Haemorrhage, Venous Thromboembolism
Conditions
Keywords
knee arthroscopy, venous thromboembolism, prevention
Brief summary
Study Objective: To assess the value of Rivaroxaban for the prevention of venous thromboembolism (VTE) after knee arthroscopy (KA) taking the placebo as standard of reference. Study Population: Patients undergoing therapeutic KA at the study Centers, irrespective of the type and duration of the procedure, will be eligible for the study. Study Design: Multicenter, randomized, double blind superiority, phase II trial comparing two arms: * (R-7d) Rivaroxaban (10 mg od os) for 7 days * (PL-7d) Placebo for 7 days. Follow-up: 3-month period after the randomization Standard of Reference:Placebo will be the standard of reference in accordance to international guidelines Study length May 2012-December 2012 Total patients number: 500 patients Primary Efficacy End-Point: Occurrence in the 3-month period after the randomization of at least one of the following events, objectively proven (by means of CCDU; multi-slice chest TC-angio; autopsy, if necessary, or clinical ground): * All-cause mortality * Symptomatic VTE * Asymptomatic proximal DVT Secondary Efficacy End-point: • Combined incidence of all DVT plus symptomatic PE Primary Safety End-point: Incidence of major bleedings. Secondary Safety End-point: Overall incidence of bleeding
Detailed description
The treatments will be administered postoperatively (1st dose 8-10 hours after procedure), for prevention of venous thromboembolism after KA. A bilateral whole-leg colour-coded Doppler ultrasonography (CCDU) is scheduled for all patients at 7 (+1) days of follow-up; additionally, CCDU was due if the patients developed symptoms or signs suggestive of venous thromboembolism earlier. Statistical & Analytical Plan and Methodology: In the absence of prophylaxis the incidence of venous thromboembolism (primary efficacy end-point) after KA, as assessed by CCDU, is about 8.0% (combining weighted results of various paper). Prophylaxis with low-molecular weight heparins assures approximately a 60-70% relative risk reduction in this setting. Based on the findings of published trials investigating the efficacy of Rivaroxaban for prevention of venous thromboembolism after elective hip and knee surgery, when using a low-molecular-weight heparin as comparator, investigators can speculate that Rivaroxaban will further reduce this incidence (at least 1.2%).
Interventions
DRUGRivaroxaban
10 mg os once daily for 1 week
DRUGplacebo
10 mg os once daily for 1 week
Sponsors
University of Padova
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult patient (18 years and older) 2. Knee arthroscopy not combined with open surgery. 3. Patients eligible for surgical treatment. 4. Patients are willing and able to continue study participation to ensure completion of all procedures and observations required by the study. 5. Written informed consent
Exclusion criteria
1. Diagnostic arthroscopy 2. Patients concomitantly treated systemically with strong concurrent CYP3A4 and P-gp-inhibitors, i.e. azole-antimycotics or HIV protease inhibitors. 3. Hypersensitivity to the active substance or to any of the excipients of study drug 4. Pregnant women or breast-feeding. 5. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk 6. Known thrombophilia (hereditary or acquired) 7. Mandatory anticoagulation. 8. Known severe bleeding tendency 9. Clinically significant active bleeding. 10. Severe renal failure (GFR\<30mL/min/1.73m2) 11. Patients participating in another clinical trial. 12. Recent mayor surgery (6 to 12 weeks)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Symptomatic Venous Thromboembolism Plus Asymptomatic Proximal Vein Thrombosis and All-cause Mortality | 3-month period | During the scheduled visit in case of suspected DVT a bilateral whole-leg colour-coded Doppler ultrasonography (CCDU) is scheduled for all patients at 7 (+1) days of follow-up; additionally, CCDU will be performed if the patients develop symptoms or signs suggestive of venous thromboembolism earlier; in case of suspected PE a multi-slice chest TC-angio is arranged; in case of death for all cause autoptic findings are requested or, if necessary, clinical ground is considered. A follow-up visit is planned 3-month period after the randomization. |
| Major Bleedings | 3 months | Major bleeding include: clinically overt haemorrhage associated with haemoglobin drop of at least 2 g/L or requiring the transfusion of two or more units of packed red-blood cells; retroperitoneal or intracranial events; bleeding requiring re-intervention; and hemarthrosis with a joint drainage of more than 450 millilitres of blood. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Combined Incidence of All DVT Plus Symptomatic PE | 3 months | As described for the assessment of the primary efficacy outcomes |
| Overall Incidence of Bleeding | 3 months | As described for the primary safety outcome |
Countries
Italy
Participant flow
Recruitment details
Between apr2012 and Mar2014, 1278 subjects were evaluated for inclusion. Of them, 241 (19%) subjects accepted to participate. Due to the unexpectedly low recruitment rate, being a spontaneous study, we were forced to stop the trial before reaching the planned sample size because we were not able to afford insurance costs anymore.
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban Oral Rivaroxaban 10 mg od for 7 days
Rivaroxaban: 10 mg os once daily for 1 week | 122 |
| Placebo oral placebo od for 7 days
placebo: 10 mg os once daily for 1 week | 119 |
| Total | 241 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 5 |
Baseline characteristics
| Characteristic | Rivaroxaban | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 44.9 years STANDARD_DEVIATION 12.8 | 45.9 years STANDARD_DEVIATION 13.9 | 45.4 years STANDARD_DEVIATION 13.3 |
| Region of Enrollment Italy | 122 participants | 119 participants | 241 participants |
| Sex: Female, Male Female | 44 Participants | 35 Participants | 79 Participants |
| Sex: Female, Male Male | 78 Participants | 84 Participants | 162 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 114 | 1 / 120 |
| serious Total, serious adverse events | 0 / 114 | 0 / 120 |
Outcome results
Primary
Incidence of Symptomatic Venous Thromboembolism Plus Asymptomatic Proximal Vein Thrombosis and All-cause Mortality
During the scheduled visit in case of suspected DVT a bilateral whole-leg colour-coded Doppler ultrasonography (CCDU) is scheduled for all patients at 7 (+1) days of follow-up; additionally, CCDU will be performed if the patients develop symptoms or signs suggestive of venous thromboembolism earlier; in case of suspected PE a multi-slice chest TC-angio is arranged; in case of death for all cause autoptic findings are requested or, if necessary, clinical ground is considered. A follow-up visit is planned 3-month period after the randomization.
Time frame: 3-month period
Population: Drop-out: seven randomized patients withdrew consent on the day of surgery, without taking the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban | Incidence of Symptomatic Venous Thromboembolism Plus Asymptomatic Proximal Vein Thrombosis and All-cause Mortality | 1 participants |
| Placebo | Incidence of Symptomatic Venous Thromboembolism Plus Asymptomatic Proximal Vein Thrombosis and All-cause Mortality | 7 participants |
p-value: 0.0395% CI: [-11.3, -0.4]Fisher Exact
Primary
Major Bleedings
Major bleeding include: clinically overt haemorrhage associated with haemoglobin drop of at least 2 g/L or requiring the transfusion of two or more units of packed red-blood cells; retroperitoneal or intracranial events; bleeding requiring re-intervention; and hemarthrosis with a joint drainage of more than 450 millilitres of blood.
Time frame: 3 months
Population: No major bleeding events were observed during the study period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban | Major Bleedings | 0 participants |
| Placebo | Major Bleedings | 0 participants |
Secondary
Combined Incidence of All DVT Plus Symptomatic PE
As described for the assessment of the primary efficacy outcomes
Time frame: 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban | Combined Incidence of All DVT Plus Symptomatic PE | 8 participants |
| Placebo | Combined Incidence of All DVT Plus Symptomatic PE | 2 participants |
p-value: 0.0395% CI: [-11.7, -0.1]Fisher Exact
Secondary
Overall Incidence of Bleeding
As described for the primary safety outcome
Time frame: 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban | Overall Incidence of Bleeding | 6 participants |
| Placebo | Overall Incidence of Bleeding | 4 participants |
p-value: 0.5395% CI: [-8, 3.7]Fisher Exact