Study Design and Oversight

A detailed description of the design of the trial has been published previously.10 The trial was conducted by the Resuscitation Outcomes Consortium (ROC). This network includes 10 clinical sites in North America that have experience conducting randomized trials involving patients with out-of-hospital cardiac arrest; the network also includes the regional EMS agencies associated with these sites and a central coordinating center in Seattle.11-13 Eight ROC sites and 114 EMS agencies participated in this trial (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Applicable institutional review boards approved the conduct of this study; the requirement for informed consent was waived because the study involved research in emergency medicine. Patients or their legally authorized representatives were informed of participation after the event.

The trial was sponsored by the National Heart, Lung, and Blood Institute, the Canadian Institutes of Health Research, and others (see the Supplementary Appendix). The investigators, including two authors who are employees of the National Institutes of Health, designed and conducted the study, analyzed the data, interpreted the results, wrote the manuscript, and made the decision to submit the manuscript for publication. The trial statisticians had full access to all the data in the study and take responsibility for the integrity of the data, the completeness and accuracy of the data and analyses, and the fidelity of this report to the trial protocol, available at NEJM.org.

Patient Population

The trial included adults with non–trauma-related out-of-hospital cardiac arrest who received chest compressions performed by providers from participating EMS agencies who were dispatched to the scene. Patients were excluded if they had an EMS-witnessed arrest, a written advance directive to not resuscitate, a traumatic injury, an asphyxial cause of arrest, uncontrolled bleeding or exsanguination, known pregnancy, or preexisting tracheostomy; were known to be prisoners; had initial CPR performed by a nonparticipating EMS provider; were treated with a mechanical chest-compression device before manual CPR by ROC EMS personnel; had advanced airway management before ROC EMS agency arrival; or had, a priori, opted not to participate in resuscitation research. Some patients were co-enrolled in a trial of antiarrhythmic therapy for recurrent ventricular fibrillation.14

Study Interventions

The trial used cluster randomization with crossovers. The 114 participating EMS agencies across the eight participating ROC sites were grouped into 47 clusters. Clusters of agencies were randomly assigned, in a 1:1 ratio, to perform continuous chest compressions or interrupted chest compressions during all the out-of-hospital cardiac arrests to which they responded. Twice per year, each cluster was crossed over to the other resuscitation strategy. The pattern of randomized cluster assignments is shown in Figure S1 in the Supplementary Appendix.

The trial required each cluster of EMS agencies to begin by enrolling patients in a run-in phase to demonstrate adherence to the protocol. Once a cluster demonstrated proficiency with the given treatment by meeting prespecified performance and compliance benchmarks as determined by an internal study monitoring committee, they were entered into the active-enrollment phase. Benchmarks included adherence to randomized treatment-group assignment, timeliness and completion of data entry, and availability of CPR-process measures recorded by the monitor–defibrillator. Details of the randomization and run-in procedures are provided in the Supplementary Appendix.

Patients assigned to the group that received continuous chest compressions (intervention group) were to receive continuous chest compressions at a rate of 100 compressions per minute, with asynchronous positive-pressure ventilations delivered at a rate of 10 ventilations per minute. Patients assigned to the group that received interrupted chest compressions (control group) were to receive compressions that were interrupted for ventilations at a ratio of 30 compressions to two ventilations; ventilations were to be given with positive pressure during a pause in compressions of less than 5 seconds in duration. Details of the CPR protocol, airway management, and use of pressors are provided in the Supplementary Appendix text and in Figures S2 and S3 in the Supplementary Appendix. Hospital-based care, including targeted temperature management, was monitored but was not standardized in this trial.

CPR-Process Monitoring

Study sites were required to acquire and report CPR-process data before beginning enrollment and throughout the trial period. Process data were measured by commercially available monitor–defibrillators during attempted resuscitation. Study-site coordinators were instructed to audit these data for accuracy. In addition, an internal study monitoring committee, whose members were unaware of the treatment outcomes, periodically reviewed these data. Their goal was to assess whether prespecified targets for performance were met for measures such as enrollment rate, treatment-adherence rate, and key elements of concurrent care and then to make recommendations regarding steps to be implemented to increase these rates.10 Details are provided in the Supplementary Appendix.

Outcomes

The primary outcome was the rate of survival to hospital discharge. Secondary outcomes included neurologic function at discharge, which was measured with the use of the modified Rankin scale (scores range from 0, indicating no symptoms, to 6, indicating death, with a score of ≤3 indicating favorable neurologic function) on the basis of review of the clinical record, and adverse events. Hospital-free survival was defined as the number of days alive and permanently out of the hospital during the first 30 days after the cardiac arrest. Other outcomes were collected for descriptive purposes. Detailed descriptions of the study outcomes are provided in the Supplementary Appendix.

Statistical Analysis

We estimated that 23,600 patients (11,800 patients per group) would need to be enrolled for the study to have 90% power to detect a rate of survival to discharge of 8.1% in the control group versus 9.4% in the intervention group, at an overall two-sided alpha level of 0.05. The estimated survival rate in the control group was based on data from the ROC Prehospital Resuscitation Impedance Valve and Early versus Delayed Analysis (ROC PRIMED) trial.12,13

The effectiveness population included all the patients who received the randomly assigned treatment during the active-enrollment phase of the study. The safety population included all the patients who received the randomly assigned treatment during either the run-in phase or the active-enrollment phase. The primary test of the null hypothesis used a difference in event rates divided by the estimated robust standard errors that were based on the Huber–White sandwich estimator.15,16 The 95% confidence intervals were calculated with adjustment for interim analyses. The comparisons of the treatment groups with respect to the distribution of the secondary outcomes used robust standard errors but were not adjusted for interim analyses. An independent data and safety monitoring board monitored trial progress and safety with the use of formal stopping boundaries; interim analyses were performed every 6 months.

The effect of treatment on the primary and secondary outcomes within subgroups that were defined according to the presence or absence of prognostic factors was examined separately, as detailed in the Supplementary Appendix. Tests for interaction were performed. The effect of treatment was also examined in two per-protocol analyses in per-protocol populations that were defined on the basis of CPR-process data. The first per-protocol analysis used an automated algorithm to define adherence to CPR process (Table S1 in the Supplementary Appendix), and the second was based on the assessment of CPR-process data by the research coordinator. In addition, multiple hot-deck imputation was used to account for missing vital-status data at discharge.17 Further details regarding the statistical analyses are provided in the Supplementary Appendix.