Trial Design and Oversight

From December 2014 through October 2017, the multicenter, randomized, double-blind, placebo-controlled PARAMEDIC2 trial was conducted by five National Health Service ambulance services in the United Kingdom. The trial protocol (available with the full text of this article at NEJM.org) was developed by the investigators and has been published previously.12 The South Central–Oxford C Research Ethics Committee and the Medicines and Healthcare Products Regulatory Authority approved the protocol. The trial was designed and conducted in accordance with Directive 2001/20/EC of the European Parliament and Council, which was transposed into legislation in the United Kingdom by the Medicines for Human Use (Clinical Trials) Regulations.

Because of the sudden and life-threatening nature of cardiac arrest, and in accordance with European legislation, the process of obtaining written informed consent was deferred until after the emergency had passed. We sought written informed consent to continue data collection after resuscitation from the patient or, if the patient lacked capacity, a legal representative. Additional details regarding the informed-consent process and patient and public involvement in the trial are provided in the Supplementary Appendix, available at NEJM.org.

The trial was funded by the Health Technology Assessment Programme of the National Institute for Health Research, with legal sponsorship provided by the University of Warwick. The funders had no role in the trial design, in the collection or analysis of the data, or in the writing of the manuscript. The Warwick Clinical Trials Unit undertook data management. The trial statisticians had full access to all the data and assume responsibility for the integrity of the data, the completeness and accuracy of the data and analysis, and the fidelity of the trial to the protocol.

Patient Population

Adult patients who had sustained an out-of-hospital cardiac arrest for which advanced life support was provided by trial-trained paramedics were eligible for inclusion. Criteria for exclusion were known or apparent pregnancy, an age of less than 16 years, cardiac arrest from anaphylaxis or asthma, or the administration of epinephrine before the arrival of the trial-trained paramedic. In one ambulance service, traumatic cardiac arrests were also excluded in accordance with local protocols.

Randomization and Treatment

Paramedic resuscitation protocols as outlined in the European Resuscitation Council Guidelines are described in the Supplementary Appendix.13 If initial attempts at resuscitation (CPR and defibrillation) were unsuccessful, the patient was randomly assigned to receive either parenteral epinephrine or saline placebo by the opening of a trial pack containing either agent. Uniquely numbered but otherwise identical-appearing trial packs contained 10 prefilled syringes, with each syringe containing either 1 mg of epinephrine or 0.9% saline. Single doses of epinephrine or saline were administered by an intravenous or intraosseous route every 3 to 5 minutes. The programming team at the Warwick Clinical Trials Unit provided randomization with concealed assignment. A randomization sequence was computer-generated by the minimization method with an overall assignment ratio of 1:1.

Ambulance services entered data into a secure electronic portal. Data definitions followed the Utstein recommendations.14 Data regarding the quality of the CPR results were obtained with the use of defibrillator downloads when available (Physiocontrol). Treatments were continued until a sustained pulse was achieved, resuscitation was discontinued, or care was handed over to clinicians in the hospital. Hospital-based care was not specified in the trial protocol but was informed by national guidelines, which covered targeted temperature management, hemodynamic and ventilatory criteria, and prognostication, as described in the Supplementary Appendix.15

Primary and Secondary Outcomes

The primary outcome was the rate of survival at 30 days. The secondary outcomes were the rate of survival until hospital admission, the lengths of stay in the hospital and in the intensive care unit (ICU), the rates of survival at hospital discharge and at 3 months, and the neurologic outcomes at hospital discharge and at 3 months. We defined survival with a favorable neurologic outcome as a score of 3 or less on the modified Rankin scale (which ranges from 0 [no symptoms] to 6 [death]).16 Outcomes were assessed by research paramedics, who were unaware of treatment assignments. We recorded serious adverse events (death, hospitalization, and disability) as trial outcomes. Other adverse events were reported directly to the trial office.

Statistical Analysis

We determined that the enrollment of 8000 patients would provide the best threshold to balance precision and practicality. With this target sample size, if the risk ratio for the epinephrine group was estimated to be 1.25, the corresponding 95% confidence interval would range from 1.07 to 1.46. A risk ratio of 1.25 corresponds to a rate of 30-day survival of 6.0% in the placebo group and 7.5% in the epinephrine group. Further information regarding the sample-size calculations is provided in the Supplementary Appendix.

The data and safety monitoring committee performed interim reviews every 3 months. We used the Lan–DeMets, O’Brien–Fleming, and Pocock alpha spending methods to determine the upper and lower stopping boundaries for the primary outcome, with no adjustment in the final analysis.

The primary analysis was performed without adjustment in the modified intention-to-treat population, which included all the patients who had undergone randomization and were confirmed to have received the assigned intervention. Trial data were summarized by the calculation of means and standard deviations for normally distributed variables, medians and interquartile ranges for non-normally distributed variables, and frequency and percentage for categorical variables.

Survival outcomes were analyzed with the use of fixed-effect regression models with and without adjustment for age, sex, the interval between the emergency call and the ambulance arrival at the scene, the interval between the ambulance arrival and the administration of a trial agent, the cause of cardiac arrest, the initial cardiac rhythm, whether the cardiac arrest was witnessed, and whether CPR was performed by a bystander. The Hodges–Lehmann method was used to estimate median differences with 95% confidence intervals for length-of-stay outcomes. In cases in which the proportional odds assumption was violated in modeling of the score on the modified Rankin scale, partial proportional odds models were used. Scores on the modified Rankin scale were also analyzed as a binary outcome (with scores of 0 to 3 classified as “good” and scores of 4 to 6 classified as “poor”). Unadjusted and adjusted odds ratios with 95% confidence intervals and mean differences with 95% confidence intervals were reported for categorical and continuous outcomes, respectively. The number needed to treat and its 95% confidence interval were calculated for survival at 30 days. To aid in interpretation, we included a Bayesian analysis for the primary outcome and for survival with a favorable neurologic outcome.

Prespecified subgroup analyses included the patient’s age, cause of cardiac arrest, initial cardiac rhythm, whether the cardiac arrest was witnessed, whether CPR was performed by a bystander, interval between the emergency call and ambulance arrival at the scene, interval between ambulance arrival and the trial-agent administration, and the interval between the emergency call and trial-agent administration. A P value for interaction was reported in each analysis. Post hoc sensitivity analyses (which incorporated best-case and worst-case scenarios and multiple imputation) were conducted for survival at 30 days, survival at hospital discharge, and survival with a good neurologic outcome at discharge. All statistical analyses were performed with the use of SAS software, version 9.4 (SAS Institute), and RStan.