Overview of Trials for Anticoagulation Therapy for COVID-19 Patients

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can potentiate all 3 sides of Virchow’s Triad of coagulopathy, including endothelial dysfunction, blood flow stasis, and hypercoagulability. Angiotensin-converting enzyme-2 (ACE-2)–dependent viral entry and the virus-induced inflammatory response can lead to endothelial dysfunction. Clotting Prevention in COVID-19 Patients, Thrombosis Prevention in COVID-19 Patients, Preventing blood clots in COVID-19 patients

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can potentiate all 3 sides of Virchow’s Triad of coagulopathy, including endothelial dysfunction, blood flow stasis and hypercoagulability. Angiotensin-converting enzyme-2 (ACE-2)–dependent viral entry and the virus-induced inflammatory response can lead to endothelial dysfunction. Additional figure included in the JACC article.

A comprehensive review or more than 80 randomized controlled trials (RCTs) investigating how to best manage optimal antithrombotic therapy in patients with COVID-19 (SARS-CoV-2) was published March 16 in the Journal of the American College of Cardiology (JACC).[1] However, so far there is not yet a definitive answer for optimal thromboprophylaxis.

The authors of the article "Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review," noted many of these trials are still ongoing and cut across inpatient, ICU and outpatient management using a wide variety of antithrombotic regimens. However, the results of these ongoing RCTs, and prospective meta-analyses of the completed studies, are expected to help clarify guidelines on how to mitigate thrombotic complications and improve patient outcomes.

The paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.

Researchers conducted a systematic literature search of trials in ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform, with the pre-defined keywords of COVID-19 and search terms for antiplatelet agents, anticoagulants, anticoagulation, fibrinolytic agents and antithrombotic agents. The identified studies were screened, and those that were designed as RCTs with at least one active arm of antithrombotic therapy (date of last search Dec. 16, 2020) were included. A supplemental table summarizes more than 80 study-level inclusion and exclusion criteria for this overview.

There has been frustration among physicians there there are no evidence-based guidelines on how to treat or prophylax COVID patients. There also is no "one-size-fits-all" solution because there are many variables in each COVID patient, and in how to treat them based on the severity of their disease.

There is no simple answer, explained study principal investigator Behnood Bikdeli, M.D., a cardiologist at Brigham and Women’s Hospital, Harvard Medical School. He is also involved in the Clinical Trials Center, Cardiovascular Research Foundation, the Center for Outcomes Research and Evaluation (CORE) at the Yale School of Medicine, and is an investigator in several trials related to use of blood thinners in COVID-19 patients.

"The one-size-fits-all approach will more often than not fail," Bikdeli said. "But the plus side of the study is that this shows there is a road map to the answer. Out of the 75 trials, there are at least four of them that are releasing their results, so for those trials we do have an answer, but we are just waiting for the data from the rest of the trials to come."

A year ago, cardiology societies recognized that COVID causes clotting in many patients and issued interim, consensus documents on how to treat and prophylax patients. However, a year into the pandemic, Bikdeli said it is time to treat patients on the latest clinical evidence, not best guesses.

"Early in 2020, it was appropriate to go by consensus recommendations, but over the past year, history has proven to us that despite the best of intentions, without randomized clinical trial evidence, we might just go the wrong direction," Bikdeli explained. "A year ago was a good time to think mechanistically about hypotheses and provide interim recommendations. Now, in my humble opinion, it is the wrong time to do so anymore. We need to have the answers and act on evidence, I don't think it is appropriate to give empiric treatment. We need to randomize patients so whatever we are doing today will give us a definitive answer for care tomorrow. It is my hope that we will have definitive answers over the new few months."

Hear more details in the VIDEO: Antithrombotic Prophylaxis in COVID-19 Patients — Interview with Behnood Bikdeli M.D.

Thrombosis is Common in COVID-19 Patients

Both venous and arterial thrombosis are prevalent in patients with COVID-19, and often are accompanied by endothelial injury and microvascular/macrovascular thrombosis.

Thrombotic complications, arterial and especially venous thromboembolism (VTE), are common clinical manifestations of coronavirus, particularly among hospitalized and critically ill patients. The authors said pooled analyses have helped in providing aggregate estimates of thrombotic events, with an overall incidence of VTE among COVID-19 inpatients estimated at about 17%, with variation based on study design and method of ascertainment. They found there is a four-fold higher incidence rate in patients in the intensive care units (ICUs) compared with non-ICU settings (28% vs. 7%).[2] In addition, the overview found post-mortem studies show frequent evidence of microvascular thrombosis in patients with COVID-19.[3,4] But the researchers said the influence of these events on mortality rates remains unknown.

Particularly in COVID-19, it is believed that the excessive inflammatory response plays an important role in the pathogenesis of thrombosis (or thrombo-inflammation), including pulmonary microthrombosis and pulmonary intravascular coagulopathy, the researchers said. It also appears COVID-19 may predispose patients to venous stasis and increase the risk of venous thrombosis. Fatigue, hypoxemia, being connected to medical devices (as in the case of hospitalized patients), or acute illness involvement such as pulmonary involvement or myocarditis with associated heart failure, also can all lead to limited mobility and venous stasis.

Pros and Cons of Antithrombotic Prophylaxis in COVID-19

Bedside observations, pathophysiological investigations and initial epidemiological data led to enthusiasm for antithrombotic prophylaxis in COVID-19, the study authors wrote. The concern for thrombotic risk was heightened by reports of VTE in 13% to 56% of patients, despite the use of standard prophylaxis. This led some experts to recommend use of escalated doses of anticoagulants. However, the researchers said the bleeding risks associated with intensified use of antithrombotic agents needs to be weighed against the presumptive benefits.

Multiple ongoing randomized controlled trials (RCTs) are evaluating a variety of antithrombotic regimens in patients with COVID-19. 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.

Antiplatelet Agents for Thrombotic Prophylaxis in COVID-19

The potential protective effect of antiplatelet agents in hospitalized patients with COVID-19 is being evaluated in 11 RCTs. These include:
• REMAP-CAP (A Randomized, 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.
• PEAC (Protective Effect of Aspirin on COVID-19 Patients; NCT04365309) aims to test the efficacy of aspirin in shortening clinical recovery time.
• RECOVERY (Randomized Evaluation of COVID-19 Therapy) is looking at the impact of aspirin on all-cause mortality among hospitalized patients is also under evaluation. This is the largest adaptive platform RCT for COVID-19 with 20,000 participants.
• 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.
• 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. These include TOLD, DICER (Dipyridamole to Prevent Coronavirus Exacerbation of Respiratory Status), and ATTAC-19 (Aggrenox To Treat Acute COVID-19). These will use 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).

Antithrombotic Drugs in COVID-19

Researchers also 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), direct oral anticoagulants (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, 43, 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.

The authors found 28 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. The majority of these RCTs have chosen a standard-dose prophylactic anticoagulation regimen as the comparator.

Intermediate-dose anticoagulation will be tested in the following trials:

• DAWn-Antico (Direct Antivirals Working Anticoagulation)
• X-COVID-19
• COVID-19 HD (Randomized 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)
• Impact of the use of low molecular weight heparins (LMWH), at prophylactic versus intermediate doses, on SARS-CoV2 infection (EUCTR2020-001891-14-ES) with 4,434 patients in total.

Conversely, researchers said a total of 18 RCTs with 19,776 patients will evaluate the efficacy of therapeutic anticoagulation in non-ICU hospitalized patients. 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 a table in the JACC article.

Recognizing that heparin not only has an anticoagulant effect but also an antiviral and anti-inflammatory effect, INHALE-HEP (Inhaled Nebulised Unfractionated Heparin for the Treatment of Hospitalized 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.

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.

Use of DOACs to Prevent Thrombotic Events in COVID Patients

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. These will look at hospitalized patients to assess outcomes such as all-cause mortality, ICU admission and intubation.

High-intensity DOACs, including rivaroxaban and apixaban, are being evaluated in large RCTs that will enroll a total of 4,750 participants. Major bleeding is the primary safety endpoint in 3 of 6 trials addressing DOACs in hospitalized non-ICU patients.
These studies include:
• ACTION (Randomized Clinical Trial to Evaluate a Routine Full Anticoagulation Strategy in Patients With Coronavirus; NCT04394377)
• COVID-PREVENT (Effect of Anticoagulation Therapy on Clinical Outcomes in COVID-19)
• FREEDOM (FREEDOM COVID Anticoagulation Strategy Randomized Trial; NCT04512079)
• XACT (Factor Xa Inhibitor Versus Standard of Care Heparin in Hospitalized Patients With COVID-19; NCT04640181).

Trials of Antithrombotic Agents in Critically Ill COVID 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%. 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.

There are 6 RCTs that include the use of tissue plasminogen activator (tPA):
• 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, Randomized, 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 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 comparison of anticoagulation for treatment of critical COVID 19 patient; 48929], Tenecteplase in Patients With COVID-19 [NCT04505592]
• The Evaluation of Tissue Plasminogen Activator (tPA) in comparison 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.

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.

Should COVID Long-haulers be Anticoagulated or Given Blood Thinners?

Bikdeli said in addition to answering questions on how to treat and protect COVID patients in the inpatient, outpatient and critical ICU stages, more recently questions have been rasied on what should be done with post-COVID recovery patients. It is now recognized that many patients become COVID long-haulers, where they continue to have symptoms for weeks or months, which is believed to be caused by clotting or damage caused by previous clotting during the acute phase of the virus.

He said in the non-COVID setting after a hospital discharge, there is often concern about thrombosis in the first few weeks and some patients are given blood thinners to prevent clot formation. However, he said the current clinical evidence does not show a clear connection with clotting in post-COVID patients.

"We can think of COVID in two different phases. One is the acute phase, and a lot of times after the acute viral infection there might be a cytokine storm, but once you get past that stage, there is also long-COVID. Some of these patients might still have symptoms for weeks or months. There are a couple studies looking at whether there is any benefit to giving blood thinners in discharged patients."

Like the treatment in other stages of COVID, he said more data is needed before a definitive answer can be given.

Read the full article for additional information, other agents and trial details.

Hear more details in the VIDEO: Antithrombotic Prophylaxis in COVID-19 Patients — Interview with Behnood Bikdeli M.D.