Wills Nicola K, Nair Nikhil, Patel Kashyap, Sikder Omaike, Adriaanse Marguerite, Eikelboom John, Wasserman Sean
Department of Medicine, University of Cape Town, Cape Town, South Africa.
Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.
medRxiv. 2022 Mar 7:2022.03.05.22271947. doi: 10.1101/2022.03.05.22271947.
Randomised controlled trials (RCTs) have reported inconsistent effects from intensified anticoagulation on clinical outcomes in Covid-19. We performed an aggregate data meta-analysis from available trials to quantify effect on non-fatal and fatal outcomes and identify subgroups who may benefit.
We searched multiple databases for RCTs comparing intensified (intermediate or therapeutic dose) versus standard prophylactic dose anticoagulation in adults with laboratory-confirmed Covid-19 through 19 January 2022. The primary efficacy outcome was all-cause mortality at end of follow-up or discharge. We used random effects meta-analysis to estimate pooled risk ratios for mortality, thrombotic, and bleeding events, and performed subgroup analysis for clinical setting and dose of intensified anticoagulation.
Eleven RCTs were included (n = 5873). Intensified anticoagulation was not associated with a reduction in mortality for up to 45 days compared with prophylactic anticoagulation: 17.5% (501/2861) died in the intensified anticoagulation group and 18.8% (513/2734) died in the prophylactic anticoagulation group, relative risk (RR) 0.93; 95%CI, 0.79 - 1.10. On subgroup analysis, there was a possible signal of mortality reduction for inpatients admitted to general wards, although with low precision and high heterogeneity (5 studies; RR 0.84; 95% CI, 0.49 - 1.44; I = 75%) and not significantly different to studies performed in the ICU (interaction P = 0.51). Risk of venous thromboembolism was reduced with intensified anticoagulation compared with prophylaxis (8 studies; RR 0.53, 95%CI 0.41 - 0.69; I = 0%). This effect was driven by therapeutic rather than intermediate dosing on subgroup analysis (interaction P =0.04). Major bleeding was increased with use of intensified anticoagulation (RR 1.73, 95% CI 1.17 - 2.56) with no interaction for dosing and clinical setting.
Intensified anticoagulation has no effect on short term mortality among hospitalised adults with Covid-19 and is associated with increased risk of bleeding. The observed reduction in venous thromboembolism risk and trend towards reduced mortality in non-ICU hospitalised patients requires exploration in additional RCTs.
In this aggregate data meta-analysis, use of intensified anticoagulation had no effect on short term mortality among hospitalised adults with Covid-19 and was associated with increased risk of bleeding.
随机对照试验（RCT）报告了强化抗凝治疗对新冠肺炎临床结局的影响不一致。我们对现有试验进行了汇总数据荟萃分析，以量化对非致命和致命结局的影响，并确定可能受益的亚组。
我们在多个数据库中检索了截至2022年1月19日比较强化（中等或治疗剂量）与标准预防性剂量抗凝治疗对实验室确诊的成年新冠肺炎患者疗效的随机对照试验。主要疗效结局是随访结束或出院时的全因死亡率。我们使用随机效应荟萃分析来估计死亡率、血栓形成和出血事件的合并风险比，并对临床环境和强化抗凝治疗的剂量进行亚组分析。
纳入了11项随机对照试验（n = 5873）。与预防性抗凝治疗相比，强化抗凝治疗在长达45天内并未降低死亡率：强化抗凝治疗组中有17.5%（501/2861）死亡，预防性抗凝治疗组中有18.8%（513/2734）死亡，相对风险（RR）为0.93；95%置信区间（CI）为0.79 - 1.10。在亚组分析中，普通病房住院患者可能有死亡率降低的迹象，尽管精度较低且异质性较高（5项研究；RR 0.84；95% CI为0.49 - 1.44；I² = 75%），且与在重症监护病房（ICU）进行的研究无显著差异（交互P = 0.51）。与预防性抗凝治疗相比，强化抗凝治疗可降低静脉血栓栓塞的风险（8项研究；RR 0.53，95% CI为0.41 - 0.69；I² = 0%）。亚组分析表明，这种效果是由治疗剂量而非中等剂量驱动的（交互P = 0.04）。强化抗凝治疗会增加大出血的风险（RR 1.73，95% CI为1.17 - 2.56），剂量和临床环境之间无交互作用。
强化抗凝治疗对住院成年新冠肺炎患者的短期死亡率无影响，且与出血风险增加相关。在非ICU住院患者中观察到的静脉血栓栓塞风险降低以及死亡率降低的趋势需要在更多随机对照试验中进行探索。
在这项汇总数据荟萃分析中，强化抗凝治疗对住院成年新冠肺炎患者的短期死亡率无影响，且与出血风险增加相关。
