Amiodarone in Cardiac Arrest: Barely ALIVE and Kicking?

Overall Study Question

The ALIVE study was conducted to determine the efficacy of intravenous (IV) amiodarone compared with lidocaine for the management of patients with out-of-hospital cardiac arrest due to shock-refractory ventricular fibrillation (VF).  Adults with non-traumatic out-of-hospital cardiac arrest were eligible for the study if VF persisted after three shocks from an external defibrillator, a single dose of IV epinephrine, and a fourth defibrillator shock, or if they had recurrent VF subsequent to successful defibrillation.  The primary endpoint was survival to admission to the hospital intensive care unit (ICU).  The secondary endpoints included survival to hospital discharge and adverse events, defined as the need to administer dopamine or atropine after administration of the study drug.

Are the Results of the Study Valid?

1. Was assignment of patients randomized?

All patients received epinephrine 1 mg IV and were then randomized to receive amiodarone 5 mg/kg IV or lidocaine 1.5 mg/kg IV.  If VF persisted after a further shock, a second dose of the study drug was administered (amiodarone 2.5 mg/kg or lidocaine 1.5 mg/kg) and attempts at resuscitation were continued.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

347 patients  met inclusion criteria and were randomized  to receive amiodarone (N=180) or lidocaine (N=167).  All patients were included in the final analysis.

3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?

The study was blinded using a double-dummy technique.  Patients received amiodarone 5 mg/kg IV (or matching placebo containing the same diluent (polysorbate 80) diluted in 30 mL of D5W) or lidocaine 1.5 mg/kg IV (or its matching placebo).  If VF persisted after a further shock, a second dose of the study drug or matching placebos were administered.

4. Were the groups similar at the start of the trial?

The baseline characteristics of the amiodarone and lidocaine groups were similar.

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

There were no differences in the further treatment of patients assigned to amiodarone or lidocaine.

What were the Results?

1. How large was the treatment effect?

The primary endpoint of survival to hospital admission was observed in 22.8% patients treated with amiodarone as compared to 12% of patients who received lidocaine, (odds ratio [OR] 2.17, 95% confidence interval [CI] 1.21-3.83, p=0.009).  This correlates to an absolute risk reduction (ARR) of 10.8% and a number needed to treat of 10.

The secondary endpoint of survival to hospital discharge was observed in 5% and 3% of patients in the amiodarone and lidocaine groups, respectively, (p=ns).  Overall, only 4% of all patients in the study survived to hospital discharge.

There was no difference between the amiodarone and lidocaine groups regarding the proportion of patients who needed treatment for bradycardia with atropine (24% vs. 23%) or pressor treatment with dopamine (7% vs. 4%).

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 (OR 2.17, 95% CI 1.21-3.83, p=0.009).

Will the Results Help Me in Caring for My Patients?

1. Can the results be applied to my patient care?

The use of intravenous amiodarone in patients with out-of-hospital cardiac arrest due to shock-refractory VF amiodarone is more effective than lidocaine in achieving survival to hospital admission.  However, the external validity to patients who experience an in-hospital VF arrest remains unclear.

2. Were all clinically important outcomes considered?

Although the ALIVE 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  for the purpose of evaluating the relative effect of amiodarone vs. lidocaine on the functional neurological status of survivors upon discharge from hospital.

3. Are the likely treatment benefits worth the potential harms and costs?

Many questions still remain unanswered regarding the use of intravenous amiodarone in patients with cardiac arrest due to shock-refractory VF.  In a trial which failed to demonstrate a survival benefit and demonstrated an overall survival of only 4%, the economic implications of using a more expensive agent (amiodarone) to a less expensive alternative (lidocaine) needs to be further evaluated.  In addition, when considering the increased admission to hospital but poor overall survival of these patients, it is apparent that an economic evaluation involving of the cost of care should be undertaken.

Commentary

Although the use of lidocaine or amiodarone is recommended in the ACLS treatment guidelines for VF arrest, the evidence supporting the use of antiarrhythmic therapy has not been clearly established in clinical trials.

(1)  The ALIVE trial follows on the heals of the ARREST trial which compared amiodarone to placebo in out-of-hospital VF or pulseless ventricular tachycardia.

(2)  While the ARREST trial was an important trial in the continuum of resuscitation research, this investigation fell short in providing any clear guidelines for use of amiodarone in clinical practice as a result of the placebo controlled design and the insufficient statistical power to demonstrate an overall survival benefit.  Although survival to hospital admission was found to be improved in amiodarone-treated patients in ALIVE and ARREST, the absolute benefit of 10% (NNT = 10) was identical in both trials.  However, this surrogate endpoint did not appear to correlate to improved overall survival.  As the study was underpowered to make any firm conclusions on overall survival and functional neurological status, a larger trial in clearly required to evaluate these endpoints.

The authors of the ALIVE trial conclude that “on the basis of these results, and the accumulated evidence from previous trials, there appears to be no indication for the administration of lidocaine to patients with shock- refractory ventricular fibrillation in the out-of-hospital setting.  We believe that if an antiarrhythmic drug is to be considered in this situation, intravenous amiodarone should be the drug of choice.”  While it is clear that the evidence supporting the use of lidocaine in shock-refractory VF arrest is weak; one could also argue that the evidence for amiodarone is not much better.  Should we administer amiodarone to patients if this drug improves the likelihood of arrival alive to the hospital, even if more than 95% of these patients succumb before discharge?  What about the external validity to in-hospital VF arrest where the endpoint used in both ALIVE and ARREST have already been achieved?  What about the economic implications of widespread use of amiodarone in all out-of-hospital VF arrests?  Based on the doses of study drug used in ALIVE implementation of amiodarone as the agent of choice in VF arrest would cost approximately $150 CAN for a 70 kg patient treated, as compared to $8 CAN in drug acquisition costs for lidocaine.  This excludes the additional costs of caring for those patients who were admitted to hospital after receiving amiodarone.  This increased economic impact on an already burdened healthcare system needs to be further evaluated.

Clinicians should be cautious in the use of amiodarone in the setting of VF arrest until further research is completed to evaluate the efficacy of drug on overall survival, and a clear assessment of the economic impact of preferentially using amiodarone for all out-of-hospital VF arrest has been established.

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