Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4A)

• ClinicalTrials.gov Identifier: NCT04505774
• Recruitment Status: Active, not recruiting
• First Posted: August 10, 2020
• Last Update Posted: April 25, 2023
• Sponsor: Matthew Neal MD
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Matthew Neal MD, University of Pittsburgh

Study Description

Brief 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

Condition or disease	Intervention/treatment	Phase
Covid19	Drug: theraputic heparin; Drug: prophylactic heparin; Drug: P2Y12; Drug: Crizanlizumab Injection; Drug: SGLT2 inhibitor	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 880 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: This is an adaptive design
• Masking: None (Open Label)
• Masking Description: There will be independent masked adjudicators.
• Primary Purpose: Treatment
• Official Title: A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic and Additional Strategies in Hospitalized Adults With COVID-19
• Actual Study Start Date: September 4, 2020
• Estimated Primary Completion Date: May 31, 2023
• Estimated Study Completion Date: November 2023

Arms and Interventions

Arm	Intervention/treatment
Therapeutic Dose Anticoagulation; 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.	Drug: theraputic heparin; increased dose of heparin above standard of care.; Other Names: unfractionated heparin; Enoxaparin; Dalteparin; Tinzaparin; Heparin
Prophylactic Dose Anticoagulation; 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)	Drug: prophylactic heparin; standard of care dose of heparin; Other Names: enoxaparin; dalteparin; Tinzaparin; Fondparinux; Heparin
Therapeutic Dose Anticoagulation + P2Y12 inhibitor; 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)	Drug: theraputic heparin; increased dose of heparin above standard of care.; Other Names: unfractionated heparin; Enoxaparin; Dalteparin; Tinzaparin; Heparin; Drug: P2Y12; added P2Y12 inhibitor; Other Names: Ticagrelor; Prasugrel; Clopidogrel
Prophylactic Dose Anticoagulation + P2Y12 inhibitor; 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.	Drug: prophylactic heparin; standard of care dose of heparin; Other Names: enoxaparin; dalteparin; Tinzaparin; Fondparinux; Heparin; Drug: P2Y12; added P2Y12 inhibitor; Other Names: Ticagrelor; Prasugrel; Clopidogrel
Standard of Care + Crizanlizumab; 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.	Drug: Crizanlizumab Injection; crizanlizumab injection
Standard of Care + SGLT2 inhibitor; Standard of care plus SGLT2 inhibitor This arm will enroll moderate and severe illness patients This arm was ended in March 2023	Drug: SGLT2 inhibitor; sglt2 inhibitor; Other Names: dapagliflozin; empagliflozin; canagliflozin; ertugliflozin

Outcome Measures

Primary Outcome Measures :

1. 21 Day Organ Support (respiratory or vasopressor) Free Days [ Time Frame: 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.

Secondary Outcome Measures :

1. Secondary Endpoint all cause mortality [ Time Frame: 28 days from study enrollment ]
   Categorization of the primary endpoint into a three-level ordinal outcome (Death, invasive mechanical ventilation without death, neither invasive mechanical ventilation nor death)
2. Other Platform Secondary Endpoints of Morbidity and Hospitalization [ Time Frame: 28 days from study enrollment ]
   Categorization of the primary endpoint into a three-level ordinal outcome (Death, organ support (any respiratory or cardiovascular) without death, neither organ support nor death) (for moderate illness severity at enrollment)
3. Days free of death [ Time Frame: 28 days from enrollment ]
   Days free of death and respiratory and cardiovascular organ support and renal replacement therapy (RRT) during Index Hospitalization through Day 28.
4. Death Composite [ Time Frame: 28 days from enrollment ]
   Composite endpoint of death, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke at hospital discharge or 28 days, whichever occurs first.
5. Acute kidney injury [ Time Frame: 90 days from enrollment ]
   Individual endpoints comprising the primary and secondary endpoint components; death during hospitalization, WHO clinical scale and 90 day mortality

Other Outcome Measures:

1. Primary Safety Endpoint of Major Bleeding [ Time Frame: 28 days from study enrollment ]
   Major bleeding (as defined by the ISTH)
2. Secondary Safety Endpoint of HIT [ Time Frame: 28 days from study enrollment ]
   Confirmed heparin induced thrombocytopenia (HIT)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama

Birmingham, Alabama, United States, 35233

United States, Arizona

University of Arizona

Tucson, Arizona, United States, 85719

United States, Arkansas

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States, 72205

United States, California

Kaiser Permanente Fontana

Fontana, California, United States, 92335

Kaiser Permanente Los Angeles

Los Angeles, California, United States, 90027

Smidt Heart Institute at Cedars-Sinai

Los Angeles, California, United States, 90048

Ronald Reagan UCLA Medical Center

Los Angeles, California, United States, 90095

UC San Diego Hillcrest

San Diego, California, United States, 92103

Zuckerberg San Francisco General Hospital

San Francisco, California, United States, 94110

UCSF San Francisco

San Francisco, California, United States, 94143

Zuckerberg San Francisco General Hospital

San Francisco, California, United States, 94410

Stanford University Medical Center

Stanford, California, United States, 94305

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Torrance, California, United States, 90502

United States, Colorado

Denver Health and Hospital Authority

Denver, Colorado, United States, 80401

St. Mary's Hospital & Regional Medical Center

Grand Junction, Colorado, United States, 81501

United States, Connecticut

Saint Francis Hospital and Medical Center

Hartford, Connecticut, United States, 06105

United States, Florida

University of Florida

Gainesville, Florida, United States, 32608

Memorial Hospital

Jacksonville, Florida, United States, 32216

AdventHealth Tampa

Tampa, Florida, United States, 33613

United States, Georgia

Emory

Atlanta, Georgia, United States, 30308

Morehouse School of Medicine

Atlanta, Georgia, United States, 30310

United States, Hawaii

Queens Medical Center

Honolulu, Hawaii, United States, 96813

United States, Illinois

Memorial Hospital

Belleville, Illinois, United States, 62226

Cook County Health

Chicago, Illinois, United States, 60612

University of Illinois at Chicago Health (UIH)

Chicago, Illinois, United States, 60612

OSF Little Company of Mary Medical Center (OSF LCM)

Evergreen Park, Illinois, United States, 60805

United States, Iowa

Indiana University Health Methodist Hospital

Indianapolis, Iowa, United States, 46202

United States, Kansas

Kansas University Medical Center

Kansas City, Kansas, United States, 66160

United States, Louisiana

Ochsner Clinic Foundation

New Orleans, Louisiana, United States, 70121

United States, Massachusetts

Boston University

Boston, Massachusetts, United States, 02118

St Elizabeth's Medical Center

Brighton, Massachusetts, United States, 02135

Baystate Medical Center

Springfield, Massachusetts, United States, 01199

University of Massachusetts

Worcester, Massachusetts, United States, 01655

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

Wayne State University

Detroit, Michigan, United States, 48201

United States, Minnesota

Hennepin County Medical Center

Minneapolis, Minnesota, United States, 55415

United States, Mississippi

University of Mississippi Medical Center

Jackson, Mississippi, United States, 39216

United States, Missouri

Washington University School of Medicine, ACCS Research

Saint Louis, Missouri, United States, 63110

United States, Nevada

University Medical Center of Southern Nevada

Las Vegas, Nevada, United States, 89102

United States, New Jersey

Cooper Health

Camden, New Jersey, United States, 08103

Englewood Health

Englewood, New Jersey, United States, 07631

Atlantic Health System

Morristown, New Jersey, United States, 07960

Rutgers New Jersey Medical School

Newark, New Jersey, United States, 07103

AtlantiCare Regional Medical Center

Pomona, New Jersey, United States, 08240

United States, New York

Albany Medical College

Albany, New York, United States, 12208

Jacobi Medical Center

Bronx, New York, United States, 10461

Montefiore Medical Center

Bronx, New York, United States, 10461

Mercy Hospital Buffalo

Buffalo, New York, United States, 14220

VA New York Harbor Healthcare System

New York, New York, United States, 10010

NYU Langone

New York, New York, United States, 10016

Mt. Sinai Hospital

New York, New York, United States, 10029

SUNY Upstate University Hospital

Syracuse, New York, United States, 13210

Westchester Medical Center

Valhalla, New York, United States, 10595

United States, North Carolina

Duke University Hospital

Durham, North Carolina, United States, 27704

Wake Forest

Winston-Salem, North Carolina, United States, 27157

United States, Ohio

Cleveland Clinic Akron General

Akron, Ohio, United States, 44307

University of Cincinnati Medical Center

Cincinnati, Ohio, United States, 45219

The MetroHealth System

Cleveland, Ohio, United States, 44109

Cleveland Clinic Foundation

Cleveland, Ohio, United States, 44195

Ohio State Universtiy Wexner Medical Center

Columbus, Ohio, United States, 43210

Mercy Health St Vincent Medical Center

Toledo, Ohio, United States, 43608

United States, Oklahoma

Ascension St. John Clinical Research Institute

Tulsa, Oklahoma, United States, 74104

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

Geisinger Research

Danville, Pennsylvania, United States, 17822

Doylestown Cardiology Associates

Doylestown, Pennsylvania, United States, 18901

Penn State Health Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States, 17033

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Temple University

Philadelphia, Pennsylvania, United States, 19141

UPMC Presbyterian

Pittsburgh, Pennsylvania, United States, 15260

United States, Rhode Island

Rhode Island Hospital

Providence, Rhode Island, United States, 02903

The Miriam Hospital

Providence, Rhode Island, United States, 02906

United States, Tennessee

Sarah Cannon and HCA Research Institute

Nashville, Tennessee, United States, 37203

Skyline Medical Center

Nashville, Tennessee, United States, 37207

United States, Texas

University of Texas at Austin

Austin, Texas, United States, 78701

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

Medical City Ft Worth

Fort Worth, Texas, United States, 76104

Baylor Scott and White Medical Center - Temple

Temple, Texas, United States, 76508

United States, Virginia

HCA Henrico Doctors Hospital

Richmond, Virginia, United States, 23229

United States, Washington

Swedish Hospital

Seattle, Washington, United States, 98122

United States, West Virginia

West Virginia University CTR

Morgantown, West Virginia, United States, 26506

United States, Wisconsin

University of Wisconsin Hospital; Meriter Hospital (UW affiliated)

Madison, Wisconsin, United States, 53715

Brazil

Hospital Universitario Sao Francisco de Assis

Braganca 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

Italy

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

Firenze, Italy

Policlinico di Napoli, Napoli

Napoli, Italy

AOU Policlinico di Palermo, Palermo

Palermo, Italy

ASL-1 Imperiese, Sanremo

Sanremo, Italy

Spain

Hospital Universitario A Coruna

A Coruna, Spain

Hospital Virgen del Mar

Almeria, 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

Hospital Clínico Universitario de Santiago de Compostela

Santiago de Compostela, Spain

Sponsors and Collaborators

Matthew Neal MD

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Study Chair: Judith Hochman, MD; New York University Grossman School of Medicine
• Principal Investigator: Scott Solomon, MD; Brigham and Women's Hospital
• Principal Investigator: Mikhail Kosiborod, MD; Saint Lukes
• Principal Investigator: Jeffrey Berger, MD; New York University Grossman School of Medicine
• Study Chair: MATTHEW D NEAL, MD; University of Pittsburgh

  Study Documents (Full-Text)

Documents provided by Matthew Neal MD, University of Pittsburgh:

Informed Consent Form  [PDF] October 22, 2021

More Information

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.

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.

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.

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.

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. Erratum In: Lancet. 2020 Mar 28;395(10229):1038. Lancet. 2020 Mar 28;395(10229):1038.

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.

Xu J, W.L., Zhao L, et al. , Risk assessment of venous thromboembolism and bleeding in COVID-19 patients. BMC Pulmonary Medicine 2020.

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.

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.

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.

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.

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.

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.

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.

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.

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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. Erratum In: J Vasc Surg Venous Lymphat Disord. 2019 Jul;7(4):621.

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.

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.

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.

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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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Matthew Neal MD, MD, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT04505774
• Obsolete Identifiers: NCT04359277
• Other Study ID Numbers: ACTIV-4 ACUTE; 1OT2HL156812-01 ( U.S. NIH Grant/Contract )
• First Posted: August 10, 2020
• Last Update Posted: April 25, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data will be shared as per NIH guidelines.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Matthew Neal MD, University of Pittsburgh:

anti-coagulation; antithrombosis; anticoagulation; ACTIV; inpatient; heparin; p2y12; endothelial dysfunction; vascular integrity; P-selectin; crizanlizumab; SGLT-2 inhibitor

Additional relevant MeSH terms:

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Dapagliflozin; Empagliflozin; Canagliflozin; Ertugliflozin; Sodium-Glucose Transporter 2 Inhibitors; Heparin; Calcium heparin; Enoxaparin; Dalteparin; Tinzaparin; Heparin, Low-Molecular-Weight; Enoxaparin sodium; Clopidogrel; Ticagrelor; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists