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

JACC State-of-the-Art Review

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

Disclosures

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

In This Article

Review of Ongoing or Completed RCTs

After identification of 918 records and manual screening of 180 records, 75 RCTs were included in this study. Supplemental Figure 1 In 13 cases, a design paper and/or study protocol was available. Of all ongoing studies, 1 RCT reported the results in peer-reviewed literature[38] and 1 shared the findings on a pre-print server.[39] For 3 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]

As of December 16, 2020, a total of 75 RCTs of antithrombotic agents for patients with COVID-19 were registered at the ClinicalTrials.gov or WHO International Clinical Trials Registry Platform databases. Figure 2 provides a graphical summary of all RCTs of antithrombotic agents in COVID-19 in a pharmacological-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 heparin 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 trials is provided in the following sections according to the clinical setting. Additional details are provided in Supplemental Tables 2 and 3.

In each section, the discussion begins with parenteral anticoagulants, followed by fibrinolytic therapy, oral anticoagulants, antiplatelet agents, 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.

Figure 3.

Graphical Summary of Ongoing RCTs of Antithrombotic Therapy in COVID-19 Based on Patient Settings
Categorizing the RCTs evaluating different agents in various settings, including those treated entirely as outpatients, patients in the non-ICU hospital wards, critically ill patients in the ICU, and post-hospital discharge. Others: dociparstat, nafamostat, and sulodexide. Abbreviations as in Figure 2.

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 enoxaparin, DOACs, aspirin, and sulodexide compared with no treatment (6 of 11) or with placebo (5 of 11). These trials are mostly (8 of 11) open-label, with the number of participants ranging from 172 to 7,000 patients, and they include patients with a hyperinflammatory or procoagulant profile (including elevated levels of C-reactive protein [1 of 11] or D-dimer [2 of 11]) and exclude patients at high risk of bleeding (e.g., those with a history of recent gastrointestinal bleeding or intracranial hemorrhage). Pregnant women and patients with severe kidney dysfunction (creatinine clearance [CrCl] levels <30 ml/min) are excluded from 8 of 11 and 6 of 11 of these trials, respectively. The most common primary efficacy outcomes in the outpatient trials include the need for hospitalization, incidence of thromboembolic events, mortality, or composite outcomes inclusive of these factors. Bleeding events (5 of 11) constitute the most commonly assessed safety endpoints in the trials with an outpatient setting.

LMWHs (at standard prophylactic dose), DOACs (at both low intensity and high intensity), aspirin, and sulodexide are the agents under investigation in the outpatient setting. ETHIC and OVID RCTs are comparing the effect of a standard prophylactic dose of enoxaparin versus no intervention on the primary outcome of hospitalization or mortality in 2,370 individuals.[41] Low-intensity rivaroxaban (10 mg once daily [QD]) is being evaluated in a total of 4,600 patients in 2 ongoing RCTs (PREVENT-HD [A Study of Rivaroxaban to Reduce the Risk of Major Venous and Arterial Thrombotic Events, Hospitalization and Death in Medically Ill Outpatients With Acute, Symptomatic Coronavirus Disease 2019 (COVID-19) Infection; NCT04508023] and Study to Evaluate Safety and Efficacy of Rivaroxaban for High Risk People With Mild COVID-19 [NCT04504032]). Low-intensity apixaban (2.5 mg twice daily [BID]) is also under investigation in the ACTIV-4b (Anti-thrombotics for Adults Hospitalized With COVID-19) 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 [Health Care Worker Prophylaxis Against COVID-19], and CONVINCE [Corona Virus Edoxaban Colchicine]). 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. The 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 [Anti-Coronavirus Therapies to Prevent Progression of Coronavirus Disease 2019 (COVID-19) Trial], LEAD COVID-19 [Low-risk, Early Aspirin and Vitamin D to Reduce COVID-19 Hospitalizations], and ACTIV-4b).

SulES-COVID (Sulodexide in the Treatment of Early Stages of COVID-19) is the only completed trial of antithrombotic therapy in outpatients with COVID-19.[39] 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: 0.60; 95% CI: 0.37 to 0.96; p = 0.03) and need for oxygen support (relative risk: 0.71; 95% CI: 0.50 to 1.00; p = 0.05), with no significant effect on mortality. The study has limitations, including frequent (22.1%) post-enrollment exclusions due to negative SARS-CoV-2 test results or loss 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 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 of 50) are open-label. The antithrombotic agents under investigation include heparin (both systemic and inhaled), DOACs, aspirin, P2Y12 inhibitors, dipyridamole, 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 levels, microthrombosis, macro-thrombosis, and worse outcomes in COVID-19,[42–44] many RCTs (16 of 50) include patients with elevated D-dimer levels with cutoffs ranging from >500 ng/ml to >1,500 ng/ml (or defined as >2 to 4 times the upper limit of normal per the local laboratory). Most trials exclude pregnant women (41 of 50) and patients with active bleeding or history of intracranial or gastrointestinal bleeding (39 of 50). Many trials also exclude patients with CrCl levels <30 ml/min (20 of 50). In most trials, the time frame for the primary outcome assessment is 28 to 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.

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 factors in hospitalized patients with COVID-19. Bleeding events is the most common (17 of 28) primary safety endpoint used in these trials. The majority of these RCTs have chosen a standard-dose prophylactic anticoagulation regimen as the comparator. Intermediate-dose anticoagulation will be tested in DAWn-Antico (Direct Antivirals Working Anticoagulation),[45] X-COVID-19, COVID-19 HD (Randomised controlled trial comparing efficacy and safety of high versus low Low-Molecular Weight Heparin dosages in hospitalized patients with severe COVID-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation), COVI-DOSE (Weight-Adjusted vs Fixed Low Doses of Low Molecular Weight Heparin for Venous Thromboembolism Prevention in COVID-19), EMOS-COVID (Enoxaparin at Prophylactic or Therapeutic Doses in COVID-19), COVID-19-associated Coagulopathy: Safety and Efficacy of Prophylactic Anticoagulation Therapy in Hospitalized Adults With COVID-19 ( NCT04360824), and Impact of the use of low molecular weight heparins (LMWH), at prophylactic versus intermediate doses, on SARS-CoV2 infection (COVID-19) [EUCTR2020-001891-14-ES] with 4,434 patients in total. Conversely, a total of 18 RCTs with 19,776 patients will evaluate the efficacy of therapeutic anticoagulation in non-ICU hospitalized patients.[46] Only 2 trials totaling 494 patients (IMPACT [InterMediate ProphylACtic Versus Therapeutic Dose Anticoagulation in Critically Ill Patients With COVID-19: A Prospective Randomized Study; NCT04406389] and HEP-COVID [Systemic Anticoagulation With Full Dose Low Molecular Weight Heparin (LMWH) Vs. Prophylactic or Intermediate Dose LMWH in High Risk COVID-19 Patients; NCT04401293]) 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 an anticoagulant effect but also an antiviral and anti-inflammatory effect,[47,48] INHALE-HEP (Inhaled Nebulised Unfractionated Heparin for the Treatment of Hospitalised Patients With COVID-19) and NEBUHEPA (Nebulized Heparin in Severe Acute Respiratory Syndrome COVID-19) 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 the partial arterial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio in 100 hospitalized patients. Standard of care (for INHALE-HEP and PACTR202007606032743) and standard-dose prophylaxis with LMWH (NEBUHEPA) are the comparators.

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 (Austrian Coronavirus Adaptive Clinical Trial) and XACT (Factor Xa Inhibitor Versus Standard of Care Heparin in Hospitalized Patients With COVID-19) 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 [Randomized Clinical Trial to Evaluate a Routine Full Anticoagulation Strategy in Patients With Coronavirus (COVID-19); NCT04394377], COVID-PREVENT [Effect of Anticoagulation Therapy on Clinical Outcomes in COVID-19], FREEDOM [FREEDOM COVID Anticoagulation Strategy Randomized Trial; NCT04512079] COVID, and XACT [Factor Xa Inhibitor Versus Standard of Care Heparin in Hospitalized Patients With COVID-19; NCT04640181]). Major bleeding is the primary safety endpoint in 3 of 6 trials addressing DOACs in hospitalized non-ICU patients.

C-19-ACS (Preventing Cardiac Complications of COVID-19 Disease with Early Acute Coronary Syndrome Therapy) 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.

The potential protective effect of antiplatelet agents in hospitalized patients with COVID-19 is being evaluated in 11 RCTs. REMAP-CAP (A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia) is a large global RCT with a multifactorial adaptive design that is planning to randomize 7,100 patients to receive multiple therapeutic interventions, including an anticoagulant arm and an antiplatelet agent arm evaluating aspirin and the P2Y12 inhibitors clopidogrel, ticagrelor, or prasugrel.[49] PEAC (Protective Effect of Aspirin on COVID-19 Patients; NCT04365309) 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 [Randomised Evaluation of COVID-19 Therapy]) with 20,000 participants.[50] RESIST (CTRI/2020/07/026791) aims to evaluate the role of aspirin plus atorvastatin in clinical deterioration characterized by progression according to the WHO clinical improvement ordinal score in 800 hospitalized patients with COVID-19.[51] CAM-Covid-19 evaluates the impact of a higher dose of aspirin (325 mg 4 times a day) along with colchicine and montelukast on inflammatory markers such as high-sensitivity C-reactive protein in 34 patients. PARTISAN (Prasugrel in Severe COVID-19 Pneumonia; 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 4 times a day and the combination of dipyridamole extended-release 200 mg twice daily and aspirin 25 mg twice daily are being evaluated in 3 small RCTs (TOLD, DICER [Dipyridamole to Prevent Coronavirus Exacerbation of Respiratory Status], and ATTAC-19 [Aggrenox To Treat Acute Covid-19]) for primary outcomes such as D-dimer level changes (for the first 2 trials) and improvement in the COVID-19 WHO ordinal scale (a scale indicting severity of illness, from 0 [not infected] to 8 [death]) (ATTAC-19).

High-mobility group box protein 1 (HMGB1) is a protein involved in the pathogenesis of inflammation. Elevated levels of HMGB1 are associated with worse outcomes in COVID-19.[52] 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 the Dociparstat for the Treatment of Severe COVID-19 in Adults at High Risk of Respiratory Failure study [NCT04389840] to assess its impacts on all-cause mortality and need for mechanical ventilation in 600 patients with severe COVID-19.[53]

Nafamostat is a synthetic serine protease inhibitor with antiviral, anti-inflammatory, and anticoagulant activity previously used for anticoagulation during hemodialysis.[54] Nafamostat is under evaluation in hospitalized patients with COVID-19 in 7 RCTs with 826 individuals in total. The primary efficacy outcome in 5 of these 7 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 Clinical Trial on the Efficacy and Safety of Bemiparin in Patients Hospitalized Because of COVID-19 (NCT04420299) have relatively small sample sizes and short periods of follow-up (7 and 10 days, respectively), rendering them susceptible to a 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

The risk of thrombotic events seems 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 to 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 enrolled mixed non-ICU and ICU populations and 15 RCTs solely enrolled ICU patients. The sample size of these studies range from 15 to 20,000 patients. These trials are studying the role of systemic anticoagulants (intermediate- to full-therapeutic-dose of heparin and direct thrombin inhibitors), inhaled UFH, fibrinolytic agents (tenecteplase and alteplase), antiplatelet agents (aspirin, clopidogrel, and dipyridamole), and nafamostat. Inclusion criteria in 11 of 33 RCTs require D-dimer cutoffs ranging from >500 ng/ml to >3,000 ng/ml (or defined as >2 to 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.

UFH and/or LMWH (19 studies) are the most common antithrombotic regimens under investigation in the ongoing trials in critically ill patients. INSPIRATION (The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial),[55] IMPROVE (Intermediate or Prophylactic-Dose Anticoagulation for Venous or Arterial Thromboembolism in Severe COVID-19: A Cluster Based Randomized Selection Trial; NCT04367831), DAWn-Antico, and COVI-DOSE are testing intermediate-dose versus standard prophylactic dose anticoagulation in >1,500 participants in total. INSPIRATION has recently completed enrollment of 600 patients.[55] Preliminary analyses indicate that intermediate-dose compared with standard-dose anticoagulation did not reduce a composite of venous or arterial thrombosis or death. The full results are imminent. IMPACT and HEP-COVID are comparing therapeutic anticoagulation with intermediate-dose anticoagulation in a total of 494 individuals. Finally, 11 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 3 trials (ACTIV-4a, REMAP-CAP, and ATTACC [Antithrombotic Therapy to Ameliorate Complications of COVID-19]) prompted the Data Safety and Monitoring Boards to pause enrollment due to futility for the endpoint of freedom from organ support at 21 days and a potential for harm due to possibly higher rates of bleeding. More details are forthcoming.[40] Conversely, in January 2021, the same study groups paused enrollment into the strata of moderately ill hospitalized patients with COVID-19 not requiring ICU level of care, in whom a preliminary analysis showed a reduction in the need for ventilatory support or other organ-supportive interventions with therapeutic-dose enoxaparin.[56] Data supporting these decisions have not yet been finalized or peer reviewed, and they are anxiously awaited.

The only published RCT in critically ill patients with COVID-19 is HESACOVID (Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial), a single-center study of 20 patients requiring invasive mechanical ventilation randomized to receive therapeutic-dose versus standard-dose anticoagulation. Therapeutic-dose anticoagulation significantly increased PaO2/FiO2 and ventilator-free days (15 days [interquartile range: 6 to 16 days] vs. 0 days [interquartile range: 0 to 11 days]; 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 in performing imaging testing, including computed tomography scanning to identify a source, in critically ill patients.[57]

CHARTER-Irl (Patients with SARS-CoV-2 Requiring Mechanical Ventilation in Ireland), CHARTER-MT (Can Nebulised Heparin Reduce Mortality and Time to Extubation in Patients With COVID-19 Requiring Mechanical Ventilation Meta-Trial), and Nebulized Heparin for the Treatment of COVID-19 Induced Lung Injury ( 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 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 the Nebulized Heparin for the Treatment of COVID-19 Induced Lung Injury study (NCT04397510) is improvement in the PaO2/FiO2 ratio within 10 days.

The use of parenteral anticoagulant agents other than UFH and LMWHs in COVID-19 is being studied in 2 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.[58]

There are 6 RCTs (AtTAC [Tissue Plasminogen Activator (tPA) Treatment for an Atypical Acute Respiratory Distress Syndrome (Microvascular COVID-19 Lung Vessels Obstructive Thromboinflammatory Syndrome (MicroCLOTS): A Multicentral Randomized; NCT04453371), STARS [Fibrinolytic Therapy to Treat ARDS in the Setting of COVID-19 Infection; NCT04357730], TRISTARDS [ThRombolysIS Therapy for ARDS A Phase IIb/III Operationally Seamless, Open-label, Randomised, Sequential, Parallel-group Adaptive Study to Evaluate the Efficacy and Safety of Daily Intravenous Alteplase Treatment Given up to 5 Days on Top of Standard of Care (SOC) Compared With SOC Alone, in Patients With Acute Respiratory Distress Syndrome (ARDS) Triggered by COVID-19; NCT04640194], TACOVID [Evaluation of Tissue Plasminogen Activator (tPA) in comparition of anticoagulation for treatment of critical COVID 19 patient; 48929], Tenecteplase in Patients With COVID-19 [NCT04505592], and the Evaluation of Tissue Plasminogen Activator (tPA) in comparition of anticoagulation for treatment of critical COVID 19 patient [IRCT20200415047080N1]) evaluating the safety and efficacy of fibrinolytic therapy (tenecteplase or alteplase) on COVID-19–related respiratory failure in a total of 485 patients.[59] 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 and 72 h; for those evaluating ventilator-free days, it is 28 days. Patients receiving therapeutic anticoagulation, and those with thrombocytopenia or a history of intracranial or gastrointestinal bleeding, are excluded from fibrinolytic therapy trials.

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 a 2 × 2 factorial design trial to receive full-dose anticoagulation versus standard-dose prophylactic anticoagulation with heparin-based regimens (first randomization) and to antiplatelet therapy with clopidogrel versus no antiplatelet therapy (second randomization). The primary efficacy outcome is the incidence of VTE or arterial thrombosis incidence 28 days after enrollment.

Nafamostat is under evaluation in 4 studies in critically ill patients with COVID-19 (DEFINE [Rapid Experimental Medicine for COVID-19; NCT04473053], RACONA [RAndomized Clinical Trial in COvid19 Patients to Assess the Efficacy of the Transmembrane Protease Serine 2 (TMPRSS2) Inhibitor NAfamostat; NCT04352400], Clinical Efficacy of Nafamostat Mesylate for COVID-19 Pneumonia [NCT04418128], and A Study Evaluating the Efficacy and Safety of CKD-314 (Nafabelltan) in Hospitalized Adult Patients Diagnosed With COVID-19 Pneumonia [ NCT04623021]) with 650 participants in total.

Research in the ICU faces several challenges for study design, data/sample collection, and patient follow-up.[60] In many cases, patients are unconscious, and obtaining informed consent requires discussion with health care proxies. This situation 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, raising the possibility of a type II error. The small sample size will mostly influence trials of thrombolytic therapy and nonheparin anticoagulants.

Ongoing Clinical Trials in Post-discharge Patients

ACTIV-4c (COVID-19 Thrombosis Prevention Trials: Post-hospital Thromboprophylaxis; NCT04650087) is a double-blind, placebo-controlled RCT that 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 (Medically Ill Hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis With Rivaroxaban ThErapy: The MICHELLE Trial; NCT04662684) is an open-label RCT with 320 participants; it 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 that will continue the already assigned antithrombotic therapy after discharge in patients who were randomized in the general medical wards or in the ICU. In the INSPIRATION study, an 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. In the COVID-PREVENT, XACT, and Effect of the Use of Anticoagulant Therapy During Hospitalization and Discharge in Patients With COVID-19 Infection (NCT04508439) RCTs, post-discharge thromboprophylaxis with rivaroxaban (10 or 20 mg QD) is being investigated in 680 participants enrolled in general medical wards to measure the incidence of VTE at 30 to 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 to treatment in the ICU or non-ICU settings to evaluate all-cause mortality rate and VTE incidence at 42 days. Finally, aspirin in the PEAC study, and dipyridamole extended-release plus aspirin in the ATTAC-19 study, will be continued after discharge in patients randomized to treatment in the non-ICU general wards.

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 >50% of the trials designed to evaluate escalated dose anticoagulation, patients with CrCl levels <15 ml/min are excluded. CoV-Hep is an open-label study that evaluates the role of low-dose (10 IU/kg per hour) 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 of 34 trials of systemic heparin compounds. Pregnant women are excluded from 25 of 34 trials of systemic heparin compounds. Although 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, Supplemental Figure 2). With limited high-quality data on the horizon for these vulnerable and high-risk subgroups, decision-making for optimal management in these patients will continue to be challenging.

Figure 4.

Illustration of How Vulnerable Populations Were or Were Not Included in the Existing Trials
Categorizing the RCTs evaluating different agents in vulnerable populations, including patients with advanced kidney disease, end-stage kidney disease (ESKD), patients with liver failure, and obese patients. Further details are illustrated in Supplemental Figure 1. Obesity is defined differently in different RCTs; body mass index >30, 35, and 40 kg/m2 and weight >100 and 120 kg are among the most-used definitions among RCTs. Others: dociparstat, nafamostat, and sulodexide. Abbreviations as in Figure 2.

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 by using the International Society on Thrombosis and Haemostasis criteria or the Bleeding Academic Research Consortium definitions.[61,62] Although observational evidence suggests low rates of major bleeding,[33,63] observational studies have the potential for under-reported 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 is especially the case because risk factors for thrombosis in COVID-19 (e.g., D-dimer) may also predict bleeding.[33]

Central Illustration.

Simplified Summary of Ongoing Antithrombotic Therapy Trials in Coronavirus Disease-2019*
Heparin-based regimens are the most frequently studied antithrombotic agents in patients with coronavirus disease-2019. Trials of fibrinolytic therapy are reserved for patients admitted to the intensive care unit (ICU). *Additional details are provided in Figure 2 and Supplemental Table 2. LMWH = low-molecular-weight heparin; UFH = unfractionated heparin.

Although 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.[64,65] In addition, there are few head-to-head comparisons for many of the experimental therapies, such as intermediate-dose regimens compared with fully therapeutic heparin-based regimens. Network meta-analytic techniques might generate insights into the comparative tradeoffs of these regimens.[66] Additional biomarker and clinical risk prediction substudies 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,[30,67,68] with the potential to reduce large-vessel thrombosis and improve outcomes. Another evolving concept is the role of microthrombosis and pulmonary intravascular coagulopathy[7,8,69] in the pathophysiology of respiratory failure in COVID-19.[70] Results from the small HESACOVID study suggested improved arterial oxygenation (PaO2/FiO2) with therapeutic versus standard-dose prophylaxis anticoagulation in critically ill patients with COVID-19.[38] However, combined investigation of 3 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.[71] Some experts recommend measuring anti–factor Xa levels in those receiving intravenous UFH, because the high levels of factor VIII observed among critically ill patients with COVID-19 may interfere with activated partial thromboplastin time assays. The necessity and optimal method for dosing and monitoring of heparins and LMWHs, in particular for patients with kidney disease or obesity, have yet to be elucidated and are even understudied outside COVID-19.[72] 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.[73] 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.[74] These changes include multispecialty 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 dissemination of the findings via fast-track publications, pre-prints, and social media accounts from scientific societies or investigators (Table 2).[75–77]

Although traditional RCTs have provided a great deal of knowledge for modern medicine, they are confined to testing a limited number of interventions. Because COVID-19 has multiorgan involvement and broad manifestations (including inflammation, acute respiratory distress syndrome, thrombosis, and others), adaptive platform trials, which allow for testing multiple interventions in a single disease based on a decisive algorithm, have gained attention.[78] This type of trial has a perpetual and multiarm, multistage design.[79] The RECOVERY trial[80] and the World Health Organization Solidarity trial[81] 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, antiviral agents, biologic agents, simvastatin, and antiplatelet therapy. The ACTIV4 platform is similarly using an adaptive design for antithrombotic agents.

Notwithstanding the good will of investigators, the constant pressure to provide a 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[74,82] 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).[57,82] Some experts consider that the pressures of working during a global pandemic make the use of placebo more aspirational than realistic. Nevertheless, when feasible, placebo control improves the internal validity of a trial. Furthermore, appropriate endpoint assessment, including blinded adjudication when feasible, and pre-specified analysis methods will remain of importance.[57]

Institutional Review Boards and independent ethics committees may experience the burden of numerous protocol submissions and amendments during the pandemic. Burnout of health care 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.[75] Investigators should attempt to foresee some of the challenges to minimize the need for protocol amendments.[83–85] 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.[83,86]

Monitoring of efficacy and safety outcomes is also critical. Execution of online Clinical Event Committee and Data and Safety Monitoring Board meetings for assessing the adverse events is a fast, safe, and efficient alternative to face-to-face meetings. If done with appropriate planning to adhere to standards of high-quality Clinical Event Committee and Data and Safety Monitoring Board meetings, such approaches may be considered even when society transitions out of the pandemic.[84,86]

Peer review and dissemination of the studies have had unique challenges and advancements as well. Journal editors and reviewers have been pressured for rapid release of the results of completed studies. This has activated the fast-track peer review process more than ever. Despite its merits, the "COVID-19 fatigue" created by the fast-track review process might negatively affect the quality of peer review, as noted by occurrence of post-publication major revisions and retractions, including in major journals.[87] 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 Level 2 evidence.[88] The process of peer review remains an imperfect, yet essential, step in the evaluation and reporting of results.[89] Pre-print 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 pre-print, key researchers in the field can discover findings sooner, indicate critical errors, or suggest new studies or data that strengthen the argument.[90] 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, health care workers, or policy makers. Indeed, many retracted papers were from pre-print servers.[87]

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.

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