Summary

• Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and nonsteroidal anti-inflammatory drugs (NSAIDs).¹
• In the ROCKET AF study, use of fibrinolytic therapy was not permitted 10 days before randomization or throughout the study, with certain exceptions. Of patients on XARELTO in the safety population, there were 9/7111 (0.13%) patients concomitantly on alteplase during the study.^2,3
• The use of fibrinolytic therapy was excluded in the EINSTEIN and RECORD clinical trial programs.^4-8
• Sharifi et al (2014)⁹ described their experience using a combination of “safe dose” thrombolysis (SDT) and XARELTO for the treatment of moderate and severe pulmonary embolism (PE) which resulted in no major or minor in-hospital bleeding.
• Cohen et al (2021)¹⁰ conducted a retrospective chart review of 29 pediatric and young adult patients (<21 years of age) with lower extremity (LE) or inferior vena cava (IVC) thrombosis that were treated with both anticoagulation and thrombolysis therapy. A total of 8 out of the 29 patients received XARETLO. Overall, thrombus resolution occurred in 34.5% (n=10) of patients. There were one major and 3 minor bleeding events that occurred, and no treatment related deaths.
• Several case reports have been published in patients receiving intravenous tissue plasminogen activator (tPA) 8-24 hours after XARELTO administration.^11-15
• Additional citation identified during the literature search are included in the REFERENCES section for your review.¹⁶

CLINICAL STUDIES

Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation (AF)

In the ROCKET AF study, use of fibrinolytic therapy was not permitted 10 days before randomization or throughout the study, with the exception of the following: A fibrinolytic agent could be administered to subjects who experienced an ST segment elevation myocardial infarction during the study and in whom primary percutaneous intervention could not be performed, and to subjects with acute stroke in whom treatment with a fibrinolytic agent was deemed appropriate.²

Treatment of Deep Vein Thrombosis (DVT), PE, and Reduction in the Risk of Recurrence of DVT and of PE

Sharifi et al (2014)⁹ described their experience using a combination of “safe dose” thrombolysis (SDT) and XARELTO for the treatment of moderate and severe PE.

Ninety-eight consecutive patients with symptomatic PE were treated with SDT and XARELTO. All patients received a modified dose of unfractionated heparin; the dose was 70 U/kg as a bolus not to exceed 6000 U, with subsequent dose adjustment to keep partial thromboplastin time (PTT) at 60-100 seconds for 24 hours. During tPA infusion and 3 hours after, the maintenance dose of heparin was kept at 8-10 U/kg/hour, not to exceed 1000 U/hr, with a subsequent adjustment to reach target PTT of 60-100 seconds. After 24 hours of infusion, heparin was discontinued and patients received 15 mg or 20 mg of XARELTO once-daily (QD), 2 hours after discontinuation of heparin infusion. SDT was given in parallel with heparin and within 2 hours of admission for most patients.

Eighty-four patients had moderate PE, 14 patients had severe PE. All patients received at least 1 month of XARELTO therapy, 18 patients had to change to warfarin later with bridging to enoxaparin (17 for insurance reasons). Ninety-four patients received XARELTO 20 mg daily. After 12 ± 2 months, 78% of patients were still on an anticoagulation regimen. None of the patients experienced major or minor in-hospital bleeding; following discharge 1 patient developed a hematoma while bridging to enoxaparin and a XARELTO-treated patient developed hematuria after being started on amiodarone. There were no recurrent venous thromboembolisms (VTEs) in the hospital; between 5 and 9 months after discharge, recurrent VTE occurred in 2 patients and PE occurred in 1 patient who was switched to warfarin, and no patients on XARELTO developed VTE. There was no in-hospital mortality.

Retrospective Chart Review in Pediatric/Young Adult Patients with Lower Extremity or Inferior Vena Cava Thrombosis

Cohen et al (2021)¹⁰ performed a retrospective chart review of pediatric and young adult patients (<21 years of age) with LE or IVC thrombosis that were treated with both anticoagulation and thrombolysis therapy. Patients received thrombolysis via an indwelling venous catheter (tPA overnight), or a bolus tPA administration during a single interventional procedure at the Texas Children’s Hospital from January 2015-March 2020 (N=29).

In order to be included in this analysis, patients must have received a therapeutic course of anticoagulation for at least 6 weeks. The median length of anticoagulation treatment was 8.5 months, for all but three patients whose anticoagulation regimens were not available. Nine of the remaining patients were on indefinite anticoagulation at the time of chart review (5 on warfarin and 4 on XARELTO).

In the 8 total patients that received XARELTO (age range, 14-18 years), dosing was consistent with the EINSTEIN Junior trial and the average time on XARELTO was 12.3 months. Seven of the eight patients switched to XARELTO after a period of unfractionated heparin treatment during or immediately following the thrombolysis procedure. One patient was switched from bivalirudin to XARELTO due to heparin-induced thrombocytopenia. Out of the 29 total patients in this analysis, one received XARELTO before the thrombolysis intervention (3.4%) and eight received XARELTO after the thrombolysis intervention (27.6%).

The main outcomes were efficacy (measured by complete thrombus resolution), and safety (measured by bleeding events following the procedure). The six month follow up image (or closest available to six months after diagnosis) was utilized to determine efficacy.

Out of the 29 patients included in this analysis, 22 received overnight catheter directed thrombolysis (CDT) and 7 received single session thrombolysis. The median time of patient follow up after thrombus diagnosis was 13 months (range 0.2-60). A total of 93.1% (n=27) and 13.8% (n=4) of the thromboses evaluated were in the LEs and IVC, respectively.

Follow up imaging revealed complete thrombus resolution in 34.5% (10/29) of patients (including 4 patients that received single session thrombolysis and 6 that received CDT). Thrombus progression or recurrence occurred in 34.5% (n=10) of patients (including 1 patient that received single session thrombolysis and 9 that received CDT).

Patients that received XARELTO had a higher rate of thrombus resolution compared to those who did not (75% vs. 19%, odds ratio=12.75, 95% confidence interval [CI]-2.10-114.33). This remained consistent after controlling for the potential confounder of ethnicity. This data is based on 8 children who also received other anticoagulants during their treatment course.

Minor bleeding complications occurred in 10.3% (3/29) of patients, with 3.4% (1/29) experiencing a major bleeding episode following interventional procedure. There were no treatment related deaths.

CASE REPORTS

Yoshida et al (2022)¹⁵ reported a case of an 83-year-old Japanese female patient who developed right hemiplegia and motor aphasia 3 days after receiving her first dose of the Pfizer/BioNTech Coronavirus Disease 2019 (COVID-19) vaccine (BNT162b2). The patient was on XARELTO for persistent AF for 10 years but had no symptomatic ischemic stroke. Blood tests revealed elevated thrombin-antithrombin complex (TAT) of 12.7 ng/mL and D-dimer of 2.8 μg/mL. Electrocardiogram (ECG) confirmed AF. Magnetic resonance imaging (MRI) showed that the proximal M1 segment of the left middle cerebral artery (MCA) was occluded, with ischemic area localized to only a part of the left insular cortex and corona radiata. Intravenous recombinant tPA was initiated, mechanical thrombectomy was performed, and the patient was successfully recanalized ~3.5 hours after onset. The patient recovered almost fully with rehabilitation and was discharged. Transthoracic echocardiography showed no thrombus in the left atrial appendage. XARELTO was replaced with edoxaban. Three weeks after the first injection, the patient received a second dose of BNT162b2, 3 days after which the patient developed left hemiplegia and left hemispatial neglect. Blood tests again showed elevated TAT of 23.0 ng/dL and D-dimer of 3.2 μg/mL. MRI showed occlusion of the right MCA proximal M1 segment, with ischemic areas only in a part of the right insular cortex, caudate, and corona radiata. As recombinant tPA was contraindicated, only mechanical thrombectomy was performed again but could not be resumed due to the hard thrombus. Repeat MRI showed that the ischemic area had spread to almost the entire right MCA area, and the symptoms did not recover. Antiphospholipid antibodies were negative, and the transoesophageal echocardiogram showed no thrombus in the left atrial appendage. Blood coagulation and fibrinolysis system markers almost normalized 2 weeks after the onset of the second stroke.

Penge et al (2015)¹³ reported a case of a 61-year-old man who presented within 150 minutes of sudden onset right-sided hemiparesis and severe dysphasia. Standard dose tPA was administered with an onset-to-needle time of approximately 180 minutes. His last dose of XARELTO 20 mg was approximately 8 hours before receiving tPA. After 8 days, the patient was discharged with clinical improvement and no complications.

van Hooff et al (2014)¹⁴ reported a case of an 80-year-old male patient with acute ischemic stroke who was treated with tPA after receiving XARELTO therapy. The last intake of XARELTO 20 mg was 24 hours before presentation. tPA therapy was initiated 135 minutes after stroke onset. The patient gradually improved with persisting motor aphasia. The only complication of therapy was mild and self-limiting hematuria.

Seiffge et al (2014)¹¹ reported two cases of patients with low plasma levels of XARELTO who were administered intravenous thrombolysis therapy.

• Case 1: A 74-year-old patient with newly diagnosed AF presented with severe right sided hemiparesis and aphasia. The last intake of XARELTO 20 mg was 18 hours prior and XARELTO plasma level was 10 ng/mL. tPA was administered with a door-to-needle time of 45 minutes. At 24-hour follow-up, the patient recovered partly with no bleeding complications.
• Case 2: A 78-year-old patient presented with fluctuating signs of posterior circulation stroke. The last intake of XARELTO 20 mg was 22 hours prior and the XARELTO plasma level was 67 ng/mL. tPA was administered with a door-to-needle time of 50 minutes. The patient recovered partly with no major bleeding complications.

Kawiorski et al (2014)¹² reported a case of an 83-year-old female patient, diagnosed with nonvalvular AF due to mesenteric embolism four months prior to admission, who presented with acute onset of aphasia and right sided hemiparesis. Her last dose of XARELTO 15 mg was 22 hours prior to admission. tPA was administered 4 hours after the onset of stroke symptoms. After 9 days, the patient was discharged without significant disability.

IN VITRO DATA

Varin et al (2008)¹⁷ tested the effects of XARELTO on clot structure and degradability by tPA. Microscopy findings showed that clots formed in the presence of XARELTO had a looser fibrin structure with wider pores and thicker fibers than the control clots. This modified clot structure was associated with an increase in permeation rates. The degradability of clots perfused with tPA showed that the modification of the clot structure and increase in clot porosity renders clots more susceptible to fibrinolytic enzymes. XARELTO improved tPA mediated thrombolysis through a decrease in thrombin generation via two mechanisms: modification of the clot structure and decrease in thrombin-activatable fibrinolysis inhibitor (TAFI).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 13 January 2025. Common examples of tissue plasminogen activators may include alteplase, reteplase, and tenecteplase.