Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial,The BMJ

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Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial
The BMJ ( IF 105.7 ) Pub Date : 2021-10-14 , DOI: 10.1136/bmj.n2400
Michelle Sholzberg ₁ , Grace H Tang ₂ , Hassan Rahhal ₃ , Musaad AlHamzah _{4,

5} , Lisa Baumann Kreuziger ₆ , Fionnuala Ní Áinle _{7,

8,

9} , Faris Alomran ₁₀ , Khalid Alayed ₁₁ , Mohammed Alsheef ₁₂ , Fahad AlSumait ₁₂ , Carlos Eduardo Pompilio ₃ , Catherine Sperlich ₁₃ , Sabrena Tangri ₁₄ , Terence Tang ₁₅ , Peter Jaksa ₁₆ , Deepa Suryanarayan ₁₇ , Mozah Almarshoodi ₁₈ , Lana A Castellucci ₁₉ , Paula D James ₂₀ , David Lillicrap ₂₁ , Marc Carrier ₁₉ , Andrew Beckett _{22,

23} , Christos Colovos _{24,

25} , Jai Jayakar ₂₆ , Marie-Pier Arsenault ₂₇ , Cynthia Wu ₂₈ , Karine Doyon ₂₉ , E Roseann Andreou ₃₀ , Vera Dounaevskaia ₃₁ , Eric K Tseng ₂₂ , Gloria Lim ₂₂ , Michael Fralick ₃₂ , Saskia Middeldorp ₃₃ , Agnes Y Y Lee ₃₄ , Fei Zuo ₃₅ , Bruno R da Costa _{35,

36} , Kevin E Thorpe _{35,

37} , Elnara Márcia Negri ₃₈ , Mary Cushman ₃₉ , Peter Jüni _{35,

40} ,

Affiliation

Departments of Medicine, and Laboratory Medicine and Pathobiology, St Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada.
Haematology-Oncology Clinical Research Group, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
Internal Medicine Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), University of São Paulo, São Paulo, Brazil.
Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Division of Vascular Surgery, King Saud University Medical City, Riyadh, Saudi Arabia.
Versiti, Medical College of Wisconsin, Milwaukee, WI, USA.
Mater Misericordiae University Hospital, Dublin, Ireland.
School of Medicine, University College Dublin, Dublin, Ireland.
Irish Network for Venous Thromboembolism Research, Dublin, Ireland.
Department of Vascular Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Medical Specialties Department, King Fahad Medical City, Riyadh, Saudi Arabia.
Charles-Lemoyne Hospital, CISSS of Montérégie-Centre, University of Sherbrooke, Greenfield Park, QC, Canada.
Department of Medicine, William Osler Health System, Brampton, ON, Canada.
Institute for Better Health, Trillium Health Partners, Department of Medicine, University of Toronto, ON, Canada.
St Joseph's Health Centre, Unity Health Toronto, Department of Medicine, University of Toronto, Toronto, ON, Canada.
Department of Medicine, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada.
Tawam Hospital, SEHA, AlAin, United Arab Emirates.
Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, ON, Canada.
Department of Medicine, Queen's University, Kingston, ON, Canada.
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
Canadian Forces Health Services, Ottawa, Ontario, Canada.
Division of Acute Care Surgery, Department of Surgery, University of Vermont Medical Center, VT, USA.
University of Vermont Larner College of Medicine, Burlington, VT, USA.
Southlake Regional Health Centre, University of Toronto, Newmarket, ON, Canada.
Maisonneuve-Rosemont Hospital, University of Montréal, Montréal, QC, Canada.
Division of Haematology, University of Alberta Hospital, University of Alberta, Edmonton, AB, Canada.
Hospital of the Sacred Heart of Montreal, University of Montréal, Montréal, QC, Canada.
Michael Garron Hospital, University of Toronto, Toronto, ON, Canada.
Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
General Internal Medicine, Sinai Health, University of Toronto, Toronto, ON, Canada.
Department of Internal Medicine and Radboud Institute of Health Sciences, Radboud University Medical Centre, Nijmegen, Netherlands.
Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
Applied Health Research Centre, St Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada.
Institute of Primary Health Care, University of Bern, Bern, Switzerland.
Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
Laboratory of Medical Investigation (LIM-59), Cellular Biology, Department of Pathology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
Departments of Medicine and Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, University of Vermont Medical Center, Burlington, VT, USA.
Departments of Medicine and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

Objective To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. Design Randomised controlled, adaptive, open label clinical trial. Setting 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. Participants 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). Interventions Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. Main outcome measures The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. Results The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m2. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). Conclusions In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. Trial registration ClinicalTrials.gov [NCT04362085][1]. Requests for data sharing should be sent to the corresponding author at michelle.sholzberg@unityhealth.to. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04362085&atom=%2Fbmj%2F375%2Fbmj.n2400.atom

中文翻译：

治疗性肝素与预防性肝素对住院的中度 COVID-19 患者死亡、机械通气或重症监护病房入院的有效性：RAPID 随机临床试验

目的比较治疗性肝素与预防性肝素在住院病房covid-19中度患者中的疗效。设计随机对照、适应性、开放标签临床试验。在巴西、加拿大、爱尔兰、沙特阿拉伯、阿拉伯联合酋长国和美国设有 28 家医院。在 2020 年 5 月 29 日至 2021 年 4 月 12 日期间，招募了 465 名因 covid-19 入住医院病房且 D-二聚体水平升高的成年人，并被随机分配至治疗剂量肝素 (n=228) 或预防剂量肝素 (n=237)。干预治疗剂量或预防剂量肝素（低分子量或普通肝素），持续到出院、第 28 天或死亡。主要结局测量主要结局是死亡、有创机械通气、无创机械通气或进入重症监护病房，评估长达 28 天。次要结局包括全因死亡、全因死亡或任何机械通气的复合结局以及静脉血栓栓塞。安全结果包括大出血。结果被盲目判定。结果参与者的平均年龄为60岁；264 (56.8%) 人为男性，平均体重指数为 30.3 kg/m2。在 28 天时，37/228 名患者（16.2%）被分配到治疗性肝素组和 52/237（21.9%）名被分配到预防性肝素组的患者中出现了主要复合结局（优势比 0.69，95% 置信区间 0.43 至 1.10；P= 0.12)。分配给治疗性肝素的 4 名患者 (1.8%) 和分配给预防性肝素的 18 名患者 (7.6%) 发生死亡 (0.22, 0.07 至 0.65; P = 0.006)。全因死亡或任何机械通气的复合发生在分配给治疗性肝素的 23 名患者（10.1%）和分配给预防性肝素的 38 名患者（16.0%）中（0.59，0.34 至 1.02；P=0.06）。分配给治疗性肝素的两名患者（0.9%）和分配给预防性肝素的六名（2.5%）患者发生了静脉血栓栓塞（0.34，0.07 至 1.71；P=0.19）。2 名患者（0.9%）被分配到治疗性肝素组和 4 名（1.7%）被分配到预防性肝素组（0.52，0.09 至 2.85；P=0.69）发生大出血。结论在住院病房的中度 COVID-19 和 D-二聚体水平升高的患者中，治疗性肝素与主要结果的降低无显着相关性，但 28 天时的死亡几率降低。在这项试验中，大出血的风险似乎很低。试验注册 ClinicalTrials.gov [NCT04362085][1]。数据共享请求应发送至 michelle.sholzberg@unityhealth.to 的通讯作者。[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04362085&atom=%2Fbmj%2F375%2Fbmj.n2400.atom

更新日期：2021-10-14

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