Summary

• In an open-label, single-arm study of patients with nonvalvular atrial fibrillation (NVAF) treated with XARELTO initiated ≤14 days after transient ischemic attack (TIA) or moderate ischemic stroke, no patients developed symptomatic hemorrhagic transformation or parenchymal hemorrhage with follow-up magnetic resonance imaging (MRI) on day 7.¹
• The Acute Stroke with XARELTO to Reduce Intracranial Hemorrhage, Recurrent Embolic Stroke, and Hospital Stay (Triple AXEL) study was a proof-of-concept, phase 2, multicenter, randomized, parallel-group, open-label, blinded endpoint evaluation study in South Korea, designed to compare the efficacy and safety of XARELTO vs dose-adjusted warfarin for prevention of early recurrent stroke in patients with atrial fibrillation (AF)-related acute ischemic stroke.^2,3
  • The XARELTO group (n=95) and the warfarin group (n=88) showed no differences in the primary composite endpoint of new ischemic lesion or new intracranial hemorrhage seen on MRI imaging at 4 weeks (49.5% vs 54.5%, relative risk [RR], 0.91; 95% confidence interval [CI], 0.69-1.20; P=0.49), or its individual components.
  • XARELTO or warfarin initiated within 5 days of stroke onset had comparable safety and efficacy in preventing early clinical ischemic stroke recurrence in patients with mild AF-related acute ischemic stroke.
• An additional citation identified during a literature search has been included in the REFERENCES section for your review.⁴

CLINICAL STUDIES

Gioia et al (2016)¹ conducted a prospective, open-label, single-arm study of patients with NVAF treated with XARELTO initiated ≤14 days after TIA or moderate ischemic stroke (National Institute of Health [NIH] Stroke Scale <9).

• Dosing of XARELTO was based on renal function (estimated glomerular filtration rate [eGFR] 30-50 mL/min: 15 mg daily, eGFR >50 mL/min: 20 mg daily).
• All patients underwent MRI at baseline and on day 7.
• The primary endpoint was symptomatic hemorrhagic transformation on day 7 (defined as parenchymal hemorrhage [PH]2 associated with ≥4-point increase in NIH Stroke Scale score).
• Sixty patients (n=49, ischemic stroke; n=11, TIA) were enrolled in the study.
• The median (interquartile range) time from symptom onset to XARELTO initiation was 3 (1.5 to 6) days.
• At baseline, hemorrhagic transformation was present in 25 (42%) patients (hemorrhagic infarct [HI]1, n=19; HI2, n=6).
• On follow-up MRI on day 7, no patients developed symptomatic hemorrhagic transformation or parenchymal hemorrhage.
• New asymptomatic HI1 developed in 3 patients, and asymptomatic progression from H1 to H2 occurred in 5 patients.
• Recurrent ischemic events included 1 TIA (day 5, MRI negative) and 1 ischemic stroke (small cerebellar infarcts on day 28 computed tomography scan in a 95-year-old patient who never left the hospital after the initial stroke and later died after withdrawal of care).
• Additionally, 1 patient died from aspiration pneumonia.
• No systemic bleeding complications or other serious adverse events occurred.

Triple AXEL

The Triple AXEL trial was a proof-of-concept, phase 2, multicenter, randomized, parallel-group, open-label, blinded-endpoint evaluation study in South Korea designed to compare the efficacy and safety of XARELTO vs dose-adjusted warfarin for prevention of early recurrent stroke in patients with AF-related acute ischemic stroke.^2,3

• Adult patients (≥19 years of age) diagnosed with NVAF (including paroxysmal AF; documented by electrocardiogram or an MRI-confirmed acute ischemic stroke within 5 days due to presumed cardioembolism) and considered suitable for early anticoagulation, after taking into account the severity of the ischemic lesion, were included in the study.
• Patients with significant hemorrhagic transformation, mechanical heart valves, stroke caused by presumed small vessel occlusion, severe renal impairment (creatinine clearance [CrCl] <30 ml/min), and at high risk of intracranial or systemic bleeding were excluded from the study.

Study Design/Methods

• Prior to randomization:
  • Patients received aspirin following MRI-confirmed acute ischemic lesion.
  • Low-dose subcutaneous heparin or low-molecular-weight heparin for the prevention of deep vein thrombosis (DVT) or pulmonary embolism (PE) was used at the discretion of the responsible physicians.
• Eligible patients were randomly allocated 1:1 to receive XARELTO or dose-adjusted warfarin (target international normalized ratio [INR]: 2-3).
  • Patients in the XARELTO arm received XARELTO 10 mg once daily for the first 5 days, followed by XARELTO 20 mg once daily (or 15 mg once daily for patients with CrCl 30-49 mL/min).
  • Aspirin was stopped 24 hours before the initiation of XARELTO. Aspirin was continued for patients in the warfarin arm until an INR of 1.7 was reached.
  • Heparin for prophylaxis of DVT or PE was stopped 24 hours before the initiation of XARELTO. Heparin was continued for patients in the warfarin arm until an INR of 1.7 was reached.
• MRIs were performed at 4 weeks to assess for new ischemic lesions and new intracranial hemorrhage. Patients who experienced clinical ischemic stroke or symptomatic intracranial hemorrhage before the end of the study underwent MRI at the time of the clinical event.
• Upon completion of the treatment phase, patients in the XARELTO arm were transitioned to warfarin with a 5-day overlap. Patients willing to pay for XARELTO at their own expense continued taking XARELTO.
• The primary outcome was the composite of new ischemic lesion or new intracranial hemorrhage on follow-up MRI at 4 weeks.
• Prespecified secondary outcomes included:
  • New ischemic lesion
  • New intracranial hemorrhage
  • Length of hospitalization
  • Major bleeding as defined by the International Society on Thrombosis and Hemostasis
  • Acute coronary syndrome
  • Composite of major vascular events, including stroke, myocardial infarction, and vascular death
  • Composite of major vascular events plus major bleeding
  • Composite of clinical ischemic events
  • Modified Rankin Scale score at 4 weeks

Results³

• In total, 195 patients were randomized: 101 to XARELTO and 94 to warfarin.
  • Of the 195 patients randomized, 183 patients were included in the modified intent-to-treat population (95 in the XARELTO group and 88 in the warfarin group).
• Baseline demographic and clinical characteristics were well balanced. However, the XARELTO arm had more patients with a history of type 2 diabetes (25.3% vs 11.4%, respectively) and a smaller median initial ischemic lesion volume on DWI (2.6 cm³ vs 5.5 cm³, respectively) compared to the warfarin arm. The median interval from stroke onset to randomization was 2 days, the mean prestroke CHA₂DS₂-VASc score was 2.5, the mean HAS-BLED score was 1.3, and the median NIH Stroke Scale score at randomization was 2.
• In the warfarin group, the proportion of patients who achieved a target INR of 2 to 3 was 40.9% at 5 days, 53.4% at 2 weeks, and 46.6% at 4 weeks. The mean (standard deviation) INR value in the warfarin group was 2.04 (0.62) at 5 days, 2.67 (0.92) at 2 weeks, and 2.39 (0.83) at 4 weeks.
• The primary outcome occurred in 47 patients (49.5%) in the XARELTO arm and in 48 patients (54.5%) in the warfarin arm (RR, 0.91; 95% CI, 0.69 to 1.20; P=0.49). The difference was also not statistically significant when adjusting for age, sex, initial ischemic lesion volume on DWI, diabetes, prior vitamin K antagonist, concomitant antiplatelet use, and center (RR, 0.97; 95% CI, 0.79-1.18; P=0.73).
• New ischemic lesions were seen in 29.5% of patients in the XARELTO arm and in 35.6% of patients in the warfarin arm (RR, 0.83; 95% CI, 0.54-1.26; P=0.38).
• New intracranial hemorrhages were seen in 31.6% of patients in the XARELTO group and in 28.7% of patients in the warfarin group (RR, 1.10; 95% CI, 0.70-1.71; P=0.68). There were no symptomatic intracranial hemorrhages in the treatment groups; all intracranial hemorrhages were asymptomatic hemorrhagic transformations within or adjacent to the qualifying ischemic lesion.
• Hospitalization length was reduced with XARELTO compared with warfarin (median, 4.0 days [interquartile range, 2.0–6.0 days] vs 6.0 days [interquartile range, 4.0-8.0]; P<0.001).
• Primary and prespecified secondary outcome results from the Triple AXEL study are presented in Table: Primary Outcome Results in the Triple AXEL Study and Table: Secondary Outcome Results in the Triple AXEL Study.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases), conducted on 05 August 2024, did not identify any relevant citations pertaining to this topic.