Thromboprophylactic low-molecular-weight heparin versus standard of care in unvaccinated, at-risk outpatients with COVID-19 (ETHIC): an open-label, multicentre, randomised, controlled, phase 3b trial

Cools, Frank; Virdone, Saverio; Sawhney, J.P.S.; Lópes, Renato D.; Jacobson, Barry; Arcelus, Juan I.; Hobbs, F D Richard; Gibbs, Harry; Himmelreich, Jelle C L; MacCallum, Peter; Schellong, Sebastian; Haas, Sylvia; Turpie, Alexander G.G.; Ageno, Walter; Kayani, Gloria; Pieper, Karen S.; Kakkar, Ajay K.; Avhad, Ajit; Antunes, Murillo de Oliveira; Rocha, Ana Thereza; Lama, Jesus Gonzales; Abyankar, Atul; Kormann, Adrian; Zyl, Louis van; Kaul, Upendra; Adams, Frances; Aloysius, Ivan; Capehorn, Matthew; Kumar, Pradeep; Mahajan, Rajesh

doi:10.1016/s2352-3026(22)00173-9

Cited by 43 publications

(30 citation statements)

References 27 publications

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“…Similar to the ACTIV-4B study, the OVID study was terminated early due to low event rates and failed to conclusively assess the futility of thromboprophylaxis under the initial study design assumptions. The same results and conclusions were reached from the investigators of the ETHIC study that randomized 219 outpatients to a prophylactic dose of enoxaparin versus standard of care (no thromboprophylaxis) [ 58 ]. The ETHIC study was also terminated early due to low event rates.…”

Section: Results—key Questions and Practical Recommendationsmentioning

confidence: 60%

“…Management options in anticoagulated patients who require Paxlovid include reducing the dose of the DOAC, using a DOAC with less drug-drug interaction potential (e.g., edoxaban), or switching to a LMWH [ 28 ]. Five RCTs have addressed the question of outpatient thromboprophylaxis [ 52 , 56 , 57 , 58 , 59 ].…”

Section: Results—key Questions and Practical Recommendationsmentioning

confidence: 99%

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Practical Recommendations for Optimal Thromboprophylaxis in Patients with COVID-19: A Consensus Statement Based on Available Clinical Trials

Kyriakoulis

Dimakakos

Kyriakoulis

et al. 2022

JCM

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Coronavirus disease 2019 (COVID-19) has been shown to be strongly associated with increased risk for venous thromboembolism events (VTE) mainly in the inpatient but also in the outpatient setting. Pharmacologic thromboprophylaxis has been shown to offer significant benefits in terms of reducing not only VTE events but also mortality, especially in acutely ill patients with COVID-19. Although the main source of evidence is derived from observational studies with several limitations, thromboprophylaxis is currently recommended for all hospitalized patients with acceptable bleeding risk by all national and international guidelines. Recently, high quality data from randomized controlled trials (RCTs) further support the role of thromboprophylaxis and provide insights into the optimal thromboprophylaxis strategy. The aim of this statement is to systematically review all the available evidence derived from RCTs regarding thromboprophylaxis strategies in patients with COVID-19 in different settings (either inpatient or outpatient) and provide evidence-based guidance to practical questions in everyday clinical practice. Clinical questions accompanied by practical recommendations are provided based on data derived from 20 RCTs that were identified and included in the present study. Overall, the main conclusions are: (i) thromboprophylaxis should be administered in all hospitalized patients with COVID-19, (ii) an optimal dose of inpatient thromboprophylaxis is dependent upon the severity of COVID-19, (iii) thromboprophylaxis should be administered on an individualized basis in post-discharge patients with COVID-19 with high thrombotic risk, and (iv) thromboprophylaxis should not be routinely administered in outpatients. Changes regarding the dominant SARS-CoV-2 variants, the wide immunization status (increasing rates of vaccination and reinfections), and the availability of antiviral therapies and monoclonal antibodies might affect the characteristics of patients with COVID-19; thus, future studies will inform us about the thrombotic risk and the optimal therapeutic strategies for these patients.

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Section: Results—key Questions and Practical Recommendationsmentioning

confidence: 60%

Section: Results—key Questions and Practical Recommendationsmentioning

confidence: 99%

Practical Recommendations for Optimal Thromboprophylaxis in Patients with COVID-19: A Consensus Statement Based on Available Clinical Trials

Kyriakoulis

Dimakakos

Kyriakoulis

et al. 2022

JCM

View full text Add to dashboard Cite

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“…42 The Early Prophylactic Low-Molecular-Weight Heparin (LMWH) in Symptomatic COVID-19 Positive Patients (ETHIC) trial included unvaccinated patients with at least one risk factor for severe disease. 69 Standard-intensity prophylactic anticoagulation with enoxaparin for 21 days was not significantly associated with a reduction in PE compared with standard of care (RR: 0.36, 95% CI: 0.01–8.78). There were two minor bleeding in patients treated with enoxaparin and one in the standard of care group.…”

Section: Preventionmentioning

confidence: 89%

COVID-19-Associated Pulmonary Embolism: Review of the Pathophysiology, Epidemiology, Prevention, Diagnosis, and Treatment

Ortega‐Paz

Talasaz

Sadeghipour

et al. 2022

Semin Thromb Hemost

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COVID-19 is associated with endothelial activation in the setting of a potent inflammatory reaction and a hypercoagulable state. The end result of this thromboinflammatory state is an excess in thrombotic events, in particular venous thromboembolism. Pulmonary embolism (PE) has been of special interest in patients with COVID-19 given its association with respiratory deterioration, increased risk of intensive care unit admission, and prolonged hospital stay. The pathophysiology and clinical characteristics of COVID-19-associated PE may differ from the conventional non–COVID-19-associated PE. In addition to embolic events from deep vein thrombi, in situ pulmonary thrombosis, particularly in smaller vascular beds, may be relevant in patients with COVID-19. Appropriate prevention of thrombotic events in COVID-19 has therefore become of critical interest. Several changes in viral biology, vaccination, and treatment management during the pandemic may have resulted in changes in incidence trends. This review provides an overview of the pathophysiology, epidemiology, clinical characteristics, and risk factors of COVID-19-associated PE. Furthermore, we briefly summarize the results from randomized controlled trials of preventive antithrombotic therapies in COVID-19, focusing on their findings related to PE. We discuss the acute treatment of COVID-19-associated PE, which is substantially similar to the management of conventional non-COVID-19 PE. Ultimately, we comment on the current knowledge gaps in the evidence and the future directions in the treatment and follow-up of COVID-19-associated PE, including long-term management, and its possible association with long-COVID.

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“…There is no discussion, instead, that routine primary thromboprophylaxis in symptomatic COVID-19 outpatients would not be clinically effective, and should hence be currently discouraged. 34 35…”

Section: Tablementioning

confidence: 99%

Strength of Anticoagulation in Moderate to Severe COVID-19 Illness: In Medio Stat Virtus?

Lippi

Favaloro

2022

Semin Thromb Hemost

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Thromboprophylactic low-molecular-weight heparin versus standard of care in unvaccinated, at-risk outpatients with COVID-19 (ETHIC): an open-label, multicentre, randomised, controlled, phase 3b trial

Cited by 43 publications

References 27 publications

Practical Recommendations for Optimal Thromboprophylaxis in Patients with COVID-19: A Consensus Statement Based on Available Clinical Trials

Practical Recommendations for Optimal Thromboprophylaxis in Patients with COVID-19: A Consensus Statement Based on Available Clinical Trials

COVID-19-Associated Pulmonary Embolism: Review of the Pathophysiology, Epidemiology, Prevention, Diagnosis, and Treatment

Strength of Anticoagulation in Moderate to Severe COVID-19 Illness: In Medio Stat Virtus?

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