Anticoagulation in Patients With COVID-19: JACC Review Topic of the Week

Michael E Farkouh, Gregg W Stone, Anuradha Lala, Emilia Bagiella, Pedro R Moreno, Girish N Nadkarni, Ori Ben-Yehuda, Juan F Granada, Ovidiu Dressler, Elizabeth O Tinuoye, Carlos Granada, Jessica Bustamante, Carlos Peyra, Lucas C Godoy, Igor F Palacios, Valentin Fuster, Michael E Farkouh, Gregg W Stone, Anuradha Lala, Emilia Bagiella, Pedro R Moreno, Girish N Nadkarni, Ori Ben-Yehuda, Juan F Granada, Ovidiu Dressler, Elizabeth O Tinuoye, Carlos Granada, Jessica Bustamante, Carlos Peyra, Lucas C Godoy, Igor F Palacios, Valentin Fuster

Abstract

Clinical, laboratory, and autopsy findings support an association between coronavirus disease-2019 (COVID-19) and thromboembolic disease. Acute COVID-19 infection is characterized by mononuclear cell reactivity and pan-endothelialitis, contributing to a high incidence of thrombosis in large and small blood vessels, both arterial and venous. Observational studies and randomized trials have investigated whether full-dose anticoagulation may improve outcomes compared with prophylactic dose heparin. Although no benefit for therapeutic heparin has been found in patients who are critically ill hospitalized with COVID-19, some studies support a possible role for therapeutic anticoagulation in patients not yet requiring intensive care unit support. We summarize the pathology, rationale, and current evidence for use of anticoagulation in patients with COVID-19 and describe the main design elements of the ongoing FREEDOM COVID-19 Anticoagulation trial, in which 3,600 hospitalized patients with COVID-19 not requiring intensive care unit level of care are being randomized to prophylactic-dose enoxaparin vs therapeutic-dose enoxaparin vs therapeutic-dose apixaban. (FREEDOM COVID-19 Anticoagulation Strategy [FREEDOM COVID]; NCT04512079).

Keywords: COVID-19; anticoagulation; clinical trial; coagulopathy.

Conflict of interest statement

Funding Support and Author Disclosures Dr Farkouh has received research grants from Amgen, Novo Nordisk, and Novartis. Dr Stone has received speaker honoraria from Infraredx; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Miracor, Neovasc, Abiomed, Ancora, Vectorious, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, and Amgen; and has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. Dr Godoy is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Research Award) from the Canadian Institutes of Health Research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Proposed Stages of COVID-19, With Suggested Therapeutic Interventions Antithrombotic medications might be helpful in all stages of disease. Other possible therapeutic interventions are shown for each disease stage, as well as a hypothetical pathophysiology mechanism. ∗Approximate distribution of primary staging of disease among symptomatic patients. Adapted from Cordon-Cardo et al. ACE2 = angiotensin-converting enzyme 2.
Figure 2
Figure 2
Principal Results From the Multiplatform REMAP-CAP, ACTIV-4a, and ATTACC Trial (A) Clinical outcomes in the strata of noncritically ill hospitalized patients with COVID-19 not requiring intensive care unit (ICU)–level of care. (Left) Survival until hospital discharge without receiving organ support. (Right) Major bleeding tended to be increased with therapeutic-dose anticoagulation (posterior probability that therapeutic-dose anticoagulation is inferior to usual-care thromboprophylaxis, leading to more bleedings: 95.5%). (B) Clinical outcomes in the strata of critically ill hospitalized patients with COVID-19 requiring ICU-level respiratory or cardiovascular organ support. (Left) The secondary outcome of survival to hospital discharge (posterior probability of inferiority: 89.2%). (Right) Major bleeding tended to be increased with therapeutic-dose anticoagulation.
Central Illustration
Central Illustration
Main Design Elements of the FREEDOM COVID-19 Anticoagulation Trial The FREEDOM COVID-19 Anticoagulation trial (NCT04512079) is a prospective, multicenter, open-label, randomized controlled comparative safety and effectiveness study that will enroll up to 3,600 patients. Enoxaparin is administered subcutaneously and apixaban is administered orally. CrCl = creatinine clearance; ICU = intensive care unit; Q12h = every 12 hours.

References

    1. COVID-19 Map - Johns Hopkins Coronavirus Resource Center.
    1. Paranjpe I., Fuster V., Lala A., et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol. 2020;76:122–124.
    1. Connors J.M., Levy J.H. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135:2033–2040.
    1. Bikdeli B., Madhavan M.V., Jimenez D., et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75:2950–2973.
    1. Godoy L.C., Goligher E.C., Lawler P.R., Slutsky A.S., Zarychanski R. Anticipating and managing coagulopathy and thrombotic manifestations of severe COVID-19. CMAJ. 2020;192:E1156–E1161.
    1. Huang L., Yao Q., Gu X., et al. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet. 2021;398:747–758.
    1. Guan W.J., Ni Z.Y., Hu Y., et al. Clinical characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382:1708–1720.
    1. Tang N., Bai H., Chen X., Gong J., Li D., Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18:1094–1099.
    1. Iba T., Warkentin T.E., Thachil J., Levi M., Levy J.H. Proposal of the definition for COVID-19-associated coagulopathy. J Clin Med. 2021;10:191.
    1. Ackermann M., Verleden S.E., Kuehnel M., et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383:120–128.
    1. Wichmann D., Sperhake J.P., Lutgehetmann M., et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med. 2020;173:268–277.
    1. Piazza G., Campia U., Hurwitz S., et al. Registry of arterial and venous thromboembolic complications in patients with COVID-19. J Am Coll Cardiol. 2020;76:2060–2072.
    1. Nadkarni G.N., Lala A., Bagiella E., et al. Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19. J Am Coll Cardiol. 2020;76:1815–1826.
    1. Rentsch C.T., Beckman J.A., Tomlinson L., et al. Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study. BMJ. 2021;372:n311.
    1. Cuker A., Tseng E.K., Nieuwlaat R., et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Advances. 2021;5:872–888.
    1. Bikdeli B., Madhavan M.V., Gupta A., et al. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost. 2020;120:1004–1024.
    1. Hoffmann M., Kleine-Weber H., Schroeder S., et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271. 280.e8.
    1. Monteil V., Kwon H., Prado P., et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020;181:905. 913.e7.
    1. Vaduganathan M., Vardeny O., Michel T., McMurray J.J.V., Pfeffer M.A., Solomon S.D. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020;382:1653–1659.
    1. Lopes R.D., Macedo A.V.S., de Barros E Silva P.G.M., et al. Effect of discontinuing vs continuing angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in patients admitted with COVID-19: a randomized clinical trial. JAMA. 2021;325:254–264.
    1. Libby P., Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 2020;41:3038–3044.
    1. Cordon-Cardo C., Pujadas E., Wajnberg A., et al. COVID-19: staging of a new disease. Cancer Cell. 2020;38:594–597.
    1. Levi M. Pathophysiology of coagulopathy in hematological malignancies and in COVID-19. HemaSphere. 2021;5:e571.
    1. McGonagle D., O'Donnell J.S., Sharif K., Emery P., Bridgewood C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatol. 2020;2:e437–e445.
    1. Fletcher-Sandersjöö A., Bellander B.-M. Is COVID-19 associated thrombosis caused by overactivation of the complement cascade? A literature review. Thromb Res. 2020;194:36–41.
    1. Levi M., Thachil J., Iba T., Levy J.H. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020;7:e438–e440.
    1. Martinelli N., Montagnana M., Pizzolo F., et al. A relative ADAMTS13 deficiency supports the presence of a secondary microangiopathy in COVID 19. Thromb Res. 2020;193:170–172.
    1. Zuo Y., Estes S.K., Ali R.A., et al. Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Sci Translational Med. 2020;12
    1. Goswami J., MacArthur T.A., Sridharan M., et al. A review of pathophysiology, clinical features, and management options of COVID-19 associated coagulopathy. Shock. 2021;55:700–716.
    1. Tang N., Li D., Wang X., Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844–847.
    1. Zhou F., Yu T., Du R., et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–1062.
    1. Al-Samkari H., Karp Leaf R.S., Dzik W.H., et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020;136:489–500.
    1. Lala A., Johnson K.W., Januzzi J.L., et al. Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection. J Am Coll Cardiol. 2020;76:533–546.
    1. Giustino G., Croft L.B., Stefanini G.G., et al. Characterization of myocardial injury in patients with COVID-19. J Am Coll Cardiol. 2020;76:2043–2055.
    1. Lushina N., Kuo J.S., Shaikh H.A. Pulmonary, cerebral, and renal thromboembolic disease in a patient with COVID-19. Radiology. 2020;296:E181–E183.
    1. Bellosta R., Luzzani L., Natalini G., et al. Acute limb ischemia in patients with COVID-19 pneumonia. J Vasc Surg. 2020;72:1864–1872.
    1. Bhayana R., Som A., Li M.D., et al. Abdominal imaging findings in COVID-19: preliminary observations. Radiology. 2020;297:E207–E215.
    1. Oxley T.J., Mocco J., Majidi S., et al. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. 2020;382:e60.
    1. Malas M.B., Naazie I.N., Elsayed N., Mathlouthi A., Marmor R., Clary B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: a systematic review and meta-analysis. EClinicalMedicine. 2020;29
    1. Jiménez D., García-Sanchez A., Rali P., et al. Incidence of VTE and bleeding among hospitalized patients with Coronavirus Disease 2019: a systematic review and meta-analysis. Chest. 2021;159:1182–1196.
    1. Poissy J., Goutay J., Caplan M., et al. Pulmonary embolism in patients with COVID-19: awareness of an increased prevalence. Circulation. 2020;142:184–186.
    1. Yu B., Li X., Chen J., et al. Evaluation of variation in D-dimer levels among COVID-19 and bacterial pneumonia: a retrospective analysis. J Thromb Thrombolysis. 2020;50:548–557.
    1. Tacquard C., Mansour A., Godon A., et al. Impact of high-dose prophylactic anticoagulation in critically ill patients with COVID-19 pneumonia. Chest. 2021;159:2417–2427.
    1. Evaluating and Caring for Patients with Post-COVID Conditions: Interim Guidance.
    1. Fogarty H., Townsend L., Morrin H., et al. Persistent endotheliopathy in the pathogenesis of long COVID syndrome. J Thromb Haemost. 2021;19:2546–2553.
    1. Giannis D., Allen S.L., Tsang J., et al. Postdischarge thromboembolic outcomes and mortality of hospitalized patients with COVID-19: the CORE-19 registry. Blood. 2021;137:2838–2847.
    1. Roberts L.N., Whyte M.B., Georgiou L., et al. Postdischarge venous thromboembolism following hospital admission with COVID-19. Blood. 2020;136:1347–1350.
    1. Anticoagulation for patients with COVID-19 being discharged from hospital – recommendation 3.
    1. Talasaz A.H., Sadeghipour P., Kakavand H., et al. Recent randomized trials of antithrombotic therapy for patients with COVID-19: JACC State-of-the-Art Review. J Am Coll Cardiol. 2021;77:1903–1921.
    1. Ramacciotti E., Agati L.B., Calderaro D., et al. Medically ill hospitalized patients for COVID-19 thrombosis extended prophylaxis with rivaroxaban therapy: rationale and design of the MICHELLE Trial. Am Heart J. 2021;242:115–122.
    1. Medically ill hospitalized patients for COVID –19 thrombosis extended prophylaxis with rivaroxaban therapy: THE MICHELLE TRIAL. Presented by Dr. Eduardo Ramacciotti at the European Society of Cardiology Virtual Congress. August 29, 2021
    1. Connors J.M., Brooks M.M., Sciurba F.C., et al. Effect of antithrombotic therapy on clinical outcomes in outpatients with clinically stable symptomatic COVID-19: the ACTIV-4B randomized clinical trial. JAMA. 2021;326:1703–1712.
    1. 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;325:1620–1630.
    1. Sholzberg M., Tang G.H., Rahhal H., et al. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;375:n2400.
    1. Spyropoulos A.C., Goldin M., Giannis D., et al. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med. 2021;181:1612–1620.
    1. Lopes R.D., de Barros e Silva P.G.M., Furtado R.H.M., et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397:2253–2263.
    1. The REMAP-CAP, ACTIV-4a, and ATTACC Investigators Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N Engl J Med. 2021;385:777–789.
    1. The ATTACC, ACTIV-4a, and REMAP-CAP Investigators Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N Engl J Med. 2021;385:790–802.
    1. ten Cate H. Surviving Covid-19 with heparin? N Engl J Med. 2021;385(9):845–846.
    1. Perepu U.S., Chambers I., Wahab A., et al. Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: a multi-center, open-label, randomized controlled trial. J Thromb Haemost. 2021;19:2225–2234.
    1. Lemos A.C.B., do Espírito Santo D.A., Miranda C.H. Therapeutic anticoagulation in COVID-19 patients. Thromb Res. 2021;203:72–73.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa