Standard-dose unfractionated heparin versus low-dose unfractionated heparin and low-molecular-weight heparin in extracorporeal life support (RATE): an open-label, randomised, non-inferiority trial.

This approach can increase bleeding without further reducing thrombosis compared with low-dose UFH.

与低剂量UFH相比，这种方法可能会增加出血风险，但并不能进一步降低血栓形成。

Robust evidence to guide anticoagulation targets is absent because anticoagulation targets in ECMO have never been assessed in a sufficiently powered randomised trial. We aimed to determine whether low-dose UFH or therapeutic low-molecular-weight heparin (LMWH) is non-inferior to standard-dose UFH in patients receiving ECMO.

由于在ECMO中从未在足够规模的随机试验中评估过抗凝目标，因此缺乏指导抗凝目标的有力证据。我们的目标是确定低剂量UFH或治疗性低分子量肝素(LMWH)是否不劣于标准剂量UFH，用于接受ECMO治疗的患者。

Methods

In this open-label, three-arm, randomised, non-inferiority trial at seven Dutch intensive care units (ICUs), adults aged 18 years or older supported with veno-venous or veno-arterial ECMO at the ICU without vital indication for full-dose anticoagulation (eg, mechanical mitral valve) were randomly assigned to intravenous standard-dose UFH (activated partial thromboplastin time 2·0-2·5 times baseline), intravenous low-dose UFH (1·5-2·0 times baseline), or therapeutic subcutaneous LMWH.

在这项开放标签、三臂、随机、非劣效试验中，荷兰的七家重症监护病房(ICUs)对18岁或以上的成人患者进行了随机分配，这些患者在ICU接受静脉-静脉或静脉-动脉ECMO支持，但没有生命迹象表明需要全剂量抗凝（例如，机械二尖瓣）。患者被随机分配接受静脉注射标准剂量UFH（活化部分凝血活酶时间2.0-2.5倍基线值）、静脉注射低剂量UFH（1.5-2.0倍基线值）或皮下注射治疗性低分子量肝素(LMWH)。

The primary outcome was a composite of severe bleeding during ECMO support, severe thromboembolic complications during ECMO support, or all-cause mortality at 6 months, and was assessed in all randomly assigned patients with deferred informed consent and 6-month follow-up data according to the intention-to-treatprinciple.

主要结果是ECMO支持期间严重出血、ECMO支持期间严重血栓栓塞并发症或6个月时全因死亡率的复合终点，根据意向治疗原则，对所有随机分配的患者进行了评估，这些患者在延迟知情同意和6个月随访数据后进行了评估。

Non-inferiority was met if the upper 95% CI limit for the absolute risk difference was less than 7·5 percentage points.

如果绝对风险差异的上限95%置信区间小于7.5个百分点，则满足非劣效性。

This trial is registered at ClinicalTrials.gov (NCT04536272) and the Dutch trial register (NL7976).

该试验已在ClinicalTrials.gov (NCT04536272)和荷兰试验注册处(NL7976)注册。

Results

Between Oct 22, 2020, and Sept 12, 2024, 330 patients were enrolled: 110 were randomly assigned to standard-dose UFH, 110 to low-dose UFH, and 110 to LMWH.

在2020年10月22日至2024年9月12日期间，共有330名患者被纳入研究：110名被随机分配到标准剂量的普通肝素（UFH），110名到低剂量的普通肝素，以及110名到低分子量肝素（LMWH）。

Of 330 enrolled patients, 320 (225 [70%] males, 95 [30%] females; median age 56 years [IQR 45-65]; 255 [80%] White ethnicity) were analysed at 6 months.

在纳入的330名患者中，有320名（男性225名[70%]，女性95名[30%]；中位年龄56岁[四分位数间距45-65]；255名[80%]为白人种族）在6个月时进行了分析。

The composite primary outcome occurred in 87 (81%) of 107 patients with standard-dose UFH, 78 (72%) of 108 with low-dose UFH (absolute risk difference -9·1 percentage points [95% CI -20·3 to 2·1]), and 79 (75%) of 105 with LMWH (-6·1 percentage points [-17·2 to 5·0]), meeting non-inferiority for both interventions.

在107名接受标准剂量UFH治疗的患者中，有87名（81%）发生了复合主要终点事件，而在108名接受低剂量UFH治疗的患者中，有78名（72%）发生了该事件（绝对风险差异为-9.1个百分点[95% CI -20.3至2.1]），在105名接受LMWH治疗的患者中，有79名（75%）发生了该事件（绝对风险差异为-6.1个百分点[95% CI -17.2至5.0]），两种干预措施均满足非劣效性。

The frequency of severe bleeding was lower with low-dose UFH and LMWH than with standard-dose UFH (63 [58%] patients and 62 [59%] vs 70 [65%]), without excess severe thromboembolic complications (11 [10%] and nine [9%] vs 12 [11%]), although these differences did not reach statistical significance.

与标准剂量普通肝素相比，低剂量普通肝素和低分子量肝素的严重出血发生率较低（分别为63 [58%]例患者和62 [59%]例，而标准剂量普通肝素为70 [65%]例），且没有出现过多的严重血栓栓塞并发症（分别为11 [10%]例和9 [9%]例，而标准剂量普通肝素为12 [11%]例），尽管这些差异没有达到统计学显著性。

At 6 months, 54 (50%) patients in the standard-dose UFH group, 45 (42%) in the low-dose UFH group, and 46 (44%) in the LMWH group had died.

在6个月时，标准剂量普通肝素组有54（50%）例患者死亡，低剂量普通肝素组有45（42%）例患者死亡，低分子量肝素组有46（44%）例患者死亡。

interpretation

Low-dose UFH and therapeutic LMWH were non-inferior to standard-dose UFH.

低剂量未分级肝素（UFH）和治疗剂量低分子量肝素（LMWH）与标准剂量UFH相比，具有非劣效性。

This finding supports reconsideration of anticoagulation targets in ECMO.

这一发现支持重新考虑体外膜肺氧合（ECMO）中的抗凝治疗目标。

Given the global expansion of ECMO, these findings suggest that reduced anticoagulation targets could substantially reduce bleeding-related harm.

鉴于ECMO在全球范围内的扩展，这些发现表明降低抗凝目标可能会显著减少与出血相关的伤害。

funding

ZonMw.

ZonMw.