Trial Outcomes & Findings for Prevention of Arteriovenous Thrombotic Events in Critically-Ill COVID-19 Patients Trial (NCT NCT04409834)

Last Updated: 2024-01-19

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

390 participants

Primary outcome timeframe

28 days or until hospital discharge, whichever earlier

Results posted on

2024-01-19

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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 venous thrombotic event (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	Standard-dose Prophylactic Anticoagulation (SDPAC) * Enoxaparin 40 mg administered subcutaneously (SC) once daily (reduce to 30 mg if creatinine clearance 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
Overall Study STARTED	197	193
Overall Study Randomized to Anti-platelet Therapy	74	78
Overall Study Randomized to no Antiplatelet Therapy	73	67
Overall Study COMPLETED	142	131
Overall Study NOT COMPLETED	55	62

Reasons for withdrawal

Reasons for withdrawal
Measure	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 venous thrombotic event (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	Standard-dose Prophylactic Anticoagulation (SDPAC) * Enoxaparin 40 mg administered subcutaneously (SC) once daily (reduce to 30 mg if creatinine clearance 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
Overall Study Death	55	62

Baseline Characteristics

Prevention of Arteriovenous Thrombotic Events in Critically-Ill COVID-19 Patients Trial

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Full-dose Anticoagulation (FDAC) n=197 Participants * 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	Standard-dose Prophylactic Anticoagulation (SDPAC) n=193 Participants * 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	Total n=390 Participants Total of all reporting groups
Age, Continuous	59 years n=5 Participants	62 years n=7 Participants	61 years n=5 Participants
Sex: Female, Male Female	75 Participants n=5 Participants	84 Participants n=7 Participants	159 Participants n=5 Participants
Sex: Female, Male Male	122 Participants n=5 Participants	109 Participants n=7 Participants	231 Participants n=5 Participants
Race/Ethnicity, Customized White	135 Participants n=5 Participants	140 Participants n=7 Participants	275 Participants n=5 Participants
Race/Ethnicity, Customized Non-white	62 Participants n=5 Participants	53 Participants n=7 Participants	115 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Full-dose Anticoagulation n=191 Participants * 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	Prophylactic Anticoagulation n=191 Participants * Enoxaparin 40 mg administered SC once daily (reduce to 30 mg if CrCl\<30 ml/min)\* * Heparin 5,000 units administered SC three times daily
Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation	4,486 Number of wins	2,351 Number of wins

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Full-dose Anticoagulation n=150 Participants * 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	Prophylactic Anticoagulation n=140 Participants * Enoxaparin 40 mg administered SC once daily (reduce to 30 mg if CrCl\<30 ml/min)\* * Heparin 5,000 units administered SC three times daily
Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy	2052 Number of wins	1994 Number of wins

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Full-dose Anticoagulation n=191 Participants * 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	Prophylactic Anticoagulation n=191 Participants * Enoxaparin 40 mg administered SC once daily (reduce to 30 mg if CrCl\<30 ml/min)\* * Heparin 5,000 units administered SC three times daily
Clinically Evident Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation	3,649 Number of wins	2,021 Number of wins

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Full-dose Anticoagulation n=150 Participants * 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	Prophylactic Anticoagulation n=140 Participants * Enoxaparin 40 mg administered SC once daily (reduce to 30 mg if CrCl\<30 ml/min)\* * Heparin 5,000 units administered SC three times daily
Clinically Evident Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy	1452 Number of wins	1900 Number of wins

Adverse Events

Full-dose Anticoagulation (FDAC)

Serious events: 16 serious events

Other events: 37 other events

Deaths: 55 deaths

Standard-dose Prophylactic Anticoagulation (SDPAC)

Serious events: 3 serious events

Other events: 22 other events

Deaths: 62 deaths

Antiplatelet Therapy

Serious events: 6 serious events

Other events: 25 other events

Deaths: 41 deaths

No Anti-platelet Therapy

Serious events: 0 serious events

Other events: 0 other events

Deaths: 34 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Full-dose Anticoagulation (FDAC) n=197 participants at risk * 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	Standard-dose Prophylactic Anticoagulation (SDPAC) n=193 participants at risk * 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	Antiplatelet Therapy n=152 participants at risk Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily on subsequent days.	No Anti-platelet Therapy n=140 participants at risk Participants did not receive anti-platelet therapy.
General disorders Bleeding	17.8% 35/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	1.6% 3/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	15.1% 23/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
Vascular disorders Venous thromboembolism	1.0% 2/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	4.7% 9/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	1.3% 2/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
Blood and lymphatic system disorders D-dimer elevation	0.00% 0/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	5.2% 10/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.

Additional Information

COVID-PACT Project Manager

Brigham and Women's Hospital

Phone: (617) 278-0145

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Full-dose Anticoagulation (FDAC) n=197 participants at risk * 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	Standard-dose Prophylactic Anticoagulation (SDPAC) n=193 participants at risk * 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	Antiplatelet Therapy n=152 participants at risk Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily on subsequent days.	No Anti-platelet Therapy n=140 participants at risk Participants did not receive anti-platelet therapy.
Gastrointestinal disorders Acute Enteritis	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
Renal and urinary disorders Acute Renal Failure	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.66% 1/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
Respiratory, thoracic and mediastinal disorders Acute Respiratory Failure	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.66% 1/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Compartment Syndrome Left Arm	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.66% 1/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
Vascular disorders Deep Venous Thrombosis	0.00% 0/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.52% 1/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
Blood and lymphatic system disorders Drug Induced Thrombocytopenia	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Gastrointestinal bleed	0.00% 0/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.52% 1/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Gross Hematuria	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.66% 1/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Hematemesis	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Intracranial Hemmorrhage	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Lower Respiratory Tract Bleed	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.66% 1/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Pulmonary bleeding from left upper lobe	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Rectus Sheath Hematoma	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Retroperitoneal Bleed	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.52% 1/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.66% 1/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Retroperitoneal hematoma	1.5% 3/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.66% 1/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Right Rectus Intramuscular Hematoma	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.66% 1/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Right upper extremity soft tissue hematoma	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.
General disorders Right wrist intramural hematoma	0.51% 1/197 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/193 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/152 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.	0.00% 0/140 • 28 days or until hospital discharge, whichever earlier Investigators are required to report: (1) Serious Adverse Events Related to Study Drug, (2) Unexpected Problems, and (3) Adverse Events Leading to Drug Discontinuation.