Reference: Kudenchuk et al. Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest. NEJM April 2016
Guest Skeptic: Dr. Rory Spiegel is a clinical instructor at University of Maryland and a recent graduate of Stony Brook’s Resuscitation Fellowship. He writes an excellent blog called EM Nerd, which he describes as nihilistic ramblings.
Case: Your local EMS agency has asked your opinion on which anti-arrhythmic medication, if any, their ambulances should stock for the management of ventricular fibrillation or pulseless ventricular tachycardia refractory to defibrillation. Additionally, they want to know how best to incorporate these agents into their current resuscitation protocol?
Background: The American Heart Association estimates there are about 350,000 EMS-assessed out-of-hospital cardiac arrests in the United States each year. Half of these arrests are witnessed with the other half being un-witnessed.
Many out-of-hospital cardiac arrests are due to ventricular fibrillation or pulseless ventricular tachycardia. Defibrillation is the treatment of choice in these cases but do not often result in sustained return of spontaneous circulation (Kudenchuk et al 2006).
Both lidocaine and amiodarone may be considered for the treatment of ventricular fibrillation or pulseless ventricular tachycardia, which is unresponsive to defibrillation (Link et al 2015).
Two randomized control trials demonstrated that the use of amiodarone led to more patients with return of spontaneous circulation at the time of hospital arrival when compared to lidocaine or placebo (Kudenchuk et al 1999 and Dorian et al 2002). But these early benefits did not translate into a benefit in survival to hospital discharge or neurologically intact survival.
Clinical Question: Does amiodarone or lidocaine improve survival to hospital discharge with good neurologic outcome in non-traumatic out of hospital cardiac arrest secondary to refractory ventricular fibrillation or pulseless ventricular tachycardia?
Reference: Kudenchuk et al. Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest. NEJM April 2016
Population: Adult patients with non-traumatic out-of-hospital cardiac arrest and shock refractory ventricular fibrillation or pulseless ventricular tachycardia after one or more shocks anytime during resuscitation.
Exclusions: Patients who had already received open-label intravenous lidocaine or amiodarone during resuscitation or had known hypersensitivity to these drugs (see supplementary appendix in NEJM for complete list of inclusion and exclusion criteria).
Intervention: Amiodarone or lidocaine
Primary: Survival to hospital discharge
Secondary: Favorable neurologic function at discharge defined as a modified Rankin Scale (mRS) of 3 or less.
Author’s Conclusions: Overall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.
Quality Checklist for Randomized Clinical Trials:
The study population included or focused on those in the ED. No. These were patients with out-of-hospital cardiac arrest.
The patients were adequately randomized. Yes
The randomization process was concealed. Yes
The patients were analyzed in the groups to which they were randomized. No. It was a per-protocol analysis not an intention-to-treat analysis for their primary outcome.
The study patients were recruited consecutively (i.e. no selection bias). Yes
The patients in both groups were similar with respect to prognostic factors. Yes
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
All groups were treated equally except for the intervention. Yes
Follow-up was complete (i.e. at least 80% for both groups). Yes
All patient-important outcomes were considered. Yes
The treatment effect was large enough and precise enough to be clinically significant. Yes/No. It was precise enough but treatment was not superior to placebo.
Key Results: There were 37,889 patients with non-traumatic out-of-hospital cardiac arrest of which 7,051 (18.6%) had shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. The intention to treat population was 4,653 and the per-protocol population was 3,026.
Survival to Hospital Discharge – No Statistical Difference
Primary Outcome: Survival to hospital discharge – No statistical difference (Amiodarone 24.4%, Lidocaine 23.7% and Placebo 21.0%)
Secondary Outcome: Favourable neurologic function at discharge – No statistical difference (Amiodarone 18.8%, Lidocaine 17.5% and Placebo 16.6%)
1) Statistical vs. Clinical Significance –. The primary outcome of survival to hospital discharge failed to find a statistical difference. The absolute difference in survival between amiodarone vs. placebo was 3.2% (95% CI, −0.4 to 7.0; P=0.08), and lidocaine vs. placebo was 2.6% (95% CI, −1.0 to 6.3; P=0.16). But there is a difference between statistical significance and clinical significance.
They powered their study to find a 6.3% difference. They would have needed 9,000 patients to establish a three percent difference. A three percent difference, if true, would translate into 1,800 lives saved yearly in North America for OHCA.
So this trial may have been under-powered, certainly patients in both the amiodarone and lidocaine groups seem to respond to the antiarrhythmic effects of the drug therapy.
Patients randomized to either the amiodarone or lidocaine arms received less defibrillation attempts before achieving ROSC and survived to hospital admission more frequently than patient randomized to the placebo arm (45.7%, 47.0% and 39.7% respectively).
But these upstream benefits did not translate into clinically important improvements in favorable neurological outcome.
2) Intention-to-Treat vs. Per-Protocol Analysis – Even with the cards stacked in favor of finding superiority with treatment they did not find a statistical difference in their primary outcome.
Let us suppose for a moment that the trends observed in the trial describe a true benefit in the treatment of refractory ventricular fibrillation in OHCA. To what end? The authors’ primary endpoint was based off a per-protocol analysis of their cohort. As such they excluded 1,627 patients from their primary analysis. This led to a highly select population, intended to optimize the trials ability to discern benefit for the treatments in question. But such an analysis comes at a cost of its external validity.
These are not the unfiltered patients seen by your EMS agency. They are certainly not the few cardiac arrest patients that reach us in the Emergency Department. Even in this artificial population the authors found only small trends to improvement in survival and had to perform further subgroup analysis to demonstrate statistical benefit.
In the intention-to-treat population even these trends towards improved survival all but disappear. Patient randomized to the amiodarone, lidocaine, placebo group had survived to hospital discharge at a rate of 19.0%, 18.4%, and17.6% respectively.
And the intention-to-treat analysis of favorable neurologic outcome was not statistically different between groups (amiodarone 14.4%, lidocaine 13.5% and placebo 13.8%).
3) Favorable Neurologic Outcome – I think what patients really care about is survival to hospital discharge neurologically intact. Favorable neurologic outcome was a secondary outcome. They seemed to make this result look a little better by defining favorable neurologic outcome as a mRS of 3 (moderate disability; requiring some help, but able to walk without assistance) or less. When you read thrombolytics for stroke literature they are usually talking about a mRS of 0-1 or 0-2 not up to 3.
This is not unheard of in clinical trials that examine events that lead to neurologically devastating outcomes. In a sense they lower their standards for a good neurological outcome. We have seen this used in the Nichols et al (NEJM 2015) trial published late last year examining continuous chest compressions.
4) Subgroup Analysis – They made a big deal about some of the subgroup findings. These should be view with some caution.
One pre-specified subgroup was whether or not a bystander witnessed the cardiac arrest. There was a statistically significant increases in patients discharged from the hospital alive in both the amiodarone and lidocaine group when compared to placebo (27.7%, 27.8% and 22.7% respectively).
If one is to believe the benefit observed in bystander witnessed arrest, then one has to conclude that early use of both amiodarone and lidocaine may be efficacious but later in the arrest these drugs are far less effective at achieving ROSC.
It is also important to remember that subgroup analysis can easily be misleading because of the risk of type 1 error increases the more observations an investigator makes.
5) Cognitive Clutter – Finally, one could argue that despite the overall minimal effect, these drugs should be administered to all comers on the rare chance they may help one individual patient. And this position seems reasonable when viewed from this single perspective.
But when each of these low yields, ineffective therapeutic strategies are stacked one on top of another, on top of another on top of another, the resulting system can become unwieldy and ineffective.
Cardiac arrest is a high acuity, time dependent disease state. We should focus on delivering a small number of high yield interventions in a timely fashion.
Continued attention on interventions, which are unable to demonstrate statistically meaningful improvements in neurological outcomes in over 3,000 patients does nothing but add cognitive clutter to an already chaotic milieu.
Comment on authors’ conclusion compared to SGEM Conclusion: The conclusions drawn by the authors are fair.
SGEM Bottom Line: Neither lidocaine or amiodarone is likely to provide a clinically important benefit in adult out-of-hospital cardiac arrest patients with refractory ventricular fibrillation or pulseless ventricular tachycardia.
Case Resolution: I would tell my local EMS agency that the evidence does not support stocking amiodarone or lidocaine for the management of shock refractory ventricular fibrillation or pulses ventricular tachycardia. This is because it does not appear to significantly improve survival to hospital discharge or favorable neurologic outcome. However, if they do chose to incorporate anti-arrhythmics into their pre-hospital protocol it should be done in a manner to limit the logistically complexity introduced by their addition.
Dr. Rory Spiegel
Clinically Application: I think this depends on your clinical environment and what other resources you have available. Refractory cardiac arrest has a dismal prognosis if return of spontaneous circulation is not achieved by the time the patient arrives to the Emergency Department. If a patient presented in refractory ventricular fibrillation or pulseless ventricular tachycardia, I certainly would not say it is wrong to give these anti-arrhythmics. However, from a big picture we have to start considering discarding ineffective treatments and start investigating more viable options. So if either lidocaine or amiodarone is to be used it should be given in a protocolozed fashion so as to avoid adding to the cognitive load of whomever is running the resuscitation.
Keener Kontest: Last weeks’ winner was Xander Miller a PharmD student at Northeastern University in Boston. Xander knew the first knight to use a chest tube to treat a tension hemopneuothorax was named Gawan.
Listen to the podcast for this weeks’ question. If you think you know the answer send it to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.
Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.
Kudenchuk PJ, Cobb LA, Copass MK, Olsufka M, Maynard C, Nichol G. Transthoracic Incremental Monophasic versus Biphasic Defibrillation by Emergency Responders (TIMBER): a randomized comparison of monophasic with biphasic waveform ascending energy defibrillation for the resuscitation of out-of-hospital cardiac arrest due to ventricular fibrillation. Circulation 2006;114:2010-8.
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; 341:871-8.
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;346:884-90.
Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support. Circulation. 2015 Nov 3;132(18 Suppl 2):S444-64
ACEP Scientific Assembly, Las Vegas, Oct 16th to 19th