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Baricitinib versus tocilizumab in mechanically ventilated patients with COVID-19: a nationwide cohort study
Critical Care ( IF 8.8 ) Pub Date : 2024-08-29 , DOI: 10.1186/s13054-024-05063-2
Seung-Hun You 1 , Moon Seong Baek 2 , Tae Wan Kim 2 , Sun-Young Jung 1, 3 , Won-Young Kim 2
Affiliation  

Dear Editor,

No large-scale study has compared baricitinib with tocilizumab specifically for critical coronavirus disease 2019 (COVID-19). An exploratory trial that included patients with COVID-19 on mechanical ventilation (MV) or extracorporeal membrane oxygenation (ECMO) demonstrated a marked reduction in 28-day mortality in the baricitinib group, although baricitinib was compared to placebo [1]. Most of the studies that have conducted head-to-head comparisons between baricitinib and tocilizumab in patients with severe COVID-19 had lower rates of disease severity (< 5% on MV) [2]. Thus, which of the two drugs is more beneficial for patients with rapidly progressing inflammatory response is unclear. Additionally, most patients in previous studies were unvaccinated, thus limiting the stratified analysis according to vaccination status.

To address the current knowledge gaps, this study was performed as a large-scale analysis of Korean health insurance claims data to compare the efficacies of baricitinib versus tocilizumab in patients with COVID-19 receiving MV.

Adult patients (age ≥ 18 years) with confirmed COVID-19 admitted from October 8, 2020 to October 31, 2022, who required MV, were analyzed. Patients who received at least one dose of baricitinib or tocilizumab during the index hospitalization were assessed. The exclusion criteria were age < 18 years, death or discharge within the first 2 days of hospitalization, cardiac arrest, palliative care, pregnancy or related conditions, and co-administration of baricitinib and tocilizumab. Propensity score (PS) matching was conducted to control for differences in the baseline variables of patients receiving either baricitinib or tocilizumab. For the PS model, baricitinib use was employed as the dependent variable, and the independent variables were all the baseline covariates listed in Table S1. Covariate balance before and after matching was evaluated by standardized mean differences, and a difference of < 0.10 was considered well-balanced. Logistic regression analyses were performed to compute the odds ratios (ORs) and 95% confidence intervals (CIs) of the outcomes associated with baricitinib use. Subgroup analyses for the outcomes were performed according to age, sex, Charlson Comorbidity Index, neuromuscular blocking agents, renal replacement therapy, and ECMO. To determine the possible confounding by the COVID-19 vaccination, baseline and outcome analyses were stratified according to the vaccination status prior to admission. All statistical analyses were performed using SAS software (version 9.4; SAS Institute, Cary, NC, USA).

Among 1630 included patients (mean [standard deviation] age, 71.4 [12.8] years; men, 58.6%), PS matching resulted in 557 patients in each group (Fig. S1). No significant differences were observed in the baseline characteristics between the PS-matched groups (Table S1). For the unmatched and PS-matched groups, the median (interquartile range) durations of baricitinib use and tocilizumab use were 8 (4–13) days and 1 (1–1) day, respectively. On day 30, significantly fewer patients died in the baricitinib group (49.4% vs. 57.8%; OR 0.71; 95% CI 0.56–0.90; Fig. 1a). This corroborates the study by Ely et al. [1], although the mortality rate in the baricitinib group (39%) was lower than that of current study. Baricitinib exhibits a more favorable response to tocilizumab possibly because of its different mechanisms of action. Although tocilizumab specifically inhibits a single cytokine [3], baricitinib inhibits multiple inflammatory pathways [4]. The administration of baricitinib over multiple days may result in the delivery of more consistent drug concentrations that maintain its anti-inflammatory effect [4].

Fig. 1
figure 1

a Kaplan–Meier curves of the probability of survival within 30 days. b Association of baricitinib on 30-day mortality by subgroups. Odds ratios (represented by squares) and 95% CIs (corresponding lines through them) are calculated for the propensity score-matched baricitinib (n = 557) and tocilizumab (n = 557) groups. ap values are for the interaction term. CI confidence interval, ECMO extracorporeal membrane oxygenation

Full size image

The association between baricitinib and 30-day mortality was consistent across all subgroups (Fig. 1b). Although limited by the small number of patients, the mortality risk was the lowest among patients receiving baricitinib and ECMO (18.0% vs. 60.8%; OR 0.14; 95% CI 0.06–0.35; p < 0.001 for interaction). This suggests that the beneficial effects of baricitinib may be more evident in patients who exhibit an increased inflammatory response. The baseline characteristics of the cohort that included only unvaccinated patients are shown in Table S2. Most baseline characteristics of the PS-matched baricitinib and tocilizumab groups were similar, except for age. After adjustment for age, patients administered baricitinib exhibited significantly lower 30-day mortality rates (46.8% vs. 59.7%; OR 0.61; 95% CI 0.44–0.87) than those who received tocilizumab. This finding is consistent with that of the study by Trøseid et al. [5] of unvaccinated participants that demonstrated lower 60-day mortality in the baricitinib group than in the placebo group. However, the unvaccinated patients were younger and had less comorbidities in both studies. The baseline characteristics of the cohort that included only vaccinated patients are shown in Table S3. Vaccination itself may not significantly affect the treatment response to baricitinib or tocilizumab once severe COVID-19 has developed. Among vaccinated patients, no significant difference was detected between the baricitinib and tocilizumab groups in the 30-day mortality (49.6% vs. 55.3%; OR 0.80; 95% CI 0.56–1.13).

For patients with COVID-19 requiring MV, baricitinib was associated with lower 30-day mortality than tocilizumab. Additional studies are needed to evaluate the efficacy of baricitinib in specific subgroups of patients with critical COVID-19.

All data generated or analyzed during this study are included in this published article and its supplementary information files.

CI:

Confidence interval

COVID-19:

Coronavirus disease 2019

ECMO:

Extracorporeal membrane oxygenation

MV:

Mechanical ventilation

OR:

Odds ratio

PS:

Propensity score

  1. Ely EW, Ramanan AV, Kartman CE, de Bono S, Liao R, Piruzeli MLB, et al. Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial. Lancet Respir Med. 2022;10:327–36.

    Article CAS PubMed PubMed Central Google Scholar

  2. Roddy J, Wells D, Schenck K, Santosh S, Santosh S. Tocilizumab versus baricitinib in patients hospitalized with COVID-19 pneumonia and hypoxemia: a multicenter retrospective cohort study. Crit Care Explor. 2022;4: e0702.

    Article PubMed PubMed Central Google Scholar

  3. Zhang S, Li L, Shen A, Chen Y, Qi Z. Rational use of tocilizumab in the treatment of novel coronavirus pneumonia. Clin Drug Investig. 2020;40:511–8.

    Article PubMed PubMed Central Google Scholar

  4. Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis. 2015;74:333–40.

    Article CAS PubMed Google Scholar

  5. Trøseid M, Arribas JR, Assoumou L, Holten AR, Poissy J, Terzić V, et al. Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial. Crit Care. 2023;27:9.

    Article PubMed PubMed Central Google Scholar

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This study used the database of the Korea Disease Control and Prevention Agency and the National Health Insurance Service for policy and academic research (KDCA-NHIS-2023-1-488).

This research was supported by the National Research Foundation of Korea grant funded by the Korea government (Ministry of Science, ICT & Future Planning) (2022R1F1A1067609). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Authors and Affiliations

  1. Department of Global Innovative Drugs, The Graduate School of Chung-Ang University, Chung-Ang University, Seoul, Republic of Korea

    Seung-Hun You & Sun-Young Jung

  2. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea

    Moon Seong Baek, Tae Wan Kim & Won-Young Kim

  3. College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea

    Sun-Young Jung

Authors
  1. Seung-Hun YouView author publications

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  2. Moon Seong BaekView author publications

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  3. Tae Wan KimView author publications

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  4. Sun-Young JungView author publications

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  5. Won-Young KimView author publications

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Contributions

WYK participated in the conception and design of study. SYJ and SHY participated in the data acquisition and data analysis. WYK, SYJ, MSB, and TWK participated in the data interpretation. WYK and SHY participated in the draft of the manuscript. SYJ, MSB, and TWK helped to revise the manuscript for important intellectual content. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Sun-Young Jung or Won-Young Kim.

Ethics approval and consent to participate

The study protocol for the utilization of de-identified patient data was exempt from review by the Institutional Review Board of Chung-Ang University (1041078-20230306-HR-055).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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You, SH., Baek, M.S., Kim, T.W. et al. Baricitinib versus tocilizumab in mechanically ventilated patients with COVID-19: a nationwide cohort study. Crit Care 28, 282 (2024). https://doi.org/10.1186/s13054-024-05063-2

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中文翻译：

Baricitinib 与托珠单抗在机械通气 COVID-19 患者中的对比：一项全国性队列研究

 尊敬的编辑：


没有大规模研究将巴瑞替尼与托珠单抗专门用于 2019 年危重冠状病毒病 （COVID-19） 进行比较。一项纳入接受机械通气（mechanical ventilation， MV）或体外膜肺氧合（extracorporeal membrane oxygenation， ECMO）的COVID-19患者的探索性试验显示，尽管将巴瑞替尼与安慰剂进行比较，但巴瑞替尼组的28日死亡率显著降低[1]。大多数在重症 COVID-19 患者中对巴瑞克替尼和托珠单抗进行头对头比较的研究疾病严重程度较低（MV 组为 < 5%）[2]。因此，两种药物中哪一种对快速进展的炎症反应患者更有益尚不清楚。此外，先前研究中大多数患者未接种疫苗，从而限制了根据疫苗接种状态的分层分析。


为了解决目前的知识差距，本研究对韩国健康保险索赔数据进行了大规模分析，以比较 baricitinib 与托珠单抗在接受 MV 的 COVID-19 患者中的疗效。


分析了 2020 年 10 月 8 日至 2022 年 10 月 31 日收治的确诊 COVID-19 的成年患者（≥ 18 岁），他们需要 MV。对在指数住院期间接受至少一剂巴瑞克替尼或托珠单抗的患者进行评估。排除标准为年龄 < 18 岁、住院前 2 天内死亡或出院、心脏骤停、姑息治疗、怀孕或相关情况，以及巴瑞克替尼和托珠单抗的共同给药。进行倾向评分 （PS） 匹配以控制接受巴瑞替尼或托珠单抗的患者基线变量的差异。对于 PS 模型，巴瑞替尼的使用被用作因变量，自变量是表 S1 中列出的所有基线协变量。通过标准化均数差评估匹配前后的协变量平衡，< 0.10 的差异被认为是均衡的。进行 Logistic 回归分析以计算与巴瑞克替尼使用相关的结果的比值比 （ORs） 和 95% 置信区间 （CIs）。根据年龄、性别、 Charlson 合并症指数、神经肌肉阻滞剂、肾脏替代疗法和 ECMO 对结局进行亚组分析。为了确定 COVID-19 疫苗接种可能产生的混杂因素，根据入院前的疫苗接种状态对基线和结果分析进行分层。所有统计分析均使用 SAS 软件（9.4 版;SAS 研究所，美国北卡罗来纳州卡里）。


在 1630 名纳入的患者中 （平均 [标准差] 年龄，71.4 [12.8] 岁;男性，58.6%），PS 匹配导致每组 557 名患者（图 S1）。在 PS 匹配组之间的基线特征中未观察到显着差异 （表 S1）。对于不匹配组和 PS 匹配组，巴瑞克替尼使用和托珠单抗使用的中位（四分位距）持续时间分别为 8 （4-13） 天和 1 （1-1） 天。第 30 天，巴瑞替尼组死亡患者显著减少 （49.4% vs. 57.8%;或 0.71;95% CI 0.56–0.90;图 1a）。这证实了 Ely 等人 [1] 的研究，尽管巴瑞替尼组的死亡率 （39%） 低于当前研究的死亡率。Baricitinib 对托珠单抗表现出更有利的反应，可能是因为它的作用机制不同。虽然托珠单抗特异性抑制单一细胞因子 [3]，但巴瑞替尼抑制多种炎症通路 [4]。巴瑞克替尼多日给药可能会导致更一致的药物浓度递送，从而维持其抗炎作用 [4]。

 图 1
figure 1


a 30 天内生存概率的 Kaplan-Meier 曲线。b 巴瑞克替尼对亚组 30 天死亡率的关联。计算倾向评分匹配的 baricitinib （n = 557） 和 tocilizumab （n = 557） 组的比值比（用方块表示）和 95% CI （通过它们的相应行）。AP 值用于交互作用项。CI 置信区间、ECMO 体外膜肺氧合

 全尺寸图像


baricitinib 与 30 天死亡率之间的关联在所有亚组中都是一致的（图 1b）。尽管受到患者数量少的限制，但接受巴瑞克替尼和 ECMO 的患者死亡风险最低 （18.0% vs. 60.8%;或 0.14;95% CI 0.06-0.35;p < 0.001 用于交互）。这表明 baricitinib 的有益作用在炎症反应增加的患者中可能更明显。表 S2 显示了仅包括未接种疫苗患者的队列的基线特征。除年龄外，PS 匹配的巴瑞克替尼组和托珠单抗组的大多数基线特征相似。调整年龄后，接受巴瑞替尼治疗的患者 30 天死亡率显著降低 （46.8% vs. 59.7%;或 0.61;95% CI 0.44–0.87）。这一发现与 Trøseid 等人 [5] 对未接种疫苗的参与者的研究一致，该研究显示巴瑞替尼组的 60 天死亡率低于安慰剂组。然而，在这两项研究中，未接种疫苗的患者更年轻，合并症较少。仅包括接种疫苗患者的队列的基线特征如表 S3 所示。一旦出现严重的 COVID-19，疫苗接种本身可能不会显着影响对巴瑞克替尼或托珠单抗的治疗反应。在接种疫苗的患者中，巴瑞克替尼组和托珠单抗组在 30 天死亡率方面没有显着差异 （49.6% vs. 55.3%;或 0.80;95% CI 0.56-1.13）。


对于需要 MV 的 COVID-19 患者，巴瑞克替尼的 30 天死亡率低于托珠单抗。需要更多的研究来评估巴瑞克替尼在危重 COVID-19 患者特定亚组中的疗效。


本研究期间生成或分析的所有数据都包含在本文及其补充信息文件中。

 词：

 置信区间

 COVID-19 冠状病毒：

 2019 冠状病毒病

 ECMO 的：


体外膜肺氧合

 MV：

 机械通气

 或：

 比值比

 附言：

 倾向评分


  1. Ely EW、Ramanan AV、Kartman CE、de Bono S、Liao R、Piruzeli MLB 等人。巴瑞替尼联合标准护理治疗接受有创机械通气或体外膜肺氧合的 COVID-19 危重住院成人患者的疗效和安全性：一项探索性、随机、安慰剂对照试验。柳叶刀呼吸医学 2022;10:327–36.


    论文： CAS PubMed， PubMed， Central Google Scholar


  2. Roddy J、Wells D、Schenck K、Santosh S、Santosh S. 托珠单抗与巴瑞替尼在 COVID-19 肺炎和低氧血症住院患者中的对比：一项多中心回顾性队列研究。暴击护理探索。2022;4： e0702.


    文章： PubMed PubMed Central Google Scholar


  3. Zhang S， Li L， Shen A， Chen Y， Qi Z. 合理使用托珠单抗治疗新型冠状病毒肺炎。临床药物调查。2020;40:511–8.


    文章： PubMed PubMed Central Google Scholar


  4. Keystone EC、Taylor PC、Drescher E、Schlichting DE、Beattie SD、Berclaz PY 等人。巴瑞克替尼在 24 周时对甲氨蝶呤反应不足的类风湿性关节炎患者的安全性和有效性。Ann Rheum Dis. 2015 年;74:333–40.


    论文 CAS PubMed Google Scholar


  5. Trøseid M， Arribas JR， Assoumou L， Holten AR， Poissy J， Terzić V， et al.巴瑞克替尼在患有严重或危重 COVID-19 的住院成人患者中的疗效和安全性 （Bari-SolidAct）：一项随机、双盲、安慰剂对照的 3 期试验。暴击护理。2023;27:9.


    文章： PubMed PubMed Central Google Scholar

 下载参考资料


本研究使用韩国疾病控制和预防局和国家健康保险公团的数据库进行政策和学术研究 （KDCA-NHIS-2023-1-488）。


这项研究得到了由韩国政府（科学、信息通信技术和未来规划部）（2022R1F1A1067609）资助的韩国国家研究基金会资助的支持。资助者在研究的设计和实施中没有作用;数据的收集、管理、分析和解释;手稿的准备、审查或批准;或决定提交手稿出版。

 作者和单位


  1. 中央大学研究生院全球创新药系， 中央大学， 首尔， 韩国

    Seung-Hun You & Sun-Young Jung


  2. 韩国首尔中央大学医学院中央大学医院内科肺与重症监护医学科


    Moon Seong Baek， Tae Wan Kim & Won-Young Kim


  3. 中央大学药学院， 首尔， 大韩民国

    Sun-Young Jung

 作者

  1. Seung-Hun You （柳承勋）查看作者出版物


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  4. Sun-Young Jung 郑善英查看作者出版物


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  5. 金元英 Won-Young Kim查看作者出版物


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 贡献


WYK 参与了研究的构思和设计。SYJ 和 SHY 参与了数据采集和数据分析。WYK、SYJ、MSB 和 TWK 参与了数据解释。WYK 和 SHY 参与了手稿的起草。SYJ、MSB 和 TWK 帮助修改了重要的知识内容手稿。所有作者都阅读并批准了最终稿件。

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与 Sun-Young Jung 或 Won-Young Kim 的通信。


道德批准和参与同意


中央大学机构审查委员会 （1041078-20230306-HR-055） 免于审查利用去识别化患者数据的研究方案。

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You， SH.， Baek， M.S.， Kim， T.W. 等人。Baricitinib 与托珠单抗在机械通气 COVID-19 患者中的对比：一项全国性队列研究。Crit Care28， 282 （2024）。https://doi.org/10.1186/s13054-024-05063-2

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