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Review
. 2021 Apr 20;77(15):1903-1921.
doi: 10.1016/j.jacc.2021.02.035. Epub 2021 Mar 16.

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review

Azita H Talasaz  1 , Parham Sadeghipour  2 , Hessam Kakavand  3 , Maryam Aghakouchakzadeh  4 , Elaheh Kordzadeh-Kermani  4 , Benjamin W Van Tassell  5 , Azin Gheymati  4 , Hamid Ariannejad  6 , Seyed Hossein Hosseini  4 , Sepehr Jamalkhani  2 , Michelle Sholzberg  7 , Manuel Monreal  8 , David Jimenez  9 , Gregory Piazza  10 , Sahil A Parikh  11 , Ajay J Kirtane  11 , John W Eikelboom  12 , Jean M Connors  13 , Beverley J Hunt  14 , Stavros V Konstantinides  15 , Mary Cushman  16 , Jeffrey I Weitz  17 , Gregg W Stone  18 , Harlan M Krumholz  19 , Gregory Y H Lip  20 , Samuel Z Goldhaber  10 , Behnood Bikdeli  21
Affiliations
Review

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review

Azita H Talasaz et al. J Am Coll Cardiol. .

Abstract

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.

Keywords: COVID-19; RCT; anticoagulant; antiplatelet; clinical trial; thrombosis.

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Conflict of interest statement

Funding Support and Author Disclosures Dr. Van Tassell has received research support from Novartis, Swedish Orphan Biovitrum, Olatec Therapeutics, and Serpin Pharma; and is a consultant of R-Pharm and Serpin Pharma. Dr. Monreal has served as an advisor or consultant for Sanofi, Leo Pharma, and Daiichi-Sankyo; and has received a nonrestricted educational grant by Sanofi and Bayer to sponsor the Computerized Registry of Patients with Venous Thromboembolism. Dr. Jimenez has served as an advisor or consultant for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Leo Pharma, Pfizer, ROVI, and Sanofi; has served as a speaker or a member of a speaker bureau for Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Leo Pharma, ROVI, and Sanofi; and has received grants for clinical research from Daiichi-Sankyo, Sanofi, and ROVI. Dr. Piazza has received research grant support from Boston Scientific Corporation, Bayer, Bristol Myers Squibb/Pfizer, Portola/Alexion Pharmaceuticals, and Janssen Pharmaceuticals; and has received consulting fees from Amgen, Pfizer, Agile, and Prairie Education and Research Cooperative. Dr. Parikh has received institutional research support from Abbott Vascular, TriReme Medical, SurModics, and Shockwave Medical; is an advisory board member for Abbott Vascular, Boston Scientific, Cardinal Health, Medtronic, Janssen, CSI, and Philips; and receives honoraria from Abiomed and Terumo. Dr. Kirtane has received institutional funding from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, and ReCor Medical; and has received travel expenses/meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron, all outside the submitted work. Dr. Eikelboom has received honoraria and grant support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Sanofi, and Eli Lilly, as well as a personal award from the Heart and Stroke Foundation. Dr. Konstantinides has received research grants from Bayer AG, Boehringer Ingelheim, and Actelion-Janssen; has received educational grants from Biocompatibles Group UK, Boston Scientific, and Daiichi-Sankyo; and has received lecture fees from Bayer AG, Bristol Myers Squibb/Pfizer, and Merck Sharp and Dohme. Dr. Weitz serves as a consultant and has received honoraria from Bayer, Janssen, Johnson & Johnson, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Novartis, Daiichi-Sankyo, Merck, Servier, Anthos, Ionis, and PhaseBio. Dr. Stone has received speaker or other honoraria from Cook, Terumo, and Orchestra Biomed; has been a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, and CardioMech; and has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus family of funds, and Valfix. Dr. Krumholz has received personal fees from UnitedHealth, IBM Watson Health, Element Science, Aetna, Facebook, Siegfried & Jensen Law Firm, Arnold & Porter Law Firm, Ben C. Martin Law Firm, and the National Center for Cardiovascular Diseases (Beijing, China); has ownership in Hugo Health and Refactor Health; and has contracts from the U.S. Centers for Medicare & Medicaid Services; and has received grants from Medtronic, the U.S. Food and Drug Administration, Johnson & Johnson, and the Shenzhen Center for Health Information, outside the submitted work. Dr. Lip is a consultant for Bayer/Janssen, Bristol Myers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon, and Daiichi-Sankyo; and is a speaker for Bayer, Bristol Myers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo (no fees are directly received personally). Dr. Goldhaber has received research support from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, Daiichi-Sankyo, Janssen, the National Heart, Lung, and Blood Institute, and the Thrombosis Research Institute; and has received consulting fees from Bayer, Agile, Boston Scientific, and Boehringer Ingelheim. Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of inferior vena cava filters. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Virchow’s Triad and COVID-19 Associated Coagulopathy Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can potentiate all 3 sides of Virchow’s triad, including endothelial dysfunction, blood flow stasis, and hypercoagulability. Angiotensin-converting enzyme-2 (ACE-2)–dependent viral entry and the virus-induced inflammatory response can lead to endothelial dysfunction. Bedridden status may lead to stasis; inflammation, viremia, and cytokine storm can produce a hypercoagulable state. Factor Xa may play a role in spike protein cleavage and endocytosis of the virus. COVID-19 = coronavirus disease-2019; DIC = disseminated intravascular coagulopathy; FDP = fibrin degradation products; GM-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; LV = left ventricular; PAI = plasminogen activator inhibitor; RNA = ribonucleic acid; SIC = sepsis-induced coagulopathy; TF = tissue factor; TNF = tumor necrosis factor; tPA = tissue type plasminogen activators; uPA = urokinase plasminogen activators; vWF = von Willebrand factor.
Figure 2
Figure 2
Summary of RCTs of Antithrombotic Agents in COVID-19 Categorized Based on Pharmacological Class Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), direct thrombin inhibitors (DTIs), direct oral anticoagulants (DOACs), antiplatelets, fibrinolytic agents, and investigational agents are being evaluated in different settings, including outpatients, inpatients (intensive care unit [ICU] and non-ICU), and post-discharge. ∗Multifactorial designs or multiple interventions. COVID = coronavirus disease-2019; RCTs = randomized controlled trials.
Figure 3
Figure 3
Graphical Summary of Ongoing RCTs of Antithrombotic Therapy in COVID-19 Based on Patient Settings Categorizing the RCTs evaluating different agents in various settings, including those treated entirely as outpatients, patients in the non-ICU hospital wards, critically ill patients in the ICU, and post-hospital discharge. Others: dociparstat, nafamostat, and sulodexide. Abbreviations as in Figure 2.
Figure 4
Figure 4
Illustration of How Vulnerable Populations Were or Were Not Included in the Existing Trials Categorizing the RCTs evaluating different agents in vulnerable populations, including patients with advanced kidney disease, end-stage kidney disease (ESKD), patients with liver failure, and obese patients. Further details are illustrated in Supplemental Figure 1. Obesity is defined differently in different RCTs; body mass index >30, 35, and 40 kg/m2 and weight >100 and 120 kg are among the most-used definitions among RCTs. Others: dociparstat, nafamostat, and sulodexide. Abbreviations as in Figure 2.
Central Illustration
Central Illustration
Simplified Summary of Ongoing Antithrombotic Therapy Trials in Coronavirus Disease-2019∗ Heparin-based regimens are the most frequently studied antithrombotic agents in patients with coronavirus disease-2019. Trials of fibrinolytic therapy are reserved for patients admitted to the intensive care unit (ICU). ∗Additional details are provided in Figure 2 and Supplemental Table 2. LMWH = low-molecular-weight heparin; UFH = unfractionated heparin.
See this image and copyright information in PMC

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