Blood Loss, Postoperative, Blood Loss, Surgical, Hemorrhage Postoperative, Hemorrhage, Surgical
Conditions
Brief summary
Prospective, Multicenter, Double-blind, Randomized, Study to Evaluate DrugSorb-ATR Removal of Apixaban and Rivaroxaban to Reduce Likelihood of Serious Bleeding in Patients Undergoing Urgent Cardiothoracic Surgery
Detailed description
The Safe and Timely Antithrombotic Removal - Direct Oral Anticoagulants (DOACs) Apixaban & Rivaroxaban (STAR-D) study is a prospective, multicenter, double-blind, randomized study that evaluated the DrugSorb™-Antithrombotic Removal (ATR) device for removal of apixaban and rivaroxaban to reduce the likelihood of serious bleeding in patients undergoing urgent cardiothoracic surgery. The objectives were * To demonstrate reductions in surgical and early post-surgical bleeding with the intraoperative use of DrugSorb-ATR in patients undergoing cardiothoracic surgery ≤36hrs since last apixaban or rivaroxaban dose. * To demonstrate reductions in apixaban or rivaroxaban blood levels (Δ\[DOAC\]) with the intraoperative use of DrugSorb-ATR. * To establish the safety of the intraoperative use of DrugSorb-ATR in the intended population.
Interventions
DEVICESham comparator
Sham comparator in similar position to the investigational device, but NOT integrated into the cardiopulmonary bypass (CPB) circuit
DEVICEDrugSorb-ATR system
Sorbent hemoperfusion system integrated into the cardiopulmonary bypass (CPB) circuit
Sponsors
CytoSorbents, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female age 18 years or older, with documented full, written informed consent 2. Requiring cardiothoracic (CT) surgery with cardiopulmonary bypass (CPB) within 36 hours from last dose of either apixaban or rivaroxaban (\*note that patients must be taking apixaban or rivaroxaban for one of the following indications: a) reduction of stroke/systemic embolism in nonvalvular atrial fibrillation, or b) initial or extended treatment of venous thromboembolism)
Exclusion criteria
1. \>48hrs between last apixaban or rivaroxaban dose and start of CT surgery 2. Patients on low dose apixaban or rivaroxaban for prophylactic indications 3. Heart-lung transplant procedures 4. Procedures for ventricular assist device (i.e., implant or revision of left ventricular assist device \[LVAD\] or right ventricular assist device \[RVAD\]) 5. Any of the below conditions that pose a known risk for increased bleeding 1. Heparin induced thrombocytopenia 2. Preoperative platelet count \<50,000u/L 3. Hemophilia 4. International normalized ratio (INR) greater than or equal to 1.8 6. Prohibited concomitant antithrombotic medications as defined in the study protocol 7. Acute sickle cell crisis 8. Known allergy to device components 9. Active (untreated) systemic infection 10. History of major organ transplantation and those currently receiving immunosuppressive medication or who are profoundly immune suppressed 11. Women with positive pregnancy test during current admission or who are breast-feeding 12. Life expectancy \<30 days 13. Inability to comply with requirements of the study protocol 14. Treatment with investigational drug or device within 30 days of current surgery 15. Previous enrollment in this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Perioperative Bleeding | Through the first 48 hours post-operation | Incidence of clinically significant perioperative bleeding events, as evaluated by a ranked composite endpoint |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Direct Oral Anticoagulant (DOAC) Drug Removal: Apixaban and Rivaroxaban | Through 30 minutes post-CPB | Percent change in blood apixaban or rivaroxaban levels from pre coronary bypass (CPB), that is, start of device use to 30 min post CPB |
| Chest Tube Drainage | Through 24 hours post-operation | Drainage volume from all chest and mediastinal tubes |
| Platelet Transfusions (Volume) | Through to discharge from index hospitalization, on average 1-2 weeks | Total platelet transfusions (mL) during hospitalization |
| Platelet Transfusions (Units) | Through to discharge from index hospitalization, on average 1-2 weeks | Total platelet transfusions (units) during hospitalization |
| Packed Red Blood Cell (PRBC) Transfusions (Volume) | Through to discharge from index hospitalization, on average 1-2 weeks | Total PRBC transfusions (mL) during hospitalization |
| PRBC Transfusions (Units) | Through to discharge from index hospitalization, on average 1-2 weeks | Total PRBC transfusions (units) during hospitalization |
| Incidence of Moderate, Severe, and Massive Perioperative Bleeding Events | Through the first day post-operation | Perioperative bleeding events classified according to the Universal Definition of Perioperative Bleeding, and analyzed by class (Class 0, 1, 2, 3, 4) |
| Surgical Re-exploration for Bleeding | Through to discharge from index hospitalization, on average 1-2 weeks | All surgical re-explorations for excessive bleeding, as adjudicated by an independent Clinical Events Committee |
| Incidence of Fatal Perioperative Bleeding | Through to discharge from index hospitalization, on average 1-2 weeks | Deaths directly attributable to procedure-related bleeding. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Control Standard of care with Sham set-up
Sham comparator: Sham comparator in similar position to the investigational device, but NOT integrated into the cardiopulmonary bypass (CPB) circuit | 5 |
| DrugSorb-ATR Intervention Standard of care + DrugSorb-ATR system
DrugSorb-ATR system: Sorbent hemoperfusion system integrated into the cardiopulmonary bypass (CPB) circuit | 4 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Control | DrugSorb-ATR Intervention |
|---|---|---|---|
| Age, Continuous | 65.3 years STANDARD_DEVIATION 13.1 | 62.8 years STANDARD_DEVIATION 14.7 | 68.5 years STANDARD_DEVIATION 12.2 |
| Coronary artery disease | 2 Participants | 1 Participants | 1 Participants |
| Heart failure | 2 Participants | 1 Participants | 1 Participants |
| Hypertension | 7 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 9 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 1 Participants |
| Subjects with apixaban | 6 Participants | 4 Participants | 2 Participants |
| Subjects with rivaroxaban | 3 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 1 / 4 |
| other Total, other adverse events | 2 / 5 | 2 / 4 |
| serious Total, serious adverse events | 1 / 5 | 2 / 4 |
Outcome results
Primary
Incidence of Perioperative Bleeding
Incidence of clinically significant perioperative bleeding events, as evaluated by a ranked composite endpoint
Time frame: Through the first 48 hours post-operation
Population: The trial was terminated before the outcome measure data were cleaned and adjudicated. All bleeding outcomes data were to be adjudicated by a Clinical Events Committee, which was not convened because the trial was terminated. Therefore, no bleeding outcomes were available.
Secondary
Chest Tube Drainage
Drainage volume from all chest and mediastinal tubes
Time frame: Through 24 hours post-operation
Population: The trial was terminated before the outcome measure data were cleaned and adjudicated. All bleeding outcomes data were to be adjudicated by a Clinical Events Committee, which was not convened because the trial was terminated. Therefore, no bleeding outcomes were available.
Secondary
Direct Oral Anticoagulant (DOAC) Drug Removal: Apixaban and Rivaroxaban
Percent change in blood apixaban or rivaroxaban levels from pre coronary bypass (CPB), that is, start of device use to 30 min post CPB
Time frame: Through 30 minutes post-CPB
Population: Because of the premature discontinuation of the study, this is the only outcome measure collected and analyzed. The change in drug levels was analyzed for both rivaroxaban and apixaban together (not separately), again due to the low number of enrolled subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control | Direct Oral Anticoagulant (DOAC) Drug Removal: Apixaban and Rivaroxaban | 27.95 percent change in drug levels | Standard Deviation 8.6 |
| DrugSorb-ATR Intervention | Direct Oral Anticoagulant (DOAC) Drug Removal: Apixaban and Rivaroxaban | 62.21 percent change in drug levels | Standard Deviation 8.9 |
p-value: 0.02Wilcoxon (Mann-Whitney)
Secondary
Incidence of Fatal Perioperative Bleeding
Deaths directly attributable to procedure-related bleeding.
Time frame: Through to discharge from index hospitalization, on average 1-2 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Incidence of Fatal Perioperative Bleeding | 0 Participants |
| DrugSorb-ATR Intervention | Incidence of Fatal Perioperative Bleeding | 0 Participants |
Secondary
Incidence of Moderate, Severe, and Massive Perioperative Bleeding Events
Perioperative bleeding events classified according to the Universal Definition of Perioperative Bleeding, and analyzed by class (Class 0, 1, 2, 3, 4)
Time frame: Through the first day post-operation
Population: The trial was terminated before the outcome measure data were cleaned and adjudicated. All bleeding outcomes data were to be adjudicated by a Clinical Events Committee, which was not convened because the trial was terminated. Therefore, no bleeding outcomes were available.
Secondary
Packed Red Blood Cell (PRBC) Transfusions (Volume)
Total PRBC transfusions (mL) during hospitalization
Time frame: Through to discharge from index hospitalization, on average 1-2 weeks
Population: The trial was terminated before the outcome measure data were cleaned and adjudicated. All bleeding outcomes data were to be adjudicated by a Clinical Events Committee, which was not convened because the trial was terminated. Therefore, no bleeding outcomes were available.
Secondary
Platelet Transfusions (Units)
Total platelet transfusions (units) during hospitalization
Time frame: Through to discharge from index hospitalization, on average 1-2 weeks
Population: The trial was terminated before the outcome measure data were cleaned and adjudicated. All bleeding outcomes data were to be adjudicated by a Clinical Events Committee, which was not convened because the trial was terminated. Therefore, no bleeding outcomes were available.
Secondary
Platelet Transfusions (Volume)
Total platelet transfusions (mL) during hospitalization
Time frame: Through to discharge from index hospitalization, on average 1-2 weeks
Population: The trial was terminated before the outcome measure data were cleaned and adjudicated. All bleeding outcomes data were to be adjudicated by a Clinical Events Committee, which was not convened because the trial was terminated. Therefore, no bleeding outcomes were available.
Secondary
PRBC Transfusions (Units)
Total PRBC transfusions (units) during hospitalization
Time frame: Through to discharge from index hospitalization, on average 1-2 weeks
Population: The trial was terminated before the outcome measure data were cleaned and adjudicated. All bleeding outcomes data were to be adjudicated by a Clinical Events Committee, which was not convened because the trial was terminated. Therefore, no bleeding outcomes were available.
Secondary
Surgical Re-exploration for Bleeding
All surgical re-explorations for excessive bleeding, as adjudicated by an independent Clinical Events Committee
Time frame: Through to discharge from index hospitalization, on average 1-2 weeks
Population: The trial was terminated before the outcome measure data were cleaned and adjudicated. All bleeding outcomes data were to be adjudicated by a Clinical Events Committee, which was not convened because the trial was terminated. Therefore, no bleeding outcomes were available.