Current and Emerging Therapies in Heart Failure

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Current and Emerging Therapies in Heart Failure

• Jose L. Evangelista M.D., F.A.C.C., F.A.C.P.,
  F.R.C.P.
• Diplomate, Internal Medicine
• Board Certified Cardiovascular Diseases
• Diplomate Nuclear Cardiology

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KNOWLEDGE IS THE ACCUMULATION OF FACTS WISDOM IS
SIMPLIFYING THEM.
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Objectives

• Statistical and epidemiologic data on Heart
  Failure.
• Patho-physiology and Staging Classification.
• Currrent treatment regimens.
• Future direction in management of Heart Failure.

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What is Heart Failure

• Heart Failure is a clinical syndrome that can
  result from any structural or functional cardiac
  disorder that impairs the ability of the left
  ventricle to fill in or eject blood.

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Heart Failure Key Issues

• Incidence rate is high and increasing.
• Managing heart failure patients is extremely
  costly.
• Readmission rate for heart failure patients is
  high.
• Diagnosis of heart failure is subjective and
  could be problematic.

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Epidemiology of Heart Failure in the U.S.

• More deaths from heart failure than from all
  forms of cancer combined
• 4.7 million symptomatic patients
• Incidence About 550,000 new cases per year

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Heart Failure A Growing Burden in the US
Prevalence 5 million Americans with heart
failure Incidence 550,000 new
cases/year Morbidity 978,000 hospital
discharges most frequent cause of
hospitalization in elderly 6 of all
hospital admissions Mortality Heart failure rate
285,000 deaths/year sudden death 6 to 9 times
more common than in general population
American Heart Association. 2002 Heart and Stroke
Statistical Update. Dallas AHA 2001.
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A Public Health Crisis Heart Failure
Hospitalizations have Tripled in 25 Years
65 years
Hospitalizations/100,000 Population
45-64 years
1970
1975
1980
1985
1990
1995
Year
NHLBI. Morbidity and Mortality 2000 Chartbook on
Cardiovascular, Lung, and Blood Diseases. Geneva
World Health Organization 1996.
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Hospitalization The Major Factor in Heart
Failure Costs in the US
38.6 Outpatient care 14.7 billion (3.4
visits/year /patient)
60.6 Hospitalization 23.1 billion
0.7 Transplants 270 million
Total 38.1 billion (5.4 of total health care
costs)
OConnell JB, Bristow MR. J Heart Lung
Transplant. 199413S107-S112.
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Average Cost Per Year of LifeCoined in 1960 -
2000

• 53,700 at 45 years of age
• 84,700 at 65 years of age
• 145,000 at gt65 years of age

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NYHA Functional Classification of HF(old)

• Class I - asymptomatic
• Class II- symptomatic with moderate exertion
• Class III - symptomatic with minimal exertion
• Class IV - symptomatic at rest

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ACC/AHA Stages in the Evolution of HF (current)

• Stage A - High Risk
• Stage B - Asymptomatic
• Stage C- Symptomatic
• Stage D - Refractory

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NYHA Functional Class Equivalent Stages

• Stage A None
• Stage B Functional Class I
• Asymptomatic

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NYHA Functional Class

• Stage C Symptomatic
• Functional Class II - Symptomatic with moderate
  exertion or moderate levels of activity
• Functional Class III - Symptomatic with minimal
  exertion or less than ordinary levels of activity

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NYHA Functional Class Equivalent Stages

• Stage D Functional Class IV
• Symptomatic even at rest

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Stage A

• At high risk for heart failure
• NO structural heart disease and
• NO symptoms of HF.
• Hypertension
• Coronary Artery Disease
• Diabetes Mellitus
• Family hx of cardiomyopathy
• - Patients using Cardiotoxins e.g. cancer drugs

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Stage B

• Has Structural heart disease but NO symptoms of
  HF such as
• Previous myocardial infarction
• Left ventricular systolic dysfunction
• Asymptomatic valvular disease

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Stage C

• Structural heart disease with prior or current
  symptoms of HF such as
• Patients with known structural heart disease
• Patients with shortness of breath and fatigue,
  Reduced exercise tolerance

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Stage D

• Refractory HF requiring specialized interventions
• Patients who are markedly symptomatic even at
  rest, despite maximal medical therapy

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Progression of Cardiovascular Disease
Coronary Artery Disease Hypertension
Cardiomyopathy Valvular Disease
MI
Systolic Dysfunction
Progressive Heart Failure / Sudden Death
Diastolic Dysfunction
LVH
LV Remodeling
Clinical Heart Failure
Normal LV Structure and Function
Subclinical LV Dysfunction
Years
Years/Months
Possible pathway of progression
Adapted from Levy et al. J Am Coll Cardiol.
199322(4)1111-1116.
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Pathophysiology of Heart Failure
Cardiac injury
Increased load
Activation of RAA System, SNS, and cytokines
Reduced systemic perfusion
Altered gene expression
Growth and remodeling
Ischemia and energy depletion
Direct toxicity
Apoptosis
Necrosis
Cell death
Adapted from Eichhorn EJ, Bristow MR.
Circulation. 1996942285-2296.
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The Renin-Angiotensin-Aldosterone (RAA) System
Kidneys secreterenin
Adrenal cortex secretes aldosterone
Liver secretes angiotensinogen
Angiotensinconvertingenzyme(ACE)
Blood
Renin
Angiotensinogen
Aldosterone
Angiotensin II
Angiotensin I
NA retention H2O retention K excretion Mg
excretion
Growthfactor stimulation
Vascular smooth muscle constriction
Sympathetic activation
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Aldosterones Role in Cardiovascular Disease
McMahon EG. Current Opinion Pharmacol.
20011190-196.
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Parameters to Record

• Body Weight.
• Blood Pressure (Sitting and Standing).
• Degree of jugular vein distention response to
  abdominal compression.
• Presence or absence of pulmonary congestion,
  presence of pulmonary rales and hepatomegaly.
• Magnitude of peripheral edema (legs, abdomen,
  pre-sacral area, scrotum,ascites

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BNP Concentration and Severity of Heart Failure
Dao Q, Krishnaswamy P, Kazanegra R, et al. J Am
Coll Cardiol. 200137379-85.
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Blockade of the Renin Angiotensin System ACEI
Blockade of the Renin Angiotensin System ACEI
Renin

• Feedback Loop
• ACEIs impact the feedback loop, resulting in
  increased PRA and Ang I

AT1 Receptor
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Blockade of the Renin Angiotensin System ARB
Renin

• Feedback Loop
• ARBs impact the feedback loop, resulting in
  increased PRA, Ang I and Ang II

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Dual Intervention in RAA System Pathways to
Target Receptor Sites
Na
K
Angiotensinogen
Aldosterone
Adrenal Vascular Myocardial Renal CNS
Renin
Other
ACTH
Chymase
CE
Angiotensin I
Angiotensin II
Bradykinin
Inactive
Angiotensin II receptor blockade
Aldosterone receptor blockade
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ACUTE DECOMPENSATED HEART FAILURE

• IV vasodilators
• IV Nitroglycerine
• IV Nitroprusside
• IV Nesiritide

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VOLUME EXPANDED ACUTE DECOMPENSATED HEART FAILURE

• Continuous IV DIURETICS (LASIX) 5-10 mg per hour
• AQUARETICS V2 receptor antagonists (Tolvaptan)
  by increasing aquaporin-2 activity in collecting
  ducts.
• ULTRA-FILTRATION invasive expensive.

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Drugs to Avoid in Heart Failure

• NSAID
• TZD
• CALCIUM CHANNEL BLOCKERS
• HERBAL TREATMENTS
• APPETITE SUPPRESSANT FENFLURAMINE
• CNS ACTIVE DRUGS

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Device Therapies for HF Resynchronization Therapy

• INDICATION Patients must have
• EF lt30 despite optimal medical therapy
• NYHA Class III-IV (ambulatory class IV)
• Normal sinus rhythm
• Cardiac dysynchrony (electrical)
• LBBB - QRS gt120 milli-sec

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Recommended Therapy Stage D or Refractory or End
Stage HF

• Referral for cardiac transplantation
• Referral to heart failure program in an academic
  setting
• Options for end of life care
• Management
• LV assist device
• Biventricular pacemaker
• Continuous IV infusion of inotropic agents
• Meticulous control of fluid restriction

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Not Recommended in Stage D or Refractory or End
Stage HF

• Intermittent IV infusion of inotropic agents e.g.
  Dobutamine tune up or Milrinone
• Partial left ventriculectomy
• Implantation of AICD if life expectancy is less
  than one year
• Nutritional supplement
• Hormonal therapy

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Device Therapy for HFImplantable Defibrillators

• Primary prevention of sudden cardiac death
• Class I indication for anyone with EF lt30 and on
• Optimal medical therapy
• NHYA Class II III symptoms
• At least 40 days post-MI for ischemics
• 3 months since diagnosis for non-ischemics
• Reasonable expectation of survival with good
  functional status for gt 1 year

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Drugs Interventions Under Investigation

• Vasopressin Receptor Inhibitors
• Intermittent Nesiritide Infusion
• Phospho-diesterase inhibitors
• External counterpulsation
• Implantable Hemodynamic Monitors
• Growth Factors
• Stem Cell Transplantation
• Rx for Sleep Disorders

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ADHERE STUDY

• ADHERE Acute Decompensated Heart Failure
  Registry
• 180,000 patients
• 51 had normal LV systolic function
• 49 had an EF less than 40
• Predictors of Mortality
• BUN greater than 43 mg /dl
• BP less than 115 systolic
• Serum Creatinine greater than 2.75 mg/dl

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EVEREST TRIAL

• EVEREST Efficacy of Vasopressin Antagonist in
  Heart Failure (Tolvaptan)
• International randomized placebo controlled study
• 359 centers in 20 countries
• CONCLUSION NO SIGNIFICANT IMPROVEMENT in
  all-cause mortality, cardiovascular mortality and
  hospitalization for HF