Acquired Antithrombin III Deficiency, Coronary Artery Bypass
Conditions
Keywords
antithrombin, ATIII, acquired deficiency, anticoagulants, cardiopulmonary bypass, surgery, complications, postoperative outcomes
Brief summary
The purpose of this trial is to study the effects of preoperative antithrombin supplementation in patients undergoing cardiac surgery with cardiopulmonary bypass in order to maintain antithrombin levels in a range greater than 58% of functional activity and, eventually, to decrease negative clinical outcomes during the ICU stay.
Interventions
DRUGAntithrombin III
Single dose of antithrombin III sufficient to achieve a preoperative level of 120%
Sponsors
Instituto Grifols, S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female * At least 18 years of age * Subject needed elective cardiac surgery with cardiopulmonary bypass except for heart transplantation * Subject had a baseline ATIII level of less than 100% and equal to or above 60% * Subject signed the informed consent form * Subject was willing to comply with all aspects of the protocol, including blood sampling, for the total duration of the study
Exclusion criteria
* Documented congenital ATIII deficiency or ATIII levels below 60% * Subject had a baseline ATIII level of 100% or higher * Subject needed emergency (non-elective) surgery * Subject needed heart transplantation * History of anaphylactic reaction(s) to blood or blood components * Allergies to excipients * Subject was pregnant * Subject had any medical condition that according to the investigators judgment worsens the surgical outcome above the expected * Subject had any medical condition which is likely to interfere with the evaluation of the study treatment and/or the satisfactory conduct of the trial according to the investigators judgment * Subject had participated in any another investigational study within the last 30 days previous to the inclusion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Postoperative ATIII Levels at the ICU Admission | ICU admission | Measurement of postoperative ATIII functional activity at ICU admission |
| Percentage of Subjects With ATIII Levels of 58% or Higher at ICU Admission | ICU admission | Percentage of subjects with ATIII levels of 58% functional activity or higher at ICU admission |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Postoperative Myocardial Infarction | During ICU stay (maximum 70 days) | Percentage of subjects with postoperative myocardial infarction defined through enzymatic criteria plus new Q-waves at the electrocardiogram |
| Percentage of Subjects With Adverse Neurologic Outcome | During ICU stay (maximum 70 days) | Percentage of subjects with adverse neurologic outcome defined as: coma, stroke or psychotic behaviors lasting \>12 hours after extubation |
| Percentage of Patients With Thromboembolic Events | During ICU stay (maximum 70 days) | Percentage of subjects with thromboembolic events defined as perioperative myocardial infarction, stroke, mesenteric infarction, peripheral thromboembolism and pulmonary embolism |
| ICU Stay Duration | During ICU stay (maximum 70 days) | — |
| In-hospital Postoperative Mortality | 70 days after ICU admission (maximum) | — |
| Need for Blood Products | During ICU stay (maximum 70 days) | Number of units of packed red blood cells, fresh frozen plasma, and/or platelets needed |
| Postoperative Blood Loss in First 12 Hours | ICU admission through 12 hours post-operative | Blood loss defined as the amount of blood collected in the cardiotomy reservoir from ICU admission through the following 12 hours |
| Percentage of Subjects With Low Cardiac Syndrome | During ICU stay (maximum 70 days) | Percentage of subjects with low cardiac syndrome defined as the need for major inotropic support or intra-aortic balloon pump |
| Percentage of Subjects With Renal Dysfunction | During ICU stay (maximum 70 days) | Percentage of subjects with renal dysfunction defined as an increase of serum creatinine levels to \>2.0 and twice the baseline level or need for renal replacement therapy |
| Mechanical Ventilation Duration | During ICU stay (maximum 70 days) | — |
| Length of Hospital Stay | During ICU stay (maximum 70 days) | Length of hospital stay (days) in both groups was defined as the discharge date minus the surgery date plus 1 day, during a maximum of 70 days after ICU admission. |
| Heparin Resistance | Immediately after anesthesia induction | Percentage of subjects with heparin resistance defined as failure to reach an activated clotting time \>450 seconds after a dose of up to 400 IU/kg of heparin, or failure to maintain this activated clotting time value despite heparin supplementations of 100 IU/kg per each dose with an interval of at least 30 minutes between doses |
| Percentage of Subjects Needing Surgical Re-exploration | During ICU stay (maximum 70 days) | Percentage of subjects needing surgical re-exploration resulting from bleeding |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Antithrombin III Treatment Group Preoperative ATIII supplementation administered immediately after anesthesia induction
Antithrombin III: Single dose of antithrombin III sufficient to achieve a preoperative level of 120% | 100 |
| Control Group No preoperative ATIII supplementation administered | 94 |
| Total | 194 |
Baseline characteristics
| Characteristic | Antithrombin III Treatment Group | Control Group | Total |
|---|---|---|---|
| Age, Continuous | 66.51 years STANDARD_DEVIATION 10.48 | 67.63 years STANDARD_DEVIATION 11.18 | 67.05 years STANDARD_DEVIATION 10.81 |
| Region of Enrollment Italy | 100 participants | 94 participants | 194 participants |
| Sex: Female, Male Female | 17 Participants | 24 Participants | 41 Participants |
| Sex: Female, Male Male | 83 Participants | 70 Participants | 153 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 96 / 100 | 97 / 99 |
| serious Total, serious adverse events | 32 / 100 | 29 / 99 |
Outcome results
Primary
Percentage of Subjects With ATIII Levels of 58% or Higher at ICU Admission
Percentage of subjects with ATIII levels of 58% functional activity or higher at ICU admission
Time frame: ICU admission
Population: Intent-to treat set and Per-protocol set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Antithrombin III Treatment Group | Percentage of Subjects With ATIII Levels of 58% or Higher at ICU Admission | 100.0 percentage of participants |
| Control Group | Percentage of Subjects With ATIII Levels of 58% or Higher at ICU Admission | 74.5 percentage of participants |
p-value: <0.0001Fisher Exact
Primary
Postoperative ATIII Levels at the ICU Admission
Measurement of postoperative ATIII functional activity at ICU admission
Time frame: ICU admission
Population: Intent-to-treat set and Per-protocol set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antithrombin III Treatment Group | Postoperative ATIII Levels at the ICU Admission | 94.06 IU | Standard Deviation 13.74 |
| Control Group | Postoperative ATIII Levels at the ICU Admission | 64.70 IU | Standard Deviation 9.89 |
p-value: <0.0001ANCOVA
Secondary
Heparin Resistance
Percentage of subjects with heparin resistance defined as failure to reach an activated clotting time \>450 seconds after a dose of up to 400 IU/kg of heparin, or failure to maintain this activated clotting time value despite heparin supplementations of 100 IU/kg per each dose with an interval of at least 30 minutes between doses
Time frame: Immediately after anesthesia induction
Population: Intent-to-treat set. One subject in the Antithrombin III treatment group was missing this data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Antithrombin III Treatment Group | Heparin Resistance | 17.2 percentage of participants |
| Control Group | Heparin Resistance | 40.4 percentage of participants |
p-value: 0.0004Fisher Exact
Secondary
ICU Stay Duration
Time frame: During ICU stay (maximum 70 days)
Population: Intent-to-treat set. One subject in the control group was missing this data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Antithrombin III Treatment Group | ICU Stay Duration | 2.00 days |
| Control Group | ICU Stay Duration | 2.00 days |
p-value: 0.3897Hodges-Lehmann test
Secondary
In-hospital Postoperative Mortality
Time frame: 70 days after ICU admission (maximum)
Population: Intent-to-treat set. One subject in the control group was missing this data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Antithrombin III Treatment Group | In-hospital Postoperative Mortality | 1.0 percentage of participants |
| Control Group | In-hospital Postoperative Mortality | 1.1 percentage of participants |
p-value: 1Fisher Exact
Secondary
Length of Hospital Stay
Length of hospital stay (days) in both groups was defined as the discharge date minus the surgery date plus 1 day, during a maximum of 70 days after ICU admission.
Time frame: During ICU stay (maximum 70 days)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Antithrombin III Treatment Group | Length of Hospital Stay | 10.00 days |
| Control Group | Length of Hospital Stay | 10.00 days |
p-value: 0.7489Hodges-Lehmann test
Secondary
Mechanical Ventilation Duration
Time frame: During ICU stay (maximum 70 days)
Population: Intent-to-treat set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Antithrombin III Treatment Group | Mechanical Ventilation Duration | 1.00 Days |
| Control Group | Mechanical Ventilation Duration | 1.00 Days |
p-value: 0.9574Hodges-Lehmann
Secondary
Need for Blood Products
Number of units of packed red blood cells, fresh frozen plasma, and/or platelets needed
Time frame: During ICU stay (maximum 70 days)
Population: Intent-to-treat set
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Antithrombin III Treatment Group | Need for Blood Products | Packed Red Blood Cells (Anbinex n=45,Control n=38) | 43.711 Units | Standard Error 3.551 |
| Antithrombin III Treatment Group | Need for Blood Products | Fresh frozen plasma (Anbinex n=16, Control n=8) | 12.188 Units | Standard Error 1.646 |
| Antithrombin III Treatment Group | Need for Blood Products | Platelets (Anbinex n=5, Control n=8) | 8.500 Units | Standard Error 1.564 |
| Control Group | Need for Blood Products | Packed Red Blood Cells (Anbinex n=45,Control n=38) | 41.987 Units | Standard Error 3.864 |
| Control Group | Need for Blood Products | Fresh frozen plasma (Anbinex n=16, Control n=8) | 13.125 Units | Standard Error 2.327 |
| Control Group | Need for Blood Products | Platelets (Anbinex n=5, Control n=8) | 6.188 Units | Standard Error 1.236 |
Comparison: Number of units of packed red blood cellsp-value: 0.7433ANCOVA
Comparison: Units of fresh frozen plasmap-value: 0.7453ANCOVA
Comparison: Units of plateletsp-value: 0.2705ANCOVA
Secondary
Percentage of Patients With Thromboembolic Events
Percentage of subjects with thromboembolic events defined as perioperative myocardial infarction, stroke, mesenteric infarction, peripheral thromboembolism and pulmonary embolism
Time frame: During ICU stay (maximum 70 days)
Population: Intent-to-treat set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Antithrombin III Treatment Group | Percentage of Patients With Thromboembolic Events | Follow-up visit (Anbinex n=76, Control n=69) | 0.0 percentage of participants |
| Antithrombin III Treatment Group | Percentage of Patients With Thromboembolic Events | ICU discharge visit (Anbinex n=99, Control n=94) | 0.0 percentage of participants |
| Control Group | Percentage of Patients With Thromboembolic Events | Follow-up visit (Anbinex n=76, Control n=69) | 0.0 percentage of participants |
| Control Group | Percentage of Patients With Thromboembolic Events | ICU discharge visit (Anbinex n=99, Control n=94) | 1.1 percentage of participants |
Comparison: ICU discharge visitp-value: 0.487Fisher Exact
Secondary
Percentage of Subjects Needing Surgical Re-exploration
Percentage of subjects needing surgical re-exploration resulting from bleeding
Time frame: During ICU stay (maximum 70 days)
Population: Intent-to-treat set. Two subjects in the Antithrombin III treatment group and 2 subjects in the Control group were missing this data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Antithrombin III Treatment Group | Percentage of Subjects Needing Surgical Re-exploration | 5.1 percentage of participants |
| Control Group | Percentage of Subjects Needing Surgical Re-exploration | 2.2 percentage of participants |
p-value: 0.446Fisher Exact
Secondary
Percentage of Subjects With Adverse Neurologic Outcome
Percentage of subjects with adverse neurologic outcome defined as: coma, stroke or psychotic behaviors lasting \>12 hours after extubation
Time frame: During ICU stay (maximum 70 days)
Population: Intent-to-treat set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Antithrombin III Treatment Group | Percentage of Subjects With Adverse Neurologic Outcome | Follow-up visit (Anbinex n=75, Control n=69) | 5.3 percentage of participants |
| Antithrombin III Treatment Group | Percentage of Subjects With Adverse Neurologic Outcome | ICU discharge visit (Anbinex n=99, Control n=93) | 1.0 percentage of participants |
| Control Group | Percentage of Subjects With Adverse Neurologic Outcome | Follow-up visit (Anbinex n=75, Control n=69) | 0.0 percentage of participants |
| Control Group | Percentage of Subjects With Adverse Neurologic Outcome | ICU discharge visit (Anbinex n=99, Control n=93) | 0.0 percentage of participants |
Comparison: Follow-up visitp-value: 0.1211Fisher Exact
Comparison: ICU discharge visitp-value: 1Fisher Exact
Secondary
Percentage of Subjects With Low Cardiac Syndrome
Percentage of subjects with low cardiac syndrome defined as the need for major inotropic support or intra-aortic balloon pump
Time frame: During ICU stay (maximum 70 days)
Population: Intent-to-treat set. Three subjects in the Antithrombin III treatment group and 1 subject in the Control group were missing this data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Antithrombin III Treatment Group | Percentage of Subjects With Low Cardiac Syndrome | 24.7 percentage of participants |
| Control Group | Percentage of Subjects With Low Cardiac Syndrome | 20.4 percentage of participants |
p-value: 0.4936Fisher Exact
Secondary
Percentage of Subjects With Postoperative Myocardial Infarction
Percentage of subjects with postoperative myocardial infarction defined through enzymatic criteria plus new Q-waves at the electrocardiogram
Time frame: During ICU stay (maximum 70 days)
Population: Intent-to-treat set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Antithrombin III Treatment Group | Percentage of Subjects With Postoperative Myocardial Infarction | Follow-up visit (Anbinex n=76, Control n=69) | 0.0 percentage of participants |
| Antithrombin III Treatment Group | Percentage of Subjects With Postoperative Myocardial Infarction | ICU discharge visit (Anbinex n=99, Control n=93) | 1.0 percentage of participants |
| Control Group | Percentage of Subjects With Postoperative Myocardial Infarction | Follow-up visit (Anbinex n=76, Control n=69) | 0.0 percentage of participants |
| Control Group | Percentage of Subjects With Postoperative Myocardial Infarction | ICU discharge visit (Anbinex n=99, Control n=93) | 2.2 percentage of participants |
Comparison: At ICU discharge visitp-value: 0.6115Fisher Exact
Secondary
Percentage of Subjects With Renal Dysfunction
Percentage of subjects with renal dysfunction defined as an increase of serum creatinine levels to \>2.0 and twice the baseline level or need for renal replacement therapy
Time frame: During ICU stay (maximum 70 days)
Population: Intent-to-treat set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Antithrombin III Treatment Group | Percentage of Subjects With Renal Dysfunction | Follow-up visit (Anbinex n=75, Control n=69) | 1.3 Percentage of participants |
| Antithrombin III Treatment Group | Percentage of Subjects With Renal Dysfunction | ICU discharge visit (Anbinex n=99, Control n=93) | 3.0 Percentage of participants |
| Control Group | Percentage of Subjects With Renal Dysfunction | Follow-up visit (Anbinex n=75, Control n=69) | 0.0 Percentage of participants |
| Control Group | Percentage of Subjects With Renal Dysfunction | ICU discharge visit (Anbinex n=99, Control n=93) | 1.1 Percentage of participants |
Comparison: Follow-up visitp-value: 1Fisher Exact
Comparison: ICU discharge visitp-value: 0.6218Fisher Exact
Secondary
Postoperative Blood Loss in First 12 Hours
Blood loss defined as the amount of blood collected in the cardiotomy reservoir from ICU admission through the following 12 hours
Time frame: ICU admission through 12 hours post-operative
Population: Intent-to-treat set. One subject in the Antithrombin III treatment group was missing this data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Antithrombin III Treatment Group | Postoperative Blood Loss in First 12 Hours | 516.11 mL | Standard Error 30.292 |
| Control Group | Postoperative Blood Loss in First 12 Hours | 415.00 mL | Standard Error 31.087 |
p-value: 0.0209ANCOVA