Trial Conduct and Oversight

The background and methods of the trial were described previously.9 Paramedics from 55 emergency medical services (EMS) agencies enrolled patients with out-of-hospital cardiac arrest at 10 North American sites participating in the Resuscitation Outcomes Consortium (ROC).10 The trial was conducted under exception from informed consent in emergency research in accordance with applicable regulatory requirements, oversight by the Food and Drug Administration and Health Canada, approval by institutional review boards in participating communities, and monitoring by an independent data and safety monitoring board appointed by the National Heart, Lung, and Blood Institute (NHLBI).

The trial was sponsored by the NHLBI, the Canadian Institutes of Health Research, and others (see the support statement at the end of the article). In addition, Baxter Healthcare provided the trial drugs without cost and tested the stability of these products over the trial duration but otherwise played no role in the trial. The investigators designed and conducted the trial; gathered, analyzed, and interpreted the data; wrote the manuscript draft (the first author); and made the decision to submit it for publication. The trial statisticians had full access to all trial data and take responsibility for their integrity, analytic accuracy, and completeness and for the fidelity of this report to the trial protocol, which is available with the full text of this article at NEJM.org.

Patients

The trial included patients 18 years of age or older with nontraumatic out-of-hospital cardiac arrest and shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, defined as confirmed persistent (nonterminating) or recurrent (restarting after successful termination) ventricular fibrillation or pulseless ventricular tachycardia after one or more shocks anytime during resuscitation (inclusive of rhythms interpreted as being shockable by an automated external defibrillator). Eligible patients were also required to have intravenous or intraosseous vascular access. We excluded patients who had already received open-label intravenous lidocaine or amiodarone during resuscitation or had known hypersensitivity to these drugs. A complete list of trial inclusion and exclusion criteria is provided in the Supplementary Appendix, available at NEJM.org.

The trial protocol specified that the primary analysis population (the per-protocol population) would include only those randomly assigned participants who actually met the eligibility criteria, who received any dose of a trial drug during shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, and who were confirmed to have an initial (rather than secondary) cardiac-arrest rhythm of ventricular fibrillation or pulseless ventricular tachycardia. Analyses were also performed in all randomly assigned patients (the intention-to-treat population).

Interventions

The trial evaluated licensed parenteral preparations of lidocaine, normal saline and a recently approved Captisol-based formulation of amiodarone (Nexterone, Baxter Healthcare) that is designed to reduce hypotensive effects.11,12 Trial drugs were packaged in identically appearing, sealed kits each having three identically formulated syringes. Each syringe held 3 ml of colorless fluid containing 150 mg of amiodarone (totaling 450 mg in the amiodarone kit), 60 mg of lidocaine (180 mg in the lidocaine kit), or normal saline. Kits and their syringe contents were indistinguishable except by numerical code and were randomly distributed to EMS providers in a ratio of 1:1:1. Randomization was performed in permuted blocks of concealed size and was stratified according to participating site and agency. Trial drugs were tested regularly for stability and were confirmed to maintain their integrity in the simulated climates of trial communities.9

Treatment Protocol

Patients with out-of-hospital cardiac arrest were treated in accordance with local EMS protocols that complied with American Heart Association (AHA) guidelines for advanced life support.13 Some patients were coenrolled in a concurrent trial comparing continuous chest compressions with interrupted chest compressions during cardiopulmonary resuscitation (CPR).14

After the failure of one or more shocks to terminate ventricular fibrillation or pulseless ventricular tachycardia or prevent its recurrence, eligible patients received a vasopressor and were then enrolled in the trial by the EMS personnel’s act of opening a trial-drug kit whose masked contents (amiodarone, lidocaine, or placebo) determined the patient’s random assignment (details are provided in the Supplementary Appendix). Patients, investigators, and trial personnel were unaware of the trial-drug assignments. The initial dose of a trial drug, approximating current clinical practice, consisted of two syringes (one syringe if the estimated body weight was <100 lb [45.4 kg]) that were administered by rapid bolus.10,15,16 If ventricular fibrillation or pulseless ventricular tachycardia persisted after the initial dose of the trial drug, standard resuscitation measures, and additional shocks, a supplemental dose (one syringe) of the same drug was administered. Thereafter, standard interventions for advanced life support ensued according to local practice, excluding open-label lidocaine or amiodarone before hospitalization.

Post–Cardiac Arrest Care

All trial interventions were completed before hospital arrival. On arrival, hospital care providers were notified of the patient’s enrollment in the trial and encouraged to provide usual post–cardiac arrest care in accordance with published AHA guidelines,17 including open-label amiodarone or lidocaine if necessary. Components of hospital care were monitored but were not standardized by the trial protocol, and their performance was reported back to hospitals periodically. A patient’s trial-drug assignment was not disclosed to care providers, investigators, or site personnel unless emergency unblinding was requested, and then only to the treating physicians.

Data Collection and Outcomes

Data from prehospital patient care records, CPR-process measures, and data from hospital medical records were collected as described in the Supplementary Appendix. The primary outcome of the trial was survival to hospital discharge. The main aim was to compare survival in amiodarone recipients versus placebo recipients, with secondary comparisons of survival in lidocaine recipients versus placebo recipients and in amiodarone recipients versus lidocaine recipients. The secondary outcome was survival with favorable neurologic status at discharge, defined as a score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) of 3 or less, indicating the ability to conduct daily activities independently or with minimal assistance.18 These outcomes were determined in both the per-protocol population (the primary analysis) and in the intention-to-treat population.

Mechanistic outcomes that were assessed for exploratory purposes included the number of defibrillation shocks administered after receipt of the trial drug, return of spontaneous circulation at hospital arrival, hospital admission, hospital treatments, and time to withdrawal of life-sustaining treatments. Prespecified subgroups were defined according to status with respect to witnessing of the cardiac arrest (witnessed by EMS, witnessed by bystander, or unwitnessed), receipt of bystander-initiated CPR (yes or no), location of the arrest (public or private), time to trial-drug administration (<15 or ≥15 minutes), route of trial-drug administration (intravenous or intraosseous), treatment group in the concurrent trial of continuous or interrupted chest compressions during CPR, baseline survival rate at the trial site (in quartiles), and EMS drug-administration practice (see the Supplementary Appendix).

Adverse events were considered to be drug-related if they were reported previously with these medications19,20 (e.g., anaphylaxis, thrombophlebitis requiring therapeutic intervention, clinical seizure activity, and bradycardia requiring temporary cardiac pacing) and if they occurred within 24 hours after trial-drug administration. Serious or unexpected adverse events attributable to trial interventions21 and complications related to vascular access were also assessed. Other adverse events such as pulmonary edema, hypotension, or pneumonia, which are common after out-of-hospital cardiac arrest, were monitored but were not considered to be drug-related unless imbalanced between trial groups.

Statistical Analysis

We estimated that a sample size of 3000 in the per-protocol population (1000 patients per group) would provide 90% power to detect an absolute difference of 6.3 percentage points in the rate of survival to hospital discharge between the amiodarone group and the placebo group (29.7% vs. 23.4%). The baseline survival rate was estimated from patients with a first recorded rhythm of ventricular fibrillation or pulseless ventricular tachycardia who received at least two shocks in previous ROC trials.22,23 The projected difference in survival with amiodarone was estimated from a previous trial database7 and was the comparison for which this trial was powered.

Survival was evaluated across groups with the use of the z-test for comparison of binomial proportions with pooled variance, with a one-sided significance level of 0.025 for comparisons between an active drug and placebo (based on the monitoring plan of the trial) and a two-sided significance level of 0.05 when comparing amiodarone with lidocaine.9 All comparisons in this report, including testing interactions, were recalculated as two-sided with P values of less than or equal to 0.05 considered to indicate statistical significance (as most comparisons were initially performed), which did not substantially change the results.

The data and safety monitoring board performed interim reviews twice a year with the use of group sequential methods with formal stopping boundaries; final differences and 95% confidence intervals for the primary outcome were adjusted accordingly.9 Apart from this, there were no adjustments for multiple comparisons.