The n e w e ng l a n d j o u r na l of m e dic i n e
Edi t or i a l
Out-of-Hospital Cardiac Arrest Are Drugs Ever the Answer?
JoseA. Joglar, M.D., and RichardL. Page, M.D.
Out-of-hospital cardiac arrest accounts for ap-
proximately 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 sup-
port as central links in management. However,
the rate of survival of out-of-hospital cardiac ar-
rest with good neurologic function remains poor,
averaging just 8.5%.1 Geographic variation ex-
ists, 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 per-
sists in some patients, and many have immedi-
ate recurrence. Antiarrhythmic medication, typi-
cally intravenous amiodarone or lidocaine, is
often used with the goal of restoring and main-
taining a stable rhythm. Both agents have a class
IIb recommendation in the 2015 American Heart
Association Guidelines Update for Cardiopulmonary Re-
suscitation 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, defi-
brillation, and a vasopressor therapy.5 The un-
certainty 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,
n engl j mednejm.org
the effect purely of the drug had not been evalu-
ated. 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 Insti-
tutes 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, double-
blind comparison of intravenous saline placebo
versus amiodarone versus lidocaine, along with
standard care, in patients with out-of-hospital car-
diac 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 formula-
tion 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 be-
tween each drug and placebo in the survival rate
(a difference of 3.2 percentage points for amio-
darone 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
1
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dose of the trial drug; fewer patients received
rhythm-control medications during hospitaliza-
tion; 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 smaller-
than-predicted drug effect. A further possibility is
that drug delivery was provided too late to over-
come the metabolic consequences of prolonged
arrest. Rates of conversion to sinus rhythm and
survival rates are highest immediately after out-
of-hospital cardiac arrest, with up to 74% sur-
vival among patients with ventricular fibrillation
or pulseless ventricular tachycardia if a shock is
administered within 3 minutes.4 This brief elec-
trical 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] person-
nel 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 sub-
group (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 differ-
ence 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 pulse-
less 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.
2 n engl j mednejm.org
of m e dic i n e
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 empha-
size the benefit of bystander-initiated CPR, for
which the current trial showed an absolute sur-
vival 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 Medi-
cine and Public Health, Madison (R.L.P.).
This article was published on April 4, 2016, at NEJM.org.
1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and
stroke statistics 2016 update: a report from the American
Heart Association. Circulation 2016;133(4):e38-360.
2. Travers AH, Rea TD, Bobrow BJ, et al. CPR overview: 2010
American Heart Association guidelines for cardiopulmonary re-
suscitation and emergency cardiovascular care. Circulation
2010;122:Suppl 3:S676-84.
3. Page RL, Joglar JA, Kowal RC, et al. Use of automated exter-
nal defibrillators by a U.S. airline. N Engl J Med 2000;343:1210-
6.
4. Valenzuela TD, Roe DJ, Nichol G, Clark LL, Spaite DW, Hard-
man RG. Outcomes of rapid defibrillation by security officers
after cardiac arrest in casinos. N Engl J Med 2000;343:1206-9.
5. Link MS, Berkow LC, Kudenchuk PJ, et al. Adult advanced
cardiovascular life support: 2015 American Heart Association
Guidelines update for cardiopulmonary resuscitation and emer-
gency cardiovascular care. Circulation 2015;132:Suppl 2:S444-
64.
6. Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for
resuscitation after out-of-hospital cardiac arrest due to ventricu-
lar fibrillation. N Engl J Med 1999;341:871-8.
7. 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.
8. Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, lido-
caine, or placebo in out-of-hospital cardiac arrest. N Engl J Med.
DOI:10.1056/NEJMoa1514204.
9. Weisfeldt ML, Becker LB. Resuscitation after cardiac arrest:
a 3-phase time-sensitive model. JAMA 2002;288:3035-8.
10. Institute of Medicine. Strategies to improve cardiac arrest
survival: a time to act. Washington, DC:National Academies
Press, 2015.
DOI: 10.1056/NEJMe1602790
Copyright 2016 Massachusetts Medical Society.