In this very interesting randomised, double-blind trial, the authors compared iv amiodarone, lidocaine, or placebo, along with standard care, in adult patients who had non-traumatic out-of-hospital cardiac arrest (OOH-CA) with shock-refractory (persistent or recurrent) ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) after at least one shock .
Patients already receiving one of the study drug (open-label) before randomisation were excluded. Patients were randomised in 1:1:1 ratio. The treatment consisted in a first bolus of 300 mg of amiodarone/120 mg lidocaine/placebo (unless patient weighing less than 45 Kg – in this case half dose was administered). A second bolus of half the standard dose of the same drug was administered if persistent/recurrent VF/VT after the initial dose. Post-CA care was not influenced by the trial. The study involved 55 emergency medical services (EMS) and enrolled patients with OOH-CA at 10 North American sites, and lasted from 7 May 2012 to the 25 October 2015. In the per-protocol population, 3026 patients were randomly assigned to amiodarone (974), lidocaine (993), or placebo (1059). The baseline characteristics were well balanced. The first drug dose was given a mean of 19 minutes after the initial call to EMS and after a median of 3 shocks.
The main findings of this trial were that survival at hospital discharge (primary outcome) and survival with good neurological outcome after discharge were similar between the three groups; however few considerations have to be made.
First, although results were not statistically significant one can see a trend towards better results for the primary outcome in the amiodarone vs placebo group. Indeed, the absolute risk difference was 3.2 percentage points (p value 0.08). This may suggest room for more research. It is worth noting that a trial conducted on this topic  enrolled just over 500 patients with VF/VT OOH-CA and found a higher rate of survival to hospital admission with amiodarone as compared with placebo. In a subsequent paper, almost 350 patients with VF/VT OOH-CA were randomised to amiodarone or lidocaine . Again, amiodarone performed better than lidocaine with a higher survival to hospital admission in patients with shock-resistant OOH-CA with VF. In these two trials time-to-drug administration was 21 and 25 minutes respectively: the present study had relatively shorter time to treatment (19 minutes) and therefore time-to-treatment cannot explain the differences with such studies.
Second (and important!), the authors found a higher rate of survival to hospital discharge of amiodarone or lidocaine vs the rate with placebo among patients with witnessed OOH-CA. Indeed, among almost 2000 patients with bystander-witnessed CA, survival rate was higher with amiodarone (27.7%) or lidocaine (27.8%) than with placebo (22.7%), while in over 800 patients with unwitnessed OOH-CA, survival did not differ significantly between the three trial groups.
A third observation stemming from this study is that amiodarone and lidocaine facilitated termination of ongoing or recurrent VF/VT with fewer shocks than placebo, and the drugs groups had higher rates of hospital admission, and resulted in a lesser need for CPR or antiarrhythmic therapies during hospitalisation. Moreover these drugs did not result in a different incidence of drug related side effects. One may argue that all these results suggest there could be some efficacy in improving the short term prognosis by anti-arrhythmic drugs, but unfortunately these are not powered enough to detect a significant result at hospital discharge. Indeed many patients admitted to hospital die of anoxic brain damage which is established in most patients when the study drug was given (average 19 minutes).
Fourth, there were significant differences in the pre-hospital drug administered (atropine, procainamide, magnesium) all together with a trend difference for beta-blocker. We do not know if this may have reduced/increased the effect of the study drugs. Last, there was a lower than estimated difference points estimate of survival in the amiodarone and placebo group which suggests the trial could have been underpowered.
"….a higher survival to hospital discharge of amiodarone or lidocaine vs placebo was found in patients with witnessed OOH-CA suggesting that shorter time-to-treatment may play a key role in the efficacy of anti-arrhythmic drugs."
In summary, although amiodarone and lidocaine had similar survival rate at hospital discharge than placebo for the treatment of adult patients suffering of non-traumatic shockable OOH-CA, a trend towards better results was found for amiodarone vs placebo, and more importantly, a higher survival to hospital discharge of amiodarone or lidocaine vs placebo was found in patients with witnessed OOH-CA suggesting that shorter time-to-treatment may play a key role in the efficacy of anti-arrhythmic drugs.
Article review submitted by ESICM Journal Review Club member Filippo Sanfilippo on behalf of the NEXT Committee.
1. Kudenchuk PJ, Brown SP1, Daya M et al. Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2016 Apr 4. [Epub ahead of print]
2. 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 Sep 16;341(12):871-8.
3. Dorian P, Cass D, Schwartz B, Cooper R, Gelaznikas R, Barr A. Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med. 2002 Mar 21;346(12):884-90.