Transcatheter Aortic Valve Replacement
Conditions
Keywords
TAVR, TAVI, Transfemoral aortic valve implantation
Brief summary
To assess whether a rivaroxaban-based anticoagulation strategy, following successful TAVR, compared to an antiplatelet-based strategy, is superior in reducing death or first thromboembolic events (DTE). To assess the primary bleeding events (PBE) of the rivaroxaban-based strategy compared to an antiplatelet-based strategy, following TAVR.
Interventions
DRUGRivaroxaban (Xarelto, BAY59-7939)
10mg OD (once-daily)
75-100mg OD
DRUGClopidogrel
75mg OD
In case of NOAF, Open-label VKA therapy to target international normalized ratio (INR) 2-3, according to guidelines
Sponsors
Janssen Research & Development, LLC
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Successful TAVR (Transcatheter Aortic Valve Replacement) of an aortic valve stenosis (either native or valve-in-valve) * By iliofemoral or subclavian access * With any approved/marketed device
Exclusion criteria
* Atrial fibrillation (AF), current or previous, with an ongoing indication for oral anticoagulant treatment * Any other indication for continued treatment with any oral anticoagulant (OAC) * Known bleeding diathesis (such as but not limited to active internal bleeding, clinically significant bleeding, platelet count ≤ 50,000/mm3 at screening, hemoglobin level \< 8.5 g/dL, active peptic ulcer or known gastrointestinal (GI) bleeding, history of intracranial hemorrhage or subdural hematoma) * Any ongoing absolute indication for dual antiplatelet therapy (DAPT) at time of screening that is unrelated to the TAVR procedure * Clinically overt stroke within the last 3 months * Planned coronary or vascular intervention or major surgery * Severe renal impairment (eGFR \< 30 mL/min/1.73 m2) or on dialysis, or post-TAVR unresolved acute kidney injury with renal dysfunction stage 2 or higher * Moderate and severe hepatic impairment (Child-Pugh Class B or C) or any hepatic disease associated with coagulopathy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Death or First Thromboembolic Event (DTE) | Through study completion, on average 14 months | Death or first adjudicated thromboembolic event (DTE), defined as composite of all-cause death, any stroke, myocardial infarction (MI), symptomatic valve thrombosis, pulmonary embolism (PE), deep vein thrombosis (DVT), and non-central nervous system (CNS) systemic embolism. |
| Number of Participants With Primary Bleeding Event (PBE) | Through study completion, on average 16 months | PBE is defined according to VARC (Valve Academic Research Consortium) definitions as the adjudicated composite of: Life-threatening, disabling or major bleeding. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With TIMI (Thrombolysis In Myocardial Infarction) Major / Minor Bleeds | Through study completion, on average 16 months | Composite of TIMI major and minor bleedings |
| Number of Participants With Net-clinical Benefit | Through study completion, on average 16 months | The net-clinical-benefit defined as the adjudicated composite of all-cause death, any stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary embolism, deep vein thrombosis, non-CNS systemic embolism (efficacy); VARC life-threatening, disabling and VARC major bleeds (safety). |
| Number of Participants With Composite Bleeding Endpoint of BARC (Bleeding Academic Research Consortium) 2, 3, or 5 Bleeds | Through study completion, on average 16 months | Composite of BARC 2,3 or 5 bleedings |
| Number of Participants With ISTH (International Society on Thrombosis and Haemostasis) Major Bleeds | Through study completion, on average 16 months | ISTH major bleeds |
| Number of Participants With Cardiovascular Death or Thromboembolic Event | Through study completion, on average 16 months | Composite of CV-death, any stroke, myocardial infarction (MI), symptomatic valve thrombosis, pulmonary embolism (PE), deep vein thrombosis (DVT), and non-central nervous system (CNS) systemic embolism (per adjudication). |
Countries
Austria, Belgium, Canada, Czechia, Denmark, France, Germany, Italy, Netherlands, Norway, Poland, South Korea, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Study was conducted at 136 centers world-wide between 16 Dec 2015 (first patient's first visit) and 27 Nov 2018 (last patient's last visit).
Pre-assignment details
A total of 1674 subjects were screened, of which 1644 were randomly assigned to either of the two treatment arms and 1608 subjects started treatment with study medication.
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) Subjects were treated with Rivaroxaban (10mg once-daily) and ASA (Acetylsalicylic Acid) (75-100mg once-daily) within first 90 days after randomization. After 90 days, ASA was discontinued and rivaroxaban (10mg once-daily) was to be continued alone. In the event of NOAF (New Onset of Atrial Fibrillation), subjects should be switched to rivaroxaban (20/15mg once-daily) and ASA (75-100mg once-daily) within first 90 days. After 90 days, ASA was discontinued and rivaroxaban (20/15mg once-daily) was to be continued alone. | 826 |
| Antiplatelet Subjects were treated with clopidogrel (75mg once-daily) and ASA (75-100mg once-daily) within first 90 days after randomization. After 90 days, clopidogrel was discontinued and ASA (75-100mg once-daily) was to be continued alone. In the event of NOAF, subjects should start treatment of open-label VKA (Vitamin K antagonist) to target INR (international normalized ratio) 2 to 3 (according to guidelines) and ASA (75-100mg once-daily) within first 90 days. After 90 days, ASA was discontinued and VKA was to be continued alone. | 818 |
| Total | 1,644 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 5 | 5 |
| Overall Study | Withdrawal by Subject | 21 | 21 |
Baseline characteristics
| Characteristic | Rivaroxaban (Xarelto, BAY59-7939) | Antiplatelet | Total |
|---|---|---|---|
| Age, Continuous | 80.38 Years STANDARD_DEVIATION 7.12 | 80.77 Years STANDARD_DEVIATION 5.99 | 80.57 Years STANDARD_DEVIATION 6.58 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 17 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 677 Participants | 694 Participants | 1371 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 123 Participants | 107 Participants | 230 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 7 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 123 Participants | 115 Participants | 238 Participants |
| Race (NIH/OMB) White | 692 Participants | 693 Participants | 1385 Participants |
| Sex: Female, Male Female | 400 Participants | 413 Participants | 813 Participants |
| Sex: Female, Male Male | 426 Participants | 405 Participants | 831 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 70 / 801 | 43 / 807 |
| other Total, other adverse events | 359 / 801 | 302 / 807 |
| serious Total, serious adverse events | 296 / 801 | 282 / 807 |
Outcome results
Primary
Number of Participants With Death or First Thromboembolic Event (DTE)
Death or first adjudicated thromboembolic event (DTE), defined as composite of all-cause death, any stroke, myocardial infarction (MI), symptomatic valve thrombosis, pulmonary embolism (PE), deep vein thrombosis (DVT), and non-central nervous system (CNS) systemic embolism.
Time frame: Through study completion, on average 16 months
Population: Full analysis set (FAS): Included all randomized subjects and results presented according to randomized treatment arm (1644 subjects overall)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Number of Participants With Death or First Thromboembolic Event (DTE) | 105 Participants |
| Antiplatelet | Number of Participants With Death or First Thromboembolic Event (DTE) | 78 Participants |
p-value: =0.0422395% CI: [1.01, 1.81]Log Rank
Primary
Number of Participants With Death or First Thromboembolic Event (DTE)
Death or first adjudicated thromboembolic event (DTE), defined as composite of all-cause death, any stroke, myocardial infarction (MI), symptomatic valve thrombosis, pulmonary embolism (PE), deep vein thrombosis (DVT), and non-central nervous system (CNS) systemic embolism.
Time frame: Through study completion, on average 14 months
Population: Safety analysis set (SAF): Included all randomized subjects who had been exposed to study drug at least once (1608 subjects overall).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Number of Participants With Death or First Thromboembolic Event (DTE) | 68 Participants |
| Antiplatelet | Number of Participants With Death or First Thromboembolic Event (DTE) | 63 Participants |
Comparison: H0: HR(t)\>=1.20 for all time points t\>=0, (i.e. the hazard for the primary efficacy endpoint in the rivaroxaban-based treatment group is more than 20% larger than that in the antiplatelet-based control group)
Primary
Number of Participants With Primary Bleeding Event (PBE)
PBE is defined according to VARC (Valve Academic Research Consortium) definitions as the adjudicated composite of: Life-threatening, disabling or major bleeding.
Time frame: Through study completion, on average 16 months
Population: Full analysis set (FAS): Included all randomized subjects and results presented according to randomized treatment arm (1644 subjects overall).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Number of Participants With Primary Bleeding Event (PBE) | 46 Participants |
| Antiplatelet | Number of Participants With Primary Bleeding Event (PBE) | 31 Participants |
p-value: =0.0774595% CI: [0.95, 2.37]Log Rank
Secondary
Number of Participants With Cardiovascular Death or Thromboembolic Event
Composite of CV-death, any stroke, myocardial infarction (MI), symptomatic valve thrombosis, pulmonary embolism (PE), deep vein thrombosis (DVT), and non-central nervous system (CNS) systemic embolism (per adjudication).
Time frame: Through study completion, on average 16 months
Population: Full analysis set (FAS): Included all randomized subjects and results presented according to randomized treatment arm (1644 subjects overall).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Number of Participants With Cardiovascular Death or Thromboembolic Event | 83 Participants |
| Antiplatelet | Number of Participants With Cardiovascular Death or Thromboembolic Event | 68 Participants |
p-value: =0.2159595% CI: [0.89, 1.69]Log Rank
Secondary
Number of Participants With Composite Bleeding Endpoint of BARC (Bleeding Academic Research Consortium) 2, 3, or 5 Bleeds
Composite of BARC 2,3 or 5 bleedings
Time frame: Through study completion, on average 16 months
Population: Full analysis set (FAS): Included all randomized subjects and results presented according to randomized treatment arm (1644 subjects overall).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Number of Participants With Composite Bleeding Endpoint of BARC (Bleeding Academic Research Consortium) 2, 3, or 5 Bleeds | 148 Participants |
| Antiplatelet | Number of Participants With Composite Bleeding Endpoint of BARC (Bleeding Academic Research Consortium) 2, 3, or 5 Bleeds | 85 Participants |
p-value: =0.0000195% CI: [1.41, 2.41]Log Rank
Secondary
Number of Participants With ISTH (International Society on Thrombosis and Haemostasis) Major Bleeds
ISTH major bleeds
Time frame: Through study completion, on average 16 months
Population: Full analysis set (FAS): Included all randomized subjects and results presented according to randomized treatment arm (1644 subjects overall).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Number of Participants With ISTH (International Society on Thrombosis and Haemostasis) Major Bleeds | 49 Participants |
| Antiplatelet | Number of Participants With ISTH (International Society on Thrombosis and Haemostasis) Major Bleeds | 30 Participants |
p-value: =0.0270295% CI: [1.05, 2.62]Log Rank
Secondary
Number of Participants With Net-clinical Benefit
The net-clinical-benefit defined as the adjudicated composite of all-cause death, any stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary embolism, deep vein thrombosis, non-CNS systemic embolism (efficacy); VARC life-threatening, disabling and VARC major bleeds (safety).
Time frame: Through study completion, on average 16 months
Population: Full analysis set (FAS): Included all randomized subjects and results presented according to randomized treatment arm (1644 subjects overall).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Number of Participants With Net-clinical Benefit | 137 Participants |
| Antiplatelet | Number of Participants With Net-clinical Benefit | 100 Participants |
p-value: =0.0115695% CI: [1.08, 1.8]Log Rank
Secondary
Number of Participants With TIMI (Thrombolysis In Myocardial Infarction) Major / Minor Bleeds
Composite of TIMI major and minor bleedings
Time frame: Through study completion, on average 16 months
Population: Full analysis set (FAS): Included all randomized subjects and results presented according to randomized treatment arm (1644 subjects overall).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban (Xarelto, BAY59-7939) | Number of Participants With TIMI (Thrombolysis In Myocardial Infarction) Major / Minor Bleeds | 42 Participants |
| Antiplatelet | Number of Participants With TIMI (Thrombolysis In Myocardial Infarction) Major / Minor Bleeds | 24 Participants |
p-value: =0.0221695% CI: [1.08, 2.94]Log Rank