Anticoagulant Therapy in Patients Hospitalized With COVID-19 | Critical Care Medicine | JAMA Internal Medicine | JAMA Network
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Invited Commentary
October 7, 2021

Anticoagulant Therapy in Patients Hospitalized With COVID-19

Author Affiliations
  • 1Division of General Internal Medicine, Duke University Medical Center, Durham, North Carolina
  • 2Division of Hematology, Duke University Medical Center, Durham, North Carolina
  • 3Department of Medicine, Department of Pathology, Duke University Medical Center, Durham, North Carolina
JAMA Intern Med. Published online October 7, 2021. doi:10.1001/jamainternmed.2021.6212

Since the early days of the COVID-19 pandemic, clinicians have reported altered coagulation in hospitalized patients, with both thrombotic as well as hemorrhagic events. Several mechanisms for the increased thrombotic risk have been identified, but many patients who are hospitalized with SARS-CoV-2 infection appear to develop a cytokine storm, leading to hyperinflammation, endothelial disruption, platelet activation, and a coagulopathy, contributing to the hemostatic and thrombotic complications.1 Early reports also suggested that standard prophylactic doses of anticoagulant therapy appeared to be inadequate for preventing thrombotic events in hospitalized patients.2 Data from several large trials recently published give us more insight into treatment strategies for hospitalized patients with COVID-19.3-7 In this issue of JAMA Internal Medicine, data from the HEP-COVID study8 contribute additional evidence in the role of therapeutic vs prophylactic heparin dosing for thromboprophylaxis in patients hospitalized for COVID-19–related illnesses.

The HEP-COVID study8 randomized hospitalized adult patients with COVID-19 and evidence of coagulopathy, defined as a D-dimer level greater than 4 times the upper limit of normal or a sepsis-induced coagulopathy score of 4 or higher, to (1) standard prophylactic or intermediate-dose low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) or (2) therapeutic-dose LMWH throughout hospitalization. They found that the primary efficacy outcome of venous thromboembolism (VTE), arterial thromboembolism (ATE), or all-cause mortality was significantly reduced with therapeutic-dose anticoagulation in the non–intensive care unit (ICU) patients, but this benefit was not observed in the ICU patients. There was no significant difference in major bleeding between groups in either the non-ICU or ICU strata, although confidence intervals were wide.

This study confirms and builds on the observations recently reported by the ATTACC, ACTIV-4a, and REMAP-CAP Investigators in 2 studies investigating therapeutic-dose anticoagulation compared with “usual-care” thromboprophylaxis in hospitalized patients with COVID-19.5,6 The primary outcome in these 2 studies was defined as organ-support–free days, defined by an ordinal scale combining in-hospital death and the number of days free of cardiovascular or respiratory organ support. In noncritically ill patients, defined as not needing respiratory or cardiovascular support in an ICU (oxygen delivered by high-flow nasal cannula, noninvasive or invasive mechanical ventilation, or the use of vasopressors or inotropes), therapeutic dosing increased the probability of survival to hospital discharge and reduced the use of cardiovascular or respiratory organ support compared with usual-care thromboprophylaxis.5 Similar to the observation by the HEP-COVID Investigators, therapeutic-dose heparin was found to have no benefit in patients with severe COVID-19, defined as needing at least 1 of the measures stated above, and was associated with a higher incidence of bleeding.6

In contrast, the RAPID Trial Investigators7 found that therapeutic-dose anticoagulation with LMWH or UFH in moderately ill hospitalized patients with COVID-19 and an elevated D-dimer level did not significantly reduce the primary outcome of ICU admission, noninvasive or invasive mechanical ventilation, or death up to 28 days compared with a prophylactic dose of LWMH or UFH. However, therapeutic-dose anticoagulation was associated with a decrease in the secondary outcome of death at 28 days in this study, and there was no increase in major bleeding compared with prophylactic anticoagulation.7 In the ICU patient population, the INSPIRATION Investigators3 reported that an intermediate dose of LMWH provided no benefit over standard prophylactic-dose anticoagulation in the prevention of the composite outcome of VTE, ATE, treatment with extracorporeal membrane oxygenation, or mortality within 30 days.

The beneficial effect of therapeutic anticoagulation in hospitalized patients with COVID-19 using heparin does not appear to extend to other classes of anticoagulant therapy. The ACTION study4 demonstrated that hospitalized patients with COVID-19 who received therapeutic anticoagulation with rivaroxaban (clinically stable patients) or enoxaparin (unstable patients) compared with prophylactic anticoagulation with LMWH or UFH did not improve the primary efficacy outcome of a hierarchical analysis of time to death, duration of hospitalization, or duration of supplemental oxygen to day 30. Therapeutic anticoagulation was associated with increased bleeding in both clinically stable and clinically unstable patients.

While there are a number of similarities across these studies, there are differences that need to be taken into consideration. The criteria for who was considered to be noncritically ill (also referred to as moderately ill, or non-ICU setting) in contrast to critically ill (severely ill, or ICU setting) differed across the studies. The composite primary outcomes also differed across the studies, although the individual components of the composite outcomes frequently overlapped. All of the studies included an elevated D-dimer level as either part of the inclusion criteria for participation in the study or in the final analysis of the outcome data, although the cutoff for an elevated D-dimer level varied between the studies (from above the upper limit of the normal range to greater than 4 times the upper limit).

Despite the methodological differences, these studies help us draw 3 important conclusions concerning the efficacy and safety of anticoagulant therapy in hospitalized patients with COVID-19. First, the data support that therapeutic anticoagulation with LMWH or UFH is associated with improved outcomes in hospitalized patients with COVID-19 who are not critically ill or in the ICU setting, particularly those patients with elevated D-dimer levels. Second, the data also indicate that patients who are critically ill and/or in the ICU do not benefit from therapeutic anticoagulation and manifest an increased risk for bleeding compared with patients receiving prophylactic-dose anticoagulation. The beneficial effect of therapeutic anticoagulation is diminished and the risk of hemorrhage is increased in patients with progressively more severe disease, potentially related to hyperinflammation, endothelial disruption, platelet activation, and coagulopathy. Third, none of the studies would support the use of an anticoagulant administered at a dose between prophylactic and therapeutic, whether for ICU or non-ICU patients.

The research community has quickly developed and modified guidelines for anticoagulation in patients hospitalized with COVID-19 based on the data. However, these studies highlight areas where more investigation is needed. The role of antiplatelet therapy remains to be determined as well as other therapies that might modulate the prothrombotic characteristics of SARS-CoV-2 in hospitalized patients. The distinction between moderate and severe disease can be better defined, specifically when it comes to oxygen requirement. In addition, the transition of patients between the ICU and non-ICU settings represents a time when the intensity of anticoagulant therapy needs to be revisited. Lastly, whether a course of extended anticoagulation following discharge from the hospital, particularly for patients who were hospitalized with a more severe clinical course of COVID-19, or who have persistently elevated D-dimer levels, remains to be determined.

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Article Information

Corresponding Author: Thomas L. Ortel, MD, PhD, Departments of Medicine and Pathology and Division of Hematology, Duke University Medical Center, Box 3422 DUMC, Durham, NC 27710 (thomas.ortel@duke.edu).

Published Online: October 7, 2021. doi:10.1001/jamainternmed.2021.6212

Conflict of Interest Disclosures: Dr Wahid reported receiving National Institutes of Health funding for ACTIV4A and ACTIV4C clinical trials. Dr Ortel reported receiving research support from Instrumentation Laboratory, Stago, and Siemens and consulting work from Instrumentation Laboratory outside the submitted work; and receiving National Institutes of Health funding for participating in clinical trials investigating the role of anticoagulant therapy in the management of patients with COVID-19.

References
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Sadeghipour  P, Talasaz  AH, Rashidi  F,  et al; INSPIRATION Investigators.  Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial.   JAMA. 2021;325(16):1620-1630. doi:10.1001/jama.2021.4152 PubMedGoogle Scholar
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Lawler  PR, Goligher  EC, Berger  JS,  et al; ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators.  Therapeutic anticoagulation with heparin in noncritically ill patients with COVID-19.   N Engl J Med. 2021;385(9):790-802. doi:10.1056/NEJMoa2105911PubMedGoogle Scholar
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    1 Comment for this article
    EXPAND ALL
    COAGULATION SYSTEM IN SARS-CoV-2-INFECTION: does heparin administration stop provisional clot formation to repair hypoxic tissue damage?
    Giuliano Ramadori, Professor of Medicine | University Clinic Göttingen Internal Mediicne
    Wahid and Ortel (1) discuss the results presented in the study of Spyropoulos et al (2). They compare the results with those  from similar studies underlining the differences, which were mostly based on d-dimer plasma levels as inclusion criterium. The authors also stress the surprising results indicating that the therapeutic dose of heparin loses its effect in critically ill patients with more severe disease potentially related to hyper-inflammation, endothelial disrupution, and coagulopathy (1). Critical questions are what causes the increase of the fibrinogen cleavage products (d-dimer) in the plasma of hospitalized patients and also if heparin is able to reduce d-dimer formation. In fact, this should have been the first easily measurable end point of the study.

    In their commentary, the authors mention the HEP-COVID-study where evidence of coagulopathy was defined as a d-dimer plasma level greater than 4-times the upper limit of normal values (1). This means that d-dimer plasma levels are increased also in hospitalized patients with mild disease and the level can increase with worsening of the disease.

    In a study I conducted, d-dimer plasma levels were measured in patients with SARS-CoV-2 infection and hypoalbuminemia (the strongest risk factor for mortality in hospitalized patients) who were given large amounts of albumin (3). The study suggested that circulatory insufficiency could be responsible for peripheral fibrinogen cleavage and fibrin formation as a component of the provisional clot for initiation of repair of hypoxic tissue damage (4).

    This process may initiate in the lung capillary as a consequence of reduction of blood volume caused by dehydration.In fact, fibrin deposition is one of the hallmarks of the autopsy description of the lung damage (4). Dehydration continues to persist and eventually leads to death as suggested by the ischemic findings in the liver and in the kidney (5).

    REFERENCES
    1 .Wahid L,Ortel TL.:Anticoagulant therapy in patients hospitalized with COVID-19.JAMA Internal Medicine,2021,online October 7.
    2. Spyropoulos AC, Goldin M, Giannis D et al.JAMA Internal Medicine2021, online October 7.
    3. Violi F,Ceccarelli G, Loffredo L et al. Albumin Supplementation Dampens Hypercoagulability in COVID-19:A Preliminary Report.Thromb.Hemost 2021;121:102-105doi: 10.1055/s-0040-1721486
    4. Ramadori G.Albumin Infusion in Critically Ill COVID-19 Patients: Hemodilution and anticoagulation.
    Int.J.Mol.Sci.2021,227126. https://doi.org/10.3390/ijms22137126.
    5.Hooper JE, Padera RFDolhnikoff M et al. A Postmortem Portrait oft he Coronavirus Disease 2019(COVID-19) Pandemic.A large Multi-istitutional Autopsy Survey Study.Arch Pathol Lab Med.2021;145:529-535; DOI:10.5858/arpa.2020-0786-SA

    CONFLICT OF INTEREST: None Reported
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