Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19

JACC State-of-the-Art Review

Azita H. Talasaz, PHARMD; Parham Sadeghipour, MD; Hessam Kakavand, PHARMD; Maryam Aghakouchakzadeh, PHARMD; Elaheh Kordzadeh-Kermani, PHARMD; Benjamin W. Van Tassell, PHARMD; Azin Gheymati, PHARMD; Hamid Ariannejad, MD; Seyed Hossein Hosseini, PHARMD; Sepehr Jamalkhani; Michelle Sholzberg, MDCM, MSC; Manuel Monreal, MD, PHD; David Jimenez, MD, PHD; Gregory Piazza, MD, MS; Sahil A. Parikh, MD; Ajay J. Kirtane, MD, SM; John W. Eikelboom, MBBS; Jean M. Connors, MD; Beverley J. Hunt, MD; Stavros V. Konstantinides, MD, PHD; Mary Cushman, MD, MSC; Jeffrey I. Weitz, MD; Gregg W. Stone, MD; Harlan M. Krumholz, MD, SM; Gregory Y.H. Lip, MD; Samuel Z. Goldhaber, MD; Behnood Bikdeli, MD, MS

Disclosures

J Am Coll Cardiol. 2021;77(15):1903-1921.

Antithrombotic Prophylaxis in COVID-19: Pros and Cons

Bedside observations, pathophysiological investigations, and initial epidemiological data led to enthusiasm for antithrombotic prophylaxis in COVID-19.^[27–31] The concern for thrombotic risk was heightened by reports of VTE in 13% to 56% of patients despite the use of standard prophylaxis.^[32–35] This led some experts to recommend empirical use of escalated doses of anticoagulant agents.^[36] However, the risks associated with intensified use of antithrombotic agents, such as bleeding, should be weighed against the presumptive benefits.^[22,27,31]

In addition, there have been variations in methodology and outcomes assessment for thrombotic events, including the concern about counting in situ thrombosis in small vessels (a recognized feature of acute lung injury also known as immunothrombosis) as pulmonary emboli. Due to these issues, as well as the concerns regarding excess bleeding, a number of guidance statements have not recommended empirical escalated-dose anticoagulation.^[27,37]

Multiple ongoing randomized controlled trials (RCTs) are evaluating a variety of antithrombotic regimens in patients with COVID-19. Figure 2 These include trials of antiplatelet agents, anticoagulants, fibrinolytic agents, or combinations of these agents. In most trials, the intensity of antithrombotic therapy is proportional to the expected thrombotic event rates in the population under study. Less intensive therapies, including antiplatelet agents, oral anticoagulants, and standard prophylactic dose of low-molecular-weight heparin (LMWH), are typically studied in the outpatient or lower acuity hospital settings. In turn, more intensive therapies, including intermediate-dose or fully therapeutic doses of anticoagulants, or even fibrinolytic therapy, are under investigation in RCTs of hospitalized critically ill patients.

(Enlarge Image)

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.

The aims of the current paper were to systematically summarize the ongoing and completed RCTs of antithrombotic therapy in patients with COVID-19 and to evaluate the strengths and limitations of the study designs, as well as the challenges and opportunities related to conducting and interpreting RCTs during a global pandemic.

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Next Section

Abstract and Introduction
Thromboembolism in Patients With Coronavirus Disease-2019
Pathophysiology of Thromboembolism in COVID-19: Virchow's Triad in Action
Antithrombotic Prophylaxis in COVID-19: Pros and Cons
Methods
Review of Ongoing or Completed RCTs
Conclusions
References
Sidebar

Table 1. Expected Knowledge Gains From Ongoing Antithrombotic Therapy Trials in COVID-19 and Ongoing Knowledge Gaps
Outpatient	Noncritical Inpatient	ICU	Post-Discharge
Expected knowledge gain
The safety/efficacy of standard prophylactic doses of LMWHs and DOACs compared with standard of care or placebo in high-risk patients with early stages of COVID-19 The impact of aspirin administration on rate of MACE, disease progression, hospitalization, and death in patients with acute, symptomatic COVID-19 The safety/efficacy of sulodexide in patients with acute, symptomatic COVID-19	The safety/efficacy of intermediate-dose and therapeutic-dose heparin derivatives or DOACs compared with standard prophylactic anticoagulation Proof-of-concept data of the role of inhaled antithrombotic therapy in patients with COVID-19 The impacts of antiplatelet agents on all-cause mortality The safety/efficacy of dociparstat and nafamostat in hospitalized patients with COVID-19	The safety/efficacy of intermediate-dose and therapeutic-dose anticoagulation compared with prophylactic anticoagulation Effects of short-term infusion of bivalirudin on the PaO₂/FiO₂ ratio The impacts of antiplatelet agents on thrombotic outcomes and mortality Proof-of-concept data on the role of fibrinolytic therapy in critically ill patients Proof-of-concept data on the role of inhaled antithrombotic therapy in mechanically ventilated patients with COVID-19	The safety/efficacy of extended anticoagulation with DOACs or LMWHs after hospital discharge
Remaining knowledge gap
PMA needed to understand the relative efficacy of antiplatelet agents, standard prophylactic dose of enoxaparin compared with DOACs The safety/efficacy of antithrombotic therapy regimens in vulnerable subgroups, including obese patients, pregnant women, and those with advanced kidney disease	The efficacy/safety of fondaparinux, DTIs, and danaparoid compared with standard prophylactic anticoagulation PMA needed to understand the tradeoffs of various investigational antithrombotic regimens Best assay for LMWH/UFH monitoring in noncritically ill patients with COVID-19 The safety/efficacy of antithrombotic therapy regimens in vulnerable subgroups, including obese patients, pregnant women, and those with advanced kidney disease	The impact of antiplatelet therapy on survival in critically ill patients with COVID-19 PMA needed to understand the tradeoffs of various investigational antithrombotic regimens Best assay for LMWH/UFH monitoring in critically ill patients with COVID-19 The safety/efficacy of antithrombotic therapy regimens in vulnerable subgroups, including obese patients, pregnant women, and those with advanced kidney disease	The role of antiplatelet agents on VTE incidence in post-discharge patients The safety/efficacy of antithrombotic therapy regimens in vulnerable subgroups, including obese patients, pregnant women, and those with advanced kidney disease

COVID-19 = coronavirus disease-2019; DOAC = direct oral anticoagulants; DTI = direct thrombin inhibitor; ICU = intensive care unit; LMWH = low-molecular-weight heparin; MACE = major adverse cardiovascular events; PaO₂/FiO₂ = partial arterial pressure of oxygen/fraction of inspired oxygen; PMA = prospective meta-analysis; UFH = unfractionated heparin; VTE = venous thromboembolism.

Table 2. Antithrombotic Therapy Trial Design Before and During the COVID-19 Pandemic
	Before COVID-19 Pandemic	During COVID-19 Pandemic
Investigators	• Single specialty-based collaboration common • Focused, often established study groups	• Specialty-based and multispecialty collaboration common • Frequent ad hoc collaborations within and between institutions and countries
Study design	• Diverse research priorities • Patient enrollment over a long time period; recruitment time could be slow or fast • Long-term follow-up a routine feature of many trials	• Distinct focus on COVID-19–related trials; some adaptations required for pre–COVID-19 trials • Time-sensitive trial design (to provide rapid access to high-quality evidence). Trial design in short period of time may lead to multiple smaller and underpowered trials rather than larger multicenter collaborations. • Urgently needed medical solutions necessitate relatively fast patient enrollment • Incorporation of pragmatic design features • Multiple projects around the world occasionally leading into several smaller trials rather than fewer large-scale trials • Short-term follow-up most common • Applicability for adaptive platform design for multiple aspects of COVID-19 trials. Multiple interventions, quick enrollment, and the possibility of re-estimation of the optimal sample size during the study • Higher certain event rates (death or re-admission) than excepted from protocol
Funding/financial support	• Time-consuming review and approval process for funding allocation	• Accelerated review, prioritizing trials that affect the response to the pandemic
IRB approval	• Time-consuming process with occasional long delays before approval	• IRBs meeting more frequently, often resulting in rapid review and approval • More permissive regulations may expedite trial initiation
Informed consent	• Based on paper forms; may be cumbersome	• In-person or remote electronic informed consent available in many trials
Participant enrollment and engagement	• Variable willingness for trial participation by patients	• Patients willing to participate and engage in trials as partners • Periodic slowdown or interruptions in enrollment for some non–COVID-19 trials; in COVID-19 trials, there may be changes in enrollment rate with COVID-19 disease waves
Monitoring and auditing	• On-site session for multiple predefined monitoring visits • On-site or in-person data audits	• Frequent off-site online sessions with more restricted on-site visits • Remote monitoring and follow-up • Rapid enrollment makes keeping up to date with monitoring difficult, with risk of greater numbers of protocol deviations going unnoticed • Ascertainment of events other than all-cause mortality may be challenging due to limitations in testing strategies during the pandemic
Clinical events adjudication	• Central blinded outcome adjudication common • Face-to-face meetings • High costs • Time-consuming process to request ad hoc data from sites, summarize, and send back to adjudication meetings	• Some trials not able to incorporate endpoint adjudication (not recommended if resources allow) • Systematic and blinded adjudication in online meeting for assessment endpoints • Remote periodic meetings • Less expensive and quicker than face-to-face adjudication
DSMB meetings	• Face-to-face meetings • High costs	• Many trials using online platforms for DSMB meetings • Less costly
Follow-up	• Face-to-face visits or telephone calls • More costly	• Remote monitoring and follow-up in many trials by telephone calls and use of digital technology • Cost-saving and more efficient
Dissemination of results	• Longer peer review process • More strict criteria for publication • Uncommon use of pre-print servers	• Fast-track peer review process expedites the dissemination of completed studies. However, very quick peer review has occasionally missed important flaws of submitted reports • Frequent use of pre-print servers to share the early results of the studies The benefits of rapid dissemination and potential limitations with lack of peer review should be considered among the audience of the results • Similar to the pre–COVID-19 era, some studies may report preliminary results by press release, with full results becoming available days or weeks later

COVID-19 = coronavirus disease-2019; DSMB = Data and Safety Monitoring Board; IRB = institutional review board; RCT = randomized controlled trial.

Authors and Disclosures

Azita H. Talasaz, PHARMD^a,b, Parham Sadeghipour, MD^c, Hessam Kakavand, PHARMD^a,b, Maryam Aghakouchakzadeh, PHARMD^a, Elaheh Kordzadeh-Kermani, PHARMD^a, Benjamin W. Van Tassell, PHARMD^d,e, Azin Gheymati, PHARMD^a, Hamid Ariannejad, MD^b, Seyed Hossein Hosseini, PHARMD^a, Sepehr Jamalkhani^c, Michelle Sholzberg, MDCM, MSC^f,g, Manuel Monreal, MD, PHD^h, David Jimenez, MD, PHDⁱ, Gregory Piazza, MD, MS^j, Sahil A. Parikh, MD^k,l, Ajay J. Kirtane, MD, SM^k,l, John W. Eikelboom, MBBS^m, Jean M. Connors, MDⁿ, Beverley J. Hunt, MD^o, Stavros V. Konstantinides, MD, PHD^p,q, Mary Cushman, MD, MSC^r,s, Jeffrey I. Weitz, MD^t,u, Gregg W. Stone, MD^k,v, Harlan M. Krumholz, MD, SM^w,x,y, Gregory Y.H. Lip, MD^z,aa, Samuel Z. Goldhaber, MD^j and Behnood Bikdeli, MD, MS^j,k,w

^aDepartment of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; ^bTehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran; ^cCardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran; ^dDepartment of Pharmacotherapy and Outcome Science, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA; ^ePauley Heart Center, Division of Cardiology, Department of Internal Medicine, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA; ^fDepartments of Medicine and Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada; ^gDepartment of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada; ^hDepartment of Internal Medicine, Hospital Universitari Germans Trials i Pujol, Universidad Católica San Antonio de Murcia, Barcelona, Spain; ⁱRespiratory Department, Hospital Ramón y Cajal and Medicine Department, Universidad de Alcalá (Instituto de Ramón y Cajal de Investigación Sanitaria), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Madrid, Spain; ^jCardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; ^kClinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA; ^lNewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA; ^mPopulation Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada; ⁿHematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; ^oHaemostasis and Thrombosis Centre, St. Thomas' Hospital, London, United Kingdom; ^pCenter for Thrombosis and Hemostasis, Johannes Gutenberg University of Mainz, Mainz, Germany; ^qDepartment of Cardiology, Democritus University of Thrace, Komotini, Greece; ^rDepartment of Medicine, University of Vermont Larner College of Medicine and University of Vermont Medical Center, Burlington, Vermont, USA; ^sDepartment of Pathology and Laboratory Medicine, University of Vermont Larner College of Medicine and University of Vermont Medical Center, Burlington, Vermont, USA; ^tDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada; ^uThrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada; ^vZena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; ^wCenter for Outcomes Research and Evaluation (CORE), Yale School of Medicine, New Haven, Connecticut, USA; ^xDepartment of Health Policy and Administration, Yale School of Public Health, New Haven, Connecticut, USA; ^ySection of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA; ^zLiverpool Centre for Cardiovascular Science, Liverpool Heart and Chest Hospital, University of Liverpool, Liverpool, United Kingdom; and the ^aaDepartment of Clinical Medicine, Aalborg University, Aalborg, Denmark. Paul F. Bray, MD, served as Guest Associate Editor for this paper. Christie Ballantyne, MD, served as Guest Editor-in-Chief for this paper.

Address for Correspondence
Dr. Behnood Bikdeli, Cardiovascular Medicine Division, Brigham and Women's Hospital, 75 Francis Street, Shapiro 5, Suite 5156, Boston, Massachusetts 02115, USA. E-mail: bbikdeli@bwh.harvard.edu OR Behnood.bikdeli@yale.edu. Twitter: @AzitaTalasaz, @bbikdeli, @BrighamResearch, @harvardmed, @crfheart.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

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.