Intracranial hemorrhagic (ICH) accounts for approximately 10 % of strokes [1]. ICH is associated with a high morbidity and 30-day mortality rate of 30 to 50 %, and only 12 % to 39 % return to independent activities of daily living after 1 year [2,3]. A spontaneous ICH can be caused by numerous factors, including hypertension, natural hematologic abnormalities, and cerebral amyloid angiopathy [1]. Another common risk factor is the use of anticoagulation. Warfarin increases the risk of an ICH by 2 to 5 times [1]. This risk increases based on anticoagulation intensity; thus, individuals that are fully anticoagulated are placed at an increased risk of ICH [1]. While Factor Xa (fXa) inhibitors are associated with lower rates of ICH compared to warfarin, the rate and severity of ICHs are higher than those not anticoagulated [1,4].

Given their ease of administration, limited monitoring, and overall improved efficacy, fXa inhibitors have emerged as the preferred anticoagulation option compared to warfarin in most indications, excluding individuals with severe mitral stenosis or mechanical prosthetic valves [5,6]. However, even though oral fXa inhibitors may appear as a safer alternative, they, like all anticoagulants, come with a possibility of serious adverse events [6]. The incidence of direct-acting oral anticoagulant-related ICH occurs in 0.3 % to 1.8 % of patients per year [5]. Anticoagulation use worsens outcomes in ICH relative to no anticoagulant use [1]. Reports have indicated mortality rates as high as 67 %, and survivors typically face severe disability [1]. Thus, particularly in ICH, rapid fXa inhibitor reversal is paramount to survival [[7], [8], [9], [10]]. In contrast to the treatment standardizations observed in AIS and MI, the treatment of fXa-related ICH varies widely across healthcare institutions [[7], [8], [9], [10]]. Reversal and blood pressure management have been associated with improved survival and functional outcomes, but until recently, no door-to-needle (DTN) times have been suggested or recommended [[8], [9], [10]]. The two agents recommended for reversal of ICH associated with fXa inhibition are andexanet alfa (AA) and four-factor prothrombin complex concentrate (4F-PCC) [10,11].

In 2011, the American Heart Association (AHA) and the American Stroke Association (ASA) published a national initiative to achieve a DTN of 60 min for at least 50 % of acute ischemic stroke (AIS). AIS is defined as an obstruction to the blood vessel in the brain while an ICH is a hemorrhage within the brain [[7], [8], [9]].This initiative in AIS saw success as a study published in 2021 analyzing over 154,221 patients found that the median DTN time decreased from 78 min before the initiative, to 50 min in a four year span [7,8]. Despite the high morbidity and mortality associated with ICH, no such metrics were in existence until recently, a Code ICH: A Call to Action was published in 2023, proposing time metrics and bundled care, which are similarly seen in ischemic stroke [9]. Research indicates that approximately 1.9 million neurons are lost for every minute a stroke remains untreated [10]. This illustrates the critical need for quicker DTN times, as delays have been associated with worsened functional status [9]. In Code ICH, they proposed a DTN time for blood pressure (BP) control (goal systolic [SBP] 130 mmHg–150 mmHg) and emergent reversal of anticoagulation within 60 min [9]. Code ICH emphasizes the fastest and most effective agents be used in the correction of elevated SBPs and reversal of any anticoagulation within 60 min. Given the difficulty in implementing a 60 min DTN time, in 2024, the AHA/ASA further built on this initiative and proposed a 90-min DTN time [11]. There are few high-quality comparative studies comparing the selection of hemostatic agent and what impact that selection has on time to administration. In both Code ICH and the AHA/ASA, they stress the importance of improved DTN time being linked with improved mortality and functional outcomes, but there are few studies comparing hemostatic agents [[9], [10], [11]].

Currently there are few real-world studies comparing AA vs. 4F-PCC administration for the treatment of fXa inhibitor-related ICH. AA being one of the newest reversal agents approved, we expected it to have longer times to administration compared to 4F-PCC. Additionally some emergency departments (ED) have implemented fixed dose 4F-PCC stored in the ED for immediate use. However, the trials comparing these agents are limited; most have small sample sizes and DTN time is often analyzed via subgroup analysis [12]. We anticipated that AA, given its more recent approval and complex dosing regiment, would have a longer time to administration compared to the traditional option of 4F-PCC. Given the Veterans Health Administration (VHA) has 6 million Veterans enrolled; this is the ideal setting for gathering a large geographically diverse sample [13]. The purpose of this study is to compare the time to administration of AA vs. 4F-PCC and its impact on patient outcomes and mortality.