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Out-of-Hospital Cardiac Arrest — Are Drugs Ever the Answer?
Jose A. Joglar, M.D., and Richard L. Page, M.D.
Out-of-hospital cardiac arrest accounts for approximately 356,000 deaths per year in the United
States,1 with many patients having ventricular
fibrillation or pulseless ventricular tachycardia
as the presenting rhythm. In an effort to reduce
mortality, the American Heart Association (AHA)
developed the “Chain of Survival,”2 including
early cardiopulmonary resuscitation (CPR), rapid
defibrillation, and “effective advanced life support” as central links in management. However,
the rate of survival of out-of-hospital cardiac arrest with good neurologic function remains poor,
averaging just 8.5%.1 Geographic variation exists, and higher rates of survival are reported in
specific locations such as aircraft3 and casinos.4
Defibrillation is effective at terminating most
sustained ventricular fibrillation or pulseless
ventricular tachycardia, but the arrhythmia persists in some patients, and many have immediate recurrence. Antiarrhythmic medication, typically intravenous amiodarone or lidocaine, is
often used with the goal of restoring and maintaining a stable rhythm. Both agents have a class
IIb recommendation in the 2015 American Heart
Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care,5 which
states that these drugs “may be considered” for
ventricular fibrillation or pulseless ventricular
tachycardia that “is unresponsive to CPR, defibrillation, and a vasopressor therapy.”5 The uncertainty in these recommendations is based on
previous trials6,7 that were not powered to make
comparisons with respect to overall survival and
that showed no survival benefit. Furthermore,
all previous trials of intravenous amiodarone were
potentially undermined by a formulation that
included a solvent that causes hypotension; thus,
the effect purely of the drug had not been evaluated. In this context, the Resuscitation Outcomes
Consortium (ROC) conducted a trial to address
an important question: are drugs the answer?
The results of this trial are now reported by
Kudenchuk et al.8 in the Journal.
The ROC is a network of regional centers across
North America, supported by the National Institutes of Health and other organizations, that
allows for well-powered randomized studies of
out-of-hospital cardiac arrest and trauma. The
trial is the first randomized, multicenter, doubleblind comparison of intravenous saline placebo
versus amiodarone versus lidocaine, along with
standard care, in patients with out-of-hospital cardiac arrest and ventricular fibrillation or pulseless
ventricular tachycardia that recurs or persists
after one or more electrical shocks. Although the
lidocaine preparation is standard, the formulation of amiodarone with a solvent that does not
cause hypotension (Nexterone, Baxter Healthcare)
is novel and allows for isolated evaluation of the
pharmacologic effect of the drug.
In the trial, neither amiodarone nor lidocaine
resulted in a significantly higher rate of survival
to hospital discharge (the primary outcome) or
favorable neurologic function at discharge (the
secondary outcome) than the rate with placebo
among the 3026 patients studied. On the other
hand, there were nonsignificant differences between each drug and placebo in the survival rate
(a difference of 3.2 percentage points for amiodarone vs. placebo and 2.6 percentage points for
lidocaine vs. placebo). Further evidence of an
antiarrhythmic effect was the significant benefit
of both drugs over placebo in several measures:
fewer shocks were administered after the first
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dose of the trial drug; fewer patients received
rhythm-control medications during hospitalization; and fewer patients required CPR during
hospitalization.
How might we explain the negative results of
the trial? One possibility, as the authors suggest,
is that the trial was underpowered for the smallerthan-predicted drug effect. A further possibility is
that drug delivery was provided too late to overcome the metabolic consequences of prolonged
arrest. Rates of conversion to sinus rhythm and
survival rates are highest immediately after outof-hospital cardiac arrest, with up to 74% survival among patients with ventricular fibrillation
or pulseless ventricular tachycardia if a shock is
administered within 3 minutes.4 This brief “electrical phase” is followed by a “hemodynamic
phase”; however, after 10 minutes, the “metabolic
phase” dominates and the chances of survival are
reduced.9
For the vast majority of the trial patients (for
whom emergency medical services [EMS] personnel were not present at the time of arrest), the
mean time to drug treatment was 19.3 minutes
— well into the metabolic phase. What if the drug
therapy were administered sooner, as we might
presume would occur for the substantial subgroup (66%) whose arrest was witnessed by a
bystander? For these patients, the rate of survival
to hospital discharge was significantly higher with
amiodarone (27.7%) or lidocaine (27.8%) than with
placebo (22.7%) — a clinically important difference of 5 percentage points.
What can we conclude from the current trial,
and how might we modify care for out-of-hospital
cardiac arrest with ventricular fibrillation or pulseless ventricular tachycardia that either recurs or
persists despite electrical shock? The data do not
support the use of amiodarone or lidocaine for all
patients, but, although they are not absolutely
conclusive, the data suggest that EMS personnel
should consider these agents when the arrest is
witnessed. There is no signal from the data as to
which drug might be preferable, however.
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We commend the ROC investigators for their
efforts to provide scientific evidence to support
emergency care, and we agree with the Institute
of Medicine recommendations10 that research must
continue, with efforts to coordinate emergency
care and quickly implement best practices on the
basis of contemporary data. Finally, we emphasize the benefit of bystander-initiated CPR, for
which the current trial showed an absolute survival benefit of almost 10 percentage points,
eclipsing any effect of drug intervention.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the University of Texas Southwestern Medical Center,
Dallas (J.A.J.); and the University of Wisconsin School of Medicine and Public Health, Madison (R.L.P.).
This article was published on April 4, 2016, at NEJM.org.
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DOI: 10.1056/NEJMe1602790
Copyright © 2016 Massachusetts Medical Society.
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