COVID-19, Venous Thromboembolism, Arterial Thrombosis
Conditions
Brief summary
The researchers wanted to learn how to help sick patients who are in the hospital because of COVID-19. They are trying to find out the best way that is safe to stop blood clots that could be dangerous from forming in patients with COVID-19. This research study happened at 34 hospitals. All patients in the study took medicines that help prevent blood clots. These medicines are called blood thinners or anticoagulants. Patients got different amounts of blood thinners to see what works better and is safer. Researchers randomly chose some patients to get more and some to get less. The researchers also wanted to know if another medicine called clopidogrel can safely help stop blood clots from forming. This kind of medicine helps keep parts of the blood, called platelets, from sticking together. In some patients who did not have other reasons to take a platelet-blocker the researchers randomly chose the patient to take clopidogrel or not. This type of medicine is also called an antiplatelet.
Detailed description
This is a multicenter, open-label, randomized-controlled trial in critically-ill patients with novel coronavirus disease 2019 (COVID-19) evaluating the efficacy and safety of full-dose vs. standard prophylactic dose anticoagulation and of antiplatelet vs. no antiplatelet therapy (in a nested second randomization) for prevention of venous and arterial thrombotic events. In a subcohort without an ongoing indication for antiplatelet therapy at screening, the second randomization is performed to either antiplatelet or no antiplatelet therapy
Interventions
Unfractionated heparin (UFH) administered intravenously with a nomogram targeting an aPTT of 1.5-2.5 times the control as per institutional therapeutic target for treatment of VTE
DRUGEnoxaparin 1 mg/kg
Enoxaparin 1 mg/kg administered subcutaneously (SC) every 12 hours
DRUGClopidogrel
Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily orally on subsequent days
DRUGUnfractionated heparin SC
Heparin 5,000 units administered subcutaneous three times daily
Enoxaparin 40 mg administered subcutaneously (SC) once daily (reduce to 30 mg if CrCl\<30 ml/min)
Sponsors
The TIMI Study Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Randomized-controlled trial - 1) full-dose anticoagulation (FDAC) versus standard-dose prophylactic anticoagulation (SDPAC) (pooled across antiplatelet regimens) and in a subset of patients 2) antiplatelet (AP) versus no AP therapy (pooled across anticoagulant regimens)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years (male or female) 2. Acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) 3. Currently admitted to an intensive care unit (ICU) Key
Exclusion criteria
1. Ongoing (\>48 hours) or planned full-dose (therapeutic) anticoagulation for any indication 2. Ongoing or planned treatment with dual antiplatelet therapy 3. Contraindication to antithrombotic therapy or high risk of bleeding due to conditions including, but not limited to, any of the following: 1. History of intracranial hemorrhage, known central nervous system (CNS) tumor or CNS vascular abnormality 2. Active or recent major bleeding within the past 30 days with untreated source 3. Platelet count \<70,000 or known functional platelet disorder 4. Fibrinogen \<200 mg/dL 5. International normalized ratio (INR) \>1.9 4. History of heparin-induced thrombocytopenia 5. Ischemic stroke within the past 2 weeks Patients who meet the following criterion are excluded from the second randomization (antiplatelet therapy vs. no antiplatelet therapy): 1\. Ongoing or planned antiplatelet therapy, including aspirin monotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation | 28 days or until hospital discharge, whichever earlier | The efficacy of these interventions was analyzed using an unmatched win ratio. * The number of wins was found by comparing every patient in the FDAC (Full-dose anticoagulation) arm to every patient in the SDPAC (Standard dose prophylactic anticoagulation) arm to determine a 'win' and totaling up the number of wins in each arm. * A 'win' is a point in the favor of the arm it is given to. For each comparison of one patient in full dose arm compared to one patient in the standard dose arm, a 'win' is given to arm with the patient who had a component of the composite endpoint either lower in the hierarchy than the paired patient, or if the patient did not have any component of the composite while the paired patient did experience a component event of the composite. * Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia, or clinically silent DVT. |
| Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy | 28 days or until hospital discharge, whichever earlier | The efficacy of these interventions was analyzed using an unmatched win ratio. * The number of wins was found by comparing every patient in the Anti-platelet group to every patient in the No Anti-platelet group arm to determine a 'win' and totaling up the number of wins in each arm. * A 'win' is a point in the favor of the arm it is given to. For each comparison of one patient in full dose arm compared to one patient in the standard dose arm, a 'win' is given to arm with the patient who had a component of the composite endpoint either lower in the hierarchy than the paired patient, or if the patient did not have any component of the composite while the paired patient did experience a component event of the composite. * Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia, or clinically silent DVT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinically Evident Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation | 28 days or until hospital discharge, whichever earlier | The efficacy of these interventions was analyzed using an unmatched win ratio. * The number of wins was found by comparing every patient in the FDAC (Full-dose anticoagulation) arm to every patient in the SDPAC (Standard dose prophylactic anticoagulation) arm to determine a 'win' and totaling up the number of wins in each arm. * A 'win' is a point in the favor of the arm it is given to. For each comparison of one patient in full dose arm compared to one patient in the standard dose arm, a 'win' is given to arm with the patient who had a component of the composite endpoint either lower in the hierarchy than the paired patient, or if the patient did not have any component of the composite while the paired patient did experience a component event of the composite. * Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia. |
| Clinically Evident Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy | 28 days or until hospital discharge, whichever earlier | The efficacy of these interventions was analyzed using an unmatched win ratio. * The number of wins was found by comparing every patient in the Anti-platelet group to every patient in the No Anti-platelet group arm to determine a 'win' and totaling up the number of wins in each arm. * A 'win' is a point in the favor of the arm it is given to. For each comparison of one patient in full dose arm compared to one patient in the standard dose arm, a 'win' is given to arm with the patient who had a component of the composite endpoint either lower in the hierarchy than the paired patient, or if the patient did not have any component of the composite while the paired patient did experience a component event of the composite. * Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia. |
Countries
United States
Participant flow
Pre-assignment details
Patients were randomized in a 1:1 allocation ratio to receive either full-dose anticoagulation (FDAC) or standard-dose prophylactic anticoagulation (SDPAC). In a subset of patients without an ongoing indication for antiplatelet (AP) therapy at baseline, a second randomization was performed in a 1:1 allocation ratio to either AP or no AP therapy. Analyses of anticoagulation were pooled across AP regimens, and AP therapy vs. no AP therapy were pooled across anticoagulant regimens.
Participants by arm
| Arm | Count |
|---|---|
| Full-dose Anticoagulation (FDAC) * Unfractionated heparin (UFH) administered intravenously with a nomogram targeting an aPTT of 1.5-2.5 times the control as per institutional therapeutic target for treatment of VTE
* Enoxaparin 1 mg/kg administered subcutaneously(SC) every 12 hours
* With or without anti-platelet therapy: Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily on subsequent days | 197 |
| Standard-dose Prophylactic Anticoagulation (SDPAC) * Enoxaparin 40 mg administered subcutaneously (SC) once daily (reduce to 30 mg if CrCl\<30 ml/min)
* Heparin 5,000 units administered subcutaneous three times daily
* With or without anti-platelet therapy: Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily on subsequent days | 193 |
| Total | 390 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 55 | 62 |
Baseline characteristics
| Characteristic | Full-dose Anticoagulation (FDAC) | Standard-dose Prophylactic Anticoagulation (SDPAC) | Total |
|---|---|---|---|
| Age, Continuous | 59 years | 62 years | 61 years |
| Race/Ethnicity, Customized Non-white | 62 Participants | 53 Participants | 115 Participants |
| Race/Ethnicity, Customized White | 135 Participants | 140 Participants | 275 Participants |
| Sex: Female, Male Female | 75 Participants | 84 Participants | 159 Participants |
| Sex: Female, Male Male | 122 Participants | 109 Participants | 231 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 55 / 197 | 62 / 193 | 41 / 152 | 34 / 140 |
| other Total, other adverse events | 37 / 197 | 22 / 193 | 25 / 152 | 0 / 140 |
| serious Total, serious adverse events | 16 / 197 | 3 / 193 | 6 / 152 | 0 / 140 |
Outcome results
Primary
Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy
The efficacy of these interventions was analyzed using an unmatched win ratio. * The number of wins was found by comparing every patient in the Anti-platelet group to every patient in the No Anti-platelet group arm to determine a 'win' and totaling up the number of wins in each arm. * A 'win' is a point in the favor of the arm it is given to. For each comparison of one patient in full dose arm compared to one patient in the standard dose arm, a 'win' is given to arm with the patient who had a component of the composite endpoint either lower in the hierarchy than the paired patient, or if the patient did not have any component of the composite while the paired patient did experience a component event of the composite. * Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia, or clinically silent DVT.
Time frame: 28 days or until hospital discharge, whichever earlier
Population: The on-treatment analysis population, consisting of all randomly assigned patients who received at least 1 dose of the randomly allocated study strategy. As is pre-specified in the Study Protocol, comparisons between anti-platelet therapy and no anti-platelet therapy are reported irrespective of which anticoagulation intervention participants received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Full-dose Anticoagulation | Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy | 2052 Number of wins |
| Prophylactic Anticoagulation | Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy | 1994 Number of wins |
p-value: 0.995% CI: [0.54, 2.01]Stratified Win-Ratio Analysis, 2-sided
Primary
Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation
The efficacy of these interventions was analyzed using an unmatched win ratio. * The number of wins was found by comparing every patient in the FDAC (Full-dose anticoagulation) arm to every patient in the SDPAC (Standard dose prophylactic anticoagulation) arm to determine a 'win' and totaling up the number of wins in each arm. * A 'win' is a point in the favor of the arm it is given to. For each comparison of one patient in full dose arm compared to one patient in the standard dose arm, a 'win' is given to arm with the patient who had a component of the composite endpoint either lower in the hierarchy than the paired patient, or if the patient did not have any component of the composite while the paired patient did experience a component event of the composite. * Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia, or clinically silent DVT.
Time frame: 28 days or until hospital discharge, whichever earlier
Population: The on-treatment analysis population, consisting of all randomly assigned patients who received at least 1 dose of the randomly allocated study strategy. As is pre-specified in the Study Protocol, comparisons between FDAC and SDPAC are reported irrespective of whether participants received anti-platelet therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Full-dose Anticoagulation | Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation | 4,486 Number of wins |
| Prophylactic Anticoagulation | Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation | 2,351 Number of wins |
Comparison: FDAC = Full Dose Anticoagulation; SDPAC = Standard Dose Prophylactic Anticoagulationp-value: 0.02895% CI: [1.08, 3.55]Stratified Win-Ratio Analysis, 2-sided
Secondary
Clinically Evident Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy
The efficacy of these interventions was analyzed using an unmatched win ratio. * The number of wins was found by comparing every patient in the Anti-platelet group to every patient in the No Anti-platelet group arm to determine a 'win' and totaling up the number of wins in each arm. * A 'win' is a point in the favor of the arm it is given to. For each comparison of one patient in full dose arm compared to one patient in the standard dose arm, a 'win' is given to arm with the patient who had a component of the composite endpoint either lower in the hierarchy than the paired patient, or if the patient did not have any component of the composite while the paired patient did experience a component event of the composite. * Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia.
Time frame: 28 days or until hospital discharge, whichever earlier
Population: The on-treatment analysis population, consisting of all randomly assigned patients who received at least 1 dose of the randomly allocated study strategy. As is pre-specified in the Study Protocol, comparisons between anti-platelet therapy and no anti-platelet therapy are reported irrespective of which anticoagulation intervention participants received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Full-dose Anticoagulation | Clinically Evident Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy | 1452 Number of wins |
| Prophylactic Anticoagulation | Clinically Evident Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy | 1900 Number of wins |
p-value: 0.5395% CI: [0.38, 1.65]Stratified Win-Ratio Analysis, 2-sided
Secondary
Clinically Evident Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation
The efficacy of these interventions was analyzed using an unmatched win ratio. * The number of wins was found by comparing every patient in the FDAC (Full-dose anticoagulation) arm to every patient in the SDPAC (Standard dose prophylactic anticoagulation) arm to determine a 'win' and totaling up the number of wins in each arm. * A 'win' is a point in the favor of the arm it is given to. For each comparison of one patient in full dose arm compared to one patient in the standard dose arm, a 'win' is given to arm with the patient who had a component of the composite endpoint either lower in the hierarchy than the paired patient, or if the patient did not have any component of the composite while the paired patient did experience a component event of the composite. * Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia.
Time frame: 28 days or until hospital discharge, whichever earlier
Population: The on-treatment analysis population, consisting of all randomly assigned patients who received at least 1 dose of the randomly allocated study strategy. The on-treatment analysis population, consisting of all randomly assigned patients who received at least 1 dose of the randomly allocated study strategy. As is pre-specified in the Study Protocol, comparisons between FDAC and SDPAC are reported irrespective of whether participants received anti-platelet therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Full-dose Anticoagulation | Clinically Evident Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation | 3,649 Number of wins |
| Prophylactic Anticoagulation | Clinically Evident Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation | 2,021 Number of wins |
Comparison: FDAC = Full Dose Anticoagulation; SDPAC = Standard Dose Prophylactic Anticoagulationp-value: 0.08795% CI: [0.92, 3.47]Stratified Win-Ratio Analysis, 2-sided