Blood Loss, Postoperative, Blood Loss, Surgical, Hemorrhage Postoperative, Hemorrhage, Surgical
Conditions
Brief summary
Prospective, multi-center, double-blind, randomized pivotal trial to evaluate the safety and effectiveness of the DrugSorb-Antithrombotic Removal (ATR) system for intraoperative removal of ticagrelor in patients undergoing urgent cardiothoracic (CT) surgery with cardiopulmonary bypass (CPB).
Detailed description
Antithrombotic agents such as ticagrelor can increase the risk of surgical bleeding in patients undergoing CT surgery if there is not adequate washout time of the drug. Patients who require urgent surgery may not be able to wait for the recommended washout time (up to 7 days). The intraoperative use of the DrugSorb-ATR device to remove active ticagrelor may help reduce the risk of postoperative surgical bleeding in these patients.
Interventions
DEVICEDrugSorb-ATR system
Sorbent hemoperfusion system integrated into the cardiopulmonary bypass (CPB) circuit
DEVICESham comparator
Sham comparator in similar position to the investigative device, but NOT integrated into the cardiopulmonary (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 18 years of age or older, with documented full, written informed consent 2. Requiring cardiothoracic (CT) surgery with cardiopulmonary bypass (CPB) within two days of ticagrelor discontinuation (day of last dose = day 0)
Exclusion criteria
1. CT surgery occurring 3 days or greater following ticagrelor discontinuation 2. Heart-lung transplant procedures 3. Procedures for implant or revision of left ventricular assist device (LVAD) or right ventricular assist device (RVAD) 4. Pre-existing conditions that pose a known risk for bleeding (i.e., heparin induced thrombocytopenia /thrombosis \[HITT\], perioperative platelet count \< 50,000u/L, hemophilia, and international normalized ratio \[INR\] \>1.5) 5. Prohibited concomitant antithrombotic medications as defined in the study protocol 6. Acute sickle cell crisis 7. Known allergy to device components 8. Active (untreated) systemic infection 9. History of major organ transplantation and those currently receiving immunosuppressive medication or who are profoundly immune suppressed 10. Women with positive pregnancy test during current admission or who are breast-feeding 11. Life expectancy \<30 days 12. Inability to comply with requirements of the study protocol 13. Treatment with investigational drug or device within 30 days of current surgery 14. Previous enrollment in this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Perioperative (Periop) Bleeding, Primary Effectiveness Composite Endpoint, Modified Intent to Treat (mITT) Population | Through the first 48hrs post-operation | Incidence of periop bleeding, primary effectiveness composite endpoint, mITT population. Primary effectiveness endpoint was a composite of (ranked) 1) fatal periop bleeding; 2) moderate, severe, or massive bleeding events based on the universal definition for periop bleeding (UDPB) \>2 classification; and 3) 24 hour chest tube drainage (CTD) volume; evaluated by an unmatched win ratio method. Using the hierarchical order of the components of each composite endpoint every patient in the Sham arm is compared with every patient in the DrugSorb-ATR arm to make Ns x Nd pairs. The numbers below are the number of 'winners' for two treatments; 'win' is given for the better outcome in the pair, eg, less bleeding. The win ratio is the total number of winners in DrugSorb-ATR arm divided by the total number of winners in Sham arm. A ratio of wins \> 1.0 favors the treatment arm. 95% confidence interval (CI) and p-value are calculated accordingly. The win ratio is 1.07 (95% CI 0.72, 1.58), p=0.748. |
| Incidence of Perioperative (Periop) Bleeding, Primary Effectiveness Composite Endpoint, Isolated Coronary Artery Bypass Grafting (I-CABG) Per Protocol (PP) Population | Through the first 48hrs post operation | Incidence of periop bleeding, primary effectiveness composite endpoint, i--CABG population. The primary effectiveness endpoint was a composite of (ranked) 1) fatal periop bleeding; 2) moderate, severe, or massive bleeding events based on the universal definition for periop bleeding (UDPB) \>2 classification; and 3) 24 hour chest tube drainage (CTD) volume; evaluated by an unmatched win ratio method. Using the hierarchical order of the components of each composite endpoint every patient in the Sham arm is compared with every patient in the DrugSorb-ATR arm to make Ns x Nd pairs. The numbers below are the number of 'winners' for two treatments; 'win' is given for the better outcome in the pair, eg, less bleeding. The win ratio is the total number of winners in DrugSorb-ATR arm divided by the total number of winners in the Sham arm. A ratio of wins \>1.0 favors the treatment arm. The win ratio was 1.33 (95% confidence interval 0.86, 2.04) p-value 0.202. |
| Incidence of Perioperative (Periop) Bleeding, Supplemental Primary Effectiveness Composite Endpoint, mITT Population | Through the first 48 hours post-operation | Incidence of Periop Bleeding, Supplemental Primary Effectiveness Composite Endpoint, mITT population. The supplementary primary effectiveness endpoint was a composite of (ranked) 1) fatal periop bleeding; 2) severe, or massive bleeding events based on the universal definition for periop bleeding (UDPB) \>3 classification; and 3) 24 hour chest tube drainage (CTD) volume; evaluated by an unmatched win ratio method. Using the hierarchical order of the components of each composite endpoint every patient in the Sham arm is compared with every patient in the DrugSorb-ATR arm to make Ns x Nd pairs. The numbers given below are the number of 'winners' for two treatments; a 'win' is given for the better outcome in the pair, eg, less bleeding. The win ratio is the total number of winners in DrugSorb-ATR arm divided by the total number of winners in Sham arm. A ratio of wins \>1.0 favors the treatment arm. The win ratio was 1.17 (95% confidence interval 0.79, 1.73) p value 0.451. |
| Incidence of Perioperative (Periop) Bleeding, Supplemental Primary Effectiveness Composite Endpoint, I-CABG Per Protocol (PP) Population | Through the first 48hrs post-operation | Incidence of Periop Bleeding, Supplemental Primary Effectiveness Composite Endpoint, I-CABG population. The supplementary primary effectiveness endpoint was a composite of (ranked) 1) fatal periop bleeding; 2) severe, or massive bleeding events based on the universal definition for periop bleeding (UDPB) \>3 classification; and 3) 24 hour chest tube drainage (CTD) volume; evaluated by an unmatched win ratio method. Using the hierarchical order of the components of each composite endpoint every patient in the Sham arm is compared with every patient in the DrugSorb-ATR arm to make Ns x Nd pairs. The numbers below are the number of 'winners' for two treatments; a 'win' is given for the better outcome in the pair, eg, less bleeding. The win ratio is the total number of winners in DrugSorb-ATR arm divided by the total number of winners in Sham arm. A ratio of wins \>1.0 favors the treatment arm. The win ratio was 1.59 (95% confidence interval 1.02, 2.46) p-value 0.041. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Transfusions (Units), mITT Population | From procedure start through to discharge from index hospitalization, on average 1-2 weeks | Total Platelet transfusions (units) during hospitalization |
| Chest Tube Drainage, mITT Population | Through 24hrs post-operation | Drainage volume from all chest and mediastinal tubes |
| Platelet Transfusions, (Units), I-CABG PP Population | From procedure start through to discharge from index hospitalization, on average 1-2 weeks | Total Platelet transfusions (units) during hospitalization |
| Chest Tube Drainage, i-CABG PP Population | Through 24hrs post-operation | Drainage volume from all chest and mediastinal tubes |
| Packed Red Blood Cell (PRBC) Transfusions (Units), mITT Population | From procedure start through to discharge from index hospitalization, on average 1-2 weeks | Total PRBC transfusions (units) during hospitalization in the mITT population |
| PRBC Transfusions, (Units) I-CABG PP Population | From procedure start through to discharge from index hospitalization, on average 1-2 weeks | Total PRBC transfusions (units) during hospitalization |
Countries
Canada, 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 investigative device, but NOT integrated into the cardiopulmonary (CPB) circuit | 66 |
| DrugSorb-ATR Intervention Standard of care + DrugSorb-ATR system
DrugSorb-Antithrombotic Removal (ATR) system: Sorbent hemoperfusion system integrated into the cardiopulmonary bypass (CPB) circuit | 66 |
| Total | 132 |
Baseline characteristics
| Characteristic | DrugSorb-ATR Intervention | Total | Control |
|---|---|---|---|
| Age, Continuous | 64.4 years STANDARD_DEVIATION 10.63 | 64.5 years STANDARD_DEVIATION 9.6 | 64.5 years STANDARD_DEVIATION 8.54 |
| Coronary artery disease | 61 Participants | 123 Participants | 62 Participants |
| Heart failure | 18 Participants | 41 Participants | 23 Participants |
| Hypertension | 54 Participants | 112 Participants | 58 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 10 Participants | 6 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 | 6 Participants | 11 Participants | 5 Participants |
| Race (NIH/OMB) White | 53 Participants | 103 Participants | 50 Participants |
| Region of Enrollment Canada | 23 participants | 45 participants | 22 participants |
| Region of Enrollment United States | 43 participants | 87 participants | 44 participants |
| Sex: Female, Male Female | 10 Participants | 20 Participants | 10 Participants |
| Sex: Female, Male Male | 56 Participants | 112 Participants | 56 Participants |
| Thrombocytopenia | 5 Participants | 11 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 66 | 1 / 66 |
| other Total, other adverse events | 57 / 66 | 58 / 66 |
| serious Total, serious adverse events | 19 / 66 | 25 / 66 |
Outcome results
Primary
Incidence of Perioperative (Periop) Bleeding, Primary Effectiveness Composite Endpoint, Isolated Coronary Artery Bypass Grafting (I-CABG) Per Protocol (PP) Population
Incidence of periop bleeding, primary effectiveness composite endpoint, i--CABG population. The primary effectiveness endpoint was a composite of (ranked) 1) fatal periop bleeding; 2) moderate, severe, or massive bleeding events based on the universal definition for periop bleeding (UDPB) \>2 classification; and 3) 24 hour chest tube drainage (CTD) volume; evaluated by an unmatched win ratio method. Using the hierarchical order of the components of each composite endpoint every patient in the Sham arm is compared with every patient in the DrugSorb-ATR arm to make Ns x Nd pairs. The numbers below are the number of 'winners' for two treatments; 'win' is given for the better outcome in the pair, eg, less bleeding. The win ratio is the total number of winners in DrugSorb-ATR arm divided by the total number of winners in the Sham arm. A ratio of wins \>1.0 favors the treatment arm. The win ratio was 1.33 (95% confidence interval 0.86, 2.04) p-value 0.202.
Time frame: Through the first 48hrs post operation
Population: i-CABG, isolated CABG, per protocol population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control | Incidence of Perioperative (Periop) Bleeding, Primary Effectiveness Composite Endpoint, Isolated Coronary Artery Bypass Grafting (I-CABG) Per Protocol (PP) Population | 1310 number of wins |
| DrugSorb-ATR Intervention | Incidence of Perioperative (Periop) Bleeding, Primary Effectiveness Composite Endpoint, Isolated Coronary Artery Bypass Grafting (I-CABG) Per Protocol (PP) Population | 1741 number of wins |
p-value: 0.20295% CI: [0.86, 2.04]Finkelstein Schoenfeld test
Primary
Incidence of Perioperative (Periop) Bleeding, Primary Effectiveness Composite Endpoint, Modified Intent to Treat (mITT) Population
Incidence of periop bleeding, primary effectiveness composite endpoint, mITT population. Primary effectiveness endpoint was a composite of (ranked) 1) fatal periop bleeding; 2) moderate, severe, or massive bleeding events based on the universal definition for periop bleeding (UDPB) \>2 classification; and 3) 24 hour chest tube drainage (CTD) volume; evaluated by an unmatched win ratio method. Using the hierarchical order of the components of each composite endpoint every patient in the Sham arm is compared with every patient in the DrugSorb-ATR arm to make Ns x Nd pairs. The numbers below are the number of 'winners' for two treatments; 'win' is given for the better outcome in the pair, eg, less bleeding. The win ratio is the total number of winners in DrugSorb-ATR arm divided by the total number of winners in Sham arm. A ratio of wins \> 1.0 favors the treatment arm. 95% confidence interval (CI) and p-value are calculated accordingly. The win ratio is 1.07 (95% CI 0.72, 1.58), p=0.748.
Time frame: Through the first 48hrs post-operation
Population: mITT, modified intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control | Incidence of Perioperative (Periop) Bleeding, Primary Effectiveness Composite Endpoint, Modified Intent to Treat (mITT) Population | 2103 number of wins |
| DrugSorb-ATR Intervention | Incidence of Perioperative (Periop) Bleeding, Primary Effectiveness Composite Endpoint, Modified Intent to Treat (mITT) Population | 2244 number of wins |
p-value: 0.74895% CI: [0.72, 1.58]Finkelstein Schoenfeld test
Primary
Incidence of Perioperative (Periop) Bleeding, Supplemental Primary Effectiveness Composite Endpoint, I-CABG Per Protocol (PP) Population
Incidence of Periop Bleeding, Supplemental Primary Effectiveness Composite Endpoint, I-CABG population. The supplementary primary effectiveness endpoint was a composite of (ranked) 1) fatal periop bleeding; 2) severe, or massive bleeding events based on the universal definition for periop bleeding (UDPB) \>3 classification; and 3) 24 hour chest tube drainage (CTD) volume; evaluated by an unmatched win ratio method. Using the hierarchical order of the components of each composite endpoint every patient in the Sham arm is compared with every patient in the DrugSorb-ATR arm to make Ns x Nd pairs. The numbers below are the number of 'winners' for two treatments; a 'win' is given for the better outcome in the pair, eg, less bleeding. The win ratio is the total number of winners in DrugSorb-ATR arm divided by the total number of winners in Sham arm. A ratio of wins \>1.0 favors the treatment arm. The win ratio was 1.59 (95% confidence interval 1.02, 2.46) p-value 0.041.
Time frame: Through the first 48hrs post-operation
Population: i-CABG PP: subjects undergoing isolated CABG procedures, per protocol (those without major protocol deviations that would affect determination of device effectiveness.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control | Incidence of Perioperative (Periop) Bleeding, Supplemental Primary Effectiveness Composite Endpoint, I-CABG Per Protocol (PP) Population | 1178 number of wins |
| DrugSorb-ATR Intervention | Incidence of Perioperative (Periop) Bleeding, Supplemental Primary Effectiveness Composite Endpoint, I-CABG Per Protocol (PP) Population | 1868 number of wins |
p-value: 0.04195% CI: [1.02, 2.46]Finkelstein Schoenfeld test
Primary
Incidence of Perioperative (Periop) Bleeding, Supplemental Primary Effectiveness Composite Endpoint, mITT Population
Incidence of Periop Bleeding, Supplemental Primary Effectiveness Composite Endpoint, mITT population. The supplementary primary effectiveness endpoint was a composite of (ranked) 1) fatal periop bleeding; 2) severe, or massive bleeding events based on the universal definition for periop bleeding (UDPB) \>3 classification; and 3) 24 hour chest tube drainage (CTD) volume; evaluated by an unmatched win ratio method. Using the hierarchical order of the components of each composite endpoint every patient in the Sham arm is compared with every patient in the DrugSorb-ATR arm to make Ns x Nd pairs. The numbers given below are the number of 'winners' for two treatments; a 'win' is given for the better outcome in the pair, eg, less bleeding. The win ratio is the total number of winners in DrugSorb-ATR arm divided by the total number of winners in Sham arm. A ratio of wins \>1.0 favors the treatment arm. The win ratio was 1.17 (95% confidence interval 0.79, 1.73) p value 0.451.
Time frame: Through the first 48 hours post-operation
Population: mITT, modified intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control | Incidence of Perioperative (Periop) Bleeding, Supplemental Primary Effectiveness Composite Endpoint, mITT Population | 2005 number of wins |
| DrugSorb-ATR Intervention | Incidence of Perioperative (Periop) Bleeding, Supplemental Primary Effectiveness Composite Endpoint, mITT Population | 2336 number of wins |
p-value: 0.45195% CI: [0.79, 1.73]Finkelstein Schoenfeld test
Secondary
Chest Tube Drainage, i-CABG PP Population
Drainage volume from all chest and mediastinal tubes
Time frame: Through 12hrs post-operation
Population: isolated CABG per protocol population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | Chest Tube Drainage, i-CABG PP Population | 487 mL |
| DrugSorb-ATR Intervention | Chest Tube Drainage, i-CABG PP Population | 410 mL |
p-value: 0.042Wilcoxon (Mann-Whitney)
Secondary
Chest Tube Drainage, i-CABG PP Population
Drainage volume from all chest and mediastinal tubes
Time frame: Through 24hrs post-operation
Population: isolated CABG per protocol population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | Chest Tube Drainage, i-CABG PP Population | 765 mL |
| DrugSorb-ATR Intervention | Chest Tube Drainage, i-CABG PP Population | 645 mL |
p-value: 0.079Wilcoxon (Mann-Whitney)
Secondary
Chest Tube Drainage, mITT Population
Drainage volume from all chest and mediastinal tubes
Time frame: Through 12hrs post-operation
Population: mITT (all enrolled subjects who received a study device)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | Chest Tube Drainage, mITT Population | 487 mL |
| DrugSorb-ATR Intervention | Chest Tube Drainage, mITT Population | 430 mL |
p-value: 0.427Wilcoxon (Mann-Whitney)
Secondary
Chest Tube Drainage, mITT Population
Drainage volume from all chest and mediastinal tubes
Time frame: Through 24hrs post-operation
Population: mITT (all enrolled subjects who received a study device)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | Chest Tube Drainage, mITT Population | 746 mL |
| DrugSorb-ATR Intervention | Chest Tube Drainage, mITT Population | 715 mL |
p-value: 0.6Wilcoxon (Mann-Whitney)
Secondary
Packed Red Blood Cell (PRBC) Transfusions (Units), mITT Population
Total PRBC transfusions (units) during hospitalization in the mITT population
Time frame: From procedure start through to discharge from index hospitalization, on average 1-2 weeks
Population: mITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | Packed Red Blood Cell (PRBC) Transfusions (Units), mITT Population | 3 PBRC Units |
| DrugSorb-ATR Intervention | Packed Red Blood Cell (PRBC) Transfusions (Units), mITT Population | 2.5 PBRC Units |
Secondary
Platelet Transfusions, (Units), I-CABG PP Population
Total Platelet transfusions (units) during hospitalization
Time frame: From procedure start through to discharge from index hospitalization, on average 1-2 weeks
Population: I-CABG PP, isolated CABG per protocol population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | Platelet Transfusions, (Units), I-CABG PP Population | 2 Platelet units |
| DrugSorb-ATR Intervention | Platelet Transfusions, (Units), I-CABG PP Population | 2 Platelet units |
Secondary
Platelet Transfusions (Units), mITT Population
Total Platelet transfusions (units) during hospitalization
Time frame: From procedure start through to discharge from index hospitalization, on average 1-2 weeks
Population: mITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | Platelet Transfusions (Units), mITT Population | 2 PBRC units |
| DrugSorb-ATR Intervention | Platelet Transfusions (Units), mITT Population | 2 PBRC units |
Secondary
PRBC Transfusions, (Units) I-CABG PP Population
Total PRBC transfusions (units) during hospitalization
Time frame: From procedure start through to discharge from index hospitalization, on average 1-2 weeks
Population: I-CABG PP, isolated CABG per protocol population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | PRBC Transfusions, (Units) I-CABG PP Population | 3 PRBC units |
| DrugSorb-ATR Intervention | PRBC Transfusions, (Units) I-CABG PP Population | 2 PRBC units |