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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
Self-Assessment Questions:
2) What are the five major classes of medicationsused to treat heart failure patients?
1) __________________________________
2) __________________________________
3) __________________________________
4) __________________________________
5) __________________________________
Self-Assessment Questions:
3) Can you name at least one important patientsafety consideration associated with each typeof heart failure medication?____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
Self-Assessment Questions:
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%
www.clinicaltrialresults.org
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
www.clinicaltrialresults.org
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
www.clinicaltrialresults.org
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%
www.clinicaltrialresults.org
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
www.clinicaltrialresults.org
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
Patient Case: Heart Failurecomplicated by Type 2 Diabetes(Adapted from JAMA 2006;295:1935-1940)
! 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 Case: Heart Failurecomplicated by Type 2 Diabetes(Adapted from JAMA 2006;295:1935-1940)
! 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
120
100
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
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CIBIS-II Investigators. The cardiac insufficiency bisoprolol study II (CIBIS-II):a randomised trial. Lancet. 1999;353;9-13
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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.