Pulmonary Embolism, Venous Thrombosis
Conditions
Keywords
Rivaroxaban, CDT (Catheter directed thrombolysis), PE (pulmonary embolism), NETs, factor Xa
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.
Interventions
DRUGrivaroxaban
Immediately following completion of alteplase infusion, patients will receive rivaroxaban 15 mg oral bid for 21 days followed by 20 mg oral daily.
DRUGwarfarin
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.
Sponsors
Janssen Scientific Affairs, LLC
Susan Smyth
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Markers of NETosis at 12h Compared to Baseline | 12h | Change in Markers of NETosis at 12h Compared to Baseline |
| Change in Markers of NETosis at 24h Compared to Baseline | 24h | Values will be reported in comparison to baseline in the two treatment groups. |
| Change in Markers of NETosis at 48h Compared to Baseline | 48h | Values will be reported in comparison to baseline in the two treatment groups. |
| Change in Markers of NETosis at 5 Days (or Day of Hospital Discharge) Compared to Baseline | 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. |
| Change in Markers of NETosis at 30 Days Compared to Baseline | 30 days | Values will be reported in comparison to baseline in the two treatment groups. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
rivaroxaban: Immediately following completion of alteplase infusion, patients will receive rivaroxaban 15 mg oral bid for 21 days followed by 20 mg oral daily. | 4 |
| 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).
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. | 6 |
| Total | 10 |
Baseline characteristics
| Characteristic | Rivaroxaban | Heparin-warfarin | Total |
|---|---|---|---|
| Age, Continuous | 54.5 years STANDARD_DEVIATION 17.5 | 50.3 years STANDARD_DEVIATION 12.5 | 52.8 years STANDARD_DEVIATION 15.1 |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 6 |
| other Total, other adverse events | 0 / 4 | 0 / 6 |
| serious Total, serious adverse events | 0 / 4 | 0 / 6 |
Outcome results
Primary
Change in Markers of NETosis at 12h Compared to Baseline
Change in Markers of NETosis at 12h Compared to Baseline
Time frame: 12h
Population: Sponsor terminated this study and withdrew funding prior to sample analysis. Therefore there was no funding to purchase assays to measure the collected samples nor was there enough samples to complete an assay.
Primary
Change in Markers of NETosis at 24h Compared to Baseline
Values will be reported in comparison to baseline in the two treatment groups.
Time frame: 24h
Population: Sponsor terminated this study and withdrew funding prior to sample analysis. Therefore there was no funding to purchase assays to measure the collected samples nor was there enough samples to complete an assay.
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.
Time frame: 30 days
Population: Sponsor terminated this study and withdrew funding prior to sample analysis. Therefore there was no funding to purchase assays to measure the collected samples nor was there enough samples to complete an assay.
Primary
Change in Markers of NETosis at 48h Compared to Baseline
Values will be reported in comparison to baseline in the two treatment groups.
Time frame: 48h
Population: Sponsor terminated this study and withdrew funding prior to sample analysis. Therefore there was no funding to purchase assays to measure the collected samples nor was there enough samples to complete an assay.
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.
Time frame: 5 days (or day of hospital discharge)
Population: Sponsor terminated this study and withdrew funding prior to sample analysis. Therefore there was no funding to purchase assays to measure the collected samples nor was there enough samples to complete an assay.