Hills Thomas E, Lorenzi Elizabeth, Berry Lindsay R, Shyamsundar Murali, Al-Beidh Farah, Annane Djillali, Arabi Yaseen, Aryal Diptesh, Au Carly, Beane Abigail, Bhimani Zahra, Bonten Marc, Bradbury Charlotte A, Brunkhorst Frank M, Burrell Aidan, Buxton Meredith, Calfee Carolyn S, Cecconi Maurizio, Cheng Allen C, Cove Matthew E, Detry Michelle A, Estcourt Lise J, Fitzgerald Mark, Goligher Ewan C, Goossens Herman, Green Cameron, Haniffa Rashan, Harrison David A, Hashmi Madiha, Higgins Alisa M, Horvat Christopher, Huang David T, Ichihara Nao, Jayakumar Deva, Kruger Peter S, Lamontagne François, Lampro Lamprini, Lawler Patrick R, Marshall John C, Mason Alexina J, McGlothlin Anna, McGuinness Shay, McQuilten Zoe K, McVerry Bryan J, Mouncey Paul R, Murthy Srinivas, Neal Matthew D, Nichol Alistair D, O'Kane Cecilia M, Parke Rachael L, Parker Jane C, Rabindrarajan Ebenezer, Reyes Luis F, Rowan Kathryn M, Saito Hiroki, Santos Marlene, Saunders Christina T, Seymour Christopher W, Shankar-Hari Manu, Sinha Pratik, Thompson B Taylor, Turgeon Alexis F, Turner Anne M, van de Veerdonk Frank, Weis Sebastian, Young Ian S, Zarychanski Ryan, Lewis Roger J, McArthur Colin J, Angus Derek C, Berry Scott M, Derde Lennie P G, Webb Steve A, Gordon Anthony C, McAuley Daniel F
From the Medical Research Institute of New Zealand, Wellington (T.E.H., S. McGuinness, A.M.T., C.J.M.), and Middlemore Hospital (T.E.H.), Te Toka Tumai Auckland City Hospital (T.E.H., S. McGuinness, R.L.P., C.J.M.), and the School of Nursing, University of Auckland (R.L.P.), Auckland - all in New Zealand; Berry Consultants, Austin, TX (E.L., L.R.B., M.A.D., M.F., A.M., C.T.S., R.J.L., S.M.B.); Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast (M. Shyamsundar, C.M.O., D.F.M.), the Department of Critical Care, Belfast Health and Social Care Trust (M. Shyamsundar, D.F.M.), and the Centre for Public Health, Queen's University Belfast, Belfast Health and Social Care Trust, and the Department of Health (I.S.Y.), Belfast, Imperial College London (F.A.-B., A.C.G.), the Intensive Care National Audit and Research Centre (C.A., D.A.H., L.L., A.J.M., P.R.M., K.M.R.), University College London Hospitals (R.H.), and Imperial College Healthcare NHS Trust (A.C.G.), London, the Institute for Regeneration and Repair (A. Beane) and the Centre for Inflammation Research (R.H., M.S.-H.), University of Edinburgh, Edinburgh, the Faculty of Health Sciences, University of Bristol, and Bristol Haematology and Oncology Centre, University Hospitals Bristol and Weston NHS Trust, Bristol (C.A.B.), and NHS Blood and Transplant, Oxford (L.J.E.) - all in the United Kingdom; Institut Hospitalo-Universitaire Prometheus, University Paris-Saclay, the Department of Intensive Care, Raymond Poincaré Hospital, Assistance Publique-Hôpitaux de Paris, University Versailles Saint Quentin-University Paris-Saclay, the Laboratory of Infection and Inflammation-Unité 173, School of Medicine Simone Veil, University Versailles Saint Quentin-University Paris-Saclay, INSERM, and Fédération Hospitalo-Universitaire SEPSIS (Saclay and Paris Seine Nord Endeavor to Personalize Interventions for Sepsis) - all in Garches, France (D. Annane); King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (Y.A.); Nepal Intensive Care Research Foundation, Kathmandu (D. Aryal); Mahidol Oxford Tropical Medicine Research Unit (MORU), Bangkok, Thailand (D. Aryal, A. Beane); Unity Health Toronto (Z.B., J.C.M., M. Santos), the Interdepartmental Division of Critical Care Medicine, University of Toronto, and Toronto General Hospital Research Institute (E.C.G.), Peter Munk Cardiac Centre at University Health Network (P.R.L.), and Keenan Centre for Biomedical Research (J.C.M.), Toronto, Université de Sherbrooke, Sherbrooke, QC (F.L.), McGill University Health Centre, Montreal (P.R.L.), the Faculty of Medicine, University of British Columbia, Vancouver (S. Murthy), the Population Health and Optimal Practices Research Unit, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, and the Department of Anesthesiology and Critical Care Medicine, Université Laval, Quebec City (A.F.T.), and the University of Manitoba and CancerCare Manitoba, Winnipeg (R.Z.) - all in Canada; Julius Center for Health Sciences and Primary Care (M. Bonten, L.P.G.D.) and the Intensive Care Center (L.P.G.D.), University Medical Center Utrecht, Utrecht University, and the European Clinical Research Alliance on Infectious Diseases (M. Bonten), Utrecht, and Radboud University Medical Center, Nijmegen (F.V.) - all in the Netherlands; the Department of Anesthesiology and Intensive Care Medicine (F.M.B., S.W.) and the Institute for Infection Disease and Infection Control (S.W.), Jena University Hospital, Friedrich-Schiller University, and Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (S.W.) - both in Jena, Germany; the School of Public Health and Preventive Medicine (A. Burrell, A.C.C., C.G., A.M.H., Z.K.M., A.D.N., J.C.P., C.J.M., S.A.W.) and the School of Clinical Sciences (A.C.C.), Monash University, Alfred Hospital (A. Burrell, A.D.N.), and Monash Health (A.C.C., Z.K.M.), Melbourne, VIC, the Faculty of Medicine, University of Queensland, and the Intensive Care Unit, Princess Alexandra Hospital, Brisbane (P.S.K.), and St. John of God Health Care, Perth, WA (S.A.W.) - all in Australia; the Global Coalition for Adaptive Research, Larkspur (M. Buxton), the Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, and the Department of Anesthesia, University of California, San Francisco, San Francisco (C.S.C.), and Harbor-UCLA Medical Center, Torrance (R.J.L.) - all in California; the Department of Biomedical Sciences, Humanitas University, and IRCCS Humanitas Research Hospital, Milan (M.C.); National University Hospital Singapore, Singapore (M.E.C.); Dr. Kamakshi Memorial Hospital (D.J.) and Apollo Speciality Hospitals (E.R.) - both in Chennai, India; the University of Antwerp, Antwerp, Belgium (H.G.); National Intensive Care Surveillance-MORU, Colombo, Sri Lanka (R.H.); Ziauddin University, Karachi, Pakistan (M.H.); the University of Pittsburgh (D.T.H., B.J.M., M.D.N., C.W.S., D.C.A.) and the University of Pittsburgh Medical Center (D.T.H., B.J.M.) - both in Pittsburgh; Jikei University School of Medicine and the University of Tokyo, Tokyo (N.I.), and St. Marianna University School of Medicine, Yokohama Seibu Hospital, Yokohama (H.S.) - all in Japan; University College Dublin Clinical Research Centre, St. Vincent's University Hospital, Dublin (A.D.N.); Universidad de La Sabana and Clínica Universidad de La Sabana - both in Chia, Colombia (L.F.R.); the Division of Clinical and Translational Research, Division of Critical Care, Department of Anesthesiology, Washington University School of Medicine, St. Louis (P.S.); and the Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (B.T.T.).
N Engl J Med. 2023 Dec 21;389(25):2341-2354. doi: 10.1056/NEJMoa2309995. Epub 2023 Oct 25.
BACKGROUND: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2). RESULTS: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control. CONCLUSIONS: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).
背景：辛伐他汀对2019冠状病毒病（Covid-19）重症患者的疗效尚不清楚。 方法：在一项正在进行的国际多因素适应性平台随机对照试验中，我们评估了辛伐他汀（每日80毫克）与无他汀类药物治疗（对照组）对基线时未接受他汀类药物治疗的Covid-19重症患者的效果。主要结局是呼吸和心血管器官无需支持的天数，通过将院内死亡（赋值为-1）和幸存者至第21天无器官支持的天数合并进行序贯评分来评估；分析采用贝叶斯分层序贯模型。适应性设计包括预先设定的优效性统计停止标准（优势比>1的后验概率>99%）和无效性标准（优势比<1.2的后验概率>95%）。 结果：2020年10月28日开始入组。2023年1月8日，由于随着Covid-19病例减少，达到预先设定停止标准的预期可能性较低，入组结束。最终分析纳入了2684例重症患者。辛伐他汀组器官无需支持天数的中位数为11天（四分位间距，-1至17天），对照组为7天（四分位间距，-1至16天）；与对照组相比，辛伐他汀的后验中位数调整优势比为1.15（95%可信区间，0.98至1.34），优效性的后验概率为95.9%。在90天时，生存风险比为1.12（95%可信区间，0.95至1.32），辛伐他汀优效性的后验概率为91.9%。次要分析结果与主要分析结果一致。与对照组相比，辛伐他汀组报告的严重不良事件，如肝酶和肌酸激酶水平升高，更为常见。 结论：尽管由于病例减少而停止了招募，但在Covid-19重症患者中，辛伐他汀未达到优于对照组的预先设定标准。（REMAP-CAP ClinicalTrials.gov编号，NCT02735707。）
N Engl J Med. 2023-12-21
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