Management of Patients With LV Systolic Dysfunction: An Evidence Based Approach

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Management of Patients With LV Systolic
Dysfunction An Evidence Based Approach

• Eric J Milie, D.O.

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General Information

• 5 Million Americans affected
• Leading cause of hospitalization in the elderly
  population
• Causes or contributes to 250,000 deaths annually
• Only major cardiovascular increasing in incidence
  and prevalence
• NYHA Class I5 year, 50 mortality NYHA Class
  IV 1yr, 50 mortality

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Definition

• A pathopysiologic state characterized by
  congestion in the pulmonary or systemic
  circulation. It is caused by the hearts
  inability to pump sufficient oxygenated blood to
  meet the metabolic needs of the tissues

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Preload

• Degree of end-diastolic fiber stretch
• For clinical purposes, the end-diastolic
  pressure, especially if above normal, is a
  reasonable indicator of preload
• Conditions that may effect preload include LV
  dilatation, hypertrophy, and changes in
  distensibility or compliance

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Afterload

• Force resisting myocardial relaxation after
  stimulation from the relaxed state
• Determined by chamber pressure, volume, and wall
  thickness at the time of aortic valve opening
• Clinically, approximates systolic BP at or neat
  the time of aortic valve opening and represents
  peak systolic wall stress

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Frank-Starling Principle

• Degree of end-diastolic fiber stretch (preload)
  within a physiologic range is proportional to the
  systolic performance of the ensuing ventricular
  contraction
• In effect in CHF, but suboptimal response because
  the ventricle function is abnormal

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Frank-Starling cont.
                                                
                                       The
effects of myocardial compliance and
contractility on the Frank-Starling mechanism.
Figure reproduced from Internal Medicine, 4th
edition, 1994, W.B. Saunders
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Frank-Starling cont.

• If Frank-Starling curve is depressed, fluid
  retention, vasoconstriction, and a cascade of
  neurohormonal responses lead to CHF
• Over time, LV remodeling, with hypertrophy and
  dilatation further compromises the hearts
  function

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Left Ventricular Failure

• Characteristically develops in association with
  CAD, HTN, and most forms of cardiomyopathy and
  congenital defects (i.e. VSD, PDA)

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Right Ventricular Failure

• Most commonly caused by prior LV failure (?
  pulmonary venous pressure and leads to pulmonary
  artery HTN) and tricuspid regurgitation
• May be seen in the face of polycythemia,
  overtransfusion, acute renal failure, or vena
  caval obstruction

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Systolic Dysfunction

• Failure to provide the tissues with adequate
  circulatory output
• Most commonly caused by HTN, CAD, and dilated
  cardiomyopathy
• More than 20 viruses shown to be causal

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Diastolic Dysfunction

• Resistance to ventricular filling (20-40 of
  cases)
• Seen in hypertrophic cardiomyopathy, marked
  ventricular hypertrophy, and amyloid infiltration
  of the myocardium

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Clinical Manifestations

• Dyspnea First on exertion, then with
  progressively less strenuous activity
• Orthopnea Increased venous return in the
  recumbent position
• PND multiple factors
• Nocturnal Angina Increased cardiac workload, 2º
  to increased venous return
• Cheyne Stokes Respiration Alternating phases of
  apnea and hyperventilation
• Fatigue low cardiac output
• Peripheral Edema

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Physical Exam

• Left Sided Failure
• Pulmonary Rales
• Tachypnea
• S3 Gallop
• Cardiac Murmurs (AS, AR, MR)
• Paradoxical Splitting of S2

• Right Sided Failure
• Jugular Venous Distention
• Peripheral Edema
• Peripheral/ Perioral cyanosis
• Hepatomegaly
• Ascites
• Hepatojugular Reflux

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Assessment of JVD
Shasham, Fadi, and Judith Mitchell, M.D.
Essentials of the Diagnosis of Heart Failure.
American Family Physician, March, 2001.
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Framingham Criteria for Diagnosis of CHF

• Minor Criteria
• Extremity Edema
• Night cough
• Dyspnea on exertion
• Hepatomegaly
• Pleural Effusion
• Vital Capacity ? ? from normal
• Tachycardia (gt120bpm)

• Major Criteria
• Paroxysmal Nocturnal Dyspnea
• Neck Vein Distention
• Rales
• Cardiomegaly
• Acute Pulmonary Edema
• S3 Gallop
• Increased Venous Pressure
• Hepatojugular reflux

Major or Minor Wt loss gt4.5 kg over 5 days of
treatment
To establish a clinical diagnosis of CHF by these
criteria, at least 1 major and 2 minor criteria
are required
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Diagnosis CXR Findings

• Cardiomegaly (Cardiothoracic ratio gt0.5)
• Large Hila with indistinct margins
• Prominence of superior pulmonary veins
• Fluid in intralobar fissures
• Kerley B lines
• Alveolar edema

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Classic CXR
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Echocardiogram

• Two view and Doppler echocardiography is useful
  to assess blood flow, global and left ventricular
  function, and ejection fraction
• Transesophageal echo offers higher quality
  images, but is invasive and is best reserved for
  when the quality of the 2D images are
  unacceptable

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Echocardiography
Two-dimensional echocardiogram showing a
four-chambers view of the heart in a patient with
systolic dysfunction. Note dilated LV.
Shasham, Fadi, and Judith Mitchell, M.D.
Essentials of the Diagnosis of Heart Failure.
American Family Physician, March, 2001.
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Echocardiography
Two-dimensional echocardiogram showing a
four-chambers view of the heart in a patient with
diastolic dysfunction. Note the normal LV size
with hypertrophy.
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EKG

• Should be performed on all patients with new
  diagnosis of CHF. No specific findings are
  indicitive of heart failure, but atrial and
  ventricular arrhythmias are common fidings.
• Atrial Fibrillation is found in roughly 25 of
  individuals with cardiomyopathy, especially
  elderly individuals with advanced failure
• Low voltage with conduction disturbances may be
  associated with amyloidosis

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B-type Natriuretic Peptide

• New diagnostic test superior to diagnostic
  decision making of the primary care physician
• Has reduced clinical indecision from 43-11
• Median BNP levels in NYHA classes I, II, III, and
  IV were 244, 389, 640, and 817 pg/ml,
  respectively.
• Values of 50 pg/ml or less had a negative
  predictive value of 96

Maisel, A et al. Rapid Measurement of B-Type
Natriuretic Peptide in the Emergency Diagnosis of
Heart Failure. New England Journal of Medicine.
2002 347(3)161-7.
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Functional ClassificationNew York Heart
Association

• Class I Symptomatic only with greater than
  normal activity
• Class II Symptomatic with ordinary activity
• Class III Symptomatic with minimal activity,
  asymptomatic at rest
• Class IV Symptomatic at rest

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Treatment

1. Removal of the precipitating cause
2. Correction of the underlying cause
3. Prevention of deterioration of cardiac function
4. Control of the congestive heart failure state

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Type of Physicians Treating Heart Failure
Primary Care Physicians Treat the Majority of
Heart Failure Patients
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Differentiating Symptoms From Disease Progression

• What Produces Symptoms?
• Hemodynamic Abnormalities

• What Produces Disease Progression?
• Sympathetic nervous system activation
• Renin-angiotensin-aldosterone axis
• Nitroso-redox balance

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Neurohormonal Activation in Heart Failure
Myocardial Injury
Initial Fall in LV Performance
Activation of RAS and SNS
Peripheral Vasoconstriction
Myocardial toxicity
Oxidative Stress
Remodeling and Progressive worsening of LV
function
Morbidity and Mortality
Heart Failure Symptoms
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Effects of Sympathetic Activation on Heart Failure
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Renin-Angiotensin-Aldosterone System
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Evolution of Drug Therapy for CHF
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Drug Treatment of Systolic Dysfunction

• Diuretics
• ACE inhibitors
• ARBs
• ?-blockers
• Digitalis
• Hydralazine ISDN

• Most patients treated with at least two of the
  above

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Diuretics
                                                                                                                                                                        
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Diuretics continued

• Loop diuretics are preferred, usually furosemide
  by mouth
• In resistant cases, Bumetanide 0.5 2.0mg or
  Metazolone PO may have additive effects
• Overuse may cause electrolyte imbalances
  (hyponatremia, hypomagnesemia, and profound
  hypokalemia) or volume deficits, so routine
  monitoring of serum electrolytes is warranted
• May induce renal failure in some patients
• Adding K sparing diuretics may be used to offset
  the K-losing effects of loop diuretics
• Spironolactone may be beneficial in advanced
  (NYHA Class III or IV) cases of CHF, decreasing
  total morbidity and mortality.

Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A,
Perez A, et al. The effect of spironolactone on
morbidity and mortality in patients with severe
heart failure. Randomized Aldactone Evaluation
Study Investigators. N Engl J Med
1999341709-17.
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Diuretics cont.

• Clinical efficacy of diuretics is heavily
  dependant on dietary sodium restriction
• Log of daily weights should be maintained (? in
  greater than 2 needs to be evaluated)
• No overall decrease in mortality, but relief of
  symptoms

Konstam MA. Heart failure evaluation and care of
patients with left-ventricular systolic
dysfunction. Rockville, Md. U.S. Dept. of Health
and Human Services, Agency for Health Care Policy
and Research, 1994 Clinical Practice Guideline
no. 11, AHCPR publication no. 94-0612.
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Digitalis

• Weak inotrope
• Blockade of AV Node
• Weak vasoconstrictor
• Improves renal blood flow
• Modestly improves LV function
• Lowers dosage needed of diuretics
• Reduces need for hospitilization

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Digitalis cont.

• Digitalis Investigation Group (DIG) study showed
  no decrease in mortality, but significant
  reduction in the number of hospitalizations in
  patients treated with digitalis

The Digitalis Investigation Group. The effect on
digoxin in mortality and morbidity in patients
with heart failure. N Eng J Med 1997336525-533
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Digitalis Toxicity

• 1st degree AV block, which may progress to
  Wenkebach. May also see life threatening
  arrhythmias (V. Fib., V. Tach.)
• Nausea, Vomiting, Anorexia, Diarrhea, Confusion,
  Amblyopia, and Xerophthalmia (yellow vision)

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Digitalis Effect- EKG
American Society of Consultant Pharmacists, Inc.
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Reassessing the Role of ACEI and Adrenergic
Blocking Agents

• Is more Better?
  Are the outcomes dose dependent?
• Is interation at multiple steps in the
  neurohormonal pathway additive or synergistic?
  Adding
  ARB or AA to ACEI
  Adding ß² and ?1 to ß1 blockade
  NO adducts antioxidants
• Is blocking at one site better than another?
  Head to
  head comparisons in CHF

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Multiple Targets and Effectors of the Renin/
Angiotensin System
Aldosterone
Non ACE
Renin
Angiotensinogen
Ang I
Ang II
AT1/AT2
Bradykinin
Vasoconstriction, Remodeling, Cell death, NO
inhibition
Vasoconstricion, Remodeling, Cell Death, NO
inhibition
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ACEI effects on mortality reduction
Trial ACEI Control
Chronic CHF
CONSENSUS I 39 54
SOLVD (Treatment) 35 40
SOLVD (Prevention) 15 16
Post-MI
SAVE 20 25
AIRE 17 23
TRACE 35 42
Average 23 27
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SOLVD
Digoxin, Diuretics, and Enalapril
Evidence for ACE inhibition
Placebo N1284 Enalapril (11.2 mg QD) N1285 61 y/o EF25 F/U 41 Months 8 on ß blocker
All Cause Mortality 510 (39.7) CV (461/35.9) 452 (35.2) CV (399/31.1) 0.0036 0.002
Mortality CV Hospitalization 736 (57.3) 613 (47.7) 0.001
Annual Mortality 15 11.5 0.01
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ATLAS
Digoxin, Diuretics, and Enalapril
Is More Better?
Low Dose (4.5 mg QD) N1596 High Dose (33mg QD) N1568 64 yo EF23 F/U 46 months
All cause Mortality 717 (44.9) CV (641/40.2) 666 (42.5) CV (583/37.2) 0.128 0.073
Mortality CV Hospitalization 1182 (74.1) 1115 (71.1) 0.036
Annual Mortality 11 9.5 NS
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Val-HeFT
Is antagonism at multiple steps beneficial?
Digoxin, Diuretics, ACE Valsartan
Placebo N2499 Valsartan (254mg QD) N2511 62yo EF27 FU 24months 35 ß-blocker
All cause mortality 484 (19.4) CV (258/10.3) 495 (19.7) CV (262/10.4) 0.8 0.9
Mortality CV Hospitalization 801 (32.1) 723 (28.6) 0.009
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CHARM ADD
Digoxin, Diuretics, ACEI, and Cancesartan
Placebo N1272 Candesartan (24mg QD) N1276 65 yo EF28 23 ß-blockers F/U 18 months
All Cause Mortality 412 (32) CV (347/27.3) 377 (30) CV (302/23.7) 0.86 0.03
Mortality CV Hospitalization 587 (46) 539 (42) 0.02
Annual Events 16.6 14.1
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Elite II
Is there a superior approach? ACEI vs. ARB
Losartan 50mg QD N1578 Captopril 50mg TID N1574 72 y/o EF31 23 ß-blocker F/U 18 months
All cause mortality 280 (17.7) CV (230/14.6) 250 (15.9) CV (199/12.6) 0.16
Mortality CV Hospitalization 752 (47.7) 707 (44.9) 0.001 0.001
Annual Mortality 11.7 10.4 0.16
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What About Aldosterone Agonists?

• Is more better?
• Are there additional benefits when added to ACEI
  and adrenergic blocking system?
• Is there superiority of one agent over the other?

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RALES
Spironolactone ACEI
Placebo N841 Spironolactone (25mg QD) N822 65 y/o EF25 F/U 24 months 10 ß-blocker
All Cause Mortality 386 (46) CV (314/37) 284 (35) CV (226/27) 0.001 0.001
Mortality CV Hospitalization 1067 741 0.001
Annual Events 25 18
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EPHESUS
Eplerenone N3319 Placebo N3313 64 y/o 28 female LVEF 33 ACEI 87 ß-blocker 75 ASA 89 Statin 47
Death 478 (14.4) 554 (16.7) 0.008
CV Death 407 (11.8) 483 (13.6) 0.005
Sudden Death 162 201 0.03
Death or CHF Hospitalization 723 (22) 945 (29.5) 0.001
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What About Aldosterone Agonists?

• Is more better?
• No.. More side effects
• Are there additional benefits when added to ACEI
  and ARB?
• Unquestionably
• Is there superiority of one agent over the other?
• Untested

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Update on RAS Interventions

• Higher doses no better than lower doses (ATLAS)
• Ading ARB to ACE does not reduce all cause
  mortality, but may reduce composite endpoints
  driven largely by reduced hospitilizations
  (RESOLVD, Val-HeFT, CHARMalt)
• As replacement for ACEI, ARBS reduce composite
  endpoints (death hospitalization) but not renal
  failure or hyperkalemia (CHARMalt)
• In head to head comparison, no benefit of one
  class over the other (Elite 2, RESOLVD, VALIANT)

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Reassessing the Role of Adrenergic Blocking Agents

• Is more better?
• Are outcomes dose dependent?
• Is interdiction at multiple steps in the
  neurohormonal pathway additive or synergistic?
• Adding ß2 and a1 to ß1 blockade
• Is blocking at one site better than another?
• Head to head comparisons in CHF

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Effects of Sympathetic Activation in Heart Failure
CNS Sympathetic outflow
Sympathetic activity to kidneys blood vessels
Cardiac sympathetic activity
ß2 receptors
a1 receptors
ß1 receptors
Activation of RAS
a1
ß1
Myocyte death Increased arrhythmias
Vasoconstriction Na retention
Disease Progression
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Major Placebo Controlled Trials in Beta-Blockade
in Heart Failure
Study Drug HF severity Patients Follow up (yrs) Target Dose (mg) Mean Dosage achieved Effect on Outcome
CIBIS Circa 1994 Bisoprolol Mod/ Severe 641 1.9 5 QD 3.8 mg/day All cause mortality NS
CIBIS-II Lancet 1999 Bisoprolol Mod/ Severe 2547 1.3 10 QD 7.5 All cause mortality ?34
MD C Lancet 1993 Metoprolol Mild/ Mod 383 1 200 QD 108 Death or transplant NS
MERIT-HF Lancet 1993 Metoprolol Mild/ Mod 3991 1 200 QD 159 All cause mortality ?34
BEST NEJM 2001 Bucindolol Mod/ Severe 2708 2 50-100 BID 152 All cause mortality NS
US Carvedilol NEJM 1996 Carvedilol Mild/ Mod 1094 6.5 months 6.25-50 BID 45 All cause mortality ?65
COPERNICUS NEJM 2001 Carvedilol severe 2289 10.4 months 25 BID 37 All cause mortality ?35
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MOCHA trial Dose dependent response to Carvedilol
Mortality
Pts receiving diuretics, ACEI, and digoxin
follow up at six months
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Copernicus

• Patient characteristics
• symptoms at of heart failure at rest or minimal
  exertion for at least 2 months
• LVEF lt25
• Receiving ACEI and diuretics (digitalis) 2
  months. Diuretics optimized to achieve euvolemia
• No need for ICU and no tx with IV inotropic
  agents or IV vasodilator therapy within 4 days of
  randomization

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COPERNICUS Clinical outcome at 8 weeks
Death or Hospitalization for Any Reason
Deaths
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COMET trial

• Randomized, double blind, parallel group
  multicenter study that compared the effect of
  metoprolol and carvedilol on survival in 3029
  patients followed for 5 years
• Greater than 14,000 patient years of follow up
  (more than any CHF trial ever)
• Designed to test whether properties of carvedilol
  beyond ß1 blockade have favorable effects on
  survival

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Baseline Characteristics
Carvedilol (n1511) Metoprolol (n1518)
Age (y, mean/SD) 61.6/11.3 62.3/11.4
Male 79.4 80.2
Months of HF 42.6 42.2
Heart Rate (bpm) 81 81
Systolic BP (mmHg) 126 126
Diastolic BP (mmHg) 77 77
AF/Flutter 20.5 19.2
DM 23.8 24.4
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COMET Median survival

• Carvedilol 8.0 years (512 deaths)
• Metoprolol 6.6 years (600 deaths)
• Carvedilol prolonged median survival by 1.4
  years, assuming constant hazard

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Reassessing Role of Adrenergic Blockade

• Are outcomes dose dependant?
• High doses required with ß1 selective, dose
  dependent relationship with combined
• Is blocking at multiple steps better?
• Better survival, hemodynamic, and metabolic
  effects seen with combined adrenergic blockade
• Is one approach superior?
• Combined adrenergic blockade superior to
  selective

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Adrenergic Blockade in Diabetic Patients

• Gemini(JAMA, 2004) randomized patients to receive
  either lopressor or carvedilol as an
  antihypertensive strategy and examined impact on
  glycemic control
• Carvedilol associated with better preservation of
  HgbA1C, fasting glucose, and insulin sensitivity
  when compared to lopressor
• Also had favorable outcome on triglycerides

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Isordil/ Hydralazine Historical Data

• ISDNHydralazine reduced mortality by 26
  compared to dig and diuretics (V-HeFT I)
• Enalapril was superior to ISDNHydralazine (26
  reduction in mortality in 1st 2 years V-HeFT II)
• Enalapril and ISDNHydralazine comparable in year
  34 of V-HeFT II
• Neither study had background of ß-blockade
• Majority of patients caucasian

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A-HeFT
Placebo (N532) ISDNHydralazine 120/225mg TID (N518) 57 y/o AA NYHA III EF 24 F/U 18 months 87 ACE/ARB 75 ß-blocker 40 Aldo agonist
All cause mortality 54 (10.2) 32 (6.2) 0.02
CHF Hospitilization 130 (24.4) 85 (16.4) 0.001
QOL 2.7 5.6 0.02
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Summary Treatment Benefits
Symptoms Morbidity Mortality
Increase Dose of ACEI No effect ? 10-15 No effect
Add ARB ? ? 10-15 No effect
Add ß-blocker ? ? 20-35 ? 35
Add Aldactone ? ? 20 ? 16-25
Add ISDN Hydralazine ? ? 30 ? 40
AHA Scientific Sessions, 2004 (Lachel et al)
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Whats Hot?

• Devices
• Arginine vasopressin agonists
• Anti-oxidants
• Erythropoetin
• Metabolic modulators (L-carnatine, D-Ribose)
• ? BNP infusion (FUSION trial underway)

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Question 1

• A 64 year old female presents to the emergency
  department with a chief complaint or nausea,
  vomiting, and yellow vision. The patient
  recently saw her family doctor, who placed her on
  a medication for heart failure. After initial
  evaluation, an EKG is performed (next slide).
  The drug most likely started by her family
  practitioner is
• Furosemide
• Carvedilol
• Digoxin
• Enalapril
• ISDN Hydralazine

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Question 2

• According to the Gemini trial, in a diabetic
  patient with CHF in whom you are considering the
  addition of a ß-blocker, which of the following
  drugs would offer proven benefit with regards to
  triglyceride levels, HgbA1C levels, and
  maintenance of insulin sensitivity, assuming no
  contraindications are present?
• A. Metoprolol
• B. Bismolol
• C. Labetalol
• D. Carvedilol
• E. Bucindolol

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Question 3

• Which of the following side effects may limit the
  usage of the aldosterone agonist Eplerenone?
• Gingival hyperplasia
• Feculent odor to breath
• Hair loss
• Sexual impotency
• Gynecomastia

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