Transcript Amiodarone IV: Indications, Dosing, Clinical Studies

Amiodarone IV:
Indications, Dosing,
Clinical Studies,
Efficacy, and
Bibliography
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INDICATIONS
AMIODARONE IV
Amiodarone I.V.
(Cordarone I.V.)
®
Indication: Amiodarone I.V. is
indicated for initiation of
treatment and prophylaxis of
frequently recurring ventricular
fibrillation and hemodynamically
unstable ventricular tachycardia
in patients refractory to other
therapy.
Amiodarone I.V.
®
(Cordarone I.V.)
• Cordarone I.V. is contraindicated in patients
with cardiogenic shock, marked sinus
bradycardia, and second- or third-degree AV
block in the absence of a functioning
pacemaker.
• Cordarone I.V. should be administered only
by physicians who are experienced in the
treatment of life-threatening arrhythmias, who
are thoroughly familiar with the risks and
benefits of Cordarone therapy, and who have
access to facilities adequate for monitoring
the effectiveness and side effects of
treatment.
Amiodarone I.V.
®
(Cordarone I.V.)
• Hypotension is the most common adverse
effect seen with Cordarone I.V. and may be
related to the rate of infusion. Hypotension
should be treated by slowing the infusion or
with standard therapy: vasopressor drugs,
positive inotropic agents, and volume
expansion.
• The most important treatment-emergent
adverse effects are hypotension (16%),
bradycardia (4.9%), liver function test
abnormalities (3.4%), cardiac arrest (2.9%), VT
(2.4%), CHF (2.1%), cardiogenic shock (1.3%),
and AV block (0.5%).
AMIODARONE IV
DOSING
Rapid Onset of Action
1-4
Antiarrhythmic effects are seen in
minutes3,4
Hypotension is the most common
adverse effect seen with Cordarone®
I.V. (amiodarone HCI) and may be
related to the rate of infusion.
1. Kadish A, Morady F. The use of intravenous amiodarone in the acute therapy of life-threatening
tachyarrhythmias. Prog Cardiovasc Disc. 1989;31:281-294.
2. Helmy I, Herre JM, Gee G, et al. Use of intravenous amiodarone for emergency treatment of lifethreatening ventricular arrhythmias. J Am Coll Cardiol. 1988;12:1015-1022.
3. Holt P, Curry P, Way B, et al. Intravenous amiodarone; an effective anti-arrhythmic agent. Am J Cardiol.
1982;49:1001. Abstract.
4. Benjamin R, Denizeau J-P, Melon J, et al. Les effets antiarythmiques de l’amiodarone injectable: à propos
de 100 cas. Arch Mal Coeur. 1976;69:513-522.
Dose Recommendations
-- First 24 Hours -Loading Infusions
First Rapid: 150 mg over the FIRST 10
minutes (15 mg/min). Add 3 mL of
Amiodarone I.V. (150 mg) to 100 mL
D5W (1.5 mg/mL) and infuse over 10
minutes.
Followed by Slow 360 mg over the
NEXT 6 hours (1 mg/min). Add 18 mL
of Amiodarone I.V. (900 mg) to 500 mL
D5W concentration = 1.8 mg/mL).
Dose Recommendations
-- First 24 Hours -Maintenance Infusion
540 mg over the REMAINING 18
hours (0.5 mg/min). Decrease the
rate of the slow loading infusion to
0.5 mg/min.
Supplemental Infusion*
Add 150 mg to 100 mL D5W; administer over
10 minutes (15 mg/min)
PVC† or glass container
•Hypotension is the most common adverse effect
seen with Amiodarone I.V. and may be related to
the rate of infusion
•Must use volumetric pump when administering
Amiodarone I.V.; an in-line filter is recommended
•Store ampuls in cartons until ready for use to
protect from light
•Prepared solutions should not be kept for more
than 24 hours
* For the management of breakthrough episodes of life-threatening VT or VF.
Alternatively, the rate of the maintenance infusion may be increased.
†
10% loss after two hours
Supplemental Infusion*
Add 150 mg to 100 mL D5W; administer over
10 minutes (15 mg/min)
PVC† or glass container
•Concentrations greater than 3 mg/mL in D5W
have been associated with a high incidence
of peripheral vein phlebitis
•For infusions longer than 1 hour, Cordarone
I.V. concentrations
should not exceed 2 mg/mL unless a central
venous catheter is used
•Evacuated glass containers for admixing
Cordarone I.V. are not recommended
A Treatment Algorithm for Cardiac Arrest*
Utilizing Cordarone I.V. (amiodarone HCI)
®
Pulseless VT/VF
Shock x 3
Persistent or recurrent
VT/VF
Continue CPR
Intubate
Obtain IV access
Epinephrine 1 mg I.V.
q 3 to 5 minutes
Cordarone I.V. 300 mg
rapid peripheral infusion
IIb Medications, e.g.,
Lidocaine
Procainamide
etc.
DF 360 J within
30 to 60 sec after each drug
“Drug-Shock”, “Drug-Shock”
*Due to persistent VF/pulseless VT
Adapted from Gonzalez ER, Kannewurf BS, Ornato JP. Resuscitation. 1998;39:33-42.
AMIODARONE IV
EFFICACY
Suppresses Highly Malignant
Ventricular Arrhythmias in Patients
1
With Severe Underlying Heart Disease
In clinical studies
• Decreased median number of life-threatening
events by 71%2
• Increased median time to first event to 13.7
hours2
• 85% of patients in controlled studies survived the
critical first 24 hours.3 Without a placebo
comparison, a mortality benefit could not be
established.
1. Kowey PR, Levine JH, Herre JM, et al. Randomized, double-blind comparison of intravenous
amiodarone and bretylium in the treatment of patients with recurrent hemodynamically destabilizing
ventricular tachycardia or fibrillation. Circulation. 1995;92:3255-3263.
2. Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone
in patients with life-threatening ventricular tachyarrhythmias. Circulation. 1995;92:3264-3272.
3. Data on file, Wyeth-Ayerst Laboratories.
Reduction of VT/VF Events
During Double-Blind Therapy1
Events/hr (median)
0.10
0.07
P=0.067
71%
Reduction
0.04
0.05
0.02
0.00
125 mg
500 mg
1000 mg
Cordarone I.V. Dosing (mg/24 Hours)
• The 125 mg dose group was used as a control group.
• Due to administration of supplemental infusions, the 1000 mg dose group actually
received 1185 mg/24 hours compared to the 125 mg dose group, which received
428 mg/24 hours
Reproduced with permission. Circulation. Copyright 1995 American Heart Association.
1. Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with lifethreatening ventricular tachyarrhythmias. Circulation. 1995;92:3264-3272.
Reduction from Baseline
in VT/VF Events1
Baseline
Median VT/VF Events
per 24 Hours
Cordarone I.V. 1000 mg
Cordarone I.V. 125 mg
4.0
3.52
(88%
reduction)
3.0
1.68
1.32
(44%
reduction)
0.48
1000 mg
125 mg
Difference
from baseline
P=0.0425
No significant difference observed between the 1000 mg dose
and the 500 mg dose or the 125 mg dose and the 500 mg dose
Reproduced with permission. Circulation. Copyright 1995 American Heart Association.
1. Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with lifethreatening ventricular tachyarrhythmias. Circulation. 1995;92:3264-3272.
AMIODARONE IV
CLINICAL
STUDIES
Amiodarone in out-of-hospital
Resuscitation of REfractory Sustained
ventricular Tachyarrhythmias (ARREST)
A prospective, randomized, double-blind, placebocontrolled comparison of ACLS guidelines with and
without intravenous amiodarone in out-of-hospital cardiac
arrest due to shock-refractory VF/VT
Kudenchuk PJ, Cobb LA, Copass LA, et al. New Engl J Med. 1999. 341:871-878.
ARREST Eligibility Criteria
• Age >18 years
• Nontraumatic out-of-hospital
cardiac arrest
• Ongoing VF/VT after 3+ shocks
• Medics and study drug on scene
• I.V. access
ARREST
Study End Points
•Primary
- Admission to hospital with a
spontaneously perfusing
rhythm (assigned to a hospital
bed)
ARREST Study End
Points
•Secondary
-Adverse effects
-Total duration of resuscitative efforts
-Number of shocks after study drug
-Need for additional antiarrhythmic drugs
•Also Evaluated
-Survival to hospital discharge*
-Neurologic status at hospital
discharge*
* Due to sample size, trial was not powered to detect significant differences
between treatment groups.
Study Algorithm
Cardiac Arrest
VF or Pulseless VT
Shock x 3
Persistent or
Recurrent VF/VT
Stable
Rhythm
ETT
I.V.
EPI
Study Drug
Standard ACLS Care
Placebo
I.V. amiodarone
Asystole
or PEA
Excluded From Study
ETT: endotracheal intubation
I.V.: intravenous access established
EPI: epinephrine
PEA: pulseless electrical activity
November 1994 – February 1997
Out-of-Hospital Cardiac Arrest
(n=3954)
Met Study Criteria
(n=667)
Eligible/Treated
(n=507)
Study Group
(n=504)
Ineligible/Not
Treated
(n=3260)
Ineligible/Treated
(n=27)
Eligible/Not
Treated
(n=160)
Drug Assignment
Unknown
(n=3)
•
•
•
•
BLS Only/DOA
Age/Trauma
PEA/Asystole
<3 Shocks
•
Insufficient
number of shocks
ROSC at time of Rx
Trauma
•
•
•
•
VF/VT terminated
before Rx
Protocol violation
BLS: basic life support
PEA: pulseless electrical activity
ROSC: return of spontaneous circulation
ARREST Patient Characteristics
I.V. Amiodarone
(n=246)
Male
Placebo
(n=258)
P-value
187 (76%)
203 (79%)
NS
66  14
65  14
NS
Cardiac History
137 (64%)
135 (59%)
NS
Other Medical History
101 (47%)
119 (52%)
NS
Witnessed Arrest
155 (70%)
182 (77%)
0.07
Bystander CPR
155 (68%)
138 (59%)
0.06
0.42  0.2
0.45  0.2
NS
Age (yrs)
VF Amplitude (mV)
Initial Cardiac Arrest Rhythm
100
83
I.V. Amiodarone
Placebo
83
% of Patients
80
60
40
20
12
4
5
11
0
VF
PEA: pulseless electrical activity
Asystole
VF
PEA
VF
Response/Treatment Times
From Dispatch
Mean  1 SD (Median) Minutes
I.V.
Amiodarone
Placebo
P-value
1st unit (EMT-D)
4.3  2.0 (4)
4.4  2.3 (4)
NS
Paramedic/ALS
8.4  4.1 (7.8)
8.8  4.9 (7.9)
NS
4.1  4.0 (3)
4.5  4.3 (3.3)
NS
8.9  5.4 (7.6)
9.5  7.5 (7.4)
NS
I.V.
13.1  4.1 (12.7)
13.7  4.1 (13.2)
NS
Intubation
14.3  5.8 (12.7)
13.8  4.6 (13.1)
NS
Study drug
21.4  8.3 (19.2)
20.5  7.0 (19.3)
NS
EMT-D ALS
1st shock
Resuscitation Characteristics
Before Study Drug
I.V.
Amiodarone
(n=246)
Placebo
(n=258)
P-value
Number of shocks
5  2 (4)*
5  2 (4)*
0.73
Transient ROSC
55 (22%)
52 (20%)
0.61
Antiarrhythmic drug
65 (26%)
91 (35%)
0.04
Bradycardia treatment
32 (13%)
51 (20%)
0.04
Pressor treatment
19 (8%)
22 (9%)
0.74
ROSC: return of
spontaneous
circulation
*Median in parentheses.
Treatment After Study Drug
% of Patients
100
80
P=0.70
80
I.V. Amiodarone
Placebo
82
P=0.04
59
60
48
P=0.004
41
40
25
20
0
Antiarrhythmic
No. Receiving Drug/
197/246
Total No.
211/258
Pressor*
91/153
69/145
* In patients with return of spontaneous circulation.
Bradycardia
treatment*
63/153
36/145
Admission to Hospital by
Arrest Characteristics
70
Patients Surviving
to Admission (%)
Amiodarone
64
Placebo
60
49
50
44
41
39
40
34
38
33
30
17
20
12
10
0
All patients
No. Surviving/
Total No.
108/246 89/258
VF
101/205 84/216
Asystole or PEA
converting to VF
7/41
PEA: pulseless electrical activity
ROSC: return of spontaneous circulation
5/42
ROSC
35/55
22/53
No ROSC
73/191 67/205
Patient Status at
Hospital Discharge
70
% of Patients
60
I.V. Amiodarone
Placebo
55
50
50
40
30
20
13.4
13.2
16
15
10
0
Outcome
Alive,
all patients
Alive,
VF only
Resumed
independent living
This trial was not designed or powered to detect significance in survival to hospital discharge.
ARREST Trial
Conclusions
•I.V. amiodarone is effective
therapy for shock-refractory VF
•Adverse effects expected, but
manageable
•Improving survival from cardiac
arrest remains an important
challenge
ACC/AHA Treatment
Recommendations
for VT/VF
Acute
Myocardial Infarction
•900,000 people in U.S.
experience an MI annually
•225,000 die
- 125,000 die “in the field”
- Most deaths are arrhythmic in
etiology
Source: Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the management of
patients with acute myocardial infarction. J Am Coll Cardiol. 1996;28:1333.
ACC/AHA Practice Guidelines
1990 – ACC/AHA Introduces “Guidelines for the Early
Management of Patients with Acute MI”
• Not a rigid prescription
• A “guide” – to be modified by clinical judgment,
patient needs,
and new findings
1994 – ACC/AHA Task Force on Practice Guidelines
Convenes
• Purpose: to review knowledge accumulated since
1990 and recommend appropriate changes to the
original guidelines
• Estimated 5,000 publications reviewed over next 1
1/2 years
1996 – ACC/AHA Publishes Revised Guidelines
Source: Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the management of patients with acute
myocardial infarction. J Am Coll Cardiol. 1996;28:1336.
ACC/AHA Treatment
Recommendations for VT/VF
Class I:
• Sustained monomorphic VT – Treat with one
of the following:
- Lidocaine: bolus 1.0 to 1.5 mg/kg
- Procainamide: 20 to 30 mg/min loading infusion,
up to 12 to 17 mg/kg. This may be followed by
an infusion of 1 to 4 mg/min
- Amiodarone IV: 150 mg infused over 10 min
followed by 1.0 mg/min for 6 hrs and then a
maintenance infusion of 0.5 mg/min
- Synchronized electrical cardioversion starting at
50 J
Amiodarone I.V. is indicated in life-threatening VT/VF refractory to other therapy.
ACC/AHA Treatment
Recommendations for VT/VF
Class I (Cont’d.):
• Sustained monomorphic VT with angina,
pulmonary edema, or hypotension (<90 mm
Hg) – synchronized cardioversion 100 J
initial energy. Increasing energies may be
used if not initially successful
• VF or sustained (>30 sec) polymorphic VT
– defibrillate up to 3 times if needed (200 J,
200 to 300 J, 360 J)
ACC/AHA Treatment
Recommendations for VT/VF
Class IIa:
• Infusions of antiarrhythmic drugs
(discontinue after 6 to 24 hours and
reassess need)
• Correction of electrolyte and acid-base
disturbances (to prevent VF
recurrence following treatment of initial
episode)
ACC/AHA Treatment
Recommendations for VT/VF
Class IIb:
• Drug-refractory polymorphic VT
- Manage aggressively with -blockers, intra-aortic
balloon pumping, PTCA/CABG surgery
- Amiodarone I.V.
Class III:
• Treating isolated PVCs, couplets, runs of
accelerated idioventricular rhythm, nonsustained
VT
• Prophylactic antiarrhythmic therapy when using
thrombolytic agents
• Amiodarone I.V. is indicated in life-threatening
VT/VF refractory to other therapy.
AMIODARONE IV
SAFETY
Clinically Manageable
Safety Profile
~9% overall discontinuation rate due
to adverse events
1
<1% incidence of proarrhythmia
1
<1% discontinuation due to CNS side
1
effects
Hypotension is the most common adverse effect seen with
Amiodarone I.V. and may be related to the rate of infusion.
Hypotension should be treated by slowing the infusion or with
standard therapy: vasopressor drugs, positive inotropic agents, and
volume expansion.
1. Data on file, Wyeth-Ayerst Laboratories.
Most Important Treatment-Emergent
Drug-Related
Adverse Events (n=1836)
Event % Incidence
% Requiring
permanent
discontinuation
Hypotension
16%
1.6%
Bradycardia
4.9%
<1%
Liver function tests abnormal
3.4%
<1%
Heart arrest
2.9%
1.2%
Ventricular tachycardia
2.4%
1.1%
Congestive heart failure
2.1%
<1%
Cardiogenic shock
1.3%
1.0%
AV block
0.5%
<1%
Fewer Drug-Related Adverse
1
Events Than Bretylium
Event
Cardiovascular events
Hypotension
Heart block
CHF
Proarrhythmia
Nodal rhythm
Phlebitis
Other events
Nausea
Confusion
Thrombocytopenia
Fever
Diarrhea
Treatment Group
Bretylium
Cordarone I.V. Cordarone I.V.
n=103
1000 mg
125 mg
n=105
n=94
33
4
5
3
0
0
6
4
3
1
5
(32%)
(4)
(5)
(3)
(6)
(4)
(3)
(1)
(5)
21 (20%)
0
0
0
3 (3)
3 (3)
2
3
1
2
0
(2)
(3)
(1)
(2)
17 (18%)
2 (2)
0
1 (1)
0
0
2
3
1
1
0
(2)
(3)
(1)
(1)
Reproduced with permission. Circulation. Copyright 1995 American Heart Association.
1. Kowey PR, Levine JH, Herre JM, et al. Randomized, double-blind comparison of intravenous amiodarone and bretylium
in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or fibrillation.
Circulation. 1995;92:3255-3263.
AMIODARONE IV
BIBLIOGRAPHY
Bibliography
•Benaim R, Denizeau J-P, Melon J, et al. Les effets
antiarythmiques de l´amiodarone injectable: à propos de 100
cas. Arch Mal Coeur. 1976;69:513-522.
•Gonzalez ER, Kannewurf BS, Ornato JP. Intravenous
amiodarone for ventricular arrhythmias: overview and clinical
use. Resuscitation. 1998;39:33-42.
•Helmy I, Herre JM, Gee G, et al. Use of intravenous
amiodarone for emergency treatment of life-threatening
ventricular arrhythmias. J Am Coll Cardiol. 1988;12:1015-1022.
•Holt P, Curry P, Way B, et al. Intravenous amiodarone; an
effective anti-arrhythmic agent. Am J Cardiol. 1982;49:1001.
Abstract
•Kadish A, Morady F. The use of intravenous amiodarone in the
acute therapy of life-threatening tachyarrhythmias. Prog
Cardiovasc Dis. 1989;31:281-294.
Bibliography
•Kowey PR, Levine JH, Herre JM, et al. Randomized, doubleblind comparison of intravenous amiodarone and bretylium in
the treatment of patients with recurrent, hemodynamically
destabilizing ventricular tachycardia or fibrillation. Circulation.
1995;92:3255-3263.
•Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for
resuscitation after out-of-hospital cardiac arrest due to
ventricular fibrillation. N Engl J Med. 1999;341:871-878.
•Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines
for the management of patients with acute myocardial
infarction. J Am Coll Cardiol. 1996;1328:1428.
•Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging
study of intravenous amiodarone in patients with lifethreatening ventricular tachyarrhythmias. Circulation.
1995;92:3264-3272.