medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Antithrombotic Therapy in COVID-19: Systematic Summary of Ongoing or Completed Randomized Trials

Azita H. Talasaz, PharmD,1, 2 Parham Sadeghipour, MD,3 Hessam Kakavand, PharmD,1, 2 Maryam Aghakouchakzadeh, PharmD,1 Elaheh Kordzadeh-Kermani, PharmD,1 Benjamin W. Van Tassell, PharmD,4, 5 Azin Gheymati, PharmD,1 Hamid Ariannejad, MD,2 Seyed Hossein Hosseini, PharmD,1 Sepehr Jamalkhani, MD(2021),3 Michelle Sholzberg, MDCM, MSc,6, 7 Manuel Monreal, MD, PhD,8 David Jimenez, MD, PhD,9 Gregory Piazza, MD, MS,10 Sahil A. Parikh, MD,11, 12 Ajay J. Kirtane, MD, SM,11, 12 John W. Eikelboom, MBBS,13 Jean M. Connors, MD,14 Beverley J. Hunt, MD,15 Stavros V. Konstantinides MD, PhD,16, 17 Mary Cushman, MD, MSc18, 19 Jeffrey I. Weitz, MD,20, 21 Gregg W. Stone, MD,11, 22 Harlan M. Krumholz, MD, SM,23, 24, 25 Gregory Y.H. Lip, MD,26, 27 Samuel Z. Goldhaber, MD,10 and Behnood Bikdeli, MD, MS, 10, 11, 23, *

Total Words Count: 9020 (including text, tables, Figure legends, but not online supplement)

Affiliations: 1. Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. 2. Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran. 3. Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran. 4. Department of Pharmacotherapy and Outcome Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA. 5. Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA. 6. Departments of Medicine and Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Canada. 7. Department of Medicine, St. Michael’s Hospital, Toronto, Canada. 8. Department of Internal Medicine, Hospital Universitari Germans Trials i Pujol, Universidad Católica San Antonio de Murcia, Barcelona, Spain. 9. Respiratory 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. 10. Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 11. Clinical Trials Center, Cardiovascular Research Foundation, New York, NY, USA. 12. New York-Presbyterian Hospital/Columbia University Irving Medical Center, New York, NY, USA. 13. Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada. 14. Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 15. Haemostasis and Thrombosis Centre, St Thomas' Hospital, Westminster Bridge Road, London, United Kingdom. 16. Center for Thrombosis and Hemostasis, Johannes Gutenberg University of Mainz, Mainz, Germany.

1

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

17. Department of Cardiology, Democritus University of Thrace, Greece. 18. Department of Medicine, University of Vermont Larner College of Medicine and University of Vermont Medical Center, Burlington, VT, USA. 19. Department of Pathology and Laboratory Medicine, University of Vermont Larner College of Medicine and University of Vermont Medical Center, Burlington, VT, USA. 20. McMaster University, Hamilton, Ontario, Canada. 21. Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada. 22. Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 23. Center for Outcomes Research and Evaluation (CORE), Yale School of Medicine, New Haven, CT, USA. 24. Department of Health Policy and Administration, Yale School of Public Health, New Haven, CT, USA. 25. Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. 26. Liverpool Centre for Cardiovascular Science, Liverpool Heart and Chest Hospital, University of Liverpool, Liverpool, United Kingdom. 27. Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.

FUNDING: None

ADDRESS FOR CORRESPONDENCE: Dr. Bikdeli, Cardiovascular Medicine Division, Brigham and Women’s Hospital, 75 Francis Street, Shapiro 5, Suite 5156. Boston, MA 02115; [email protected], [email protected]

TWEET: Several #RCTs are underway to understand the optimal prophylactic #antithrombotic regimen across the spectrum of disease severity in patients with #COVID19.

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ABSTRACT

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiologic

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

critically-ill patients with COVID-19. This manuscript 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.

KEY WORDS COVID-19, anticoagulant, antiplatelet, clinical trial, RCT, thrombosis

ABBREVIATIONS AND ACRONYMS COVID-19 = coronavirus disease 2019 DOAC = direct oral anticoagulant DTI = direct thrombin inhibitor ICU = intensive care unit LMWH = low molecular weight heparin RCT = randomized controlled trial SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2 UFH = unfractionated heparin VTE = venous thromboembolism

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INTRODUCTION

Thromboembolism in Patients with COVID-19

Microvascular and macrovascular thrombotic complications including arterial and especially

venous thromboembolism (VTE) appear to be common clinical manifestations of coronavirus

disease 2019 (COVID-19), particularly among hospitalized and critically-ill patients (1-4). Pooled

analyses have helped in providing aggregate estimates of thrombotic events (4, 5). In a recent

systematic review and meta-analysis, the overall incidence of VTE among inpatients with COVID-

19 was estimated at 17% (95% confidence interval [CI], 13.4%-20.9%), with variation based on

study design and method of ascertainment, with a four-fold higher incidence rate in patients in the

intensive care units (ICU) compared with non-ICU settings (28% vs. 7%) (6). In addition, post-

mortem studies show frequent evidence of microvascular thrombosis in patients with COVID-19

(7, 8). The influence of these events on mortality rates remains unknown (9).

Pathophysiology of Thromboembolism in COVID-19: Virchow’s Triad in Action

COVID-19 can potentiate all three components of Virchow’s triad and increase the risk of

thrombosis (Figure 1). First, SARS-CoV-2 infection may trigger endothelial dysfunction. Using

the angiotensin converting enzyme (ACE)-2, expressed on the surface of many cells, SARS-CoV-

2 enters endothelial cells and may impair their intrinsic antithrombotic properties. It is proposed

that viremia, hypoxia, the inflammatory response, increased expression of tissue factor, and

elevated levels of neutrophil extracellular traps (NETs) can together disrupt the hemostasis

equilibrium, and promote endothelial activation (10-12). This induction of a procoagulant state

along with the reduction in plasminogen activators, further results in increased platelet reactivity

(13-15). Inflammatory cytokines and endothelial activation can lead to downregulation of

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antithrombin and protein C expression, and an increase in the levels of plasminogen activator

inhibitor, fibrinogen, factors V, VII, VIII, and X, in addition to von Willebrand factor (16).

Increased platelet reactivity, NETosis and alterations in the aforementioned hemostatic factors

result in a hypercoagulable state (17-22). Particularly in COVID-19, it is thought that the excessive

inflammatory response plays an important role in the pathogenesis of thrombosis

(thromboinflammation), including pulmonary microthrombosis and pulmonary intravascular

coagulopathy (7,8). Antiphospholipid antibodies have been identified in some patients (23) but

their clinical significance is uncertain (24). Finally, venous stasis may synergistically combine

with this prothrombotic milieu in patients more severely affected by the clinical syndrome of

COVID-19 constituting of extreme fatigue with decreased daily activity, immobility due to oxygen

requirements in the hospital. This may be further exacerbated by development of complications

such as viral myocarditis and left ventricular systolic dysfunction (25, 26). All the aforementioned

mechanisms may increase the risk of arterial and venous thrombosis, thereby impacting the

severity of illness.

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 empiric use of escalated doses of

anticoagulants (36). However, the risks associated with intensified use of antithrombotic agents

such as bleeding should be weighed against the presumptive benefits (22, 27, 31).

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In addition, there have been variations in methodology and outcomes assessment for thrombotic

events –including the concern about counting 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 well as the concerns for excess bleeding, a number of guidance statements have not

recommended empiric 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.

The aims of this article are to systematically summarize the ongoing and completed RCTs

of antithrombotic therapy in patients with COVID-19, 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.

METHODS

We conducted a systematic literature search of trials in clinicaltrials.gov and World Health

Organization International Clinical Trials Registry Platform (WHO ICTRP), with the pre-defined

keywords of COVID-19, and search terms for antiplatelet agents, anticoagulants, anticoagulation,

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fibrinolytic agents, and antithrombotic agents. We screened the identified studies and included

those that were designed as RCTs with at least one active arm of antithrombotic therapy (date of

last search: December 16, 2020). Supplemental Table 1 summarizes study-level inclusion and

exclusion criteria for this review.

For the included studies, we searched PubMed and MedRxiv for design papers, study

protocols or published results of those studies. The list was complemented by hand-searching and

discussion within the author group.

After identification of 918 records and manual screening of 180 records, we included 75

RCTs (Supplemental figure 1). In 13 cases, a design paper and/or study protocol was available. Of

all ongoing studies, one RCT reported the results in peer-reviewed literature (38) and one shared

the findings on a pre-print server (39). For three RCTs, final results are unknown but patient

enrollment was paused in critically-ill patients due to concern for futility and potential excess of

safety events (40).

REVIEW OF ONGOING OR COMPLETED RANDOMIZED CONTROLLED TRIALS

As of December 16, 2020, 75 RCTs of antithrombotic agents for patients with COVID-19 were

registered at ClinicalTrials.gov or WHO ICTRP databases. Figure 2 provides a graphical summary

of all RCTs of antithrombotic agents in COVID-19 in a pharmacologic-based approach. Agents

used in these trials include antiplatelet agents, unfractionated heparin (UFH) and heparin

derivatives, parenteral direct thrombin inhibitors (DTIs), direct oral anticoagulants (DOACs),

fibrinolytic agents, sulodexide (a mixture of heparan sulfate and dermatan sulfate) (39), dociparstat

(a heparin derivative with anti-inflammatory properties), and nafamostat (a synthetic serine

protease inhibitor with anticoagulant activity). A succinct discussion of the design features of these

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trials is provided below according to the clinical setting (see Supplemental Tables 2 and 3 for more

details). Supplemental Table 4 summarizes the RCTs of other investigational agents with

antithrombotic properties but not meeting our eligibility criteria for the current manuscript.

In each section, the discussion starts with antiplatelet agents, followed by oral

anticoagulants, parenteral anticoagulants, fibrinolytic therapy, and investigational agents with

antithrombotic properties. This sequence is arbitrary and does not indicate treatment preference.

Figure 3 illustrates how RCTs of various agents can fill the knowledge gaps about antithrombotic

therapy in COVID-19 in various settings of illness severity.

Ongoing Clinical Trials of Antithrombotic Agents in the Outpatient Setting

Eleven RCTs of antithrombotic therapy in outpatients with COVID-19 have been registered in

clinical trials databases and are studying aspirin, DOACs, enoxaparin, and sulodexide compared

with no treatment (6/11) or with placebo (5/11). These trials are mostly (8/11) open-label, with the

number of participants ranging from 172 to 7,000 patients, and include patients with a

hyperinflammatory or procoagulant profile (including elevated levels of C-reactive protein [CRP]

(1/11) or d-dimer [2/11]) and exclude patients at high risk of bleeding (such as those with history

of recent gastrointestinal bleeding or intracranial hemorrhage). Pregnant women and patients with

severe kidney dysfunction (creatinine clearance [CrCl] < 30 mL/min) are excluded from 8 and 6

of these trials, respectively. The most common primary outcome in the outpatient trials include the

need for hospitalization, incidence of thromboembolic events, mortality or composite outcomes

inclusive of these within 21 to 90 days after randomization.

Aspirin, DOACs (at both low-intensity and high-intensity), LMWHs (at standard

prophylactic dose), and sulodexide are the agents under investigation in the outpatient setting. The

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impact of low-dose aspirin on the composite rate of hospitalizations and mortality is being

evaluated in 3 RCTs with a total of 12,080 patients with COVID-19 (ACTCOVID19, LEAD

COVID-19, and ACTIV-4b). Low-intensity rivaroxaban (10 mg QD) is being evaluated in a total

of 4,600 patients in two ongoing RCTs (PREVENT-HD [NCT04508023] and NCT04504032).

Low-intensity apixaban (2.5 mg BID) is also under investigation in the ACTIV-4b trial in up to

7,000 patients. High-intensity DOACs including rivaroxaban (20 mg QD), apixaban (5 mg BID),

and edoxaban (60 mg QD) are being investigated among 7,992 patients in 4 RCTs (COVID-

PREVENT, ACTIV-4b, HERO-19, and CONVINCE). The primary outcome for the COVID-

PREVENT, HERO-19 and CONVINCE trials is the composite of mortality and arterial and venous

thromboembolism; the primary outcome for the randomized double-blind placebo controlled

ACTIV-4b trial is a composite of venous and arterial thromboembolism, hospitalization for

cardiovascular/pulmonary events and all-cause mortality. ETHIC and OVID RCTs are comparing

the effect of standard prophylactic dose of enoxaparin versus no intervention on the primary

outcome of hospitalization or mortality in 2,370 individuals (41).

SulES-COVID is the only completed trial of antithrombotic therapy in outpatients with

COVID-19. This single-center study of 243 participants assessed the efficacy of sulodexide,

compared with placebo on 21-day rates of hospitalization and need for use of supplemental

oxygen. Use of sulodexide was associated with reduced hospital admissions (relative risk [RR],

0.6; 95% CI, 0.37-0.96; p=0.03) and need for oxygen support (RR, 0.71; 95% CI, 0.5 to 1; p=0.05),

without a significant effect on mortality (39). The study has limitations, including frequent (22.1%)

post-enrollment exclusions due to negative SARS-CoV2 test results or lost to follow-up.

Many of the outpatient antithrombotic therapy trials for COVID-19 are large and the

follow-up windows are sufficient to capture the intended primary outcomes. An issue with some

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of these trials is an open-label design, which is a pragmatic feature facilitating the design and

enrollment but potentially limits the internal validity, especially for outcomes that may be less

bias-resistant. In addition, the available data do not clarify whether dose adjustments are made for

renal or liver dysfunction.

Ongoing Clinical trials of Antithrombotic Agents in Hospitalized non-ICU Patients

We identified 50 ongoing RCTs related to antithrombotic therapy in hospitalized non-ICU patients

with COVID-19. Most trials (44/50) are open-label. The antithrombotic agents under investigation

include aspirin, P2Y12 inhibitors, dipyridamole, DOACs, heparin (both systemic and inhaled),

dociparstat, nafamostat, and a combination of these drugs. The planned sample sizes range

between 34 and 20,000 patients. Considering the potential link between elevated D-dimer, micro

and macro-thrombosis in COVID-19, and worse outcomes in COVID-19 (42-44), many RCTs

(N=16) include patients with elevated D-dimer levels with cut-offs ranging from >500 ng/mL to

>1,500 ng/mL (or defined as >2-4 times the upper limit of normal per the local laboratory). Most

trials exclude pregnant women (41 studies) and patients with active bleeding or history of

intracranial or gastrointestinal bleeding (39 studies). Many trials also excluded patients with CrCl

< 30 mL/min (20 studies). In most trials, the time frame for the primary outcome assessment is 28-

30 days, although a few studies are designed to assess the primary outcomes at earlier or longer

durations. These RCTs are focused on primary efficacy outcomes including all-cause mortality,

VTE, arterial thrombosis, requirement for respiratory support, or a composite of these outcomes.

The potential protective effect of antiplatelet agents in hospitalized patients with COVID-

19 is being evaluated in 11 RCTs. REMAP-CAP is a large global RCT with a multifactorial

adaptive design which is planning to randomize 7,100 patients to multiple therapeutic interventions

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including an anticoagulant arm and antiplatelet agent arm looking ats aspirin, and the P2Y12

inhibitors clopidogrel, ticagrelor or prasugrel (45). PEAC aims to test the efficacy of aspirin in

shortening clinical recovery time. The impact of aspirin on all-cause mortality among hospitalized

patients is also under evaluation in the largest adaptive platform RCT for COVID-19

(RECOVERY) with 20,000 participants (46). RESIST (CTRI/2020/07/026791) aims to evaluate

the role of aspirin plus atorvastatin in clinical deterioration characterized by progression to WHO

clinical improvement ordinal score in 800 hospitalized patients with COVID-19 (47). CAM-

Covid-19 evaluates the impact of higher dose of aspirin (325 mg QID) along with colchicine and

montelukast on inflammatory markers such as hs-CRP in 34 patients. PARTISAN

(NCT04445623) will be comparing the effect of prasugrel versus placebo among 128 patients with

COVID-19 on the primary outcome of improved oxygenation expressed as the PaO2/FiO2 ratio at

7-day follow-up. Some RCTs are evaluating the impact of dipyridamole in hospitalized patients

with COVID-19. Dipyridamole 100 mg QID and the combination of dipyridamole ER 200mg/

aspirin 25mg are being evaluated in 3 small RCTs (TOLD, DICER and ATTAC-19) for primary

outcomes such as D-dimer level changes (for the first two trials) and improvement in COVID-19

WHO Ordinal Scale (a scale indicting severity of illness, from 0 [not infected] to 8 [death])

(ATTAC-19).

The use of DOACs in hospitalized ward patients with COVID-19 is under investigation in

5 RCTs. Low-intensity rivaroxaban is being investigated in 650 planned participants in the

ACOVACT and XACT trials of hospitalized patients to assess outcomes such as all-cause

mortality, ICU admission, and intubation. High-intensity (but not loading-intensity) DOACs

including rivaroxaban and apixaban are being evaluated in large RCTs that will enroll a total of

4,750 participants (ACTION, COVID-PREVENT, FREEDOM COVID, and XACT).

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C-19-ACS is an adaptive RCT conducted to evaluate the impact of the combination of low-

dose rivaroxaban (2.5 mg BID) plus aspirin 75 mg/day plus clopidogrel 75 mg/day along with

atorvastatin and omeprazole on 30-day all-cause mortality in 3,170 hospitalized patients with

COVID-19. Patients with definite acute coronary syndromes are excluded from this RCT. The

effect of dual pathway inhibition using the combination of low-dose rivaroxaban and aspirin is

being evaluated in the adaptive ACTCOVID19 inpatient study. In this RCT of 4,000 patients, the

rate of invasive mechanical ventilation or death is assessed at 45 days post-randomization.

Twenty-eight ongoing studies are being conducted to examine the efficacy of heparin-

based regimens on primary outcomes such as all-cause mortality, venous and arterial thrombosis,

re-hospitalization, the need for invasive mechanical ventilation, or composite outcomes inclusive

of these in hospitalized patients with COVID-19. The majority of these RCTs has chosen standard-

dose prophylactic anticoagulation regimen as the comparator. Intermediate-dose anticoagulation

will be tested in DAWn-Antico (48), X-COVID-19, COVID-19 HD, COVI-DOSE, EMOS-

COVID, NCT04360824, and EUCTR2020-001891-14-ES with 4,434 patients in total. On the

other hand, a total of 18 RCTs with 19,776 patients will evaluate the efficacy of therapeutic

anticoagulation in non-ICU hospitalized patients (49). Only two trials totaling 494 patients

(IMPACT and HEP-COVID) will directly compare therapeutic and intermediate doses of heparin.

The different intensities of heparin derivatives are summarized in Supplemental Table 3.

Recognizing that heparin has more than an anticoagulant effect but also an antiviral and

anti-inflammatory effect, INHALE-HEP and NEBUHEPA are evaluating the impact of nebulized

UFH on the rate of intubation in 856 hospitalized patients with COVID-19.

PACTR202007606032743 evaluates the impact of nebulized UFH on PaO2/FiO2 ratio in 100

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hospitalized patients. Standard of care (for INHALE-HEP and PACTR202007606032743) and

standard-dose prophylaxis with LMWH (NEBUHEPA) are the comparators, respectively.

High mobility group box protein 1 (HMGB1) is a protein involved in the pathogenesis of

inflammation. Elevated levels of HMGB1 is associated with worse the outcomes in COVID-19

(50). Dociparstat, a heparin derivative with presumed anticoagulant and anti-inflammatory

properties, inhibits HMGB1 and may reduce the formation of NETs and the risk of thrombosis.

The drug is being studied in NCT04389840 to assess its impacts on all-cause mortality and need

for mechanical ventilation in 600 patients with severe COVID-19 (51).

Nafamostat is a synthetic serine protease inhibitor with anti-viral, anti-inflammatory, and

anticoagulant activity previously used for anticoagulation during hemodialysis (52). Nafamostat

is under evaluation in hospitalized patients with COVID-19 in 7 RCTs with 826 individuals in

total. The primary efficacy outcome in most (5/7) of these trials is time to recovery.

The strengths of many of the antithrombotic trials among inpatients with COVID-19

include relatively large sample sizes and ample follow-up for detection of events. With multiple

large clinical trials underway, robust evidence should soon be available comparing the

intermediate/therapeutic doses of heparinoids versus usual care. However, studies such as

PARTISAN and NCT04420299 have relatively small sample sizes and short periods of follow-up

(7 days and 10 days, respectively), rendering them susceptible to type II error. There is also

variability across the trials in methods for identification and ascertainment of thrombotic

outcomes. Lack of blinding and blinded outcome adjudication are practical limitations for some of

these trials.

Ongoing Clinical Trials of Antithrombotic Agents in Critically-Ill Patients

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The risk of thrombotic events appears to be highest among critically-ill patients with COVID-19.

A systematic review estimated that VTE event rates in critically-ill patients with COVID-19 would

be estimated at 27.9% (95% CI, 22.1%-34.1%) (6). Currently, there are 33 ongoing RCTs

evaluating the role of antithrombotic agents in critically-ill patients with COVID-19 of which 18

RCTs enroll mixed non-ICU and ICU populations and 16 RCTs solely enroll ICU patients. The

sample size of these studies range from 15 to 20,000 patients. These trials study the role of

antiplatelet agents (aspirin, clopidogrel and dipyridamole), systemic anticoagulants (intermediate

to full-therapeutic-dose of heparin and DTIs), inhaled UFH, fibrinolytic agents (tenecteplase and

alteplase), and nafamostat. Inclusion criteria in 11 of 34 RCTs require D-dimer cut-offs ranging

from >500 ng/ml to >3,000 ng/ml (or defined as >2-6 times the upper limit of normal limit). All-

cause mortality, venous and arterial thrombotic complications, and oxygenation (expressed mostly

as PaO2/FiO2) status are the most common components of the primary efficacy outcomes.

Bleeding complications are the most widely used primary safety outcome among these studies.

The role of antiplatelet agents is under investigation in critically-ill patients in 4 trials. As

previously described, dipyridamole (TOLD) and aspirin (RECOVERY and CAM-Covid-19) are

under evaluation. COVID-PACT is a multicenter, open-label study that will randomize 750

patients with 2 x 2 factorial design trial to full-dose anticoagulation vs. standard-dose prophylactic

anticoagulation with heparin-based regimens (first randomization), and to antiplatelet therapy with

clopidogrel vs. no antiplatelet therapy (second randomization). The primary efficacy outcome is

the incidence of VTE or arterial thrombosis incidence 28 days after enrollment.

UFH and/or LMWH (19 studies) are the most common antithrombotic regimens under

investigation in the ongoing trials in critically-ill patients. INSPIRATION, IMPROVE, DAWn-

Antico, and COVI-DOSE are testing intermediate-dose versus standard prophylactic dose

14 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

anticoagulation in more than 1,500 participants in total. INSPIRATION has recently completed

enrollment of 600 patients and the results are imminent (53). Eleven RCTs are evaluating the

potential role of therapeutic-dose versus standard prophylactic dose anticoagulation in 5,142

patients. In December 2020, preliminary results of an interim analysis of pooled critically ill

patients enrolled in the three trials (ACTIV-4a, REMAP CAP, and ATTACC) by the Data Safety

and Monitoring boards paused enrollment of critically ill patients due to futility for the endpoint

of freedom from organ support at 21 days. Enrollment of moderately ill patients in this composite

trial continues. This decision was based on the determination of futility, and a potential for harm

due to possibly higher rates of bleeding. More details are forthcoming (40). Finally, IMPACT and

HEP-COVID are comparing therapeutic anticoagulation with intermediate-dose anticoagulation

in a total of 494 individuals.

The only published RCT in critically-ill patients with COVID-19 is HESACOVID, a

single-center study of 20 patients requiring invasive mechanical ventilation randomized to

therapeutic versus standard-dose anticoagulation. Therapeutic-dose anticoagulation significantly

increased PaO2/FiO2 and ventilator free days (15 days [IQR 6–16] versus 0 days [IQR 0–11],

p = 0.028) (38). The study did not have sufficient power to compare all-cause mortality between

the study groups. Bleeding may have been underestimated due to barriers of performing imaging

testing, including computed tomography to identify a source, in critically-ill patients (54).

CHARTER-Irl, CHARTER-MT, and NCT04397510 are evaluating the utility of nebulized

UFH in 292 mechanically-ventilated critically-ill patients with COVID-19. The primary outcome

for CHARTER-Irl is the alterations in D-dimer area under the curve (AUC) within a 10-day

follow-up, and for CHARTER-MT is ventilator-free days with a follow-up duration of 28 days;

the primary outcome for NCT04397510 is improvement in PaO2/FiO2 ratio within 10 days.

15 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

The use of parenteral anticoagulants other than UFH and LMWHs in COVID-19 is being

studied in two trials. IMPACT will randomize 100 ICU patients with COVID-19 into 4 arms to

compare fondaparinux, argatroban, intermediate-dose heparin and therapeutic-dose heparin

(UFH/LMWH) with the primary outcomes of 30-day mortality. In ANTI-CO, bivalirudin is being

investigated in 100 critically-ill patients for the primary outcome of improvement in oxygenation

as determined by the PaO2/FiO2 ratio (55).

There are six RCTs (AtTAC, STARS, TRISTARDS, TACOVID, NCT04505592, and

IRCT20200415047080N1) evaluating the safety and efficacy of fibrinolytic therapy (tenecteplase

or alteplase) on COVID-19 related respiratory failure in a total of 440 patients (56). Most of these

trials include patients with severe disease (severe acute respiratory distress syndrome, elevated

troponin levels, and elevated D-dimer levels). The primary outcomes in 5 of these trials include

the improvement in PaO2/FiO2 ratio or ventilator free days. The time frame for studies evaluating

the change in PaO2/FiO2 ratio is between 48-72 hours and for those which evaluate ventilator free

days is 28 days. Patients receiving therapeutic anticoagulation, and those with thrombocytopenia,

or history of intracranial or gastrointestinal bleeding are excluded from fibrinolytic therapy trials.

Nafamostat is under evaluation in 4 studies in critically-ill patients with COVID-19

(DEFINE, RACONA, NCT04418128, and NCT04623021) with 650 participants in total.

Research in the ICU faces several challenges for study design, data/sample collection, and

patient follow-up (57). In many cases, patients are unconscious and obtaining informed consent

requires discussion with healthcare proxies. This is further complicated because visitors are

prohibited. The strengths of the aforementioned studies in the ICU include the diversity of studied

antithrombotic agents, and sample size in many RCTs. There are also a number of notable

limitations to these trials. The most important limitation is the small sample size in several studies,

16 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

raising the possibility of type II error. The small sample size will mostly influence trials of

thrombolytic therapy and non-heparin anticoagulants.

Ongoing Clinical Trials in Post-Discharge Patients

ACTIV-4c (NCT04650087) is a double-blind, placebo-controlled RCT which will evaluate the

impact of apixaban 2.5 mg BID on the rate of all-cause mortality, and arterial and venous

thromboembolism on 5,320 post-discharge patients. MICHELLE (NCT04662684) is an open-

label RCT with 320 participants aims to evaluate the safety and efficacy of rivaroxaban 10 mg QD

for 35+/-4 days versus no intervention after hospital discharge with a composite efficacy outcome

of VTE and VTE-related death.

In addition, there are 7 RCTs with a projected total of 1,452 participants which will

continue the already assigned antithrombotic therapy after discharge in patients who were

randomized in the general medical wards or in the ICU. In COVID-PREVENT, XACT, and

NCT04508439 RCTs, post-discharge thromboprophylaxis with rivaroxaban (10 or 20 mg QD) is

being investigated in 680 participants who were enrolled in general medical wards to measure the

incidence of VTE at 30-35 days after discharge. In the HERO-19 study, edoxaban 60 mg QD or

placebo will continue after discharge in 172 patients who were randomized in the ICU or non-ICU

settings to evaluate all-cause mortality rate and VTE incidence at 42 days. In the INSPIRATION

study, intermediate or standard prophylactic dose of enoxaparin will be continued after discharge

in 600 patients who were randomized in the ICU to evaluate the rate of VTE. Finally, aspirin in

the PEAC study, and dipyridamole ER plus aspirin in the ATTAC-19 study, will be continued

after discharge in patients randomized in the non-ICU general wards.

17 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Incorporation of Vulnerable Populations in the Ongoing Trials

Most of the ongoing RCTs are excluding patients at increased risk of bleeding, or with acute and

chronic hepatic failure. In more than 50% of the trials designed to evaluate escalated dose

anticoagulation, patients with CrCl < 15 mL/min are excluded. CoV-Hep is an open-label study

which evaluates the role of low-dose (10 IU/kg/h) intravenous UFH on the rate of clotted dialyzers

in 90 critically-ill patients with COVID-19 undergoing continuous venous-venous hemodialysis

with a follow-up duration of 3 days. Specific dose adjustment for obesity is considered for 10 out

of 34 trials of systemic heparin compounds. Pregnant women are excluded from 25 out of 34 trials

of systemic heparin compounds. While patient selection in these studies is based on practical

considerations, it is unlikely that high-quality evidence will soon be available for antithrombotic

therapy in such vulnerable subgroups (Figure 4 and Supplemental Figure 2).

The Impact of RCTs on the Future Practice of Antithrombotic Therapy

A large number of RCTs will help to delineate the efficacy and safety of antithrombotic agents in

patients with COVID-19 (Central Illustration). Until the results accrue, participation in these RCTs

is encouraged. Efficacy outcomes vary based on the location of enrollment; i.e., between outpatient

trials and inpatient trials. As for safety outcomes, many of the trials are systematically assessing

major bleeding using the International Society on Thrombosis and Haemostasis (ISTH) criteria or

the Bleeding Academic Research Consortium definitions (58, 59). While observational evidence

suggests low rates of major bleeding, (33, 60), observational studies have the potential for

underreported outcomes and therefore RCTs with systematic and prospective capture of both

thrombotic and bleeding events will help determine the true risk-benefit ratio for treatments. This

18 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

is especially the case since risk factors for thrombosis in COVID-19, such as D-dimer, may also

predict bleeding (33).

While results from the individual trials may inform interim practice, some challenges

persist. The large number of antithrombotic agents under investigation, the variable dosing

regimens tested, and variability in trial conduct as well as methods of outcome detection and

adjudication may complicate the identification of the optimal regimens. A prospective meta-

analysis of RCTs, ideally with individual participant data, will help to assess the effects of distinct

agents across the spectrum of disease severity and may address the clinical and statistical

heterogeneity of the upcoming results. Efforts to harmonize endpoints have been advocated, with

creation of common data elements for VTE for example, to aid in pooling trial results (61, 62). In

addition, there are few head-to-head comparisons for many of the experimental therapies, such as

intermediate-dose compared with fully-therapeutic heparin-based regimens. Network meta-

analytic techniques might generate insights into the comparative tradeoffs of these regimens (63).

Additional biomarker and clinical risk prediction sub-studies can also further elucidate subgroups

with more favorable net benefit profiles from distinct regimens. Moreover, the remaining

knowledge gaps summarized in Table 1 should be kept in mind so that the design of additional

studies could be considered.

Anti-inflammatory properties and activity against thromboinflammation have been

attributed to several antithrombotic regimens including heparin derivatives and antiplatelet agents

(30, 64, 65), with the potential to reduce large-vessel thrombosis and improve outcomes. Another

evolving concept is the role of microthrombosis and pulmonary intravascular coagulopathy (7, 8,

66) in the pathophysiology of respiratory failure in COVID-19 (67). Results from the small

HESACOVID study suggested improved arterial oxygenation (PaO2/FiO2) with therapeutic

19 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

versus standard-dose prophylaxis anticoagulation in critically-ill patients with COVID-19 (38).

However, combined investigation of three large-scale randomized trials of therapeutic

anticoagulation (ACTIV-4a, REMAP CAP, and ATTACC) paused enrollment of critically ill

patients for futility; we await further clarifications (40).

Therapeutic drug monitoring of the investigational agents is also important. Even when an

agent is selected (e.g., UFH), the best method for dose titration or adjustment remains uncertain

(68). Some experts recommend measuring anti-Xa levels in those receiving intravenous

unfractionated heparin, since the high levels of Factor VIII observed among critically-ill patients

with COVID-19 may interfere with aPTT assays. The necessity and optimal method for dosing

and monitoring of heparins and LMWHs, in particular for patients with kidney disease or obesity

is yet to be elucidated, and is even understudied outside COVID-19 (69). Ideally, future strategy

trials should test the merits and limitations of these monitoring tests.

Clinical Trial Enterprise During COVID-19 Pandemic: Is a Quantum Leap Taking Place?

The clinical trial enterprise has been significantly affected during the COVID-19 pandemic (70).

Patient recruitment in many ongoing pre-COVID-19 trials was temporarily halted. Notable

challenges such as barriers to follow-up and site-monitoring persist. However, the desire to provide

an evidence-based response has been one of the key drivers of positive changes during the

pandemic (71). These changes include multi-specialty study teams, harmonization of multicenter

protocols, expedited multi-institutional agreement execution and institutional review board and

governmental agency approvals, accelerated informed consent, and enrollment with digital

contact-free technology, expeditious outcomes ascertainment, remote monitoring, and

20 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

dissemination of the findings via fast-track publications, pre-prints, and social media accounts

from scientific societies or investigators (Table 2) (72-74).

Although traditional RCTs have provided a great deal of knowledge for modern medicine,

they are confined to testing a limited number of interventions. Since COVID-19 has multi-organ

involvement and broad manifestations (including inflammation, ARDS, thrombosis and others),

adaptive platform trials –which allow for testing multiple interventions in a single disease based

on a decisive algorithm– have gained attention (75). This type of trial has a perpetual and multi-

arm-multi-stage design.(76) The RECOVERY Trial (77) and the World Health Organization

Solidarity Trial (78) have tested different steroid and antiviral regimens, respectively, and have

some additional agents under investigation, including aspirin in one of the hypotheses from

RECOVERY. REMAP-CAP is testing several interventions including steroids, antivirals, biologic

agents, simvastatin, and antiplatelet therapy. ACTIV4 platform is similarly using an adaptive

design for antithrombotic agents.

Notwithstanding the good will of investigators, the constant pressure to provide rapid

pandemic response may pose challenges, as well. In some cases, multiple small single-center RCTs

underpowered for their clinical points or using surrogate endpoints with short follow-up have been

designed (71, 79) and may compete against larger multicenter, and potentially more definitive,

studies. The large numbers of these trials alone, in addition to the intense pressure to present

broadly and publish these findings suggests at least some potential for Type I error with

amplification of these results through rapid dissemination of the results.

Additional methodological aspects deserve attention. Interpretation of these trial results

may be limited by underutilization of placebo (perhaps except for the outcome of mortality) (54,

79). Some experts consider that the pressures of working during a global pandemic makes the use

21 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

of placebo more aspirational than realistic. Nevertheless, when feasible, placebo control improves

the internal validity of a trial. Further, appropriate endpoint assessment, including blinded

adjudication when feasible, and pre-specified analysis methods will remain of importance (54).

IRBs and independent ethics committees may experience the burden of numerous protocol

submissions and amendments during the pandemic. Burnout of healthcare systems during the

pandemic, and the risks to the research teams are unique challenges that should also be considered

when designing and executing study protocols (72). Investigators should attempt to foresee some

of the challenges in order to minimize the need for protocol amendments (80-82). Moreover, the

informed consent process has become adapted to facilitate discussions by telephone or video

conference, followed by verbal confirmation, and documentation of consent using approved

software programs and electronic signature, where acceptable (80, 83).

Efficacy and safety outcomes monitoring is also critical. Execution of online Clinical Event

Committee (CEC) and Data and Safety Monitoring Board (DSMB) meetings for assessing the

adverse events is a fast safe, efficient alternative to face-to-face meetings. If done with appropriate

planning to adhere to standards of high-quality CEC and DSMB meetings, such approaches may

be considered even when society transitions out of the pandemic (81, 83).

Peer-review and dissemination of the studies has had unique challenges and advancements,

too. Journal editors and reviewers have been pressured for rapid release of the results of completed

studies. This has activated fast-track peer-review process more than ever. Despite its merits, the

“COVID-19 fatigue” created by the fast-track review process might negatively impact the quality

of peer-review, as noted by occurrence of post-publication major revisions and retractions,

including in major journals (84). In a recent study, only 29% of the clinical trials of patients with

COVID-19 reviewed on ClinicalTrials.gov met the Oxford Centre for Evidence-Based Medicine

22 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

(OCEBM) level 2 evidence (85). The process of peer-review remains an imperfect –yet essential–

step in the evaluation and reporting of results (86). Preprint servers include full drafts of research

studies shared publicly before peer-review. Pre-prints have the potential benefit of early

dissemination and opportunity for feedback and discussion, and could be of substantial benefit

during the pandemic. With a preprint, key researchers in the field can discover findings sooner;

indicate critical errors, or suggest new studies or data that strengthen the argument (87). The

limitations of pre-prints should be also communicated transparently, so that similar weight is not

placed on pre-print and peer-reviewed literature by the lay people, the press, healthcare workers,

or policy-makers. Indeed many retracted papers were from pre-print servers (84).

Prospectively planned meta-analyses would be of particular help during the pandemic.

Such studies can help understand the heterogeneity of the findings between interventions, between

distinct studies, and within subgroups. Prospective meta-analysis can also help with pooled

comparisons for interventions with small individual studies, as well as indirect comparisons for

interventions that do not have sufficiently-large head-to-head comparisons in existing studies.

CONCLUSIONS

Optimal antithrombotic therapy in patients with COVID-19 is yet to be determined. Results of

these ongoing RCTs, and prospective meta-analyses of the completed studies will help clarify

whether any of the plentiful antithrombotic regimens under investigation can safely mitigate

thrombotic complications and improve patient outcomes.

FUNDING: None

23 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

DISCLOSURES: Dr. Van Tassell received the research support from Novartis, Swedish Orphan

Biovitrum, Olatec Therapeutics, Serpin Pharm. He is a consultant of R-Pharm, Serpin Pharma. Dr.

Monreal reports that he served as an advisor or consultant for Sanofi, Leo Pharma and Daiichi

Sankyo. Also, he received a nonrestricted educational grant by Sanofi and Bayer to sponsor the

RIETE registry. 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; served as a speaker or a member of a speakers’ bureau for Bayer

HealthCare Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Leo

Pharma, ROVI and Sanofi; 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 reports institutional research support from Abbott Vascular, TriReme

Medical, Surmodics, and Shockwave Medical. He is an advisory board member for Abbott

Vascular, Boston Scientific, Cardinal Health, Medtronic, Janssen, CSI and Philips. He receives

honoraria from Abiomed and Terumo. Dr. Kirtane reports Dr Kirtane reports institutional funding

from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, CSI, CathWorks, Siemens, Philips,

ReCor Medical and 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 reports honoraria and grant support

from Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb/Pfizer, Daiichi Sankyo,

Glaxo Smith Kline, Janssen , Sanofi Aventis, and Eli Lilly, aswell as a personnel award from the

Heart and Stroke Foundation. Dr. Konstantinides reports research grants from Bayer AG,

24 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Boehringer Ingelheim, Actelion - Janssen; educational grants from Biocompatibles Group UK -

Boston Scientific, Daiichi Sankyo; lecture fees from Bayer AG, Pfizer-Bristol-Myers Squibb,

MSD. Dr. Weitz serves as a consultant and received honoraria from Bayer, Janssen, JnJ, BMS,

Pfizer, Boehringer Ingelheim, Novartis, Daiichi-Sankyo, Merck, Servier, Anthos, Ionis, and

PhaseBio. Dr. Stone reports speaker or other honoraria from Cook, Terumo, and Orchestra

Biomed; Consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative

Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious,

Reva, Matrizyme, Cardiomech; Equity/options from Ancora, Cagent, Applied Therapeutics,

Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus

family of funds, Valfix. Dr. Krumholz reports 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); ownership of Hugo Health and Refactor Health; contracts from the US Centers for

Medicare & Medicaid Services; and grants from Medtronic, US Food and Drug Administration,

Johnson and Johnson, and Shenzhen Center for Health Information, outside the submitted work.

Dr. Lip reports that he is a Consultant for Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer

Ingelheim, Novartis, Verseon and Daiichi-Sankyo and a speaker for Bayer, BMS/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, and the National Heart, Blood, and Lung

Institute, and the Thrombosis Research Institute; he has received consulting fees from Bayer,

Agile, Boston Scientific, and Boehringer Ingelheim. Dr. Bikdeli reports that he is a consulting

25 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters.

The other authors report no Disclosures.

ACKNOWLEDGEMENTS: The authors would like to express their sincere gratitude to Fatemeh

Esmaeili, MS, for her kind assistance in graphic designs.

26 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

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HIGHLIGHTS

• Venous and arterial thrombosis are among the prevalent manifestations of COVID-19.

• The optimal thromboprophylactic regimens still remain unknown in patients with COVID-

19.

• At this time, dozens of RCTs are evaluating the role of antithrombotic regimens among

outpatients and inpatients with COVID-19.

• COVID-19 has led to changes in the design, conduct, analysis, and reporting of the RCT

results.

38 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Figure legends

Figure 1. Virchow’s Triad and COVID-19 Associated Coagulopathy. Caption: SARS-CoV-2

can potentiate all three sides of Virchow’s triad including endothelial dysfunction, blood flow

stasis, and hypercoagulability. ACE-2 dependent viral entry and the virus-induced inflammatory

response can lead to endothelial dysfunction; Bedridden status may lead to stasis; and

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. ACE: Angiotensin Converting

Enzyme; COVID: Coronavirus Disease 2019; DIC: Disseminated Intravascular Coagulopathy;

FDP: Fibrin Degradation Products; GM-CSF: Granulocyte-macrophage colony-stimulating factor;

HF: Heart Failure; IL: Interleukin; LV: Left Ventricular; PAI: plasminogen activator inhibitor;

RAAS: Renin Angiotensin Aldosterone System; 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. Summary of randomized controlled trials of antithrombotic agents in COVID-19

categorized based on pharmacologic class. Caption: UFH, LMWH, DTI, DOACs, antiplatelets,

fibrinolytic, and investigational agents are evaluating in different settings including outpatients,

inpatients (ICU and non-ICU), and post-discharge. *: Multifactorial designs or multiple

interventions. DOAC: Direct Oral Anticoagulant; DTI: Direct Thrombin Inhibitors; ICU: Intensive

Care Unit; LMWH: Low Molecular Weight Heparin; UFH: Unfractionated Heparin.

Figure 3. Graphical Summary of ongoing RCTs of antithrombotic therapy in COVID-19

based on patient settings. Caption: Categorizing the RCTs evaluating different agents in different

39 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

settings including those treated entirely as outpatient, patients in the non-ICU hospital wards,

critically ill patients in the ICU, and post-hospital discharge. Others: dociparstat, nafamostat, and

sulodexide. DOAC: Direct Oral Anticoagulants; DTI: Direct Thrombin Inhibitors; LMWH: Low

Molecular Weight Heparin; RCT: Randomized Clinical Trials; UFH: Unfractionated Heparin.

Figure 4. Illustration of how vulnerable populations were/ were not included in the existing

trials. Caption: Categorizing the RCTs evaluating different agents in vulnerable populations

including patients with advanced 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 greater than 30, 35, and 40 kg/m2 and weight more than 100 and

120 kg are among the most used definitions among RCTs. Others: dociparstat, nafamostat, and

sulodexide. DOAC: Direct Oral Anticoagulants, DTI: Direct Thrombin Inhibitors, ESKD: End

Stage Kidney Disease; LMWH: Low Molecular Weight Heparin; RCT: Randomized Clinical

Trials; UFH: Unfractionated Heparin.

Central Illustration. Succinct Summary of ongoing RCTs of antithrombotic therapy in

COVID-19. DOAC: Direct Oral Anticoagulant; DTI: Direct Thrombin Inhibitors; H-I: High-

Intensity; ICU: Intensive Care Unit; L-I: Low-Intensity; LD: Low Dose; LMWH: Low Molecular

Weight Heparin; N: Number of Participants; RCTs: Randomized Controlled Trials; UFH:

Unfractionated Heparin.

40

medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Table 1. Expected Knowledge Gains from Ongoing Antithrombotic Therapy Trials in COVID-19 and Ongoing Knowledge Gaps

Outpatient Non-Critical Inpatient ICU Post-Discharge

- The safety/efficacy of standard -The safety/efficacy of intermediate dose and therapeutic -The safety/efficacy of intermediate dose and -The safety/efficacy prophylactic doses of LMWHs and DOACs dose heparin derivatives or DOACs compared to standard therapeutic dose anticoagulation compared with of extended compared to standard of care or placebo in prophylactic anticoagulation prophylactic anticoagulation anticoagulation with high risk patients with early stage of the DOACs or ain COVID-19 - Proof of concept data of the role of inhaled antithrombotic -Effects of short-term infusion of bivaliridun on LMWHs after G therapy in patients with COVID-19 PaO2/FiO2 ratio hospital discharge - The impact of aspirin administration on rate of MACE, disease progression, - The impacts of antiplatelet agents on all-cause mortality - The impacts of antiplatelet agents on

nowledge hospitalization, and death in patients with thrombotic outcomes and mortality

K acute, symptomatic COVID-19 - The safety/efficacy of dociparstat and nafamostat in hospitalized patients with COVID-19 - Proof of concept data on the role of fibrinolytic - The safety/efficacy of sulodexide in patients therapy in critically ill patients with acute, symptomatic COVID-19 Expected

- Proof of concept data of the role inhaled antithrombotic therapy in mechanically

ventilated patients with COVID-19

- PMA needed to understand the relative - The efficacy/safety of fondaparinux, DTIs, and danaparoid -The role of efficacy of antiplatelet agents, standard compared to standard prophylactic anticoagulation - The impact of antiplatelet therapy on survival antiplatelet agents prophylactic dose of enoxaparin in in critically ill patients with COVID-19 on VTE incidence in ap

G comparison with DOACs - PMA needed to understand the tradeoffs of various post-discharge investigational antithrombotic regimens - PMA needed to understand the tradeoffs of patients various investigational antithrombotic regimens - Best assay for LMWH/UFH monitoring in non-critically ill patients with COVID-19 - Best assay for LMWH/UFH monitoring in critically ill patients with COVID-19 Remaining Knowledge

COVID-19: Coronavirus Disease 2019, DOAC: Direct Oral Anticoagulants, DTI: Direct Thrombin Inhibitors, ICU: Intensive Care Unit, MACE: Major Adverse Cardiovascular Events, PMA: Prospective Meta-Analysis, UFH: Unfractionated Heparin, VTE: Venous Thromboembolism.

41

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Table 2. Antithrombotic Therapy Trial Design Before and During the COVID-19 Pandemic. Various Areas of Before COVID-19 Pandemic During COVID-19 Pandemic Clinical Research • Single specialty-based collaboration common • Specialty-based and multi-specialty collaboration common Investigators • Focused, often established study groups • Frequent ad hoc collaborations within and between institutions and countries • Diverse research priorities • Distinct focus on COVID-19-related trials, some adaptations required for pre-COVID-19 trials. • Patient enrollment over a long time period, recruitment time could be • Time-sensitive trial design (to provide rapid access to high quality evidence). Trial design in short period of time may slow of fast lead to multiple smaller and underpowered trials rather than larger multicenter collaborations • Long-term follow up a routine feature of many trials • Urgently needed medical solutions necessitate relatively fast patient enrollment • Incorporation of pragmatic design features. Study Design • Multiple projects around the world occasionally leading into several smaller trials rather than fewer large-scaler 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) that excepted from protocol Funding/ Financial • Time-consuming review and approval process for funding allocation • Accelerated review, prioritizing trials that impact the response to the pandemic Support • Time-consuming process with occasional long delays prior to approval • IRBs meeting more frequently, often resulting in rapid review and approval IRB 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 • Variable willingness for trial participation by patients • Patients willing to participate and engage in trials as partners Participants Enrollment and • 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. Engagement

• On site session for multiple predefined monitoring visits • Frequent off-site online sessions with more restricted onsite visit • On site or in-person data audits • Remote monitoring and follow up Monitoring and • Rapid enrollment makes keeping up to date with monitoring difficult, with risk of greater numbers of protocol Auditing deviations going un-noticed. • Ascertainment of events other than all-cause mortality may be challenging due to limitations in testing strategies during the pandemic • Central blinded outcome adjudication common • Some trials not able to incorporate endpoint adjudication (not recommended if resources allow) • Face to face meetings • Systematic and blinded adjudication in online meeting for assessment endpoints Clinical Events • High costs • Remote periodic meetings Adjudication • Time consuming process to request ad-hoc data from sites, summarize, • Less expensive and quicker than face to face adjudication and send back to adjudication meetings • Face to face meetings • Many trials using online platforms for DSMB meetings DSMB Meetings • High costs • Less costly • Face to face visits or phone calls • Remote monitoring and follow-up in many trials by phone calls and use of digital technology Follow-Up • More costly • Cost-saving and more efficient • Fast-track peer-review process expedites the dissemination of completed studies. However, very quick peer-review has • Longer peer-review process Dissemination of occasionally missed important flaws of submitted reports. • More strict criteria for publication Results • Frequent use of pre-print servers to share the early results of the studies. The benefits of rapid dissemination and • Uncommon use of pre-print servers potential limitations with lack of peer-review should be considered among the audience of the results. APT: Adaptive platform trials, COVID-19: Coronavirus Disease 2019, DSMB: Data and Safety Monitoring Board, IRB: Institutional Review Board, RCT: Randomized Clinical Trials, RFA: Request for Application.

42 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Figure 1. Virchow’s Triad and COVID-19 Associated Coagulopathy

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Keywords: COVID-19 and coagulation, thrombosis, thrombotic, thromboembolism, thromboembolic, anticoagulation, anticoagulant, antithrombotic, antiplatelet, aspirin, dipyridamole, Aggrenox, cilostazol, P2Y12 inhibitor, clopidogrel, ticagrelor, prasugrel, ticlopidine, vorapaxar, eptifibatide, tirofiban, abciximab, heparin, UFH, LMWH, enoxaparin, dalteparin, tinzaparin, bemiparin, nadroparin, fondaparinux, danaparoid, DTI, bivalirudin, argatroban, lepirudin DOAC, apixaban, rivaroxaban, edoxaban, betrixaban, dabigatran, sulodexide, dociparstat, nafaostat, ulinastatin, defibrotide, crizanlizumab, rNAPc2, recombinant antithrombin III, ATryn, thrombomodulin, activated protein C, drotrecogin alpha, thrombolytic, firinolytic, alteplase, reteplase, tnecteplas. COVID-19: Coronavirus Disease 2019, DOAC: Direct Oral Anticoagulant, DTI: Direct Thrombin Inhibitors, LMWH: Low Molecular Weight Heparin, rNAPc2: Recombinant Nematode Anticoagulant Protein c2, UFH: Unfractionated Heparin, WHO ICTRP: World Health Organization International Clinical Trials Registry Platform

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Supplemental Table 1. Study-level Inclusion and Exclusion Criteria for the Systematic Review Inclusion Criteria Exclusion Criteria • Focused on patients with COVID-19 • Studies of patients without COVID-19 • Designed as a randomized controlled trial • Non-randomized design medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was• Registered not certified by at peer clinicaltrials.gov review) is the author/funder, or the who WHO has granted• Minimum medRxiv a license detail to display the including preprint in perpetuity. the ICTRP (or identifiedAll via rights hand reserved.-searching No reuse byallowed withoutintervention, permission. eligibility criteria and authors), date of last search: December 16, 2020 estimated sample size not available

• At least one active randomized arm including • Studies of pediatric patients widely available antithrombotic agents such as antiplatelet agents, anticoagulants, fibrinolytic therapy (or investigational antithrombotic agents with at least 500 total patients across all trials or a single trial with more than 200 patients, for being discussed in the full text of the current manuscript); Supplemental table 4 shows investigational agents which did not meet inclusion criteria. • The following characteristics being available • Studies which focus on the treatment of • Planned sample size diagnosed thrombotic events (rather than • Defined study intervention prophylactic treatment) • Inclusion and exclusion criteria • Primary endpoint COVID-19: Coronavirus Disease 2019, WHO ICTRP: World Health Organization International Clinical Trials Registry Platform

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Supplemental Table 2. Review of RCTs Categorized Based on Patient Settings Efficacy Outcomes (If composite, may include more than - 1 component)

Dose Adjustments

Primary

Secondary

up period period up - Inclusion Criteria

Exclusion Criteria (Brief)* Outcomes

(Brief)* (days)

(daily) (daily) Blinding Drug Drug - Agent Used Agent Sample Size Sample Comparator MV VTE VTE Therapy (days) Therapy Other Safety Safety Disease Actual Dose Used Dose Actual Used Dose Actual Obesity Trial Code/ Name Code/ Trial P/F ratio P/F ratio P/F up Duration (days) Duration up Mortality Mortality Composite Composite Interaction Drug Final follow Final Duration of Randomized Randomized of Duration Chronic Kidney Kidney Chronic Primary Outcome Follow Outcome Primary clinical endpoint clinical

Ongoing trials in outpatient setting Contraindication to use of

antithrombotic agents,

4b Apixaban 2.5 mg BID Age ranged 40 -79 years, hospitalized patients, ✓ - † Up Double confirmed COVID-19 in pregnancy, active cancer, Major Exclude ‡ placebo - 7000 45 45 to NP NP NP NP NP NP Blind past 14 days, platelet count indication for AC, single or bleeding ✓ ✓ ✓ -- ✓ 75 CrCl<30 > 100,000/fL dual antiplatelet therapy, high ACTIV ml/min

NCT04498273 Apixaban 5 mg BID bleeding risk, CrCl < 30ml/min, DDI Aspirin 81 mg

Confirmed COVID-19 by Advanced kidney disease, ✓ laboratory findings, within advanced liver failure, Exclude Open Aspirin 75-100 mg NP 4000 7 days of diagnosis or pregnancy, breastfeeding, high 28 45 45 MACE NP NP NP NP ✓ NP ✓ NP ✓ Advanced -- -- Label worsening clinically, high- bleeding risk, use of other kidney risk Patients antithrombotic agents disease NCT04324463 ACTCOVID19 Standard of care of Standard

High risk bleeding, liver failure, pregnancy, Open ✓ Confirmed COVID-19 by breastfeeding, use of Exclude Label Edoxaban 60 mg - 420 25 25 25 NP NP NP NP NP NP NP -- -- PCR therapeutic AC, use of DAPT, ✓ ✓ ✓ CrCl<15 use of HCQ, CrCl < 15 ml/min CONVINCE NCT04516941 No intervention No mL/min, amputation

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20 mg (15 High bleeding risk, pregnancy,

mg for Confirmed COVID-19 by breastfeeding, CrCl<30 ml ✓ 30ml/min < PCR in the last 14 days, at /min, liver failure, active Open eGFR < 50 least one of these criteria: cancer, HIV, use of therapeutic Exclude Rivaroxaban NP 400 35 35 35 NP NP NP NP NP NP NP NP -- -- PREVENT ✓ ✓ eGFR <

- Label ml /min) D-dimer > 1.5 ULN and/or AC, use of DAPT ticagrelor or 30 ml Reduce to TnT > 2 ULN + CAD or prasugrel, 7 days prior to /min NCT04416048

10 mg after care of Standard DM or CS randomization, aspirin>100

COVID 7 days mg, NSAIDs

Age ≥ 55 years, confirmed

High bleeding risk, PCI or COVID-19 †, at least two 40 mg sc thrombolytic therapy in the last ✓ Open risk factors: Exclude Enoxaparin (40 mg BID - 1370 24 hours, pregnancy, GFR < 30 21 90 90 Bleeding NP ✓ ✓ ✓ NP ✓ ✓ NP NP ✓ NP Label Age ≥ 70 years, BMI > 25 GFR < 30

ETHIC ETHIC if ≥ 100 kg) mL/min, use of other kg/m2, COPD, Diabetes, antithrombotic ml /min NCT04492254 No intervention No CVD, Use of corticosteroid

Life expectancy less than 3 Confirmed COVID-19 † months, resuscitation > 30 Excluded 19 - Double within 10 days, and minutes, high bleeding risk, if Edoxaban 60mg Placebo - 172 NP 42 42 NP NP NP NP NP NP NP -- -- Blind troponin ≥ ULN and/or D- other indication for ✓ ✓ ✓ CrCl<15

HERO dimer ≥0.5 mg anticoagulation, GFR < 15 ml/min

NCT04542408 ml/min

19 - † Pregnancy, high bleeding risk,

Open Confirmed COVID-19 Aspirin 81 mg - 1080 use of NSAIDs or steroids, 14 14 14 NP NP NP NP NP NP NP NP NP ------Label within 24 hours ✓ LEAD liver failure, CKD COVID NCT04363840 No intervention No

Use of anticoagulant, high

Age ≥ 50 years, confirmed bleeding risk, CrCl < 30 ✓ Open COVID-19 † in the past 5 mL/min contraindications to Major Exclude Enoxaparin 40 mg sc - 1000 14 30 90 NP NP ✓ NP NP ✓ ✓ NP ✓ -- -- Label days, respiratory enoxaparin therapy, use of bleeding CrCl < 30 OVID symptoms, temp >37.5° C DAPT, liver failure with ml /min NCT04400799 No intervention No coagulopathy, non-adherence

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Age> 18 years, confirmed

COVID-19 by PCR, at least 1 additional risk

HD High bleeding risk, severe liver - factors: age ≥ 60 years, Bleeding failure, intolerance to Double BMI > 35 kg/m2, D- (Non- Rivaroxaban 10 mg placebo - 4000 rivaroxaban, positive COVID- 35 35 37 NP NP NP NP NP NP ------Blind dimer> 2 ULN, major, ✓ ✓ ✓ 19 serology after 2 weeks, use thrombophilia, history of Major, of therapeutic AC, APS NCT04508023

PREVENT VTE, CAD, PAD, Fatal) cerebrovascular disease, diabetes, cancer Negative COVID-19 PCR test

(post enrollment exclusion) , Age> 40 years, 3 days or previous treatment for COVID- less with clinical COVID- Double 500unit 19, pregnancy, chronic use of Major COVID

- Sulodexide Placebo - 243 19 symptoms 21 21 21 NP NP NP NP NP ------Blind BID steroid, use of therapeutic AC, bleeding ✓ ✓ ✓ ✓ High risk patients history of DVT, and bed 18

NCT04504032 immunocompromised pregnancy, breastfeeding, CKD patients, HTN, DM, any (stage IV or receiving dialysis) high-risk chronic disease, BMI ≥ 35kg/m2) § Ongoing trials in hospital ward setting

Symptomatic patients with Pregnancy, breastfeeding, liver ✓ Open 2.5-5 mg confirmed COVID-19 by Exclude Rivaroxaban LMWH NP 500 failure, CrCl<20 ml/min, NP 29 29 NP NP NP NP ✓ NP NP ✓ ✓ -- -- Label BID laboratory findings who CrCl < 20 cancer, high bleeding risk ✓ require hospitalization ml /min ACOVACT NCT04351724

MV>72 hours, advanced Symptomatic patients aged kidney disease, advanced liver ✓ 75-100 mg ≥ 18 yrs confirmed failure, high bleeding risk, use Exclude Open Aspirin+ ✓ + Control - 4000 COVID-19 by laboratory of P2Y12 inhibitors, pregnancy, 28 45 45 MACE NP ✓ ✓ ✓ NP NP ✓ NP ✓ Advanced -- Label Rivaroxaban Excluded 2.5 mg BID findings within 72 hours of breastfeeding kidney admission DDI with DOACs disease NCT04324463 ACTCOVID19

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1 mg/Kg Enoxaparin SC BID

CrCl<30 ml/min, liver failure,

Age ≥ 18 yrs, confirmed pregnancy, breastfeeding, HIV, ✓ To target COVID-19 † within 14 cancer, high bleeding risk, (excluded Single UFH Major aPTT NP 600 days, symptomatic patients DIC, on aspirin>100 mg, Use 30 30 30 NP NP NP NP NP NP NP -- Blind bleeding ✓ ✓ if ✓ admitted to hospital with of DAPT, use of AC, CrCl<30 ACTION ACTION 20 mg if D-dimer> 3 ULN rivaroxaban hypersensitivity ml/min) NCT04394377 CrCl≥50 and DDIs ml/min and

Rivaroxaban 15 mg if 30 anticoagulation Prophylactic ml/min ≤CrCl≤49 ml/min

Dipyridamol Age ≥ 18 yrs, Pregnancy, G6PD Deficiency,

19 - e ER + 200 mg confirmed COVID-19 by high bleeding risk, vasodilatory

Open 15- 8 Aspirin+ BID + 25 NP 132 RT-PCR or hospitalized shock, uncontrolled HTN, 14 15 NP NP NP NP ✓ NP ✓ ✓ ✓ ------

Label Care 28 NP Standard mg BID patients who are clinically recent MI, use of antiplatelet, Standard of of Standard ATTAC

NCT0441032 care suspicious for COVID-19 severe liver or kidney failure

1.5 mg/Kg/d Enoxaparin SC or 1

mg/Kg SC mg 40 Enoxaprin BID

200 U/Kg/d

Dalteparin SC or 100

5000 U 5000 U/Kg BID Age ≥18 yrs, hospitalized

Enoxaparin Invasive ventilation, HIT, high patients (anticipated to last Major Open bleeding risk, pregnancy, use 14- 3000 ≥72 hours), confirmed 30 bleeding NP ✓ NP NP ------Label of DAPT, bacterial 90 ✓ ✓ ✓ ✓ ✓ COVID-19 by HIT

ATTACC endocarditis, use of AC microbiological test NCT04372589 175 U/Kg Tinzaparin SC 4500 U 4500 Tinzaparin 14 or until hospital discharge hospital until or 14

80 units/kg

IV bolus UFH UFH followed BID

by 18 U 5000 units/kg/h

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Age ≥ 18 yrs, confirmed

COVID-19 by PCR or

other validated test who

Adjusted to U require hospitalization Open Bemiparin body 164 (CURB65<3 points; Sat. NP 10 10 NP NP NP NP NP ✓ ✓ NP NP NP NP ------Label

weight 3500 O2>90%), 3-4 points Bemiparin BEMICOP according to the WHO NCT04604327 ordinal scale, and D-dimer >500 ng/ml

Age ≥ 18 yrs, confirmed 19 - COVID-19 by RT-PCR or CrCl<30 ml/min, pregnancy, Bleeding patients who are clinically ICU admission, liver or Excluded Single events Bemiparin NP 120 suspicious for COVID-19) pancreas failure, high bleeding 10 10 28 NP NP NP NP NP Crcl<30m -- -- Blind Adverse ✓ ✓ ✓ ✓ with D-dimer > 500 ng/ml risk, bacterial endocarditis, use l/min

Bemiparin effects at the time of hospital of AC NCT04420299 Prophylactic dose Prophylactic BEMICOVID admission

Confirmed COVID-19 †, Aspirin+ 75 mg+ age ranged 40-85 yrs, or ACS, myocarditis, life

ACS Open - Clopidogrel+ 75 mg+ - 3170 diabetic, hypertensive or expectancy <3 months, NP 30 30 NP NP NP NP NP NP NP ------Label ✓ NP ✓ 19

- Rivaroxaban 2.5 mg BID coronary disease patients, pregnancy, high bleeding risk C hospitalized patients NCT04333407 No intervention No

Age ranged 18-80 yrs, Invasive ventilation, high Excluded

U confirmed severe COVID- 19 HD 19

- Open 70 U/Kg bleeding risk, HIT, pregnancy, if Enoxaparin 300 by RT PCR who have SIC 30 30 NP NP NP NP ✓ NP -- -- Label SC BID breastfeeding, use of DAPT, ✓ ✓ ✓ ✓ CrCl<30

4000 score>4 and D-dimer> 4

Enoxaparin CrCl<30 ml/min, age>80 years ml/min

ULN hospital Until NCT04408235 COVID discharge or 30 days 30 or discharge

20 mg (15

mg for 30 Age > 18 yrs, confirmed

ml/min moderate to severe 1.5 ULN and/or of DAPT, ticagrelor, prasugrel, CrCl<30 TnT > 2 ULN + CAD or aspirin>100 mg or NSAIDs ml/min) NCT04416048 DM or CS Reduce COVID to10mg 28

after 7 days LMWHUFH or Prophylactic

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Age > 18 yrs, confirmed MV, pregnancy, breastfeeding,

COVID-19 † who are liver failure, high bleeding risk, Single 100 mg hospitalized ≤ 72 hours therapy with cytokine Placebo 80 14 28 28 NP NP NP NP NP NP NP ------Blind QID and require supplemental inhibitors, antithrombotic, ✓ ✓ ✓ DICER oxygen ≤ 6 liters per SBP<90 mmHg, unlikely to Dipyridamole Every 6 hours 6 Every NCT04391179 minute by nasal cannula survive >48 hours

High bleeding risk, coagulation

abnormalities

Age ranged 18-80 yrs, if body DAPT, AC, major surgery < 1 confirmed moderate-severe Excluded U month; neurosurgery <3 70 U/kg COVID-19 †, respiratory Major if COVID

- Open Enoxaparin 300 months; eye surgery <3 28 30 NP ✓ ✓ NP NP ✓ ✓ ✓ NP ✓ -- BID failure (PaO2/FiO2 <250) bleeding CrCl<30

Label (6000 months, pregnancy, arterial

and/or increased D-dimer months 6 ml/min Enoxaparin U hypertension, CrCl <30 ml/min NCT04646655 weight>100 kg) weight>100 EMOS level (>2000 ng/mL) ICU admission or endotracheal

4000 intubation

1 mg/Kg

SC BID if CrCl≥30 ml/min Hospitalized patients, Enoxaparin 1 mg/Kg confirmed COVID-19 by

SC if RT PC or/ antigen test or

CrCl<30 suspected COVID-19 who MV, ESKD, history of HIT, ml/min meet the clinical criteria of pregnancy, high bleeding risk, Temp≥38℃ and O2 Sat≤94 hospital stay <72 hours, use of Open 5 mg BID 30- Major ✓ 3600 and existence of one AC, bleeding diatheses, NP 30 NP NP NP ✓ ✓ ✓ ✓ ✓ ✓ (excluded -- -- Label 90 bleeding 2.5 mg BID abnormal biomarker (D- bacterial endocarditis, clinical if ESKD) Enoxaparin dimer ≥1.0 μg /mL or CRP condition with short life NCT04512079 if at least >2 mg/L or ferritin >300 expectancy

FREEDOMCOVID two of three Apixaban of age ≥80 μg /L or lymphopenia years, <1500 cells /m3) weight ≤60

kg or serum mL/min<30 CrCl mgSCfor 30 mgSC; 40 creatinine ≥1.5 mg/dL

Age ≥ 18 yrs, confirmed Pregnancy, bleeding, advanced COVID-19†, patients with neurological impairment, HEP

- 25000 U Double Inhaled WHO ordinal scale of 3-5 advanced oncological disease, every 6 NP 656 21 28 7 NP NP NP ✓ NP NP NP NP ------Blind heparin who require hospitalization aPTT> 120 seconds, not due to ✓ ✓ hours but no immediate anticoagulant therapy, platelet 9 NCT04635241 INHALE

Standard of Care of Standard requirement for MV count <20 x 10 /L

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5000 U Age ranged 18-100 yrs,

every 8 confirmed or suspected of

Pregnancy, bleeding, advanced hours plus COVID-19 by CXR or CT Nebulized neurological impairment, Enoxaparin and with Open Heparin plus advanced oncological disease, ✓ 40mg /d or 200 at least one of the NP 15 60 NP NP ✓ NP NP NP NP ✓ ✓ ------Label SC aPTT> 120 seconds, not due to 60 mgSC 60

60mg/d, - following: Enoxaparin anticoagulant therapy, platelet Enoxaparin 40 NEBUHEPA adjusted by D-Dimer > 1ug/dl 9 NCT04530578 count <20 x 10 /L BMI and ferritin>500 ng/ml CrCl fibrinogen>50 mg/dl

Pregnancy, breastfeeding, high Age ranged 18-99 yrs, bleeding risk, severe liver Double LD: 60 mg 15- Major Prasugrel Placebo - 128 confirmed COVID-19 failure, cancer, 15 7 NP ✓ NP NP NP NP ✓ ✓ ✓ ------Blind then 10 mg 30 bleeding pneumonia† contraindications to use of

PARTISAN antiplatelet, Use of AC NCT04445623

Pregnancy, breastfeeding, high

bleeding risk, allergy to

aspirin, malignant tumors,

Open - Symptomatic COVID-19 blood diseases, liver failure, Aspirin 100 mg 128 14 NP NP NP NP NP NP NP NP NP NP ------Label (Fever, cough, RR>24) AIDS, viral hepatitis ✓ PEAC

cardiac stent placement (< 1 discharge 14 days after after days 14 NCT04365309 No intervention No year), alcohol abuse, other viral pneumonia coagulopathy 1.5 mg/Kg/dSC Enoxaparin

or 1 mg/Kg Age ≥ 18 yrs, confirmed

SC BID COVID-19 by RT-PCR, Pregnancy, NIPPV, MV, high 200 U/Kg/d hospitalized patients, Major Open bleeding risk, use of DAPT, Dalteparin SC or 100 462 elevated D-dimer≥2ULN 28 28 28 bleeding NP NP NP ✓ ✓ NP ✓ ✓ ✓ ✓ ✓ --

Label UFH pregnancy, history of HIT, use

U/Kg BID LMWH or D -dimer above ULN HIT of AC, ICU admission

175 U/Kg Fondaparinux and SaO2 ≤ 93% on room NCT04362085 Tinzaparin SC dose Prophylactic air

RAPID COVID COAG COVID RAPID Weight UFH based

LMWH NP

More than 14 days of hospital ✓ CAP

- NP Hospitalized patients, (Only Open Standard admission, patients expected to 21- 7100 suspected or confirmed 21 NP NP NP NP NP -- -- Label be discharged or dead in the 90 ✓ NP ✓ ✓ ✓ for UFH NP COVID-19† Prasu thromboprophylaxis next 24 hours discharge grel) REMAP NCT02735707

75-100 Aspirin mg/day - hospital until or days 14 No No interv Clopidogrel 75 mg/day ention

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60 mg LD then 10 mg (if <75 years and Prasugrel Wt>60 Kg ) and 5 mg (if >75 years or Wt<60 Kg) Ticagrelor 60 mg BID

Critical illness with WHO clinical improvement ordinal

Age ranged 40-75 yrs, score >5, AST/ALT > 240, confirmed COVID-19 by Open CPK > 5 ULN, prior aspirin Adverse Aspirin 75 mg NP 800 RT-PCR and WHO ordinal NP ✓ ✓ ✓ NP NP NP ✓ ✓ ------label use (within 30 days), high effects score 3 to 5 who require RESIST bleeding risk, pregnancy, hospitalization breastfeeding, unable to take

Conventional therapy Conventional oral or nasogastric medications CTRI/2020/07/026791 CTRI/2020/07/026791 10 days or until discharge until or days 10 discharge until or days 10 discharge until or days 10

Pregnancy, breastfeeding, Age ≥ 18 year, confirmed QTc>500ms, heart electrical

Fadj † Excluded - COVID-19 pneumonia dysfunction, clinically Open 0.1-0.2 10- if Nafamostat - 186 with clinical status from 3 significant heart diseases, 7 15 NP NP NP NP NP NP ✓ NP ✓ ✓ -- --

CoV label mg/kg/h 14 CrCl<30 - to 5 on the seven-category Child-Puch score B or C, CrCl ml/min ordinal scale < 30 mL/min, liver failure, NCT04390594 Standard of care of Standard SEN HIV infection

Excluded Age > 18 year, confirmed CrCl<15 ml/min, ICU Open 40 mg SC if Enoxaparin 2712 COVID-19 †, hospitalized admission NP 30 30 NP NP NP NP NP NP -- -- Label BID ✓ ✓ ✓ ✓ CrCl<15 Covid 19 Covid

- patients use of AC 40 mgSC 40 ml/min Enoxaparin X NCT04366960

high bleeding risk, use of Age ranged 18-100 yrs,

therapeutic AC or DAPT, HD, confirmed COVID-19†, GFR<30 ml/min, cirrhosis or Excluded Not requiring full liver failure, hepatorenal Bleeding if Open Rivaroxaban 10 mg 150 therapeutic AC, Not be 28 30 30 NP ✓ NP NP NP NP -- -- syndrome, use events ✓ ✓ ✓ CrCl<30 XACT XACT Label intubated, Immunosuppressants, life ml/min Enoxaparin Not be admitted for CNS NCT04640181 expectancy of less than 6 diagnosis 40 mg or 40 mgBID 40 mgor 40 months

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20 mg Enoxaparin 1 mg/KgBID 1

Pregnancy, breastfeeding, Age > 18 years, confirmed ECMO, MV, multiple organ

COVID -19 by chest failure, CrCl<30 ml/min, Child Excluded imaging and RT-PCR with Pugh score ≥ 10 , infections,

Open 0.1 if 0 Nafamostat 40 Respiratory rate 15 to 30 high bleeding risk, altered 10 14 28 NP NP NP NP NP NP NP -- -- label mg/kg/hr ✓ ✓ ✓ CrCl<30 breaths/minute SaO2- mental state, retinopathy or

1mg/kg SC1mg/kg ml/min Enoxaparin SpO2 90%-94% OR PaO2/ macular degeneration, G6PD FiO2: 200- 300 mmHg deficiency, HI , at risk of CTRI/2020/06/02622 arrhythmia

Age ranged 18-65y, confirmed COVID-19 by MV, pregnancy, breastfeeding, Bleeding Blind Aspirin 75 mg NP 60 10 7 28 NP ✓ NP NP NP NP ✓ ✓ NP ------care laboratory findings with high bleeding risk events

8/027503 SpO2 < 94% Standard of of Standard CTRI/2020/0

Pregnancy, high bleeding risk

14 Age ≥ 18 year, confirmed - allergy to LMWH, BMI>40 Open COVID-19 by PCR, bleeding Enoxaparin NP 140 Kg/m2. AC therapy, high-flow NP 30 30 NP ✓ NP NP NP NP NP ------Label hospitalized patients, events ✓ ✓ oxygen therapy or MV at the 001891 40 mgSC 40 weight ≥60 Kg Enoxaparin -

EUCTR2020 time of study recruitment

2 ; 30 2

kg/m

1 mg/kg SC Age ranged 18-100 yrs, if BMI <30 ✓ confirmed COVID-19 by kg/m2 or CrCl<30 ml/min, high bleeding Excluded

Open laboratory findings, Major Enoxaparin 0.5mg/kg 170 risk, history of HIT, weight<40 NP 30 30 NP NP NP NP NP NP -- Label hospitalized patients, Bleeding ✓ ✓ ✓ if ✓ SC BID if Kg, AKI CrCl<30

Enoxaparin modified ISTH Overt DIC BMI ≥ ml/min NCT04360824 score ≥ 3 30kg/m2 mg BID or 40 mg BID BMI ≥ 30 30 ≥ BMI BID mg 40 or BID mg 40 mg subcutaneously if BMI <30 kg/m BMI<30 if mgsubcutaneously 40

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4 mg/kg IV Age ranged 18-85 yrs, MV, high bleeding risk, use of Exclude bolus confirmed COVID-19 by Double corticosteroid, AC, antiplatelet, if Dociparastat followed by Placebo - 600 RT-PCR, SaO2 < 94%, 7 28 28 NP NP NP NP NP NP NP -- -- Blind immunomodulators, liver ✓ ✓ ✓ CrCl<30 continuous Require supplemental O2 failure, CrCl<30 ml/min ml/min IV infusion or NIV NCT04389840

Age ≥ 18 year, confirmed Imminence of orotracheal 1mg/kg COVID-19 by RT-PCR or Enoxaparin intubation, high bleeding risk, ✓For BID serology, Lung image with Open pregnancy, breastfeeding, 28 90 CrCl<40 NP 268 involvement of at least 7 NP NP ✓ NP ✓ NP NP NP NP ✓ -- -- Label bleeding, HD,QT interval ml/min 25%, O2sat < 93%, aPTT 1.5- 2 prolongation, use of UFH UFH alteration in D-dimer, NCT04485429 X care of Standard therapeutic AC CRP, Ferritin, LDH

1 mg/Kg Enoxaparin

SC BID Excluded Enoxaparin

1 mg/KgSC 1 Age > 18yrs, confirmed Pregnancy, cancer, CKD stage CKD Double COVID-19 by RQ-PCR, III or stage III

130 30 30 NP NP NP NP NP NP NP NP -- -- Blind hospitalized patients who ESKD, high bleeding risk, ✓ ✓ ✓ or require supplemental O2 Age>75 years, Use of AC ESKD

NCT04508439 Rivaroxaban 10 mg - No intervention No

Serious chronic disease,

Age ≥ 18yrs, confirmed pregnancy, breastfeeding, MV, COVID-19 by RT-PCR HIV infection, corticosteroid Excluded Open within 3 days, with therapy, child-Pugh B or C, Nafamostat NP NP 100 NP 28 28 NP NP NP NP NP NP NP Crcl<30 -- -- label Clinical status of 4 or 5 on hyperkalemia, liver failure, ✓ ✓ ✓ ml/min the seven-category ordinal CrCl < 30 ml/min, QTc NCT04628143

Standard of care of Standard scale >500ms, rapidly deteriorating clinical condition

Malignancies, heart, liver failure, kidney diseases, poorly controlled metabolic diseases, Excluded 1,000 U/kg) Age ranged 18-60 yrs, Nebulized pregnancy, breastfeeding, if NP every 6 NP 100 confirmed COVID-19 by 7 7 14 NP NP NP NP NP NP NP NP NP -- -- UFH Child Pugh C, , CrCl<30 ✓ CrCl<30

PACTR hours PCR within 24 hours ml/min, dialysis, HIT, high ml/min

Standard of care of Standard bleeding risk, mild and severe 202007606032743 COVID-19 Ongoing trials in ICU setting

To target Age ≥ 18 years, - Contraindication to use of

aPTT or hospitalized patients, ✓

§ Open anticoagulant, use of UFH anti-Xa 2000 confirmed COVID-19 by 21 90 Bleeding NP ✓ ✓ ✓ NP NP ✓ ✓ ✓ For ✓ -- 4a until until 5774 Label therapeutic anticoagulation or lation of care of days or or days ic Dose (0.3-0.7 positive microbiological hospital Standard Standard ACTIV CrCl<30 discharge NCT0450 Anticoagu Prophylact DAPT, high bleeding risk, 14 least At U/mL) test within 72 hours,

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1 mg/kg SC expected to require pregnancy, requirement for ml/min BID hospitalization for > 72 chronic MV, imminent death UFH Enoxaparin or hours 1.5 mg/kg SC 200 units/kg SC or Dalteparin 100 units/kg SC BID 175 Tinzaparin units/kg SC

CO Age ≥ 18 years, confirmed - Double Pregnancy, inherited Bivalirudin NP NP 100 COVID-19†, 3 3 3 NP NP NP NP NP NP NP NP NP -- Blind coagulation abnormality ✓ ✓ ✓ MV, D-dimer>1.2 mg/L ANTI NCT04445935 Standard of care of Standard

Confirmed COVID-19 †, P/F ratio <200 mmHg> 70

25 mg IV mmHg, CT scan positive Age < 18, high bleeding risk, over

for pulmonary thrombosis pregnancy, breastfeeding, Alteplase 2hours, Exclude Double or CT scan negative for severe vasoplegic shock: NEP followed by followed by NP 50 1 3 28 NP NP ✓ NP NP NP NP NP NP ✓ GFR<30 -- -- Blind pulmonary thrombosis > 300 ng/kg*min, GFR<30 AtTAC UFH a 25 mg infusion ml/min with ml/min, Contraindication to over NCT04453371

Ringer's solution solution Ringer's D-Dimer > 10 mcg/mL, or use of anticoagulant 22hours 5 < D-dimer < 10 mcg/mL and CRP> 100 mg/dL

19

-

Age ranged 18-99 yrs, 325 mg Exclude Open confirmed CrCl<30 ml/min, severe Aspirin every 6 NP 34 NP NP NP NP NP NP NP GFR<30 -- -- Covid † ✓ ✓ ✓

- label COVID-19 , hospitalized asthma, severe COPD 28088 hours ml/min patients with SaO2 <90% months 4 months 3 Until discharge Until Standard of care of Standard CAM CTRI/2020/09/0 Age>18 years, confirmed

High bleeding risk, pregnancy, or suspected COVID-19†, Irl

- ECMO or HFOV, myopathy, ICU admission 25000 U spinal cord injury, or nerve

Open Nebulized intubation (<24hour) every 6 40 injury or disease, imminent 10 60 60 ADR NP NP NP NP NP NP ------Label heparin PaO2/FiO2<300, acute ✓ ✓ ✓ hours death, NP opacities on chest imaging the use or anticipated use of NCT04511923 CHARTER Standard of care of Standard affecting at least one lung nebulized tobramycin quadrant

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- Age > 18 years, Nebulise confirmed COVID-19 by High bleeding risk, pregnancy,

25000 U Double Nebulized d 0.9% PCR or CXR or CT, ICU ECMO or HFOV, myopathy, every 6 202 10 28 NP NP NP NP NP NP ✓ NP NP NP NP ------MT

Blind heparin Sodium hours admission, intubation spinal cord injury, or nerve hours Chloride (<24hour) injury or disease 5 ml every 6 every ml 5 CHARTER

NCT04545541 PaO2/FiO2<300

4000 U 4000 Enoxaparin Tinzaparin 175 U/kg

§ Not requiring ICU at

admission with mild

3500 U 3500

COAG disease to severe Tinzaparin - pneumopathy with CrCl<20 Open High bleeding risk, HIT, 808 symptom onset before 14 14 14 90 Bleeding NP NP ✓ NP NP NP ml/min -- -- Label endocarditis ✓ ✓ ✓

days, with need O2 but no UFH

U NIV or high flow, ICU NCT04344756 admission

5000 with MV and DNR order CORIMMUNO Dalteparin anti-Xa 0.5 UFH - 0.7 U/mL

Heparin ml/min) 5000 U BIDU 5000 (forCrCl <30

Confirmed or probable Previous coagulopathy or

†

COVID-19 , thrombophilia, risk of citrate

Hep Open 10U / Kg / presence of AKI with poisoning (Lactate> 30mg / dL, - 0 UFH 90 NP 3 3 NP NP NP NP NP NP NP NP -- -- Label h indication for renal RNI> 2.5, total bilirubin> NP ✓ ✓ citrate Sodium Sodium CoV

4 mmol / L mmol/ 4 continuous venous venous 15mg / dL), pregnancy, NCT0448799 hemodialysis. contraindication to use of UFH

High bleeding risk, CrCl<15

ml/min, AKI, use of §

prophylactic AC > 3 days or 4000 U SC Probable or confirmed therapeutic AC > 1day, ECMO 28 Single BID Bleeding DOSE

- Enoxaparin 602 COVID-19 by PCR or required, HIT, impossibility to NP 28 + NP NP NP NP NP -- Blind (Weight ✓ ✓ ✓ ✓ ✓ ✓ serology perform a doppler ultrasound, 60 based) Enoxaparin ICUsetting) contraindication to use of NCT04373707 COVI LMWH or blood-derived setting) andBID (for setting) 4000 U SC (for ward ward SC(for U 4000 products

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Tinzaparin NP NP Tinzaparin

Dalteparin NP NP Dalteparin

Nadroparin NP NP Nadroparin

UFH UFH

§ Single confirmed COVID-19†, High bleeding risk, HIT,

HEP ✓

- Blind, Non-ICU with D-dimer> endocarditis, use of DAPT or NP 200 30 30 Bleeding NP NP NP NP NP NP ------Open 1000 ng/mL or therapeutic AC, pregnancy, Wt ✓ ✓ AR Label ICU <40kg or >150kg DS NCT04345848 Until discharge Until COVID Enoxaparin LMWH Prophylactic anticoagulation Prophylactic

1mg/kg Enoxaparin BID aPTT 1.5 -

UFH 2.5 X NP

Enoxaparin 1mg/kg 40 mgSC 40

+ BID + 75 Enoxaparin High bleeding risk, use of Clopidogrel mg Age ≥ 18 years, confirmed DAPT or antiplatelet or PACT

- Open 750 COVID-19†, ICU therapeutic AC, HIT, NP NP ✓ NP NP ✓ NP ✓ NP NP ------Label aPTT 1.5- admission contraindication to use of UFH + 2.5 X + 75 antithrombotic agents NCT04409834 COVID Clopidogrel

mg DISCHARGE or 28 DISCHARGE or 28 Enoxaparin

40 mg + 75 TID SC + UFH mg U Clopidogrel

UFH + 5000 TDS 5,000 Clopidogrel + 75 mg

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50 U/Kg

SC BID § -

Age ≥ 18 years, confirmed

(For ward high bleeding risk, liver failure, ✓

28 COVID-19 by - 2020 setting) CrCl<20 ml/min, pregnancy, (UFH for - Open 210 radiographic infiltrates or Adverse Antico

- LMWH LMWH breastfeeding, bacterial 28 - NP NP NP NP ✓ NP ✓ ✓ CrCl<15 -- -- Label clinically findings and events 75 U/Kg endocarditis, Therapeutic AC, ml/min) discharge

001739 SpO2 ≤ 94% or require BID (For SCU/Kg 50 alcoholism ✓ EUCTR 15 days or until until or days 15

DAWn oxygen support ICU setting) Severe, progressive, and/or uncontrolled cardiac disease

(NYHA class IV), DM,

significant electrolyte Age > 16 years, confirmed disturbance, eGFR <30 Single 0.2mg/kg/h Adverse Nafamostat NP 60 COVID-19 † mL/min/1.73 m2, dialysis, 90 NP NP NP NP NP NP NP -- -- Blind r events ✓ ✓ ✓ severe liver failure, bone 6 months 6 DEFINE marrow failure, breastfeeding, NCT04473053 Standard of Care of Standard

pregnancy, use of AC or 7 to up or discharge antiplatelet, receiving potassium sparing diuretics

SC

UFH U BID/TID

5000 U BID/TID or 7500 7500 or BID/TID

1mg/kg Age ≥ 18 years, confirmed NP § BID (0.5 COVID-19 by PCR or

High bleeding risk, pregnancy, mg/kg BID serology, within 72 hours Double use of DAPT or therapeutic AC Enoxaparin for 15 308 of hospital admission, need NP 30 30 Bleeding NP NP NP ✓ NP ✓ ✓ ✓ ✓ -- -- COVID

- Blind CrCl<15 ml/min, liver failure, ml/mi < for oxygen have: HIT

GFR < 30 BID) SC D- Dimer > 4.0 X ULN or NCT04401293 HEP Enoxaparin ml/mi) (0.5mg/kg BID SIC ≥ 4 or or 30mg and 40mgSC 30mgand

or or

U U 5000 2500 Dalteparin

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18 U/kg/h (To target

aPTT 1.5-2 /kg/h *reference U 18

value) target aPTT 1.5

UFH + value) *reference UFH Tocilizumab (To

Hospitalized patients,

§ confirmed COVID-19 by PCR within 10 days or by High bleeding risk, history of 5,000 U every Open

every 8 U 308 CXR or CT, need for ≥ 4 L HIT, pregnancy, breastfeeding, NP 30 90 NP NP NP NP ✓ NP ✓ ✓ ✓ ✓ ------Label

hours hours 8 of supplemental oxygen to use of therapeutic AC

HEPMAB maintain SaO2≥93% or 5,000 5,000 NCT04600141 need MV

1 mg/Kg SC BID

Enoxaparin BID SC 1 mg/Kg 1 +

Tocilizumab Enoxaparin 40 mg 40 mg 40

LMWH NP LMWH

Dose

Prophylactic Prophylactic

§ Confirmed COVID-19 †, ✓ 19 Use of therapeutic AC, - Double hospitalization on ward or Exclude 172 GFR<15 ml/min, high bleeding NP 42 42 NP NP NP NP NP -- -- Blind ICU, COVID-19 with Tn> ✓ ✓ ✓ ✓ ✓ risk GFR < 15 ULN or D-dimer> 0.5 ml/min HERO Edoxaban

NCT04542408 (After 60 mg OD Placebo - DISCHARG E)

High bleeding risk, GFR< 10 Confirmed COVID-19 by To target ml/min, Age> 85 years, RT-PCR, severe

aPTT (1.5- kg) 20 circulatory shock, liver failure, UFH for Open respiratory failure 949z6v UFH 2 * UFH 20 active cancer, HF (NYHA III, 4 28 28 Bleeding NP NP NP NP GFR < 10 -- - ✓ ✓ ✓ ✓ ✓ Label requiring MV, D-dimer> reference IV class), chronic disease, ml/min 1000 microg/L

RBR value) pregnancy, use of therapeutic HESACOVID

weight> 1 weight> (>7500U TDS for AC 5000 U every 8 hours 8 every U 5000 ✓

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1 mg/kg BID 7- Enoxaparin (weight and 10 age Enoxaparin adjusted) for BID SC weight > 120 kg) 120 > weight 40 mg SC (40 mg mgSC(40 40

aPTT goal or antiXa UFH UFH 0.3-0.7

U/mL (ForAKI) 7500 U TDSU 7500

1 mg/kg Age > 18 years, confirmed

Enoxaparin BID vs. 0.5 COVID-19 by RT-PCR,

§ mg/kg BID serology, ICU or non-ICU ✓ mL/min) Enoxaparin on MV or BiPAP, 100% High bleeding ris, DVT or PE, Open ✓ For 186 non-rebreather mask, or use of therapeutic NP 30 Bleeding NP NP NP NP NP NP -- Label ✓ NP ✓ AKI UFH fonda 0.5 mg/kg SC BID (0.5 (0.5 SCBID mg/kg 0.5 mg/kg SC for CrcL< 30 30 CrcL< for SC mg/kg high flow oxygen or anticoagulation parinu 6 months 6 IMPACT oxygen of at least 4 L/min x NCT04406389 ≥100 kg: nasal, D-dimer> 700 10mg ng/mL <100 kg

but ≥50 kg: 7.5 mg

Fondaparinux <50 kg: ymg Fondaparinux

Argatroban NP HIT) mgSC(If 2.5

High bleeding risk, wt <50 kg, Age ranged 18-80 yrs, ✓ severe chronic liver failure, If 10 U/kg/h confirmed COVID-19 by Single contraindication to use of GFR<30 (for UFH anti-Xa 0.1 UFH 100 RT-PCR, ICU admission NP 30 30 Bleeding NP NP NP NP NP NP -- Blind anticoagulant, congenital ✓ ✓ ✓ ml/min: comp -0.3 U/mL within 5 days, not on arator 40 mgSC 40 bleeding diatheses, DNR /DNI UFH IMPROVE (Adjustedto therapeutic anticoagulation ) BMI and GFR) and BMI NCT04367831 or CMO orders

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Enoxaparin 1 mg/kg SC Enoxaparin (Adjustedto BMI and GFR) and BMI 5000 U SCBIDU 5000

For CrCl ≤ 15 mg/dL: UFH UFH 10000 U SC BID mg/dL: For CrCl ≤ 15 15 ≤ CrCl For

5000 USCBID 5000 High bleeding risk, history of

HIT or immune

Age ≥ 18 years, confirmed thrombocytopenia, use of AC Single COVID-19 by PCR, ICU for another indications, Blind, 1 mg/kg SC admitted within 7 days, not (CrCl> 600 ischemic stroke in the past 2 30 30 30 ✓ NP NP NP NP ✓ NP ✓ ✓ ✓ ✓ ✓ --

Open have another indication for weeks, pregnancy, Wt <40 kg, Label 30ml/min anticoagulation, estimated Wt>120 kg or BMI > 35 kg/m2

NCT04486508 and

INSPIRATION survival of at least 24 h weight< with CrCl<30 ml/min Enoxaparin 120kg) Adjusted Enoxaparin

based 120kg) weight< weight and CrCl 40 mg SC (CrCl> 30ml/min and and 30ml/min mgSC(CrCl> 40 Adjusted based weight and CrCl CrCl and weight based Adjusted

Pregnancy, breastfeeding,

Age ranged 18-75 yrs, eGFR < 30 ml/m, liver failure

hospitalized Patients, (Child-Pugh score> 10), confirmed COVID-19 † , requiring high doses of loop Excluded SaO2 ≤94% or PaO2/FiO2 Double diuretics (i.e., > 240 mg eGFR < Nafamostat Placebo - 256 ratio ≤300 mmHg but > NP 28 28 NP NP NP NP NP NP NP NP -- Blind furosemide daily), HIT, ✓ ✓ 30 ✓ 100 mmHg, if patient on

RACONA bleeding, unstable ml/min supplemental oxygen or NCT04352400 hemodynamic, CVD, ECMO, SpO2/FiO2<200 if no Continuous Infusion Continuous hyperkalemia, uncontrolled ABG available comorbidities

§ Age <18 years, known

Hospitalized patients, hypersensitivity to aspirin, Open confirmed COVID-19 by recent major bleeding that Aspirin 150 mg NP 28 Bleeding NP NP NP NP NP NP ------Label clinically suspected or precludes use of aspirin, ✓ ✓ ✓ 20000

laboratory current use of antiplatelet months 6 NCT04381936 Until discharge Until RECOVERY

Standard of Care of Standard therapy

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50 mg (10 mg bolus Age ranged 18-75 yrs, High bleeding risk, known +40 mg patients on MV for ≤ 10

contraindications for over 2 days with PaO2/FiO2 ratio thrombolytics, MI in the last 3

hours) < 150 or inferred Alteplase weeks or cardiac arrest during Exclude Open PaO2/FiO2 ratio from SpO2 Bleeding followed by NP 60 hospitalization, hemodynamic 2 28 NP NP NP NP NP AKI on -- -- Label if ABG is unavailable ✓ NP ✓ ✓ 2 hours 2

STARS UFH instability, acute renal failure HD persisting for > 4 hours requiring dialysis, liver failure, NCT04357730

Standard of Care of Standard despite optimal MV tamponade, endocarditis, + neurologic exam without 100 mg (10 pregnancy mg bolus focal signs or new deficit +90 mg over 2 hours)

25 over 22

Alteplase hors then Age ranged 15-70 yrs,

followed by 25 mg for COVID 19 patients † with 1 Single UFH next 22 P/F ratio <100 and Control - 15 High bleeding risk 6 NP NP NP NP NP NP NP NP NP ------blinded hours D.dimer > 3000 without ✓ ✓ 7456N1 response to other

TACOVID To Target UFH aPTT more medications NP IRCT2020051504 than 50

Age ≥ 18 years, confirmed High bleeding risk, pregnancy, § COVID-19 by RT-PCR in Open 100 mg MV, existing severe medical NP 100 3 levels: 7 9 9 NP NP NP NP NP NP NP ------Label TDS illnesses unrelated to COVID- ✓ ✓ ✓

TOLD Moderate 19

Dipyridamole Severe NCT04424901 Standard of Care of Standard Critical

Age ≥ 18 years (UK: age ≥ 16 years), confirmed

COVID-19 by RT-PCR,

ARDS with 100< Chronic MV (>48 hours), Low dose PaO2/FiO2 ratio ≤300, chronic pulmonary disease, PE Bleeding Open Alteplase NP 270 either on non-invasive with hemodynamic instability, 5 28 28 NP NP NP NP NP NP ------✓ ✓ ✓ Label ventilator support, OR on use of OAC, high bleeding

TRISTARDS mechanical ventilation risk, DNI or DNR NCT04640194 Standard of Care of Standard (<48 hours since intubation), High dose Fibrinogen level ≥ ULN D-Dimer ≥ 3*ULN

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25-50 mg Confirmed COVID-19 by

over 2 laboratory confirmation, High bleeding risk, severe hours IV infection clinical and renal disease (GFR<50 Alteplase infusion by Excluded radiological confirmation ml/min), severe liver failure ✓ Open followed by 25-50 /22 NP 30 1 28 ADR NP NP ✓ ✓ ✓ NP NP ✓ GFR< 50 -- --

80N1 of ARDS (PaO2/FiO2≤300 (Child-Pugh score > 12), not Label enoxaparin hours up to ml/min or SaO2≤ 315mmHg or expected to survive the next 24 maximum until discharge until

Standard of Care of Standard CPAP≥ 5 cmH2O, or non- hours dose of 0.9 IRCT202004150470 ventilated) mg/kg/d

Age> 18 years, confirmed § COVID-19†, ward or ICU ARDS, high bleeding risk, UFH NP admission without severe Recei Open Care HIT, therapeutic AC, NSAIDs, Receive NP 300 ARDS (P/F ratio<100) NP 84 84 Bleeding NP NP NP NP ✓ ✓ NP NP NP ve -- Label of Standard HCQ, antihistamine, UFH D-dimer > 1.5 g/mL UFH pregnancy, use of AC, aspirin Fibrinogen > 100 mg/dL NCT04377997 LMWH Platelet>50000 /mm3

Age> 18 years

25000 U , ICU Admission,

Double Nebulized High bleeding risk, Adverse 0 every 6 50 confirmed COVID-19 by 10 10 30 NP ✓ NP NP ✓ NP NP ✓ ✓ ------

Blind Heparin hours O2 dependent at baseline events hours PCR, MV for ≤ 48 hrs, Chloride 5 mL every 6 mLevery 5 0.9% Sodium 0.9%

NCT0439751 PaO2/FiO2 ≤300

Age ranged 18-85 yrs, confirmed COVID-19 by Pregnancy, Breastfeeding, Open 0.1-0.2 10- Adverse Nafamostat NP 84 RT-PCR or chest CT Child-Pugh B or C or liver 28 28 NP NP NP ✓ NP NP ------Label mg/kg/h 14 events ✓ ✓ ✓

therapy within 3 days, hospitalized failure, HIV or AIDS

Conventional Conventional patients NCT04418128

Age ranged 18-75 yrs, High bleeding risk, pregnancy, 0.25 mg/kg confirmed COVID-19 by Double Tenecteplase breastfeeding, liver failure, Placebo - 60 PCR within 14 days, D- NP 28 28 Bleeding NP NP ✓ NP NP NP ------Blind + UFH Child-Pugh B or C, use of ✓ ✓ ✓ dimer> 6 ULN, need therapeutic AC, MV> 24 hrs respiratory support NCT04505592 0.50 mg/kg

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D-dimer <1 mg/dl Weight: dose <100kg: 40mg 100-150kg:

40mg BID >150kg

§ 60mg BID

High bleeding risk, history of D-dimer 1- Confirmed COVID-19 by HIT, pregnancy, CrCl<30 Single 3 PCR, hospitalized patients ml/min, AKI, use of DAPT Enoxaparin 50 NP NP NP NP NP NP NP NP -- -- Blind mg/ dl in ward or ICU therapy, bacterial endocarditis, ✓ ✓ ✓ ✓

Weight: Enoxaparin contraindication to use of NCT04584580 dose SCBID mg/kg 1 antithrombotic agents <100kg: 40mg BID discharge until or days 28 discharge until or days 28 150kg: 80mg BID >150kg: 120mg BID D-dimer >3 mg/ dl 80mg BID

Breastfeeding, pregnancy, high bleeding risk, Child-Pugh B or Age> 18 years Exculded Open C, liver failure, eGFR< Nafamostat NP 100 Confirmed COVID-19 by NP 28 28 NP NP NP NP NP NP NP NP eGFR< -- -- label 30ml/min and hemodialysis or ✓ ✓ CXR or CT 30ml/min hemofiltration, chronic disease, NCT04623021

Standard of care of Standard QTc>500 msec, HIV or AIDS Continuous Infusion Continuous

Ongoing trials in post-discharge setting Contraindication to use of

antithrombotic agents, use of

4c AC or DAPT, high bleeding

- Confirmed COVID-19 by ✓ Double risk, eGFR < 30 mL/min, Major Exclude Apixaban 2.5 mg BID Placebo - 5320 PCR, hospitalized for 48 30 30 90 NP NP NP NP ✓ NP ✓ NP ✓ -- ✓ Blind pregnancy, life expectancy < bleeding hours or more hours CrCl<30

ACTIV 3months, strong ml/min \

NCT04650087 inducers/inhibitors of p-gp or CYP3A4

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Age>18 years, confirmed

Use of therapeutic AC, high

COVID-19 by RT-PCR, bleeding risk active cancer, pneumonia and modified pregnancy, breastfeeding, HIV 35 35 35 Open IMPROVE risk score of 4 Major Rivaroxaban 10 mg - 320 infection, unstable +/- +/- +/- NP NP NP NP NP NP NP NP -- -- label or higher who have bleeding ✓ ✓ cardiovascular diseases, 4 4 4 received CrCl<30 ml/min, use of strong MICHELLE NCT04662684 No intervention No thromboprophylaxis during CYP3A4 and PGP inhibitors hospitalization

*The full list of inclusion and exclusion criteria should be found in the original trial records. †Not mentioned at the registration platform. ‡Not pointed. §The joint RCTs of ICU and non-ICU settings come in the ICU part of the table only. ABG: Arterial Blood Gas, AC: Anticoagulant, AIDS: Acquired Immunodeficiency Syndrome, AKI: Acute Kidney Injury, APS: Antiphospholipid Antibody Syndrome, ARDS: Acute Respiratory Distress Syndrome, BiPAP: Biphasic Intermittent Positive Airway Pressure, BMI: Body Mass Index, CAD: Coronary Artery Disease, CBC: Complete Blood Count, CHF: Congestive Heart Failure, CKD: Chronic Kidney Disease, COPD: Chronic Obstructive Pulmonary Disease, COVID-19: Coronavirus Disease 2019, CMO: Comfort Measures Only, CPK: Creatine Phosphokinase, CrCl: Creatinine Clearance, CRP: C-Reactive Protein, CS: Current Smoker, CT: Computerized Tomography, CVD: Cardiovascular Disease, DAPT: Dual Antiplatelet Therapy, DDI: Drug- Drug Interaction, DIC: Disseminated Intravascular Coagulation, DM: Diabetes Mellitus, DNI: Do Not Intubate, DNR: Do Not Resuscitate, DVT: Deep Vein Thrombosis, ECMO: Extracorporeal Membrane Oxygenation, eGFR: estimated Glomerular Filtration Rate, ER: Extended Release, ESKD: End-Stage Kidney Disease, ESR: Erythrocyte Sedimentation Rate, GFR: Glomerular Filtration Rate, Hgb: Hemoglobin, HCQ: Hydroxychloroquine, HD: Hemodialysis, HFOV: high frequency oscillatory ventilation, HIV: Human Immunodeficiency Virus, HIT: Heparin‐Induced Thrombocytopenia, HTN: Hypertension, I: Intermediate, ICH: Intracerebral Hemorrhage, ICU: Intensive Care Unit, IL-1: Interleukin-1, IL- 6: Interleukin-6, IMPROVE: International Medical Prevention Registry on Venous Thromboembolism, INR: International Normalized Ratio, ISTH: International Society of Thrombosis and Haemostasis, IU: International Unit, IV: Intravenous, G6PD: Glucose-6-Phosphate Dehydrogenase, GIB: Gastrointestinal Bleeding, LD: Loading Dose, LDH: Lactate Dehydrogenase, LFT: Liver Function Tests, LMWH: Low Molecular Weight Heparin, L/N ratio: Lymphocyte/Neutrophil ratio, LRU: Lipoprotein Lipase Releasing Units, MI: Myocardial Ischemia, MV: Mechanical Ventilation, NEP: Norepinephrine, NIPPV: Nasal Intermittent Positive Pressure Ventilation, NIV: Non-Invasive Ventilation, NP: Not Provided, NSAID: Nonsteroidal Anti-Inflammatory Drug, NT-proBNP: N-Terminal-pro hormone B-type Natriuretic Peptide, O2 Sat: Oxygen Saturation Level, P: Prophylactic, PCI: Percutaneous Coronary Intervention, PCR: Polymerase Chain Reaction, PE: Pulmonary Embolism, P/F ratio (PaO2/FiO2) ratio: The ratio of arterial oxygen partial pressure to fractional inspired oxygen, PHV: Prosthetic Heart Valve, RR: Respiratory Rate, RVD: Right Ventricular Dysfunction, RQ-PCR: Real-time Quantitative Polymerase Chain Reaction, RT-PCR: Reverse Transcription Polymerase Chain Reaction, SARS-CoV-2: Severe Acute Respiratory Syndrome-Coronavirus-2, SC: Sub Cutaneous, SCr: Serum Creatinine, SIC: Sepsis-Induced Coagulopathy, SpO2: Peripheral Oxygen Saturation, T: Therapeutic, Temp: Temperature, TIA: Transient Ischemic Attack, TnT: Troponin T, tPA: tissue-Plasminogen Activator, UFH: Unfractionated Heparin, ULN: Upper Limit Normal, VTE: Venous Thromboembolism, WBC: White Blood Cell, Wt: Weight

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Supplemental Table 3. The intensities of heparin derivatives In the Studied RCTs Renal Dose Drug Standard Dose Weight Adjustment Adjustment Standard prophylaxis with heparin-based regimens across trials medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holderExclude for this the preprint use of (which was not certified by peer review) is the author/funder, who has granted medRxivIf weight a license ≥ 100 to kg:display the preprintenoxaparin in perpetuity. in patients Enoxaparin 40 mg SC daily 1, 2 All rights reserved. No reuse allowed without40 permission. mg SC BD 1 with CrCl<30 mL/min 1, 2 Intermediate dose heparin-based regimens across trials Double dose of standard Prophylactic Weight adjusted *,3 15

90 mg BID 131–150 kg †,10 100 mg BID 151–170 kg CrCl> 30 mL/min 110 mg BID †,10 171–180 kg †,10 40 mg daily 41–80 kg 15 < CrCl ≤ 30 mg /dL 50 mg daily 81–100 kg †,10 60 mg daily †,10 101–110 kg †,10 Double dose of standard prophylactic 15120 kgI mg/dL 10 Fully-therapeutic anticoagulation across trials

Bemiparin Weight based ‡,12 NP NP 200 U/Kg SC Daily or BMI ≥ 40kg/m2: Exclude CrCl<30 Dalteparin 100 U/Kg SC BD 13, 14 100 U/Kg SC BD 14 mL/min 14 Exclude CrCl<40 1 mg/Kg SC BD 13, 14, 15, 16, 17, 18, 19, 20, BMI ≥ 40kg/m2: mL/min 17 Enoxaparin 21, 22 1 mg/Kg SC BD 14 Exclude CrCl<30 mL/min 14, 15

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Excluded if ESKD 16, 18, 20 Age (Years) 23 No adjustment for weight23 CrCl <75 >75 1 mg/kg BD 0.75 mg/kg/BD NP 23 > 50 mL/min 23 0.75 mg/kg/BD 1 mg/kg/daily NP 23 30 - 50 mL/min medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified 1by mg/kg/daily peer review) is the author/funder,0.75 mg/kg who daily has granted medRxiv aNP license 23 to display the preprint in10 perpetuity. - 30 mL/mi All rights reserved. No reuse allowed without permission. 1.5 mg/Kg SC Daily 13, 14 Excluded weight <40 kg and > 1 mg/Kg SC QD if 150 kg 24 CrCl<30 mL/min 16 0.5 mg/kg BD for 15 < GFR < 30 mL/min 20 D-dimer (mg/dl) 25 Excluded CrCl<30 <1 1-3 >3 Weight 25 mL/min 25

80mg 40mg daily 40mg BD < 100 kg BD

40mg BD 80mg BD 80mg 100-150 kg BD

120mg 80mg > 150 kg 60mg BD BD BD Exclude CrCl<30 BMI ≥ 40kg/m2: mL/min 14 Tinzaparin 175 U/Kg SC daily 13, 14, 26 175 U/Kg SC daily 14 Exclude CrCl<20 mL/min 26 Exclude CrCl<30 18 U/kg/hour 21 mL/min 15 To target aPTT 13, 14, 15, 17, 19, 21, 22, 27 Excluded weight <40 kg and > CrCl< 10 mL/min (1.5-2* reference value) 17, 21 150 kg 24 To target aPTT (1.5-2.5* reference value) 13, 19, 28 (1.5-2* reference value) UFH 23

13, 14, 22, 26, 27 To target anti-Xa 14, 26 14, 22 14 To target anti-Xa (level 0.3 - 0.7 U/mL) To target anti-Xa 14 26 14 (level 0.3 - 0.7 U/mL) (level 0.5 - 0.7 U/mL) (level 0.3 - 0.7 U/mL) 26 (level 0.5 - 0.7 U/mL)

1: ETHIC, 2: OVID, 3: COVI-DOSE, 4: COVID-19 HD, 5: EMOS-COVID, 6: X-Covid 19, 7: DAWn-Antico, 8: NCT04360824, 9: IMPROVE, 10: INSPIRATION, 11: CoV-Hep, 12: BEMICOP, 13: ATTACC, 14: ACTIV-4a, 15: ACTION, 16: FREEDOM COVID, 17: NCT04485429, 18: NCT04508439, 19: COVID-PACT, 20: HEP-COVID, 21: HEPMAB, 22: IMPACT, 23: HESACOVID, 24: COVID-HEP, 25: NCT04584580, 26: CORIMMUNO-COAG, 27: RAPID COVID COAG, 28: TACOVID. *COVI-DOSE trial information in clinicaltrials.gov did not include definite intermediate doses and standard prophylactic doses for LMWH except enoxaparin, and a double dose of standard prophylactic dose of enoxaparin, adjusted to body weight, described as the intermediate dose. (Standard prophylactic doses of dalteparin, nadroparin, tinzaparin are 5000 U every 24 hours, 3800 U every 24 hours, 4500 U every 24 hours, respectively.) † We created a second section for INSPIRATION because in INSPIRATION trial, 1 mg/kg SC daily of enoxaparin as intermediate dose anticoagulation is only used for CrCl> 30 mL/min and weight< 120 kg, and for other situations (CrCl> 30 mL/min and weight> 120 kg or 15

79 medRxiv preprint doi: https://doi.org/10.1101/2021.01.04.21249227; this version posted January 6, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

Supplemental Table 4. Additional Investigational Agents with Antithrombotic Properties Studied in COVID-19 Ongoing Sample Agent Mechanism of Action Setting Primary Outcomes Include Randomized Trials Size A monoclonal antibody targeting P-selectin. Crizanlizumab CRITICAL Crizanlizumab can decrease inflammation by binding to P-selectin, Ward Level of soluble P-selectin in ng/ml 50 (NCT04435184) blocking leucocyte and platelet adherence to the vessel wall. Augmenting plasmin activity to hydrolyze fibrin clots; reducing endothelial cell activation, increasing endothelial Ward DEFACOVID Defibrotide cell-mediated fibrinolysis, increasing tissue plasminogen and All-cause mortality 120 (NCT04348383) activator and thrombomodulin expression; decreasing von ICU Willebrand factor and plasminogen activator inhibitor-1. Inactivation of thrombin, plasmin, and other serine proteases Recombinant of coagulation (factors IXa, Xa, XIIa). The inactivation of ANTITROMBINA Composite of mortality and need for antithrombin proteases is a major step in the normal clotting process and (EUCT2020- Ward non-invasive ventilation or 46 III thrombosis would be caused by active serine proteases if 001659-42) mechanical ventilation they were not inhibited by antithrombin. Recombinant nematode Change in D-dimer level from Inhibition of tissue factor/factor VIIa, attenuates coagulation anticoagulant ASPEN-COVID-19 Ward baseline, time to recovery within 30 100 and the interleukin-10 response in human endotoxemia. protein c2 days (rNAPc2) Time to recovery defined as NCT04393311 Ward attaining a score of 6, 7, or 8 on the 160 COVID-19 disease severity scale Number of days of use of As a urinary serine protease inhibitor, it inactivates plasmin, CTRI/2020/06/0257 mechanical ventilation, Ward 120 elastase, thrombin, factors IXa, Xa, XIa, and XlIa. It also 04 change from baseline in PaO2/FiO2 Ulinastatin inhibits several pro-inflammatory proteases and decreases ratio inflammatory cytokine. ChiCTR2000030779 ICU Blood gas, SOFA score 100 Mild cases: the critical illness rate Ward ChiCTR2000032135 of subjects at weeks 2 and 50 Severe or critical cases: changes of ICU PaO2/FiO2 from baseline COVID-19: coronavirus disease 2019; ICU: intensive care unit; SOFA: sequential organ failure assessment.

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