Effect of weight-adjusted intermediate-dose versus fixed-dose prophylactic anticoagulation with low-molecular-weight heparin on venous thromboembolism among noncritically and critically ill patients with COVID-19: the COVI-DOSE trial, a multicenter, randomised, open-label, phase 4 trial

Stéphane Zuily, Benjamin Lefèvre, Olivier Sanchez, Ombeline Empis de Vendin, Guillaume de Ciancio, Jean-Benoît Arlet, Lina Khider, Béatrice Terriat, Hélène Greigert, Céline S Robert, Guillaume Louis, Albert Trinh-Duc, Patrick Rispal, Sandrine Accassat, Guillaume Thiery, David Montani, Réza Azarian, Nicolas Meneveau, Simon Soudet, Raphaël Le Mao, François Maurier, Vincent Le Moing, Isabelle Quéré, Cécile M Yelnik, Nicolas Lefebvre, Martin Martinot, Maxime Delrue, Ygal Benhamou, Florence Parent, Pierre-Marie Roy, Emilie Presles, François Goehringer, Patrick Mismetti, Laurent Bertoletti, Patrick Rossignol, Francis Couturaud, Denis Wahl, Nathalie Thilly, Silvy Laporte, COVI-DOSE investigators, Stéphane Zuily, Francis Couturaud, François Goehringer, Silvy Laporte, Patrick Mismetti, Emilie Presles, Patrick Rossignol, Nathalie Thilly, Denis Wahl, Thomas Lecompte, Emmanuel Oger, Marie-Antoinette Sevestre, Florence Parent, Ygal Benhamou, Pierre-Marie Roy, Tristan Gigante, Morgane Gilg, Pierre-Luc Maclot, Bénédicte Rossignol, Jonathan Udot, Hélène Bouteille, Andréa Buchmuller, Céline Peurière, El Mehdi Siaghy, Valérie Bouaziz, Charlotte Daguin, Benjamin Grosjean, Véronique Saunier, Laurence Verger, Madlyne Jacquot, Nadine Petitpain, Martin Charly, Laurent Tordella, Emilie Presles, Guillaume Baronnet, Elisabeth Baux, Athanase Benetos, Jean-Baptiste Blanvillain, Marie Conrad, Guilhem Courte, Aurélie Cravoisy-Popovic, Virginie Dufrost, Sébastien Gibot, Philippe Guerci, Laure Joly, Antoine Kimmoun, Matthieu Koszutski, Alexandrine Larue, Bruno Levy, Marie-Reine Losser, Mathieu Mattei, Lionel Nace, Emmanuel Novy, Pierre Perez, Jean-Pierre Pertek, Camille Rigaux, Alexis Sauvage, Evelyne Schvoerer, Carine Thivilier, Lev Volkov, Piotr Zieminski, Manil Benlounes, Charles Cheng, Jean-Baptiste de Fréminville, Grégoire Détriché, Emmanuel Flammarion, Guillaume Goudot, Amer Hamdan, Raphaël Hindré, Corina Manoli, Emmanuel Messas, Adrien Michon, Tristan Mirault, Jean Pastré, Marie-Aude Penet, Benjamin Planquette, Geoffroy Volle, Rémy Hamdan, Aline Laubriet-Jazayeri, Vincent Petit, Lionel Piroth, Jean Pierre Quenot, Mélissa Saccu, Damien Barraud, Zoé Cavalli, Rostane Gaci, Mathilde Andreu, Laurent Bertoletti, Andréa Buchmuller, Elodie De Magalhaes, Sophie Bulifon, Athénaïs Boucly, Nathan Ebstein, Marc Humbert, Xavier Jaïs, Mitja Jevnikar, Laurent Savale, Andrei Horia Seferian, Charlotte Colin, Timothée Ganem, Mehdi Roumila, Romain Chopard, Matthieu Besutti, Basile Mouhat, Claire Andrejak, Stéphane Dupas, Gaëlle Le Roy, Santhi Samy-Modeliar, Anne Coste, Alexandre Fauche, David Goetghebeur, Christophe Gut-Gobert, Clément Hoffmann, Baptiste Hourmant, Cécile L'hévéder, Emmanuelle Lemoigne, Olivier Nepveu, Raphaël Paret, Gaël Picart, Saïd Azerkan, Chadia Boudaa, Julien Campagne, Peter Eszto, Benoît Godbert, Jean-François Guichard, Marion Heschung, Antoine Legoff, Jacques Mariot, Pascale Martin, Magalie Mercy, Julie Perrin, Stéphane Raymond, Nathalie Vernier, Pierre Fesler, Pierrick Henneton, Cédric Mercuzot, Nathalie Pansu, Lucas Perez, Loïc Andre, Edgar Bakhache, Marie-Charlotte Chopin, Marie Gilbert, Marc Lambert, Mohammad Ryadh Pokeerbux, François Danion, Yves Hansmann, Estelle Rougier, Yvon Ruch, Dominique Stéphan, Axel Ursenbach, Isabelle Connerade, Simon Gravier, Damien Kayser, Jean-Marc Michel, Mahsa Mohseni, Waël Younes, Ruxandra Burlacu, Amanda Lopes, Stéphane Mouly, Kladoum Nassarmadji, Damien Sène, Virginie Siguret, Alain Stepanian, Cédric Annweiler, Antoine Brangier, Vincent Dubee, Samir Henni, Jeanne Hersant, Jocelyne Loison, Léa Kern, Jean-Baptiste Laine, Claire Neveux-Brecheteau, Lucia Perez, Ruben Benainous, Bénédicte Giroux-Leprieur, Marilucy Lopez-Sublet, Saïda Khaled-Jousselin, Yohann Bernard, Amélie Amiot, Jessica Breistroff, Emilie Detry, Kadidiatou Diallo, Agnès Didier, Nathalie Dumont, Julie Egensperger, Aurélie Emmerich, Nelly François, Fanny Gallo, Valérie George, Quentin Gérome, Aurélie Gutehrle, Laure Lehman, Séverine Petit, Vanessa Piard, Maximilien Saint-Gilles, Olivier Terenzi, Amélie Marquette, Hélène Mortelette, Mathilde Audry, Amélie Cransac, Marine Maillard, Anaïs Boyer, Floriana Gallo, Arielle Urbing, Imane Zahaf, Alexandra Byczko, Amina Chaalal, Georgette Berlier, Corinne Bernabe, Souad Bezzeghoud, Caroline Chaudier, Carole Chauvet, Marina Davier, Carine Labruyere, Estelle Perrin, Michaël Pierre, Claire-Annissa Chekirine, Florence Voivret, Ramdane Meftali, Ouaffa Sabri, Anaïs Beulaygue, Julie Gall, Laure Girard, Soumia Haddaoui, Scheherazade Rami, Auriane Couderc, Aude Le Breton, Marie-Line Perruche, Cindy Claudon, Ludivine Roussel, Aude Barnier, Tiphaine Blanchard, Bénédicte Le Gall, Mélanie Pelouin, Anne-Sophie Veillon, Quam Aquereburu, Charlène Delaygue, Zahoua Ait Idir, Jérémy Drugeon, Déborah Dubrulle, Rabah Tezkratt, Anne-Sophie Frantz, Julie Drouaine, Jacqueline Dubois, Magali Eyriey, Elina Haerrel, Mélinda Beaudenon, Mialy Guenet, Thibaud Lecerf, Stéphanie Marechal-Girault, Sami Rehaiem, Romain Simon, Florence Dangeul-Potier, Morgane Goulvent, Souha Fliss, Fadhila Messani, Béatrice Mizejewski, Brigitte Mugnier, Valérie Opderbeck, Brigitte Risse, Stéphane Zuily, Benjamin Lefèvre, Olivier Sanchez, Ombeline Empis de Vendin, Guillaume de Ciancio, Jean-Benoît Arlet, Lina Khider, Béatrice Terriat, Hélène Greigert, Céline S Robert, Guillaume Louis, Albert Trinh-Duc, Patrick Rispal, Sandrine Accassat, Guillaume Thiery, David Montani, Réza Azarian, Nicolas Meneveau, Simon Soudet, Raphaël Le Mao, François Maurier, Vincent Le Moing, Isabelle Quéré, Cécile M Yelnik, Nicolas Lefebvre, Martin Martinot, Maxime Delrue, Ygal Benhamou, Florence Parent, Pierre-Marie Roy, Emilie Presles, François Goehringer, Patrick Mismetti, Laurent Bertoletti, Patrick Rossignol, Francis Couturaud, Denis Wahl, Nathalie Thilly, Silvy Laporte, COVI-DOSE investigators, Stéphane Zuily, Francis Couturaud, François Goehringer, Silvy Laporte, Patrick Mismetti, Emilie Presles, Patrick Rossignol, Nathalie Thilly, Denis Wahl, Thomas Lecompte, Emmanuel Oger, Marie-Antoinette Sevestre, Florence Parent, Ygal Benhamou, Pierre-Marie Roy, Tristan Gigante, Morgane Gilg, Pierre-Luc Maclot, Bénédicte Rossignol, Jonathan Udot, Hélène Bouteille, Andréa Buchmuller, Céline Peurière, El Mehdi Siaghy, Valérie Bouaziz, Charlotte Daguin, Benjamin Grosjean, Véronique Saunier, Laurence Verger, Madlyne Jacquot, Nadine Petitpain, Martin Charly, Laurent Tordella, Emilie Presles, Guillaume Baronnet, Elisabeth Baux, Athanase Benetos, Jean-Baptiste Blanvillain, Marie Conrad, Guilhem Courte, Aurélie Cravoisy-Popovic, Virginie Dufrost, Sébastien Gibot, Philippe Guerci, Laure Joly, Antoine Kimmoun, Matthieu Koszutski, Alexandrine Larue, Bruno Levy, Marie-Reine Losser, Mathieu Mattei, Lionel Nace, Emmanuel Novy, Pierre Perez, Jean-Pierre Pertek, Camille Rigaux, Alexis Sauvage, Evelyne Schvoerer, Carine Thivilier, Lev Volkov, Piotr Zieminski, Manil Benlounes, Charles Cheng, Jean-Baptiste de Fréminville, Grégoire Détriché, Emmanuel Flammarion, Guillaume Goudot, Amer Hamdan, Raphaël Hindré, Corina Manoli, Emmanuel Messas, Adrien Michon, Tristan Mirault, Jean Pastré, Marie-Aude Penet, Benjamin Planquette, Geoffroy Volle, Rémy Hamdan, Aline Laubriet-Jazayeri, Vincent Petit, Lionel Piroth, Jean Pierre Quenot, Mélissa Saccu, Damien Barraud, Zoé Cavalli, Rostane Gaci, Mathilde Andreu, Laurent Bertoletti, Andréa Buchmuller, Elodie De Magalhaes, Sophie Bulifon, Athénaïs Boucly, Nathan Ebstein, Marc Humbert, Xavier Jaïs, Mitja Jevnikar, Laurent Savale, Andrei Horia Seferian, Charlotte Colin, Timothée Ganem, Mehdi Roumila, Romain Chopard, Matthieu Besutti, Basile Mouhat, Claire Andrejak, Stéphane Dupas, Gaëlle Le Roy, Santhi Samy-Modeliar, Anne Coste, Alexandre Fauche, David Goetghebeur, Christophe Gut-Gobert, Clément Hoffmann, Baptiste Hourmant, Cécile L'hévéder, Emmanuelle Lemoigne, Olivier Nepveu, Raphaël Paret, Gaël Picart, Saïd Azerkan, Chadia Boudaa, Julien Campagne, Peter Eszto, Benoît Godbert, Jean-François Guichard, Marion Heschung, Antoine Legoff, Jacques Mariot, Pascale Martin, Magalie Mercy, Julie Perrin, Stéphane Raymond, Nathalie Vernier, Pierre Fesler, Pierrick Henneton, Cédric Mercuzot, Nathalie Pansu, Lucas Perez, Loïc Andre, Edgar Bakhache, Marie-Charlotte Chopin, Marie Gilbert, Marc Lambert, Mohammad Ryadh Pokeerbux, François Danion, Yves Hansmann, Estelle Rougier, Yvon Ruch, Dominique Stéphan, Axel Ursenbach, Isabelle Connerade, Simon Gravier, Damien Kayser, Jean-Marc Michel, Mahsa Mohseni, Waël Younes, Ruxandra Burlacu, Amanda Lopes, Stéphane Mouly, Kladoum Nassarmadji, Damien Sène, Virginie Siguret, Alain Stepanian, Cédric Annweiler, Antoine Brangier, Vincent Dubee, Samir Henni, Jeanne Hersant, Jocelyne Loison, Léa Kern, Jean-Baptiste Laine, Claire Neveux-Brecheteau, Lucia Perez, Ruben Benainous, Bénédicte Giroux-Leprieur, Marilucy Lopez-Sublet, Saïda Khaled-Jousselin, Yohann Bernard, Amélie Amiot, Jessica Breistroff, Emilie Detry, Kadidiatou Diallo, Agnès Didier, Nathalie Dumont, Julie Egensperger, Aurélie Emmerich, Nelly François, Fanny Gallo, Valérie George, Quentin Gérome, Aurélie Gutehrle, Laure Lehman, Séverine Petit, Vanessa Piard, Maximilien Saint-Gilles, Olivier Terenzi, Amélie Marquette, Hélène Mortelette, Mathilde Audry, Amélie Cransac, Marine Maillard, Anaïs Boyer, Floriana Gallo, Arielle Urbing, Imane Zahaf, Alexandra Byczko, Amina Chaalal, Georgette Berlier, Corinne Bernabe, Souad Bezzeghoud, Caroline Chaudier, Carole Chauvet, Marina Davier, Carine Labruyere, Estelle Perrin, Michaël Pierre, Claire-Annissa Chekirine, Florence Voivret, Ramdane Meftali, Ouaffa Sabri, Anaïs Beulaygue, Julie Gall, Laure Girard, Soumia Haddaoui, Scheherazade Rami, Auriane Couderc, Aude Le Breton, Marie-Line Perruche, Cindy Claudon, Ludivine Roussel, Aude Barnier, Tiphaine Blanchard, Bénédicte Le Gall, Mélanie Pelouin, Anne-Sophie Veillon, Quam Aquereburu, Charlène Delaygue, Zahoua Ait Idir, Jérémy Drugeon, Déborah Dubrulle, Rabah Tezkratt, Anne-Sophie Frantz, Julie Drouaine, Jacqueline Dubois, Magali Eyriey, Elina Haerrel, Mélinda Beaudenon, Mialy Guenet, Thibaud Lecerf, Stéphanie Marechal-Girault, Sami Rehaiem, Romain Simon, Florence Dangeul-Potier, Morgane Goulvent, Souha Fliss, Fadhila Messani, Béatrice Mizejewski, Brigitte Mugnier, Valérie Opderbeck, Brigitte Risse

Abstract

Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients.

Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707).

Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034).

Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens.

Funding: French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole.

Keywords: Anticoagulation; COVID-19; Heparin; Venous thromboembolism.

Conflict of interest statement

Dr. Zuily reports grants from French Ministry of Health, grants from The Grand Est Regional Council, grants from The Grand Nancy Métropole, grants from The Comité ad hoc de pilotage national des essais thérapeutiques et autres recherches sur le COVID-19 (CAPNET, label Priorité Nationale de Recherche–National Research Priority), during the conduct of the study; personal fees from Leo Pharma, personal fees from Bristol Myers Squibb, personal fees from Pfizer, personal fees from Novartis, personal fees from GlaxoSmithKline, personal fees from Amgen, personal fees from Viatris, personal fees from Sanofi, grants from Boehringer Ingelheim, grants from Bayer, outside the submitted work; Dr. Lefevre reports grants from Gilead, grants from ViiV, outside the submitted work; Dr. Sanchez reports grants and personal fees from Bristol Myers Squibb, grants and personal fees from Pfizer, grants and personal fees from Bayer, grants and personal fees from MSD, grants and personal fees from Boehringer Ingelheim, personal fees from Inari, personal fees from Boston Scientific, personal fees from Sanofi, personal fees from Leo Pharma, personal fees from Chiesi, grants from Oxyvie, outside the submitted work; Dr. Empis De Vendin has nothing to disclose; Dr. De Ciancio has nothing to disclose; Dr. Arlet reports grants from Addmedical, grants and other from Novartis, outside the submitted work; Dr. Khider has nothing to disclose; Dr. Terriat has nothing to disclose; Dr. Greigert has nothing to disclose; Dr. Robert has nothing to disclose; Dr. Louis has nothing to disclose; Dr. Trinh-Duc has nothing to disclose; Dr. Rispal has nothing to disclose; Dr. Accassat reports other from Leo Pharma, other from Janssen, other from MSD, outside the submitted work; Dr. Thiery has nothing to disclose; Dr. Montani reports grants and personal fees from Acceleron, grants and personal fees from Janssen, grants and personal fees from Merck, personal fees from Bayer, outside the submitted work; Dr. Azarian has nothing to disclose; Dr. Meneveau reports grants, personal fees and other from Bayer, grants, personal fees and other from Bristol Myers Squibb, grants, personal fees and other from Pfizer, grants from Medtronic, grants and personal fees from Boston Scientific, grants, personal fees and other from Abbott, personal fees from Inari, personal fees from Terumo, outside the submitted work; Dr. Soudet reports grants and personal fees from Leo Pharma, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Pfizer, outside the submitted work; Dr. Le Mao has nothing to disclose; Dr. Maurier has nothing to disclose; Dr. Le Moing has nothing to disclose; Dr. Quéré reports other from Leo Pharma, outside the submitted work; Dr. Yelnik has nothing to disclose; Dr. Lefebvre reports personal fees and other from Pfizer, other from Eumedica, outside the submitted work; Dr. Martinot reports other from Menarini, other from Overcome, outside the submitted work; Dr. Delrue has nothing to disclose; Dr. Benhamou has nothing to disclose; Dr. Parent reports grants from Oxyvie, personal fees from MSD, outside the submitted work; Dr. Roy reports personal fees and other from Bayer, personal fees and other from Boehringer Ingelheim, personal fees and other from Bristol Myers Squibb, personal fees and other from Pfizer, personal fees and other from Aspen, personal fees and other from Sanofi, outside the submitted work; Ms. Presles has nothing to disclose; Dr. Goehringer has nothing to disclose; Dr. Mismetti reports personal fees from Bayer Healthcare, personal fees from Bristol Myers Squibb, personal fees from Boehringer Ingelheim, personal fees from Sanofi, personal fees from Leo Pharma, personal fees from Aspen, personal fees from Pfizer, outside the submitted work; Dr. Bertoletti reports grants from Bayer, grants and personal fees from MSD, personal fees and other from Leo Pharma, personal fees and other from Bristol Myers Squibb, personal fees and other from Pfizer, outside the submitted work; Dr. Rossignol reports personal fees from AstraZeneca, personal fees from Bayer, personal fees from Boehringer-Ingelheim, personal fees from Cincor, personal fees from KBP, personal fees from Novartis, personal fees from NovoNordisk, personal fees from Roche, personal fees from Vifor/Relypsa, personal fees from Fresenius, personal fees and other from CardioRenal, personal fees from Idorsia, personal fees from Sequana, personal fees from Vifor, non-financial support from G3P, outside the submitted work; Dr. Couturaud reports grants and personal fees (board memberships, symposia or travel) from Bayer, grants and personal fees (board memberships, symposia or travel) from Bristol-Myers Squibb/Pfizer, personal fees (board memberships, symposia or travel) from Merck Sharp and Dohme, personal fees (board memberships, symposia or travel) from Astra Zeneca, personal fees (board memberships or symposia) from Sanofi, personal fees (board memberships or symposia) from Janssen, personal fees (board memberships, symposia or travel) from Leo Pharma, outside the submitted work; Dr. Wahl has nothing to disclose; Dr. Thilly has nothing to disclose; Dr. Laporte reports personal fees from Lilly/Boehringer Ingelheim, personal fees from Bristol Myers Squibb/Pfizer, personal fees from Merck, personal fees from Leo-Pharma, outside the submitted work.

© 2023 The Authors.

Figures

Fig. 1
Fig. 1
Flow chart. Between May 2020 and April 2021, 1005 patients were included in 20 centers: 502 were randomly assigned to receive a weight-adjusted prophylactic dose of low-molecular-weight heparin, and 498 received a fixed prophylactic dose. Thus, 1000 patients were considered in the intention-to-treat analysis.
Fig. 2
Fig. 2
Cumulative Event Rates for the Primary Outcome. The curves are shown for the first occurrence of the primary outcome of adjudicated symptomatic recurrent venous thromboembolism defined as symptomatic deep-vein thrombosis or pulmonary embolism or venous thromboembolism-related death during the hospital stay. The inset shows the same data on an expanded y-axis.
Fig. 3
Fig. 3
Descriptive Subgroup Analyses for the Primary Outcome. Subgroup analyses were conducted in the intention-to-treat population. The size of each square indicates the treatment effect, and arrows indicate 95% confidence intervals that extend past the boundary of the graph. Body mass index is the weight in kilograms divided by the square of the height in meters. Abbreviation: ECMO: extracorporeal membrane oxygenation.

References

    1. Surviving Covid-19 with heparin? N Engl J Med. 2021;385:1056.
    1. REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, et al. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N Engl J Med. 2021;385:777–789.
    1. Cai Q., Chen F., Wang T., et al. Obesity and COVID-19 severity in a designated hospital in Shenzhen, China. Diabetes Care. 2020;43:1392–1398.
    1. Tritschler T., Mathieu M.E., Skeith L., et al. Anticoagulant interventions in hospitalized patients with COVID-19: a scoping review of randomized controlled trials and call for international collaboration. J Thromb Haemost. 2020;18:2958–2967.
    1. Kay A.B., Majercik S., Sorensen J., et al. Weight-based enoxaparin dosing and deep vein thrombosis in hospitalized trauma patients: a double-blind, randomized, pilot study. Surgery. 2018;S0039-6060(18):30094–30101.
    1. Wang T.F., Milligan P.E., Wong C.A., Deal E.N., Thoelke M.S., Gage B.F. Efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients. Thromb Haemost. 2014;111:88–93.
    1. Song J.Q., Xuan L.Z., Wu W., Huang J.F., Zhong M. Low molecular weight heparin once versus twice for thromboprophylaxis following esophagectomy: a randomised, double-blind and placebo-controlled trial. J Thorac Dis. 2015;7:1158–1164.
    1. Bistervels I.M., Buchmüller A., Wiegers H.M.G., et al. Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial. Lancet. 2022;400:1777–1787.
    1. World Health Organization . 2020. Clinical management of COVID-19 (Interim Guidance) published online May 27.
    1. Konstantinides S.V., Meyer G., Becattini C., et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS) Eur Heart J. 2020;41:543–603.
    1. Franco L., Becattini C., Beyer-Westendorf J., et al. Definition of major bleeding: prognostic classification. J Thromb Haemost. 2020;18:2852–2860.
    1. Kaatz S., Ahmad D., Spyropoulos A.C., Schulman S., Subcommittee on Control of Anticoagulation Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13:2119–2126.
    1. Latouche A., Porcher R. Sample size calculations in the presence of competing risks. Stat Med. 2007;26:5370–5380.
    1. Klok F.A., Kruip M.J.H.A., van der Meer N.J.M., et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145–147. S0049384820301201.
    1. Laporte S., Chapelle C., Bertoletti L., et al. Indirect comparison meta-analysis of two enoxaparin regimens in patients undergoing major orthopaedic surgery. Impact on the interpretation of thromboprophylactic effects of new anticoagulant drugs. Thromb Haemost. 2014;112:503–510.
    1. Middeldorp S., Coppens M., van Haaps T.F., et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18:1995–2002.
    1. Prentice R.L., Kalbfleisch J.D., Peterson A.V., Flournoy N., Farewell V.T., Breslow N.E. The analysis of failure times in the presence of competing risks. Biometrics. 1978;34:541–554.
    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. Inspiration Investigators. Sadeghipour P., Talasaz A.H., et al. 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. Bikdeli B., Talasaz A.H., Rashidi F., et al. Intermediate-dose versus standard-dose prophylactic anticoagulation in patients with COVID-19 admitted to the intensive care unit: 90-day results from the INSPIRATION randomized trial. Thromb Haemost. 2021;122 doi: 10.1055/a-1485-2372. published online April 17.
    1. Muñoz-Rivas N., Aibar J., Gabara-Xancó C., et al. Efficacy and safety of tinzaparin in prophylactic, intermediate and therapeutic doses in non-critically ill patients hospitalized with COVID-19: the PROTHROMCOVID randomized controlled trial. J Clin Med. 2022;11:5632.
    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 doi: 10.1001/jamainternmed.2021.6203. published online Oct 7.
    1. ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, et al. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N Engl J Med. 2021;385:790–802.
    1. Schulman S., Sholzberg M., Spyropoulos A.C., et al. ISTH guidelines for antithrombotic treatment in COVID-19. J Thromb Haemost. 2022;20:2214–2225.
    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. Di Minno A., Ambrosino P., Calcaterra I., Di Minno M.N.D. COVID-19 and venous thromboembolism: a meta-analysis of literature studies. Semin Thromb Hemost. 2020;46:763–771.
    1. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Sterne J.A.C., Murthy S., et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324:1330–1341.
    1. Polack F.P., Thomas S.J., Kitchin N., et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383:2603–2615.
    1. Susen S., Tacquard C.A., Godon A., et al. Prevention of thrombotic risk in hospitalized patients with COVID-19 and hemostasis monitoring. Crit Care. 2020;24:364.
    1. Spyropoulos A.C., Raskob G.E., Cohen A.T., et al. Association of bleeding severity with mortality in extended thromboprophylaxis of medically ill patients in the MAGELLAN and MARINER trials. Circulation. 2022;145:1471–1479.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir