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

Lefèvre, Brigitte; Sanchez, Olivier; Vendin, Ombeline Empis de; Ciancìo, Giovanni; Arlet, Jean‐Benoît; Khider, Lina; Terriat, Béatrice; Greigert, Hélène; Robert, Céline; Louis, Guillaume; Trinh-Duc, Albert; Rispal, P; Accassat, Sandrine; Thiéry, Guillaume; Montani, David; Azarian, R.; Meneveau, Nicolas; Soudet, S.; Mao, Raphaël Le; Maurier, F.; Moing, Vincent Le; Quéré, Isabelle; Yelnik, Cécile; Lefèbvre, Nicolas; Martinot, M.; Delrue, Maxime; Zuily, Stéphane; Couturaud, F.; Goehringer, François; Laporte, Silvy; Mismetti, Patrick; Rossignol, Patrick; Thilly, Nathalie; Wahl, Denis; Lecompte, T.; Oger, Emmanuel; Sevestre, Marie‐Antoinette; Parent, Florence; Benhamou, Y.; Roy, Pierre‐Marie; Gigante, Tristan; Gilg, Morgane; Maclot, Pierre-Luc; Rossignol, Bénédicte; Udot, Jonathan; Bouteille, H; Peurière, Céline; Siaghy, El-Mehdi; Bouaziz, Valérie; Daguin, Charlotte; Grosjean, Benjamin; Saunier, Véronique; Verger, Laurence; Jacquot, Madlyne; Petitpain, Nadine; Charly, Martin; Tordella, Laurent; Presles, Émilie; Baronnet, G.; Baux, Elisabeth; Bénétos, Athanase; Blanvillain, Jean-Baptiste; Conrad, Marie; Courte, Guilhem; Cravoisy-Popovic, Aurélie; Dufrost, Virginie; Gibot, Sébastien; Guerci, Philippe; Joly, Laure; Kimmoun, Antoine; Koszutski, Matthieu; Larue, Alexandrine; Lévy, Bruno; Losser, Marie-Reine; Mattéi, M.; Nace, Lionel; Novy, Emmanuel; Perez, Pierre; Pertek, Jean-Pierre; Rigaux, Camille; Sauvage, A.; Schvoerer, Évelyne; Thivilier, Carine; Volkov, Lev; Zieminski, Piotr; Benlounes, Manil; Cheng, Charles; Fréminville, Jean-Baptiste de; Détriché, Grégoire; Flammarion, Emmanuel; Goudot, Guillaume; Hamdan, Amer Cavalheiro; Hindré, R.; Manoli, Corina; Messas, Emmanuel; Michon, A.; Mirault, Tristan; Pastré, Jean; Penet, Marie-Aude; Planquette, Benjamin; Volle, Geoffroy; Hamdan, Rémy; Laubriet-Jazayeri, Aline; Petit, Vincent; Piroth, Lionel; Quenot, Jean‐Pierre; Saccu, Mélissa; Barraud, Damien; Cavalli, Zoé; Gaci, Rostane; Andreu, Mathilde; Bertoletti, Laurent; Buchmüller, Andréa; Magalhaes, Élodie De; Bulifon, Sophie; Boucly, Athénaïs; Ebstein, Nathan; Humbert, Marc; Jaïs, Xavier; Jevnikar, Mitja; Savale, Laurent; Seferian, Andrei; Colin, Charlotte; Ganem, Timothée; Roumila, Mehdi; Chopard, Romain; Besutti, Matthieu; Mouhat, B.; Andréjak, Claire; Dupas, S.; Roy, Gaëlle Le; Samy-Modeliar, Santhi; Coste, Anne; Fauché, Alexandre; Goetghebeur, David; Gut-Gobert, Christophe; Hoffmann, Clément; Hourmant, Baptiste; L'hévéder, Cécile; Lemoigne, Emmanuelle; Nepveu, Olivier; Paret, R.; Picart, Gael; Azerkan, Saïd; Boudaa, C; Campagne, J.; Eszto, Peter; Godbert, B.; Guichard, Jean-François; Heschung, Marion; Mariot, Jacques; Martin, P.; Mercy, Magalie; Perrin, J.; Raymond, Stéphane; Vernier, N.; Fesler, Pierre; Henneton, P.; Mercuzot, Cédric; Pansu, Nathalie; Perez, Lucas; Andre, Loïc; Bakhache, E; Chopin, Marie‐Charlotte; Gilbert, Marie; Lambert, Marc; Pokeerbux, Mohammad Ryadh; Danion, François; Hansmann, Yves; Rougier, Estelle; Ruch, Yvon; Stephan, D.; Ursenbach, Axel; Connerade, Isabelle; Gravier, Simon; Kayser, Diana; Michel, Jean-Marc; Mohseni, Masood; Younes, W.; Burlacu, Ruxandra; Lopes, Amanda; Mouly, Stéphane; Nassarmadji, Kladoum; Sène, Damien; Siguret, V.; Stepanian, Alain; Annweiler, Cédric; Brangier, Antoine; Dubée, Vincent; Henni, Samir; Hersant, Jeanne; Loison, J.; Kern, Lukas; Laine, Jean-Baptiste; Neveux-Brecheteau, Claire; Pérez, Lucía; Benainous, Ruben; Giroux-Leprieur, B.; Lopez‐Sublet, Marilucy; Khaled-Jousselin, Saïda; Bernard, Yohann; Amiot, Aurélien; Breistroff, Jessica; Detry, Emilie; Diallo, K; Didier, Agnès; Dumont, Nathalie; Egensperger, Julie; Emmerich, Aurélie; François, Nelly; Gallo, F; George, Valérie; Gérome, Quentin; Gutehrle, Aurélie; Lehman, Li-wei H.; Petit, Séverine; Piard, Vanessa; Saint-Gilles, Maximilien; Terenzi, Olivier; Marquette, Amélie; Mortelette, Hélène; Audry, Mathilde; Cransac, Amélie; Maillard, Marc; Boyer, A.; Gallo, Floriana; Urbing, Arielle; Zahaf, Imane; Byczko, Alexandra; Chaalal, Amina; Berlier, Georgette; Bernabé, Carmen María Marín; Bezzeghoud, Souad; Chauvet, C.; Davier, M.; Labruyère, Carine; Perrin, Estelle; St.Pierre, Michael; Chekirine, Claire-Annissa; Voivret, Florence; Meftali, Ramdane; Sabri, O.; Beulaygue, Anaïs; Gall, Julie; Girard, L.; Haddaoui, Soumia; Rami, S; Couderc, Auriane; Breton, Aude Le; Perruche, Marie-Line; Claudon, Cindy; Roussel, Laurent; Barnier, Anne; Blanchard, Tiphaine; Gall, Bénédicte Le; Pelouin, Mélanie; Veillon, Anne-Sophie; Aquereburu, Quam; Delaygue, Charlène; Idir, Zahoua Ait; Drugeon, Jérémy; Dubrulle, Déborah; Tezkratt, Rabah; Frantz, A.-S.; Drouaine, J; Dubois, Jacqueline; Eyriey, Magali; Haerrel, Elina; Beaudenon, Mélinda; Guenet, Mialy; Lecerf, Thibaud; Marechal-Girault, Stéphanie; Rehaiem, Sami; Simon, Romain; Dangeul-Potier, Florence; Goulvent, Morgane; Fliss, Souha; Messani, Fadhila; Mizejewski, Béatrice; Mugnier, Bénédicte; Opderbeck, Valérie; Risse, Brigitte

doi:10.1016/j.eclinm.2023.102031

Cited by 9 publications

(3 citation statements)

References 29 publications

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“…Our findings align with a metaanalysis by J. Ena and V. Valls [36], where the rate of major bleeding events was reported as 0.99% in not critically ill patients undergoing prophylactic dosages of anticoagulant therapy. Also, another meta-analysis by S. Zuily et al [37], comparing fixed and weight-based dose anticoagulant prophylaxis, found a low rate of major bleeding (1% in the weight base group and 1.3% in the fixed dose group), comparable with our findings.…”

Section: Discussionsupporting

confidence: 92%

“…We found that length of stay (median days) was significantly longer in patients with a major bleeding event [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] vs. 14 (IQR 8-24), p < 0.0001)] (Table 3). Death was more frequently observed in patients with major bleeding (34.5% vs. 18.0%, p = 0.039).…”

Section: Outcome Of Subjects With a Major Bleeding Eventmentioning

confidence: 92%

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Major Bleeding Events in Hospitalized COVID-19 Patients: A Retrospective Observational Study

Poloni,

Casalini,

Pozza

et al. 2024

Medicina

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Thromboprophylaxis/anticoagulation treatment is often required in hospitalized COVID-19 patients. We aimed to estimate the prevalence of major bleeding events in hospitalized COVID-19 patients. This was a retrospective observational study including all COVID-19 hospitalized patients ≥18 years of age at one reference center in northern Italy. The crude prevalence (between February 2020–2022) of major bleeding events was estimated as the number of major bleeding episodes divided by patients at risk. Uni- and multivariable Cox models were built to assess factors potentially associated with major bleeding events. Twenty-nine (0.98%) out of 2,945 COVID-19 patients experienced a major bleeding event [prevalence of 0.55% (95%CI 0.37–0.79)], of which five were fatal. Patients who experienced a major bleeding event were older [78 years (72–84 IQR) vs. 67 years (55–78 IQR), p-value < 0.001] and more frequently exposed to anti-aggregating therapy (44.8% vs. 20.0%, p-value 0.002) when compared to those who did not. In the multivariable Cox model, age [per 1 year more AHR 1.05 (CI95% 1.02–1.09)] was independently associated with an increased risk of major bleeding events. A strict monitoring of older hospitalized COVID-19 patients is warranted due to the risk of major bleeding events.

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Section: Discussionsupporting

confidence: 92%

Section: Outcome Of Subjects With a Major Bleeding Eventmentioning

confidence: 92%

Major Bleeding Events in Hospitalized COVID-19 Patients: A Retrospective Observational Study

Poloni,

Casalini,

Pozza

et al. 2024

Medicina

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show abstract

“…In studies 12 , 32 , 36 , 37 investigating the use of intermediate doses for noncritically ill patients, the intermediate dose showed a statistically significant lower risk of thromboembolism events compared to the prophylactic dose (RR, 0.38; 95% CI: 0.21–0.69) (Fig. 4 A).…”

Section: Resultsmentioning

confidence: 97%

Appropriate thromboprophylaxis strategy for COVID-19 patients on dosage, antiplatelet therapy, outpatient, and postdischarge prophylaxis: a meta-analysis of randomized controlled trials

Meng,

Tang,

Xiao

et al. 2024

International Journal of Surgery

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Background: There was controversy surrounding the optimal thromboprophylaxis strategy for COVID-19 patients. This included debates on the dosage of anticoagulants for thromboembolism prophylaxis, the requirement for additional antiplatelet therapy, and the necessity of prophylaxis for outpatients and post-discharge. To explore this, we performed a meta-analysis of randomized controlled trials. Methods: PubMed, Cochrane Library, Embase, and Web of Science were last searched on 26 July 2023 for studies comparing the effect of different dose of anticoagulation, additional antiplatelet and post-discharge prophylaxis for COVID-19 patients. The results of eligible studies were analyzed in terms of thromboembolism events, major bleeding and all-cause mortality during follow-up. Results: Our study included a total of 25 randomized controlled trials, involving 17,911 patients. Our results revealed that, compared to prophylactic dose, therapeutic dose showed lower thrombotic risk (RR, 0.66; 95%CI, 0.45 to 0.96) but had similar major bleeding risk for critically ill patients with COVID-19. On the other hand, intermediate dose and prophylactic dose demonstrated similar thromboembolism risk and major bleeding risk. For non-critically ill patients with COVID-19, therapeutic dose of anticoagulants was associated with lower thrombotic risk (RR, 0.50; 95%CI 0.34 to 0.72) but, at the same time, increased the risk of major bleeding (RR, 2.01; 95%CI 1.22 to 3.33). However, intermediate dose showed lower thromboembolism risk (RR, 0.38; 95%CI 0.21 to 0.69) while maintaining a similar major bleeding risk. In critically ill patients, additional antiplatelet therapy showed similar thromboembolism, major bleeding risk, and mortality when compared to no treatment. For outpatients, additional prophylactic anticoagulation showed similar thromboembolism, major bleeding risk, and mortality when compared to no treatment. For post-discharge patients, post-discharge prophylaxis reduced thromboembolism risk (RR, 0.49; 95%CI 0.31 to 0.76) but increased major bleeding risk (RR, 2.63; 95%CI, 1.13 to 6.14). Conclusion: For non-critically ill patients, therapeutic dose prophylactic anticoagulation significantly reduced venous thromboembolism but increases major bleeding risk. Intermediate dose effectively lowered venous thromboembolism without raising major bleeding risk. The optimal dose and need for additional antiplatelet therapy in critically ill patients, as well as the necessity of prophylactic anticoagulation in outpatient and post-discharge patients, required further investigation and confirmation through rigorous evidence studies.

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Embracing Imatinib: a novel approach to safeguarding the endothelial barrier in patients with COVID-19

2023

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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

Cited by 9 publications

References 29 publications

Major Bleeding Events in Hospitalized COVID-19 Patients: A Retrospective Observational Study

Major Bleeding Events in Hospitalized COVID-19 Patients: A Retrospective Observational Study

Appropriate thromboprophylaxis strategy for COVID-19 patients on dosage, antiplatelet therapy, outpatient, and postdischarge prophylaxis: a meta-analysis of randomized controlled trials

Embracing Imatinib: a novel approach to safeguarding the endothelial barrier in patients with COVID-19

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