TL;DR: ⚪ Concordant null — independently conducted Danish trial confirms no significant difference between IO-first and IV-first access in OHCA; secondary outcomes trended opposite to PARAMEDIC-3's.
1. Publication
- Title: Intraosseous or Intravenous Vascular Access for Out-of-Hospital Cardiac Arrest
- Acronym: IVIO
- Year & Journal: New England Journal of Medicine, published October 31, 2024 (2025;392(4):349-360)
- Citation: Vallentin MF, Granfeldt A, Klitgaard TL, et al. N Engl J Med. 2025;392(4):349-360. doi:10.1056/NEJMoa2407616
2. Context & Rationale
Background: Guidelines recommend IV access first, considering IO only if IV fails, but based on very low-certainty evidence. This independently conducted Danish trial provides a second, methodologically distinct RCT (individually randomized, physician-administered) on the same question as PARAMEDIC-3 (this handbook).
Research Question/Hypothesis: In adult non-traumatic OHCA, does initial IO access differ from IV access in effectiveness for achieving return of spontaneous circulation?
3. Design & Methods
- Study Type: Randomized, parallel-group superiority trial
- Setting & Centers: Denmark; physician-manned units involved (physician could terminate resuscitation)
- Population: 1479 adults with non-traumatic OHCA (of planned 1470)
- Intervention: IO access first (further randomized 1:1 to humeral or tibial site)
- Comparator: IV access first
- Randomization: Blinded, performed by onsite physician, 1:1
- Statistical Power & Follow-Up: Primary: sustained ROSC. Secondary: survival and favorable neurologic outcome at 30 days.
4. Key Results
1479 patients randomized.
Outcome | IO Access | IV Access | Effect Size | 95% CI | Notes |
Sustained ROSC (primary) | No significant difference | No significant difference | — | — | Clear null on primary |
30-day survival | 12% (85) | 10% (75) | RR 1.16 | 0.87–1.56 | Not significant; numerically favored IO |
Favorable neurologic outcome at 30d | 9% (67) | 8% (59) | RR 1.16 | 0.83–1.62 | Not significant; numerically favored IO |
Prespecified adverse events | Uncommon | Uncommon | — | — | No safety signal |
5. Internal Validity Assessment
Individually randomized (rather than cluster), physician-administered RCT with blinded randomization. Overall: Strong — clean null primary result with reassuring safety data; notably, this trial's secondary outcomes trended in the OPPOSITE direction (favoring IO) compared with PARAMEDIC-3's secondary ROSC signal (favoring IV) — an important point of genuine discordance between the two concordant-on-primary-outcome trials.
6. External Validity Assessment
Danish OHCA population with physician-manned response units — a somewhat different prehospital care model than PARAMEDIC-3's UK paramedic-only system, a relevant consideration for generalizability.
7. Strengths & Limitations
Strengths: Individually randomized (methodologically cleaner than PARAMEDIC-3's approach for this specific comparison); blinded randomization process; comprehensive secondary and safety outcome assessment; further randomization to humeral vs tibial IO site adds mechanistic detail.
Limitations: Smaller sample (1479) than PARAMEDIC-3 (6082), limiting precision for secondary outcomes; different prehospital care model (physician-manned units) than many other health systems.
8. Interpretation & Practice Impact
Supports equipoise between IO-first and IV-first vascular access strategies for OHCA — no significant difference in the primary (ROSC) or secondary (survival, neurologic outcome) outcomes, with numerically favorable but non-significant trends toward IO on secondary outcomes (contrasting with PARAMEDIC-3's numerically-favorable-toward-IV ROSC signal).
9. Controversies & Subsequent Evidence
A subsequent Bayesian secondary analysis of this trial's data (Resuscitation, May 2025) applied a probabilistic framework incorporating various prior beliefs to further evaluate the likelihood of benefit for each access method — reflecting ongoing statistical interest in extracting additional insight from this dataset beyond the frequentist null result. The discordant secondary-outcome directionality between IVIO (favoring IO numerically) and PARAMEDIC-3 (favoring IV numerically on ROSC) is an important nuance for any combined meta-analytic interpretation.
10. Summary & Executive Takeaway
Summary: IVIO, an individually randomized Danish trial, randomized 1479 adults with non-traumatic OHCA to IO-first or IV-first vascular access. Sustained ROSC (primary) showed no significant difference; 30-day survival (12% vs 10%, RR 1.16) and favorable neurologic outcome (9% vs 8%, RR 1.16) also showed no significant difference, with adverse events uncommon in both groups.
Overall Takeaway: IVIO, independently conducted alongside PARAMEDIC-3, confirms no significant difference between IO-first and IV-first vascular access strategies in OHCA — though the two trials' secondary outcomes trended in opposite directions, an important nuance underscoring that neither strategy has been shown definitively superior and guideline-level equipoise remains reasonable.
11. Bibliography
- Couper K, Ji C, Deakin CD, et al. PARAMEDIC-3. N Engl J Med. 2025;392(4):336-348 (this handbook).
- Couper K, Andersen LW, Drennan IR, et al. Intraosseous and intravenous vascular access during adult cardiac arrest: systematic review and meta-analysis. Resuscitation. 2025;207:110481.