Amiodarone for Cardiac ARREST: Implications for Change of Current Practice?

Original Citation

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.

Overall Study Question

ARREST 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 and ventricular fibrillation of pulse-less 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 secondary endpoints 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 Valid?

Was assignment of patients randomized?

Yes. All patients received epinephrine 1 mg intravenously (IV) and were then randomized to received amiodarone 300 mg IV or the diluent, polysorbate 80, as placebo.  Only a single dose of amiodarone or placebo was administered.

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).

Were patients, their clinicians, and study personnel ‘blind’ to treatment?
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.
Were the groups similar at the start of the trial?

Yes.  The baseline characteristics of the amiodarone and placebo groups were similar.  The only apparent 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).

Aside from the experimental intervention, were the groups treated equally?

Yes.

Overall, are the results of the study valid?
Yes.

What were the Results?

1. How large was the treatment effect? 

The 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. The 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), respectively).

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 hospital admission.

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?
Many 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.

Commentary

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) trial) is completed and clinical data is available to compare the efficacy of intravenous amiodarone on overall survival in trials with an appropriate antiarrhythmic control group.

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