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• P: Adults with OHCA, shock-refractory VF/pVT, ≥1 shock delivered, IV/IO access
• I: IV Amiodarone 300 mg (+150 mg supplement) = 450 mg max
• C: IV Lidocaine 120 mg OR Normal Saline Placebo (triple-arm, 1:1:1)
• O (Primary): Survival to hospital discharge - no significant difference (24.4% vs 23.7% vs 21.0%; all p>0.05) - but witnessed arrest subgroup showed +5 pp benefit with both drugs

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ALPS TRIAL

Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest

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Slide 2 — Agenda: What We'll Cover

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Slide 3 — Background: Why Does This Trial Matter?

300,000+ OHCA deaths per year in North America

• VF/pVT is the most treatable OHCA rhythm — responsive to defibrillation
• Most defibrillation attempts do NOT result in sustained ROSC
• VF/pVT persists or recurs in many patients → shock-refractory state
• Amiodarone & lidocaine are widely used, but prior RCTs only showed ROSC/hospital admission benefit — no proven survival-to-discharge benefit
• Previous small RCTs (Kudenchuk 1999; Dorian 2002) favored amiodarone for short-term endpoints only

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Slide 4 — PICO Framework

P — POPULATION

• Adults ≥18 yrs with nontraumatic OHCA
• Initial rhythm: VF or pVT
• Shock-refractory (≥1 shock delivered)
• IV/IO vascular access obtained
• Enrolled by paramedics at 10 North American sites
• Excluded: prior open-label amiodarone/lidocaine, known hypersensitivity

I — INTERVENTION

• IV Amiodarone (Captisol-based Nexterone formulation)
• Initial dose: 300 mg (2 syringes × 150 mg)
• Supplemental dose: 150 mg (1 syringe) if VF/pVT persisted
• Total maximum dose: 450 mg
• Given after vasopressor, during ongoing ACLS
• Administered by EMS paramedics prehospital

C — COMPARISON

• Arm 1: IV Lidocaine 120 mg initial (2 × 60 mg) + 60 mg supplement
• Arm 2: Normal Saline Placebo (identically packaged)
• Triple-arm, double-blind, placebo-controlled
• Syringes identically appearing — indistinguishable by appearance
• Randomized 1:1:1 by EMS kit-opening
• Standard ACLS continued in all arms

O — OUTCOME

• PRIMARY: Survival to hospital discharge
• SECONDARY: Favorable neurologic outcome at discharge (modified Rankin Scale ≤3)
• MECHANISTIC: ROSC at ED arrival, hospital admission rate, shocks delivered after drug
• SAFETY: Adverse events within 24 hrs (bradycardia, seizures, anaphylaxis)
• SUBGROUP: Witnessed vs. unwitnessed arrest treatment interaction

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Slide 5 — Study Design & Methods

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Slide 6 — Patient Enrollment & Allocation

37,889 OHCA Patients Screened
        ↓
7,051 (18.6%) Potentially Eligible — shock-refractory VF/pVT
        ↓
4,667 Randomized (EMS kit opened)
        ↓
4,653 Intention-to-Treat Population
        ↓
  ┌──────────────────────────────────────┐
  │               │                     │
AMIODARONE    LIDOCAINE             PLACEBO
  n = 974        n = 993             n = 1,059
(per-protocol) (per-protocol)     (per-protocol)

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Slide 7 — Primary Results: Survival to Hospital Discharge

Pairwise Comparisons

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Slide 8 — Secondary & Subgroup Results

Secondary Outcome: Favorable Neurologic Status (mRS ≤3)

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Key Subgroup: Witnessed Status (Heterogeneity p = 0.05)

• Amiodarone: 27.7% | Lidocaine: 27.8% | Placebo: 22.7%
• Amiodarone vs Placebo: +5.0 pp (95% CI 0.3–9.7, p = 0.04) ✓
• Lidocaine vs Placebo: +5.2 pp (95% CI 0.5–9.9, p = 0.03) ✓

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Mechanistic Outcomes (Exploratory)

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Slide 9 — Adverse Events (Per-Protocol Population)

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Slide 10 — Critical Appraisal

Strengths ✓

1. Largest RCT of antiarrhythmics in OHCA (n = 3,026 per-protocol)
2. Triple-arm design — simultaneously tests amiodarone vs lidocaine vs placebo
3. Double-blind with identically packaged syringes — robust blinding
4. Real-world prehospital setting — high external validity
5. Well-balanced baseline characteristics across all three groups
6. Mechanistic outcomes provide biological plausibility
7. Prespecified subgroup analysis (witnessed arrest)
8. Independent DSMB; FDA/Health Canada oversight; exception from informed consent protocol

Limitations ✗

1. Possibly underpowered — actual survival difference was smaller than projected (3 pp vs. 6.3 pp assumed)
2. ~9,000 patients across three groups would be needed to confirm a 3 pp absolute difference with 90% power
3. Late drug administration (avg ~19 min from call) may have attenuated the treatment effect
4. In-hospital care was NOT standardized — potential confounding after ROSC
5. Single dosing strategy only; no active-treatment crossover; other strategies not tested
6. Selection bias possible — reasons for non-enrollment tracked but some patients may be systematically excluded
7. Witnessed arrest subgroup is interpreted in the context of a negative primary outcome and was not adjusted for multiple comparisons

Bias Assessment

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Slide 11 — Clinical Implications: What Should Change at the Bedside?

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Slide 12 — Take-Home Messages

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Slide 13 — Discussion Questions