Effect of sodium–glucose co-transporter-2 inhibitors on survival free of organ support in patients hospitalised for COVID-19 (ACTIV-4a): a pragmatic, multicentre, open-label, randomised, controlled, platform trial,The Lancet Diabetes & Endocrinology

当前位置： X-MOL 学术 › Lancet Diabetes Endocrinol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Effect of sodium–glucose co-transporter-2 inhibitors on survival free of organ support in patients hospitalised for COVID-19 (ACTIV-4a): a pragmatic, multicentre, open-label, randomised, controlled, platform trial
The Lancet Diabetes & Endocrinology ( IF 44.0 ) Pub Date : 2024-09-06 , DOI: 10.1016/s2213-8587(24)00218-3
Mikhail N Kosiborod ₁ , Sheryl L Windsor ₂ , Orly Vardeny ₃ , Jeffrey S Berger ₄ , Harmony R Reynolds ₄ , Stavroula Boumakis ₄ , Andrew D Althouse ₅ , Scott D Solomon ₆ , Ankeet S Bhatt ₇ , Alexander Peikert ₆ , James F Luther ₅ , Eric S Leifer ₈ , Andrei L Kindzelski ₈ , Mary Cushman ₉ , Michelle Ng Gong ₁₀ , Lucy Z Kornblith ₁₁ , Pooja Khatri ₁₂ , Keri S Kim ₁₃ , Lisa Baumann Kreuziger ₁₄ , Ali Javaheri ₁₅ , Carlos Carpio ₁₆ , Lana Wahid ₁₇ , Jose Lopez-Sendon Moreno ₁₈ , Alvaro Alonso ₁₉ , Minh Quang Ho ₂₀ , Jose Lopez-Sendon ₂₁ , Renato D Lopes ₂₂ , Jeffrey L Curtis ₂₃ , Bridget-Anne Kirwan ₂₄ , Mark W Geraci ₅ , Matthew D Neal ₅ , Judith S Hochman ₄ ,

Affiliation

Saint Luke's Mid America Heart Institute, Kansas City, MO, USA; University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
Saint Luke's Mid America Heart Institute, Kansas City, MO, USA.
University of Minnesota and the Minneapolis VA Medical Center, Minneapolis, MN, USA.
Cardiovascular Clinical Research Center, NYU Grossman School of Medicine, New York, NY, USA.
University of Pittsburgh, Pittsburgh, PA, USA.
Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Kaiser Permanente San Francisco Medical Center, San Francisco, CA, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA, USA.
National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
University of California, San Francisco, CA, USA.
University of Cincinnati Medical Center, Cincinnati, OH, USA.
University of Illinois, Chicago, IL, USA.
Versiti Blood Research Institute, Milwaukee, WI, USA.
Washington University School of Medicine and John Cochran VA, St Louis, MO, USA.
Respiratory Medicine Department, Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.
Duke University Medical Center, Durham, NC, USA.
Servicio de Neurología, Hospital Ramón y Caja, IRYCIS, Madrid, Spain.
University of Massachusetts Chan Medical School and Memorial Medical Center, Worchester, MA, USA.
Orlando VA Healthcare System, University of Central Florida, College of Medicine, Orlando, FL, USA.
IdiPaz Research Institute, La Paz University Hospital, UAM, Madrid, Spain.
Duke University Medical Center, Durham, NC, USA; Brazilian Clinical Research Institute, Sao Paolo, SP, Brazil.
Pulmonary and Critical Care Division, University of Michigan and VA Ann Arbor Healthcare System, Ann Arbor, MI, USA.
SOCAR Research SA, Nyon, Switzerland.

Background

Patients hospitalised for COVID-19 are at risk for multiorgan failure and death. Sodium–glucose co-transporter-2 (SGLT2) inhibitors provide cardiovascular and kidney protection in patients with cardiometabolic conditions and could provide organ protection during COVID-19. We aimed to investigate whether SGLT2 inhibitors can reduce the need for organ support in patients hospitalised for COVID-19.

Methods

This pragmatic, multicentre, open-label, randomised, controlled, platform trial was conducted across 63 sites in the USA, Spain, Brazil, Italy, and Mexico. Patients aged at least 18 years hospitalised for COVID-19 (moderate or severe illness) were randomly assigned (1:1), via an interactive voice system or web-response system, to receive locally available SGLT2 inhibitor (administered orally, once daily) plus standard-of-care or standard-of-care for 30 days. The primary outcome was organ support-free days evaluated through 21 days, assessed using intention-to-treat approach. This trial is registered on ClinicalTrials.gov, NCT04505774.

Findings

The first patient was randomly assigned to the SGLT2 inhibitor domain on Dec 3, 2021. On March 31, 2023, at the recommendation of the data and safety monitoring board, enrolment in the SGLT2 inhibitor domain for both moderately and severely ill hospitalised patients was stopped prematurely for futility due to a low likelihood of finding a treatment benefit. The final randomised population consisted of 575 patients (mean age 72 years [SD 13], 242 (42%) female and 154 (27%) Hispanic; 504 in the moderate illness group and 71 in the severe illness group). 573 patients had a known 21-day outcome; 215 (75%) of 285 patients in the SGLT2 inhibitor plus standard-of-care group did not require respiratory or cardiovascular organ support versus 231 (80%) of 288 patients in the standard-of-care group. The adjusted odds ratio (OR) for an SGLT2 inhibitor effect on organ support-free days was 0·74 (95% Credible Interval [CrI] 0·48–1·13; where OR higher than 1 indicated treatment benefit, yielding a posterior probability of futility P(OR <1·2) of 99% and a posterior probability of inferiority P(OR<1·0) of 91%). There were 37 deaths (13%) in the SGLT2 inhibitor plus standard-of-care group and 42 deaths (15%) in the standard-of-care group at 90 days (hazard ratio 0·91 [95% CrI 0·58–1·43], probability of hazard ratio <1 of 66%). No safety concerns were observed with SGLT2 inhibitors, including no cases of ketoacidosis.

Interpretation

SGLT2 inhibitors did not significantly increase days free of organ support or reduce mortality in patients hospitalised with COVID-19. SGLT2 inhibitors were well tolerated with no observed safety concerns. Overall, these findings do not support the use of SGLT2 inhibitors as standard care in patients hospitalised with COVID-19.

Funding

National Institutes of Health.

中文翻译：

钠-葡萄糖协同转运蛋白 2 抑制剂对因 COVID-19 住院患者的无器官支持生存的影响 (ACTIV-4a)：一项务实、多中心、开放标签、随机、对照、平台试验

背景

因 COVID-19 住院的患者面临多器官衰竭和死亡的风险。钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂可为患有心脏代谢疾病的患者提供心血管和肾脏保护，并可在 COVID-19 期间提供器官保护。我们的目的是研究 SGLT2 抑制剂是否可以减少因 COVID-19 住院的患者对器官支持的需求。

方法

这项务实、多中心、开放标签、随机、对照的平台试验在美国、西班牙、巴西、意大利和墨西哥的 63 个地点进行。因 COVID-19（中度或重度疾病）住院的年满 18 岁的患者被随机分配（1:1），通过交互式语音系统或网络响应系统，接受当地可用的 SGLT2 抑制剂（口服，每天一次）加上标准护理或 30 天的标准护理。主要结局是在 21 天的时间内评估无器官支持天数，采用意向治疗方法进行评估。该试验已在ClinicalTrials.gov上注册, NCT04505774 。

发现

首例患者于 2021 年 12 月 3 日被随机分配至 SGLT2 抑制剂领域。2023 年 3 月 31 日，根据数据和安全监测委员会的建议，停止对中度和重度住院患者进行 SGLT2 抑制剂领域的招募由于发现治疗益处的可能性很低，因此过早地认为是徒劳的。最终的随机人群包括 575 名患者（平均年龄 72 岁 [SD 13]，242 名 (42%) 女性和 154 名 (27%) 西班牙裔患者；中度疾病组 504 人，重度疾病组 71 人）。 573 名患者的 21 天结果已知； SGLT2抑制剂加标准护理组的 285 名患者中有 215 名患者 (75%) 不需要呼吸或心血管器官支持，而标准护理组的 288 名患者中有 231 名患者 (80%) 不需要呼吸或心血管器官支持。 SGLT2 抑制剂对无器官支持天数的影响的调整优势比 (OR) 为 0·74（95% 可信区间 [CrI] 0·48–1·13；其中 OR 高于 1 表明治疗获益，产生后验无效概率 P(OR<1·2) 为 99%，自卑后验概率 P(OR<1·0) 为 91%。 90 天时，SGLT2 抑制剂加标准护理组有 37 例死亡 (13%)，标准护理组有 42 例死亡 (15%)（风险比 0·91 [95% CrI 0·58] –1·43]，危险比 <1 的概率为 66%)。 SGLT2 抑制剂没有观察到安全性问题，包括没有酮症酸中毒病例。