XENITH: Rivaroxaban for Pulmonary Embolism Managed With Catheter Directed Thrombolysis

Pulmonary Embolism Clinical Trial

— XENITH  

Official title:

XENITH: Rivaroxaban for Pulmonary Embolism Managed With Catheter Directed Thrombolysis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02506985
• Other study ID #: 15-0275-F6A
• Status: Terminated
• Phase: Phase 4
• Start date: July 2015
• Est. completion date: June 29, 2016

Study information

• Verified date: August 2018
• Source: University of Kentucky
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 10
• Est. completion date: June 29, 2016
• Est. primary completion date: June 29, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Embolism
• Pulmonary Embolism
• Thrombosis
• Venous Thrombosis

Intervention

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.
• 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.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Susan Smyth	Janssen Scientific Affairs, LLC

References & Publications (14)

Bain J, Oyler DR, Smyth SS, Macaulay TE. Pathophysiology and pharmacologic treatment of venous thromboembolism. Curr Drug Targets. 2014 Feb;15(2):199-209. Review. — View Citation

Brill A, Fuchs TA, Savchenko AS, Thomas GM, Martinod K, De Meyer SF, Bhandari AA, Wagner DD. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost. 2012 Jan;10(1):136-44. doi: 10.1111/j.1538-7836.2011.04544.x. — View Citation

Bugert P, Pabinger I, Stamer K, Vormittag R, Skeate RC, Wahi MM, Panzer S. The risk for thromboembolic disease in lupus anticoagulant patients due to pathways involving P-selectin and CD154. Thromb Haemost. 2007 Apr;97(4):573-80. — View Citation

Dahlbäck B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood. 2008 Jul 1;112(1):19-27. doi: 10.1182/blood-2008-01-077909. Review. — View Citation

Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15880-5. doi: 10.1073/pnas.1005743107. Epub 2010 Aug 23. — View Citation

Fuchs TA, Brill A, Wagner DD. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):1777-83. doi: 10.1161/ATVBAHA.111.242859. Epub 2012 May 31. Review. — View Citation

Kucher N, Boekstegers P, Müller OJ, Kupatt C, Beyer-Westendorf J, Heitzer T, Tebbe U, Horstkotte J, Müller R, Blessing E, Greif M, Lange P, Hoffmann RT, Werth S, Barmeyer A, Härtel D, Grünwald H, Empen K, Baumgartner I. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014 Jan 28;129(4):479-86. doi: 10.1161/CIRCULATIONAHA.113.005544. Epub 2013 Nov 13. — View Citation

Longstaff C, Varjú I, Sótonyi P, Szabó L, Krumrey M, Hoell A, Bóta A, Varga Z, Komorowicz E, Kolev K. Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones. J Biol Chem. 2013 Mar 8;288(10):6946-56. doi: 10.1074/jbc.M112.404301. Epub 2013 Jan 4. — View Citation

López JA, Kearon C, Lee AY. Deep venous thrombosis. Hematology Am Soc Hematol Educ Program. 2004:439-56. Review. — View Citation

Ramacciotti E, Myers DD Jr, Wrobleski SK, Deatrick KB, Londy FJ, Rectenwald JE, Henke PK, Schaub RG, Wakefield TW. P-selectin/ PSGL-1 inhibitors versus enoxaparin in the resolution of venous thrombosis: a meta-analysis. Thromb Res. 2010 Apr;125(4):e138-42. doi: 10.1016/j.thromres.2009.10.022. Epub 2009 Dec 4. — View Citation

Smith SA, Choi SH, Collins JN, Travers RJ, Cooley BC, Morrissey JH. Inhibition of polyphosphate as a novel strategy for preventing thrombosis and inflammation. Blood. 2012 Dec 20;120(26):5103-10. doi: 10.1182/blood-2012-07-444935. Epub 2012 Sep 11. — View Citation

Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):903-8. Epub 2006 Jan 12. — View Citation

von Brühl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, Khandoga A, Tirniceriu A, Coletti R, Köllnberger M, Byrne RA, Laitinen I, Walch A, Brill A, Pfeiler S, Manukyan D, Braun S, Lange P, Riegger J, Ware J, Eckart A, Haidari S, Rudelius M, Schulz C, Echtler K, Brinkmann V, Schwaiger M, Preissner KT, Wagner DD, Mackman N, Engelmann B, Massberg S. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012 Apr 9;209(4):819-35. doi: 10.1084/jem.20112322. Epub 2012 Mar 26. — View Citation

Zhou J, May L, Liao P, Gross PL, Weitz JI. Inferior vena cava ligation rapidly induces tissue factor expression and venous thrombosis in rats. Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):863-9. doi: 10.1161/ATVBAHA.109.185678. Epub 2009 Mar 5. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Markers of NETosis at 12h Compared to Baseline	Change in Markers of NETosis at 12h Compared to Baseline	12h
Primary	Change in Markers of NETosis at 24h Compared to Baseline	Values will be reported in comparison to baseline in the two treatment groups.	24h
Primary	Change in Markers of NETosis at 48h Compared to Baseline	Values will be reported in comparison to baseline in the two treatment groups.	48h
Primary	Change in Markers of NETosis at 5 Days (or Day of Hospital Discharge) Compared to Baseline	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)
Primary	Change in Markers of NETosis at 30 Days Compared to Baseline	Values will be reported in comparison to baseline in the two treatment groups.	30 days