SUMMARY  

• RIVA-TWICE, a prospective study assessed the safety and efficacy of XARELTO 15 mg twice a day (BID) for 8 weeks for lysis of thrombus in the left atrial appendage (LAA) in patients with nonvalvular atrial fibrillation (NVAF) despite treatment with XARELTO 20 mg once daily. Of the 15 patients qualified for the study, 46.7% experienced (n=7) complete resolution of the thrombus.¹
• X-TRA, a prospective study that explored use of once daily XARELTO in the treatment of transesophageal echocardiography (TEE)-detected left atrial (LA)/LAA thrombus in patients with NVAF or atrial flutter, showed that thrombus resolution and reduction following XARELTO treatment was evident and consistent with LA/LAA thrombus resolution observed with vitamin K antagonist (VKA) therapy in prior retrospective, observational case series and the retrospective CLOT-AF registry.^2,3
• CLOT-AF, a retrospective registry independent from the prospective X-TRA study, was designed to collect baseline data and thrombus-related patient outcome data following standard-of-care anticoagulant treatment in patients with NVAF or atrial flutter who had TEE-confirmed LA/LAA thrombus. This data is to be used as a reference for the prospective X-TRA study described above.^2,3
• XARELTO is not indicated for the treatment of atrial thrombus. Case reports of this offlabel use have been summarized below.^4-18
• A retrospective, single-center observational study designed to compare the effectiveness of XARELTO, warfarin, and dabigatran for resolution of LA thrombus in hospitalized patients with NVAF found no significant difference in thrombus reduction among the three treatment groups (P=0.493).¹⁹
• In a retrospective study designed to assess prevalence and predictors of LAA thrombus by means of TEE performed prior to elective electrical cardioversion or catheter ablation in patients with atrial fibrillation (AF) treated with different novel oral anticoagulants (NOACs; XARELTO, apixaban, or dabigatran), the incidence of LAA thrombus was low and similar among the 3 treatment groups.²⁰
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^21-25

CLINICAL DATA

RIVA-TWICE

Piotrowski et al (2020)¹ conducted a prospective, open label study with non-blinded patients and blinded assessors to assess the safety and efficacy of XARELTO 15 mg BID for 8 weeks for lysis of thrombus in the LAA in patients with NVAF. All patients had developed a thrombus despite been treated with XARELTO 20 mg once daily.

Study Design/Methods

• At baseline and after 8 weeks, TEE was performed on eligible patients ≤80 years old, had a thrombus in the LAA while on XARELTO once daily dose, creatinine clearance (CrCl) ≥30mL/min/1.73m², no serious liver dysfunction, and no history of major bleeding. Patients of childbearing potential were included with documentation of effective contraception.
• XARELTO dosing was scheduled for morning and evening with a meal.
• Using the anti-factor Xa chromogenic method, the anticoagulant effects of XARELTO were assessed. Measurements were taken during once daily dosing and after 8 weeks of BID dosing at 3, 12, and 24 hours after the morning dose during both 20 mg once daily and after switching to 15 mg BID.
• Reported bleeding events were classified using the Bleeding Academic Research Consortium (BARC) scale.

Results

• A total of 15 patients, 60% male and mean age 63±10 years, qualified for the study.
• Seven (46.7%) patients experienced completed resolution of the thrombus in the LAA.
• A lower CHA₂DS₂-VASc (congestive heart failure, hypertension, age ≥75 [doubled], diabetes, stroke [doubled], vascular disease, age 65 to 74 and sex category [female]) score (2.3±1.5 vs 4.0±1.5, P=0.0463) and HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, age >65, drugs/alcohol concomitantly) score (0.7±0.8 vs 1.8±0.7, P=0.0168) was observed in the 7 patients with dissolved thrombus. The same patients had a higher mean LAA emptying velocity (0.27±0.09 vs 0.18+0.02 m/s, P=0.0198).
• XARELTO 20 mg once daily dose duration prior to the XARELTO 15 mg BID dose was similar between the patients with thrombus resolution (n=7) versus patients with persistent thrombus (n=8).
• Anti-Xa activity was higher during BID dosing than once daily dosing of XARELTO. No significant differences were observed in the mean values of anti-Xa factor activity between the thrombus resolution patients and the persistent thrombus patients.
• There were no bleeding events reported, all patients had a BARC scale score of 0.

X-TRA

Lip et al (2016)^2,3 conducted a prospective, single-arm, open-label, multicenter study to explore the use of XARELTO for the treatment of LA/LAA thrombus in patients with NVAF or atrial flutter.

Study Design/Methods

• Eligible patients had to be: ≥18 years of age with hemodynamically stable NVAF or atrial flutter and LA/LAA thrombus documented by TEE up to 72 hours prior to start of study drug treatment; and VKA/NOAC-naïve or untreated within 1 month prior to signing the consent form (treatment up to 72 hours with VKA, heparin, or a lowmolecular-weight heparin was allowed prior to XARELTO initiation), or, following an amendment, VKA-pretreated, but with suboptimal or ineffective international normalized ratio (INR) levels within the last 6 weeks.
• Patients with previous intracardiac thrombus, free-floating ball thrombus, intracardiac tumor, known left ventricular or aortic thrombosis, active endocarditis, CrCl <15 mL/min at screening, or hepatic disease associated with coagulopathy and leading to clinically relevant bleeding risk were excluded from the study.³
• Patients received XARELTO 20 mg once daily (15 mg once daily in patients with CrCl 1549 mL/min) for 6 weeks, followed by standard-of-care treatment during the 30-day follow-up period.
• The primary outcome was complete LA/LAA thrombus resolution rate on the centrally adjudicated TEE at the end of treatment (EOT) following 6 weeks of treatment with XARELTO.
• Secondary outcomes included: centrally adjudicated categories of thrombus outcome (resolved, reduced, unchanged, larger, or new) confirmed on TEE at EOT; incidence of the composite of stroke and non-central nervous system (non-CNS) systemic embolism at EOT and during follow-up; and incidence of all bleeding events (major bleeding according to International Society on Thrombosis and Hemostasis [ISTH] criteria and nonmajor bleeding) at EOT and during follow-up.

Results

• Sixty patients were included in the intention-to-treat (ITT) population and 53 patients with complete TEE data were included in the modified intention-to-treat (mITT) population.²
• The majority of patients (95.0%) were from Eastern European countries, 50% were male, mean age was 70 years, 76.6% had persistent, long-standing persistent, or permanent AF, and the median CHADS₂ (congestive heart failure, hypertension, age ≥75, diabetes, stroke [doubled]) and CHA₂DS₂-VASc scores were 2 and 4, respectively.²
• A total of 81.7% of the ITT patients received oral XARELTO 20 mg once daily and 18.3% with moderate-to-severe renal impairment received XARELTO at a dose of 15 mg once daily.²
• The adjudicated thrombus resolution rate was 41.5% (22/53 mITT patients, 95% confidence interval [CI]: 28.1%-55.9%) based on central TEE assessments. Resolved or reduced thrombus was observed in 60.4% of patients (32/53 mITT patients, 95% CI: 46.0%-73.6%).²
  • Those who experienced thrombus resolution had lower thromboembolic risk scores (CHADS₂/CHA₂DS₂-VASc) and were older (>75 years of age).
• Stroke, non-CNS systemic embolism, and major bleeding were not reported during the treatment period or 30-day follow-up period; nonmajor bleeding events were reported in 5 patients.²
• Treatment-emergent adverse events (TEAEs) were reported in 36.7% of patients. Overall, 3 patients experienced TEAEs that were considered to be XARELTO-related (1 event each of ear hemorrhage, gingival bleeding, and petechia).²

CLOT-AF

The objective of the CLOT-AF registry, a retrospective, observational study, was to provide thrombus-related patient outcome data following standard-of-care anticoagulant treatment in patients with NVAF or atrial flutter who had TEE-documented LA/LAA thrombi.^2,3 This data is to be used as a reference for the prospective X-TRA study described above.

Study Design/Methods

• Patients ≥18 years of age with hemodynamically stable NVAF or atrial flutter, in whom LA/LAA thrombus had been documented by baseline TEE, were evaluated.³
• Patients were excluded if they had valvular AF, a history of cardiac thrombus (confirmed on TEE), intracardiac tumors, or active endocarditis.³
• As the study was retrospective and observational in nature, the choice of anticoagulant was at the discretion of the treating physician.³
• The primary outcome was the reported thrombus resolution rate confirmed on a TEE following 3 to 12 weeks of anticoagulation therapy, based on the routine practice of the participating centers without central adjudication.
• Secondary outcomes included: rates of stroke or non-CNS systemic thromboembolism and all bleeding events (major [ISTH criteria], nonmajor, unknown severity).

Results

• Medical records at the study sites encompassed the period between January 2010 to February 2013.²
• The ITT population included 156 patients (at 23 centers of the same 7 countries as XTRA study); the mITT population with complete TEE data included 96 patients.²
• A total of 52.6% of patients were from Eastern countries and 47.4% were from Western countries, 66.0% were male, mean age was 68 years, 62.0% were ≥65 years of age, 56.4% had persistent, long-standing persistent, or permanent AF, and the median CHADS₂ and CHA₂DS₂-VASc scores were 2.0 and 3.0, respectively.²
• A total of 148/156 (94.9%) patients had a record of anticoagulation treatment, with VKA being used in the majority of patients (127/156 [81.4%] patients), either alone or in combination with another treatment.²
• The reported thrombus resolution rate was 62.5% (60/96 mITT patients, 95% CI: 52.0%-72.2%) and appeared better in Western European countries (34/50 [68.0%] patients) vs Eastern European countries (26/46 [56.5%] patients).²
• Stroke/non-CNS systemic embolism after baseline TEE or with unknown start date was reported in 4/156 patients. Major bleeding was reported in 1 patient who had spontaneous nonhemorrhoidal bleeding in the gastrointestinal tract (with INR <2.0).²

CASE REPORTS

REAL-World Evidence

Yang et al (2023)¹⁹ conducted a retrospective, single-center observational study to compare the effectiveness of XARELTO, warfarin, and dabigatran for resolution of LA thrombus in hospitalized patients with NVAF and valvular atrial fibrillation (VAF) from June 2018 to December 2021. A total of 103 patients (43.7% male; mean age 58.9±11.9 years; 50 had NVAF and 53 had VAF) were anticoagulated using XARELTO (n=30), warfarin (n=59) and dabigatran (n=14).

• Of the 50 patients with NVAF, 30 (60%), 6 (12%), and 14 (28%) patients were treated with XARELTO, warfarin, and dabigatran, respectively.
  • No significant difference was found between anticoagulant medications for reducing thrombus in LA (P=0.493). LA thrombus resolved in 80% of patients treated with XARELTO.

Bertaglia et al (2017)²⁰ conducted a retrospective, multicenter, observational study to determine the incidence and predictors of LA thrombus in patients with NVAF who received XARELTO, apixaban, or dabigatran for ≥3 weeks. The study analyzed 414 consecutive, adult patients (60.6% male, mean age: 67.3 years) with a CHA₂DS₂-VASc score of ≥1, who were referred for catheter ablation (n=220, 53.1%) or electrical cardioversion (n=194, 46.9%). Patients were anticoagulated on dabigatran (n=160), XARELTO (n=150), or apixaban (n=104) for ≥3 weeks. All patients underwent TEE, which was performed within 12 hours prior to ablation or just before cardioversion. XARELTO was discontinued 24 hours prior to ablation, while apixaban and dabigatran were discontinued 12 hours prior.

• Data from 414 consecutive patients on NOACs, referred for AF catheter ablation (n=220, 53.1%) or scheduled electrical cardioversion (n=194, 46.9%), were collected.
  • Of these, 150 (36.2%) were treated with XARELTO, 104 (25.1%) were treated with apixaban, and 160 (38.7%) were treated with dabigatran.
• Clinical and echocardiographic characteristics were similar between treatment groups.
• Preprocedural TEE revealed LA thrombus in 15/414 (3.6%) patients, all located in the LAA (apixaban, 3/104 [2.9%], dabigatran, 5/160 [3.1%], and XARELTO, 7/150 [4.7%]; P=0.69).
  • Patients with LAA thrombus had a mean CHA₂DS₂-VASc score of 3 and a mean LA volume of 78 mL; a total of 14 of these 15 patients had persistent AF.
  • Higher CHA₂DS₂-VASc score (P=0.02), but not the type of NOAC, significantly predicted LA thrombus.
    • History of heart failure, diabetes, and prior stroke/transient ischemic attack (TIA) were among the variables of the CHA₂DS₂-VASc score that predicted LAA thrombus.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 03 May 2024.