Colchicine and high-intensity rosuvastatin in the treatment of non-critically ill patients hospitalised with COVID-19: a randomised clinical trial

DOI record: { "DOI": "10.1136/bmjopen-2022-067910", "ISSN": [ "2044-6055", "2044-6055" ], "URL": "http://dx.doi.org/10.1136/bmjopen-2022-067910", "abstract": "<jats:sec><jats:title>Objective</jats:title><jats:p>To evaluate the effect of colchicine and high-intensity rosuvastatin in addition to standard of care on the progression of COVID-19 disease in hospitalised patients.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>A pragmatic, open-label, multicentre, randomised controlled trial conducted from October 2020 to September 2021. Follow-up was conducted at 30 and 60 days. The electronic medical record was used at all stages of the trial including screening, enrolment, randomisation, event ascertainment and follow-up.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>Four centres in the Yale New Haven Health System.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>Non-critically ill hospitalised patients with COVID-19.</jats:p></jats:sec><jats:sec><jats:title>Interventions</jats:title><jats:p>Patients were randomised 1:1 to either colchicine plus high-intensity rosuvastatin in addition to standard of care versus standard of care alone. Assigned treatment was continued for the duration of index hospitalisation or 30 days, whichever was shorter.</jats:p></jats:sec><jats:sec><jats:title>Primary and secondary outcome measures</jats:title><jats:p>The prespecified primary endpoint was progression to severe COVID-19 disease (new high-flow or non-invasive ventilation, mechanical ventilation, need for vasopressors, renal replacement therapy or extracorporeal membrane oxygenation, or death) or arterial/venous thromboembolic events (ischaemic stroke, myocardial infarction, deep venous thrombosis or pulmonary embolism) evaluated at 30 days.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Among the 250 patients randomised in this trial (125 to each arm), the median age was 61 years, 44% were women, 15% were Black and 26% were Hispanic/Latino. As part of the standard of care, patients received remdesivir (87%), dexamethasone (92%), tocilizumab (18%), baricitinib (2%), prophylactic/therapeutic anticoagulation (98%) and aspirin (91%). The trial was terminated early by the data and safety monitoring board for futility. No patients were lost to follow-up due to electronic medical record follow-up. There was no significant difference in the primary endpoint at 30 days between the active arm and standard of care arm (15.2% vs 8.8%, respectively, p=0.17).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>In this small, open-label, randomised trial of non-critically ill hospitalised patients with COVID-19, the combination of colchicine and rosuvastatin in addition to standard of care did not appear to reduce the risk of progression of COVID-19 disease or thromboembolic events, although the trial was underpowered due to a lower-than-expected event rate. The trial leveraged the power of electronic medical records for efficiency and improved follow-up and demonstrates the utility of incorporating electronic medical records into future trials.</jats:p></jats:sec><jats:sec><jats:title>Trial registration</jats:title><jats:p><jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04472611\">NCT04472611</jats:ext-link>.</jats:p></jats:sec>", "alternative-id": [ "10.1136/bmjopen-2022-067910" ], "author": [ { "affiliation": [], "family": "Shah", "given": "Tayyab", "sequence": "first" }, { "affiliation": [], "family": "McCarthy", "given": "Marianne", "sequence": "additional" }, { "affiliation": [], "family": "Nasir", "given": "Irem", "sequence": "additional" }, { "affiliation": [], "family": "Archer", "given": "Herb", "sequence": "additional" }, { "affiliation": [], "family": "Ragheb", "given": "Elio", "sequence": "additional" }, { "affiliation": [], "family": "Kluger", "given": "Jonathan", 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"volume": "10", "year": "2013" }, { "DOI": "10.1016/j.bcp.2014.11.013", "doi-asserted-by": "publisher", "key": "2023022418152730000_13.2.e067910.22" }, { "DOI": "10.1164/rccm.201209-1718OC", "doi-asserted-by": "publisher", "key": "2023022418152730000_13.2.e067910.23" }, { "DOI": "10.1186/cc11895", "doi-asserted-by": "crossref", "key": "2023022418152730000_13.2.e067910.24", "unstructured": "Patel JM , Snaith C , Thickett DR , et al . Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (asepsis trial). Crit Care 2012;16:R231. doi:10.1186/cc11895" }, { "DOI": "10.1016/j.jacc.2021.08.021", "doi-asserted-by": "publisher", "key": "2023022418152730000_13.2.e067910.25" }, { "DOI": "10.1001/jamanetworkopen.2020.13136", "doi-asserted-by": "crossref", "key": "2023022418152730000_13.2.e067910.26", "unstructured": "Deftereos SG , Giannopoulos G , Vrachatis DA , et al . Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Netw Open 2020;3:e2013136. doi:10.1001/jamanetworkopen.2020.13136" }, { "DOI": "10.1136/rmdopen-2020-001455", "doi-asserted-by": "crossref", "key": "2023022418152730000_13.2.e067910.27", "unstructured": "Lopes MI , Bonjorno LP , Giannini MC , et al . Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open 2021;7:e001455. doi:10.1136/rmdopen-2020-001455" }, { "DOI": "10.1016/S2213-2600(21)00222-8", "article-title": "Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial", "author": "Tardif", "doi-asserted-by": "crossref", "first-page": "924", "journal-title": "Lancet Respir Med", "key": "2023022418152730000_13.2.e067910.28", "volume": "9", "year": "2021" }, { "DOI": "10.1016/S2213-2600(21)00435-5", "article-title": "Colchicine in patients admitted to hospital with COVID-19 (recovery): a randomised, controlled, open-label, platform trial", "author": "Group", "doi-asserted-by": "crossref", "first-page": "1419", "journal-title": "Lancet Respir Med", "key": "2023022418152730000_13.2.e067910.29", "volume": "9", "year": "2021" }, { "DOI": "10.1002/ptr.7319", "article-title": "Efficacy and safety of colchicine treatment in patients with COVID-19: a prospective, multicenter, randomized clinical trial", "author": "Pourdowlat", "doi-asserted-by": "crossref", "first-page": "891", "journal-title": "Phytother Res", "key": "2023022418152730000_13.2.e067910.30", "volume": "36", "year": "2022" }, { "DOI": "10.1016/j.eclinm.2021.101242", "doi-asserted-by": "crossref", "key": "2023022418152730000_13.2.e067910.31", "unstructured": "Gaitán-Duarte HG , Álvarez-Moreno C , Rincón-Rodríguez CJ , et al . Effectiveness of rosuvastatin plus colchicine, emtricitabine/tenofovir and combinations thereof in hospitalized patients with COVID-19: a pragmatic, open-label randomized trial. EClinicalMedicine 2022;43:101242. doi:10.1016/j.eclinm.2021.101242" }, { "DOI": "10.1038/s41467-021-21553-1", "doi-asserted-by": "crossref", "key": "2023022418152730000_13.2.e067910.32", "unstructured": "Gupta A , Madhavan MV , Poterucha TJ , et al . Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19. Nat Commun 2021;12:1325. doi:10.1038/s41467-021-21553-1" }, { "DOI": "10.1016/amjcard.202008.004", "doi-asserted-by": "publisher", "key": "2023022418152730000_13.2.e067910.33" }, { "DOI": "10.1136/bmj-2021-068407", "doi-asserted-by": "crossref", "key": "2023022418152730000_13.2.e067910.34", "unstructured": "INSPIRATION-S Investigators . Atorvastatin versus placebo in patients with COVID-19 in intensive care: randomized controlled trial. BMJ 2022;376:e068407. doi:10.1136/bmj-2021-068407" }, { "DOI": "10.1016/j.diabet.2020.10.001", "article-title": "Routine use of statins and increased COVID-19 related mortality in inpatients with type 2 diabetes: results from the CORONADO study", "author": "Cariou", "doi-asserted-by": "crossref", "first-page": "101202", "journal-title": "Diabetes Metab", "key": "2023022418152730000_13.2.e067910.35", "volume": "47", "year": "2021" }, { "DOI": "10.1371/journal.pone.0256899", "doi-asserted-by": "crossref", "key": "2023022418152730000_13.2.e067910.36", "unstructured": "Ayeh SK , Abbey EJ , Khalifa BAA , et al . Statins use and COVID-19 outcomes in hospitalized patients. PLoS One 2021;16:e0256899. doi:10.1371/journal.pone.0256899" }, { "DOI": "10.1186/1476-511X-13-67", "doi-asserted-by": "crossref", "key": "2023022418152730000_13.2.e067910.37", "unstructured": "Huang C , Cen C , Wang C , et al . Synergistic effects of colchicine combined with atorvastatin in rats with hyperlipidemia. Lipids Health Dis 2014;13:67. doi:10.1186/1476-511X-13-67" }, { "DOI": "10.1016/j.cct.2021.106547", "article-title": "Design and rationale of the colchicine/statin for the prevention of COVID-19 complications (COLSTAT) trial", "author": "Shah", "doi-asserted-by": "crossref", "first-page": "106547", "journal-title": "Contemp Clin Trials", "key": "2023022418152730000_13.2.e067910.38", "volume": "110", "year": "2021" }, { "DOI": "10.1016/j.jacc.2018.08.1038", "doi-asserted-by": "publisher", "key": "2023022418152730000_13.2.e067910.39" }, { "DOI": "10.1016/j.jacc.2016.11.045", "doi-asserted-by": "publisher", "key": "2023022418152730000_13.2.e067910.40" }, { "DOI": "10.1152/ajpheart.00755.2020", "article-title": "Sex differences in COVID-19: candidate pathways, genetics of ACE2, and sex hormones", "author": "Viveiros", "doi-asserted-by": "crossref", "first-page": "H296", "journal-title": "Am J Physiol Heart Circ Physiol", "key": "2023022418152730000_13.2.e067910.41", "volume": "320", "year": "2021" }, { "DOI": "10.1001/jama.2021.11517", "article-title": "Effect of oral azithromycin vs placebo on COVID-19 symptoms in outpatients with SARS-cov-2 infection: a randomized clinical trial", "author": "Oldenburg", "doi-asserted-by": "crossref", "first-page": "490", "journal-title": "JAMA", "key": "2023022418152730000_13.2.e067910.42", "volume": "326", "year": "2021" }, { "DOI": "10.1001/jama.2021.9508", "article-title": "Effect of canakinumab vs placebo on survival without invasive mechanical ventilation in patients hospitalized with severe COVID-19: a randomized clinical trial", "author": "Caricchio", "doi-asserted-by": "crossref", "first-page": "230", "journal-title": "JAMA", "key": "2023022418152730000_13.2.e067910.43", "volume": "326", "year": "2021" }, { "DOI": "10.1001/jamanetworkopen.2021.6468", "doi-asserted-by": "crossref", "key": "2023022418152730000_13.2.e067910.44", "unstructured": "Reis G , Moreira Silva E , Medeiros Silva DC , et al . Effect of early treatment with hydroxychloroquine or lopinavir and ritonavir on risk of hospitalization among patients with COVID-19: the together randomized clinical trial. JAMA Netw Open 2021;4:e216468. doi:10.1001/jamanetworkopen.2021.6468" } ], "reference-count": 44, "references-count": 44, "relation": {}, "resource": { "primary": { "URL": "https://bmjopen.bmj.com/lookup/doi/10.1136/bmjopen-2022-067910" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [ "General Medicine" ], "subtitle": [], "title": "Colchicine and high-intensity rosuvastatin in the treatment of non-critically ill patients hospitalised with COVID-19: a randomised clinical trial", "type": "journal-article", "update-policy": "http://dx.doi.org/10.1136/crossmarkpolicy", "volume": "13" }