Maximizing Heart Failure Care

1
Maximizing Heart Failure Care

• Opportunities to Improve Patient Outcomes in the
  Emergency Department

A CME National Faculty Program
2
Key Learning Objectives

• Natural history and prevalence of acutely
  decompensated heart failure (ADHF)
• Pathophysiology and diagnosis of ADHF
• Treatment approaches
• Nesiritide for treatment of ADHF
• Opportunities to improve patient outcomes

3
Congestive Heart FailureScope of the Problem

• Nearly 900,000 annual hospital admissions
  (increased 90 in past 10 years)1
• Most common discharge diagnosis for patients
  older than 65 years2
• 6.5 million hospital days per year1
• Single largest expense for Medicare1
• Annual hospital/nursing home costs 15.4 billion3

• Hunt SA et al. ACC/AHA Guidelines for the
  Evaluation and Management of Chronic Heart
  Failure in the Adult. 2001.
• Graves EJ, Gillum BS. 1994 Summary National
  Hospital Discharge Survey. National Center for
  Health Statistics 1996.
• American Heart Association. 2002 Heart and Stroke
  Statistical Update. 2001.

4
Outcomes of Acutely Decompensated Heart Failure

• Median length of hospital stay 6 days1
• Hospital readmissions
• 20 at 30 days1
• 50 at 6 months1
• Mortality
• 11.6 at 30 days2
• 33.1 at 12 months2
• 50 at 5 years1

• Aghababian RV. Rev Cardiovasc Med. 20023(suppl
  4)S3S9.
• Jong P et al. Arch Intern Med. 200216216891694.
  

5
Cardiovascular-Related Visits to the ED
4000
3500
3000
2500
Number of Visits (thousands)
2000
1500
1000
500
0
Chest Pain
Heart Disease
Excluding ischemic. McCaig LF, Ly N. Adv
Data. 2002326132.
6
Epidemiology of Heart Failure in the United States

• 4.79 million patients1 estimated 10 million in
  20372
• Incidence about 550,000 new cases each year1
• Prevalence is 2 in persons aged 40 to 59 years,
  progressively increasing to 10 for those aged 70
  years and older3
• Sudden cardiac death is 6 to 9 times higher in
  the heart failure population1

Patients in US (millions)
Year
1. American Heart Association. 2002 Heart and
Stroke Statistical Update. 2001. 2. Croft JB et
al. J Am Geriatr Soc. 199745270275. 3.
National Heart, Lung, and Blood Institute.
Congestive Heart Failure Data Fact Sheet.
Available at http//www.nhlbi.nih.gov/health/publ
ic/heart/other/CHF.htm.
7
Long-Term Trends in the Incidence of Heart Failure
Men
Women
Incidence of Heart Failure
Incidence of Heart Failure
Period
All values were adjusted for age (lt55, 5564,
6574, 7584, and 85 years). Values in
parentheses are 95 confidence intervals. This
period served as the reference period.
Levy D et al. N Engl J Med. 200234713971402.
8
Long-Term Trends in Mortality With Heart Failure
Period
All values were adjusted for age (lt55, 5564,
6574, 7584, and 85 years). Levy D et al. N
Engl J Med. 200234713971402.
9
Heart Failure Hospitalizations
The Number of Heart Failure Hospitalizations Is
Increasing in Both Men and Women
600,000
500,000
400,000
Annual Discharges
300,000
200,000
100,000
0
'79
'81
'83
'85
'87
'89
'91
'93
'95
'97
'99
Year
CDC/NCHS hospital discharges include patients
both living and dead. American Heart
Association. 2002 Heart and Stroke Statistical
Update. 2001.
10
Hospital Visits for Congestive Heart Failure
Emergency Department Presentations
Initial Episodes 21
Repeat Visits 79
Approximately 80 of ED visits for HF result in
hospitalizations
Requires full evaluation for reversible causes
of heart failure.
Aghababian RV. Rev Cardiovasc Med. 20023(suppl
4)S3S9.
11
Rates of Hospital Readmission
Patients Readmitted ()
60
50
50
40
30
20
20
10
2
0
Within 2
Within 1
Within 6
Days
Month
Months
Aghababian RV. Rev Cardiovasc Med. 20023(suppl
4)S3S9.
12
Estimated Total Direct Costs of Heart Failure in
the United States
Physicians/Other Professionals 1.6 billion
Hospital/ Nursing Home 15.4 billion
Medications/Other Medical Durables 2.0 billion
Home Health Care 2.4 billion
Total cost 21.4 billion
American Heart Association. 2002 Heart and
Stroke Statistical Update. 2001.
13
Maximizing Heart Failure Care

• Pathophysiology and Diagnosis

14
Heart Failure Pathophysiology
Fall in LV Performance
Myocardial Injury
Activation of RAAS, SNS, ET, and Others
Peripheral Vasoconstriction Hemodynamic
Alterations
ANP BNP
Myocardial Toxicity
Remodeling and Progressive Worsening of LV
Function
Heart Failure Symptoms
Morbidity and Mortality
Shah M et al. Rev Cardiovasc Med. 20012(suppl
2)S2S6.
15
Physiologic Effects of the RAAS
and NPS

• RAAS (Renin-Angiotensin-Aldosterone System)
• Activation of AT1 receptors Vasoconstriction
• by angiotensin II Sodium retention
• Increased aldosterone release
• Increased cellular growth
• Increased sympathetic nervous activity
• NPS (Natriuretic Peptide System)
• ANP, BNP Vasodilation
• Sodium excretion
• Decreased aldosterone levels
• Inhibition of RAAS
• Inhibition of sympathetic nervous activity
• Antiproliferation of vascular smooth muscle
  cells

AT1 angiotensin I ANP atrial natriuretic
peptide BNP B-type natriuretic peptide.
Burnett JC Jr. J Hypertens. 199917(suppl
1)S37S43.

• Reference
• Shah M, Ali V, Lamba S, Abraham WT.
  Pathophysiology and clinical spectrum of acute
  congestive heart failure. Rev Cardiovasc Med.
  20012(suppl 2)S2S6.

16
Relation of Neurohumoral Activation to Myocardial
Remodeling
Relatively normal chamber size and geometry1
Myocyte dysfunction Structural alteration
Cardiac adrenergic RAAS signaling
Improved functionReverse remodeling
ACE Inhibitors and ß-blocker therapy (ANP/BNP?)2

• Cohn JN et al. J Am Coll Cardiol.
  200035569582.
• Burnett JC Jr. J Hypertens. 199917(suppl
  1)S37S43.

17
Natriuretic Peptide System
Sympathoinhibitory
ANP BNP
Antifibrotic Lusitropic
ANP BNP
ANP
ET inhibition Vasodilation
BNP
Aldosteroneinhibition
ANP
BNP
CNP
ANP
BNP
Natriuresis Renin inhibition
Antiproliferation effect
Burnett JC Jr. J Hypertens. 199917(suppl
1)S37S43.
18
The NPS Is Overwhelmed in Acutely Decompensated
Heart Failure
Adapted from Shah M et al. Rev Cardiovasc Med.
20012(suppl 2)S2S6.
19
Nesiritide Reverses Acute CHF

• Maisel A. Rev Cardiovasc Med. 20023(suppl
  4)S10S17.
• Fonarow GC. Rev Cardiovasc Med. 20023(suppl
  4)S18S27.

20
Diagnosis of CHFClinical Challenge

• Signs and symptoms of heart failure, such as
  shortness of breath and edema, have a broad
  differential diagnosis1
• Chest x-ray findings have limited accuracy for
  CHF1
• 2040 of patients with CHF have normal systolic
  function2

• Dao Q et al. J Am Coll Cardiol. 200137379385.
• Hunt SA et al. ACC/AHA Guidelines for the
  Evaluation and Management of Chronic Heart
  Failure in the Adult. 2001.

21
Diagnosis of ADHF

• Medical History
• Prior history of CHF taking medication for CHF
• Prior history of MI or unstable angina, taking
  medication for coronary artery disease
• Prior history of obstructive valvular heart
  disease or cardiomyopathy
• Admitted noncompliance with prescribed
  medication, dietary indiscretion, or recent NSAID
  use

22
Diagnosis of ADHF

• Examination
• Rales
• Tachycardia
• S3 gallop and/or murmur suggesting obstructive or
  regurgitant valvular disease
• Pedal edema
• JVD or other evidence of increased LV filling
  pressure (hepatojugular reflex, ascites,
  hepatomegaly)
• Increased LV filling pressure (?20 mg Hg)
  confirmed by pulmonary artery catheter

23
Diagnosis of ADHF

• Test Results
• Chest x-ray enlarged cardiac silhouette,
  enlarged pulmonary vessels, pulmonary edema
• Echocardiogram LV dysfunction
• Radionuclide ventriculography
• Cardiac catheterization

24
Diagnosis of ADHF

• Test Results (contd)
• BNP CHF Serum Markers
• BNP level of 100 pg/mL has a sensitivity of 90,
  a specificity of 76, and an accuracy of 83 of
  differentiating CHF from other causes of dyspnea
• BNP level of 50 pg/mL has a negative predictive
  value of 96
• BNP level is more accurate than NHANES criteria
  (67) and Framingham criteria (73), the two
  criteria most commonly used to diagnose CHF

25
Diagnosis of ADHF

• Differential Diagnosis
• Pulmonary infection
• Acute COPD/asthma exacerbation
• Reactive airway disease
• Acute coronary syndrome
• Pulmonary emboli
• Pneumothorax, pleural effusions
• Aortic dissection

26
B-Type Natriuretic Peptide (BNP)

• 32-amino acid peptide secreted primarily from the
  ventricles of the heart
• Released in response to stretch and increased
  volume in the ventricles
• BNP levels correlate with
• LV end diastolic pressure
• NYHA classification
• Rapid, point-of-care assay for BNP is now
  available to facilitate diagnosis of CHF and for
  use as a prognostic marker

Dao Q et al. J Am Coll Cardiol. 200137379385.
27
BNP Levels of Patients Without CHF, With Baseline
LV Dysfunction, and With CHF
P lt 0.001
1076 138
Mean BNP Concentration (pg/mL)
141 31
38 4
Asymptomatic LV Dysfunction (n 14)
No CHF (n 139)
CHF (n 97)
Dao Q et al. J Am Coll Cardiol. 200137379385.
28
Clinical Indecision in the ED
Physician Report on Clinical Probability of CHF
350
300
250
200
Number of Cases
150
100
50
0
0
10
20
30
40
50
60
70
80
90
100
Pretest Probability of CHF ()
McCullough PA et al. Circulation.
2002106416422.
29
BNP Study Primary End Point
ED Probability of CHF Recorded
74.0
Clinical Judgment
81.2
BNP
81.5
Combined
70
72
74
76
78
80
82
N 1538
Diagnostic Accuracy ()
P lt 0.0001 from clinical judgment to combined.
McCullough PA et al. Circulation.
2002106416422.
30
BNP vs NHANES and Framingham Criteria
Comparative Accuracy
90
83
Accuracy ()
70
73
67
50
NHANES
Framingham
BNP
N 1586
Maisel AS et al. N Engl J Med. 2002347161167.
31
Heart Failure Diagnostic Algorithm
Patient with dyspnea or other CHF signs/symptoms
Diagnostic for CHF
History/physical exam/ECG/chest x-ray
Acute/chronic CHF management (echocardiography,
if not done previously)
Nondiagnostic
Positive
BNP blood test
Negative
Evaluate for non-CHF etiologies (echocardiography
usually not indicated)
Adapted from Maisel A. Rev Cardiovasc Med.
20023(suppl 4)S10S17.
32
Possible Evidence of Low Perfusion

• Narrow pulse pressure
• Sleepy/obtunded
• Low serum sodium
• Cool extremities
• Hypotension with ACE inhibitor
• Renal dysfunction (one cause)

Stevenson LW. Eur J Heart Fail. 19991251257.
33
Maximizing Heart Failure Care

• Treatment Approaches for Acutely Decompensated
  Heart Failure

34
Conventional Treatments of Acute Heart Failure
Fonarow GC. Rev Cardiovasc Med. 20012(suppl
2)S7S12.
35
Patient Selection and Treatment
Fonarow GC. Rev Cardiovasc Med. 20012(suppl
2)S7S12.
36
Therapeutic Goals for Acutely Decompensated Heart
Failure
Goals
End Points

• Dyspnea and other signs and symptoms of heart
  failure1
• Lower PCWP with adequate systemic perfusion1
• Use of ACE inhibitors, aldosterone antagonists,
  and ß-blockers before hospital discharge1
• Shorten length of stay, minimize use of intensive
  care unit, reduce readmissions1
• Inhibit RAAS system, monitor inflammation caused
  by infection following a major surgery or
  trauma2,3

• Relieve symptoms
• Reverse acute hemodynamic abnormalities
• Initiate treatments that will slow disease
  progression and improve long-term survival
• Apply treatment cost- effectively
• Prevent end-organ dysfunction

• Fonarow GC. Rev Cardiovasc Med. 20023(suppl
  4)S18S27.
• Stier CT Jr et al. Cardiol Rev. 20021097107.
• Masai T et al. Ann Thorac Surg. 200273549555.

37
Rapid Near-Normalization of Hemodynamics Without
Use of Inotropic Agents in ADHF
All 25 Patients
P lt 0.05, baseline vs 2472 h P 0.09 P lt
0.05, 2472 h vs 8 mo.
RAP right atrial pressure SV stroke volume
MAP mean arterial pressure. Steimle AE et al.
Circulation. 19979611651172.
38
PCWP Predicts Subsequent Mortality
Mortality Risk ()
Mortality Risk ()
60
60
50
50
40
40
PCWP gt 16 mm Hg
CI gt 2.6 L/min-m2
30
30
199
CI lt 2.6 L/min-m2
20
20
PCWP lt 16 mm Hg
236
10
10
220
257
P 0.001
P NS
0
0
0
6
12
18
24
0
6
12
18
24
Time (m)
Hemodynamic measurement in 456 heart failure
patients after tailored vasodilator therapy.
Fonarow GC et al. Circulation. 199490(4 pt
2)I-488.
39
Treatment Goals
Clinical
Hemodynamic
SBP gt 80 mm Hg No orthopnea No peripheral
edema No hepatomegaly/ascites JVP lt 8 cm Warm
extremities
SBP gt 80 mm Hg PCWP lt 15 mm Hg RAP lt 8 mm
Hg SVRI lt 1200 dyne-s-cm-5
JVP jugular venous pressure.
40
Freedom From Congestion Predicts Survival Despite
Previous Class IV Symptoms of HF

• 146 patients hospitalized with class IV heart
  failure
• Assessed 4 to 6 weeks after hospitalization for
  congestion
• Patients with persistent orthopnea (n 33)
• 2-year survival 38
• Patients with resolution of orthopnea (n 113)
• 2-year survival 77 (P 0.0001)

Lucas C et al. Am Heart J. 2000140840847.
41
Nesiritide and Serum BNP in Patients With
Decompensated CHF
Infusion
Postinfusion
Change in Serum BNP ()
Time (h)
Maisel AS et al. Heart Failure Society of America
Annual Meeting September 2225, 2002 Boca
Raton, FL.
42
BNP Concentration for the Prediction of Clinical
Events
From Time of Hospital Discharge
55
50
45
40
BNP gt 480 pg/mL
35
Cumulative Probability of CHF Visit, Admission,
or Death ()
30
25
20
BNP 230480 pg/mL
15
10
5
BNP lt 230 pg/mL
0
0
20
40
60
80
100
120
140
160
180
Time (d)
Harrison A et al. Ann Emerg Med. 200239131138.
43
Outpatient BNP Levels Predict Heart Failure
Mortality Independent of Other Markers
18-Month Heart Failure Mortality Rates
Diagnostic Test Below Median Above Median RR
P Value BNP 1/145 (0.7) 23/151 (15.2) 22.1
0.000001 LVEF 7/150 (4.7) 17/129 (13.2)
2.5 0.0279
297 outpatients with LV dysfunction/CHF in the
Australia-New Zealand trial median BNP, 99
pmol/L LVEF, 0.29.
RR respiratory rate. Richards AM. J Am Coll
Cardiol. 20013717811787.
44
Elevated LV Filling Pressure and Outcomes
Persistent Elevation in LV Filling Pressure
Indicated by Any of the Following Is Associated
With Increased HF Symptoms, Adverse Clinical
Outcomes, and Mortality

• Direct hemodynamic measurements1
• Symptoms of orthopnea2
• S3 heart sound3
• Assessed by biologic assay (BNP)4

• Fonarow GC. Rev Cardiovasc Med. 20012(suppl
  2)S7S12.
• Lucas C et al. Am Heart J. 2000140840847.
• Drazner MH et al. N Engl J Med. 2001345574581.
• Cheng V et al. J Am Coll Cardiol. 200137386391.

45
Acute Decompensation of Heart Failure Is
Afterload Mismatch

• Primary pathophysiology elevation of LV filling
  pressure and fluid redistribution to the lungs1
  as a result of afterload mismatch (excess
  vasoconstriction) rather than decrease in
  contractility2
• The interaction between a rise in SVR and
  myocardial systolic and diastolic reserve is the
  major mechanism for elevated filling pressures
  and decompensation1
• Reduction of LV filling pressure (via balanced
  vasodilation /- diuresis) results in rapid
  relief in symptoms and is associated with reduced
  risk of rehospitalization and improved survival3

• Fonarow GC. Rev Cardiovasc Med. 20023(suppl
  4)S19S29.
• Shah M et al. Rev Cardiovasc Med. 20012(suppl
  2)S2S6.
• Aghababian RV. Rev Cardiovasc Med. 20023(suppl
  4)S3S9.

46
Mortality in Large Placebo-Controlled Trials of
Inotropes for Heart Failure
Trial Inotrope NYHA N Mortality vs Placebo
PROMISE Milrinone III, IV 1088 28 Increase
VEST Vesnarinone III, IV 3833 11
Increase Xamoterol Xamoterol III, IV 516
Hazard ratio 2.5 PRIME II Ibopamine III, IV
1906 Hazard ratio 1.26 PICO Pimodendan II,
III 317 Hazard ratio 1.8
PROMISE Prospective Randomized Milrinone
Survival Evaluation VEST Vesnarinone Trial
PRIME Prospective Randomized Ibopamine
Mortality Evaluation PICO Pimobendan in
Congestive Heart Failure.
Felker GM, OConnor CM. Am Heart J.
2001142393401.
47
Flolan International Randomized Survival Trial
(FIRST)

• Study Design
• 471 patients randomized to receive dobutamine (n
  80) or standard care (n 391)
• Median dose of dobutamine 4 µg/kg/min
• Primary study end point survival

Califf RM et al. Am Heart J. 19971344454.
48
Flolan International Randomized Survival Trial
(FIRST)
Use of Dobutamine in FIRST Increased Mortality
1.0
OConnor CM et al. Am Heart J. 19991387886.
49
IV Inotropic Agents During Hospitalization for
Decompensated Heart Failure

• OPTIME-CHF Study Design
• Prospective, randomized, double-blind,
  placebo-controlled trial
• Study of the effect of short-term milrinone in
  addition to standard therapy in 951 patients
  hospitalized for an exacerbation of heart failure
• Mean age 65 y
• NYHA class II (7.0), III (45.2), or IV (47.5)
• Mean LVEF 23
• Serum creatinine 3.0 mg/dL
• No myocardial ischemia within 3 months or
  sustained ventricular tachycardia or ventricular
  fibrillation
• Exacerbation occurred no more than 48 hours
  before study
• Patients received 48-hour infusions of either
• Milrinone, 0.5 µg/kg/min (n 477)
• Saline placebo (n 472)

2 patients randomized to the milrinone group
withdrew their consent before analysis. Added to
standard therapy.

Cuffe MS et al. JAMA. 200228715411547.
50
IV Inotropic Agents During Hospitalization for
Decompensated Heart Failure
OPTIME-CHF In-hospital Adverse Events
Event Rate ()
20
P lt 0.001
Milrinone
P lt 0.001
Placebo
15
P 0.004
10
P 0.19
P 0.18
5
0
Treatment Failure From Adverse Event (48 h)
Sustained Hypotension
Acute MI
Mortality
Afib
Cuffe MS et al. JAMA. 200228715411547.
51
IV Inotropic Agents During Hospitalization for
Decompensated Heart Failure

• Conclusions
• In the OPTIME-CHF study, patients who received
  milrinone had an increase of in-hospital adverse
  events (ie, acute MI, mortality)
• The routine use of milrinone is not recommended
  for patients hospitalized with an exacerbation of
  CHF

Cuffe MS et al. JAMA. 200228715411547.
52
Effect of Dobutamine on Neurohormones 10 to 14
Days Post-Therapy
700

600

400
pg/mL
pg/mL
50
30
20
10
PRA
Ald
NE
ET-1
TNF-?
P lt 0.001. PRA plasma renin activity NE
norepinephrine. Aronson D, Burger AJ. Eur Heart
J. 200122397.
53
Role of Inotropic Therapy in Patients With Heart
Failure

• The routine use of inotropes as heart failure
  therapy is not indicated in either the short- or
  long-term setting
• The use of inotropes as a treatment of
  cardiogenic shock, diuretic/ACE
  inhibitorrefractory heart failure
  decompensations, or as a short-term bridge to
  definitive treatment, such as revascularization
  or cardiac transplantation, is potentially
  appropriate
• Inotropes may be appropriate as a palliative
  measure in patients with truly end-stage heart
  failure as part of hospice care

Felker GM. Am Heart J. 2001142393401.
54
Dopamine and Heart Failure

• Studies of dopamine in heart failure, after
  aortic surgery or during septic shock, failed to
  find expected renal effects1
• In PRIME-II, there was a higher mortality rate
  among heart failure patients taking ibopamine
  (oral dopamine agonist) than among those taking
  placebo (RR, 1.26 CI, 1.041.53 P 0.017)2
• Low-dose dopamine should not be used for
  selective renal vasodilatory and natriuretic
  actions until its efficacy is established in
  randomized controlled trials3

PRIME II Second Prospective Randomized Study of
Ibopamine on Mortality and Efficacy.

• Smit AJ. Clin Exp Hypertens. 200022269276.
• Hampton JR et al. Lancet. 1997349971977.
• Power DA et al.Clin Exp Pharmacol Physiol Suppl.
  199926S23S28.

55
Diuretics and Heart Failure
There have been no long-term studies of diuretic
therapy for the treatment of heart failure and,
thus, its effects on morbidity and mortality are
not known.1 Patients may become unresponsive to
high doses of diuretic drugs if they

• Consume large amounts of dietary sodium2
• Are taking agents that can block the effects of
  diuretics (eg, NSAIDs, COX-2 inhibitors)1
• Have significant impairment of renal function or
  perfusion1
• Diuretic resistance can generally be overcome
• By the IV administration of diuretics2
• The use of two or more diuretics in combination2

• Ravnan SL et al. Congest Heart Fail.
  200288085.
• Brater DC. Drugs. 198530427443.

56
Nitroglycerin and Neurohormones in Heart Failure

• IV nitroglycerin at a mean dose of 276 µg/min
  significantly increased renin and aldosterone
  levels in patients with class III/IV heart
  failure1
• In patients with CHF, IV nitroglycerin dosed to
  lower PCWP by 30 increased levels of aldosterone
  and cortisol however, there was no change in
  plasma norepinephrine2
• High-dose transdermal nitroglycerin did not
  result in changes in serum catecholamine or renin
  concentration3

• Dakak N et al. Eur Heart J. 199314836844.
• Webster MW et al. Am J Cardiol. 198963217221.
• Elkayam U et al. Am J Cardiol. 198556555559.

57
Intravenous Inotropic Agent Strategy to Reverse
Heart Failure Decompensation

• Targets a physiologic parameter not associated
  with improved clinical outcomes (resting cardiac
  index)
• Can be associated with worsened ischemia
• Can be associated with precipitation of
  ventricular arrhythmias
• Weaning from support done slowly
• Tolerance (dobutamine)

Fonarow GC. Rev Cardiovasc Med. 20012(suppl
2)S7S12.
58
Inotrope Infusion ACC/AHA 2001 Guidelines

• Because of lack of evidence to support their
  efficacy and concerns about their toxicity,
  physicians should not utilize intermittent
  infusions of positive inotropic agents (at home,
  in an outpatient clinic, or in a short-stay unit)
  in the long-term treatment of HF, even in its
  advanced stages.

Hunt SA et al. ACC/AHA Guidelines for Evaluation
and Management of Chronic Heart Failure in the
Adult. 200127.
59
Effects of Diuretics on Neurohormones

• Direct effects of diuretics
• Natriuresis, diuresis
• Electrolyte excretion K, Ca, Mg
• Indirect effects of diuretics
• Volume depletion, decreased circulating volume
• Decreased renal perfusion and increased release
  of antidiuretic hormone
• Increased renin production, RAAS activation
• Increased sympathetic activation
• Reflex vasoconstriction, increased SVR,
  diminished CO
• Increased water and sodium retention
• Metabolic alkalosis

Kaplan NM. Treatment of hypertension drug
therapy in clinical hypertension. In Kaplan NM,
Lieberman E, Neal WW, eds. Clinical Hypertension.
1994199211.
60
The Effects of Diuretics on Mortality and
Nonrecovery of Renal Function
Odds Ratio (95 CI)
Covariate and Propensity Score Adjusted
Covariate adjusted for age sex log urine
output serum creatinine level blood urea
nitrogen level respiratory, hepatic, and
hematologic failure and heart rate. The referent
group was no diuretics time was first day of ICU
consultation. Area under receiver operating
characteristic (ROC) curve 0.76
goodness-of-fit ?2 P 0.89. Area under ROC
curve 0.82 goodness-of-fit ?2 P 0.39. Area
under ROC curve 0.85 goodness-of-fit ?2 P
0.84. Area under ROC curve 0.81
goodness-of-fit ?2 P 0.58.
Mehta RL et al. JAMA. 200228825472553.
61
The Effects of Diuretics on Mortality and
Nonrecovery of Renal Function
Time to Death or Dialysis From Day of
Consultation in ICU
Mehta RL et al. JAMA. 200228825472553.
62
Furosemide and Heart Failure Bolus
Injection vs Continuous Infusion
Urinary Volume, Sodium, and Potassium (mean
SEM) 24 Hours After Furosemide Administration
Dormans TPJ et al. J Am Coll Cardiol.
199628376382.
63
Doses for Continuous Intravenous Infusion of Loop
Diuretics
Infusion Rate, mg/h



Creatinine Clearance lt 25 mL/min
Creatinine Clearance 2575 mL/min
Creatinine Clearance gt 75 mL/min
IV Loading Dose, mg
Diuretic
10 0.5 5
10 then 20 0.5 then 1 5 then 10
20 then 40 1 then 2 10 then 20
40 1 20
Furosemide Bumetanide Torsemide
Before the infusion rate is increased, the
loading dose should be readministered.
Brater DC. N Engl J Med. 1998339387395.
64
Complications of Diuretic Therapy for Heart
Failure
Diuretic Therapy
Saluresis and Diuresis
? Plasma Volume
? Cardiac Output
? Renal Blood Flow
? PRA
? GFR
? Aldosterone
Postural Hypotension
? Distal CaReabsorption
? ProximalReabsorption
Kaliuresis
Pre-renalAzotemia
Hypokalemia
? Uric AcidClearance
? CalciumClearance
Glucose Intolerance
Hypocalcemia
Hyperuricemia
GFR glomerular filtration rate PRA plasma
renin activity. Kaplan NM. Treatment of
hypertension drug therapy in clinical
hypertension. In Kaplan NM, Lieberman E, Neal
WW, eds. Clinical Hypertension. 1994203.
65
Acute Vasoconstrictor Response to IV Furosemide
in CHF
Hemodynamic 20 min After IVVariable Baseline Fu
rosemide P Value
PAWP (mm Hg) 28 7 33 9 lt0.01
SVI (mL/min-m2) 27 8 24
7 lt0.01 HR (bpm) 87 13 91
16 lt0.01 MAP (mm Hg) 90 15 96
15 lt0.01 SVR (dyne-s-cm-5) 1454 394 1676
415 lt0.01 PRA (ng/mL) 9.9 8.5
17.8 16 lt0.05 PNE (pg/mL)
667 390 839 368 lt0.01
Each patient received an average dose of 1.3
0.6 mg/kg body weight of furosemide given over 1
to 2 minutes. SVI stroke volume index MAP
mean arterial pressure PRA plasma renin
activity PNE plasma norepinephrine.
Francis GS. Ann Int Med. 198510316.
66
Marked Activation of the RAAS by Loop Diuretics
50
10
Mean Confidence Interval
Plasma Renin Activity (ng/mL/h)
2.5
0.5
After Diuretic (n 11)
Before Diuretic (n 12)
Bayliss J et al. Br Heart J. 1987571722.
67
Ideal Agent for Acute Heart Failure

• Vasodilation (venous and arterial)
• Rapidly decreases ventricular filling pressures
• Rapidly decreases symptoms of congestion
• Does not increase heart rate or directly increase
  contractility (decreases myocardial oxygen
  demand)
• Is not proarrhythmic
• Has no tachyphylaxis
• Provides neurohormonal suppression
• Promotes diuresis/natriuresis
• Is conveniently dosed (can be used with or
  without pulmonary artery catheterization)
• Minimal titration needed

Fonarow GC. Rev Cardiovasc Med. 20012(suppl
2)S7S12.
68
Traditional Vasodilators Limitations

• Tachyphylaxis
• Headache
• Underdosed
• Titration required

Nitroglycerin
Difficult titration ICU ( arterial
line) Coronary steal Toxic metabolites Increased
renin
Nitroprusside
Fonarow GC. Rev Cardiovasc Med. 20012(suppl
2)S7S12.
69
Maximizing Heart Failure Care

• Nesiritide for AcutelyDecompensated Heart Failure

70
Nesiritide (hBNP) Is Identical to the Endogenous
Hormone
I
S
R
S
D
S
M
S
K
G
R
L
G
H
G
F
R
C
S
R
S
C
L
K
V
G
K
P
M
S
Precise amino acid sequence Identical
pharmacologic profile
S
V
G
Q
Clemens LE et al. J Pharmacol Exp Ther.
19982876771.
71
Beneficial Effects of BNP
Cardiac Myocyte ? Hypertrophy Decreased O2
consumption Decreased wall stress Improved
relaxation
Fibroblast ? Hyperplasia ? Collagen synthesis
Antifibrotic
Peripheral Artery Vasodilation ? Endothelial
function Hypertrophy Improved compliance
Coronary Artery Vasodilation ? Endothelial
function
Adapted from Burnett JC. J Hypertens.
199917(suppl 1)S37S43.
72
Pharmacologic Actions of hBNP

• Hemodynamic1,2
• (balanced vasodilation)
• veins
• arteries
• coronary arteries

Neurohumoral2 aldosterone4 endothelin2
norepinephrine4
Renal1,5 diuresis natriuresis

• Cardiac3
• lusitropic
• antifibrotic
• antiremodeling

• Marcus LS et al. Circulation. 19969431843189.
• Zellner C et al. Am J Physiol. 1999276(3 pt
  2)H1049H1057.
• Tamura N et al. Proc Natl Acad Sci U S A.
  20009742394244.
• Abraham WT et al. J Card Fail. 199843744.
• Clemens LE et al. J Pharmacol Exp Ther.
  19982876771.

73
Nesiritide Mechanism of Action
NPR natriuretic peptide receptor GTP
guanosine triphosphate cGMP cyclic guanosine
monophosphate.
Abraham WT on behalf of the VMAC Study Group.
Presented at AHA Scientific Sessions 2001
November 1114, 2001 Anaheim, CA.
74
Effects of Natriuretic Peptides on the Kidney

• Dilatation of afferent and constriction of
  efferent renal arterioles, leading to pressure
  augmentation within the glomerular capillaries
  and, thus, to increased GFR1
• Relaxation of mesangial cells, which enhances
  effective surface area for filtration2
• Inhibition of angiotensin IIstimulated sodium
  and water reabsorption in proximal convoluted
  tubules2
• Inhibition of tubular water transport by
  antagonizing effect of vasopressin2
• Decrease in plasma renin and aldosterone3

• Rayburn BK, Bourge RC. Rev Cardiovasc Med.
  20012(suppl 2)S25S31.
• Appel RG. Am J Physiol. 1990251F1036F1042.
• Holmes SJ et al. J Clin Endocrinol Metab.
  1993769196.

75
Reasons for Decreased Responsiveness to
Natriuretic Peptides in CHF

• Excessive stimulation of the RAAS
• Natriuretic peptide receptor downregulation
• Change in renal hemodynamics
• Increased neutral endopeptidase activity

Nathisuwan S et al. Pharmacotherapy.
2002222742.
76
Pharmacologic Effects of Nesiritide in CHF
? Diuresis1
? Natriuresis1
? Preload2
? PCWP2
? Aldosterone2
NESIRITIDE
? Endothelin4
? Afterload2
? Dyspnea3

• Clemens LE et al. J Pharmacol Exp Ther.
  19982876771.
• Abraham WT, et al. J Card Fail. 199843744.
• Natrecor package insert. Sunnyvale, CA Scios
  Inc August 2001.
• Zellner C et al. Am J Physiol. 1999276H1049H105
  7.

77
Hemodynamic and Renal Effects of hBNP Infusion
in CHF

• Study Design
• Double-blind, placebo-controlled, crossover trial
  of 20 patients with severe CHF
• Patients received either placebo or incremental
  90-minute infusions of hBNP (0.003, 0.01, 0.03,
  and 0.1 µg/kg/min) for 2 days

Marcus LS et al. Circulation. 19969431843189.
78
Baseline Urinary Excretion Data Before Infusion
of hBNP or Placebo
Before hBNP
Marcus LS et al. Circulation. 19969431843189.
79
Nesiritide Efficacy Trial Study Design

• Randomized
• Double-blind
• Placebo-controlled
• Parallel arm
• - Placebo ? Standard therapy (after 6
  hours)
• - Nesiritide, 0.015 ?g/kg/min
• - Nesiritide, 0.030 ?g/kg/min
• N 127
• Baseline characteristics
• PLC NES 0.015 NES 0.030
• N 42 43 42
• CI 2.0 1.8 1.9
• PCWP 29 28 28
• BNP 1153 1008 1331

Values are group means CI (L/min/m2) PCWP (mm
Hg) BNP (pg/mL). Colucci WS et al. N Engl J
Med. 2000343246253.
80
Nesiritide Efficacy Trial Clinical Outcomes
Added to standard therapy. Colucci WS et
al. N Engl J Med. 2000343246253.
81
Nesiritide Efficacy Trial Effect of Nesiritide
on PCWP
Added to standard therapy. Colucci WS et al. N
Engl J Med. 2000343246253.
82
Nesiritide Efficacy Trial Heart Failure Signs
and Symptoms
Appetite
Fatigue
Edema
Peripheral Circulation
Dyspnea
0
10
20
30
40
50
60
Percent Improved (6 hours of treatment)
Placebo (n 42)
Nesiritide, 0.015 µg/kg/min (n 43)
Nesritide, 0.030 µg/kg/min (n 42)
Added to standard therapy. Colucci WS et al. N
Engl J Med. 2000343246253.
83
Nesiritide Efficacy Trial Effects of Nesiritide
on Urine Output and Diuretic Use
Colucci WS et al. N Engl J Med. 2000343246253.
84
Nesiritide Efficacy Trial Effects of Nesiritide
on Neurohormones
Plasma Aldosterone
Plasma Norepinephrine
Nesiritide 0.015 µg/kg/min
Nesiritide 0.030 µg/kg/min
Nesiritide 0.015 µg/kg/min
Nesiritide 0.030 µg/kg/min
Placebo
Placebo
P NS
P 0.03
36 pg/mL
75 pg/mL
8 pg/mL
2.5 ng/dL
1.6 ng/dL
0.6 ng/dL
Added to standard therapy. Colucci WS et al. N
Engl J Med. 2000343246253.
85
The Effects of Nesiritide on Neurohormones

• Abraham WT et al. J Card Fail. 199843744.
• Aronson D et al. J Am Coll Cardiol. 200137(2
  suppl A)148A.

86
Maladaptive Effects of Aldosterone
Cardiac Myocyte Hypertrophy Norepinephrine
release
Fibroblast Hyperplasia Collagen synthesis
Fibrosis
Peripheral Artery Vasoconstriction Endothelial
dysfunction Hypertrophy Decreased compliance
Kidney Potassium loss Sodium retention
Francis GS. In Topol EJ, ed. Textbook of
Cardiovascular Medicine. Philadelphia, PA
Lippincott-Raven 199821792203.
87
Maladaptive Effects of Epinephrine and
Norepinephrine
Cardiac Myocyte Hypertrophy Apoptosis
Necrosis Increased wall stress Increased O2
consumption Impaired relaxation
Fibroblast Hyperplasia Collagen synthesis
Fibrosis
Peripheral Artery Vasoconstriction Endothelial
dysfunction Hypertrophy Decreased compliance
Coronary Artery Vasoconstriction Endothelial
dysfunction Atherosclerosis Thrombosis
Sackner-Bernstein JD, Mancini DM. JAMA.
199527414621467.
88
Effects of BNP on SNS/RAAS
Organ Source Adrenal Kidney Lung
Adrenal/?Heart
Norepinenphrine ? Renin ? Angiotensin II ?
Aldosterone
3,5,8
57
15
? Circulating aldosterone

• ? Circulating norepinephrine
• ? Renal and cardiac norepinephrine synthesis
• ? Adrenal norepinephrine secretion
• ? Adrenal norepinephrine reuptake

• ? Circulating renin
• ? Renal renin release

• Vatta MS et al. Peptides. 19971814831489.
• Brunner-LaRocca HP et al. J Am Coll Cardiol.
  20013712211227.
• Colucci WS et al. N Engl J Med.
  2000343246253.
• Abraham WT et al. J Card Fail. 199843744.
• Yoshimura M et al. Circulation.
  19918415811588.
• Akabane S et al. Eur J Pharmacol.
  1991198143148.
• Jensen KT et al. Am J Physiol. 1998274(1 pt
  2)F63F72.
• Clarkson PB et al. Circulation.
  19969320372042.

Reduction by BNP
89
Vasodilation in the Management of Acute
Congestive Heart Failure (VMAC) Trial

• Design
• Phase III randomized, double-blind,
  placebo-controlled
• Multicenter (55) in the United States
• Randomization strategy based on right-sided heart
  catheterization
• 489 patients enrolled from October 1999 to July
  2000
• Acutely decompensated heart failure with dyspnea
  on admission
• Nesiritide vs IV nitroglycerin vs placebo
• fixed-dose IV nesiritide
• variable-dose IV nesiritide
• IV nitroglycerin
• placebo

Added to standard therapy. VMAC Investigators.
JAMA. 200218715311540.
90
VMAC Study Design
Scios Inc. NDA 20-920 Cardiovascular and Renal
Drugs Advisory Committee Briefing Document
Natrecor (nesiritide) for Injection. Sunnyvale,
CA Scios Inc May 25, 2001.
91
VMAC Standard Therapy

• Standard therapy could include
• IV/oral diuretics
• Dobutamine
• Dopamine
• Long-term cardiac or non-cardiac therapies

Scios Inc. NDA 20-920 Cardiovascular and Renal
Drugs Advisory Committee Briefing Document
Natrecor (nesiritide) for Injection. Sunnyvale,
CA Scios Inc May 25, 2001.
92
VMAC Pharmacodynamic Modeling Simulated PCWP vs
Time
10,000 Simulated Subjects for Each Treatment
93
VMAC Pharmacodynamic Modeling Simulated SBP vs
Time
10,000 Simulated Subjects for Each Treatment
94
VMAC Pharmacodynamic Modeling Probability of
SBP(t) lt 90 vs Time
10,000 Simulated Subjects for Each Treatment
95
VMAC Clinical Presentation at Baseline

• Clinical Presentation All Subjects
  (N 489)
• Acute coronary syndromes
  61 (12)
• LVEF (mean), 27
  14
• Ejection fraction gt 40
  65 (13)
• Baseline Hemodynamics
• SBP, mm Hg
  121 22
• PCWP, mm Hg
  27.8 6.3
• Cardiac index, L/min/m2
  2.2 0.7

Catheterized subjects (n 246).
VMAC Investigators. JAMA. 200218715311540.
96
VMAC Baseline Cardiac Therapy1
Long-Term Therapy
Subjects(N 489)

• Diuretics 422 (86)
• Digoxin 296 (61)
• ACE inhibitors 294 (60)
• Ang II receptor antagonists 51 (10)
• ß-Blockers 161 (33)
• Nitrates 173 (35)
• Warfarin 160 (33)
• Statins 122 (25)
• Aldosterone antagonists 107 (22)
• Class III antiarrhythmics 77 (16)
• Aspirin 218 (45)
• Hydralazine 39 (8)
• Calcium channel blockers 66 (13)

IV Therapy at Randomization2Baseline
dobutamine, 15Baseline dopamine, 3

• Ang II angiotensin II.
• VMAC Investigators. JAMA. 200218715311540.
• Scios Inc. NDA 20-920 Cardiovascular and Renal
  Drugs Advisory Committee Briefing Document
  Natrecor (nesiritide) for Injection. Sunnyvale,
  CA Scios Inc May 25, 2001.

97
VMAC PCWP Through 3 Hours
98
VMAC PCWP Through 48 Hours
P lt 0.05 pooled nesiritide vs nitroglycerin.
Added to standard therapy. VMAC Investigators.
JAMA. 200218715311540.
99
VMAC Nesiritide Results in Greater Pulmonary
Vasodilation Than Nitroglycerin
2
100
VMAC Primary End Point
Dyspnea at 3 Hours
P values are based on van Elteren test with
7-point ordinal scale
P 0.034
P 0.191
Improved ()
Worsened ()
Nesiritide
Placebo
Nitroglycerin
Added to standard therapy.
Scios Inc. NDA 20-920 Cardiovascular and Renal
Drugs Advisory Committee Briefing Document
Natrecor (nesiritide) for Injection. Sunnyvale,
CA Scios Inc May 25, 2001.
101
VMAC Symptoms at 24 Hours
Noncatheterized Subjects as Randomized
Dyspnea
Global Assessment
P 0.01
P 0.03
Proportion of Patients Improved ()
Nitroglycerin (n 123/124)
Nesiritide Fixed (n 118/119)
Nitroglycerin(n 122/124)
Nesiritide Fixed(n 118/119)
Added to standard therapy. Wilcoxon
procedure.Young JB on behalf of the VMAC study
group. Poster presented at HFSA 5th Annual
Scientific Meeting September 912, 2001
Washington, DC.
102
VMAC Kaplan-Meier Estimate of Mortality Rate by
Treatment Group
100
Nitroglycerin (n 216) Nesiritide, 0.01
µg/kg/min (n 211) All Nesiritide (n 273)
90
80
70
60
Cumulative Mortality Rate ()
50
40
30
20
10
0
0
30
60
90
120
150
180
Time Observed From the Start of Treatment (d)
Stratified log-rank test Nitroglycerin vs
nesiritide, 0.01 µg/kg/min, P
0.616Nitroglycerin vs all nesiritide, P 0.319
Added to standard therapy. Scios Inc. NDA 20920
Cardiovascular and Renal Drugs Advisory Committee
Briefing Document Natrecor (nesiritide) for
Injection. Sunnyvale, CA Scios Inc May 25, 2001.
103
Nesiritide Effects on Serum Creatinine in VMAC
Added to standard therapy. Compared with
nitroglycerin, no statistically significant
differences were noted. Hemodialysis IV
nitroglycerin (n 5 2) vs IV nesiritide (n
9 3). Increased to ? 2.0 mg/dL and increased
by at least 50. Scios Inc. NDA 20920
Cardiovascular and Renal Drugs Advisory Committee
Briefing Document Natrecor (nesiritide) for
Injection. Sunnyvale, CA Scios Inc May 25, 2001.
104
Refractory Heart Failure Frequently Equals Renal
Failure

• Potential therapies
• Nesiritide
• Adenosine receptor antagonists
• Vasopressin antagonists
• Ultrafiltration
• Dialysis

105
VMAC Evidence of Nitrate Tolerance
Nitroglycerin Dosing in Catheterized Patients
P 0.003, change in nitroglycerin from 3 h to 24
h.
Added to standard therapy. Scios Inc. NDA 20-920
Cardiovascular and Renal Drugs Advisory Committee
Briefing Document Natrecor (nesiritide) for
Injection. Sunnyvale, CA Scios Inc May 25, 2001.
106
IV Nitroglycerin Dosing in USC Subset of VMAC
Patients
Added to standard therapy. USC University of
Southern California. Elkayam U for the VMAC Study
Group. NAIP Fifth Annual Meeting Research and
Clinical Vignette Abstract Book. 20027.
107
Change in PCWP IV Nitroglycerin vs Nesiritide in
USC Subset of VMAC Patients
P lt 0.05 vs IV nitroglycerin.
Added to standard therapy. Elkayam U for the VMAC
Study Group. NAIP Fifth Annual Meeting Research
and Clinical Vignette Abstract Book. 20027.
108
VMAC Relationship Between Decrease in PCWP and
Decrease in SBP With Vasodilation
Stevenson LW on behalf of the VMAC Study Group.
Presented at HFSA 5th Annual Scientific Meeting
2001 September 912, 2001 Washington, DC.
109
VMAC Use of ß-Blockers With Nesiritide Enhances
Efficacy Without Adverse Effects
Time From Start of Study Drug (h)
BL
0.25
0.5
1
2
3
Mean Change From Baseline in PCWP (mm Hg)
0
1
2

3
4





5

n 30
6


7
n 94

8
P lt 0.001, nesiritide vs baseline P 0.05 NES
BB () vs NES BB (-).
BB () subject received ß-blockers within 24
hours prior to study drug. BB (-) subject did
not receive ß-blockers within 24 hours prior to
study drug. Abraham WT on behalf of the VMAC
Study Group. Presented at AHA Scientific
Sessions 2001 November 1114, 2001 Anaheim, CA.
110
Lack of Ischemic Cardiovascular Adverse Events in
VMAC
Adverse Events 24 Hours After Start of Study Drug

• Nitroglycerin All Nesiritide
• (n 216) (n 273)
• Myocardial infarction 3 (1.4) 2 (0.7)
• Angina 5 (2) 5 (2)
• Ventricular tachycardia 11 (5) 9 (3)
• Symptomatic hypotension 10 (5) 12 (4)

P not significant.
Added to standard therapy. VMAC Investigators.
JAMA. 200218715311540.
111
VMAC Clinical Implications

• Nesiritide rapidly reduced PCWP and relieved
  symptoms in patients with acute heart failure
  more effectively than standard care alone and
  standard care plus IV nitroglycerin
• Nesiritide was as safe as and better tolerated
  than IV nitroglycerin

VMAC Investigators. JAMA. 200218715311540.
112
Nesiritide vs Dobutamine Clinical Effects and
Proarrhythmic Potential
PRECEDENT Trial

• Randomized, controlled
• Parallel arm
• Dobutamine gt 5 ?g/kg/min
• Nesiritide, 0.015 ?g/kg/min
• Nesiritide, 0.030 ?g/kg/min
• N 255
• Acutely decompensated CHF
• NYHA class III or IV
• 24-h baseline Holter
• 24-h Holter during treatment

Burger AJ et al. Am Heart J. 200214411021108.
113
Nesiritide vs Dobutamine Clinical Effects and
Proarrhythmic Potential

• There were significantly fewer serious
  ventricular arrhythmias in patients who received
  nesiritide compared with dobutamine

P lt 0.001
25
20
Dobutamine
Nesiritide (0.015 and 0.030 µg/kg/min)
P 0.001
15
Patients Meeting Proarrhythmia Criteria ()
10
5
0
CAPS
Velebit
Burger AJ et al. Am Heart J. 200214411021108.
114
Ventricular Arrhythmias in Patients With ADHF
Dobutamine vs Nesiritide
Nesiritide, Nesiritide, Clinical
Dobutamine 0.015 ?g/kg/min 0.030 ?g/kg/min
Overall Event (n 58) (n 103) (n 100) P
Value Cardiac arrest 5 0 0 0.011
VT 22 17 8 0.032 Nonsustained VT 17
17 6 0.029 Sustained VT 7 0 2 0.014
305 patients with heart failure requiring IV
vasoactive therapy.
VT ventricular tachycardia. Burger AJ et al. Am
J Cardiol. 2001883539.
115
Duration of IV Medication Administration in
Acutely Decompensated Heart Failure
Duration of administration of IV agent until the
patient was stabilized on oral medications.
Silver MA et al. J Am Coll Cardiol.
200239798803.
116
Effect of Nesiritide vs Dobutamine on Hospital
Readmission Rate
P lt 0.05
20
P lt 0.06
13
Patients Readmitted ()
11
8
4
4
All Readmissions
CHF Readmissions
21-Day Readmission Rate
Silver MA et al. J Am Coll Cardiol.
200239798803.
117
Effect of Short-Term Nesiritide vs Dobutamine on
6-Month Survival
Log-rank testDobutamine vs nesiritide, 0.015
?g/kg/min P 0.040Dobutamine vs nesiritide,
0.030 ?g/kg/min P 0.366
Cumulative Mortality Rate ()
Treatment Duration (d)
Silver MA et al. J Am Coll Cardiol.
200239798803.
118
Nesiritide vs Dobutamine Clinical Implications

• Nesiritide had no proarrhythmic effects, whereas
  dobutamine was associated with an increased risk
  of SVT and cardiac arrest
• Nesiritide use resulted in shorter duration of IV
  medications and lower rate of rehospitalization
• Nesiritide, 0.015 µg/kg/min, use in-hospital was
  associated with improved 6-month survival
  compared with in-hospital use of dobutamine

SVT sustained ventricular tachycardia. Silver
MA et al. J Am Coll Cardiol. 200239798803.
119
Nesiritide Summary

• Rapid symptom improvement
• No need for titration
• Reduces time in the ICU

120
Maximizing Heart Failure Care

• Opportunities to Improve Patient Outcomes

121
PROACTION Emergency Medicine Pilot Trial
53 Remain Stable After Discharge
51 Discharged (n 61)
59 Patients Admitted
Nesiritide SC (n 120)
6 Rehosp w/in 30 Days
4.6-Day LOS (index readmit)
Eligible CHF Patients (n 250)
12 hours
SC (n 117)
15 Patients Rehosp w/in 30 Days
64 Patients Admitted
8.3-Day LOS (index readmit)
45 Discharged (n 53)
49 Remain Stable After Discharge
ED/OU

Outpatient Care (APC Code)
Readmission w/in 30 Days
Inpatient Care (DRG Reimbursement)
LOS length of stay SC standard care ED/OU
emergency department/observation unit APC
ambulatory payment classification DRG
diagnosis-related group. Data on file. Scios,
Inc. August 2002.
122
Initial Treatment Algorithm for Acute Heart
Failure
Acutely Decompensated Heart Failure (Volume
Overloaded, Dyspnea, With SBP gt 90 mm Hg)
Oxygen
IV Diuretics
Initial Therapy
Nesiritide (2 ?g/kg bolus followed by 0.01
?g/kg/min infusion)
Inadequate Response
Hemodynamic Monitoring
IV Inotropic Agent(s)
Mechanical Assist
Increase Nesiritide Dose
Refractory Therapy
Abraham WT et al. Rev Cardiovasc Med.
20012235236.
123
If symptoms improved
Continue Standard Therapy
124
Key Goals in the Management of the Hospitalized
Heart Failure Patient

• Stabilize the Patient
• Reduce symptoms by relieving congestion (IV
  diuretics IV nesiritide followed by oral
  diuretic regimen)
• Stabilize the Disease
• Keep the patient alive, out of the hospital, and
  feeling better (initiate and titrate therapies
  that prevent the progression of heart
  failureACE inhibitors and ß-blockers)

Fonarow GC. Rev Cardiovasc Med. 20012(suppl
2)S7S12.
125
Heart Failure Therapies Demonstrated to Reduce
Mortality and/or Hospitalizations
Hospitalizations Only
Mortality and Hospitalizations
ACE inhibitors1 ß-Blockers2 Aldosterone
antagonists3 ICD4 Cardiac resynchronization5
Digoxin6 Angiotensin receptor antagonists7 Amiodar
one8 Dofetilide9

• ICD implantable cardioverter-defibrillator.
• The CONSENSUS Trial Study Group. N Engl J Med.
  198731614291435.
• Packer M et al. N Engl J Med. 199633413491355.
• Pitt B et al. N Engl J Med. 1999341709717.
• Moss A et al. N Engl J Med. 199633519331940.
• Abraham WT et al. N Engl J Med.
  200234618451853.
• Digitalis Investigation Group. N Engl J Med.
  1997336525533.
• Pitt B et al. J Card Fail. 199954654.
• Singh S et al. N Engl J Med. 19953337782.
• Torp-Pedersen C et al. N Engl J Med.
  1999341857865.

126
Intravenous Medications in Decompensated Heart
Failure
Nesiritide is the IV medication most extensively
studied in heart failure, with demonstrated
benefit in placebo-control and active-control
studies when added to standard care Efficacy S
afety Nesiritide Yes1,2 Yes1 Diuretics No
No Dobutamine No No Milrinone No
No Nitroglycerin No Yes1 Nitroprusside No
No

• VMAC Investigators. JAMA. 200218715311540.
• Colucci WS et al. N Engl J Med. 2000343246253.

127
ADHERE First Inpatient Unit
Discharges in the Previous 12 Months (10/01/2001
to 09/30/2002)
ADHERE Acute Decompensated Heart Failure
National Registry ICU/CCU intensive care
unit/critical care unit. The ADHERE Registry
database. Third Quarter 2002 Benchmark Report.
Sunnyvale CA Scios Inc September 2002.
128
Timing in ADHEREEvents of Hospitalization
9.4 Days LOS if vasoactive med post-EMC
EMC/Direct admit arrival
3 days IV diuretic
3 days IV vasoactive Rx
8 hours to first IV diuretic (mean)
Discharge 4.5 days median LOS
29 hours to IV vasoactive therapy (mean)
EMC emergency medical center. Emerman CL et al.
Ann Emerg Med. 200240(4 pt 2)162.
129
Inpatient IV Medications Systolic Dysfunction
Heart Failure
IV Heart Failure Medications
The ADHERE Registry database. Data from 7931
patients collected between July 2001 and July
2002 (unpublished data).
130
Impact of ED vs Inpatient Initiation of IV
Vasoactive Therapy on LOS
Hospital Length of Stay
9.4
6.3
Length of Stay (d)
ED Initiation
Inpatient Initiation
P 0.04.
IV Vasoactive Therapy
ADHERE Registry 14.7 of patients started IV
therapy in the ED compared with 25.5 who started
inpatient. Emerman CL et al. Ann Emerg Med.
200240(4 pt 2)162.
131
Possible Future Applicationsand Investigations
With Nesiritide

• Outpatient Infusions
• Serial
• Subcutaneous
• Continuous
• Perioperative Cardiothoracic Surgery
• Reductions in pulmonary pressures
• CABG, valvular repair/replacement
• Transplant surgery setting
• Bridge to transplant/destination therapy
• Use with LVADs
• Prevention/Reversal of Remodeling

CABG coronary artery bypass graph LVAD left
ventricular assist device.
132
Cost-Effectiveness of Nesiritide

• Total of 40 patients with ADHF were admitted to
  the CCU (20 control and 20 receiving nesiritide)
• Patients receiving nesiritide had shorter
  lengths of stay fewer diuretic and potassium
  doses fewer blood draws for electrolytes/renal
  function required less dobutamine, dopamine, IV
  nitroglycerin, and milrinone
• Health-care costs were 444 less in nesiritide
  group than in controls
• Treatment with nesiritide, when added to
  conventional therapy within the first 48 hours of
  hospital admission for ADHF, results in a
  reduction in health care resource utilization and
  cost

Hunter CB et al. Impact of nesiritide on health
care resource utilization in acute decompensated
heart failure. Poster presented at Heart Failure
Society of America Annual Meeting September
2225, 2002 Boca Raton, FL.
133
Why a Hospital-Based System forHeart Failure
Management?

• Patients
• Patient captures the point
• Have attention of patient/family teachable
  moment
• Predictor of care in the community
• Hospital structure
• Standardized processes/protocols/orders/teams
• JCAHO ORYX core measures
• Process improvement examples
• Centers for Medicare and Medicaid
  Servicespeer-review organizations
• HEDIS (post-discharge)

HEDIS health plan employer data and
information set.
134
JCAHO Core Measures
Hospital Core Performance Measures/ORYX

• Complete discharge instructions in the medical
  record
• Appropriate use of ACE inhibitors at discharge
• LVEF evaluated before or during admission or
  planned after discharge
• Smoking cessation advice/counseling

Heart failure (HF) measures. JCAHO Web site.
Available at http//www.jcaho.org/ accreditedorg
anizations/hospitals/oryx/coremeasures/
informationonfinal specifications.htmHeart.
Accessed January 2003.
135
Nesiritide Overall Clinical Profile

• Vasodilation (venous gt arterial)1
• Rapidly improves symptoms of congestion1
• Does not increase heart rate (decreases
  myocardial oxygen demand)1
• Is not proarrhythmic1
• Neurohormonal suppression (decreases
  aldosterone)1
• Mild diuresis/natriuresis2
• No evidence of tachyphylaxis3
• Symptomatic hypotension as low as 4 in VMAC
  study1
• Dosing convenience (bolus standard-dose IV
  infusion)3

• Fonarow GC. Rev Cardiovasc Med. 20012(suppl
  2)S32S35.
• Rayburn BK, Bourge RC. Rev Cardiovasc Med.
  20012(suppl 2)S25S31.
• Natrecor (nesiritide) package insert.
  Sunnyvale, CA Scios Inc 2001.

136
Role of Nesiritide Summary

• Safe and effective intravenous therapy for
  patients with acutely decompensated heart failure
• Has an excellent benefit/risk profile
• Predictable and rapid hemodynamic effects
• Easy to use and can be safely administered
  without invasive monitoring
• First in a new class of drugs for the initial
  treatment of acutely decompensated heart failure,
  used in addition to diuretics and before
  conventional vasodilators and inotropes

137
Summary

• Patients with acutely decompensated heart
  failure without cardiogenic shock or systemic
  hypoperfusion
• Nesiritide should be administered with an initial
  bolus dose (2 µg/kg) followed by a fixed-dose
  infusion (0.01 µg/kg/min)
• Patients requiring a greater hemodynamic effect
  may receive an increased infusion rate of
  nesiritide up to 0.03 µg/kg/min

Fonarow GC. Rev Cardiovasc Med. 20012(suppl
2)S32S35.
138
Summary

• Use nesiritide early in conjunction with IV
  diuretics ACE inhibitor and/or ß-blocker therapy
  may be continued
• Once the patient is compensated and free of
  congestion, discontinue nesiritide
• Optimize survival-enhancing oral medications (ACE
  inhibitors, ß-blockers, spironolactone)
• Optimize patient education and heart failure
  disease management

Fonarow GC. Rev Cardiovasc Med. 20012(suppl
2)S32S35.
139
Acutely Decompensated Heart Failure How to
Improve Outcomes

• Rapidly reverse decompensation and congestion
  achieve clinical stability
• Initiate patient education and survival-enhancing
  medications before discharge
• Optimize survival-enhancing oral medications (ACE
  inhibitors, ß-blockers, spironolactone)