Hematoma Expansion and Clinical Outcomes in Patients With Factor-Xa Inhibitor–Related Atraumatic Intracerebral Hemorrhage Treated Within the ANNEXA-4 Trial Versus Real-World Usual Care

Stroke ◽  
2021 ◽  
Author(s):  
Hagen B. Huttner ◽  
Stefan T. Gerner ◽  
Joji B. Kuramatsu ◽  
Stuart J. Connolly ◽  
Jan Beyer-Westendorf ◽  
...  

Background and Purpose: It is unestablished whether andexanet alfa, compared with guideline-based usual care including prothrombin complex concentrates, is associated with reduced hematoma expansion (HE) and mortality in patients with factor-Xa inhibitor–related intracerebral hemorrhage (ICH). We compared the occurrence of HE and clinical outcomes in patients treated either with andexanet alfa or with usual care during the acute phase of factor-Xa inhibitor–related ICH. Methods: Data were extracted from the multicenter, prospective, single-arm ANNEXA-4 trial (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) and a multicenter observational cohort study, RETRACE-II (German-Wide Multicenter Analysis of Oral Anticoagulant-Associated Intracerebral Hemorrhage - Part Two). HE was based on computed tomography scans performed within 36 hours from baseline imaging. Inverse probability of treatment weighting was performed to adjust for baseline comorbidities and ICH severity. Patients presenting with atraumatic ICH while receiving apixaban or rivaroxaban within 18 hours of admission were included. Patients with secondary ICH or not fulfilling the inclusion criteria for the ANNEXA-4 trial were excluded. We compared ANNEXA-4 patients, who received andexanet alfa for hemostatic treatment, with RETRACE-II patients who were treated with usual care, primarily administration of prothrombin complex concentrates. Primary outcome was rate of HE defined as relative increase of ≥35%. Secondary outcomes comprised mean absolute change in hematoma volume, as well as in-hospital mortality and functional outcome. Results: Overall, 182 patients with factor-Xa inhibitor–related ICH (85 receiving andexanet alfa versus 97 receiving usual care) were selected for analysis. There were no relevant differences regarding demographic or clinical characteristics between both groups. HE occurred in 11 of 80 (14%) andexanet alfa patients compared with 21 of 67 (36%) usual care patients (adjusted relative risk, 0.40 [95% CI, 0.20–0.78]; P =0.005), with a reduction in mean overall hematoma volume change of 7 mL. There were no statistically significant differences among in-hospital mortality or functional outcomes. Sensitivity analysis including only usual care patients receiving prothrombin complex concentrates demonstrated consistent results. Conclusions: As compared with usual care, andexanet alfa was associated with a lower rate of HE in atraumatic factor-Xa inhibitor–related ICH, however, without translating into significantly improved clinical outcomes. A comparative trial is needed to confirm the benefit on limiting HE and to explore clinical outcomes across patient subgroups and by time to treatment.

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Syed Daniyal Asad ◽  
Stephanie R Lombardi ◽  
Ilene Staff ◽  
Amre M Nouh ◽  
Mark J Alberts

Background: Intracerebral hemorrhage (ICH) is a devastating condition with high 30- day mortality. Up to a third of patients experience hematoma expansion within the first 24 hours; anticoagulation with factor Xa inhibitors may increase the risk of expansion and poor outcomes. Objective: We assessed our experience using Andexanet alfa (Aα) by evaluating stabilization of the hematoma and ischemic complications. Methods: We conducted a single center prospective observational study on all patients receiving Aα for reversal of anticoagulation in the setting of an ICH and use of Factor Xa inhibitors. The degree of hematoma expansion within 12 hours of drug administration on non-contrast head CT was categorized as 'excellent' (<20% increase in hematoma size), ‘good' ( > 20-<35%), and 'poor' ( > 35%). Secondary outcomes included dosage, median length of stay, mortality, modified Rankin score (mRS), discharge disposition, and ischemic complications. Results: Fifteen patients received Aα (5=lobar, 5=deep, 5= multicompartment). One patient with a presumed deep hemorrhage was excluded because subsequent imaging showed chronic mineralization. The predominant etiologies were hypertension (40%), amyloid angiopathy (26.6%) and trauma (13.3%). The median age was 86 years (IQR 19) and median ICH score on arrival was 2 (IQR 2), and median hematoma size was 14.3 mL (IQR 34.5). Most patients (71.4%) received the low dose formulation. Based on hematoma expansion, 64.3%, 14.3% and 21.4% of patients achieved excellent, good and poor hemostasis, respectively. Reduction in hematoma size was seen in 20% (n=3) while 13.3% (n=2) patients had no expansion. Median ICU and hospital length of stays were 2.0 days (IQR 2.2) and 6.6 days (IQR 9.78) respectively. Mortality was 28.6% and median mRS upon discharge was 4 (IQR 2), with most patients discharged to rehabilitation facilities (60%). There were no ischemic complications. Conclusion: Our experience is consistent with the results of the ANNEXA 4 study with 78.6% of patients showing excellent or good hemostasis. These results led to improved clinical outcomes, with 60% of patients being discharged to rehabilitation. These data support the efficacy of this treatment paradigm in a real-world setting.


2021 ◽  
Vol 17 (1) ◽  
pp. 127-135
Author(s):  
Craig I Coleman ◽  
Paul P Dobesh ◽  
Sherry Danese ◽  
Julie Ulloa ◽  
Belinda Lovelace

Aim: We describe the real-world utilization and outcomes associated with managing oral factor Xa inhibitor (FXai)-related major bleeds. Materials & methods: Electronic records from 45 US hospitals were queried (ICD-10-CM billing codes D68.32, T45.515x or T45.525x) to identify major bleed hospitalizations related to FXai use. Patient demographics, bleed type (intracranial hemorrhage, gastrointestinal, critical compartment, traumatic, other), FXai taken, reversal or replacement agents administered (including andexanet alfa, four-factor prothrombin complex concentrate, fresh frozen plasma, others), in-hospital mortality and length of stay were recorded. Results: Of 3030 FXai-related hospitalizations for major bleeds, patients averaged 68 years old and 47% were women. In-hospital mortality was highest for intracranial hemorrhage (23%, n = 507) and lowest for gastrointestinal bleeds (4%, n = 1453). In-hospital mortality was lowest (4%) for bleeds managed with andexanet alfa (n = 342), compared with 10% for four-factor prothrombin complex concentrate (n = 733), 11% for fresh frozen plasma (n = 925) and 8% for both other agents (n = 794) and no agents (n = 438). Median length of stay was 5 days across all agents, while ICU length of stay was shorter andexanet alfa (2 days) compared with other agents (3 days). Conclusion: In-hospital mortality differed by bleed type and agents administered. Andexanet alfa was associated with the lowest rate of in-hospital mortality across all bleed types.


Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 204-208 ◽  
Author(s):  
Miriam Kimpton ◽  
Deborah M. Siegal

Abstract A 77-year-old man with atrial fibrillation and a CHA2DS2Vasc score of 6 for hypertension, age, diabetes, and previous stroke is brought to the emergency department with decreased level of consciousness. He is anticoagulated with rivaroxaban (a direct oral factor Xa inhibitor [FXaI]) and received his last dose about 4 hours before presentation. Urgent computed tomography of the head shows intracerebral hemorrhage. Because of his previous stroke, the patient’s family is concerned about treating the bleed with pharmacological agents that may increase the risk of stroke. What are the risks of thrombosis and mortality related to the use of prothrombin complex concentrates (PCCs) and andexanet alfa for patients with direct oral FXaI-associated major bleeding?


Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Andrew Blake Buletko ◽  
Tapan Thacker ◽  
Ken Uchino ◽  
Jennifer Frontera

Intro: There have been case reports of ischemic infarcts after treatment with prothrombotics for anticoagulation reversal following spontaneous intracerebral hemorrhage (ICH), though there have been no systematic studies evaluating MRI infarction following prothrombin complex concentrate (PCC) or factor eight inhibitor bypassing activity (FEIBA) administration. We evaluated the prevalence of ischemic infarcts on diffusion-weighted imaging (DWI) in ICH patients who received prothrombotics compared to those who did not. Methods: We performed a retrospective review of patients admitted with ICH between January 2013 and April 2016 in whom MRI brain with DWI imaging was performed within 2 weeks of admission and prior to digital subtraction angiography. PCC (4-factor Kcentra, weight, and INR based dosing) was administered to patients on warfarin at the time of ictus with a INR≥1.4 and FEIBA (50 u/kg) was given to patients exposed to an oral Factor Xa inhibitor or direct thrombin inhibitor if ICH occurred within 3-5 half lives of the last dose. Acute ischemia was defined as DWI hyperintensity with corresponding apparent diffusion coefficient hypointensity. Perihematoma lesions, and procedure-related infarctions were excluded from analysis. Groups were compared using chi-square and Wilcoxon Rank Sum tests. Results: A total of 254 patients were enrolled. Of these, 41 (16%) received either 4-factor PCC (n=33) or FEIBA (n=8). Comparing those who received prothrombotics to those who did not, there was no difference in age (median 68 with prothrombotics and without; p=0.724), sex (44% female in both groups; p=0.977), initial NIH Stroke Scale (median 6 versus 8, p=0.838), or hematoma volume (median 15ml versus 10ml; p=0.207). Patients who received prothrombotics were more likely to have lobar ICH than deep ICH (71% versus 47%; p=0.005). DWI infarctions were found in 16% of patients who receive PCC or FEIBA compared with 22% who did not (p=0.404). Conclusions: Our data suggests prothrombotics do not increase the risk of acute ischemic infarcts within two weeks of administration.


Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Satoshi Suda ◽  
Yasuyuki Iguchi ◽  
Shigeru Fujimoto ◽  
Yoshiki Yagita ◽  
Takayuki Mizunari ◽  
...  

Background and Purpose: The characteristics of direct oral anticoagulant (DOAC)-related intracerebral hemorrhage (ICH) have not been fully clarified. We planned to recruit patients prospectively and to investigate the characteristics and outcomes in patients with ICH receiving direct oral anticoagulant (DOAC) and warfarin treatment. Methods: The prospective analysis of stroke patients taking anticoagulants (PASTA) registry study is an observational, multicenter, prospective registry of stroke patients receiving OAC. Patient enrollment started in April 2016 at 25 tertiary centers across Japan. We compared imaging, clinical characteristics, and discharge modified Rankin Scale (mRS) between DOAC- and warfarin-related ICH patients with atrial fibrillation (AF). Results: A total of 154 patients (51 women; median age 77 [quartiles 69-87] years) were analyzed. Of these, 111 patients (72%) received prior DOAC treatment and the remaining 43 (28%) received prior warfarin treatment (Fig. A, B and C). There were no relevant differences in clinical and hematoma characteristics between DOAC- and warfarin-related ICH regarding baseline hematoma volume (median [quartiles]: DOAC, 11 [5-23] mL vs. warfarin, 12 [5-30] mL; P =0.95), rate of hematoma expansion (DOAC, 12/111 [11%] vs. warfarin, 4/43 [9%]; P =0.80), rate of subcortical hemorrhage (DOAC, 15/111 [11%] vs. warfarin, 10/43 [9%]; P =0.80) and the proportion of patients with unfavorable outcome (mRS, 4-6: DOAC 76/108 [70%] vs. warfarin 23/38 [61%]; P =0.26). Cerebral microbleeds (CMBs) were detected more frequently in DOAC group than in warfarin (47/76 [62%] vs. 11/32 [34%]; P <0.01). Subgroup analyses showed that type of DOAC agent did not result in relevant differences in imaging characteristics or outcome (Fig. D and E). Conclusions: Our results showed that there were no significant differences in hematoma characteristics and functional outcome among AF patients with DOAC- or warfarin-related ICH.


Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Nerses Sanossian ◽  
Adrian M Burgos ◽  
David S Liebeskind ◽  
Sidney Starkman ◽  
Pablo Villablanca ◽  
...  

Background: Early neurologic deterioration (END) occurs commonly in intracerebral hemorrhage (ICH) patients being transported by EMS ambulances, but the imaging correlates of END have not been previously delineated. Methods: We analyzed consecutive ICH patients in the Field Administration of Stroke Therapy - Magnesium (FAST-MAG) Trial, a phase 3, multicenter of paramedic-initiated magnesium sulfate vs. placebo for stroke patients presenting within 2 hours of symptom onset. END was defined as a 2-point or greater decrease in the Glasgow Coma Scale (GCS) from paramedic evaluation to ED evaluation. Baseline imaging studies were independently analyzed by 2 neurologists for ICH location, volume, presence of intraventricular hemorrhage (IVH), heterogeneity (defined as >20 point difference in Hounsfield units), irregular hematoma borders, multilobulated appearance, and substantial edema (defined as >0.5cm thickness). Leukoaraiosis was graded using the Fazekas scale for periventricular and deep white matter changes (0-3 for each). Results: Among 127 patients, mean age was 66 (SD 14) years, 34% were women, 35% were Hispanic ethnicity, 83% white, and 84% had a history of HTN. Patients were evaluated by paramedics a median of 23 (IQR 16, 39) minutes after last known well time (LKWT). At that time, the median GCS was 15 (IQR 15-15) and mean SBP/DBP was 177/95 (SD 34/22). Initial post-arrival brain imaging was performed a median of 94 (IQR 77, 117) min after LKWT. Post-arrival study GCS scores were obtained at a median of 108 (IQR 70, 144) min after LWKT. Early neurologic deterioration occurred in 37 (29%) patients. Among these patients, median first ED GCS was 3 (IQR 3-10). On first imaging, compared with neurologically stable patients, END patients had larger hematoma volume (33 cc v 16 cc, p<0.0001), and more frequent presence of intraventricular extension (45% v 20%, p=0.003), midline shift (58% v 22%), substantial edema (54% v 26%, p=0.038), heterogeneous density (50% v 22%, p=0.006), multilobulated appearance (44% v 18%, p=0.002), and irregular border (39% v 14%, p=0.010). Leukoaraiosis and cortical v subcortical location did not affect rates of END. In multivariate analysis, hematoma volume and presence of IVH were imaging findings independently associated with early neurologic deterioration. Conclusions: About 3 in 10 patients with hyperacute ICH neurologically deteriorate during the prehospital and early emergency department course, often before neuroimaging is obtained. Patients with early neurologic deterioration have larger hematoma volume and occurrence of IVH on initial imaging. These findings suggest hematoma expansion prior to ED arrival drives early neurologic deterioration in ICH and emphasize the need for prehospital interventions.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yong Soo Kim ◽  
Han-Gil Jeong ◽  
Hee-Yun Chae ◽  
Beom Joon Kim ◽  
Jihoon Kang ◽  
...  

AbstractLow hemoglobin levels are known to be associated with hematoma expansion (HE) and poor functional outcome in patients with intracerebral hemorrhage (ICH). However, it is not yet known whether low hemoglobin itself causes HE directly or is merely a confounder. Thus, we investigated the mediation effect of the mean Hounsfield unit (HU) of hematoma on the relationship between low hemoglobin and expansion of ICH. Overall, 232 consecutive patients with ICH who underwent non-contrast computed tomography (NCCT) within 12 h since onset were included. The mean HU and hematoma volume on NCCT were investigated using semi-automated planimetry. HE was defined as an increase in hematoma volume > 33% or 6 mL. The respective associations among the hemoglobin level, mean HU, and HE were analyzed using multivariable regression analysis, adjusting for age, sex, and known HE predictors. Mediation analysis was performed to examine the potential causal association among the three. HE occurred in 34.5% of patients; hemoglobin levels were inversely associated with HE occurrence (adjusted odds ratio, 0.90; p = 0.03). The mean HU of the hematoma was lower in patients with HE than in patients without HE (58.5 ± 3.3 vs. 56.8 ± 3.0; p < 0.01). Hemoglobin levels on admission were linearly related to the mean HU (adjusted β, 0.33; p < 0.01) after adjusting for known HE predictors (time from onset to CT, antithrombotic use, hematoma volume). Causal mediation analysis showed a significant mediation effect of the mean HU on the association between hemoglobin levels and HE (p = 0.04). The proportion of indirect effect through the mean HU among the total effect was 19% (p = 0.05). The mediation effect became nonsignificant in the when the multivariable model was adjusted with additional covariates (baseline systolic blood pressure and hematoma location). The mean HU of the hematoma mediated the association between hemoglobin levels and HE occurrence. Therefore, the mean HU of the hematoma may be a potential marker of impaired hemostasis in patients with ICH.


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