Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial

Summary

Background

Among patients with out-of-hospital cardiac arrest (OHCA) and ventricular fibrillation, more than half present with refractory ventricular fibrillation unresponsive to initial standard advanced cardiac life support (ACLS) treatment. We did the first randomised clinical trial in the USA of extracorporeal membrane oxygenation (ECMO)-facilitated resuscitation versus standard ACLS treatment in patients with OHCA and refractory ventricular fibrillation.

Methods

For this phase 2, single centre, open-label, adaptive, safety and efficacy randomised clinical trial, we included adults aged 18–75 years presenting to the University of Minnesota Medical Center (MN, USA) with OHCA and refractory ventricular fibrillation, no return of spontaneous circulation after three shocks, automated cardiopulmonary resuscitation with a Lund University Cardiac Arrest System, and estimated transfer time shorter than 30 min. Patients were randomly assigned to early ECMO-facilitated resuscitation or standard ACLS treatment on hospital arrival by use of a secure schedule generated with permuted blocks of randomly varying block sizes. Allocation concealment was achieved by use of a randomisation schedule that required scratching off an opaque layer to reveal assignment. The primary outcome was survival to hospital discharge. Secondary outcomes were safety, survival, and functional assessment at hospital discharge and at 3 months and 6 months after discharge. All analyses were done on an intention-to-treat basis. The study qualified for exception from informed consent (21 Code of Federal Regulations 50.24). The ARREST trial is registered with ClinicalTrials.gov, NCT03880565.

Findings

Between Aug 8, 2019, and June 14, 2020, 36 patients were assessed for inclusion. After exclusion of six patients, 30 were randomly assigned to standard ACLS treatment (n=15) or to early ECMO-facilitated resuscitation (n=15). One patient in the ECMO-facilitated resuscitation group withdrew from the study before discharge. The mean age was 59 years (range 36–73), and 25 (83%) of 30 patients were men. Survival to hospital discharge was observed in one (7%) of 15 patients (95% credible interval 1·6–30·2) in the standard ACLS treatment group versus six (43%) of 14 patients (21·3–67·7) in the early ECMO-facilitated resuscitation group (risk difference 36·2%, 3·7–59·2; posterior probability of ECMO superiority 0·9861). The study was terminated at the first preplanned interim analysis by the National Heart, Lung, and Blood Institute after unanimous recommendation from the Data Safety Monitoring Board after enrolling 30 patients because the posterior probability of ECMO superiority exceeded the prespecified monitoring boundary. Cumulative 6-month survival was significantly better in the early ECMO group than in the standard ACLS group. No unanticipated serious adverse events were observed.

Interpretation

Early ECMO-facilitated resuscitation for patients with OHCA and refractory ventricular fibrillation significantly improved survival to hospital discharge compared with standard ACLS treatment.

Funding

National Heart, Lung, and Blood Institute.

Introduction

Out-of-hospital cardiac arrest (OHCA) is responsible for more than 350 000 deaths each year in North America.1, 2 A large proportion (60–80%) of patients surviving OHCA present with an initial shockable rhythm (ventricular fibrillation).1, 2 However, even in this population that is most frequently resuscitated, half of patients with OHCA and ventricular fibrillation present with refractory ventricular fibrillation unresponsive to initial standard treatment, and thus have a poor prognosis. Among patients requiring more than 40 min of cardiopulmonary resuscitation almost all die.3, 4, 5 Most patients (70–85%) presenting with OHCA and refractory ventricular fibrillation (defined as failure of at least three shocks to establish return of spontaneous circulation [ROSC]) have coronary artery disease which, combined with poor perfusion during cardiopulmonary resuscitation, renders prolonged, standard, advanced cardiac life support (ACLS) ineffective.2, 6, 7

Research in context

Evidence before this study

Survival from cardiac arrest has remained poor for decades. Refractory cardiac arrest is the most time-sensitive emergency and leads to death unless it can be reversed in a timely manner. Patients presenting with long resuscitation times, requiring cardiopulmonary resuscitation for longer than 30–40 min, essentially have no chance to survive with standard advanced cardiac life support (ACLS). This has been documented in multiple observational cohorts in the USA, Europe, and Japan. Over the past 5 years, several observational cohort studies have been published. Those studies assessed extracorporeal cardiopulmonary resuscitation, using peripheral extracorporeal membrane oxygenation (ECMO) devices, as a way to resuscitate and provide cardiopulmonary support in patients that did not have prompt return of spontaneous circulation. Most of those studies have shown promise and suggested an increase in survival for patients with refractory cardiac arrest. This was especially true for those patients presenting initially with a shockable rhythm. Other studies showed small or no effect on survival. No literature search was done because this subject has been extensively investigated and recently reported in a scientific statement from the American Heart Association about the role of the cardiac catheterisation laboratory in out-of-hospital cardiac arrest and in a statement by the Society of Cardiac Angiography and Interventions, in both of which DY had a contributing role.

Added value of this study

To our knowledge, the ARREST trial is the first randomised interventional trial to assess the effect of early ECMO-facilitated resuscitation compared with standard ACLS treatment for survival of patients with out-of-hospital refractory cardiac arrest. The results showed that, in a well organised and experienced system, survival for patients with refractory cardiac arrest can be significantly increased by the early implementation of ECMO. The results were materialised in a high-volume resuscitation centre that used interventional cardiologists as the lead resuscitators in the ECMO group, with technical expertise that is not widely available. The results also reflect a community based, systematic restructuring of the emergency medical service response for these patients that facilitated early transport and prompt activation and deployment of the ECMO team within 20 min of the prehospital 911 call.

Implications of all the available evidence

The ARREST trial, being a single centre trial, shows what it might be possible but does not definitively answer the question of whether this can be widely implemented. Reassuringly, the results of the ARREST trial accord with multiple cohorts. This suggests that the observed results might be replicated in other programmes. A definitive answer on this subject will require a multicentre phase 3 trial, but only after programmes have matured and restructured the systemic responses to these patients. A blue print of a community-wide programme expansion is provided in an accompanying paper published separately.

The Cardiovascular Division of The University of Minnesota (Minneapolis, MN, USA), in collaboration with three emergency medical services systems established an early veno-arterial extracorporeal membrane oxygenation (ECMO)-facilitated resuscitation protocol for OHCA and refractory ventricular fibrillation in the USA.3, 6, 8, 9 Preliminary data suggested that survival could be improved by early transport from the field and expedited access to the cardiac catheterisation laboratory for ECMO-facilitated resuscitation. At the same time, programmes around the world have increased the use of ECMO-facilitated resuscitation without direct evidence that this expensive and resource-intensive therapeutic strategy increases survival. The purpose of the ARREST trial was to compare survival to hospital discharge between two standards of care in our community, after arrival at the hospital: emergency department-based standard ACLS resuscitation versus early ECMO-facilitated resuscitation.