Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE

NCT04505774 — Phase 4, Completed, 3591 participants, Matthew Neal MD

ClinicalTrials Daily · Areas · Conditions · Drugs · Sponsors ·

A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic and Additional Strategies in Hospitalized Adults With COVID-19

Registry	NCT04505774, acronym ACTIV-4A
Status	Completed
Phase	Phase 4
Study type	Interventional; randomized, sequential, masking: none, treatment
Enrollment	3591 (Actual)
Sponsor	Matthew Neal MD (Other); collaborators: National Heart, Lung, and Blood Institute (NHLBI)
Conditions	Covid19
Interventions	theraputic heparin, prophylactic heparin, P2Y12, Crizanlizumab Injection, SGLT2 inhibitor (Drug)
Dates	start 2020-09-04, primary completion 2023-08-31, completion 2024-01-26, first posted 2020-08-10, last updated 2024-12-30
Locations	101 sites in United States, Brazil, Italy, Spain

-Summary

This is a randomized, open label, adaptive platform trial to compare the effectiveness of antithrombotic and additional strategies for prevention of adverse outcomes in COVID-19 positive inpatients

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+Detailed description

The severe acute respiratory syndrome coronavirus 2, which causes the highly contagious coronavirus disease 2019 (COVID-19), has resulted in a global pandemic.

The clinical spectrum of COVID-19 infection is broad, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and death. The risk of thrombotic complications is increased, even as compared to other viral respiratory illnesses, such as influenza. A pro-inflammatory cytokine response as well as induction of procoagulant factors associated with COVID-19 has been proposed to contribute to thrombosis as well as plaque rupture through local inflammation. Patients with COVID-19 are at increased risk for arterial and vein thromboembolism, with high rates observed despite thromboprophylaxis. Autopsy reports have noted micro and macro vascular thrombosis across multiple organ beds consistent with an early hypercoagulable state.

Notably, in COVID-19, data in the U.K. and U.S. document that infection and outcomes of infection are worse in African and Hispanic descent persons than in other groups. The reasons for this are uncertain.

Viral Infection and Thrombosis A large body of literature links inflammation and coagulation; altered hemostasis is a known complication of respiratory viral infections. Procoagulant markers are severely elevated in viral infections. Specifically, proinflammatory cytokines in viral infections upregulate expression of tissue factor, markers of thrombin generation, platelet activation, and down-regulate natural anticoagulant proteins C and S.

Studies have demonstrated significant risk of deep venous thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) associated with viral respiratory infections. In a series of patients with fatal influenza H1N1, 75% had pulmonary thrombi on autopsy (a rate considerably higher than reported on autopsy studies among the general intensive care unit population). Incidence ratio for acute myocardial infarction in the context of Influenza A is over 10. Severe acute respiratory syndrome coronavirus-1 (SARS CoV-1) and influenza have been associated with disseminated intravascular coagulation (DIC), endothelial damage, DVT, PE, and large artery ischemic stroke. Patients with Influenza H1N1 and acute respiratory distress syndrome (ARDS) had a 23.3-fold higher risk for pulmonary embolism, and a 17.9-fold increased risk for deep vein thrombosis. Compared to those treated with systemic anticoagulation, those without treatment were 33 times more likely to suffer a VTE.

Thrombosis, both microvascular and macrovascular, is a prominent feature in multiple organs at autopsy in fatal cases of COVID-19. Thrombosis may thus contribute to respiratory failure, renal failure, and hepatic injury in COVID-19. The number of megakaryocytes in tissues is higher than in other forms of ARDS, and thrombi are platelet-rich based on specific staining. Thrombotic stroke has been reported in young COVID-19 patients with no cardiovascular risk factors. Both arterial and venous thrombotic events have been seen in increasing numbers of hospitalized patients infected with COVID-19. The incidence of thrombosis has ranged from 10 to 30% in hospitalized patients; however, this varies by type of thrombosis captured (arterial or vein) and severity of illness (ICU level care, requiring mechanical ventilation, etc.).

Additional treatment strategies Data from the multiplatform randomized controlled trial (mpRCT) demonstrated that (1) therapeutic dose anticoagulation with heparin was not beneficial in improving clinical outcomes compared to standard of care prophylactic dose heparin in severely ill (ICU level of care) patients, and (2) therapeutic dose anticoagulation with heparin was beneficial in improving organ support free days compared to standard of care prophylactic dose heparin in moderately ill (hospitalized and not requiring organ support) patients. However, there remains significant residual risk for adverse clinical outcomes and excess mortality for severely ill as well as moderately ill patients.

Antithrombotic regimens that are shown to be efficacious will be combined in clinical practice with other agents to treat COVID-19 hospitalized patients. This adaptive platform trial will test other promising agents when added to proven therapies, such as heparin. The rationale and risks for each agent will be included in the arm-specific appendix. Two specific agents to be added as arms, effective October 2021, include the P-selectin inhibitor, Crizanlizumab as well as SGLT2 inhibitors. P-selectin may play a proximal role in the inflammatory and thrombotic cascade in patients with COVID-19 and P-selectin inhibition may be a effective in preventing downstream sequelae. In addition, SGLT-2 inhibitors have been shown to decrease capillary leak and may promote vascular integrity in COVID-19.

This platform trial will have multiple arms, which may be dropped or added as the platform trial progresses. Sample size will be flexible: the trial will be stopped for efficacy or futility based on pre-determined statistical thresholds as defined in the arm-specific appendices. Each arm will have an adaptive component for determinations of futility or success.

Randomization assignments are at the participant level, stratified by enrolling site and by ICU level of care vs non-ICU level of care and/or other arm-specific criteria.

+Arms and interventions

Arm	Type	Interventions	Description
Therapeutic Dose Anticoagulation	Other	Drug: theraputic heparin	increased dose of heparin above standard of care. 1.0 - This arm was stopped in severe patients in December 2020 and results are published in PMID: 34351722 (NEJM, August, 2021) (see reference section for citation). This arm was stopped for moderate patients in January 2021.
Prophylactic Dose Anticoagulation	Other	Drug: prophylactic heparin	Heparin standard of care 1.0 - this arm was stopped for all patients in January, 2021 and results are published in PMID: 34351721 (NEJM, August, 2021) (see reference section for citation)
Therapeutic Dose Anticoagulation + P2Y12 inhibitor	Other	Drug: theraputic heparin; Drug: P2Y12	increased dose of heparin above standard of care with an added P2Y12 inhibitor This Arm enrolled moderate illness patients only. Enrollment of moderate illness patients in the trial was ended per DSMB on June 19, 2021 and results are published in PMID: PMID: 35040887 (JAMA, January, 2022) (see reference section for citation)
Prophylactic Dose Anticoagulation + P2Y12 inhibitor	Other	Drug: prophylactic heparin; Drug: P2Y12	Heparin standard of care with an added P2Y12 inhibitor This Arm enrolled severe illness patients only. Enrollment of severe illness patients in the trial was ended per DSMB in June 2022.
Standard of Care + Crizanlizumab	Other	Drug: Crizanlizumab Injection	Standard of care plus crizanlizumab infusion This arm will enroll moderate and severe illness patients This arm was ended for all patients per the DSMB in September 2022.
Standard of Care + SGLT2 inhibitor	Other	Drug: SGLT2 inhibitor	Standard of care plus SGLT2 inhibitor This arm will enroll moderate and severe illness patients This arm was ended in March 2023
Standard of Care (SGLT2 arm)	Other	Drug: SGLT2 inhibitor	Standard of care only This arm will enroll moderate and severe illness patients This arm was ended in March 2023
Standard of Care (Criza)	Other	Drug: Crizanlizumab Injection	Standard of care only This arm will enroll moderate and severe illness patients This arm was ended for all patients per the DSMB in September 2022.

theraputic heparin (Drug), also known as unfractionated heparin, Enoxaparin, Dalteparin, Tinzaparin, Heparin: increased dose of heparin above standard of care.
prophylactic heparin (Drug), also known as enoxaparin, dalteparin, Tinzaparin, Fondparinux, Heparin: standard of care dose of heparin
P2Y12 (Drug), also known as Ticagrelor, Prasugrel, Clopidogrel: added P2Y12 inhibitor
Crizanlizumab Injection (Drug): crizanlizumab injection
SGLT2 inhibitor (Drug), also known as dapagliflozin, empagliflozin, canagliflozin, ertugliflozin: sglt2 inhibitor

+Outcome measures

Primary outcomes

21 Day Organ Support (Respiratory or Vasopressor) Free Days [21 days from study enrollment]: which is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ Support is defined as receipt of non-invasive mechanical ventilation, high flow nasal canula oxygen, mechanical ventilation, or vasopressor therapy, with death at any time during the index hospitalization assigned -1 days. This outcome variable was designed to exceed day 21 on the IQR. It goes above 21 days because it include baseline day 0 in their design.

Secondary outcomes

Death Within 28 Days [28 days from enrollment]
Acute Kidney Injury [90 days from enrollment]: Acute Kidney Injury Acute kidney injury after enrollment is defined by KDIGO criteria for Acute Kidney Injury in the setting of not meeting these criteria upon enrollment: Modified Stages: ∙ Stage 2: Serum Cr 2.0-2.9 times baseline ∙ Stage 3: Serum Cr ≥ 3.0 times baseline, OR Increase in serum creatinine to ≥ 4.0mg/dl, OR Initiation of renal replacement therapy
Major Thrombotic Event or in Hospital Death [28 days]: A composite endpoint of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke during hospitalization or at 28 days after enrollment (whichever is earlier) - "major thrombotic events or death"
Any Thrombotic Event or in Hospital Death [28 days]: A composite endpoint of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, DVT, or ischemic stroke during hospitalization or at 28 days after enrollment (whichever is earlier)
Any Renal Replacement Therapy [28 days]
Days Free of Organ Support and Renal Replacement Therapy [28 days]: This outcome variable was designed to exceed day 28 on the IQR. It goes above 28 days because it include baseline day 0 in their design.
Ventilator Free Days up to Day 28 [28 days]: This outcome variable was designed to exceed day 28 on the IQR. It goes above 28 days because it include baseline day 0 in their design.
Days Free of Vasopressors [28 days]: This outcome variable was designed to exceed day 28 on the IQR. It goes above 28 days because it include baseline day 0 in their design.
Progression to Intubation or Death [28 days]: analysis completed on the Heparin protocol
Survival Until Discharge [28 days]

+Eligibility

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* ≥ 18 years of age
* Hospitalized for COVID-19
* Enrolled within 72 hours of hospital admittance or 72 hours of positive COVID test
* Expected to require hospitalization for > 72 hours

Exclusion Criteria:

* Imminent death
* Requirement for chronic mechanical ventilation via tracheostomy prior to hospitalization
* Pregnancy

Inclusion Criteria for Arm E

Inclusion criteria contained in the master protocol in addition to the following:

Moderate illness severity - defined as non-ICU level of care at the time of randomization (not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO) OR Severe illness severity - defined as ICU level of care at the time of randomization (receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)

For moderate illness severity, participants are required to meet one or more of the following risk criteria:

1. Age ≥ 65 years or
2. ≥2 of the following -

   * O2 supplementation > 2 liters per minute
   * BMI ≥ 35
   * GFR ≤ 60
   * History of Type 2 diabetes
   * History of heart failure (regardless of ejection fraction)
   * D dimer ≥ 2x the site's upper limit of normal (ULN)
   * Troponin ≥ 2x the site's ULN
   * BNP≥100 pg/mL or NT-proBNP≥300 pg/mL
   * CRP ≥50 mg/L

Exclusion Criteria for Arm E

* Exclusion criteria contained in the master protocol, and
* Any condition that, in the opinion of the investigator, precludes the use of crizanlizumab such as uncontrolled bleeding or severe anemia (hemoglobin<4 g/dL)
* Open label treatment with crizanlizumab within the past three months

Inclusion Criteria for Arm F

Inclusion criteria contained in the master protocol in addition to the following:

Moderate illness severity - defined as non-ICU level of care at the time of randomization (not receiving high flow nasal oxygen (HFNO), non-invasive ventilation (NIV), invasive ventilation (IV), vasopressors or inotropes, or extracorporeal membrane oxygenation (ECMO)) OR Severe illness severity - defined as ICU level of care at the time of randomization (receiving HFNO, NIV, IV, vasopressors or inotropes, or ECMO)

For moderate illness severity, participants are required to meet one or more of the following risk criteria:

1. Age ≥ 65 years or
2. ≥2 of the following-

   * O2 supplementation > 2 liters per minute
   * BMI ≥ 35
   * GFR ≤ 60
   * History of Type 2 diabetes
   * History of heart failure (regardless of ejection fraction)
   * D dimer ≥ 2x the site's upper limit of normal (ULN)
   * Troponin ≥ 2x the site's ULN
   * BNP≥100 pg/mL or NT-proBNP≥300 pg/mL
   * CRP ≥50 mg/L

Exclusion Criteria for Arm F

In addition to the exclusion criteria noted in the master protocol, arm-specific exclusion criteria are as follows:

* Known hypersensitivity to any SGLT2 inhibitors
* Type 1 diabetes
* History of diabetic ketoacidosis
* eGFR <20 and/or requirement for renal replacement therapy
* Open label treatment with any SGLT2 inhibitor

  * Based on a recommendation from the ACTIV4 DSMB on December 19, 2020, enrollment of patients requiring ICU level of care into the therapeutic anti-coagulation arm was stopped due to meeting a futility threshold and a potential for harm for this sub-group could not be excluded. Enrollment continues for moderately ill hospitalized COVID-19 patients.
  * Based on a recommendation from the ACTIV4 DSMB on June 18, 2021, enrollment of patients not requiring ICU level of care and randomized to P2Y12 or standard care was stopped due to meeting a futility threshold. Enrollment continues for severely ill (ICU level of care) hospitalized COVID-19 patients.

+Posted results

Participant flow

Milestone	Therapeutic Dose Anticoagulation	Prophylactic Dose Anticoagulation	Therapeutic Dose Anticoagulation + P2Y12 Inhibitor	Prophylactic Dose Anticoagulation + P2Y12 Inhibitor	Standard of Care + SGLT2 Inhibitor	Standard of Care (SGLT2)	Standard of Care + Crizanlizumab	Standard of Care (Criza)
Started	569	514	772	739	287	288	211	211
Completed	565	511	766	735	280	287	210	209
Not completed	4	3	6	4	7	1	1	2

Outcome results

21 Day Organ Support (Respiratory or Vasopressor) Free Days (Primary), Median, days: Therapeutic Dose Anticoagulation 22 (18 to 22); Prophylactic Dose Anticoagulation 22 (17 to 22); Therapeutic Dose Anticoagulation + P2Y12 Inhibitor 17 (1 to 21); Prophylactic Dose Anticoagulation + P2Y12 Inhibitor 17 (0 to 21); Standard of Care + SGLT2 Inhibitor 22 (22 to 22); Standard of Care (SGLT2) 22 (22 to 22); Standard of Care + Crizanlizumab 22 (22 to 22); Standard of Care (Criza) 22 (22 to 22) (p .6778)
Death Within 28 Days (Secondary), Count of participants, Participants: Therapeutic Dose Anticoagulation 39; Prophylactic Dose Anticoagulation 52; Therapeutic Dose Anticoagulation + P2Y12 Inhibitor 120; Prophylactic Dose Anticoagulation + P2Y12 Inhibitor 114; Standard of Care + SGLT2 Inhibitor 37; Standard of Care (SGLT2) 42; Standard of Care + Crizanlizumab 23; Standard of Care (Criza) 13 (p .1959)
Acute Kidney Injury (Secondary), Count of participants, Participants: Therapeutic Dose Anticoagulation 0; Prophylactic Dose Anticoagulation 0; Therapeutic Dose Anticoagulation + P2Y12 Inhibitor 38; Prophylactic Dose Anticoagulation + P2Y12 Inhibitor 36; Standard of Care + SGLT2 Inhibitor 5; Standard of Care (SGLT2) 5; Standard of Care + Crizanlizumab 10; Standard of Care (Criza) 10 (p 1.0)
Major Thrombotic Event or in Hospital Death (Secondary), Count of participants, Participants: Therapeutic Dose Anticoagulation 450; Prophylactic Dose Anticoagulation 462; Therapeutic Dose Anticoagulation + P2Y12 Inhibitor 174; Prophylactic Dose Anticoagulation + P2Y12 Inhibitor 177; Standard of Care + SGLT2 Inhibitor 28; Standard of Care (SGLT2) 33; Standard of Care + Crizanlizumab 32; Standard of Care (Criza) 22 (p .0577)
Any Thrombotic Event or in Hospital Death (Secondary), Count of participants, Participants: Therapeutic Dose Anticoagulation 450; Prophylactic Dose Anticoagulation 463; Therapeutic Dose Anticoagulation + P2Y12 Inhibitor 187; Prophylactic Dose Anticoagulation + P2Y12 Inhibitor 177; Standard of Care + SGLT2 Inhibitor 28; Standard of Care (SGLT2) 33; Standard of Care + Crizanlizumab 32; Standard of Care (Criza) 22 (p .0732)
Any Renal Replacement Therapy (Secondary), Count of participants, Participants: Therapeutic Dose Anticoagulation 12; Prophylactic Dose Anticoagulation 12; Therapeutic Dose Anticoagulation + P2Y12 Inhibitor 37; Prophylactic Dose Anticoagulation + P2Y12 Inhibitor 36; Standard of Care + SGLT2 Inhibitor 1; Standard of Care (SGLT2) 1; Standard of Care + Crizanlizumab 6; Standard of Care (Criza) 4 (p .8837)
Days Free of Organ Support and Renal Replacement Therapy (Secondary), Median, days: Therapeutic Dose Anticoagulation 29 (25 to 29); Prophylactic Dose Anticoagulation 29 (24 to 29); Therapeutic Dose Anticoagulation + P2Y12 Inhibitor 24 (8 to 29); Prophylactic Dose Anticoagulation + P2Y12 Inhibitor 24 (2 to 29); Standard of Care + SGLT2 Inhibitor 29 (29 to 29); Standard of Care (SGLT2) 29 (29 to 29); Standard of Care + Crizanlizumab 29 (29 to 29); Standard of Care (Criza) 29 (29 to 29) (p .6636)
Ventilator Free Days up to Day 28 (Secondary), Mean, days: Therapeutic Dose Anticoagulation 24.89 (29 to 29); Prophylactic Dose Anticoagulation 24.63 (29 to 29); Therapeutic Dose Anticoagulation + P2Y12 Inhibitor 21.09 (14 to 29); Prophylactic Dose Anticoagulation + P2Y12 Inhibitor 20.83 (10 to 29); Standard of Care + SGLT2 Inhibitor 26.22 (29 to 29); Standard of Care (SGLT2) 26.42 (29 to 29); Standard of Care + Crizanlizumab 25.32 (29 to 29); Standard of Care (Criza) 26.69 (29 to 29) (p .6780)
Days Free of Vasopressors (Secondary), Median, days: Therapeutic Dose Anticoagulation 29 (29 to 29); Prophylactic Dose Anticoagulation 29 (29 to 29); Therapeutic Dose Anticoagulation + P2Y12 Inhibitor 29 (26 to 29); Prophylactic Dose Anticoagulation + P2Y12 Inhibitor 29 (25 to 29); Standard of Care + SGLT2 Inhibitor 29 (29 to 29); Standard of Care (SGLT2) 29 (29 to 29); Standard of Care + Crizanlizumab 29 (29 to 29); Standard of Care (Criza) 29 (29 to 29) (p .4016)
Progression to Intubation or Death (Secondary), Count of participants, Participants: Therapeutic Dose Anticoagulation 450; Prophylactic Dose Anticoagulation 463; Therapeutic Dose Anticoagulation + P2Y12 Inhibitor 768; Prophylactic Dose Anticoagulation + P2Y12 Inhibitor 735; Standard of Care + SGLT2 Inhibitor 273; Standard of Care (SGLT2) 278; Standard of Care + Crizanlizumab 209; Standard of Care (Criza) 199 (p .3135)
Survival Until Discharge (Secondary), Count of participants, Participants: Therapeutic Dose Anticoagulation 406; Prophylactic Dose Anticoagulation 409; Therapeutic Dose Anticoagulation + P2Y12 Inhibitor 633; Prophylactic Dose Anticoagulation + P2Y12 Inhibitor 598; Standard of Care + SGLT2 Inhibitor 264; Standard of Care (SGLT2) 266; Standard of Care + Crizanlizumab 186; Standard of Care (Criza) 197 (p .3575)

Adverse events

Time frame: Discharge, Death or Day 28

Arm	Deaths	Serious adverse events
Therapeutic Dose Anticoagulation	69/569 (12.1%)	46/569 (8.1%)
Prophylactic Dose Anticoagulation	65/514 (12.6%)	57/514 (11.1%)
Therapeutic Dose Anticoagulation + P2Y12 Inhibitor	147/772 (19.0%)	151/772 (19.6%)
Prophylactic Dose Anticoagulation + P2Y12 Inhibitor	149/739 (20.2%)	133/739 (18.0%)
Standard of Care + SGLT2 Inhibitor	37/287 (12.9%)	20/287 (7.0%)
Standard of Care (sglt2)	42/288 (14.6%)	33/288 (11.5%)
Standard of Care + Crizanlizumab	37/211 (17.5%)	24/211 (11.4%)
Standard of Care (Criza)	28/211 (13.3%)	28/211 (13.3%)

Serious adverse events by term

Term	Organ system	Therapeutic Dose Anticoagulation	Prophylactic Dose Anticoagulation	Therapeutic Dose Anticoagulation + P2Y12 Inhibitor	Prophylactic Dose Anticoagulation + P2Y12 Inhibitor	Standard of Care + SGLT2 Inhibitor	Standard of Care (sglt2)	Standard of Care + Crizanlizumab	Standard of Care (Criza)
Deep Vein Thrombosis	Vascular disorders	1/569	2/514	1/772	0/739	0/287	3/288	1/211	1/211
Pulmonary Embolism	Respiratory, thoracic and mediastinal disorders	10/569	18/514	41/772	26/739	2/287	3/288	0/211	4/211
myocardial infarction	Cardiac disorders	2/569	2/514	7/772	4/739	0/287	1/288	2/211	1/211
ischemmic stroke	Vascular disorders	3/569	3/514	11/772	3/739	0/287	1/288	0/211	0/211
Other arterial or venous thromboembolism event	Vascular disorders	1/569	0/514	0/772	0/739	0/287	1/288	0/211	0/211
disseminated intravascular coagulation	Vascular disorders	0/569	3/514	0/772	0/739	0/287	0/288	0/211	0/211
symptomatic intracranial or intracerebral hemorrhage	Vascular disorders	0/569	0/514	0/772	1/739	0/287	0/288	0/211	0/211
major bleeding	Vascular disorders	13/569	8/514	21/772	17/739	4/287	3/288	6/211	4/211
heparin induced thrombocytopenia	Injury, poisoning and procedural complications	2/569	3/514	3/772	3/739	0/287	0/288	0/211	0/211
diabetic ketoacidosis	Renal and urinary disorders	0/569	0/514	0/772	0/739	0/287	0/288	0/211	0/211
acute kidney injury	Renal and urinary disorders	0/569	0/514	3/772	0/739	4/287	7/288	9/211	10/211
anaphylaxis	Respiratory, thoracic and mediastinal disorders	0/569	0/514	0/772	0/739	0/287	0/288	0/211	0/211
pregnancy	Pregnancy, puerperium and perinatal conditions	0/569	0/514	0/772	0/739	0/287	0/288	0/211	0/211
other	Injury, poisoning and procedural complications	2/569	3/514	24/772	34/739	9/287	8/288	4/211	1/211
arterial thromboembolic event	Vascular disorders	2/569	2/514	0/772	2/739	0/287	1/288	0/211	2/211
Venus thrombosis	Vascular disorders	10/569	14/514	47/772	47/739	1/287	5/288	4/211	6/211

+Locations (101)

Facility	City	Country
University of Alabama	Birmingham, Alabama	United States
University of Arizona	Tucson, Arizona	United States
University of Arkansas for Medical Sciences	Little Rock, Arkansas	United States
Kaiser Permanente Fontana	Fontana, California	United States
Kaiser Permanente Los Angeles	Los Angeles, California	United States
Smidt Heart Institute at Cedars-Sinai	Los Angeles, California	United States
Ronald Reagan UCLA Medical Center	Los Angeles, California	United States
UC San Diego Hillcrest	San Diego, California	United States
Zuckerberg San Francisco General Hospital	San Francisco, California	United States
UCSF San Francisco	San Francisco, California	United States
Zuckerberg San Francisco General Hospital	San Francisco, California	United States
Stanford University Medical Center	Stanford, California	United States
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center	Torrance, California	United States
Denver Health and Hospital Authority	Denver, Colorado	United States
St. Mary's Hospital & Regional Medical Center	Grand Junction, Colorado	United States
Saint Francis Hospital and Medical Center	Hartford, Connecticut	United States
University of Florida	Gainesville, Florida	United States
Memorial Hospital	Jacksonville, Florida	United States
AdventHealth Tampa	Tampa, Florida	United States
Emory	Atlanta, Georgia	United States
Morehouse School of Medicine	Atlanta, Georgia	United States
Queens Medical Center	Honolulu, Hawaii	United States
Memorial Hospital	Belleville, Illinois	United States
Cook County Health	Chicago, Illinois	United States
University of Illinois at Chicago Health (UIH)	Chicago, Illinois	United States
OSF Little Company of Mary Medical Center (OSF LCM)	Evergreen Park, Illinois	United States
Indiana University Health Methodist Hospital	Indianapolis, Iowa	United States
Kansas University Medical Center	Kansas City, Kansas	United States
Ochsner Clinic Foundation	New Orleans, Louisiana	United States
Boston University	Boston, Massachusetts	United States
St Elizabeth's Medical Center	Brighton, Massachusetts	United States
Baystate Medical Center	Springfield, Massachusetts	United States
University of Massachusetts	Worcester, Massachusetts	United States
University of Michigan	Ann Arbor, Michigan	United States
Wayne State University	Detroit, Michigan	United States
Hennepin County Medical Center	Minneapolis, Minnesota	United States
University of Mississippi Medical Center	Jackson, Mississippi	United States
Washington University School of Medicine, ACCS Research	St Louis, Missouri	United States
University Medical Center of Southern Nevada	Las Vegas, Nevada	United States
Cooper Health	Camden, New Jersey	United States
Englewood Health	Englewood, New Jersey	United States
Atlantic Health System	Morristown, New Jersey	United States
Rutgers New Jersey Medical School	Newark, New Jersey	United States
AtlantiCare Regional Medical Center	Pomona, New Jersey	United States
Albany Medical College	Albany, New York	United States
Mercy Hospital Buffalo	Buffalo, New York	United States
VA New York Harbor Healthcare System	New York, New York	United States
NYU Langone	New York, New York	United States
Mt. Sinai Hospital	New York, New York	United States
SUNY Upstate University Hospital	Syracuse, New York	United States
Jacobi Medical Center	The Bronx, New York	United States
Montefiore Medical Center	The Bronx, New York	United States
Westchester Medical Center	Valhalla, New York	United States
Duke University Hospital	Durham, North Carolina	United States
Wake Forest	Winston-Salem, North Carolina	United States
Cleveland Clinic Akron General	Akron, Ohio	United States
University of Cincinnati Medical Center	Cincinnati, Ohio	United States
The MetroHealth System	Cleveland, Ohio	United States
Cleveland Clinic Foundation	Cleveland, Ohio	United States
Ohio State Universtiy Wexner Medical Center	Columbus, Ohio	United States
Mercy Health St Vincent Medical Center	Toledo, Ohio	United States
Ascension St. John Clinical Research Institute	Tulsa, Oklahoma	United States
Oregon Health and Science University	Portland, Oregon	United States
Geisinger Research	Danville, Pennsylvania	United States
Doylestown Cardiology Associates	Doylestown, Pennsylvania	United States
Penn State Health Milton S. Hershey Medical Center	Hershey, Pennsylvania	United States
Hospital of the University of Pennsylvania	Philadelphia, Pennsylvania	United States
Temple University	Philadelphia, Pennsylvania	United States
UPMC Presbyterian	Pittsburgh, Pennsylvania	United States
Rhode Island Hospital	Providence, Rhode Island	United States
The Miriam Hospital	Providence, Rhode Island	United States
Sarah Cannon and HCA Research Institute	Nashville, Tennessee	United States
Skyline Medical Center	Nashville, Tennessee	United States
University of Texas at Austin	Austin, Texas	United States
University of Texas Southwestern Medical Center	Dallas, Texas	United States
Medical City Ft Worth	Fort Worth, Texas	United States
Baylor Scott and White Medical Center - Temple	Temple, Texas	United States
HCA Henrico Doctors Hospital	Richmond, Virginia	United States
Swedish Hospital	Seattle, Washington	United States
West Virginia University CTR	Morgantown, West Virginia	United States
University of Wisconsin Hospital; Meriter Hospital (UW affiliated)	Madison, Wisconsin	United States
Hospital Universitario Sao Francisco de Assis	Bragança Paulista	Brazil
União Brasileira de Educação e Assistência - Hospital São Lucas da PUCRS	Porto Alegre	Brazil
Centro de Estudos Clínicos do Hospital Cárdio Pulmonar	Salvador	Brazil
Fundação Faculdade Regional De Medicina De São José Do Rio Preto	São José do Rio Preto	Brazil
Instituto Dante Pazzanese de Cardiologia	São Paulo	Brazil
Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP-InCor-HCFMUSP	São Paulo	Brazil
Azienda Ospedaliero Sant Anna e San Sebastiano	Caserta	Italy
Maria Cecilia Hospital , Cotignola, Ravenna	Cotignola	Italy
Università degli Studi di Ferrara, Ferrara	Ferrara	Italy
Azienda Ospedaliero -Universitaria Careggi	Florence	Italy
Policlinico di Napoli, Napoli	Naples	Italy
AOU Policlinico di Palermo, Palermo	Palermo	Italy
ASL-1 Imperiese, Sanremo	Sanremo	Italy
Hospital Universitario A Coruna	A Coruña	Spain
Hospital Virgen del Mar	Almería	Spain
Hospital Arnau de Vilanova	Lleida	Spain
Hospital Universitario La Paz	Madrid	Spain
Hospital Universitario Ramon Y Cajal	Madrid	Spain
Hospital Clínico Universitario de Salamanca	Salamanca	Spain

1 more sites not listed.

+Publications

Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, Nigoghossian C, Ageno W, Madjid M, Guo Y, Tang LV, Hu Y, Giri J, Cushman M, Quere I, Dimakakos EP, Gibson CM, Lippi G, Favaloro EJ, Fareed J, Caprini JA, Tafur AJ, Burton JR, Francese DP, Wang EY, Falanga A, McLintock C, Hunt BJ, Spyropoulos AC, Barnes GD, Eikelboom JW, Weinberg I, Schulman S, Carrier M, Piazza G, Beckman JA, Steg PG, Stone GW, Rosenkranz S, Goldhaber SZ, Parikh SA, Monreal M, Krumholz HM, Konstantinides SV, Weitz JI, Lip GYH; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Jun 16;75(23):2950-2973. doi: 10.1016/j.jacc.2020.04.031. Epub 2020 Apr 17. PMID 32311448
Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 Jul;191:145-147. doi: 10.1016/j.thromres.2020.04.013. Epub 2020 Apr 10. PMID 32291094
Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Muller MCA, Bouman CCS, Beenen LFM, Kootte RS, Heijmans J, Smits LP, Bonta PI, van Es N. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020 Aug;18(8):1995-2002. doi: 10.1111/jth.14888. Epub 2020 Jul 27. PMID 32369666
Poissy J, Goutay J, Caplan M, Parmentier E, Duburcq T, Lassalle F, Jeanpierre E, Rauch A, Labreuche J, Susen S; Lille ICU Haemostasis COVID-19 Group. Pulmonary Embolism in Patients With COVID-19: Awareness of an Increased Prevalence. Circulation. 2020 Jul 14;142(2):184-186. doi: 10.1161/CIRCULATIONAHA.120.047430. Epub 2020 Apr 24. No abstract available. PMID 32330083
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. PMID 32171076
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 May;18(5):1094-1099. doi: 10.1111/jth.14817. Epub 2020 Apr 27. PMID 32220112
Wang L, Zhao L, Li F, Liu J, Zhang L, Li Q, Gu J, Liang S, Zhao Q, Liu J, Xu JF. Risk assessment of venous thromboembolism and bleeding in COVID-19 patients. Clin Respir J. 2022 Mar;16(3):182-189. doi: 10.1111/crj.13467. Epub 2022 Jan 21. PMID 35060325
Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J. 2020 May 14;41(19):1858. doi: 10.1093/eurheartj/ehaa254. No abstract available. PMID 32227120
Xie Y, Wang X, Yang P, Zhang S. COVID-19 Complicated by Acute Pulmonary Embolism. Radiol Cardiothorac Imaging. 2020 Mar 16;2(2):e200067. doi: 10.1148/ryct.2020200067. eCollection 2020 Apr. No abstract available. PMID 33778561
Beristain-Covarrubias N, Perez-Toledo M, Thomas MR, Henderson IR, Watson SP, Cunningham AF. Understanding Infection-Induced Thrombosis: Lessons Learned From Animal Models. Front Immunol. 2019 Nov 5;10:2569. doi: 10.3389/fimmu.2019.02569. eCollection 2019. PMID 31749809
Clayton TC, Gaskin M, Meade TW. Recent respiratory infection and risk of venous thromboembolism: case-control study through a general practice database. Int J Epidemiol. 2011 Jun;40(3):819-27. doi: 10.1093/ije/dyr012. Epub 2011 Feb 15. PMID 21324940
Goeijenbier M, van Wissen M, van de Weg C, Jong E, Gerdes VE, Meijers JC, Brandjes DP, van Gorp EC. Review: Viral infections and mechanisms of thrombosis and bleeding. J Med Virol. 2012 Oct;84(10):1680-96. doi: 10.1002/jmv.23354. PMID 22930518
Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet. 2006 Apr 1;367(9516):1075-1079. doi: 10.1016/S0140-6736(06)68474-2. PMID 16581406
Harms PW, Schmidt LA, Smith LB, Newton DW, Pletneva MA, Walters LL, Tomlins SA, Fisher-Hubbard A, Napolitano LM, Park PK, Blaivas M, Fantone J, Myers JL, Jentzen JM. Autopsy findings in eight patients with fatal H1N1 influenza. Am J Clin Pathol. 2010 Jul;134(1):27-35. doi: 10.1309/AJCP35KOZSAVNQZW. PMID 20551263
Kwong JC, Schwartz KL, Campitelli MA, Chung H, Crowcroft NS, Karnauchow T, Katz K, Ko DT, McGeer AJ, McNally D, Richardson DC, Rosella LC, Simor A, Smieja M, Zahariadis G, Gubbay JB. Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection. N Engl J Med. 2018 Jan 25;378(4):345-353. doi: 10.1056/NEJMoa1702090. PMID 29365305
Wong RS, Wu A, To KF, Lee N, Lam CW, Wong CK, Chan PK, Ng MH, Yu LM, Hui DS, Tam JS, Cheng G, Sung JJ. Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis. BMJ. 2003 Jun 21;326(7403):1358-62. doi: 10.1136/bmj.326.7403.1358. PMID 12816821
Obi AT, Tignanelli CJ, Jacobs BN, Arya S, Park PK, Wakefield TW, Henke PK, Napolitano LM. Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients. J Vasc Surg Venous Lymphat Disord. 2019 May;7(3):317-324. doi: 10.1016/j.jvsv.2018.08.010. Epub 2018 Nov 23. PMID 30477976
Rapkiewicz AV, Mai X, Carsons SE, Pittaluga S, Kleiner DE, Berger JS, Thomas S, Adler NM, Charytan DM, Gasmi B, Hochman JS, Reynolds HR. Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: A case series. EClinicalMedicine. 2020 Jun 25;24:100434. doi: 10.1016/j.eclinm.2020.100434. eCollection 2020 Jul. PMID 32766543
Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, De Leacy RA, Shigematsu T, Ladner TR, Yaeger KA, Skliut M, Weinberger J, Dangayach NS, Bederson JB, Tuhrim S, Fifi JT. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. N Engl J Med. 2020 May 14;382(20):e60. doi: 10.1056/NEJMc2009787. Epub 2020 Apr 28. No abstract available. PMID 32343504
Al-Samkari H, Karp Leaf RS, Dzik WH, Carlson JCT, Fogerty AE, Waheed A, Goodarzi K, Bendapudi PK, Bornikova L, Gupta S, Leaf DE, Kuter DJ, Rosovsky RP. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020 Jul 23;136(4):489-500. doi: 10.1182/blood.2020006520. PMID 32492712
Centers for Disease Control and Prevention. COVID-19 in Racial and Ethnic Minority Groups. 2020.
Price-Haywood EG, Burton J, Fort D, Seoane L. Hospitalization and Mortality among Black Patients and White Patients with Covid-19. N Engl J Med. 2020 Jun 25;382(26):2534-2543. doi: 10.1056/NEJMsa2011686. Epub 2020 May 27. PMID 32459916
Aldridge RW, Lewer D, Katikireddi SV, Mathur R, Pathak N, Burns R, Fragaszy EB, Johnson AM, Devakumar D, Abubakar I, Hayward A. Black, Asian and Minority Ethnic groups in England are at increased risk of death from COVID-19: indirect standardisation of NHS mortality data. Wellcome Open Res. 2020 Jun 24;5:88. doi: 10.12688/wellcomeopenres.15922.2. eCollection 2020. PMID 32613083
Niedzwiedz CL, O'Donnell CA, Jani BD, Demou E, Ho FK, Celis-Morales C, Nicholl BI, Mair FS, Welsh P, Sattar N, Pell JP, Katikireddi SV. Ethnic and socioeconomic differences in SARS-CoV-2 infection: prospective cohort study using UK Biobank. BMC Med. 2020 May 29;18(1):160. doi: 10.1186/s12916-020-01640-8. PMID 32466757
Millett GA, Jones AT, Benkeser D, Baral S, Mercer L, Beyrer C, Honermann B, Lankiewicz E, Mena L, Crowley JS, Sherwood J, Sullivan PS. Assessing differential impacts of COVID-19 on black communities. Ann Epidemiol. 2020 Jul;47:37-44. doi: 10.1016/j.annepidem.2020.05.003. Epub 2020 May 14. PMID 32419766
Kamin Mukaz D, Gergi M, Koh I, Zakai NA, Judd SE, Sholzberg M, Baumann Kreuziger L, Freeman K, Colovos C, Olson NC, Cushman M. Thrombo-inflammatory biomarkers and D-dimer in a biracial cohort study. Res Pract Thromb Haemost. 2021 Dec 7;5(8):e12632. doi: 10.1002/rth2.12632. eCollection 2021 Dec. PMID 34934895
Kosiborod MN, Esterline R, Furtado RHM, Oscarsson J, Gasparyan SB, Koch GG, Martinez F, Mukhtar O, Verma S, Chopra V, Buenconsejo J, Langkilde AM, Ambery P, Tang F, Gosch K, Windsor SL, Akin EE, Soares RVP, Moia DDF, Aboudara M, Hoffmann Filho CR, Feitosa ADM, Fonseca A, Garla V, Gordon RA, Javaheri A, Jaeger CP, Leaes PE, Nassif M, Pursley M, Silveira FS, Barroso WKS, Lazcano Soto JR, Nigro Maia L, Berwanger O. Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2021 Sep;9(9):586-594. doi: 10.1016/S2213-8587(21)00180-7. Epub 2021 Jul 21. PMID 34302745
Leucker TM, Osburn WO, Reventun P, Smith K, Claggett B, Kirwan BA, de Brouwer S, Williams MS, Gerstenblith G, Hager DN, Streiff MB, Solomon SD, Lowenstein CJ. Effect of Crizanlizumab, a P-Selectin Inhibitor, in COVID-19: A Placebo-Controlled, Randomized Trial. JACC Basic Transl Sci. 2021 Dec;6(12):935-945. doi: 10.1016/j.jacbts.2021.09.013. Epub 2021 Dec 8. PMID 34904132
ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators; Lawler PR, Goligher EC, Berger JS, Neal MD, McVerry BJ, Nicolau JC, Gong MN, Carrier M, Rosenson RS, Reynolds HR, Turgeon AF, Escobedo J, Huang DT, Bradbury CA, Houston BL, Kornblith LZ, Kumar A, Kahn SR, Cushman M, McQuilten Z, Slutsky AS, Kim KS, Gordon AC, Kirwan BA, Brooks MM, Higgins AM, Lewis RJ, Lorenzi E, Berry SM, Berry LR, Aday AW, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen JT, Cheng AC, Chkhikvadze T, Coiffard B, Costantini TW, de Brouwer S, Derde LPG, Detry MA, Duggal A, Dzavik V, Effron MB, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Galanaud JP, Galen BT, Gandotra S, Garcia-Madrona S, Girard TD, Godoy LC, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Hamburg NM, Haniffa R, Hanna G, Hanna N, Hegde SM, Hendrickson CM, Hite RD, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Hudock K, Hunt BJ, Husain M, Hyzy RC, Iyer VN, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski AL, King AJ, Knudson MM, Kornblith AE, Krishnan V, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Lima FG, Linstrum K, Litton E, Lopez-Sendon J, Lopez-Sendon Moreno JL, Lother SA, Malhotra S, Marcos M, Saud Marinez A, Marshall JC, Marten N, Matthay MA, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Moore SC, Morillo Guerrero R, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nunez-Garcia B, Pandey A, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Perez Gonzalez YS, Pompilio M, Prekker ME, Quigley JG, Rost NS, Rowan K, Santos FO, Santos M, Olombrada Santos M, Satterwhite L, Saunders CT, Schutgens REG, Seymour CW, Siegal DM, Silva DG Jr, Shankar-Hari M, Sheehan JP, Singhal AB, Solvason D, Stanworth SJ, Tritschler T, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Wells BJ, Widmer RJ, Wilson JG, Yuriditsky E, Zampieri FG, Angus DC, McArthur CJ, Webb SA, Farkouh ME, Hochman JS, Zarychanski R. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):790-802. doi: 10.1056/NEJMoa2105911. Epub 2021 Aug 4. PMID 34351721
REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators; Goligher EC, Bradbury CA, McVerry BJ, Lawler PR, Berger JS, Gong MN, Carrier M, Reynolds HR, Kumar A, Turgeon AF, Kornblith LZ, Kahn SR, Marshall JC, Kim KS, Houston BL, Derde LPG, Cushman M, Tritschler T, Angus DC, Godoy LC, McQuilten Z, Kirwan BA, Farkouh ME, Brooks MM, Lewis RJ, Berry LR, Lorenzi E, Gordon AC, Ahuja T, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen JT, Cheng AC, Chkhikvadze T, Coiffard B, Contreras A, Costantini TW, de Brouwer S, Detry MA, Duggal A, Dzavik V, Effron MB, Eng HF, Escobedo J, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Froess JD, Fu Z, Galanaud JP, Galen BT, Gandotra S, Girard TD, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Haniffa R, Hegde SM, Hendrickson CM, Higgins AM, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Huang DT, Hudock K, Hunt BJ, Husain M, Hyzy RC, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski A, King AJ, Knudson MM, Kornblith AE, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Gallego Lima F, Linstrum K, Litton E, Lopez-Sendon J, Lother SA, Marten N, Saud Marinez A, Martinez M, Mateos Garcia E, Mavromichalis S, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nicolau JC, Nunez-Garcia B, Park JJ, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Pompilio M, Quigley JG, Rosenson RS, Rost NS, Rowan K, Santos FO, Santos M, Santos MO, Satterwhite L, Saunders CT, Schreiber J, Schutgens REG, Seymour CW, Siegal DM, Silva DG Jr, Singhal AB, Slutsky AS, Solvason D, Stanworth SJ, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Widmer RJ, Wilson JG, Yuriditsky E, Zhong Y, Berry SM, McArthur CJ, Neal MD, Hochman JS, Webb SA, Zarychanski R. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):777-789. doi: 10.1056/NEJMoa2103417. Epub 2021 Aug 4. PMID 34351722
Berger JS, Kornblith LZ, Gong MN, Reynolds HR, Cushman M, Cheng Y, McVerry BJ, Kim KS, Lopes RD, Atassi B, Berry S, Bochicchio G, de Oliveira Antunes M, Farkouh ME, Greenstein Y, Hade EM, Hudock K, Hyzy R, Khatri P, Kindzelski A, Kirwan BA, Baumann Kreuziger L, Lawler PR, Leifer E, Lopez-Sendon Moreno J, Lopez-Sendon J, Luther JF, Nigro Maia L, Quigley J, Sherwin R, Wahid L, Wilson J, Hochman JS, Neal MD; ACTIV-4a Investigators. Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non-Critically Ill Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2022 Jan 18;327(3):227-236. doi: 10.1001/jama.2021.23605. PMID 35040887
Results publication: Zuchelkowski BE, Inman KW, Nouraie SM, Beru N, Naqvi A, Qin S, Yeh CH, Zhang Y, Shah FA, Sharma L, Dela Cruz CS, Zhang L, McVerry BJ, Morris A, Neal MD, Seheult J, Kitsios GD, Mellors JW, Lawrence DA, Kim PY, Jacobs JL, Bain WG. Soluble Thrombomodulin Links Viremia and Mortality During COVID-19: Results From the ACTIV-4a Trial. J Am Heart Assoc. 2026 May 19;15(10):e047693. doi: 10.1161/JAHA.125.047693. Epub 2026 May 6. PMID 42089155
Results publication: Kosiborod MN, Windsor SL, Vardeny O, Berger JS, Reynolds HR, Boumakis S, Althouse AD, Solomon SD, Bhatt AS, Peikert A, Luther JF, Leifer ES, Kindzelski AL, Cushman M, Ng Gong M, Kornblith LZ, Khatri P, Kim KS, Baumann Kreuziger L, Javaheri A, Carpio C, Wahid L, Lopez-Sendon Moreno J, Alonso A, Ho MQ, Lopez-Sendon J, Lopes RD, Curtis JL, Kirwan BA, Geraci MW, Neal MD, Hochman JS; ACTIV-4a Investigators. Effect of sodium-glucose co-transporter-2 inhibitors on survival free of organ support in patients hospitalised for COVID-19 (ACTIV-4a): a pragmatic, multicentre, open-label, randomised, controlled, platform trial. Lancet Diabetes Endocrinol. 2024 Oct;12(10):725-734. doi: 10.1016/S2213-8587(24)00218-3. Epub 2024 Sep 6. PMID 39250922
Results publication: Greenstein YY, Hubel K, Froess J, Wisniewski SR, Venugopal V, Lai YH, Berger JS, Chang SY, Colovos C, Shah F, Kornblith LZ, Lawler PR, Gaddh M, Guerrero RM, Nkemdirim W, Lopes RD, Reynolds HR, Amigo JS, Wahid L, Zahra A, Goligher EC, Zarychanski R, Leifer E, Huang DT, Neal MD, Hochman JS, Cushman M, Gong MN. Symptoms and Impaired Quality of Life After COVID-19 Hospitalization: Effect of Therapeutic Heparin in Non-ICU Patients in the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute Trial: Effect on 3-Month Symptoms and Quality of Life. Chest. 2024 Apr;165(4):785-799. doi: 10.1016/j.chest.2023.11.019. Epub 2023 Nov 17. PMID 37979717
Results publication: Fischer AL, Messer S, Riera R, Martimbianco ALC, Stegemann M, Estcourt LJ, Weibel S, Monsef I, Andreas M, Pacheco RL, Skoetz N. Antiplatelet agents for the treatment of adults with COVID-19. Cochrane Database Syst Rev. 2023 Jul 25;7(7):CD015078. doi: 10.1002/14651858.CD015078. PMID 37489818
Results publication: Solomon SD, Lowenstein CJ, Bhatt AS, Peikert A, Vardeny O, Kosiborod MN, Berger JS, Reynolds HR, Mavromichalis S, Barytol A, Althouse AD, Luther JF, Leifer ES, Kindzelski AL, Cushman M, Gong MN, Kornblith LZ, Khatri P, Kim KS, Baumann Kreuziger L, Wahid L, Kirwan BA, Geraci MW, Neal MD, Hochman JS; ACTIV4a Investigators. Effect of the P-Selectin Inhibitor Crizanlizumab on Survival Free of Organ Support in Patients Hospitalized for COVID-19: A Randomized Controlled Trial. Circulation. 2023 Aug;148(5):381-390. doi: 10.1161/CIRCULATIONAHA.123.065190. Epub 2023 Jun 25. PMID 37356038
Results publication: Berger JS, Neal MD, Kornblith LZ, Gong MN, Reynolds HR, Cushman M, Althouse AD, Lawler PR, McVerry BJ, Kim KS, Baumann Kreuziger L, Solomon SD, Kosiborod MN, Berry SM, Bochicchio GV, Contoli M, Farkouh ME, Froess JD, Gandotra S, Greenstein Y, Hade EM, Hanna N, Hudock K, Hyzy RC, Ibanez Estellez F, Iovine N, Khanna AK, Khatri P, Kirwan BA, Kutcher ME, Leifer E, Lim G, Lopes RD, Lopez-Sendon JL, Luther JF, Nigro Maia L, Quigley JG, Wahid L, Wilson JG, Zarychanski R, Kindzelski A, Geraci MW, Hochman JS; ACTIV-4a Investigators. Effect of P2Y12 Inhibitors on Organ Support-Free Survival in Critically Ill Patients Hospitalized for COVID-19: A Randomized Clinical Trial. JAMA Netw Open. 2023 May 1;6(5):e2314428. doi: 10.1001/jamanetworkopen.2023.14428. PMID 37227729
Results publication: Goligher EC, Lawler PR, Jensen TP, Talisa V, Berry LR, Lorenzi E, McVerry BJ, Chang CH, Leifer E, Bradbury C, Berger J, Hunt BJ, Castellucci LA, Kornblith LZ, Gordon AC, McArthur C, Webb S, Hochman J, Neal MD, Zarychanski R, Berry S, Angus DC; REMAP-CAP, ATTACC, and ACTIV-4a Investigators. Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19. JAMA. 2023 Apr 4;329(13):1066-1077. doi: 10.1001/jama.2023.3651. PMID 36942550
Results publication: Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2. PMID 34473343
Results publication: Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739. PMID 33502773

+Study documents

Study Protocol (PDF, 2021-10-19)
Statistical Analysis Plan (PDF, 2021-06-04)
Informed Consent Form (PDF, 2021-10-22)

+Investigators

Judith Hochman, MD, Study chair, NYU Langone Health
Scott Solomon, MD, Principal investigator, Brigham and Women's Hospital
Mikhail Kosiborod, MD, Principal investigator, Saint Lukes
Jeffrey Berger, MD, Principal investigator, NYU Langone Health
MATTHEW D NEAL, MD, Study chair, University of Pittsburgh

+Funding

NIH grants: 1OT2HL156812-01