Acute Hypoxemic Respiratory Failure, Anticoagulant-induced Bleeding, Thromboembolism
Conditions
Keywords
ARDS, Hypoxemic respiratory failure, Extracorporeal Membrane Oxygenation
Brief summary
Moderate intensity titrated dose anticoagulation has been used in patients receiving extracorporeal membrane oxygenation (ECMO) to prevent thromboembolism and thrombotic mechanical complications. As technology has improved, however, the incidence of thromboembolic events has decreased, leading to re-evaluation of the risks of anticoagulation, particularly during venovenous (V-V) ECMO. Recent data suggest that bleeding complications during V-V ECMO may be more strongly associated with mortality than thromboembolic complications, and case series have suggested that V-V ECMO can be safely performed without moderate or high intensity anticoagulation. At present, there is significant variability between institutions in the approach to anticoagulation during V-V ECMO. A definitive randomized controlled trial is needed to compare the effects of a low intensity fixed dose anticoagulation (low intensity) versus moderate intensity titrated dose anticoagulation (moderate intensity) on clinical outcomes during V-V ECMO. Before such a trial can be conducted, however, additional data are needed to inform the feasibility of the future trial.
Detailed description
Since the inception of Extracorporeal Membrane Oxygenation (ECMO), moderate intensity titrated dose anticoagulation has been used to prevent clinically harmful thromboembolism and thrombotic mechanical complications. The impact of thromboembolic events on clinical outcomes during venovenous (V-V) extracorporeal membrane oxygenation (ECMO), however, is unclear, and complications related to bleeding are common and associated with increased morbidity and mortality. These findings have led many experts to suggest that anticoagulation strategies during V-V ECMO should be re-evaluated. Critical illness, in general, is associated with both coagulopathy and impaired hemostasis. These problems are compounded during ECMO by the artificial interface between blood and the non-biologic surface of the circuit components, which leads to activation of the coagulation system, consumptive thrombocytopenia, fibrinolysis, and thrombin generation. The sheer stress on blood components during ECMO also lead to destruction of high-molecular-weight von Willebrand multimers, interrupting primary hemostasis. Both bleeding and thromboembolism are common complications during ECMO. Bleeding events have been associated with poor clinical outcomes, likely mediated by an increased incidence of intracranial hemorrhage during ECMO. During intra-operative cardiopulmonary bypass and venoarterial (V-A) ECMO, ischemic strokes are a common and potentially deadly complication. During V-V ECMO, however, the majority of thromboembolic events are cannula-associated DVT and circuit thromboses requiring exchange, which are of unclear clinical significance. Various anticoagulation strategies have been proposed to balance the risks of bleeding and thromboembolism during V-V ECMO, including high intensity anticoagulation, moderate intensity anticoagulation, and low intensity anticoagulation (the equivalent of DVT prophylaxis). Observational studies have suggested that, compared to moderate intensity anticoagulation, low intensity anticoagulation reduces transfusion requirements without affecting the incidence of thrombosis, hemorrhage, or death. In one case series of 60 patients who were treated with only low-intensity subcutaneous heparin during V-V ECMO, rates of transfusions were lower than historical controls without any effect on the rate of thrombotic events. Similarly, a recent systematic review suggested that the rates of thromboembolism and circuit thrombosis among patients managed with a moderate intensity anticoagulation strategy during V-V ECMO were comparable to the rates reported among patients managed with a less intense anticoagulation strategy. To date, there are no randomized controlled trials comparing low intensity to moderate intensity anticoagulation during V-V ECMO. Guidelines from the Extracorporeal Life Support Organization (ELSO), the pre-eminent group for ECMO education and research, provide little guidance for the selection of anticoagulation strategy, and anticoagulation practices are highly variable across institutions. A large, multicenter, randomized trial is needed to determine the ideal strategy to anticoagulation during V-V ECMO. Before such a trial can be conducted, however, additional data are needed on the feasibility of randomizing patients to a specific anticoagulation strategy and study measurements. To facilitate a large, multicenter randomized controlled trial comparing low intensity anticoagulation to moderate intensity anticoagulation during V-V ECMO, a pilot trial is needed to establish feasibility and the performance of the primary outcome measures. Primary aim of the study: To demonstrate feasibility of a future large, multi-center randomized controlled trial comparing low intensity to moderate intensity anticoagulation among adults receiving V-V ECMO by demonstrating the ability to recruit and randomize participants, adhere to assigned anticoagulation strategy, and demonstrate adequate separation between groups in therapy delivered and intensity of anticoagulation achieved with the assigned anticoagulation strategies. Secondary aim of the study: To define and estimate the frequency of the primary efficacy, primary safety, and secondary outcomes of a future large, multi-center randomized controlled trial comparing low intensity vs moderate intensity anticoagulation among adults receiving V-V ECMO.
Interventions
OTHERLow intensity anticoagulation
Participants assigned to the low intensity anticoagulation strategy will receive anticoagulation at doses used for DVT prophylaxis in critically ill patients. The choice of agent (e.g. heparin or enoxaparin) and specific dosing will be at the discretion of the treating clinicians and will be prospectively recorded.
OTHERModerate Intensity Anticoagulation
Patients assigned to the moderate intensity anticoagulation strategy will receive anticoagulation targeting a PTT goal of 40-60 seconds or anti-Xa level of 0.2 to 0.3 IU/mL. Choice of anticoagulant and monitoring strategy (PTT or anti-Xa level) will be at the discretion of the treating clinicians and will be prospectively recorded. Anticoagulant drips will be titrated according to institutional protocols. For patients who survive to decannulation, the infusion will be stopped one hour prior to decannulation. This approach to anticoagulation reflects the current approach for patients receiving V-V ECMO at Vanderbilt University Medical Center and is similar to protocols widely adopted for patients receiving V-V ECMO at other centers.
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single center, open-label, parallel-group, randomized pilot trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient receiving V-V ECMO 2. Patient is located in a participating unit of the Vanderbilt University Medical Center (VUMC) adult hospital.
Exclusion criteria
1. Patient is pregnant 2. Patient is a prisoner 3. Patient is \< 18 years old 4. Patient underwent ECMO cannulation greater than 24 hours prior to screening 5. Presence of an indication for systemic anticoagulation: 1. Ongoing receipt of systemic anticoagulation 2. Planned administration of anticoagulation for an indication other than ECMO 3. Presence of or plan to insert an arterial ECMO cannula 6. Presence of a contraindication to anticoagulation: 1. Active bleeding determined by treating clinicians to make anticoagulation unsafe 2. Major surgery or trauma less than 72 hours prior to randomization 3. Known history of a bleeding diathesis 4. Ongoing severe thrombocytopenia (platelet count \< 30,000) 5. History of heparin-induced thrombocytopenia (HIT) 6. Heparin allergy 7. Positive SARS-CoV-2 test within prior 21 days or high clinical suspicion for COVID-19 8. The treating clinician determines that the patient's risks of thromboembolism or bleeding necessitate a specific approach to anticoagulation management during V-V ECMO
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Major Bleeding Events | From randomization to the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days. | Major bleeding event, according to the International Society on Thrombosis and Hemostasis, defined as: 1. Fatal bleeding 2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome 3. Clinically overt bleeding associated with either a drop in hemoglobin level by at least 2.0 grams/dL or leading to transfusion of two or more units of packed red blood cells |
| Number of Participants With Thromboembolic Events | From randomization to the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days. | Thromboembolic event defined as: 1. Deep venous thrombosis (DVT) 2. Acute pulmonary embolism (PE) 3. Intra-cardiac thrombosis 4. Ischemic stroke 5. Acute circuit thrombosis requiring urgent circuit exchange 6. Acute arterial thromboembolism |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Circuit or Circuit Component Exchanges | From randomization to the date of death or decannulation, whichever came first, through study completion, up to 134 days | Circuit or circuit component exchange during ECMO support |
| New Heparin Induced Thrombocytopenia Diagnosis | From randomization to the date of death or decannulation, whichever came first, through study completion, up to 134 days | New diagnosis of Heparin Induced Thrombocytopenia as measured by clinically obtained serotonin release assay |
| Lowest Platelet Count | From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days | Lowest clinically obtained platelet count |
| Highest Total Bilirubin Values | From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days | Highest clinically obtained total bilirubin values |
| Highest Lactate Dehydrogenase Value | From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days | Highest clinically obtained lactate dehydrogenase value |
| Death Attributable to a Thromboembolic Event | From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days | In-hospital mortality attributable to a thromboembolic event |
| Ventilator-free Days | From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days | Number of days alive and free from mechanical ventilation between randomization and day 28. |
| ICU Length of Stay | From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days | Number of days in the ICU following randomization. |
| Hospital Length of Stay | From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days | Number of days in the hospital following randomization |
| In-hospital Mortality | From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days | Death prior to hospital discharge |
| Death Attributable to a Major Bleeding Event | From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days | In-hospital mortality attributable to a major bleeding event |
| Number of Participants With Cannula-associated Deep Vein Thrombosis | 24-72 hours after decannulation | Cannula-associated deep vein thrombosis, as measured by four-extremity venous ultrasounds obtained 24-72 hours following decannulation among patients who were decannulation |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of and Specific Reasons for Missed Enrollments | From ECMO cannulation to 24 hours after ECMO cannulation. | Reasons for missed enrollments (e.g. unavailability of research staff, refusal of clinical team to allow randomization, patient refusal of informed consent) |
| Duration of the Intervention Period (Days) | From randomization to the first of decannulation or death, up to 134 days. | Duration of the intervention period, defined as the time from randomization to the first of: diagnosis of a major bleeding event, diagnosis of a thromboembolic event, placement of an arterial ECMO cannula, decannulation from ECMO, or death (days) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Intensity Anticoagulation Low intensity anticoagulation: Participants assigned to the low intensity anticoagulation strategy will receive anticoagulation at doses used for DVT prophylaxis in critically ill patients. The choice of agent (e.g. heparin or enoxaparin) and specific dosing will be at the discretion of the treating clinicians and will be prospectively recorded. | 12 |
| Moderate Intensity Anticoagulation Moderate Intensity Anticoagulation: Participants assigned to the moderate intensity anticoagulation strategy will receive anticoagulation targeting a PTT goal of 40-60 seconds or anti-Xa level of 0.2 to 0.3 IU/mL. Choice of anticoagulant and monitoring strategy (PTT or anti-Xa level) will be at the discretion of the treating clinicians and will be prospectively recorded. Anticoagulant drips will be titrated according to institutional protocols.
This approach to anticoagulation reflects the current approach for patients receiving V-V ECMO at Vanderbilt University Medical Center and is similar to protocols widely adopted for patients receiving V-V ECMO at other centers. | 14 |
| Total | 26 |
Baseline characteristics
| Characteristic | Moderate Intensity Anticoagulation | Total | Low Intensity Anticoagulation |
|---|---|---|---|
| Age, Continuous | 40 years | 35.5 years | 34 years |
| Race/Ethnicity, Customized Asian Non-Hispanic | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black Non-Hispanic | 2 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized White Non-Hispanic | 10 Participants | 18 Participants | 8 Participants |
| Sex: Female, Male Female | 10 Participants | 17 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 9 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 14 | 0 / 12 |
| other Total, other adverse events | 0 / 14 | 0 / 12 |
| serious Total, serious adverse events | 0 / 14 | 0 / 12 |
Outcome results
Primary
Number of Participants With Major Bleeding Events
Major bleeding event, according to the International Society on Thrombosis and Hemostasis, defined as: 1. Fatal bleeding 2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome 3. Clinically overt bleeding associated with either a drop in hemoglobin level by at least 2.0 grams/dL or leading to transfusion of two or more units of packed red blood cells
Time frame: From randomization to the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Intensity Anticoagulation | Number of Participants With Major Bleeding Events | 1 Participants |
| Moderate Intensity Anticoagulation | Number of Participants With Major Bleeding Events | 4 Participants |
Primary
Number of Participants With Thromboembolic Events
Thromboembolic event defined as: 1. Deep venous thrombosis (DVT) 2. Acute pulmonary embolism (PE) 3. Intra-cardiac thrombosis 4. Ischemic stroke 5. Acute circuit thrombosis requiring urgent circuit exchange 6. Acute arterial thromboembolism
Time frame: From randomization to the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Intensity Anticoagulation | Number of Participants With Thromboembolic Events | 0 Participants |
| Moderate Intensity Anticoagulation | Number of Participants With Thromboembolic Events | 1 Participants |
Secondary
Death Attributable to a Major Bleeding Event
In-hospital mortality attributable to a major bleeding event
Time frame: From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Intensity Anticoagulation | Death Attributable to a Major Bleeding Event | 0 Participants |
| Moderate Intensity Anticoagulation | Death Attributable to a Major Bleeding Event | 0 Participants |
Secondary
Death Attributable to a Thromboembolic Event
In-hospital mortality attributable to a thromboembolic event
Time frame: From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Intensity Anticoagulation | Death Attributable to a Thromboembolic Event | 0 Participants |
| Moderate Intensity Anticoagulation | Death Attributable to a Thromboembolic Event | 0 Participants |
Secondary
Highest Lactate Dehydrogenase Value
Highest clinically obtained lactate dehydrogenase value
Time frame: From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Intensity Anticoagulation | Highest Lactate Dehydrogenase Value | 492 U/L |
| Moderate Intensity Anticoagulation | Highest Lactate Dehydrogenase Value | 711 U/L |
Secondary
Highest Total Bilirubin Values
Highest clinically obtained total bilirubin values
Time frame: From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Intensity Anticoagulation | Highest Total Bilirubin Values | 1.2 mg/dL |
| Moderate Intensity Anticoagulation | Highest Total Bilirubin Values | 0.9 mg/dL |
Secondary
Hospital Length of Stay
Number of days in the hospital following randomization
Time frame: From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Intensity Anticoagulation | Hospital Length of Stay | 19 days |
| Moderate Intensity Anticoagulation | Hospital Length of Stay | 23 days |
Secondary
ICU Length of Stay
Number of days in the ICU following randomization.
Time frame: From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Intensity Anticoagulation | ICU Length of Stay | 11 days |
| Moderate Intensity Anticoagulation | ICU Length of Stay | 15 days |
Secondary
In-hospital Mortality
Death prior to hospital discharge
Time frame: From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Intensity Anticoagulation | In-hospital Mortality | 2 Participants |
| Moderate Intensity Anticoagulation | In-hospital Mortality | 0 Participants |
Secondary
Lowest Platelet Count
Lowest clinically obtained platelet count
Time frame: From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Intensity Anticoagulation | Lowest Platelet Count | 88 cells per mcL |
| Moderate Intensity Anticoagulation | Lowest Platelet Count | 130 cells per mcL |
Secondary
New Heparin Induced Thrombocytopenia Diagnosis
New diagnosis of Heparin Induced Thrombocytopenia as measured by clinically obtained serotonin release assay
Time frame: From randomization to the date of death or decannulation, whichever came first, through study completion, up to 134 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Intensity Anticoagulation | New Heparin Induced Thrombocytopenia Diagnosis | 0 Participants |
| Moderate Intensity Anticoagulation | New Heparin Induced Thrombocytopenia Diagnosis | 0 Participants |
Secondary
Number of Circuit or Circuit Component Exchanges
Circuit or circuit component exchange during ECMO support
Time frame: From randomization to the date of death or decannulation, whichever came first, through study completion, up to 134 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Intensity Anticoagulation | Number of Circuit or Circuit Component Exchanges | 2 Exchanges |
| Moderate Intensity Anticoagulation | Number of Circuit or Circuit Component Exchanges | 1 Exchanges |
Secondary
Number of Participants With Cannula-associated Deep Vein Thrombosis
Cannula-associated deep vein thrombosis, as measured by four-extremity venous ultrasounds obtained 24-72 hours following decannulation among patients who were decannulation
Time frame: 24-72 hours after decannulation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Intensity Anticoagulation | Number of Participants With Cannula-associated Deep Vein Thrombosis | 7 Participants |
| Moderate Intensity Anticoagulation | Number of Participants With Cannula-associated Deep Vein Thrombosis | 5 Participants |
p-value: <0.05Fisher Exact
Secondary
Ventilator-free Days
Number of days alive and free from mechanical ventilation between randomization and day 28.
Time frame: From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Intensity Anticoagulation | Ventilator-free Days | 54 days |
| Moderate Intensity Anticoagulation | Ventilator-free Days | 47 days |
Other Pre-specified
Duration of the Intervention Period (Days)
Duration of the intervention period, defined as the time from randomization to the first of: diagnosis of a major bleeding event, diagnosis of a thromboembolic event, placement of an arterial ECMO cannula, decannulation from ECMO, or death (days)
Time frame: From randomization to the first of decannulation or death, up to 134 days.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Intensity Anticoagulation | Duration of the Intervention Period (Days) | 4.6 days |
| Moderate Intensity Anticoagulation | Duration of the Intervention Period (Days) | 4.6 days |
Other Pre-specified
Number of and Specific Reasons for Missed Enrollments
Reasons for missed enrollments (e.g. unavailability of research staff, refusal of clinical team to allow randomization, patient refusal of informed consent)
Time frame: From ECMO cannulation to 24 hours after ECMO cannulation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Intensity Anticoagulation | Number of and Specific Reasons for Missed Enrollments | 0 Participants |
| Moderate Intensity Anticoagulation | Number of and Specific Reasons for Missed Enrollments | 0 Participants |