Superficial Vein Thrombosis
Conditions
Keywords
superficial vein thrombosis, thrombosis, SVT
Brief summary
The purpose of this study is to evaluate the efficacy and safety of rivaroxaban versus fondaparinux in the treatment of superficial vein thrombosis (SVT).
Detailed description
Evaluation of efficacy and safety of 45 days of rivaroxaban 10 mg vs. fondaparinux 2.5 mg in the treatment of superficial vein thrombosis of risk patients for major VTE complications to prove non-inferiority of oral rivaroxaban treatment
Interventions
DRUGRivaroxaban
Dose: 10 mg Duration: 45 (±5) days Frequency: once daily Application: oral
DRUGFondaparinux
Fondaparinux Dose: 2.5 mg Duration: 45 (±5) days Frequency: once daily Application: subcutaneous
Sponsors
Bayer
GWT-TUD GmbH
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
* acute symptomatic supragenual superficial vein thrombosis of the leg * at least one of the following major risk factor for VTE: * age \> 65 years or * male sex or * history of DVT/PE/SVT or * history of cancer or active cancer or * autoimmune disease or * SVT of a non-varicose vein * thrombus extension of at least 5 cm * proximal thrombus end with more than 3 cm distance to the saphenofemoral junction (SFJ) * age \> 18 years * written informed consent
Exclusion criteria
* other indication for therapeutic anticoagulation such as acute deep vein thrombosis, acute pulmonary embolism, atrial fibrillation with indication for anticoagulant therapy * any PE or DVT within last 6 months before inclusion * clinical signs of PE without objective exclusion (CT or VQ scan, angiography) * SVT without signs of thrombotic/inflammatory activity (activity signs: diameter \> 4 mm, pain, redness, elevated local or systemic temperature) * SVT after sclerotherapy * Duration of symptoms \> 3 weeks * pretreatment of more than 72 h with therapeutic dosages of oral or parenteral anticoagulants * pretreatment of more than 5 days with subtherapeutic oral or parenteral anticoagulants * indication for escalated antiplatelet therapy (monotherapy with aspirin \> 325 g/d and any dual antiplatelet therapy) * SVT closer than 3 cm to saphenofemoral junction (SVJ) * anticipated superficial vein surgery within 90 days * anticipated thrombolytic therapy within 90 days * manifest clinically relevant bleeding * clinically relevant bleeding in the last 30 days before study inclusion * major surgery within last 30 days before inclusion * ophthalmic, spinal or cerebral surgery within last 90 days * severe head trauma within last 90 days * hemorrhagic stroke within last 12 months * hereditary or acquired severe hemorrhagic diathesis * gastrointestinal bleeding within last 90 days requiring endoscopy * uncontrolled arterial hypertension (systolic \> 180 mm Hg, diastolic \> 110 mm Hg) * acute endocarditis * low platelet count (\< 100 x 109/l) * Prothrombin time \< 50 % * calculated creatinine clearance \< 30 ml/min * significant liver disease such as acute hepatitis, chronic active hepatitis, cirrhosis * life expectancy \< 3 months * any contraindications listed for rivaroxaban or fondaparinux * women of child bearing potential without safe contraception method * pregnant or breastfeeding women * participation in another trial with pharmacological intervention
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Objectively Confirmed VTE Complications | 45 +/- 5 days | The primary efficacy outcome was the composite of death from any cause, symptomatic pulmonary embolism (confirmed by ventilation-perfusion scanning, helical computed tomography, pulmonary angiography, or autopsy), symptomatic deep vein thrombosis (confirmed by ultrasonography or venography), or symptomatic extension towards the saphenofemoral junction or symptomatic recurrence of superficial vein thrombosis (confirmed by ultrasonography) up to day 45. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite Primary Efficacy Outcome | 90 +/- 10 days | For this, secondary efficacy outcomes were the composite primary efficacy outcome up to Day 90 and the following outcomes up to Day 45 and Day 90: each component of the primary efficacy outcome, the rate of major VTE (composite of symptomatic pulmonary embolism or symptomatic proximal DVT or VTE-related death) and the rates of surgery for SVT. |
| Rate of Major VTE | 90 +/-10 days | composite of: * symptomatic pulmonary embolism * symptomatic proximal DVT * VTE-related death |
| Rates of Surgery for SVT | 90 +/-10 days | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Major Bleeding (Main Safety Outcome) | 45 +/- 5 days | * associated with a fall of hemoglobin of 2 g/l or more, or; * leading to a transfusion of 2 or more units of packed red blood cells or whole blood, or; * occurring into a critical site such as intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal, or; * fatal bleeding. |
| Clinically Relevant Non-major, Minor and Total (Any) Bleeding | 45 +/- 5 days | Clinically relevant, non-major bleeding is defined as any overt bleeding and * associated with a medical intervention, or * unscheduled contact with the physician (presence or telephone contact) * temporary or complete cessation of study drug * associated with any relevant discomfort to the patient (pain, impairment of activities of daily life) |
Countries
Germany
Participant flow
Recruitment details
From 25th April 2012 through 18th February 2016, a total of 485 patients were screened at 23 study sites in Germany. Of them, 9 patients did not meet the eligibility criteria. For another 4 subjects, signatures either on informed consent form or data protection waiver were not provided and therefore, these 4 subjects were not included in the study.
Pre-assignment details
472 patients were randomized to one of the two treatment groups. One patient in the fondaparinux group withdrew consent after randomization but before the first study drug administration.
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban Rivaroxaban for 45 days oral dose: 10 mg OD
Rivaroxaban: Dose: 10 mg Duration: 45 (±5) days Frequency: once daily Application: oral | 236 |
| Fondaparinux Fondaparinux for 45 days subcutaneous application: 2,5 mg OD
Fondaparinux: Fondaparinux Dose: 2.5 mg Duration: 45 (±5) days Frequency: once daily Application: subcutaneous | 235 |
| Total | 471 |
Baseline characteristics
| Characteristic | Fondaparinux | Total | Rivaroxaban |
|---|---|---|---|
| Age, Continuous | 59.8 years | 60.3 years | 60.7 years |
| BMI | 30.2 kg/m^2 | 30.0 kg/m^2 | 29.8 kg/m^2 |
| Height | 171 cm | 170 cm | 170 cm |
| Race/Ethnicity, Customized Race Caucasian | 234 Participants | 467 Participants | 233 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 4 Participants | 3 Participants |
| Risk factors Age > 65 years | 84 Participants | 166 Participants | 82 Participants |
| Risk factors Autoimmune disease | 4 Participants | 7 Participants | 3 Participants |
| Risk factors History of cancer or active cancer | 21 Participants | 37 Participants | 16 Participants |
| Risk factors History of DVT/PE/SVT | 106 Participants | 211 Participants | 105 Participants |
| Risk factors Male | 84 Participants | 173 Participants | 89 Participants |
| Risk factors SVT of non-varicose vein | 72 Participants | 132 Participants | 60 Participants |
| Sex: Female, Male Female | 148 Participants | 284 Participants | 136 Participants |
| Sex: Female, Male Male | 87 Participants | 187 Participants | 100 Participants |
| Weight | 88.0 kg | 87.1 kg | 86.2 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 235 | 1 / 236 |
| other Total, other adverse events | 0 / 235 | 0 / 236 |
| serious Total, serious adverse events | 3 / 235 | 7 / 236 |
Outcome results
Primary
Rate of Objectively Confirmed VTE Complications
The primary efficacy outcome was the composite of death from any cause, symptomatic pulmonary embolism (confirmed by ventilation-perfusion scanning, helical computed tomography, pulmonary angiography, or autopsy), symptomatic deep vein thrombosis (confirmed by ultrasonography or venography), or symptomatic extension towards the saphenofemoral junction or symptomatic recurrence of superficial vein thrombosis (confirmed by ultrasonography) up to day 45.
Time frame: 45 +/- 5 days
Population: Per protocol set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban | Rate of Objectively Confirmed VTE Complications | 7 Participants |
| Fondaparinux | Rate of Objectively Confirmed VTE Complications | 4 Participants |
p-value: 0.0252asymptotic test for non-inferiority
Secondary
Composite Primary Efficacy Outcome
For this, secondary efficacy outcomes were the composite primary efficacy outcome up to Day 90 and the following outcomes up to Day 45 and Day 90: each component of the primary efficacy outcome, the rate of major VTE (composite of symptomatic pulmonary embolism or symptomatic proximal DVT or VTE-related death) and the rates of surgery for SVT.
Time frame: 90 +/- 10 days
Population: Per protocol analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban | Composite Primary Efficacy Outcome | 15 Participants |
| Fondaparinux | Composite Primary Efficacy Outcome | 15 Participants |
Secondary
Rate of Major VTE
composite of: * symptomatic pulmonary embolism * symptomatic proximal DVT * VTE-related death
Time frame: 90 +/-10 days
Population: Per protocol set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rivaroxaban | Rate of Major VTE | Deep vein thrombosis | 6 Participants |
| Rivaroxaban | Rate of Major VTE | Pulmonary embolism | 0 Participants |
| Rivaroxaban | Rate of Major VTE | VTE-related death | 0 Participants |
| Fondaparinux | Rate of Major VTE | Deep vein thrombosis | 2 Participants |
| Fondaparinux | Rate of Major VTE | Pulmonary embolism | 0 Participants |
| Fondaparinux | Rate of Major VTE | VTE-related death | 0 Participants |
Secondary
Rates of Surgery for SVT
Time frame: 90 +/-10 days
Population: Per protocol set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban | Rates of Surgery for SVT | 0 Participants |
| Fondaparinux | Rates of Surgery for SVT | 2 Participants |
Other Pre-specified
Clinically Relevant Non-major, Minor and Total (Any) Bleeding
Clinically relevant, non-major bleeding is defined as any overt bleeding and * associated with a medical intervention, or * unscheduled contact with the physician (presence or telephone contact) * temporary or complete cessation of study drug * associated with any relevant discomfort to the patient (pain, impairment of activities of daily life)
Time frame: 45 +/- 5 days
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rivaroxaban | Clinically Relevant Non-major, Minor and Total (Any) Bleeding | CRNM bleeding | 6 Participants |
| Rivaroxaban | Clinically Relevant Non-major, Minor and Total (Any) Bleeding | Minor bleeding | 15 Participants |
| Rivaroxaban | Clinically Relevant Non-major, Minor and Total (Any) Bleeding | Any bleeding | 20 Participants |
| Fondaparinux | Clinically Relevant Non-major, Minor and Total (Any) Bleeding | CRNM bleeding | 1 Participants |
| Fondaparinux | Clinically Relevant Non-major, Minor and Total (Any) Bleeding | Minor bleeding | 15 Participants |
| Fondaparinux | Clinically Relevant Non-major, Minor and Total (Any) Bleeding | Any bleeding | 16 Participants |
Other Pre-specified
Major Bleeding (Main Safety Outcome)
* associated with a fall of hemoglobin of 2 g/l or more, or; * leading to a transfusion of 2 or more units of packed red blood cells or whole blood, or; * occurring into a critical site such as intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal, or; * fatal bleeding.
Time frame: 45 +/- 5 days
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban | Major Bleeding (Main Safety Outcome) | 0 Participants |
| Fondaparinux | Major Bleeding (Main Safety Outcome) | 0 Participants |