Evidence Based Review Article
The Journal of Informed Pharmacotherapy
Amiodarone for Cardiac ARREST: Implications for
Change of Current Practice?
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Reviewer: Peter J. Zed, B.Sc., B.Sc.(Pharm), Pharm.D.
Reviewer's email address: firstname.lastname@example.org
Reviewer's profession/specialty: Pharmacy/Emergency Medicine
Kudenchuk PJ, Cobb LA, Copass MK, Cummins RO, Doherty AM, Fahrenbruch CE,
Hallstrom AP, Murray WA, Olsufka M, Walsh T. Amiodarone for resuscitation
after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl
J Med 1999;341:871-8. PubMed
Overall Study Question
was conducted to determine the efficacy of intravenous amiodarone for the
management of shock-refractory ventricular fibrillation or tachycardia in
patients with out-of hospital cardiac arrest. Adults with non-traumatic
out-of-hospital cardiac arrest were eligible for enrollment if intravenous
access had been established
fibrillation of pulseless ventricular tachycardia (on initial presentation or at
any time in the course of resuscitation attempt) was
present after three or more precordial shocks had been given. The
primary endpoint was admission to hospital with a spontaneous perfusing rhythm.
Patients who died in
the emergency department were not considered admitted. The
were adverse effects, number of precordial shocks required following the
administration of amiodarone or placebo, the total duration of resuscitative
measures and the need for additional
antiarrhythmic drugs. Survival to discharge from hospital and functional
neurological status were also evaluated, although the trial did not have
statistical power to demonstrate differences in these outcomes.
Are the Results of the Study
1. Was assignment of patients randomized?
patients received epinephrine 1 mg intravenously (IV) and were then randomized
to received amiodarone 300 mg IV or the
80, as placebo. Only a single
dose of amiodarone or placebo
2. Were all patients who entered the trial properly accounted for and
attributed at its conclusion?
Of the 667 patients who initially
met inclusion criteria, 160 patients did not receive amiodarone or placebo
because of spontaneous conversion of their arrhythmia, technical problems or
protocol violations. An additional 27 recipients of amiodarone or placebo
were determined to be ineligible for the study, but were included in the final
analysis. Three eligible patients were excluded from the final analysis,
as the treatment assignment was not known due
to the loss of an empty study vial. The final study population consisted
of 504 patients (246 in the amiodarone group and 258 in the placebo group).
3. Were patients, their clinicians, and study personnel 'blind' to
- Yes. Amiodarone and placebo were packaged identically in unlabelled,
amber-colored 6 ml glass vials. Each vial was labeled with an
identifying number code. Following randomization, the contents of a
single vial was drawn into a sterile syringe, diluted to 20 ml with 5% D5W
and injected rapidly into a peripheral line that was simultaneously being
rapidly infused with 5% D5W. Cardiopulmonary resuscitation was continued
during this process. All data were collected and analyzed by investigators
who had no knowledge of treatment assignments.
4. Were the groups similar at the start of the trial?
Yes. The baseline
characteristics of the amiodarone and placebo groups were similar. The
difference appeared in
the initiation of bystander cardiopulmonary resuscitation, which was higher
in the amiodarone
group (68%) compared to the placebo group (59%, p value unknown).
5. Aside from the experimental intervention, were the groups treated
6. Overall, are the results of the study valid?
What were the Results?
1. How large was the treatment effect?
primary endpoint, survival to hospital admission, occurred in 44% patients
treated with amiodarone compared to 34% of patients who received placebo,
(odds ratio [OR] 1.5, 95% confidence interval [CI] 1.04-2.1, p=0.03).
This correlates to and absolute risk reduction (ARR) of 10% and a number
needed to treat of 10. The endpoint was based on admission to
hospital so the time frame is from the time of arrest to admission.
secondary endpoint of survival to hospital discharge was not different between
the amiodarone and placebo groups treatment groups (13.4% vs. 13.2%, respectively). Only
52% of all patients who survived to hospital discharge were able to resume
independent living activities or returned to work. There was no
difference between treatment groups.
There were no differences between treatment groups for any of the other
secondary endpoints including the number of precordial shocks required
after the administration of amiodarone or placebo, the total duration of
resuscitative measures and the need for additional antiarrhythmic drugs.
Overall, amiodarone-treated patients experienced more hypotension requiring
pressor therapy compared to placebo (59% vs. 48% (p=0.04)) and more
bradycardia requiring treatment (41% vs. 25% (p=0.004),
2. How precise was the estimate of the treatment effect?
The 95% CI for the primary endpoint of survival to hospital admission do
not include zero indicating statistical significance.
Will the Results Help Me in Caring for My Patients?
1. Can the results be applied to my patient care?
- Yes. The use of intravenous amiodarone in patients with out-of
hospital cardiac arrest due to shock-refractory ventricular fibrillation or
tachycardia amiodarone is more effective than placebo in survival to
2. Were all clinically important outcomes considered?
- Although the ARREST trial was able to demonstrate a benefit in the
surrogate endpoint of survival to hospital admission the trial was
underpowered to evaluate the more clinically relevant endpoint of survival
to hospital discharge. In addition, the trial was also underpowered to
evaluate the functional neurological status upon discharge from hospital.
3. Are the likely treatment benefits worth the potential harms and costs?
questions remain unanswered regarding the use of intravenous amiodarone in
patients with cardiac arrest
due to shock-refractory ventricular fibrillation or tachycardia. In
addition to the increased cost, it would appear that from an adverse effect
perspective, hypotension and bradycardia occur in a large proportion of
amiodarone-treated patients. Unfortunately, the ARREST trial did not
evaluate the use of amiodarone in comparison with first-line antiarrhythmic
therapy used in the Advanced Cardiac Life Support (ACLS) guidelines for
ventricular fibrillation or pulseless ventricular tachycardia precluding any
definitive conclusions on the role of amiodarone.
Although lidocaine, bretylium and
procainamide are recommended for use in the ACLS treatment guidelines for
ventricular fibrillation and pulseless ventricular tachycardia, the evidence
supporting the use of antiarrhythmic therapy has not been clearly established in
clinical trials. The ARREST trial is an important trial in the continuum
of resuscitation research, but falls short in providing
any clear recommendations for use in clinical practice. Although survival
to hospital admission was found to be improved in amiodarone-treated patients,
this surrogate endpoint did not appear to correlate to improved overall survival
nor did it's use appear to improve functional neurological status in surviving
patients. As the study was underpowered to make any firm conclusions on
overall survival and functional neurological status, a larger trial will be
required to assess the impact of amiodarone on these endpoints. Since
this trial was placebo-controlled (as opposed to a comparison to what would
be considered current first-line therapy), these results do not
clearly elucidate the role of amiodarone in the current ACLS
treatment guidelines for ventricular fibrillation or pulseless ventricular
tachycardia. Despite the lack of clear evidence supporting the currently
recommended antiarrhythmic agents, clinicians should be cautious when
considering the use of amiodarone in this setting until ongoing research (e.g.
the ALIVE (Amiodarone versus Lidocaine In Ventricular fibrillation Evaluation)
completed and clinical data is available to compare the efficacy of intravenous
amiodarone on overall survival in trials with an appropriate antiarrhythmic
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Pharmacotherapy. All rights reserved.