CCB Evolution

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New Concepts in the Treatment of Acute
Decompensated HF Uri Elkayam, MD Professor of
Medicine Director of Heart Failure
Program University of Southern California School
of Medicine Los Angeles, California
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ADHERE Registry Demographics
All Enrolled Discharges in the Last 12 Months
(07.01.2002 - 06.30.2003)
(N58,919)
Demographics/Patient Characteristics
75.3 48
Median Age (yrs) Patients gt75 Years ()
48 52
Gender Male () Female ()
5 57 (n33,572) 46
Chronic Renal Dialysis () LVEF Measured
In-hospital () LVEF lt40 or Mod/Sev Impairment
()
.
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ADHERE Registry Demographics
All Enrolled Discharges in the Last 12 Months
(07.01.2002 - 06.30.2003)
(N58,919)
57 31 72 35 23 17 31 9 1 20 lt1 lt1 18 30 5
Coronary Artery Disease () Myocardial Infarction
() Hypertension () Hyperlipidemia/Dyslipidemia
() Cardiac Valvular Disease () Stroke or TIA
() Atrial Fibrillation () Ventricular
Tachycardia () Ventricular Fibrillation
() Pacemaker or ICD () LVAD () IABP
() Peripheral Vascular Disease () Chronic Renal
Insufficiency () Chronic Dialysis ()
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Decompensated Heart FailureScope of the Problem

• In-hospital mortality 2.9-4.0
• Hospital readmissions
• 22-28 at 60 days (IMPACT-HF 2003)
• 50 at 6 to 12 months
• Mortality
• 7 at 60 days (IMPACT-HF 2003)
• 20-40 at 6 to 12 months

.
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Decompensated Heart FailureGoals of Treatment

• Early improvement of symptoms
• Early hemodynamic improvement
• Effective removal of fluids
• Renal protection
• Early discharge
• Reduced rehospitalizations
• Reduced early and late mortality

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New Therapies Investigated for AHF

• Endothelin-receptor antagonists (Tezosentan
  VERITAS)
• Vasopressin-receptor antagonists
  (Tolvaptan EVEREST)
• Calcium sensitizers
  (Levosimendan REVIVE)
• Nesiritide (hBNP)

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The Natriuretic Peptides

• ANP (atria) active forms ANP99-126,ANP1-30
  (28aa)
• BNP (brain, ventricles) active form 32aa
• CNP (endothelium,kidney) active form 22aa
• Urodilatin (kidney) active form is ANP95-126

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Physiologic Effects of Natriuretic Peptides
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BNP Concentration for the Degree of CHF Severity
2500
2013 266
2000
1500
BNP Concentration (pg/ml)
791 165
1000
500
186 22
0
Moderate (n34)
Mild (n27)
Severe (n36)
Maisel A et al. J Am Coll Cardiol.
200137(2)379-385.
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The Natriuretic Peptide System Is Overwhelmed in
Acute Decompensated Heart Failure
A hallmark of HF is BNP resistance...
ANP
BNP
Endothelin Aldosterone Angiotensin II Epinephrine
just as Diabetes is an Insulin-resistance disease
Adapted from Burnett JC. J Hypertens.
199917(Suppl 1)S37-S43.
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What Have We LearnedAbout Nesiritide?

• Most extensively investigated agent for
  decompensated HF
• Early and predictable hemodynamic effect with a
  predetermined dose
• Moderate diuretic and natriuretic effect
• Significant enhancement of diuretics effect

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What Have We LearnedAbout Nesiritide?

• Enhances coronary blood flow
• Probably safer then inotropic agents
• More effective then NTG (earlier and more
  predictable effect, no tolerance)
• Seems to provide renal protection

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Percent Change in Different Cardiac
HemodynamicVariables During Nesiritide Infusion
Compared to Baseline
HR
MBP
PCWP
RA
MPA
CI
SVR
PVR
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Efficacy Trial Global Assessment ofClinical
Status at 6 Hours
by Physician
by Subject
100
100

80
80



60
60
40
40
Percent ()ofsubjects improved
20
20
n42
n40
n39
n42
n40
n39
0
0
Percent ()ofsubjects worsened
20
20
placebo
0.015
0.030
Placebo
0.015
0.030
Nesiritide
Nesiritide
Plt0.001 vs placebo 2-sample Wilcoxon
P0.001 vs placebo 2-sample Wilcoxon
Colucci, Elkayam, Horton, et al. N Engl J Med.
2000343246-253.
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Effects of Natriuretic Peptideson the Kidney

• Dilatation of afferent gt efferent renal
  arterioles leading to pressure augmentation
  within the glomerular capillaries and thus to
  increased glomerular filtration rate (GFR)
• Relaxation of mesangial cells, which results in
  enhancing effective surface area for filtration
• Inhibition of angiotensin II effect to stimulate
  Na and water reabsorbtion in proximal convulated
  tubules
• Inhibition of tubular water transport by
  antagonizing effect of vasopressin
• Decrease in plasma renin and aldosterone

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Natriuretic Petide Causes Pre-Glomerular
Vasodilation And Post-GlomerularVasoconstriction
in the Rat Kidney

• Martin-Grez et al. Nature. 1986324473.

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Change in Renal Artery Diameter at Baseline, Post
Nesiritide Bolus, and During a 15-Minute Infusion
of Nesiritide
APV 30 m/s RBF 291 mL/min
APV 32 m/s RBF 365 mL/min
APV 22m/s RBF 292 mL/min
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Effects of Natriuretic Peptideson the Kidney

• Relaxation of mesangial cells, which results in
  enhancing effective surface area for filtration

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Effects of Natriuretic Peptideson the Kidney

• Dilatation of afferent gt efferent renal
  arterioles leading to pressure augmentation
  within the glomerular capillaries and thus to
  increased glomerular filtration rate (GFR)
• Relaxation of mesangial cells, which results in
  enhancing effective surface area for filtration
• Inhibition of angiotensin II effect to stimulate
  Na and water reabsorbtion in proximal convulated
  tubules
• Inhibition of tubular water transport by
  antagonizing effect of vasopressin
• Decrease in plasma renin and aldosterone

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Urinary Excretion Data for hBNP
4
4
A
C
Plt0.05
3
3
Urinary potassium excretion (mEq/hr)
Urinary sodium excretion (mEq/hr)
2
2
1
1
0
0
Placebo
BNP
Placebo
BNP
125
Plt0.01
100
B
D
100
75
75
Urinary volume (mL/hr)
Creatinine clearance (mL/min)
50
50
25
25
0
0
Placebo
Placebo
BNP
BNP
Marcus LS et al. Circulation. 1996943184-3189.
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Effects of Nesiritide on Urine Outputand
Diuretic Use
P0.004
659
700
552
600
500
383
400
6-Hour Urine Output (mL)
300
200
100
0
Placebo (n42)
Nesiritide 0.015 mcg/kg/min (n43)
Nesiritide 0.030 mcg/kg/min (n43)
90
72
50
Receiving Diuretics (24 hours)
Plt0.001
Colucci, Elkayam, Horton et al. New Engl J Med.
2000343246-253.
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Effect of Nesiritide onCoronary Blood Flow

• 10 patients undergoing cardiac cath, mean age
  58 yrs mean EF 48
• Hemodynamic effect
• MBP 11.SVR - 6. BP 19
• PCW 46
• Coronary effect
• CVR 23. CBF 35
• Oxygen uptake 8

Michaels et al. Circulation. 20031072697.
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Nesiritide Coronary Hemodynamics
CAD
CBF
CVR
O2 uptake
40
35
30
20
15
10
Percent ()
P0.036
P0.043
0
P0.007
P0.007
-10
-8
-20
-23
-30
Michaels et al. Circulation. 20031072697.
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Coronary Hemodynamics IV Nesiritide vs
Intracoronary NTG
Coronary Artery Diameter
CoronaryBlood Flow
50
42
45
40
35
35
30
Percent ()
25
20
15
15
8
10
5
0
NTG
Nesiritide
NTG
Nesiritide
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PRECEDENT Effect of Nesiritide and Dobutamine
Holter Study
Nesiritide 0.015 µg/kg/min
Nesiritide 0.030 µg/kg/min
Baseline Holter Monitoring
Dobutamine ? 5 µg/kg/min
Hours
-24
0
24
Holter Baseline and at 24 hours
Blood Pressure, Heart Rate At baseline, 15 30
minutes, 3, 8, 16 and 24 hrs Global clinical
status At baseline, 3 and 24 hrs
Burger AJ et al. Am Heart J. 20021441102-1108.
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PRECEDENT Primary Endpoints
Nesiritide 0.015mg/kg/min (n28)
Nesiritide 0.030 mg/kg/min (n29)
Dobutamine (n28)
Holter Endpoint
P value
56 148
-1  62
-8 60
0.038
PVCs/hr
Repetitive beats (total beats in vent.
Couplets/VT)
5 14
-3 11
-1 4
0.020
Heart rate (beats/min)
4 8
0 6
-1 6
0.042
Burger AJ et al. Am Heart J. 20021441102-1108.
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Short-Term Effect of Nesiritide or Dobutamine
Therapy on Long-Term Survival
Log - rank Test Dobutamine vs nesiritide 0.015
?g/kg/min P0.041 Dobutamine vs nesiritide 0.030
?g/kg/min P0.445 Nes 0.015 ?g/kg/min vs nes
0.030 ?g/kg/min P0.187
Dobutamine (n141)
Nes 0.030 ?g/kg/min (n179)
Nes 0.015 ?g/kg/min (n187)
35
30
25
20
Cumulative Mortality Rate ()
15
10
5
0
0
30
60
90
120
150
180
Time from start of treatment (days)
Elkayam U et al. J Cardiac Failure. 20006(Suppl
2)169.
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CASINO STUDYPresented in the 2004 ACC Scientific
Meeting
Study was discontinued prematurely because of the
clear mortality benefit of levosimendan
Zairis et al. J Am Coll Cardiol. 200443206A.
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HF Etiology and Response to Milrinone in
Decompensated HF (OPTIME Study)
P-value for the etiology treatment interaction
term in the multivariable model
Felker et al. J Am Coll Cardiol. 200341997-1003.
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Effect Of IV Vasoactive Drugs onIn-Hospital
Mortility The Adhere Registry
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6-Month Death by IV Medication Use
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VMAC Primary Endpoint PCWP through 3 Hours
Placebo
Nitroglycerin
Nesiritide
Mean change (mmHg)
Mean observed value (mmHg)
30
-1
28

26


-4






24









22
-7
20
18
-10
BL
BL
1 hr
1 hr
3 hr
3 hr
2 hr
2 hr
15 m
15 m
30 m
30 m
Plt0.05 versus placebo Plt0.05 versus NTG
JAMA. 2002.
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VMAC Mean Nitroglycerin Dose vs TimeImpact of
Invasive Monitoring on Dosing
70
Catheterized
60
50
40
Mean dose (µg/min)
Non-Catheterized
30
20
10
P0.003, ? in NTG dose from 3 hr to 24 hr
0
BL
1 h
2 h
3 h
6 h
12 h
24 h
30 m
Young JB et al. AHA Meeting 2000 Late Breaking
Trials Session.
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Nesiritide vs High Dose NitroglycerinThe VMAC
Trial-USC Pts
180
160
140
120
100
Dose (mcg/min)
80
60
40
20
0
15 min
30 min
1 hr
2 hrs
3 hrs
6 hrs
9 hrs
12 hrs
24 hrs
Time
Catheterized patients Non-catheterized
patients All Patients
Elkayam et al. Am J Cardiol. 200493237-240.
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Change in PCWP from Baseline
Nesiritide vs High Dose Nitroglycerin
Time
15 min
30 min
1 hr
2 hrs
3 hrs
0
1
2
3
mmHg
4
5
6
7
8
Nitroglycerin (n9) Placebo (n5) Natrecor (n13)
Elkayam et al. Am J Cardiol. 200493237-240.
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Change in PCWP
Nesiritide vs High Dose Nitroglycerin
Time
15 min
30 min
1 hr
2 hrs
3 hrs
6 hrs
9 hrs
12 hrs
24 hrs
0
2
4
6
Change in PWC from Baseline (mmHg)
8
10
12
14
Nitroglycerin (n9 through 3 hours, n12 after 3
hours) Natrecor (n13 through 3 hours, n15 after
3 hours)
Elkayam et al. Am J Cardiol. 200493237-240.
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Effect of Renal Function and Its Worsening on
Outcome in Hospitalized Patients with
Decompensated CHF
Table 6. Comparison in Outcome Between Patients
With and Without a gt0.5 mg/dL
Increase in Serum Creatinine at Any Time During
Hospitalization
Analysis of VMAC study Elkayam et al. Am J
Cardiol. October 2004.
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Diruretics and Worsening Renal Functionin
Decompensated Heart Failure
Loop diruretics
Metolazone
250
Patients ()
Average Dose (mg)
199 195 mg
10
9
Plt0.05
200
Plt0.05
143 119 mg
150
5
100
50
3
0
Cases
Control
Cases
Control
Butler et al. Am Heart J. 2004147331.
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A1 Adenosine Antagonists in CHF
Renal Function and Renal Output in Edematous
Heart Failure Patients Treatedwith Furosemide
(80 mg IV) and/or BG9719 (Biogen Study C97-1205)
Gottlieb et al. Circulation. 20021051348-1353.
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Renal Action of Furosemide Plus BNP in CHF
Cataliotti et al. Circulation. 20041091680-1685.
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Renal Action of Furosemide Plus BNP in CHF
Cataliotti et al. Circulation. 20041091680-1685.
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Use of Nesiritide and Furosemide in Patients with
Congestive Heart Failure
Scr
gt1.5 ml/DL
lt1.5 ml/DL
Furosemide 40 mg IV bolus followed by 10 mg/hr
Furosemide 20 mg IV bolus followed by 5 mg/hr
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Use of Nesiritide and Furosemide in Patients with
Congestive Heart Failure
SBP
lt90 mmHg
gt90 mmHg
Nesiritide
Nesiritide
0.01 mcg/kg/min
2 mcg/kg IV bolus
followed by 0.01 mcg/kg/min
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Furosemide in Severe CHFBolus Injection vs
Continuous Infusion
Renal Function and Renal Output in Edematous
Heart Failure Patients Treated with Furosemide (
80 mg IV )and/or BG9719 (Biogen Study C97-1205)
Dormans et al. J Am Coll Cardiol. 199628376-382.
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Furosemide in Heart FailureBolus Injection vs
Continuous Infusion
P Value
Infusion
Bolus
Parameters
0.0005
2860240
2260150
Urinary volume (ml)
0.0045
21040
15020
Urinary sodium(mmol)
805
705
Urinary potassium (mmol)
lt0.0001
Dormans et al. J Am Coll Cardiol. 199628376.
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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 et al. Circulation. 20041101622.
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Urine Output (ml) Fluid Intake (ml)
3075 cc
2065 cc
990 cc
750 cc
1087 cc
225 cc
264 cc
520 cc
Time (hours)
Furosemide 20mg IVP
Furosemide 5 mg/hr
Nesiritide 0.01 mcg/kg/min
80 mmHg
90 mmHg
90 mmHg
90 mmHg
Systolic BP Serum Cr (mg/dl) Serum Na
1.2 134
1.0 134
1.1 136
1.1 138
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Effect of Nesiritide on Hospital
LOSRetrospective Evaluation of 130 Consecutive
PatientsDischarged from CCU Diagnosed with Heart
Failure
NesGroup (n58)
Non-NesGroup (n72)
Parameters
P Values
SBP (mmHg)
115
126
0.011
BUN
50
40
0.067
SrCr (mg/dL)
1.97
1.57
0.023
Ejection Fraction
18
24
0.023
Results
Change in BUN
-1.9
-1.4
0.843
Change in SrCr
-0.11
-0.01
0.636
Change in Wt (lb)
10.5
11
0.74
LOS (days)
2.87
3.79
0.002
Haywood et al. LomaLinda University. Presented
at American College of Cardiology Annual
Scientific Session. 2003.