Arnold Donald M, Heddle Nancy M, Cook Richard J, Hsia Cyrus, Blostein Mark, Jamula Erin, Sholzberg Michelle, Lin Yulia, Kassis Jeannine, Larratt Loree, Tinmouth Alan, Amini Sufia, Schipperus Martin, Lim Wendy, Vishnu Prakash, Warner Margaret, Carruthers Julie, Li Na, Lane Shannon, Kelton John G
Michael G DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada; McMaster Centre for Transfusion Research, Department of Medicine, McMaster University, Hamilton, ON, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada; Canadian Blood Services, Ancaster, ON, Canada.
Michael G DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada; McMaster Centre for Transfusion Research, Department of Medicine, McMaster University, Hamilton, ON, Canada.
Lancet Haematol. 2020 Sep;7(9):e640-e648. doi: 10.1016/S2352-3026(20)30227-1.
Patients with immune thrombocytopenia are at risk of bleeding during surgery, and intravenous immunoglobulin is commonly used to increase the platelet count. We aimed to establish whether perioperative eltrombopag was non-inferior to intravenous immunoglobulin.
We did a randomised, open-label trial in eight academic hospitals in Canada. Patients were aged at least 18 years, with primary or secondary immune thrombocytopenia and platelet counts less than 100 × 10 cells per L before major surgery or less than 50 × 10 cells per L before minor surgery. Previous intravenous immunoglobulin within 2 weeks or thrombopoietin receptor agonists within 4 weeks before randomisation were not permitted. Patients were randomly assigned to receive oral daily eltrombopag 50 mg from 21 days preoperatively to postoperative day 7 or intravenous immunoglobulin 1 g/kg or 2 g/kg 7 days before surgery. Eltrombopag dose adjustments were allowed weekly based on platelet counts. The randomisation sequence was generated by a computerised random number generator, concealed and stratified by centre and surgery type (major or minor). The central study statistician was masked to treatment allocation. The primary outcome was achievement of perioperative platelet count targets (90 × 10 cells per L before major surgery or 45 × 10 cells per L before minor surgery) without rescue treatment. We did intention-to-treat and per-protocol analyses using an absolute non-inferiority margin of -10%. This trial is registered with ClinicalTrials.gov, NCT01621204.
Between June 5, 2013, and March 7, 2019, 92 patients with immune thrombocytopenia were screened, of whom 74 (80%) were randomly assigned: 38 to eltrombopag and 36 to intravenous immunoglobulin. Median follow-up was 50 days (IQR 49-55). By intention-to-treat analysis, perioperative platelet targets were achieved for 30 (79%) of 38 patients assigned to eltrombopag and 22 (61%) of 36 patients assigned to intravenous immunoglobulin (absolute risk difference 17·8%, one-sided lower limit of the 95% CI 0·4%; p=0·005). In the per-protocol analysis, perioperative platelet targets were achieved for 29 (78%) of 37 patients in the eltrombopag group and 20 (63%) of 32 in the intravenous immunoglobulin group (absolute risk difference 15·9%, one-sided lower limit of the 95% CI -2·1%; p=0·009). Two serious adverse events occurred in the eltrombopag group: one treatment-related pulmonary embolism and one vertigo. Five serious adverse events occurred in the intravenous immunoglobulin group (atrial fibrillation, pancreatitis, vulvar pain, chest tube malfunction and conversion to open splenectomy); all were related to complications of surgery. No treatment-related deaths occurred.
Eltrombopag is an effective alternative to intravenous immunoglobulin for perioperative treatment of immune thrombocytopenia. However, treatment with eltrombopag might increase risk of thrombosis. The decision to choose one treatment over the other will depend on patient preference, resource limitations, cost, and individual risk profiles.
GlaxoSmithKline and Novartis.
免疫性血小板减少症患者在手术期间有出血风险，静脉注射免疫球蛋白常用于提高血小板计数。我们旨在确定围手术期艾曲泊帕是否不劣于静脉注射免疫球蛋白。
我们在加拿大的八家学术医院进行了一项随机、开放标签试验。患者年龄至少18岁，患有原发性或继发性免疫性血小板减少症，在大手术前血小板计数低于100×10⁹/L，或在小手术前低于50×10⁹/L。随机分组前2周内曾使用静脉注射免疫球蛋白或4周内曾使用血小板生成素受体激动剂的患者不被纳入。患者被随机分配，从术前21天至术后第7天每天口服50毫克艾曲泊帕，或在手术前7天静脉注射1克/千克或2克/千克免疫球蛋白。根据血小板计数，允许每周调整艾曲泊帕剂量。随机序列由计算机随机数字生成器生成，并按中心和手术类型（大手术或小手术）进行隐藏和分层。中心研究统计人员对治疗分配情况保密。主要结局是在不进行挽救治疗的情况下实现围手术期血小板计数目标（大手术前90×10⁹/L或小手术前45×10⁹/L）。我们使用-10%的绝对非劣效性界值进行意向性分析和符合方案分析。该试验已在ClinicalTrials.gov注册，注册号为NCT01621204。
在2013年6月5日至2019年3月7日期间，筛查了92例免疫性血小板减少症患者，其中74例（80%）被随机分组：38例接受艾曲泊帕治疗，36例接受静脉注射免疫球蛋白治疗。中位随访时间为50天（四分位间距49 - 55天）。在意向性分析中，接受艾曲泊帕治疗的38例患者中有30例（79%）实现了围手术期血小板目标，接受静脉注射免疫球蛋白治疗的36例患者中有22例（61%）实现了围手术期血小板目标（绝对风险差异17.8%，95%置信区间的单侧下限0.4%；p = 0.005）。在符合方案分析中，艾曲泊帕组37例患者中有29例（78%）实现了围手术期血小板目标，静脉注射免疫球蛋白组32例患者中有20例（63%）实现了围手术期血小板目标（绝对风险差异15.9%，95%置信区间的单侧下限-2.1%；p = 0.009）。艾曲泊帕组发生了两例严重不良事件：一例与治疗相关的肺栓塞和一例眩晕。静脉注射免疫球蛋白组发生了五例严重不良事件（心房颤动、胰腺炎、外阴疼痛、胸管故障和转为开放性脾切除术）；所有这些均与手术并发症相关。未发生与治疗相关的死亡。
艾曲泊帕是免疫性血小板减少症围手术期治疗中静脉注射免疫球蛋白的有效替代药物。然而，使用艾曲泊帕治疗可能会增加血栓形成的风险。选择一种治疗方法而非另一种治疗方法的决定将取决于患者的偏好、资源限制、成本和个体风险状况。
葛兰素史克公司和诺华公司。
