Acute Decompensated Heart Failure and the Use of Vasodilator Therapy in Canada

1
Acute Decompensated Heart Failure and the Use of
Vasodilator Therapy in
Canada

• CME Program
• Introduction
• Sponsored by an Educational Grant from
  Ortho-Biotech

All trademark rights used under license.
2
Faculty Members

• This program has been developed in consultation
  with
• Dr. Jonathan Howlett
• University of Calgary, Foothills Medical Centre,
  Calgary, AB
• Dr. Gordon Moe
• University of Toronto, St Michael's Hospital,
  Toronto, ON
• Dr. Debra Isaac
• University of Calgary, Foothills Medical Centre,
  Calgary, AB
• Dr. Malcolm Arnold
• University of Western Ontario, London Health
  Sciences Centre, London, ON
• Dr. Michel White
• Montreal Heart Institute, Montreal, QC

3
Session Objectives

• 1) Understand the impact of acute decompensated
  heart failure (ADHF) in Canada
• 2) Understand how to diagnose ADHF
• 3) Identify current treatment goals and options
• 4) Understand the role of vasodilators and their
  appropriate use in the treatment of ADHF
• 5) Understand the role of nesiritide (NATRECOR)
  and identify the appropriate patient for use

4
Heart Failure Risk in Patients with Diabetes,
Hypertension or MI

• Over 10 years, heart failure develops in
• 17 of men
• 18 of women with diabetes1
• 10 of men
• 4 of women with hypertension2
• 27 of men
• 30 of women with myocardial infarction1

1. Kannel WB et al. Br Heart J 199472S39. 2.
Levy D et al. JAMA 19962751557-72.
5
Epidemiology of Heart Failure (HF)

• Approximately 500,000 Canadians currently have
  HF1
• This number is expected to rise

• Projected number of incident hospitalizations for
  CHF patients using high, medium
  and low population growth
  projections in Canada 1996-20502

1. Ross H et al. Can J Cardiol 200622(9)749-54.
2. Adapted from Johansen H et al. Can J Cardiol
200319(4)430-5.
6
The Economic Burden of
Standard-of-care Management for HF

• HF has a role in 106,000 hospitalizations/year1
  and almost1.4 million hospital days in Canada
  per year1
• HF inpatients spend an average of 10 days in
  hospital3
• 15 of patients are readmitted within 30 days2
• 50 of patients are readmitted within one year2
• 26.4 days of hospital resources are consumed by
  the average HF patients their first year2
• 1.4-2.3 billion per year is spent managing class
  III/IV heart failure patients in Canada3
• HF patients have a poor prognosis with the
  average 1-year mortality rate of 334

1. Shibata MC et al. Can J Cardiol
2005211301-06. 2. Johansen H et al. Can J
Cardiol 200319430-35. 3. Bentkover JD et al.
Int J Card 20038833-41. 4. Lee DS et al. Can J
Cardiol 200420(6)599-607.
7
Improving CHF Outcomes With
Combination Therapy
2
3
1
1. SOLVD Inv. N Engl J Med 1991325(5)293-302.
2. CIBIS-II. Lancet 1999353(9146)9-13. 3.
Young JB et al. Circulation 2004110(17)2618-26.
8
The Major Reason for Heart Failure
Hospitalizations
Cleland JG et al. Eur Heart J 200324442.
9
Preserved Systolic Function in Heart Failure
1
2
1. Cleland JG et al. Eur Heart J 200324442-63.
2. Yancy et al. J Am Coll Cardiol
200647(1)76-84.
10
ADHF Clinical Presentation in US

• HF with SBP gt140 mm Hg (50)
• HF with SBP 90 140 mm Hg (47)
• HF with SBP lt90 mm Hg (3)
• Cardiogenic shock (lt1)
• Pulmonary edema(lt3)
• CXR in 90 Radiographic pulmonary
  congestion in 76
• Isolated right-sided HF (?)
• ACS with HF
• 30 of ACS have HF, 10 of ADHF have ACS

Fonarow GC et al. Rev Cardiovasc Med 20034(Suppl
7)21.
11
Clinical Outcomes in the ESCAPE Trial
ESCAPE Inv. JAMA 2005294(13)1625-33.
12
Mortality vs. Symptoms

• Patients asked at beginning of the study If you
  had 24 months to live in your current
  state of health, how many months would you trade
  to feel better?
• The answer an average of 9 months1
• Dr. Stevenson .. At the same time we are
  designing trials to test survival, the patients
  are saying that what matters to them most was not
  to live longer, but to live better."2

1. Lewis DA et al. J Heart Lung Transpl
200120(9)1016-24. 2. Stevenson LW. Oral
presentation, HFSA, 2001.
13
Mortality of Patients Admitted with CHF Nova
Scotia vs. Ontario
1
2
1. Howlett J et al. Can J Cardiol
200319(4)439-4. 2. Lee D et al. Can J Cardiol
200420(6)599-607.
14
Mortality of Patients Admitted with CHF
National Representation
Lee D et al. Can J Cardiol 200420(6)599-607.
15
PCWP Predicts Subsequent Mortality
Early response of PCWP but not CI predicts
subsequent mortality in advanced heart failure
Hemodynamic measurement in 456 heart failure
patients after tailored vasodilator therapy.
Fonarow GC et al. Rev Cardiov Med 20012(Suppl
2)S7-12.
16
Clinical Assessment and Outcomes of Patients
with Severe CHF
Nohria A et al. J Am Coll Cardiol
2003411797-804.
17
ADHERE CART Predictors of Mortality
Fonarow GC et al. JAMA 2005293(5)572-80.
18
Acute Heart Failure Neglected?
1-year mortality for ADHF is 20-30 and for
Acute MI is 10-15
19
Acute Heart Failure Neglected? State of the
Art, circa 1974

• Diuretics
• Vasodilators
• Oxygen
• Consider inotropic therapy

and now?
Ramirez A et al. N Engl J Med 1974290(9)499-501.

20
Heart Failure Paradigm
21
Mechanisms for Inflammatory Immune Activation in
CHF
Anker SD et al. Heart 200490464-70.
22
Clinical Presentation of ADHF

• Dyspnea in 89 of patients at presentation
• Rales in 68
• Peripheral edema in 66
• SBP lt90 mm Hg in 3

Adams KF et al. Am Heart J 2005149(2)209-16.
23
Diagnosis of HF

• Best clinician diagnosis is about 801
• Average time in ER before diuretic is 3 hours
• Most common drugs in ER Salbutamol, antibiotics,
  furosemide
• Better diagnostic methods needed2
• BNP, NT- pro-BNP
• IMPROVE- CHF CANADA Study3

1. Maisel A. Rev Card Med 20023(Suppl 4)S10-7.
2. Arnold et al. Can J Cardiol 200622 (1)23-45.
3. Moe GW et al. Circulation 20071153103-10.
24
The BNP Study First Evidence that Adding BNP to
Testing Improves Diagnostic Accuracy
Strunk A et al. Am J Med 2006119(1)69.e1-11.
25
BNP Concentration for the Prediction of Clinical
Events
Death or Heart Failure Hospitalization
45
40
35
30
25
20
15
10
5
0
Harrison A et al. Ann Emerg Med 200139(2).
0
20
40
60
80
100
26
Causes of Increased BNP

• LV systolic dysfunction
• LVH with diastolic abnormalities
• Significant pulmonary embolism
• Cor pulmonale
• Pulmonary HTN
• Aging (modest increases)
• Renal insufficiency
• Gender
• Malignancy

Moe GW. Heart Fail Monitor 20054(4)116-22.
27
What does the CCS Say about BNP Testing?

• Recommendations
• BNP or NT-proBNP should be measured to help
  confirm or rule out a diagnosis of HF in the
  acute or ambulatory care setting in patients in
  whom the clinical diagnosis is in doubt
  (Class I, Level A)
• Measurement may also be considered in patients
  with known HF for prognostic stratification
• (Class IIa, Level A)
• Sequential measurement of BNP/NT-proBNP levels
  may be considered to guide therapy in HF patients
  
• (Class IIb, Level B)

Arnold JMO et al. Can J Cardiol 200723(1)21-45.
28
BNP and NT-proBNP in HF
Cut Points for HF Diagnosis
Arnold JMO et al. Can J Cardiol 200723(1)21-45.
29
Therapeutic Goals for ADHF
1. Fonarow GC. Rev Cardiovasc Med
20023(4)S18-S27. 2. Stier Jr CT et al. Cardiol
Rev 20021097-107.

3. Masai T et al. Ann
Thorac Surg 200273549-55. 4. VMAC. JAMA
20022871531-40.
30
Treatment Goals and Modalities - ADHF
HFSA Guidelines. J Card Fail 200612(1)e86-e103.
31
Initial Management of ADHF

• Recommendations
• Measure vital signs frequently until patient is
  stable (BP, HR, O2 sat)
• (Class IIa, Level C)
• Monitor fluid balance including urine output (may
  require bladder catheterization)
• (Class I, Level C)

Arnold JMO et al. Can J Cardiol 200723(1)21-45.
32
Medical Treatment of AHF

• Recommendations
• Identify and promptly correct underlying/
  precipitating cause when possible
• (Class I, Level B)
• Give oxygen initially to all patients with acute
  HF and hypoxia
• (Class I, Level C)
• If hypoxemia persists despite increasing
  incremental fraction of oxygen, consider CPAP,
  BIPAP or endotrachial intubation
• (Class IIa, Level B)

Arnold JMO et al. Can J Cardiol 200723(1)21-45.
33
Medical Treatment of AHF

• Recommendations
• Intravenous diuretics should be given as
  first-line therapy for patients with acute HF and
  congestion
• (Class I, Level B)
• Consider vasodilators for patients with dyspnea
  at rest
• (Class I, Level C)
• Reserve positive inotropes for patients in
  cardiogenic shock and/or volume overload with
  diuretic resistance and use short-term to
  stabilize patient. In hypotensive patients
  (SBPlt90 mm Hg), dobutamine is preferred over
  milrinone.
• (Class I, Level C)

Arnold JMO et al. Can J Cardiol 200723(1)21-45.
34
Patient Selection and Treatment
Stevenson LW. Eur J Heart Fail 19991251-7.
Fonarow GC. Rev Cardiovasc Med 20012(Suppl
2)S7-S12.
35
CCC Treatment Algorithm for Acute HF
Arnold JMO et al. Can J Cardiol 200622(1)23-45.
36
Current ADHF Treatment Options

• Diuretics
• Reduce fluid volume1
• Provide symptomatic relief, not therapeutic1
• Are associated with adverse renal effects
  activation of RAAS1
• Development of diuretic resistance can lead to
  use of toxic doses2
• High doses associated with increased mortality2

1. Fonarow GC. Rev Cardiovasc Med 20012(Suppl
2)S7-S12. 2. Esfhagian S et al. Am J Cardiol
2006971759-64.
37
Diuretics Activate Neurohormonal Systems in Heart
Failure
Bayliss J et al. Br J Heart 19875717-22.
38
Furosemide in Experimental Heart Failure

• Pigs randomized to daily furosemide or placebo
  (blinded)
• LV dysfunction created with a pacing model
• Time to LV dysfunction and neurohormones measured
• Furosemide treatment resulted in
• Shorter time to LV dysfunction development
• Higher aldosterone
• Lower sodium

McCurley JM et al. J Am Cardiol 2004441301.
39
Large Fraction of Patients Admitted for Acute
Heart Failure Show No Weight Loss
All Enrolled Discharges from 01.01.2001 to
03.31.2006. Change in weight was assessed in
96,094 patient episodes
Discharged Home (including home with additional
and/or outpatient care)
Enrolled Discharges
ADHERE Final Report 2006.
40
Determinants of Diuretic Response
Ellison D. Cardiology 200196132-43.
41
Some Mechanisms Involved with Diuretic
Resistance

• Volume depletion
• Neurohumoral activation
• Rebound Na uptake
• Distal nephron hypertrophy
• Transrenal perfusion pressure

• Reduced tubular secretion
• Low cardiac output reduced renal perfusion
• Poor sodium compliance
• Impaired absorption
• ? GFR

Liu P. Can J Cardiol 200824(B)25B-29B.
42
Neurohormonal Control of Sodium and Water
Retention in HF
Adapted from Cadnapaphornchai M. Cardiology
200196122-31.
43
Newer Diuretic Therapies

• Pharmacological
• Positive inotropes and vasodilators
• Nesiritide
• Vasopressin receptor antagonists
• A1 adenosine receptor antagonists
• Non-pharmacological
• Ultrafiltration

Liu P. Can J Cardiol 200824(B)25B-29B.
44
IV Milrinone During Hospitalization for
Decompensated Heart Failure Not Low Output
OPTIME-CHF In-hospital Adverse Events
Cuffe MS et al. JAMA 20022871541-7.
45
Vasopressin Antagonist
46
EVEREST - Vasopressin Antagonist Composite
Endpoints (Day 7 or Discharge)
P0.52
EVEREST Inv. JAMA 20072971332-43.
47
EVEREST Short Term Symptoms Improvement
Everest Inv. JAMA 20072971332-43.
48
MK-7418 (KW-3902) Selective Renal Arterial
Vasodilator for the Treatment of Acute Heart
Failure
Gottlieb SS. Circulation 20021051348-53.
Givertz MM et al. J Am Coll
Cardiol 2007501551-60.
49
Ultrafiltration
50
UNLOAD Trial

• Study Parameters
• Open-label RCT, 200 patients
• UF with System 100 vs. standard diuretics
• Randomized within 24 hrs of hospitalization
• Primary Endpoints
• Efficacy weight loss, dyspnea
• Safety renal function

Costanzo MR et al. J Am Coll Cardiol
200749675-83.
51
Primary Endpoint Weight Loss at 48 Hrs
Costanzo MR et al. J Am Coll Cardiol
200749675-83.
52
Safety Endpoints Change in Serum Creatinine
Costanzo MR et al. J Am Coll Cardiol
200749675-83.
53
Baseline Renal Dysfunction and Worsening Renal
Function (WRF) are Additive in Predicting
Mortality in HF Patients
de Silva R et al. Eur Heart J 200627569-81.
54
IV Vasodilators in the Treatment of ADHF
Adapted from Fonarow G. Rev Card Med 20023(Suppl
4)S18-S27.
55
Neurohormonal Activation Rapidly Decreases after
Intravenous Therapy with Diuretics
and Vasodilators for Class IV Heart Failure
Johnson W et al. J Am Coll Cardiol
200239(10)1623-9.
56
Nitrates vs. Furosemide Outpatient CHF-Mobile ER
Units
Cotter G et al. Lancet 1998351389.
57
Traditional Vasodilators Limitations

• Nitroglycerin
• ? efficacy in CHF
• Labour-intensive titration
• Tachycardia
• Tachyphylaxis
• Neurohormonal activation due to reflexive
  sympathetic activity
• Wide range of dosages used in clinical studies

• Nitroprusside
• Labour-intensive titration
• ICU/arterial line monitoring due to excessive
  hypotension risk
• Tachycardia
• Tachyphylaxis
• Coronary steal
• Pulmonary shunting
• Toxic metabolites
• Neurohormonal activation due to reflexive
  sympathetic activity
• Wide range of dosages used in clinical studies

Fonarow GC. Rev Cardiovasc Med 20023(Suppl
4)S27.
58
What About ACE Inhibitors?

• Not infrequently used for ADHF
• Small Case series reported
• 3 Randomized trials
• None were properly blinded
• 2 were open label
• Only acute outcomes (lt1 week) were reported
• Methods for subjective data collection not
  published

Lamond N, Howlett J. Heart Fail Monitor
20075(3)70-6.
59
Most Common Vasoactive MedicationsADHERE
International vs. U.S. Data
ADHERE International final benchmark report, 2007.
60
A New Option for Warm Wet Patients

• An analysis of 452 consecutive patients
  hospitalized with heart failure demonstrated
  that
• 49 presented with the warm and wet profile
• nesiritide is a rational treatment choice in
  these patients1

• Possible evidence of low perfusion2
• Narrow pulse pressure
• Sleepy/obtunded
• Low serum sodium
• Cool extremities
• Hypotension with ACE inhibitor
• Renal dysfunction

• Signs/symptoms of congestion2
• Orthopnea/PND
• Jugular venous distension (JVD)
• Ascites
• Edema
• Rales (rare in heart failure)

1Nohria A et al. J Am Coll Cardiol
200341(10)1797-1804. 2Fonarow GC. Rev
Cardiovasc Med 20023(Suppl 4)S27.
61
NATRECOR (nesiritide)

• NATRECOR is indicated for the treatment of
  hospitalized symptomatic acute decompensated
  heart failure (ADHF) patients, presenting with
  moderate to severe dyspnea

• These are patients who present with signs and
  symptoms of persistent heart failure despite 2
  hours of treatment with intravenous loop
  diuretics

NATRECOR Product Monograph, May 2008.
62
Physiology of BNP
1. Marcus LS et al. Circulation 1996943184-9.
2. Zellner C et al. Am J Physiol 1999276(3 pt
2)H1049-H1057. 3. Tamura N et al. Proc Natl
Acad Sci USA 2000974239-44. 4. Abraham WT et
al. J Card Fail 1998437-44. 5. Clemens LE et
al. J Pharmacol Exp Ther 199828767-71. 6.
Rayburn BK, Bourge RC. Rev Cardiovasc Med
20012(Suppl 2)S25-S31. 7. Akerman MJ et al.
Chest 200613066-72.
63
The Natriuretic Peptide System is
Overwhelmed in ADHF
Shah M et al. Rev Cardiovasc Med 20012(Suppl
2)S2-S6.
64
Recombinant Human B-type Natriuretic Peptide
Pharmacologic Effects

• NATRECOR (nesiritide) has the same 32 amino acid
  sequence as the endogenous peptide
• Human BNP increases intracellular cGMP, which
  serves as second messenger to dilate veins and
  arteries
• Systemic Hemodynamic Effects
• preload reduction
• afterload reduction
• increased cardiac index
• no significant increase in heart rate

NATRECOR Product Monograph, May 2008. Colucci
WS et al. N Engl J Med 2000343246-53. Abraham
WT et al. J Card Fail 1998437.
65
Cardiac Hemodynamic Changes with Nesiritide
(percentage change compared to baseline)
Michael S et al. J Card Fail 200511425-31.
66
PROACTION Study Effect of Nesiritide on SBP
in Patients with Elevated SBP
Peacock WF. J Am Coll Cardiol 200341(Suppl
A)336A.
67
Does Nesiritide Enhance Diuretic Effect
of Loop Diuretics?

Elkayam U. Case study, personal communication,
2008.
68
Urine Output Before and After Nesiritide
Therapy
Feldman DS et al. J Card Fail 200410292-6.
69
Renal Function and Nesiritide
Figure 1. Urine flow rate for each time period
and the entire 24 hours for placebo and
nesiritide infusions. There was no effect of
nesiritide on urine output.
Figure 2. Sodium excretion for each time period
and the entire 24 hours for placebo and
nesiritide infusions. There was no effect of
nesiritide on sodium excretion.
Wang DG et al. Circulation 20041101620-25.
70
NAPA TrialPostoperative Urine Output (First 24
Hours)
Mentzer RM et al. J Am Coll Cardiol
200749716-26.
71
Effect of Vasodilators and Diuretics
on
Neurohormonal Activation
Johnson W et al. J Am Coll Cardiol
2002391623-29.
72
VMAC Nesiritide Demonstrated Significant
Reductions in PCWP
VMAC Inv. JAMA 20021871531-40.
73
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 Sept 9-12, 2001 Washington, DC.
74
Hemodynamic Effect with Nitroglycerin was Delayed

• The effect of nitroglycerin diminished over 24
  hours
• Nitroglycerin required constant titration and
  higher doses

Elkayam U et al. Am J Cardiol 200493237-40.
75
Nesiritide Efficacy Dyspnea Improvement in VMAC
Trial
VMAC Inv. JAMA 2002287(12)1531-40.
76
Nesiritide Overall Clinical Profile

• Vasodilation (venous gt arterial)1
• Rapidly improves symptoms of congestion 1,3
• Neurohormonal suppression1
• Mild diuresis natriuresis2
• Does not increase heart rate (no reflex
  tachycardia)1
• Is not proarrhythmic1
• No tachyphylaxis3
• Hypotension is low (4)3
• No titration required3

1. Fonarow GC. Rev Cardiovasc Med 20012S32-S35.
2. Rayburn BK et al. Rev Cardiovasc Med
20012S25-S31. 3. NATRECOR Product Monograph,
May 2008.
77
Nesiritide Safety
NATRECOR Product Monograph, May 2008.
78
VMAC Trial Effect of Therapy
on Serum Creatinine
Renal insufficiency defined as SCr 2.0 mg/dL
(177 umol/L) Study drug discontinued following
2448 hr of treatment in majority of patients in
VMAC
Butler J et al. Nephrol Dial Transplant
200419391.
79
Odds Ratios of SCr Increase gt0.5 mg/dL (44
µmol/L) by Nesiritide Initiation Dose
Includes data from 5 studies Mills, et al.,
Efficacy, Comparative, PRECEDENT, and VMAC
(n1,222)
Abraham WT. J Card Fail 200511(6)S156. Abstract
427.
80
Nesiritide Renal Effects
Sackner-Bernestein JD et al. Circulation
20051111487-91.
81
Rate of SCr Increase gt0.5 mg/dL (44 µmol/L) from
Baseline in VMAC
Heywood JT et al. J Card Fail 200511(6)s154.
82
NAPA TrialMean Change from Baseline in Post-Op
SCr
Mentzer Jr RM et al. J Am Coll Cardiol
200749(6)716-26.
83
Mortality Meta-analysis
Sackner-Bernstein JD et al. JAMA
2005293(15)1900-5.
84
Short and Long-term Mortality with Nesiritide

• Meta analysis of 7 large randomized controlled
  non-mortality trials with available data on
  30-day mortality
• 4 of them also had data on 180-day mortality
• Unlike a previous analysis, this meta-analysis
  indicates that nesiritide is not associated with
  a higher 30- or 180-day mortality

Arora RR et al. Am Heart J 20071521084-90.
85
30-day Mortality Hazard Ratios
Adapted from Arora RR et al. Am Heart J
20061521084-90. Sackner-Bernstein JD et al.
JAMA 2005293(15)1900-5. NATRECOR Product
Monograph, May 2008.
86
180-day Unadjusted Mortality Hazard Ratios
Data collected through week 16 Excludes
FUSION I and NAPA Excludes FUSION I
Adapted from Arora RR et al. Am Heart J
20061521084-90. Mentzer Jr RM et al. J Am Coll
Cardiol 200749(6)716-26.

87
Cardio-Renal Expert Panel ReportChaired by Dr.
Eugene Braunwald June 8, 2005 Boston, MA

• Effect of Nesiritide on Renal Function
• The mechanism and clinical significance of
  NATRECORs renal effects are unclear
• There is no evidence that NATRECOR improves
  renal function
• Effect of Nesiritide on Mortality
• Completed trials show a trend toward increased
  mortality at 30 days
• There are potentially important imbalances in
  baseline characteristics and in other treatments
  received concomitantly and the trials differ with
  respect to the treatments with which nesiritide
  was compared
• No increased hazard is observed at 180 days
• Regarding Nesiritide Clinical Trials
• The panel strongly recommends continued
  enrollment in ongoing clinical trials
• The panel endorses Scios plan to conduct a large
  outcomes trial

Husten L. www.theheart.or/article/506037.
88
ASCEND Study Design Overview
Armstrong P, Rouleau J. Can J Cardiol
200824(suppl B)30B-32B. Clinical Trials
Registration NCT 00475852.
89
Current Guidelines for ADHF
1. HFSA. J Card Fail 200612(1)e86-e103. 2.
Nieminen MS et al. Eur Heart J 2005. 3. Arnold
JMO et al. Can J Cardiol 200622(1)23-45. 4.
Arnold JMO et al. Can J Cardiol 200723(1)21-45.
90
Acute Decompensated Heart Failure
HFSA. J Card Fail 200612(1)e86-e103.
91
ADHF Summary

• A common problem
• Huge health care implications
• Relatively few approved therapies
• Vasodilator therapy indicated in the WET/WARM
  patient not responsive to initial diuretics
• Newer option nesiritide now available
• Ongoing trials will firmly establish morbidity
  and mortality of newer medications for ADHF

92
Additional Slides
93
Elevated BNP Predictive of HF
BNP is secreted by ventricular myocytes in
response to excessive stretch

BNP Trial ROC curves for BNP predicting
diagnosis of CHF in patients with or without CHF
history
Strunk A et al. Am J Med 200611969e1-11.
94
NT-proBNP Complements Clinical Judgement
Moe GW et al. Circulation 2007115(24)3103-10.
95
BNP/NT-proBNP in Heart Failure

• Practical Tips
• Biomarkers such as BNP and NT-proBNP are
  complementary to, but do not replace, good
  clinical evaluation
• No compelling factors favour the use of BNP
  versus NT-proBNP
• The choice of assay is dictated by
• availability
• clinicians familiarity and ability to interpret
  the results

Arnold JMO et al. Can J Cardiol 200723(1)21-45.
96
BNP and NT-proBNP In HF
Cut Points for HF Diagnosis
Arnold JMO et al. Can J Cardiol 200723(1)21-45.
97
Effect of Vasodilators and Diuretics
on
Neurohormonal Activation
Johnson W et al. J Am Coll Cardiol 2002391623-9.
98
Effect of Vasodilators and Diuretics
on Neurohormonal
Activation
Johnson W et al. J Am Coll Cardiol 2002391623-9.
99
The Cardio-Renal Syndrome in Heart Failure
Decreased cardiac output
Decreased cardiac performance
Neurohormonal Activation
Increased water and Na retention
Diminished blood flow
Impaired renal function
Decreased renal perfusion
100
Change in CAD and CBF with IV Nesiritide and
Intracoronary NTG
2
Coronary Blood flow
Coronary Artery Diameter
1
1. Elkayam U. Am J Pharm Therap 2004. 2.
Michaels AD et al. 2003107(21)2697-701.
101
Nesiritide Demonstrated No Increased Risk of
Hypotension at Approved Dose
Rate of Symptomatic Hypotension (By Initial Dose)
(n216)
(n211)
(n62)
Initial dose 0.01 µg/kg/min with possible
titration up to 0.03 µg/kg/min
NATRECOR Product Monograph, May 2008.
102
VMAC Primary Endpoint PCWP Through 3 Hours
plt 0.05 vs NTG plt 0.05 vs placebo
Adapted from JAMA 20022871531-40.
103
Nesiritide vs. High-dose Nitroglycerin
Change in PCWP
Elkayam U et al. Am J Cardiol 200493237-240.
104
VMAC Mean Nitroglycerin Dose and Impact of
Invasive Monitoring on Dosing
VMAC Inv. JAMA 20022871531-40.
105
Use of Nesiritide and High-dose
Diuretics VMAC
56 of NES and 62 of NTG patients received
high-dose diuretics (p0.19)
Rate of SCr Increase gt0.5 mg/dL
Heywood J 200511(6)S154. Abstract 240.
106
Baseline ImbalancesBaseline SBP 100 mm Hg
Subgroup
a Prior Dobutamine/Dopamine Use is use of either
medication prior to receiving study drug. b
704.311, 704.325, 704.326, 704.329 (PRECEDENT),
704.339 (VMAC), 704.341 (PROACTION), 704.348
(FUSION I) c Patients missing column-specific
data have been dropped from the denominator.
Adapted from Arora RR et al. Am Heart J
20061521084-90.
107
Impact of Nesiritide on Renal Function in
Patients with ADHF
Incidence of 20 rise in SCr by discharge or day
7 of the hospitalization. No significant
difference was observed in the primary end point
of worsened renal function (increase in serum Cr
20)(p0.85).
Witteles RM et al. J Am Coll Cardiol
200750(19)1835-40.
108
Impact of Nesiritide on Renal Function in
Patients with ADHF
Blood pressure change is recorded in reference to
the start of the infusion (time0). Time off
refers to 3 h after the infusion was stopped.
Plt0.05 vs. placebo at 6 and 12 h for systolic
blood pressure, and at 3 h for diastolic blood
pressure.
Witteles RM et al. J Am Coll Cardiol
200750(19)1835-40.
109
Mortality in Patients With and Without SCr
Increases 5 Studies Pooled
Number of Deaths/Number of patients with SCr
Increase gt0.5mg/dL 30-day mortality data
available for 5 studies
Elkayam U et al. Clin Cardiol, in Press.
110
180-day Unadjusted Mortality Hazard Ratios
Data collected through week 16 Excludes
FUSION I and NAPA Excludes FUSION I

Adapted from Arora RR et al. Am Heart J
20061521084-90. Mentzer RM et al. J Am Coll
Cardiol 200749(6)716-26.
111
ADHERE In-Hospital Mortality and Use of
Parenteral Vasoactive Medications
Abraham WT et al. J Am Coll Cardiol
200546(1)57-64.
112
Odds Ratios Of Worsening Serum Creatinine
(gt0.5 mg/dL or 44 µmol/L) by Nesiritide Dose
Includes data from 5 studies Mills et al.,
Efficacy, Comparative, PRECEDENT, and VMAC
Includes data from 5 studies Mills, et al.,
Efficacy, Comparative, PRECEDENT, and VMAC
(n1,222)
Abraham WT. J Card Fail 200511(6)S156. Abstract
427.
113
EFFECT Study - Community HF

• 2,802 consecutive pts admitted with
  first episode of heart failure to 113 hospitals
• ICD-9 diagnosis meeting modified Framingham
• All had LV evaluation

Bhatia S et al. N Engl J Med 200655260-9.