BACKGROUND
Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied.


METHODS
We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death.


RESULTS
A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days.


CONCLUSIONS
Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

<h2>Summary</h2> Atrial fibrillation is one of the most common cardiac arrhythmias and is a major cause of ischaemic stroke. Recent findings indicate the importance of atrial fibrillation burden (device-detected, subclinical, or paroxysmal and persistent or permanent) and whether atrial fibrillation was known before stroke onset or diagnosed after stroke for the risk of recurrence. Secondary prevention in patients with atrial fibrillation and stroke aims to reduce the risk of recurrent ischaemic stroke. Findings from randomised controlled trials assessing the optimal timing to introduce direct oral anticoagulant therapy after a stroke show that early start (ie, within 48 h for minor to moderate strokes and within 4–5 days for large strokes) seems safe and could reduce the risk of early recurrence. Other promising developments regarding early rhythm control, left atrial appendage occlusion, and novel factor XI inhibitor oral anticoagulants suggest that these therapies have the potential to further reduce the risk of stroke. Secondary prevention strategies in patients with atrial fibrillation who have a stroke despite oral anticoagulation therapy is an unmet medical need. Research advances suggest a heterogeneous spectrum of causes, and ongoing trials are investigating new approaches for secondary prevention in this vulnerable patient group. In patients with atrial fibrillation and a history of intracerebral haemorrhage, the latest data from randomised controlled trials on stroke prevention shows that oral anticoagulation reduces the risk of ischaemic stroke but more data are needed to define the safety profile. 

Secondary stroke prevention in people with atrial fibrillation: treatments and trials

Assessing the risk of recurrent intracerebral hemorrhage (ICH) is of high clinical importance. MRI-based cerebral small vessel disease (SVD) markers may help establish ICH etiological subtypes (including cryptogenic ICH) relevant for recurrence risk.We investigated the risk of recurrent ICH in a large cohort of consecutive ICH survivors with available MRI at baseline. Patients with macrovascular, structural or other identified secondary causes (other than SVD) were excluded. Based on MRI findings, ICH etiology was defined as probable cerebral amyloid angiopathy (CAA) according to the Boston 2.0 criteria, arteriolosclerosis (non-lobar ICH and additional markers of arteriolosclerosis, absent lobar hemorrhagic lesions), mixed SVD (mixed deep and lobar hemorrhagic changes) or cryptogenic (no MRI markers of SVD). Recurrent ICH was determined using electronic health records and confirmed by neuroimaging. Data from an independent multi-center cohort (CROMIS-2 ICH) was used to confirm core findings.Of 443 patients with ICH (mean age 67±13 years, 41% female), ICH etiology was mixed SVD in 36.7%, arteriolosclerosis in 23.6%, CAA in 23.0%, and cryptogenic in 16.7%. During a median follow-up period of 5.7 years (IQR 2.9-10.0, 2682 patient-years), recurrent ICH were found in 59 individual patients (13.3%). The highest recurrence rate per 100 person-years was detected in patients with CAA (8.5, 95% CI 6.1-11.7), followed by mixed SVD (1.8, 95% CI 1.1-2.9) and arteriolosclerosis (0.6, 95% CI 0.3-1.5). No recurrent ICH occurred in patients with cryptogenic ICH during 510 person-years follow-up (97.5% CI, 0-0.7); this finding was confirmed in an independent cohort (CROMIS-2 ICH, n=216), in which there was also no recurrence in patients with cryptogenic ICH. In patients with CAA, cortical superficial siderosis was the imaging feature strongest related with ICH recurrence (hazard ratio 5.7, 95% CI 2.4-13.6).MRI-based etiological subtypes are helpful in determining the recurrence risk of ICH; while the highest recurrence risk was found in CAA, recurrence risk was low for arteriolosclerosis, and negligible for cryptogenic ICH. 

/pdf/association-of-presence-and-pattern-of-mri-markers-of-3o2npfp6.pdf

Association of Presence and Pattern of MRI Markers of Cerebral Small Vessel Disease With Recurrent Intracerebral Hemorrhage

BACKGROUND
Data comparing the specific reversal agent andexanet alfa with non-specific treatments in patients with non-traumatic intracerebral hemorrhage (ICH) associated with factor-Xa inhibitor (FXaI) use are scarce.


AIM
To determine the association between use of andexanet alfa (compared to non-specific treatments) with rate of hematoma expansion and thromboembolic complications in patients with FXaI-associated ICH.


METHODS
We performed an individual patient data analysis combining two independent, prospective studies: ANNEXA-4 (180 patients receiving andexanet alfa, NCT02329327) and TICH-NOAC (63 patients receiving tranexamic acid or placebo +/- prothrombin complex concentrate, NCT02866838). The primary efficacy outcome was hematoma expansion on follow-up imaging. The primary safety outcome was any thromboembolic complication (ischemic stroke, myocardial infarction, pulmonary embolism or deep vein thrombosis) at 30 days. We used binary logistic regression models adjusted for baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI and symptom onset to treatment, respectively.


RESULTS
Among 243 participants included, the median age was 80 years (IQR 75-84), baseline hematoma volume was 9.1ml (IQR 3.4-21) and anti-Xa activity 118ng/ml (IQR 78-222). Times from last FXaI intake and symptom onset to treatment were 11 hours (IQR 7-16) and 4.7 hours (IQR 3.0-7.6), respectively. Overall, 21% (n=50) of the patients experienced hematoma expansion (ANNEXA-4: 13%, n=24; TICH-NOAC: 41%, n=25). After adjusting for pre-specified confounders (baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI and symptom onset to treatment, respectively), treatment with andexanet alfa was independently associated with decreased odds for hematoma expansion (aOR 0.33, 95%CI 0.13-0.80, p=0.015). Overall, 11% (n=26) of patients had any thromboembolic complication within 30 days (ANNEXA-4: 11%, n=20; TICH-NOAC: 10%, n=6). There was no association between any thromboembolic complication and treatment with andexanet alfa (aOR 0.70, 95%CI 0.16-3.12, p=0.641).


CONCLUSIONS
Use of andexanet alfa compared to any other non-specific treatment strategy was associated with decreased odds for hematoma expansion, without increased odds for thromboembolic complications.

Andexanet alfa vs non-specific treatments for intracerebral hemorrhage in patients taking factor xa inhibitors - individual patient data analysis of annexa-4 and tich-noac.

Key Points Question Is prothrombin complex concentrate (PCC) treatment useful for patients who develop intracerebral hemorrhage (ICH) during direct oral anticoagulant (DOAC) usage? Findings In this cohort study of 232 patients in Hong Kong, 31% of patients with DOAC-associated ICH achieved good neurological recovery and 39% died within 90 days. PCC treatment was not associated with neurological outcomes, hematoma expansion, or survival. Meaning In this study, PCC treatment was not associated with improved functional outcome, hematoma expansion, or mortality among patients with DOAC-associated ICH.

Prothrombin Complex Concentrate vs Conservative Management in ICH Associated With Direct Oral Anticoagulants

Background and Purpose Knowledge about different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their outcomes is scarce. Methods We assessed prevalence of pre-specified ICH etiologies and their association with outcomes in consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014 to 2019). Results We included 2,650 patients (mean±standard deviation age 72±14 years, 46.5% female, median National Institutes of Health Stroke Scale 8 [interquartile range, 3 to 15]). Etiology was as follows: hypertension, 1,238 (46.7%); unknown, 566 (21.4%); antithrombotic therapy, 227 (8.6%); cerebral amyloid angiopathy (CAA), 217 (8.2%); macrovascular cause, 128 (4.8%); other determined etiology, 274 patients (10.3%). At 3 months, 880 patients (33.2%) were functionally independent and 664 had died (25.1%). ICH due to hypertension had a higher odds of functional independence (adjusted odds ratio [aOR], 1.33; 95% confidence interval [CI], 1.00 to 1.77; P=0.05) and lower mortality (aOR, 0.64; 95% CI, 0.47 to 0.86; P=0.003). ICH due to antithrombotic therapy had higher mortality (aOR, 1.62; 95% CI, 1.01 to 2.61; P=0.045). Within 3 months, 4.2% of patients had cerebrovascular events. The rate of ischemic stroke was higher than that of recurrent ICH in all etiologies but CAA and unknown etiology. CAA had high odds of recurrent ICH (aOR, 3.38; 95% CI, 1.48 to 7.69; P=0.004) while the odds was lower in ICH due to hypertension (aOR, 0.42; 95% CI, 0.19 to 0.93; P=0.031). Conclusions Although hypertension is the leading etiology of ICH, other etiologies are frequent. One-third of ICH patients are functionally independent at 3 months. Except for patients with presumed CAA, the risk of ischemic stroke within 3 months of ICH was higher than the risk of recurrent hemorrhage.

/pdf/etiology-3-month-functional-outcome-and-recurrent-events-in-3v6e2d6o.pdf

Etiology, 3-Month Functional Outcome and Recurrent Events in Non-Traumatic Intracerebral Hemorrhage

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Etiology, 3-Month Functional Outcome and Recurrent Events in Non-Traumatic Intracerebral Hemorrhage

Andexanet alfa vs non-specific treatments for intracerebral hemorrhage in patients taking factor xa inhibitors - individual patient data analysis of annexa-4 and tich-noac.