XENITH: Rivaroxaban for Pulmonary Embolism Managed With Catheter Directed Thrombolysis (XENITH)

August 30, 2018 updated by: Susan Smyth
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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Phase 4

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: rivaroxaban
For the first 3 weeks, patients will receive rivaroxaban 15mg twice-daily; thereafter they will take rivaroxaban 20mg once-daily as per the drug label. Rivaroxaban will be initiated immediately following completion of alterplase infusion, and heparin will be discontinued at the time of rivaroxaban administration.
Drug: rivaroxaban
Immediately following completion of alteplase infusion, patients will receive rivaroxaban 15 mg oral bid for 21 days followed by 20 mg oral daily.
Other Names:
  • Xarelto
Experimental: heparin-warfarin
Unfractioned heparin (UFH), following hospital protocol to achieve a target PTT or enoxaparin, 1.0mg/kg twice-daily, for a minimal duration of treatment of 5 days. Warfarin may be started on the night after CDT. UFH or enoxaparin should continue until the INR is >= 2.0 on two consecutive measurements at least 24 hours apart with an advised overlap with VKA for 4 to 5 days. VKA dosages will be adjusted to maintain the INR within the therapeutic range (target 2.5, range 2.0 - 3.0).
Drug: warfarin
Immediately following completion of alteplase infusion, patients will continue on unfractionated heparin or low-molecular weight heparin with initiation of warfarin adjusted to INR of 2-3.
Other Names:
  • Coumadin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Markers of NETosis at 12h Compared to Baseline
Time Frame: 12h
Change in Markers of NETosis at 12h Compared to Baseline
12h
Change in Markers of NETosis at 24h Compared to Baseline
Time Frame: 24h
Values will be reported in comparison to baseline in the two treatment groups.
24h
Change in Markers of NETosis at 48h Compared to Baseline
Time Frame: 48h
Values will be reported in comparison to baseline in the two treatment groups.
48h
Change in Markers of NETosis at 5 Days (or Day of Hospital Discharge) Compared to Baseline
Time Frame: 5 days (or day of hospital discharge)
Change in Markers of NETosis at 5 days (or day of hospital discharge) Compared to Baseline. Values will be reported in comparison to baseline in the two treatment groups.
5 days (or day of hospital discharge)
Change in Markers of NETosis at 30 Days Compared to Baseline
Time Frame: 30 days
Values will be reported in comparison to baseline in the two treatment groups.
30 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Susan Smyth

Collaborators

Janssen Scientific Affairs, LLC

Investigators

  • Principal Investigator: Susan S Smyth, MD PhD, University Of Kentucky

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2015

Primary Completion (Actual)

June 29, 2016

Study Completion (Actual)

June 29, 2016

Study Registration Dates

First Submitted

June 17, 2015

First Submitted That Met QC Criteria

July 21, 2015

First Posted (Estimate)

July 23, 2015

Study Record Updates

Last Update Posted (Actual)

September 27, 2018

Last Update Submitted That Met QC Criteria

August 30, 2018

Last Verified

August 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 15-0275-F6A

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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