{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T11:43:36Z","timestamp":1782301416840,"version":"3.54.5"},"reference-count":45,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T00:00:00Z","timestamp":1665446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>(1) Background: In COVID-19 patients, the occurrence of thromboembolic complications contributes to disease progression and mortality. In patients at increased risk for thrombotic complications, therapeutic enoxaparin should be considered. However, critically ill COVID-19 patients could develop resistance to enoxaparin. Bivalirudin, a thrombin inhibitor, may be an alternative. This pilot multicenter randomized controlled trial aims to ascertain if bivalirudin may reduce the time spent under invasive mechanical ventilation, as compared to enoxaparin. (2) Methods: Intubated COVID-19 patients at risk for thrombo-embolic complications were randomized to receive therapeutic doses of enoxaparin or bivalirudin. We ascertained the time spent under invasive mechanical ventilation during the first 28 days from Intensive Care Unit (ICU) admission. A standardized weaning protocol was implemented in all centers. In addition, we assessed the occurrence of thromboembolic complications, the number of patients requiring percutaneous tracheostomy, the gas exchange, the reintubation rate, the ICU length of stay, the ICU and 28-days mortalities. (3) Results: We enrolled 58 consecutive patients. Bivalirudin did not reduce the time spent under invasive mechanical ventilation as compared to enoxaparin (12 [8; 13] vs. 13 [10; 15] days, respectively; p = 0.078). Thrombotic (p = 0.056) and embolic (p = 0.423) complications, need for tracheostomy (p = 0.423) or reintubation (p = 0.999), the ICU length of stay (p = 0.076) and mortality (p = 0.777) were also similar between treatments. Patients randomized to bivalirudin showed a higher oxygenation at day 7 and 15 after randomization, when compared to enoxaparin group. (4) Conclusions: In intubated COVID-19 patients at increased risk for thromboembolic complications, bivalirudin did not reduce the time spent under invasive mechanical ventilation, nor improved any other clinical outcomes.<\/jats:p>","DOI":"10.3390\/jcm11205992","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T22:18:13Z","timestamp":1665526693000},"page":"5992","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Bivalirudin vs. Enoxaparin in Intubated COVID-19 Patients: A Pilot Multicenter Randomized Controlled Trial"],"prefix":"10.3390","volume":"11","author":[{"given":"Eugenio","family":"Garofalo","sequence":"first","affiliation":[{"name":"Anesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, \u201cMagna Graecia\u201d University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianmaria","family":"Cammarota","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Intensive Care Medicine, University of Perugia, 06121 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Neri","sequence":"additional","affiliation":[{"name":"Anesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, \u201cMagna Graecia\u201d University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Macheda","sequence":"additional","affiliation":[{"name":"Anesthesia and Intensive Care Unit, Grande Ospedale Metropolitano, 89121 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Biamonte","sequence":"additional","affiliation":[{"name":"Anesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, \u201cMagna Graecia\u201d University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pino","family":"Pasqua","sequence":"additional","affiliation":[{"name":"Anesthesia and Intensive Care Unit, Annunziata Hospital, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Laura","family":"Guzzo","sequence":"additional","affiliation":[{"name":"Anesthesia and Intensive Care Unit, \u201cPugliese Ciaccio\u201d Hospital, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6970-7202","authenticated-orcid":false,"given":"Federico","family":"Longhini","sequence":"additional","affiliation":[{"name":"Anesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, \u201cMagna Graecia\u201d University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Bruni","sequence":"additional","affiliation":[{"name":"Anesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, \u201cMagna Graecia\u201d University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.cca.2020.06.017","article-title":"Cytokine storm induced by SARS-CoV-2","volume":"509","author":"Song","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1055\/s-0040-1714350","article-title":"COVID-19-Related Severe Hypercoagulability in Patients Admitted to Intensive Care Unit for Acute Respiratory Failure","volume":"120","author":"Spiezia","year":"2020","journal-title":"Thromb. Haemost."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.trsl.2020.04.007","article-title":"Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases","volume":"220","author":"Magro","year":"2020","journal-title":"Transl. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13017-020-00320-5","article-title":"Histopathological findings in a COVID-19 patient affected by ischemic gangrenous cholecystitis","volume":"15","author":"Bruni","year":"2020","journal-title":"World J. Emerg. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1001\/jamaneurol.2020.2065","article-title":"Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review","volume":"77","author":"Zubair","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"216","DOI":"10.2174\/1574887115666201016153031","article-title":"Erythema Pernio-Like in Four Adolescents in the Era of the Coronavirus-2 Infection","volume":"16","author":"Promenzio","year":"2021","journal-title":"Rev. Recent Clin. Trials"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1001\/jamainternmed.2020.0994","article-title":"Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China","volume":"180","author":"Wu","year":"2020","journal-title":"JAMA Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"599502","DOI":"10.3389\/fonc.2020.599502","article-title":"COVID-19: High-JAKing of the Inflammatory \u201cFlight\u201d by Ruxolitinib to Avoid the Cytokine Storm","volume":"10","author":"Botta","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"m2980","DOI":"10.1136\/bmj.m2980","article-title":"Drug treatments for covid-19: Living systematic review and network meta-analysis","volume":"370","author":"Siemieniuk","year":"2020","journal-title":"BMJ"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1055\/s-0040-1713152","article-title":"Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research","volume":"120","author":"Bikdeli","year":"2020","journal-title":"Thromb. Haemost."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1055\/s-0040-1712097","article-title":"Pulmonary Embolism or Pulmonary Thrombosis in COVID-19? Is the Recommendation to Use High-Dose Heparin for Thromboprophylaxis Justified?","volume":"120","author":"Cattaneo","year":"2020","journal-title":"Thromb. Haemost."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.cmi.2021.11.007","article-title":"ESCMID COVID-19 living guidelines: Drug treatment and clinical management","volume":"28","author":"Bartoletti","year":"2022","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1056\/NEJMoa2103417","article-title":"Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19","volume":"385","author":"Goligher","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_14","first-page":"167","article-title":"COVID-19 and haemostasis: A position paper from Italian Society on Thrombosis and Haemostasis (SISET)","volume":"18","author":"Marietta","year":"2020","journal-title":"Blood Transfus."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1016\/j.jacc.2020.08.041","article-title":"Anticoagulation, Bleeding, Mortality, and Pathology in Hospitalized Patients With COVID-19","volume":"76","author":"Nadkarni","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1111\/jth.14817","article-title":"Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy","volume":"18","author":"Tang","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.thromres.2006.10.011","article-title":"Thrombelastography monitoring of resistance to enoxaparin anticoagulation in thrombophilic pregnancy patients","volume":"120","author":"Carroll","year":"2007","journal-title":"Thromb. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1177\/147323000903700518","article-title":"Role of enoxaparin resistance in recurrent chest pain in the intensive care unit","volume":"37","author":"Kaya","year":"2009","journal-title":"J. Int. Med. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.beha.2004.02.002","article-title":"Bivalent direct thrombin inhibitors: Hirudin and bivalirudin","volume":"17","author":"Warkentin","year":"2004","journal-title":"Best Pract. Res. Clin. Haematol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1053\/j.jvca.2020.06.059","article-title":"Bivalirudin for Maintenance Anticoagulation During Venovenous Extracorporeal Membrane Oxygenation for COVID-19","volume":"35","author":"Seelhammer","year":"2021","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1053\/j.jvca.2021.10.026","article-title":"Efficacy of Bivalirudin for Therapeutic Anticoagulation in COVID-19 Patients Requiring ECMO Support","volume":"36","author":"Trigonis","year":"2022","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1001\/jamainternmed.2021.6203","article-title":"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","volume":"181","author":"Spyropoulos","year":"2021","journal-title":"JAMA Intern. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e219","DOI":"10.1097\/CCM.0000000000004899","article-title":"Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU: First Update","volume":"49","author":"Alhazzani","year":"2021","journal-title":"Crit. Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e440","DOI":"10.1097\/CCM.0000000000004363","article-title":"Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19)","volume":"48","author":"Alhazzani","year":"2020","journal-title":"Crit. Care Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13418","DOI":"10.1038\/s41598-021-92960-z","article-title":"Early extubation with immediate non-invasive ventilation versus standard weaning in intubated patients for coronavirus disease 2019: A retrospective multicenter study","volume":"11","author":"Cammarota","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s13613-019-0565-0","article-title":"Electrical impedance tomography during spontaneous breathing trials and after extubation in critically ill patients at high risk for extubation failure: A multicenter observational study","volume":"9","author":"Longhini","year":"2019","journal-title":"Ann. Intensive Care"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1007\/s00134-018-5478-0","article-title":"Early extubation followed by immediate noninvasive ventilation vs. standard extubation in hypoxemic patients: A randomized clinical trial","volume":"45","author":"Vaschetto","year":"2019","journal-title":"Intensive Care Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1602426","DOI":"10.1183\/13993003.02426-2016","article-title":"Official ERS\/ATS clinical practice guidelines: Noninvasive ventilation for acute respiratory failure","volume":"50","author":"Rochwerg","year":"2017","journal-title":"Eur Respir. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2101574","DOI":"10.1183\/13993003.01574-2021","article-title":"ERS clinical practice guidelines: High-flow nasal cannula in acute respiratory failure","volume":"59","author":"Oczkowski","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Maggiore, S.M., Jaber, S., Grieco, D.L., Mancebo, J., Zakynthinos, S., Demoule, A., Ricard, J.D., Navalesi, P., Vaschetto, R., and Hraiech, S. (2022). High-Flow Versus VenturiMask Oxygen Therapy to Prevent Re-Intubation in Hypoxemic Patients After Extubation: A Multicenter, Randomized Clinical Trial. Am. J. Respir. Crit. Care Med.","DOI":"10.1164\/rccm.202201-0065OC"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1164\/rccm.201810-2050CP","article-title":"Reappraisal of Ventilator-Free Days in Critical Care Research","volume":"200","author":"Yehya","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1111\/j.1538-7836.2010.04044.x","article-title":"A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: The Padua Prediction Score","volume":"8","author":"Barbar","year":"2010","journal-title":"J. Thromb. Haemost."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1093\/qjmed\/hcaa224","article-title":"Association of Padua prediction score with in-hospital prognosis in COVID-19 patients","volume":"113","author":"Zeng","year":"2020","journal-title":"QJM"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ijid.2021.11.038","article-title":"Predictive scores for the diagnosis of Pulmonary Embolism in COVID-19: A systematic review","volume":"115","author":"Rindi","year":"2022","journal-title":"Int. J. Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1001\/jamainternmed.2020.3539","article-title":"Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy","volume":"180","author":"Grasselli","year":"2020","journal-title":"JAMA Intern. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wan, X., Wang, W., Liu, J., and Tong, T. (2014). Estimating the sample mean and standard deviation from the sample size, median, range and\/or interquartile range. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-135"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1097\/CCM.0000000000004944","article-title":"Comparison of Anticoagulation Strategies in Patients Requiring Venovenous Extracorporeal Membrane Oxygenation: Heparin Versus Bivalirudin","volume":"49","author":"Rivosecchi","year":"2021","journal-title":"Crit. Care Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1111\/aor.12168","article-title":"Primary anticoagulation with bivalirudin for patients with implantable ventricular assist devices","volume":"38","author":"Pieri","year":"2014","journal-title":"Artif. Organs"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1053\/j.jvca.2012.07.019","article-title":"Bivalirudin versus heparin as an anticoagulant during extracorporeal membrane oxygenation: A case-control study","volume":"27","author":"Pieri","year":"2013","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2961","DOI":"10.1053\/j.jvca.2022.03.004","article-title":"Anticoagulation Strategies in Critically Ill Patients With SARS-CoV-2 Infection: The Role of Direct Thrombin Inhibitors","volume":"36","author":"Pieri","year":"2022","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1111\/anae.15745","article-title":"Right ventricular dysfunction in patients with COVID-19 pneumonitis whose lungs are mechanically ventilated: A multicentre prospective cohort study","volume":"77","author":"McCall","year":"2022","journal-title":"Anaesthesia"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Serapide, F., Quirino, A., Scaglione, V., Morrone, H.L., Longhini, F., Bruni, A., Garofalo, E., Matera, G., Marascio, N., and Scarlata, G.G.M. (2022). Is the Pendulum of Antimicrobial Drug Resistance Swinging Back after COVID-19?. Microorganisms, 10.","DOI":"10.3390\/microorganisms10050957"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1007\/s00134-012-2652-7","article-title":"Noninvasive ventilation after early extubation in patients recovering from hypoxemic acute respiratory failure: A single-centre feasibility study","volume":"38","author":"Vaschetto","year":"2012","journal-title":"Intensive Care Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4975","DOI":"10.1182\/bloodadvances.2022007940","article-title":"American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis for patients with COVID-19: March 2022 update on the use of anticoagulation in critically ill patients","volume":"6","author":"Cuker","year":"2022","journal-title":"Blood Adv."},{"key":"ref_45","unstructured":"(2022). ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: Part 2-care pathways, treatment, and follow-up. Cardiovasc. Res., 118, 1618\u20131666."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/20\/5992\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:49:58Z","timestamp":1760143798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/20\/5992"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,11]]},"references-count":45,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["jcm11205992"],"URL":"https:\/\/doi.org\/10.3390\/jcm11205992","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,11]]}}}