Publication

• Title: Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest
• Acronym: ALPS
• Year: 2016
• Journal published in: New England Journal of Medicine
• Citation: Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest. N Engl J Med. 2016;374(18):1711-1722.

Context & Rationale

• Background

  Antiarrhythmic drugs (notably amiodarone, and historically lidocaine) were incorporated into resuscitation algorithms for shock-refractory VF/pulseless VT largely on the basis of modest prehospital trials demonstrating improved short-term endpoints (e.g., survival to hospital admission), with persistent uncertainty about patient-centred outcomes (survival with good neurological function).
• Research Question/Hypothesis

  In adults with out-of-hospital cardiac arrest and shock-refractory VF/pulseless VT, does treatment with amiodarone or lidocaine (vs placebo) improve survival to hospital discharge, and is amiodarone superior to lidocaine?
• Why This Matters

  This was the definitive, multicentre, blinded, placebo-controlled evaluation of two widely used antiarrhythmic strategies in a modern EMS system, targeting survival to discharge (and functional survival) rather than intermediate rhythm outcomes.

Design & Methods

• Research Question: Among adults with OHCA due to shock-refractory VF/pulseless VT, does prehospital amiodarone or lidocaine improve survival to hospital discharge compared with placebo (and does amiodarone outperform lidocaine)?
• Study Type: Randomised, multicentre, double-blind, placebo-controlled, prehospital, parallel-group (1:1:1), Resuscitation Outcomes Consortium (ROC); conducted under exception from informed consent.¹
• Population:
  • Setting: EMS-treated OHCA in ROC catchment (10 North American ROC centres; >200 EMS agencies; >250 receiving hospitals).¹
  • Inclusion: Adults with OHCA and persistent/recurrent VF or pulseless VT after at least one shock, with IV/IO access and an indication for antiarrhythmic therapy.
  • Key exclusions: Traumatic arrest; DNR/“opt out”; known pregnancy/prisoner; known allergy to study drugs; receipt of an antiarrhythmic before randomisation; non-shockable rhythms at the time of intended dosing (handled via post-randomisation exclusion from the per-protocol “efficacy” population).
• Intervention:
  • Amiodarone (PM101 formulation): 150 mg per syringe; initial dose 300 mg (2 syringes) after shock-refractory VF/pVT, with an additional 150 mg (1 syringe) if VF/pVT persisted/recured (maximum 450 mg).¹
  • Lidocaine: 60 mg per syringe; initial dose 120 mg (2 syringes), with an additional 60 mg (1 syringe) if VF/pVT persisted/recured (maximum 180 mg).¹
• Comparison:
  • Placebo (normal saline), visually identical syringes and dosing schedule to maintain blinding.
• Blinding: Double-blind (EMS clinicians, in-hospital clinicians, investigators, and outcome assessors blinded); emergency unblinding permitted via prespecified process (infrequent).
• Statistics: A target of 3000 patients in the per-protocol (“efficacy”) population provided 90% power to detect an absolute increase in survival to discharge from 23.4% to 29.7%; group-sequential design with one-sided significance level 0.025 for each active drug vs placebo and two-sided 0.05 for amiodarone vs lidocaine; primary analysis conducted in the per-protocol population with confidence intervals adjusted for sequential monitoring; intention-to-treat analyses prespecified/available in the supplement.¹²
• Follow-Up Period: Through index hospital discharge (primary endpoint: survival to discharge; key secondary endpoint: functionally favourable survival at discharge, Modified Rankin Scale ≤3).

Key Results

This trial was not stopped early. Planned group-sequential monitoring occurred, with enrolment reaching 3026 in the per-protocol population.

• Neither amiodarone nor lidocaine significantly improved survival to discharge versus placebo in the prespecified primary (per-protocol) analysis, despite clear improvements in “upstream” outcomes (hospital admission).
• Benefit appeared concentrated in witnessed arrests (interaction P=0.05), with amiodarone and lidocaine each improving discharge survival vs placebo in bystander-witnessed arrests (risk differences ~+5 percentage points).
• Intention-to-treat analyses (randomised at kit opening) showed smaller, non-significant differences in discharge survival (amiodarone 19.0% vs lidocaine 18.4% vs placebo 17.6%).²

Internal Validity

• Randomisation and allocation concealment: Allocation occurred via opening a blinded trial-drug kit with central randomisation; concealment and blinding were strong by design (prehospital environment, identical syringes).
• Post-randomisation exclusions and analysis population: 4667 randomised; 4653 included in intention-to-treat; 3026 included in the per-protocol population; primary endpoint analysis used 970 (amiodarone), 985 (lidocaine), 1056 (placebo), after additional small exclusions for missing outcome data (4 in per-protocol). This large post-randomisation attrition from the primary analysis set is a major threat to strict ITT inference.
• Performance/detection bias: Double-blind design mitigated differential co-interventions; unblinding was rare (24/3026, 0.8%).
• Protocol adherence and separation: Time from 911 call to first dose was similar (amiodarone 19.3±7.4 min vs lidocaine 19.3±7.4 min vs placebo 19.3±7.2 min); shocks after first dose were also similar (3.6±4.8 vs 3.4±4.5 vs 3.5±4.6), supporting comparable exposure windows.
• Baseline comparability: Per-protocol groups were well balanced: mean age 63.5±13.6 vs 63.5±13.8 vs 63.3±13.6 years; men 77.9% vs 77.5% vs 78.9%; bystander witnessed 58.4% vs 57.6% vs 58.8%; bystander CPR 56.8% vs 57.9% vs 59.5%; time from call to EMS arrival 5.0±2.7 vs 5.1±2.9 vs 5.0±2.7 min.
• Heterogeneity and timing: A priori subgroup interaction for witnessed arrest (P=0.05) suggests time-dependent efficacy (plausibly reflecting myocardial viability and pharmacokinetic constraints), but subgroup multiplicity and modest absolute differences temper certainty.
• Adjunctive therapies: High and similar epinephrine exposure (98.7–98.8%); modest differences in magnesium use (8.0% amiodarone vs 6.8% lidocaine vs 11.2% placebo); open-label antiarrhythmic use was low but numerically higher in placebo (amiodarone 1.4% and lidocaine 1.2% in placebo vs ≤1.3% in active arms), reducing risk of major “contamination”.
• Outcome assessment: Survival to discharge is objective; functional outcome used mRS at discharge (subject to discharge practice variation, but standardised outcome definitions and blinded assessment reduce bias).
• Statistical rigour: Group-sequential monitoring and prespecified alpha spending were appropriate; primary per-protocol analysis choice (rather than ITT) remains the most important analytic vulnerability because it redefines the estimand after randomisation.

Conclusion on Internal Validity: Moderate—randomisation, blinding, and baseline balance were strong, but reliance on a per-protocol primary analysis with substantial post-randomisation exclusions limits the robustness of causal inference for the trial’s primary estimand.

External Validity

• Population representativeness: Reflects adult OHCA with shock-refractory VF/pVT managed by advanced EMS systems capable of IV/IO access, defibrillation, and protocolised ALS; excludes non-shockable rhythms and trauma.
• System and resource dependence: Applicability is highest in systems resembling ROC (high-quality CPR/defibrillation infrastructure, transport and post-arrest care capacity); generalisability is reduced where drug delivery is delayed, vascular access is not feasible, or post-arrest care differs substantially.
• Intervention generalisability: Amiodarone formulation (PM101) and dose schedule were aligned with contemporary ALS practice, but formulation differences may matter in other settings.

Conclusion on External Validity: Good for shock-refractory VF/pVT OHCA in well-developed EMS systems; limited for non-shockable arrests and for systems without timely drug delivery or comparable post-arrest pathways.

Strengths & Limitations

• Strengths: Large, multicentre, blinded, placebo-controlled design; pragmatic prehospital implementation within a mature research network; clinically important primary endpoint (survival to discharge) with functional outcome captured; prespecified subgroup hypothesis (witnessed arrest).
• Limitations: Primary reliance on a per-protocol (“efficacy”) population with extensive post-randomisation exclusions; drug administration occurred relatively late in the resuscitation timeline (mean ~19 minutes from 911 call), potentially diluting effect; hospital and post-arrest care not protocolised (pragmatic but introduces downstream variability); three-arm comparisons with multiple secondary endpoints increase interpretive complexity.

Interpretation & Why It Matters

• Clinical meaning

  In contemporary OHCA care, antiarrhythmic drugs for shock-refractory VF/pVT improve intermediate resuscitation success (hospital admission) but do not clearly increase survival to discharge overall; practice emphasis remains rapid defibrillation and high-quality CPR.
• Where a signal may exist

  Witnessed arrests (particularly bystander-witnessed) showed absolute improvements in discharge survival of ~5 percentage points versus placebo, consistent with a time-dependent biology: pharmacological rhythm stabilisation may help only while neurological salvage remains plausible.
• Guideline translation

  Current international resuscitation recommendations generally support amiodarone or lidocaine as reasonable options for shock-refractory VF/pVT, acknowledging modest evidence and uncertainty regarding long-term outcomes.⁷⁹

Controversies & Subsequent Evidence

• Per-protocol as the primary analysis set: The trial’s principal causal estimate was anchored to a post-randomisation “efficacy/per-protocol” population, which risks bias if exclusions relate to prognosis or are influenced by early resuscitation dynamics; this design choice drove post-publication critique in editorial and correspondence.³⁴
• “Upstream benefit, downstream attenuation”: Both active drugs improved admission to hospital, but the effect attenuated by discharge—raising questions about (i) drug timing (pharmacology delivered after prolonged low-flow), (ii) post-arrest brain injury dominating prognosis, and (iii) downstream care variability rather than absence of physiological effect.³
• Subgroup credibility: The witnessed-arrest interaction (P=0.05) is clinically coherent but near the conventional threshold; it must be interpreted in the context of multiple subgroup tests and the modest absolute effect sizes.
• Meta-analytic synthesis: Post-ALPS systematic reviews and network meta-analyses generally support improved ROSC/survival to hospital admission with amiodarone/lidocaine, with inconsistent or modest effects on survival to discharge and neurological outcomes, mirroring ALPS’ pattern of results.⁵⁶
• Guideline positioning: Subsequent guideline statements continue to endorse either amiodarone or lidocaine as reasonable therapies for shock-refractory VF/pVT, while emphasising that the certainty for improvement in patient-centred outcomes remains limited.⁷⁸

Summary

• ALPS was a large, double-blind, placebo-controlled, three-arm prehospital trial testing amiodarone and lidocaine for shock-refractory VF/pVT OHCA.
• Neither active drug significantly improved survival to hospital discharge in the prespecified primary (per-protocol) analysis (amiodarone 24.4%, lidocaine 23.7%, placebo 21.0%).
• Both drugs improved intermediate outcomes (notably hospital admission), suggesting physiological benefit that did not consistently translate into discharge survival.
• Witnessed arrests showed the clearest signal of improved discharge survival versus placebo (absolute risk differences ~+5 percentage points), supporting a time-dependent treatment effect hypothesis.
• Primary reliance on a per-protocol analysis with substantial post-randomisation exclusions is the central methodological controversy and tempers the certainty of inference.

Further Reading

Other Trials

• 1999Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med. 1999;341(12):871-878.
• 2002Dorian P, Cass D, Schwartz B, et al. Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med. 2002;346(12):884-890.
• 2002Hassan TB, Jagger C, Barnett DB. A randomised trial to investigate the efficacy of magnesium sulphate for refractory ventricular fibrillation. Emerg Med J. 2002;19(1):57-62.
• 1981Haynes RE, Coleman DE. Bretylium tosylate versus lidocaine in ventricular fibrillation. Am J Cardiol. 1981;48(1):73-77.
• 2014Harayama N, Nihei S, Nagata K, et al. Comparison of nifekalant and amiodarone for resuscitation of shock-resistant ventricular fibrillation. J Anesth. 2014;28(4):587-592.

Systematic Review & Meta Analysis

• 2016Sanfilippo F, Corredor C, Fletcher N, et al. Amiodarone or lidocaine for cardiac arrest: a systematic review and meta-analysis. Resuscitation. 2016;107:31-37.
• 2017McLeod SL, Brignardello-Petersen R, Worster A, You JJ, Iansavichene A. Comparative effectiveness of antiarrhythmics for out-of-hospital cardiac arrest: a systematic review and network meta-analysis. Resuscitation. 2017;119:90-97.
• 2018Ali MU, Fitzpatrick-Lewis D, Kenny M, Raina P, Sherifali D. Effectiveness of antiarrhythmic drugs for shockable cardiac arrest: a systematic review. Resuscitation. 2018;132:63-72.
• 2018Chowdhury AE, Aitken RJ, Baranchuk A. Antiarrhythmic drugs for shock-refractory ventricular fibrillation and pulseless ventricular tachycardia: systematic review and meta-analysis. Heart Lung Circ. 2018;27(4):449-456.
• 2023Wang Q, Sun R, Sun D, et al. Antiarrhythmic drugs for ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest: a systematic review and meta-analysis. Medicine (Baltimore). 2023;102(18):e32965.

Observational Studies

• 2016Tagami T, Hirata K, Takeshige T, et al. Impact of amiodarone and lidocaine on survival in out-of-hospital cardiac arrest patients with refractory ventricular fibrillation. J Cardiovasc Pharmacol Ther. 2016;21(6):540-546.
• 2020Daya MR, Leroux B, Rea TD, et al. Intraosseous versus intravenous access for antiarrhythmic drug delivery in out-of-hospital cardiac arrest: a secondary analysis of a randomised trial. Circulation. 2020;141(7):536-546.
• 2022Rahimi K, Kudenchuk PJ, Rea TD, et al. Effect of time to treatment with antiarrhythmic drugs on outcomes after out-of-hospital cardiac arrest with shock-refractory ventricular fibrillation/pulseless ventricular tachycardia. J Am Heart Assoc. 2022;11(5):e023958.
• 2023Lupton JR, Kudenchuk PJ, Leroux B, et al. Survival by time to administration of amiodarone, lidocaine, or placebo in shock-refractory out-of-hospital cardiac arrest. Acad Emerg Med. 2023;30(3):255-266.
• 2025Smida T, Schmitz D, Gräsner J-T, et al. Lidocaine compared with amiodarone for shock-refractory out-of-hospital cardiac arrest: a target trial emulation. Resuscitation. 2025;197:109892.

Guidelines

• 2020Panchal AR, Bartos JA, Cabañas JG, et al. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020;142(16_suppl_2):S366-S468.
• 2018Panchal AR, Berg KM, Hirsch KG, et al. 2018 American Heart Association Focused Update on Advanced Cardiovascular Life Support Use of Antiarrhythmic Drugs During and Immediately After Cardiac Arrest. Circulation. 2018;138(23):e740-e749.
• 2021Soar J, Böttiger BW, Carli P, et al. European Resuscitation Council Guidelines 2021: Adult advanced life support. Resuscitation. 2021;161:115-151.
• 2020Berg KM, Soar J, Andersen LW, et al. Adult Advanced Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2020;142(16_suppl_1):S92-S139.
• 2025Wigginton JG, Agarwal S, Bartos JA, et al. Part 9: Advanced Life Support: 2025 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2025;152(suppl_2):S538-S577.

Notes

• ALPS was conducted alongside the ROC CPR Trial (partial factorial co-enrolment), but trialists anticipated minimal interaction given the differing resuscitation phases and monitoring by the same DSMB.¹

Overall Takeaway

ALPS reframed antiarrhythmic use in shock-refractory VF/pVT as a therapy with clear effects on early resuscitation milestones but uncertain impact on survival to discharge in the overall population. Its most enduring contribution is methodological (large, blinded, placebo-controlled prehospital drug trial) and conceptual: any meaningful benefit is likely time- and context-dependent, emerging most plausibly in witnessed arrests where neurological salvage remains achievable.

Bibliography

• 1Kudenchuk PJ, Brown SP, Daya M, et al. Protocol for: Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest. N Engl J Med. 2016. Link
• 2Kudenchuk PJ, Brown SP, Daya M, et al. Supplementary appendix for: Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest. N Engl J Med. 2016. Link
• 3Joglar JA, Mazer CD. Out-of-hospital cardiac arrest—are drugs ever the answer? N Engl J Med. 2016;374(18):1760-1761. Link
• 4Pollak PM, Spence C, Patel V. Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest. N Engl J Med. 2016;375(8):801-802. Link
• 5Ali MU, Fitzpatrick-Lewis D, Kenny M, Raina P, Sherifali D. Effectiveness of antiarrhythmic drugs for shockable cardiac arrest: a systematic review. Resuscitation. 2018;132:63-72. Link
• 6McLeod SL, Brignardello-Petersen R, Worster A, You JJ, Iansavichene A. Comparative effectiveness of antiarrhythmics for out-of-hospital cardiac arrest: a systematic review and network meta-analysis. Resuscitation. 2017;119:90-97. Link
• 7Panchal AR, Bartos JA, Cabañas JG, et al. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020;142(16_suppl_2):S366-S468. Link
• 8Berg KM, Soar J, Andersen LW, et al. Adult Advanced Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2020;142(16_suppl_1):S92-S139. Link
• 9Soar J, Böttiger BW, Carli P, et al. European Resuscitation Council Guidelines 2021: Adult advanced life support. Resuscitation. 2021;161:115-151. Link