoon to try to control her pre-dinner glucose levels

! Her diet is high in rice and other complex carbohydrates! Her provider is concerned about her rising FBG levelsand plans to ( her pioglitazone dose to 45mg/day inorder to improve her Hgb A1C

! As the consultant pharmacist what concerns do youhave?" Which medicines should go, which should stay, should we addanything???

Patient Case: Heart Failurecomplicated by Type 2 Diabetes

Renal Dysfunction complicatingthe management of Heart Failure:

! SD is a 74 year oldCaucasian man withACC/AHA Stage CHeart Failure

!His heart failure regimenincludes the followingmedications:" Lisinopril, Carvedilol and Spironolactone

Renal Dysfunction complicatingthe management of Heart Failure:

! SD’s primary care physician recently increasedhis lisinopril dosage from 5mg twice daily to 10mgBID

! SD’s baseline serum creatinine increased from1.8 to 2.2mg/dL leading his physician todiscontinue lisinopril due to renal dysfunction.

! As the consultant pharmacist, do you have anyrecommendations?

ACE-Blocking Drugs andRenal Function:

! An initial rise in creatinine is expected, even inindividuals with normal renal function at baseline

! An ( in serum creatinine, if it occurs, typically willhappen within the first 2 weeks of therapy

! What is an acceptable rise in serum creatinine, as apercentage from baseline, in a geriatric patient startedon an ACE-blocking drug?_____________________

Bakris GL, Weir MR. Angiotensin-Converting Enzyme Inhibitor-Associated Elevations in Serum Creatinine:Is This a Cause for Concern? Arch Intern Med 2000;160:685-693

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80

60

40

20

0 1 2 3 4 5Serum Creatinine (mg/dL)

General Population

> 65 years of age or < 50kg

EstimatedGlomerularFiltrationRatemL/minute

Lab Abnormalities of Renal Failuretypically start, e.g. elevated phosphorus,mild anemia

Bakris GL, Weir MR. Angiotensin-Converting Enzyme Inhibitor-Associated Elevationsin Serum Creatinine: Is This a Cause for Concern? Arch Intern Med 2000;160:685-693

The Non-Linear Relationship of Serum Creatinine to GFR/CrCL:

ACE Inhibitor/ARB-Induced RenalFailure:

!Contributing factors to ACE-I/ARB associatedrenal dysfunction:" Beginning or increasing the dose of currentlyprescribed diuretics

" Self-medication (OTC) or physician prescribedNSAIDs

" Development of volume depletion through non-diureticinduced means: e.g. gastroenteritis

Baseline 1 2 3 4

Serum

Creatininemg/dL

2.3

2.1

1.9

1.7

1.5

1.3

1.1

0.9

0.7

-"

"

"

"

"

##

# # #

ACE-I or ARBstarted

Possible Changes in Creatinine in Patients BeginningAngiotensin-Blocking Drugs

#"

Patient with normal renal functionPatient with volume depletion, HF or bilateral renal artery stenosisPatient with abnormal renal function at baseline withoutconditions noted above

WeeksBakris GL, Weir MR. Angiotensin-Converting Enzyme Inhibitor-Associated Elevations in Serum Creatinine:Is This a Cause for Concern? Arch Intern Med 2000;160:685-693

( [email protected]

References

The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severecongestive heart failure: results of the cooperative north scandinavian enalaprilsurvival study (CONSENSUS). N Engl J Med. 1987;326:1429-1435

The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity inpatients with heart failure. N Engl J Med. 1997;336:525-533.

The SOLVD Investigators. Effect of enalapril on survival in patients with reducedleft ventricular ejection fractions and congestive heart failure.N Engl J Med.1991;325;293-302.

The MERIT-HF Investigators. Effect of metoprolol CR/XL in chronic heart failure:metoprolol CR/XL randomised intervention trial in congestive heart failure.Lancet. 1999;353; 2001-2007

CIBIS-II Investigators. The cardiac insufficiency bisoprolol study II (CIBIS-II):a randomised trial. Lancet. 1999;353;9-13

References

The Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect ofcarvedilol on survival in severe chronic heart failure (COPERNICUS).N Engl J Med 2001;344:1651-1658.

Randomized Aldactone Evaluation Study Investigators. The effect of spironolactoneon morbidity and mortality in patients with severe heart failure. N Engl J Med1999;341:709-717.

The ELITE II Investigators. Effect of losartan compared with captopril on mortality inpatients with symptomatic heart failure: randomised trial.the losartan heart failuresurvival study ELITE II. Lancet 2000;355:1582-1587.

The Valsartan Heart Failure Trial Investigators. A randomized trial of theangiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med2001;345:1667-1675.

The RESOLVD Pilot Study Investigators. Comparison of candesartan, enalapril andtheir combination in congestive heart failure. Randomized Evaluation of Strategiesfor Left Ventricular Dysfunction (RESOLVD) Pilot Study.Circulation 1999;100:1056-1064

ReferencesThe Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and SurvivalStudy Investigators. Eplerenone, a selective aldosterone blocker, in patients with leftventricular dysfunction after myocardial infarction (EPHESUS Trial).N Engl J Med 2003;348:1309-1321.

Burger MR, Burger AJ. BNP in decompensated heart failure: diagnostic, prognosticand therapeutic potential. Curr Opin Investig Drugs 2001;2:929-935.

Cowie MR, Zaphiriou A. Recent developments: management of chronic heartfailure. BMJ 2002;325:422-425.

Morris S, Hatcher F, D Reddy. Digoxin therapy for heart failure: An update.Am Fam Physician 2006;74:613-618.

Morris S, Van Swol M, Udani B. The Less Familiar Side of Heart Failure: SymptomaticDiastolic Dysfunction. J Fam Practice 2005;54:501-11.

References

Gomberg-Maitland M, Baran DA, Fuster V. Treatment of congestive heart failure:guidelines for the primary care physician and the heart failure specialist.Arch Int Med 2001;161:342-352.

Nohria A, Lewis E, Stevenson LW. Medical management of advanced heartfailure. JAMA 2002;287:628-640.

Packer M. End of the oldest controversy in medicine.are we ready to concludethe debate on digitalis? N Engl J Med 1997;336:575-576.

Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentrationand outcomes in patients with heart failure. JAMA 2003;289:871-878.

Rathore SS, Wang Y, Krumholz H. Sex-based differences in the effect of digoxinfor the treatment of heart failure. N Engl J Med 2002;347:1403-1411.

Terra SG, Washam JB, Dunham GD, Gattis WA. Therapeutic range of digoxin’sefficacy in heart failure: what is the evidence? Pharmacotherapy 1999;19:1123-1126.

Documents

Pharmacological Treatment of Heart Failure in the Elderlys3.amazonaws.com/zanran_storage/ filePharmacological Treatment of Heart Failure in the Elderly ASCP Annual Meeting and Exhibition