BACKGROUND Dosing of replacement therapy with factor VIII concentrate in patients with haemophilia A in the perioperative setting is challenging. Underdosing and overdosing of factor VIII concentrate should be avoided to minimise risk of perioperative bleeding and treatment costs. We hypothesised that dosing of factor VIII concentrate on the basis of a patient's pharmacokinetic profile instead of bodyweight, which is standard treatment, would reduce factor VIII consumption and improve the accuracy of attained factor VIII levels. METHODS In this open-label, multicentre, randomised, controlled trial (OPTI-CLOT), patients were recruited from nine centres in Rotterdam, Groningen, Utrecht, Nijmegen, The Hague, Leiden, Amsterdam, Eindhoven, and Maastricht in The Netherlands. Eligible patients were aged 12 years or older with severe or moderate haemophilia A (severe haemophilia was defined as factor VIII concentrations of <0·01 IU/mL, and moderate haemophilia as 0·01-0·05 IU/mL), without factor VIII inhibitors, and planned for elective low or medium risk surgery as defined by surgical risk score. Patients were randomly assigned (1:1) using a web-based randomisation system and treatment minimisation, stratified by method of administration of factor VIII concentrate (continuous infusion vs bolus administration) and risk level of surgery (low and medium risk surgery), to the pharmacokinetic-guided or standard treatment group. The primary endpoint was total amount of infused factor VIII concentrate (IU per kg bodyweight) during perioperative period (from day of surgery up to 14 days after surgery). Analysis was by intention to treat and the safety analysis population comprised all participants who underwent surgery with factor VIII concentrate. This study is registered with the Netherlands Trial Registry, NL3955, and is now closed to accrual. FINDINGS Between May 1, 2014, and March 1, 2020, 98 patients were assessed for eligibility and 66 were enrolled in the trial and randomly assigned to the pharmacokinetic-guided treatment group (34 [52%]) or the standard treatment group (32 [48%]). Median age was 49·1 years (IQR 35·0 to 62·1) and all participants were male. No difference was seen in consumption of factor VIII concentrate during the perioperative period between groups (mean consumption of 365 IU/kg [SD 202] in pharmacokinetic-guided treatment group vs 379 IU/kg [202] in standard treatment group; adjusted difference -6 IU/kg [95% CI -88 to 100]). Postoperative bleeding occurred in six (18%) of 34 patients in the pharmacokinetic-guided treatment group and three (9%) of 32 in the standard treatment group. One grade 4 postoperative bleeding event occurred, which was in one (3%) patient in the standard treatment group. No treatment-related deaths occurred. INTERPRETATION Although perioperative pharmacokinetic-guided dosing is safe, it leads to similar perioperative factor VIII consumption when compared with standard treatment. However, pharmacokinetic-guided dosing showed an improvement in obtaining factor VIII concentrations within the desired perioperative factor VIII range. These findings provide support to further investigation of pharmacokinetic-guided dosing in perioperative haemophilia care. FUNDING Dutch Research Council (NWO)-ZonMw and Takeda.

中文翻译：

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血友病患者围手术期药代动力学指导的凝血因子 VIII 浓缩物给药（OPTI-CLOT 试验）：一项开放标签、多中心、随机、对照试验。

背景 在围手术期对 A 型血友病患者进行凝血因子 VIII 浓缩物替代治疗的剂量具有挑战性。应避免因子 VIII 浓缩物的剂量不足和过量，以尽量减少围手术期出血的风险和治疗费用。我们假设，根据患者的药代动力学特征而不是体重（这是标准治疗）来浓缩因子 VIII 的剂量将减少因子 VIII 消耗并提高所达到的因子 VIII 水平的准确性。方法 在这项开放标签、多中心、随机、对照试验 (OPTI-CLOT) 中，患者来自鹿特丹、格罗宁根、乌得勒支、奈梅亨、海牙、莱顿、阿姆斯特丹、埃因霍温和荷兰马斯特里赫特的九个中心。符合条件的患者为 12 岁或以上患有重度或中度血友病 A（重度血友病定义为因子 VIII 浓度 <0·01 IU/mL，中度血友病定义为 0·01-0·05 IU/mL），无因子VIII 抑制剂，并计划进行手术风险评分定义的择期低风险或中风险手术。患者被随机分配 (1:1) 使用基于网络的随机化系统和治疗最小化，通过因子 VIII 浓缩物的给药方法（连续输注与推注给药）和手术风险水平（低风险和中风险手术）进行分层，以药代动力学指导或标准治疗组。主要终点是围手术期（从手术当天到手术后 14 天）输注的凝血因子 VIII 浓缩物总量（每公斤体重 IU）。分析是按意向治疗进行的，安全性分析人群包括所有接受过凝血因子 VIII 浓缩物手术的参与者。该研究已在荷兰试验注册中心 NL3955 注册，现已关闭。结果 在 2014 年 5 月 1 日至 2020 年 3 月 1 日期间，对 98 名患者进行了资格评估，66 名患者被纳入试验并随机分配到药代动力学指导治疗组（34 [52%]）或标准治疗组（32 [48%]）。中位年龄为 49·1 岁（IQR 35·0 至 62·1），所有参与者均为男性。组间围手术期 VIII 浓缩物的消耗量没有差异（药代动力学指导治疗组的平均消耗量为 365 IU/kg [SD 202]，标准治疗组为 379 IU/kg [202]；调整后的差异 -6 IU/kg [95% CI -88 至 100]）。药代动力学指导治疗组 34 名患者中有 6 名 (18%) 发生术后出血，标准治疗组 32 名患者中有 3 名 (9%) 发生术后出血。发生了 1 次 4 级术后出血事件，发生在标准治疗组的 1 名 (3%) 患者中。没有发生与治疗相关的死亡。解释 尽管围手术期药代动力学指导的给药是安全的，但与标准治疗相比，它导致围手术期因子 VIII 消耗量相似。然而，药代动力学指导的给药显示在获得所需的围手术期因子 VIII 范围内的因子 VIII 浓度方面有所改善。这些发现为进一步研究围手术期血友病护理中药代动力学指导的给药提供了支持。