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Foundational Trials

ARREST

Yannopoulos D, Bartos JA, Raveendran G, Walser E, Connett J, Murray TA, et al. 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. Lancet. 2020;396(10265):1807-1816

Image: Shutterstock / ChaNaWiT

Publication

  • Title: 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
  • Acronym: ARREST
  • Year: 2020 (published online 13 Nov)
  • Journal published in: The Lancet
  • Citation: Yannopoulos D, Bartos JA, Raveendran G, Walser E, Connett J, Murray TA, et al. 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. Lancet. 2020; published online 13 Nov.

Context & Rationale

  • Background
    • Adults with out-of-hospital cardiac arrest (OHCA) and persistent shockable rhythms after multiple defibrillations have very low survival with conventional advanced cardiac life support (ACLS).
    • Extracorporeal cardiopulmonary resuscitation (ECPR; typically VA-ECMO) plus immediate coronary angiography/PCI had shown promising outcomes in observational cohorts, but confounding by selection and system factors limited causal inference.
    • Key uncertainties included whether a protocolised “ECMO-facilitated resuscitation” strategy improves hard outcomes versus best conventional resuscitation, and whether benefits persist with acceptable neurological recovery.
  • Research Question/Hypothesis
    • In adults with refractory ventricular fibrillation/pulseless VT OHCA meeting strict transport and device criteria, does early ECMO-facilitated resuscitation (including immediate catheterisation laboratory management and reperfusion) increase survival to hospital discharge compared with continued standard ACLS?
  • Why This Matters
    • If effective, the intervention implies a system-of-care redesign (prehospital triage, mechanical CPR, rapid transport, 24/7 cath lab + ECMO team) rather than a simple bedside “add-on”.
    • Positive findings would justify expansion of ECPR programmes for selected refractory shockable OHCA; negative findings would argue against high-cost, high-risk escalation without clearer benefit.

Design & Methods

  • Research Question: Among adults (18–75 years) with refractory VF/VT OHCA treated under a protocolised prehospital pathway, does early ECMO-facilitated resuscitation improve survival to hospital discharge compared with standard ACLS?
  • Study Type: Phase 2, single-centre, open-label, pragmatic, randomised controlled trial with a hybrid Bayesian group-sequential design and response-adaptive randomisation (initial cohort randomised 1:1); emergency department + catheterisation laboratory setting within an integrated regional EMS system.
  • Population:
    • Setting: Out-of-hospital arrests triaged by EMS and transported to an ECMO-capable centre; randomisation occurred on hospital arrival.
    • Key inclusion criteria: Age 18–75 years; refractory VF/VT (ongoing VF/VT after 3 defibrillations); no sustained ROSC; automated mechanical CPR device in use; estimated transport time <30 minutes.
    • Key exclusion criteria (as applied in screening): Non-shockable rhythm (PEA/asystole); sustained ROSC achieved within the first 3 shocks; estimated transport time >30 minutes; no automated mechanical CPR.
    • Screening yield: 36 assessed; 6 excluded before randomisation due to protocol misclassification (2 PEA; 1 transport time 48 minutes; 3 sustained ROSC after the second shock).
  • Intervention:
    • Early ECMO-facilitated resuscitation strategy: Immediate transfer to the catheterisation laboratory for invasive management.
    • VA-ECMO: Rapid initiation of VA-ECMO where indicated/feasible; in the trial, VA-ECMO was initiated in 12/15 (80%).
    • Coronary strategy: Coronary angiography (and PCI where indicated) integrated with ECMO-facilitated resuscitation; in the trial, angiography was performed in 13/15 (87%).
    • Post-resuscitation care: Protocolised intensive care management with blinded functional outcome assessment at discharge, 3 months, and 6 months.
  • Comparison:
    • Standard ACLS strategy: Continued conventional resuscitation in the emergency department without VA-ECMO capability (0/15 received VA-ECMO).
    • Rescue pathway after ROSC: Patients who achieved ROSC could proceed to standard post-arrest care and invasive coronary management as clinically indicated (2/15 achieved ROSC and were transferred to the catheterisation laboratory).
  • Blinding: Open-label treatment assignment after randomisation; emergency teams were masked before randomisation; critical care team was masked to randomisation status; functional assessments were performed by blinded evaluators.
  • Statistics: Simulated design targeted survival probabilities of 0.37 (early ECMO) vs 0.12 (standard ACLS), with ~5% type I error and 90% power; maximum sample size 150 evaluable outcomes (planned randomisation up to 174 to account for withdrawals/false positives); primary analysis used a Bayesian beta-binomial model (weakly informative Beta[0.1,0.1] prior) and intention-to-treat principles (primary outcome available for 29/30 due to one withdrawal).
  • Follow-Up Period: Survival to hospital discharge (primary) and survival/functional status to 3 and 6 months.

Key Results

This trial was stopped early. Terminated by the data and safety monitoring board after the first interim analysis of 30 randomised participants because the early ECMO strategy met the prespecified stopping rule for efficacy (posterior probability of benefit 0.9861 for survival to discharge).

Outcome Early ECMO strategy Standard ACLS Effect p value / 95% CI Notes
Survival to hospital discharge (primary) 6/14 (43%; 95% CI 21.3 to 67.7) 1/15 (7%; 95% CI 1.0 to 31.4) Risk difference 36.2% 95% credible interval 3.7 to 59.2; posterior probability=0.9861 Primary outcome obtained in 29/30 (one early-ECMO patient withdrew on day 3).
Survival to 3 months 6/14 (43%; 95% CI 21.3 to 67.7) 0/15 (0%; 95% CI 0.0 to 20.4) Not reported P=0.0063 No survivors in the standard ACLS arm beyond discharge except one in-hospital survivor (CPC 4, mRS 5).
Survival to 6 months 6/14 (43%; 95% CI 21.3 to 67.7) 0/15 (0%; 95% CI 0.0 to 20.4) Not reported P=0.0063 Among survivors in the early ECMO arm: mean CPC 1.16 ± 0.4 (n=6) and mean mRS 1.3 ± 0.8 (n=6) at 6 months.
Cumulative survival (time-to-event) Higher cumulative survival Lower cumulative survival HR 0.16 95% CI 0.06 to 0.41; log-rank P<0.0001 Cox model of survival time to death/discharge.
VA-ECMO initiated 12/15 (80%) 0/15 (0%) Not reported Not reported Two early-ECMO patients were pronounced dead due to severe metabolic derangements before cannulation.
Key timing (process separation) 911-to-VA-ECMO initiation 59 ± 28 min (n=12) Not applicable Not reported Not reported Randomisation-to-VA-ECMO initiation 12 ± 6 min; catheterisation lab arrival-to-VA-ECMO initiation 7 ± 4 min.
Procedure-related complications (ICU subgroup) Access-site bleeding requiring >3 units PRBC: 2/13 (15%) Not applicable Not reported Not reported Complications reported among ICU admissions (early ECMO arm n=13; standard ACLS arm n=2).
Procedure-related complications (ICU subgroup) IVC trauma/retroperitoneal bleeding: 1/13 (8%) Not applicable Not reported Not reported No unanticipated device-related adverse events were reported.
  • Despite similar prehospital resuscitation timing (911-to-ED arrival 43 ± 15 min vs 45 ± 12 min), the early ECMO strategy created clear separation in exposure to invasive resuscitation (VA-ECMO 80% vs 0%).
  • The survival difference was large (43% vs 7% to discharge), but precision was limited by early stopping and a small sample (95% credible interval for the risk difference 3.7 to 59.2).
  • Among early-ECMO survivors, longer-term neurological recovery appeared favourable (mean CPC 1.16 ± 0.4 and mean mRS 1.3 ± 0.8 at 6 months; n=6).

Internal Validity

  • Randomisation and allocation concealment: Secure randomisation schedule using permuted blocks (sizes 2, 4, 6) with allocation concealed by a scratch-off opaque layer; emergency teams were masked before randomisation.
  • Dropout/exclusions: 6/36 screened patients excluded pre-randomisation due to protocol misclassification; 30 randomised; 1/30 (early ECMO) withdrew consent on day 3 leading to missing primary outcome (primary endpoint analysed in 14 vs 15).
  • Performance/detection bias: Open-label delivery is unavoidable; the primary endpoint (survival) is objective; ICU clinicians were masked to allocation; functional outcome assessment used blinded evaluators.
  • Protocol adherence: Early ECMO arm: all transferred to the catheterisation laboratory; VA-ECMO initiated in 12/15; 2/15 were declared dead due to severe metabolic derangements; standard ACLS arm: VA-ECMO not available/used (0/15), with 2/15 transferred to the catheterisation laboratory after ROSC.
  • Baseline comparability: Groups were broadly similar for prehospital timings and characteristics (e.g., 911-to-EMS arrival 6 ± 2.3 min vs 7 ± 2.5 min; transport time 19 ± 7 min vs 20 ± 10 min); small imbalances (male sex 93.3% vs 73.3%) are difficult to interpret with n=30.
  • Heterogeneity: Minimal clinical/practice heterogeneity (single-centre, integrated EMS-to-hospital pathway), strengthening consistency but limiting inference beyond this system.
  • Timing: Randomisation occurred late in the arrest trajectory (time from 911 call to randomisation 48.5 ± 21 min vs 51.8 ± 13 min); VA-ECMO initiation occurred at 59 ± 28 min from 911 call (n=12), a key determinant of biological plausibility for ECPR benefit.
  • Separation of the variable of interest: VA-ECMO exposure differed markedly (12/15 vs 0/15); randomisation-to-VA-ECMO initiation was 12 ± 6 min (early ECMO) versus not applicable; catheterisation lab arrival-to-VA-ECMO initiation was 7 ± 4 min.
  • Outcome assessment: Survival is objective; CPC and mRS were reported at discharge, 3 months, and 6 months among survivors with blinded evaluation.
  • Statistical rigour: Prespecified Bayesian monitoring and early stopping were applied; however, early termination at the first interim analysis increases risk of effect-size overestimation and yields wide uncertainty intervals.

Conclusion on Internal Validity: Overall, internal validity is moderate: allocation concealment and objective primary outcome support credibility, but early stopping, small sample size, open-label delivery, and one missing primary endpoint meaningfully limit precision and robustness.

External Validity

  • Population representativeness: Highly selected cohort (18–75 years, refractory VF/VT after 3 shocks, mechanical CPR in use, and estimated transport time <30 minutes) within a specialised regional system; excludes non-shockable rhythms and longer transport/low-resource contexts.
  • System dependence: Findings are tightly coupled to a coordinated EMS-to-cath-lab pathway with immediate access to VA-ECMO cannulation and coronary intervention; many systems cannot replicate time-to-cannulation (mean 59 minutes from 911 call).
  • Intervention generalisability: The tested strategy is a bundled pathway (triage, transport, invasive management, and intensive care), so translation requires reproducing the bundle rather than adopting a single component.

Conclusion on External Validity: External validity is limited: results best generalise to mature ECPR-capable systems with short low-flow times and strict selection for refractory shockable OHCA.

Strengths & Limitations

  • Strengths: Randomised evaluation of an ECPR-based system-of-care; prespecified adaptive/Bayesian monitoring; clear intervention–control separation (VA-ECMO 80% vs 0%); objective primary outcome; blinded ICU team and blinded functional outcome assessors; detailed time-metric reporting.
  • Limitations: Single centre; very small sample; early stopping at first interim analysis; open-label delivery; one withdrawal leading to missing primary outcome; comparator reflects ED-based ACLS without ECPR access and may not represent the best achievable conventional strategy in all regions; adverse event comparisons are hard to interpret because most standard-arm patients died before ICU admission.

Interpretation & Why It Matters

  • Clinical signal
    In a rigorously selected refractory VF/VT OHCA cohort, the early ECMO strategy was associated with substantially higher survival to discharge (43% vs 7%) and preserved 6-month survival (43% vs 0%), with favourable functional outcomes among survivors (mean CPC 1.16 ± 0.4; mean mRS 1.3 ± 0.8 at 6 months; n=6).
  • What was actually tested
    A bundled hyperinvasive resuscitation pathway (prehospital triage + mechanical CPR + rapid transport + cath lab-based VA-ECMO/angiography/PCI + protocolised ICU care), rather than ECMO alone.
  • Practice implication
    The trial supports the plausibility of benefit for ECPR in refractory shockable OHCA when systems can deliver rapid cannulation and invasive management; it does not justify indiscriminate ECPR expansion without the ability to reproduce timing and selection.

Controversies & Subsequent Evidence

  • Timing and randomisation point: Published correspondence argued that “timing is crucial” in refractory arrest and questioned whether randomising on hospital arrival (mean 48.5 ± 21 minutes from 911 call in the early-ECMO arm) optimally captures the time-sensitive biology of ECPR, highlighting the potential importance of earlier triage/randomisation around the decision to transport; the trialists’ reply emphasised protocolisation and system-of-care implementation as the tested construct.12
  • Early stopping and small-sample inferential fragility: Termination after 30 participants raises the likelihood of effect-size inflation and leaves wide uncertainty (95% credible interval for the primary risk difference 3.7 to 59.2); this influences how strongly ARREST alone should drive programme-level decisions.
  • Bundle versus single-component attribution: The intervention combines ECPR with immediate invasive coronary evaluation and highly organised logistics; clinical translation requires reproducing the system bundle, and causal attribution to VA-ECMO alone is not supported by the design.
  • Subsequent randomised trials: The INCEPTION trial did not demonstrate a statistically significant increase in 30-day survival with favourable neurological outcome (14/70 [20%] vs 10/64 [16%]; OR 1.4; 95% CI 0.5 to 3.5; P=0.52), and excluded 26/160 after randomisation because eligibility criteria were not met at hospital admission, emphasising the practical challenges of strict selection and delivery fidelity at scale.3
  • Evidence synthesis: An individual patient data pooled analysis combining ARREST and PRAGUE OHCA data explored how patient selection and low-flow times may modify benefit, reinforcing that generalisability depends on both biology (time) and system performance.4
  • Meta-analyses: Recent systematic reviews focusing on ECPR (including randomised and high-quality observational evidence) generally conclude that any overall benefit is uncertain and likely context-dependent, with heterogeneity driven by selection criteria, low-flow time, and system maturity.56
  • Guideline positioning: Contemporary international resuscitation guidance supports considering ECPR in selected refractory cardiac arrest patients where it can be delivered within experienced systems and with careful selection, rather than as routine escalation in all settings.7

Summary

  • Phase 2, single-centre, open-label RCT in refractory VF/VT OHCA (18–75 years) within an integrated EMS-to-cath-lab pathway; randomised on hospital arrival.
  • Stopped early after 30 participants because the early ECMO strategy met a prespecified Bayesian efficacy stopping rule (posterior probability 0.9861 for improved survival to discharge).
  • Survival to discharge: 6/14 (43%) with early ECMO strategy vs 1/15 (7%) with standard ACLS; risk difference 36.2% (95% credible interval 3.7 to 59.2).
  • Survival to 6 months: 6/14 (43%) vs 0/15 (0%); survivors in the early ECMO arm had favourable functional outcomes (mean CPC 1.16 ± 0.4; mean mRS 1.3 ± 0.8 at 6 months; n=6).
  • Interpretation is constrained by early stopping, small sample size, and bundle attribution; generalisability is limited to high-performance ECPR systems with short low-flow times.

Further Reading

Other Trials

Systematic Review & Meta Analysis

Observational Studies

Guidelines

Notes

  • When interpreting ARREST, prioritise time-to-cannulation performance metrics (low-flow time) and selection criteria fidelity; these are likely dominant effect modifiers across ECPR programmes.

Overall Takeaway

ARREST is a landmark because it provided randomised evidence that a tightly coordinated, ECMO-enabled hyperinvasive resuscitation pathway can produce markedly higher survival in selected refractory shockable OHCA. Its impact is tempered by early stopping and limited generalisability, but it shifted the field from observational enthusiasm to trial-based system design, crystallising time-to-cannulation and selection fidelity as the central determinants of potential benefit.

Overall Summary

  • In a highly selected refractory VF/VT OHCA cohort, an ECMO-facilitated hyperinvasive pathway improved survival to discharge (43% vs 7%) and maintained 6-month survival (43% vs 0%), but inference is constrained by early stopping and system dependence.

Bibliography