Clinical trial NCT02506985: XENITH: Rivaroxaban for Pulmonary Embolism Managed With Catheter Directed Thrombolysis
Official title: XENITH: Rivaroxaban for Pulmonary Embolism Managed With Catheter Directed Thrombolysis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Pulmonary Embolism
Venous Thrombosis
Keywords: Rivaroxaban
CDT (Catheter directed thrombolysis)
PE (pulmonary embolism)
NETs
factor Xa
Lead sponsor: University of Kentucky
Sponsor class: OTHER
Collaborators: name: Janssen Scientific Affairs, LLC
First posted: 2015-07-23
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The trial is an open-label, randomized, trial examining novel biomarkers of thrombosis in patients managed with rivaroxaban vs. standard care following treatment of pulmonary embolism (PE) with catheter-guided alteplase. Patients \>18 years old who present with PE and are managed with catheter-guided alteplase will be screened for study inclusion. Patient's meeting inclusion/exclusion criteria will undergo informed consent. Immediately following completion of alteplase infusion, patients will be randomized to receipt of rivaroxaban 15 mg oral bid for 21 days followed by 20mg oral daily or continuation on unfractioned heparin or low-molecular weight heparin with initiation of warfarin adjusted to INR of 2-3. Blood samples will be taken within 2 hours of CDT completion prior to receipt of study treatment (study day 1), at 8h-12h, 24h, 48h, 5d (or prior to hospital discharge), and at 30 day follow-up. Clinical endpoints, including bleeding, evidence of thrombosis progression, and death will be tracked during index hospitalization and at follow-up 30 days post-discharge.

Detailed description: Catheter-guided alteplase has a growing role in the management of acute pulmonary embolism (PE). Following a 12-24 hour alteplase infusion (for bilateral or unilateral PE, respectively) patients are routinely managed with therapeutic unfractionated heparin (UFH) as a bridge to chronic warfarin therapy. It is our desire to study the effects of rivaroxaban vs. standard care following catheter-guided alteplase thrombolytic therapy (CDT) in patients with acute pulmonary embolism. Use of rivaroxaban may offer several important advantages compared to standard therapy in this setting. Among these is the potential for rivaroxaban to improve novel biomarkers of thrombosis including inhibition neutrophil extracellular traps (NETs), tissue factor-positive microparticles, and markers of inflammation. Neutrophil release of extracellular DNA may provide a scaffold upon which venous thrombosis propagates. NETs are associated with thrombus organization. Their dissolution may facilitate thrombolysis. Circulating DNA, a surrogate marker for NETs, is elevated 2-3 fold in patients with venous thromboembolism (VTE) and correlates strongly with plasma myeloperoxidase (MPO), an inflammatory marker of neutrophil and monocyte activation. The investigators have previously demonstrated that heparin can trigger MPO release from leukocytes. Thus, it is resonable to speculate that anti-Xa therapy may reduce inflammation, MPO, and NET levels in circulation. Further, the investigators have observed that catheter-directed thrombolysis may increase length of stay (time frame = 8 hours to 30 days following administration of study drugs) and the investigators would also propose treatment with rivaroxaban may balance this by eliminating a "bridging" period.

Eligibility criteria: Inclusion Criteria:

* Provisions of informed consent prior to any study specific procedure
* Diagnosis of acute PE
* Evidence of RV strain as defined by one of the following:
* 1. an RV-to-LV diameter ratio\>0.9
* 2. elevated troponin
* 3. elevated BNP
* Plan for CDT for PE.

Exclusion Criteria:

* Arterial hypotension and cardiogenic shock at the time of enrollment. Arterial hypotension defined as a systolic arterial pressure \<90mm Hg or a drop in systolic arterial pressure of at least 40 mm Hg for at least 15 minutes with tissue hypoperfusion and/or hypoxia)
* Hypersensitivity or other reaction to rivaroxaban
* Other indication for VKA than PE
* Creatinine clearance \<30 ml/min
* Significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or ALT \> 3 x ULN
* Life expectancy \<3 months

Primary outcomes:
measure: Change in Markers of NETosis at 12h Compared to Baseline
timeFrame: 12h
measure: Change in Markers of NETosis at 24h Compared to Baseline
timeFrame: 24h
measure: Change in Markers of NETosis at 48h Compared to Baseline
timeFrame: 48h
measure: Change in Markers of NETosis at 5 Days (or Day of Hospital Discharge) Compared to Baseline
timeFrame: 5 days (or day of hospital discharge)
measure: Change in Markers of NETosis at 30 Days Compared to Baseline
timeFrame: 30 days
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: University of Kentucky
name: Susan S Smyth, MD PhD
role: PRINCIPAL_INVESTIGATOR
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