New Strategies in the Management of Heart Failure

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New Strategies in the Management of Heart Failure

• Dr. Hassan Chamsi Pasha
• MD, FRCP(Lond), FRCP(Ire),
• FRCP(Glasg), FACC
• Head, NonInvasive Cardiology
• King Fahd Armed Forces Hospital

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Heart failure

• Approximately 4.6 million Americans currently
  have heart failure.
• 400,000 new cases occur each year.
• Prevalence of the disease increases with age,
  affecting approximately 1 of persons in their
  fifth decade and nearly 10 of those aged 80 to
  89.
• South Med J 2001 ,94(2)166-174

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Heart failure

• Contributes directly or indirectly to
  approximately 260,000 deaths annually.
• Primary diagnosis in 870,000 hospital discharges.
• Five-year survival after the diagnosis is only
  25 in men and 38 in women.
• In more severe disease, 1-year mortality
  approaches 30-50.
• For all patients, median survival is 1.7 years in
  men and 3.2 years in women.
• Annual cost exceeding 34 billion.
• Pharmacotherapy
  20(7)787-804, 2000.

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• One third of patients who are hospitalized for
  heart failure either die or require readmission
  within 60 days of hospital discharge.
• One half are readmitted within 90 days.

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Mechanisms of Heart Failure

• Disease progression is related to structural
  changes in the heart and blood vessels that lead
  to ventricular remodeling.
• Remodeling process is characterized by
  alterations in the size and shape of the left
  ventricle and is triggered by activation of
  endogenous neurohormonal systems, primarily the
  renin-angiotensin system (RAS) and the
  sympathetic nervous system (SNS).

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Goals of Treatment

• The primary goal of treatment has shifted from
  symptomatic relief to slowing or arresting
  disease progression.
• Neurohormonal abnormalities, not hemodynamic
  abnormalities, are responsible for disease
  progression

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Usual Treatment Today

• AIMS OF HEART FAILURE MANAGEMENT
• TO IMPROVE SYMPTOMS
• DIURETICS
• DIGOXIN
• ACE INHIBITORS
• TO IMPROVE SURVIVAL
• ACE INHIBITORS
• ? BLOCKERS
• ORAL NITRATES PLUS HYDRALAZINE
• SPIRONOLACTONE
• 
  
• Davies et al. BMJ 2000320428-431

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HF Mortality Remains High

• ACEI RISK REDUCTION 35 (MORTALITY AND
  HOSPITALIZATIONS)1
• ? BLOCKERS RISK REDUCTION 38 (MORTALITY AND
  HOSPITALIZATIONS)2
• ORAL NITRATES AND HYDRALAZINEBENEFIT VS.
  PLACEBO INFERIOR TO ENALAPRIL (MORTALITY)
• HOWEVER 4-YEAR MORTALITY REMAINS 40
• Davies et al. BMJ 2000320428-431 (metanalysis
  32 trials, n7105) 2 Gibbs et al. BMJ
  2000320495-498 (metanalysis 18 trials, n3023)
  

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Nonpharmacologic interventions

• smoking cessation.
• Weight reduction
• Avoidance of alcohol.
• Limiting sodium intake (no more than 3 g daily).
• Daily weight.
• Contact physician if body weight increases by 2
  lb or more.

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• Benefits of ACE inhibitor therapy may not become
  apparent for 1 or 2 months after initiation of
  treatment.
• Approximately 90 of patients with heart failure
  tolerate long-term ACE inhibitor therapy.

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Aspirin-ACE Inhibitor Interaction

• Studies are largely contradictory, but do
  reiterate the possibility of an interaction.
• Low dosages (lt/ 100 mg/day) of aspirin appear
  to be safer than higher dosages.
• Pharmacotherapy 20(6)698-710,
  2000

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B blockers

• Four randomized, double-blind, placebo-controlled
  clinical trials
• mortality reduced 65 by carvedilol,
• 34 by metoprolol,
• 33 by bisoprolol
• trials were ended early.
• Bucindolol no significant effect on mortality.
• Am J Health-Syst Pharm 58(02)140-145, 2001.

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MERIT-HF study

• 3991 patients with heart failure from 313 centers
  in 14 countries randomly assigned to metoprolol
  CR/XL or placebo, in addition to their standard
  heart failure regimens.

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JAMA 2000 283 1295-1302
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Carvedilol

• Four US studies
• 1,094 patients with mild, moderate, or severe
  heart failure receiving standard therapy with a
  diuretic, an ACE inhibitor, and digoxin.
• Overall mortality in carvedilol group was 3.2
  vs 7.8, a reduction of 65.
• 27 reduction in hospitalization
• 38 reduction in the combined risk of
  hospitalization or death.

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COPERNICUS trial

• Enrolled 2289 patients with severe HF (LVEF
  lt25), randomized to carvedilol in a target dose
  of 25 mg bid for up to 29 months.
• Trial was stopped early for efficacy.

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CAPRICORN trial

• Examined the effect of carvedilol in patients
  with left ventricular dysfunction (LVEF lt 40)
  after an MI, with or without HF.

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• Packer
• Instead of prescribing carvedilol to such
  patients in the midst of their acute illness, it
  would be prudent first to take measures to
  stabilize their clinical condition"
• N Engl J Med 2001 344(22)1651-8. 3

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• Packer
• The use of carvedilol for severe HF would prevent
  approximately 70 deaths per 1000 patients treated
  for 1 year
• This compares with 20-40 deaths prevented with
  ACE inhibitors or beta blockers in mild to
  moderate HF, and with about 50 deaths prevented
  with an aldosterone antagonist in severe HF.
• N Engl J Med 2001 344(22)1651-8.

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CIBIS-II

• Cardiac Insufficiency Bisoprolol Study II
  (CIBIS-II) compared a ß-blocker-containing
  regimen with standard therapy alone (diuretic
  plus ACE inhibitor) in 2,647 patients with NYHA
  class III or IV heart failure
• Bisoprolol
• 34 reduction in mortality
• 32 reduction in hospitalization.
• 
  Lancet 1999 3539-13

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BEST trial

• The Beta-blocker Evaluation of Survival Trial.
• Randomized 2708 patients with NYHA Class III
  (92) or IV (8) HF and an ejection fraction of
  35 or lower to bucindolol or placebo.
• Mortality was not significantly different between
  the two groups .
• May 31, 2001 issue of the New England Journal
  of Medicine.

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COMET TRIAL

• The ongoing Carvedilol and Metoprolol European
  Trial, which involves 3,000 patients with NYHA
  class II to class IV heart failure, is testing
  the hypothesis that multiple-receptor blockade
  with carvedilol offers a therapeutic advantage
  over selective adrenergic blockage with
  metoprolol.

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ß-blocker therapy

• Although ejection fraction continues to improve
  at the highest dosage of Carvedilol (25 mg
  twice daily or 50 mg twice daily in heavier
  patients), significant treatment effect (two
  thirds or more of maximum mortality benefit) is
  seen at 6.25 mg twice daily.
• Continue at a minimum dosage of 6.25 mg twice
  daily and do not abandon therapy if higher doses
  are not tolerated.

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beta-Blocker withdrawal The song of Orpheus

• Morimoto
• 13 patients with dilated cardiomyopathy who were
  receiving long-term beta-blockade
• Investigators withdrew the therapy to see if the
  patients would continue to do well.
• Seven of the 13 patients deteriorated, including
  4 who died either suddenly or of progressive pump
  dysfunction.
• Am Heart J 1999138387-9.

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ATLAS study

• Increasing ACE inhibitor doses from low to
  high confers relatively modest absolute
  reductions in mortality (8).
• Eur Heart J 1998 19(suppl)142

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• Adding ß-blockade to intermediate doses of
  ACEI reduces mortality by 30 or more.
• Lancet 1999 3539-13
• Lancet 1999 3532001-2007

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• To optimally slow disease progression, it may,
  therefore, be preferable to add ß-blockade to
  moderate doses of ACE inhibitors, then increase
  the ACE inhibitor dose later, titrating upward as
  each successive dose is tolerated.

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ß-blocker therapy

• Taking the ACE inhibitor 2 hours after the
  carvedilol or taking carvedilol with food may
  reduce this hypotensive effect.
• A temporary reduction in the dose of the ACE
  inhibitor may also be required.
• Am J Cardiol 1999 83(suppl 2A)1A-38A

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ELITE Study

• Evaluation of Losartan in the Elderly (ELITE)
  study
• 722 patients to compare effects of losartan and
  captopril on renal function.
• losartan associated with a 46 lower risk of
  mortality than captopril.
• 
  Lancet 1996 247-54

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ELITE Study

• The study was not powered to investigate
  mortality, and after adjustment for the
  multiplicity of end points, no difference was
  seen in frequency of hospitalization or combined
  morbidity and mortality risk
• 
  Pharmacotherapy 20(7)787-804, 2000

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RESOLVD study

• Randomized Evaluation of Strategies for Left
  Ventricular Dysfunction (RESOLVD) study involved
  768 patients.
• No significant differences in the rate of cardiac
  events among patients treated with candesartan,
  enalapril, or the combination.
• Eur Heart J
  1998 19(suppl)
•  

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VALSARTAN Heart Failure Trial

• LONG-TERM CARDIAC MORBIDITY MORTALITY TRIAL
• CHRONIC STABLE HEART FAILURE PATIENTS
• VALSARTAN ADDED TO USUAL HEART FAILURE THERAPY
  (ACEIS DIURETICS DIGOXIN ? BLOCKERS)
• 5,010 PATIENTS
• 300 CENTERS IN 16 COUNTRIES

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Val-HeFT DESIGN
HF PATIENTSgt18 YR EF lt40 NYHA II-IV

• Cohn et al. J Card Fail 19995155-160

RECEIVING USUAL THERAPY INCLUDING ACEI,
DIURETICS, DIGOXIN, ? BLOCKERS (STRATIFIED
RANDOMIZATION)
RANDOMIZED TO
VALSARTAN40 MG BID TITRATED TO160 MG BID
Placebo
906 DEATHS (EVENTS RECORDED)
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All Cause Mortality
1.0
P 0.8

0.9
SURVIVAL PROBABILITY

0.8
PLACEBO
VALSARTAN
0.7

0
3
6
9
12
21
18
15
24
27
TIME SINCE RANDOMIZATION (MONTHS)
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TIME SINCE RANDOMIZATION (MONTHS)
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TIME SINCE RANDOMIZATION (MONTHS)
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COMBINED MORBIDITY/MORTALITYIN SUBGROUPS
FAVORS VALSARTAN
Patients
FAVORS PLACEBO
All Patients
100
47
lt 65
³
65
53
Male
80
Female
20
EF lt 27
50
50
EF
³
27
ACEI (Yes)
93
ACEI (No)
7
BB (Yes)
35
BB (No)
65
IHD (Yes)
57
IHD (No)
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0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
1.2
1.3
1.4
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• ARBs offer an alternative to ACE inhibitors in
  the management of hypertension, especially for
  ACE-inhibitor-intolerant patients. ACE inhibitors
  remain the drugs of choice for patients with
  heart failure, left ventricular dysfunction after
  MI, and diabetic nephropathy ARBs offer these
  patients an alternative when ACE inhibitor
  therapy is not tolerated.
• Am J Health-Syst Pharm 2001 58(8)671-683

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Combination therapy

• The addition of an ARB offers more complete
  angiotensin II receptor blockade of the RAS than
  can be obtained by ACE inhibitors alone.
• Combination therapy preserves the benefits of
  bradykinin potentiation offered by ACE inhibitors
  while providing potential antitrophic influences
  of AT2 receptor stimulation
• May play an increased role in the treatment of
  chronic HF in the future.
• Am Heart J 2000 140(3)361-366

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Aldosterone Antagonists

• Randomized Aldactone Evaluation Study involved
  1,663 patients with severe heart failure (NYHA
  class III or IV) of ischemic or nonischemic
  origin.
• Most patients received dosages of 25 mg daily in
  addition to the conventional background therapy
• N Engl J Med 1999 341709-717

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Aldosterone Inhibition and Heart Failure Too
Good to Be True?

• The Randomized Aldactone Evaluation Study (RALES)
  h stunningly positive results.
• Spironolactone, available for more than 40 years
• Reduce the mortality rate by 30 in patients with
  advanced heart failure.
• Hospitalization rate for worsening heart failure
  was reduced by 35.
• American Heart Journal 2001,1141

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DIG trial

• Digitalis Investigation Group (DIG), the National
  Institutes of Health .
• To study to digoxin's effect on survival and
  morbidity in 7788 patients who remained
  symptomatic while taking diuretics and ACE
  inhibitors
• No significant difference when deaths from all
  cardiovascular causes (29.9 digoxin vs 29.5
  placebo, RR1.10, p0.78)

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DIG trial

• Digoxin significantly reduced the rate of
  hospitalizations (26.8) compared with placebo
  (34.7, RR0.72, plt0.001).
• Admissions were fewer when all cardiovascular
  reasons were combined, including myocardial
  infarction and supraventricular arrhythmias
  (49.9 vs 54.4, RR0.87, plt0.001).

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• Intermittent inotropic infusion therapy reported
  excess mortality with dobutamine. Dobutamine
  infusions were titrated to produce an optimal
  hemodynamic profile mean dosages were 8.1
  µg/kg/minute (maximum 15 µg/kg/min).
• Death occurred in 32 (10/31) of
  dobutamine-treated patients compared with 14
  (4/29) of placebo-treated patients over 24 weeks.
• Causes of death assumed to result from
  arrhythmias (sudden cardiac death).
• Lower dosages of inotropes may be associated with
  improvements in quality of life with lower risk
  of mortality.

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• Long-term therapy with phosphodiesterase
  inhibitors (e.g., milrinone, venarinone) excess
  mortality
• Intermittent intravenous inotropic agent may be
  of value in improving the quality of life or as a
  bridge to cardiac transplantation.
• Catecholamine infusions have been associated with
  excess mortality.
• Cardiac transplantation, left ventricular assist
  devices, and total artificial hearts are limited
  by technical, logistic, and cost issues
• Pharmacotherapy 20(7)787-804, 2000.

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• Hydralazine-isosorbide dinitrate should be
  considered in patients with contraindications to
  ACE inhibitors. The major limitation with the
  combination is the frequency of adverse effects
  at dosages recommended for heart failure.

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Calcium Channel Antagonists

• May worsen heart failure
• Trials of verapamil, diltiazem, and nifedipine
  showed detrimental effects in heart failure.
• Vasoselective dihydropyridines, such as
  amlodipine and felodipine no negative effects.

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PRAISE trial

• Amlodipine 10 mg/day or placebo to 1153 patients
  with class III-IV disease. All patients also
  received digoxin, a diuretic, and an ACE
  Inhibitor.
• No difference was observed in all-cause mortality
  or combined end points of death and adverse
  clinical events in the two groups (p0.07).
• Amlodipine and felodipine have few or no
  beneficial effects..

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DDD pacing

• Intraventricular conduction delay may hamper the
  ability of the heart to contract in an organized
  manner, with contraction of different segments
  occurring at less than optimal times
• DDD pacing of the right sided chambers may be
  beneficial in selected dilated cardiomyopathy
  patients

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Diastolic Heart Failure

• Half of heart failure subjects in the community
  have normal LV systolic function.
• Major contributor to hospital admissions, but is
  often overlooked in studies that focus only on
  patients with impaired systolic function
• Hypertension, coronary artery disease, the normal
  aging process, obesity, and diabetes mellitus are
  associated with diastolic dysfunction
• Cardiology Clinics 2000 18 ,3

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Diastolic heart failure

• Currently, there are no therapies that
  specifically affect the rate of calcium
  sequestration or protein phosphorylation, which
  would produce specific therapy for diastolic
  failure.
• Therapy currently is based on the underlying
  cardiovascular disorder and the use of
  pharmacologic agents that appear to specifically
  influence known pathophysiologic abnormalities
• Optimal treatment of diastolic heart failure has
  not yet been defined.

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Goals of Therapy for Diastolic Heart Failure

• Treat underlying cardiovascular disease
• Coronary artery disease
• Hypertension
• Diabetes
• Atrial fibrillation

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• Avoid volume depletion ( may predispose to
• Orthostatic symptomsTachycardiaStimulation
  of vasodepressor syncope

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• Facilitate diastolic filling timeSlow heart
  rate. beta Blockade
• Avoid chronotropic/inotropic stimulation. with
  agents, such as Digoxin Theophylline
• Ephedrine and decongestants Caffeine

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• Reverse or minimize ventricular hypertrophy
• Afterload reductionAngiotensin II blockade
• Cardiology ClinicsVolume 18 Number 3 August
  2000

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www.khayma.com/chamsipasha
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Heart Failure Society Guidelines A Model of
Consensus and Excellence

• Committee Members Kirkwood F. Adams, Jr., MD,
  Chair, Kenneth L. Baughman, MD Marvin A. Konstam,
  MD, William G. Dec, MD Peter Liu, MD, Uri
  Elkayam, MD Barry M. Massie, MD, Alan D. Forker,
  MD J. Herbert Patterson, PharmD, Mihai
  Gheorghiade, MD Marc A. Silver, MD, Denise
  Hermann, MD Lynne Warner Stevenson, MDExecutive
  Council Arthur M. Feldman, MD, PhD, President,
  Jay N. Cohn, MD Bertram Pitt, MD, Gary S.
  Francis, MD Marc A. Silver, MD, Barry Greenberg,
  MD Edmund Sonnenblick, MD, Marvin A. Konstam, MD
  John Strobeck, MD, PhD, Carl Leier, MD Richard
  Walsh, MD, Beverly H. Lorell, MD Salim Yusuf,
  MBBS, PhD, Milton Packer, MD
• Phamacotherapy 2000, 20(5)495-522

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• Emphasis is placed on
• the results of well-designed and adequately
  controlled clinical trials (Strength of Evidence
  A)
• other useful investigations, including cohort
  studies (Strength of Evidence B).
• Expert opinion is the basis for a recommendation
  (Strength of Evidence C).
• Phamacotherapy 2000, 20(5)495-522

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ß-blocker therapy

• Recommendation
• ß-blocker therapy should be routinely
  administered to clinically stable patients with
  left ventricular systolic dysfunction (left
  ventricular ejection fraction less than or equal
  to 40) and mild to moderate heart failure
  symptoms (ie, NYHA class II-III, Appendix A) who
  are on standard therapy, which typically includes
  ACE inhibitors, diuretics as needed to control
  fluid retention, and digoxin (Strength of
  Evidence A).
• Phamacotherapy 2000, 20(5)495-522

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ß-blocker therapy

• Recommendation
• There is insufficient evidence to recommend the
  use of ß-blocker therapy for inpatients or
  outpatients with symptoms of heart failure at
  rest (ie, NYHA class IV) (Strength of Evidence
  C).
• Phamacotherapy 2000, 20(5)495-522

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ß-blocker therapy

• Recommendation
• ß-blocker should be initiated at low doses and
  uptitrated slowly, no sooner than at 2-week
  intervals.
• Patients who develop worsening heart failure or
  other side effects require adjustment of
  concomitant medications. May also require a
  reduction in ß-blocker dose or a temporary or
  permanent withdrawal of this therapy (Strength of
  Evidence B).
• Phamacotherapy 2000, 20(5)495-522

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Digoxin

• Recommendation
• Digoxin should be considered for patients who
  have symptoms of heart failure (NYHA class
  II-III, Strength of Evidence A and NYHA class
  IV, Strength of Evidence C) while receiving
  standard therapy.
• Phamacotherapy 2000, 20(5)495-522

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Digoxin

• Recommendation
• In the majority of patients, the dosage of
  digoxin should be .125 mg to .25 mg daily
  (Strength of Evidence C).
• Target dose of digoxin should be lower than
  traditionally assumed.
• Phamacotherapy 2000, 20(5)495-522

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Digoxin

• Recommendation
• In patients with heart failure and atrial
  fibrillation with a rapid ventricular response,
  the administration of high doses of digoxin
  (greater than .25 mg) for rate control is not
  recommended.
• When necessary, additional rate control should
  be achieved by the addition of ß-blocker therapy
  or amiodarone (Strength of Evidence C).
• Phamacotherapy 2000, 20(5)495-522

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Anticoagulation

• Recommendation
• All patients with heart failure and atrial
  fibrillation should be treated with warfarin
  (goal INR 2.0 to 3.0) unless contraindicated
• (Strength of Evidence A).
• Phamacotherapy 2000, 20(5)495-522

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Anticoagulation

• Recommendation
• Warfarin anticoagulation merits consideration
  for patients with left ventricular ejection
  fraction of 35 or less. Careful assessment of
  the risks and benefits of anticoagulation should
  be undertaken in individual patients (Strength of
  Evidence B).
• Phamacotherapy 2000, 20(5)495-522

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Antiplatelets

• Recommendation
• Currently, there is insufficient evidence
  concerning the potential negative therapeutic
  interaction between ASA and ACE inhibitors to
  warrant withholding either of these medications
  in which an indication exists (Strength of
  Evidence C).
• Phamacotherapy 2000, 20(5)495-522

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ACE inhibitors

• Recommendation
• ACE inhibitors rather than ARBs continue to be
  the agents of choice for blockade of the renin
  angiotensin system in heart failure, and they
  remain the cornerstone of standard therapy for
  patients with left ventricular systolic
  dysfunction with or without symptomatic heart
  failure (Strength of Evidence A).
• Phamacotherapy 2000, 20(5)495-522

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Antiarrhythmic Therapy

• Recommendation
• Amiodarone is not recommended for the primary
  prevention of death in patients with chronic
  heart failure (Strength of Evidence A).
• Phamacotherapy 2000, 20(5)495-522

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ICD

• Recommendation
• patients with heart failure resuscitated from
  primary ventricular fibrillation or who have
  experienced hemodynamically destabilizing
  sustained ventricular tachycardia be treated with
  ICDs (Strength of Evidence B).
• Phamacotherapy 2000, 20(5)495-522

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Antiarrhythmic therapy

• Recommendation
• Amiodarone is the preferred drug when
  antiarrhythmic therapy is indicated in patients
  with heart failure for supraventricular
  tachycardia not controlled by digoxin or
  ß-blocker or for patients with life-threatening
  ventricular arrhythmia who are not candidates for
  ICD placement (Strength of Evidence B).
• Phamacotherapy 2000, 20(5)495-522

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Aldosterone Antagonists

• Recommendation
• Spironolactone at low dose (ie, 12.5 mg to 25 mg
  once daily) should be considered for patients
  receiving standard therapy who have severe heart
  failure (with recent or current NYHA class IV).
• Potassium level (less than 5.0 mmol/L) and
  adequate renal function (creatinine less than 2.5
  mg/dL) (Strength of Evidence A).
• Serum potassium should be monitored after the
  first week and at regular intervals (Strength of
  Evidence A).
• phamacotherapy 2000, 20(5)495-522