Accelerating Reversal and Refining Transfer Are Imperative for Anticoagulation‐Associated Intracerebral Hemorrhage

Anticoagulation‐associated intracerebral hemorrhage (AC‐ICH) is a time‐critical emergency, where every minute translates into hematoma progression, neurotoxicity, and survival. The key question becomes, essentially, when and where the reversal should occur. Using contemporary data from 354 US hospitals in the American Heart Association’s GWTG–Stroke (Get With The Guidelines–Stroke) registry, Royan and colleagues provide a pragmatic, system‐level lens on timeliness and outcomes for patients with AC‐ICH who present directly versus after interhospital transfer. Their findings in this issue of the Journal of the American Heart Association (JAHA) reinforce the need to initiate reversal as early as possible—ideally, before transferring—while simultaneously optimizing transfer workflows. ¹

In a cross‐sectional cohort of 30 590 patients with AC‐ICH from 2015 to 2021, 48.6% arrived as interhospital transfers. Among those who received reversal at the admitting hospital, onset‐to‐treatment times were substantially longer for transferred patients (512 [interquartile range, 328–840] minutes) than for direct admissions (273 [interquartile range, 153–579] minutes). In contrast, door‐to‐treatment times at the receiving hospital were similar between groups (median, ≈80 minutes), indicating that most delay occurs before or during transfer rather than after arrival. Transfer patients had lower admission severity (median National Institutes of Health Stroke Scale score, 7 versus 11; lower intracerebral hemorrhage [ICH] scores) and lower adjusted odds of in‐hospital death or hospice (adjusted odds ratio, 0.78 [95% CI, 0.72–0.85]) than direct admissions, yet no difference in discharge disability or likelihood of going home after multivariable adjustment. ¹ Notably, among warfarin‐treated patients, a significant proportion of transfers arrived with an international normalized ratio >1.4, suggesting incomplete or absent reversal before transfer, a care gap specifically cautioned against by the 2022 American Heart Association/American Stroke Association ICH guideline, which prefers reversal before transfer when feasible. ¹ , ² , ³

These observations triangulate with parallel evidence that median door‐in–door‐out times for transferred patients with stroke approach 3 hours, creating a considerable headwind for any time‐sensitive therapy. ⁴ Moreover, earlier reversal in ICH is independently associated with better survival. ⁵ Together, the message is clear: Time lost upstream becomes outcome lost downstream. ¹

At first glance, the coexistence of longer onset‐to‐treatment time yet lower adjusted mortality rate in transfer patients seems paradoxical. Three explanations help reconcile this. First, selection and triage effects likely play a role, as clinicians may preferentially transfer patients with more favorable prognostic profiles (lower National Institutes of Health Stroke Scale/ICH score, lower systolic blood pressure); a residual confounding factor even after adjustment. ¹ , ⁶ , ⁷ Second, a center‐level effect may be present, since transferred patients more often arrive at comprehensive stroke centers with higher ICH volumes and dedicated neurocritical care, where adherence to evidence‐based ICH bundles for blood pressure, coagulopathy, temperature, and glucose can reduce death without necessarily altering functional outcome at discharge. ¹ , ⁸ Finally, competing risks and timing of goal‐of‐care discussions matter; early withdrawal of care at presenting hospitals may limit transfers in patients with an anticipated poor prognosis, whereas transferred patients may survive the acute phase yet still be discharged with substantial disability. ¹ , ⁹ The clinical takeaway is not that delays are benign, but that delays persist despite the protective selection of transferred patients. ¹ , ⁹ , ¹⁰

A practical path forward begins with adopting a “reversal‐first” strategy at the originating site whenever feasible. The 2022 American Heart Association/American Stroke Association ICH guideline prefers initiating reversal before transfer, and standardized order sets for warfarin (vitamin K plus prothrombin complex concentrate) and direct oral anticoagulants (idarucizumab for dabigatran; targeted factor Xa reversal or prothrombin complex concentrate for apixaban, rivaroxaban, or edoxaban) should be preauthorized in emergency departments with standing drug availability and pharmacy‐led activation. ² In parallel, systems must measure and manage the “transfer time tax” by embedding door‐in–door‐out and referral‐to‐needle metrics in dashboards for ICH. ⁴ , ⁵ The door‐to‐treatment parity reported by Royan et al indicates the bottleneck is prearrival, emphasizing the need to shorten imaging‐to‐transfer and transfer‐activation‐to‐departure intervals. ¹ Regional agreements should standardize “no‐pause transfer” criteria following reversal initiation.

Furthermore, health systems must close the documentation gap on the reversal initiation. Royan et al could not reliably capture the reversal initiated at the referring hospital; thus, time‐stamped documentation of reversal initiation and agent type should become required transfer fields. Care should be bundled beyond reversal by protocolizing a “Code ICH” bundle covering blood pressure targets, rapid imaging, stroke team activation, and neurosurgical triage from first contact through handoff.

Finally, systems should favor precision triage rather than reflexive bypass. ⁸ While direct bypass to high‐capability centers sounds intuitive, secondary analyses suggest bypassing the nearest stroke center may worsen outcomes for some patients with ICH by prolonging prehospital times. These findings support a data‐driven, regionally tailored approach to triage rather than a universal bypass strategy. ¹¹

These findings carry substantial policy and system design implications. Uninterrupted access to prothrombin complex concentrates and specific direct oral anticoagulant reversal agents must be ensured at referring hospitals through formulary and financing structures that allow pharmacy‐led stewardship:managing cost exposure without hindering time‐to‐first dose. Regional interfacility compacts should codify “reversal‐first” activation criteria and standardized handoff elements. Quality measures, such as the adoption of the 2024 American Heart Association/American Stroke Association performance measure of door‐to‐reversal ≤90 minutes, should explicitly apply to transfer candidates with shared accountability between sending and receiving facilities. ¹² Mature ICH networks should operate as learning health systems, conducting rapid‐cycle audits tying time metrics to 30‐ and 90‐day outcomes.

Research priorities must also evolve: prospective evaluation of pretransfer reversal using randomized or pragmatic designs, defining the completeness of warfarin reversal under real‐world conditions, and conducting head‐to‐head comparisons of direct oral anticoagulant–specific pathways in transfer contexts. Prehospital innovation also warrants attention, particularly the evaluation of mobile stroke units and telepharmacy‐guided protocols. ¹³ Finally, future work should explore whether reversal and transfer delays vary by race, ethnicity, rurality, and payer status and whether targeted interventions can close these gaps. ¹

Royan and colleagues highlight a solvable paradox in AC‐ICH care: Our hospitals treat efficiently once patients arrive, yet many patients lose critical hours before they reach them. ¹ The remedy is neither exotic nor aspirational: Initiate reversal early, measure and minimize transfer delays, document meticulously, and bundle care throughout the continuum. If regional systems embrace this discipline, the next violin plot of onset‐to‐treatment time will narrow, and more patients will enter the postacute phase of AC‐ICH with a genuine chance at recovery.

Disclosures

None.