Abstract
Background
There is a lack of evidence regarding which defibrillation strategy is the most effective during resuscitation. Anterior-posterior pad placement and double sequential defibrillation have been proposed as alternatives to standard anterior-lateral defibrillation for patients with refractory shockable rhythms, but evidence remains limited.
Objective
This trial will investigate whether there is a difference in 30-day survival when using anterior-posterior and double sequential defibrillation as compared to standard anterior-lateral defibrillation in adults with out-of-hospital cardiac arrest and a shockable rhythm.
Methods
This trial is an investigator-initiated, individually randomised, 3-group, clinical trial enrolling adult patients with out-of-hospital cardiac arrest with at least one emergency medical services defibrillation attempt and if the last known rhythm is shockable and two manual defibrillators are available. Participants are randomised 1:1:1 to anterior-lateral defibrillation, anterior-posterior defibrillation, or double sequential defibrillation. The trial is planned to be conducted in Denmark, Finland, Belgium, and Ireland.
The primary outcome is 30-day survival, with key secondary outcomes of 90-day survival and neurological status at 30 and 90-days assessed using the modified Rankin Scale. Additional outcomes include return of spontaneous circulation, hospital disposition, health-related quality of life, and longer-term survival and neurological outcomes.
The planned sample size is 909 participants. Enrollment began in March 2025. 320 patients have been enrolled by September 2026. The trial is registered at ClinicalTrials.gov (identifier: NCT06781892).
Keywords: Out-of-hospital cardiac arrest, Cardiopulmonary resuscitation, Defibrillation, Shockable rhythms, Double sequential defibrillation, Anterior-posterior pad positioning, Randomised controlled trial
Introduction
Out-of-hospital cardiac arrest (OHCA) occurs in an estimated 4 million people each year globally of which approximately 275.000 are in Denmark.1, 2 OHCA is a detrimental condition with only approximately 7.5%% of the patients being alive after 30 days in Denmark. Fifteen to twenty percent of cardiac arrest patients have an initial shockable rhythm (i.e., ventricular fibrillation [VF] or pulseless ventricular tachycardia [pVT]). These patients have higher survival compared to patients with an initial non-shockable rhythm (i.e., asystole or pulseless electrical activity).3 Approximately 75% of patients with a shockable rhythm do not respond to initial defibrillation and these patients are unlikely to survive.4, 5 In our previous trials in Denmark,6, 7 patients with OHCA who received at least one defibrillation attempt by emergency medical services only had a 20% chance of surviving to 30 days.
There is a lack of evidence regarding which defibrillation strategy is the most effective during resuscitation.8 The current 2025 European guidelines recommend that the initial pad placement for adults with cardiac arrest is anterior-lateral.9 An alternative strategy exist where the pad placement is changed from anterior-lateral to anterior-posterior for patients with refractory shockable rhythms. A third option is double sequential defibrillation, where patients are shocked twice in immediate succession with pads placed anterior-lateral and anterior-posterior using two separate defibrillators.
The current evidence regarding these alternative defibrillation strategies are limited. Only one cluster-randomised clinical trial has compared these alternative defibrillation strategies. The Defibrillation Strategies for Refractory Ventricular Fibrillation (DOSE-VF) trial included patients with refractory VF, defined as three failed defibrillation attempts, and compared anterior-lateral positioning (the standard approach) with anterior-posterior positioning, and double sequential defibrillation. The trial found improved survival to hospital discharge with the two alternative strategies.10 Due to methodological limitations, the trial’s results led to a weak treatment recommendation by the International Liaison Committee on Resuscitation, stating that the alternative defibrillation strategies may be considered for patients with refractory shockable rhythms (weak recommendation, low certainty of evidence). The European Resuscitation Council have suggested against the routine use of double sequential defibrillation.9
To address the knowledge gap regarding the efficacy of alternative defibrillation strategies during cardiac arrest, we are presently conducting a randomised, clinical trial investigating defibrillation strategies during OHCA; the Strategies for Defibrillation during Out-of-Hospital Cardiac Arrest trial (STRAT-DEFI). This trial will investigate whether there is a difference in survival and survival with a favourable neurological outcome when using anterior-posterior and double sequential defibrillation as compared to standard anterior-lateral defibrillation in adults with OHCA and a shockable rhythm.
Methods
Overview
This paper presents the methodological details of the STRAT-DEFI trial. The trial is an investigator-initiated, individually randomised, 3-group, clinical trial comparing standard anterior-lateral pad positioning with anterior-posterior positioning and double sequential defibrillation during adult out-of-hospital cardiac arrest. The trial is planned to be conducted in Denmark, Finland, Belgium, and Ireland. The trial flowchart provides a quick overview of trial enrollment (Fig. 1).
Fig. 1.
Trial flow chart.
Setting
All participating countries use a multi-unit response to cardiac arrest. This typically includes a primary ambulance and a paramedic-manned rapid response vehicle or a physician-manned unit (car or helicopter). This setup ensures that two manual defibrillators are present on scene, making it possible to perform double sequential defibrillation. All participating countries use anterior-lateral as the initial standard pad placement.
Patients will be eligible for inclusion if they have an out-of-hospital cardiac arrest, are aged 18 years or older, have received at least one defibrillation attempt by emergency medical services, have a shockable rhythm as the last known rhythm, and have two manual defibrillators present on site.
Inclusion criteria
-
(1)
Out-of-hospital cardiac arrest.
-
(2)
Age ≥ 18 years.
-
(3)
≥1 defibrillation attempt by emergency medical services.
-
(4)
Shockable rhythm as the last known rhythm.
-
(5)
Two manual defibrillators present on-site.
Exclusion criteria
-
(1)
Blunt trauma, penetrating trauma, or burn injury suspected to be the cause of the cardiac arrest.
-
(2)
Prior enrollment in the trial.
-
(3)
Posterior pad placement not deemed possible by on-site clinician.
The posterior pad placement in both the anterior-posterior and the double sequential defibrillation arm of the trial, requires that the patient is turned or rotated. This may be impossible, e.g. due to patient size, location of the cardiac arrest, or lack of available personnel. If this is the case prior to randomisation, the patients will not be included. Patients will not be excluded if this is determined after randomization.
Randomisation and blinding
Randomisation will occur on-scene once the patient is eligible by opening an opaque randomisation envelope. A note inside the envelope contains the unique trial identification number along with the allocation (anterior-lateral, anterior-posterior, or double sequential defibrillation). The clinical team will then prepare the allocated defibrillation method, ideally before the next rhythm check.
The randomisation envelopes will be prepared and packed by personnel independent of the trial. The randomised allocation list is created using a random number generator, with allocation in a 1:1:1 ratio using blocks of 12, stratified by country.
As the intervention requires a change in pad placement and defibrillation procedures during active resuscitation, the clinicians delivering the intervention cannot be blinded. Patients and outcome assessors conducting long-term follow-up interviews will be blinded.
Interventions and comparator
Comparator: Anterior-lateral pad placement
At time of randomisation, pads will be placed in the anterior-lateral position, as this is the current standard of care. Patients randomised to anterior-lateral pad placement must adhere to this strategy for all defibrillation attempts.
Intervention 1: Anterior-posterior pad placement
As soon as possible after randomisation, a new set of pads will be placed in the anterior-posterior position. The anterior pad will be placed to the left of the sternum. The posterior pad should be placed to the left of the thoracic spine and below the spine of the scapula. After correct pad placement, all subsequent defibrillation attempts, including any prehospital re-arrest after return of spontaneous circulation, should use the anterior-posterior pad placement.
Intervention 2: Double sequential defibrillation
Participants allocated to double sequential defibrillation will have a second set of pads placed in the anterior-posterior position in addition to the initial anterior-lateral pads. Both defibrillators are operated by the same clinician, delivering both shocks separately but sequentially, ideally as close together as possible. The order of triggering is not protocolised. After pad placement, all subsequent defibrillation attempts should use double sequential defibrillation. If it is not possible to transport the patient with two defibrillators, additional defibrillation attempts will be performed using the anterior-posterior pad placement.
All pad placements are shown in Fig. 2.
Fig. 2.
Defibrillator pad placements (created withBioRender.com).
Prior to patient enrollment and throughout the enrollment period, participating clinicians are educated about the trial, including its background, objectives, eligibility criteria, interventions, and trial specific procedures. Training includes demonstration of the correct intervention procedures and in-person simulation training will be provided when feasible.
Outcomes
The primary outcome is 30-day survival after cardiac arrest as it is regarded as a meaningful outcome by both clinicians and patients. This measure is linked to long-term survival as the majority of 30-day survivors are expected to present a favourable functional outcome at one-year follow-up.11
Key secondary outcomes include survival at 90 days and neurological outcome at 30 and 90 days. Neurological outcome will be assessed with the modified Rankin Scale, reported both across the full 0–6 scale and as a dichotomised outcome of favourable (0–3) versus unfavourable (4–6).
Other outcomes include any return of spontaneous circulation, return of spontaneous circulation at hospital arrival, sustained return of spontaneous circulation, hospital disposition, and health-related quality of life measured with the Euro-Qol five dimensions five levels questionnaire (EQ-5D-5L). Extended follow-up at 180 days and 1 year will collect survival, neurological outcomes, and health-related quality of life. These will be reported separately. Additional outcomes included in the Core Outcome Set for Cardiac Arrest (COSCA)-initiative will also be collected, see Table 1 for an overview.12
Table 1.
Outcomes.
| Outcome | Timepoints |
|---|---|
| Survival | 30 days, 90 days, 180 days, 1 year |
| Modified Rankin scale | 30 days, 90 days, 180 days, 1 year |
| Cerebral performance category | 30 days, 90 days, 180 days, 1 year |
| EQ-5D-5L | 30 days, 90 days, 180 days, 1 year |
| Return of spontaneous circulation | Sustained, any, hospital arrival |
| Hospital disposition | Discharge from an acute care hospital |
Sample size calculation
Estimates used for the sample size calculation are based on data from previous OHCA trials in Denmark6, 7 and the DOSE-VF trial.10 We anticipate that 20% will survive to 30 days in the standard anterior-lateral pad placement group. An alpha of 4.5% for the final analysis was calculated based on the O’Brien-Fleming approach, and two interim analyses, using an overall significance level of 5%. Based on this, a 30-day survival of 30% in the intervention groups (corresponding to a risk ratio of 1.50), and a chi-squared test, we will need 303 patients per group, for a total of 909 patients, to have 80% power to detect a statistically significant difference between either of the intervention groups and the standard group. The trial is not powered to detect a difference between the two intervention groups.
Statistical analysis plan
The trial will primarily be analysed within a frequentist framework. All analyses will, unless noted otherwise, be conducted on a modified intention-to-treat basis including all randomised patients that met all inclusion criteria and no exclusion criteria at the time of randomisation. The patient is considered randomised once the randomisation envelope has been opened. Patients will be analysed according to their assigned group. Participant flow, including screened patients and reasons for non-inclusion or exclusion, will be shown in a CONSORT diagram, and baseline characteristics will be described using descriptive statistics.
Binary outcome variables will be presented as counts and proportions in each group. Differences between groups will be presented as risk ratios and risk differences. To increase power, all models will include adjustment for country stratification and prespecified strong prognostic factors, including age, witnessed status, and early cardiopulmonary resuscitation (bystander cardiopulmonary resuscitation or emergency medical services witnessed arrest).13, 14
Continuous data will be presented as means with standard deviations or medians with first and third quartiles depending on the distribution of the data. Differences between groups in continuous outcomes are presented as mean differences with 95% confidence intervals with adjustment for country stratification and prognostic variables.
The trial will have two interim analyses for the primary outcome as a part of an independent data monitoring committee’s oversight of the trial. The trial will have predefined stopping criteria for benefit and harm based on 30-day survival, but not for futility.
Null-hypothesis significance testing for the primary and key secondary outcomes will be performed in a sequential order such that the subsequent outcome will be tested for statistical significance only if the previous outcome had a P value ≤ 0.045.15 Additional details regarding the statistical analysis plan can be found in the trial protocol (supplemental 1).
Consent and follow-up
The trial is approved through relevant research ethics committees. The trial is investigator initiated and overseen by a steering committee. An independent data-monitoring committee oversees participant safety and the overall conduct of the trial. The decision to include and randomise a patient will be made by the on-scene clinicians. For patients who survive to intensive care unit admission but remain unable to consent, written consent will be sought as soon as possible from legally designated representatives. Procedures for consent vary between participating countries.
A blinded, trained researcher from each study site will assess long-term follow-up through telephone interviews. Neurological outcomes collected during these interviews will include the modified Rankin Scale and the Cerebral Performance Category. Health-related quality of life will be assessed using the EQ-5D-5L questionnaire.
Discussion
Since the start of the trial, the 2025 European Resuscitation Council adult advanced life support guidelines have been published. These guidelines further emphasise the need for additional evidence regarding the efficacy of alternative defibrillation strategies. The STRAT-DEFI trial is cited in these guidelines as a future trial that will help inform recommendations on the use of double sequential defibrillation.9 The population in the STRAT-DEFI trial will differ from the DOSE-VF population. In the DOSE-VF trial the patients were required to have an initial shockable rhythm and three consecutive failed defibrillation attempts. In STRAT-DEFI the patients can be enrolled even if they have an initial non-shockable rhythm, if they receive a shock by emergency medical services at any point during the resuscitation. Furthermore, the patients can be enrolled after just one defibrillation attempt.10
To our knowledge, three other European trials are also investigating alternative defibrillation strategies. All these trials will compare standard defibrillation with anterior-lateral pad placement with double sequential defibrillation. The “Early double sequential defibrillation in out-of-hospital cardiac arrest” trial will enroll patients with an initial shockable rhythm who remain in cardiac arrest after at least one shock (clinicaltrials.gov registration ID: NCT07174986). The “Initial Double Sequential External Defibrillation in Out of Hospital Cardiac Arrest” trial is a cluster randomised trial investigating the effect of double sequential defibrillation for the initial defibrillation attempt (clinicaltrials.gov registration ID: NCT06672159). The “Double sequential external defibrillation in refractory ventricular fibrillation (DOSEVF2)” trial is a cluster randomised trial enrolling patients with an initial shockable rhythm and three consecutive failed defibrillation attempts (German Clinical Trials Register ID: DRKS00032830).
The STRAT-DEFI trial has some potential limitations. The trial will only enroll patients when two defibrillators are present. Some of the procedures in the trial are new to the emergency medical services personnel, and no standardised methods exist for the timing of shocks in double sequential defibrillation. Consequently, a potential effect driven by shock timing might be diminished, due to the lack of standardisation. Procedural outcome data will be registered to ensure that the personnel delivered the allocated intervention. This data will be verified by defibrillator data when available. Finally, the trial is not powered to compare the two intervention groups directly.
Some points of concern have been raised regarding double sequential defibrillation. Potential damage to defibrillators has been a concern based on previous data.16 This damage was only found when delivering the two shocks simultaneously. In the STRAT-DEFI trial, the clinicians are instructed to deliver the shocks in a sequential fashion. We will monitor reports regarding defibrillator damage as well as accidental shocks to personnel and unexpected adverse events.
Secondary analyses from the DOSE-VF trial suggested benefits of the alternative defibrillation strategies both for refractory and recurrent ventricular fibrillation, as well as improved outcomes associated with shorter intervals in the timing of the two shocks in the double sequential defibrillation attempts.17 Data will be collected in the STRAT-DEFI trial to corroborate these findings. For the analysis of ventricular fibrillation subtypes, refractory ventricular fibrillation will be defined as ventricular fibrillation that is not terminated by defibrillation. Recurrent ventricular fibrillation will be defined as ventricular fibrillation that is successfully terminated by defibrillation but subsequently refibrillate before the next rhythm check.
Status
Patient enrollment started in March 2025 in the Central Denmark Region. Since then, all Danish participating sites have initiated enrollment. As of September 2026, 320 patients have been enrolled. During the spring of 2026, patient enrollment also commenced at selected sites in Finland and Belgium. In Ireland, ethical approval for the trial is currently being sought. The trial has been registered at ClinicalTrials.gov (identifier: NCT06781892).
CRediT authorship contribution statement
Bertram Lahn Kirkegaard: Conceptualization, Funding acquisition, Methodology, Project administration, Writing – original draft, Writing – review & editing. Mikael Fink Vallentin: Conceptualization, Funding acquisition, Methodology, Project administration, Writing – review & editing. Carsten Meilandt: Conceptualization, Methodology, Writing – review & editing. Christian Juhl Terkelsen: Conceptualization, Methodology, Writing – review & editing. Allan Bach: Conceptualization, Methodology, Writing – review & editing. Kristian Blumensaadt Winther: Conceptualization, Methodology, Writing – review & editing. Søren Mikkelsen: Conceptualization, Methodology, Writing – review & editing. Helle Collatz Christensen: Conceptualization, Methodology, Writing – review & editing. Steffen Christensen: Conceptualization, Methodology, Writing – review & editing. Thomas Dissing: Conceptualization, Methodology, Writing – review & editing. Thomas Lass Klitgaard: Conceptualization, Methodology, Writing – review & editing. Fredrik Folke: Conceptualization, Methodology, Writing – review & editing. Jacob Steinmetz: Conceptualization, Methodology, Writing – review & editing. Markus B. Skrifvars: Conceptualization, Methodology, Writing – review & editing. Cornelia Genbrugge: Conceptualization, Methodology, Writing – review & editing. Siobhan Masterson: Conceptualization, Methodology, Writing – review & editing. Marko Hoikka: Conceptualization, Methodology, Writing – review & editing. Asger Granfeldt: Conceptualization, Funding acquisition, Methodology, Project administration, Writing – review & editing. Lars W. Andersen: Conceptualization, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review & editing.
Funding
The trial is funded by the Independent Research Fund Denmark, The Novo Nordisk Foundation, and the Danish Heart Foundation. The Finnish sites are partly funded by Sydäntutkimussäätiö (applicant Markus Skrifvars) 2026 and Sigrid Juselius Stiftelse (applicant Markus Skrifvars) 2026–2027. The funding agencies have no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
Declaration of competing interest
Christian Juhl Terkelsen has received teaching honoraria from Edwards Lifesciences and Meril Life Science related to heart valves and from Terumo related to ultrasound, and unrestricted research grants from Meril Life Sciences and Medtronic for studies in patients treated with TAVI. Jacob Steinmetz reports professorship funding from the Norwegian Air Ambulance Foundation. Markus Skrifvars has received speaker fees from BARD Medical (Ireland). Siobhan Masterson is a member of the ILCOR Scientific Advisory Committee. All other steering committee members report no potential conflicts of interest.
Lars Wiuff Andersen and Asger Granfeldt are part of the editorial board of Resusciation Plus.
Footnotes
Supplementary material to this article can be found online at https://doi.org/10.1016/j.resplu.2026.101512.
Appendix A. Supplementary material
The following are the Supplementary material to this article:
Trial Protocol
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol