Development and validation of a LC–MS/MS method for determination of bivalirudin in human plasma: Application to a clinical pharmacokinetic study

A simple, sensitive and rapid LC–MS/MS method has been developed and validated for the identification and quantification of bivalirudin in human plasma using nafarelin as the internal standard. Following protein precipitation with methanol, the analytes were separated on a C₁₈ column interfaced with a triple-quadrupole tandem mass spectrometer using positive electrospray ionization. Quantification of bivalirudin was conducted by multiple reaction monitoring (MRM) of the transitions of m/z 1091.4 → (356.4 + 227.4) for bivalirudin and m/z 662.4 → 328.5 for IS. The lower limit of quantification was 1.25 ng/ml, and the assay exhibited a linear range of 1.25–500 ng/ml. The developed assay method was successfully applied to a pharmacokinetic (PK) study in healthy volunteers after intravenous administration of bivalirudin.     

Utilization of anticoagulants and outcomes in STEMI patients undergoing PPCI in the US hospitals: Bivalirudin,heparin plus GPI or heparin alone?

Objective. Despite major trials showing the opposite, one of three small randomized trials conducted outside the US has raised questions about whether heparin alone is a viable antithrombotic strategy for primary percutaneous coronary interventions (PPCI). We determined the frequency and in-hospital outcomes of anticoagulation strategies in patients undergoing PPCI. Methods. We analyzed records from 2008 through 2013 in the Premier Research Database of patients hospitalized with ST-segment elevation myocardial infarction (STEMI) undergoing PPCI. Patients were categorized into one of four anticoagulation strategies: bivalirudin alone, bivalirudin plus glycoprotein IIb/IIIa inhibitors (GPI), unfractionated or low-molecular-weight heparin alone or heparin plus GPI. In-hospital clinical outcomes were compared between treatment groups after propensity score matching. Results. Among 114,134 eligible STEMI patients, heparin alone was the least frequent anticoagulation strategy, used in 14.4% to 18.1% of cases per year. Bivalirudin alone nearly tripled during the study period, from 12.7% to 37.8% and surpassed that of heparin plus GPI by 2013. Bivalirudin alone performed better than heparin alone for mortality (4.7% vs 5.3%, p = 0.010), clinically apparent bleeding (5.7% vs 6.7%, p < 0.001), transfusion rates (4.1% vs 4.8%, p = 0.003) and mean length of stay (4.1 vs 4.2 days, p < 0.001). The in-hospital death rate was lower with heparin plus GPI than with heparin alone (4.9% vs 5.9%, p < 0.001), but clinically apparent bleeding was higher in heparin plus GPI than in heparin alone (9.4% vs 7.1%, p < 0.001). Conclusion: In patients hospitalized for STEMI undergoing PPCI, heparin alone is not commonly used and is inferior to bivalirudin for mortality, bleeding and length of stay outcomes. Heparin is also inferior to heparin plus GPI for ischemic protection but associated with less bleeding.     

冠脉内注射比伐芦定对急性ST段抬高型心肌梗死直接PCI术中冠脉血流及临床事件影响

目的探讨在直接经皮冠状动脉介入(PPCI)术中,冠脉内注射比伐芦定对急性ST段抬高型心肌梗死(STEMI)患者罪犯冠脉血流恢复情况,以及术后30 d内临床事件的影响。方法本研究为前瞻性、随机对照探索性临床研究,选择2015年7月至2015年12月收治的拟行PPCI的急性STEMI患者84例,将患者随机分为对照组(n=40)和比伐芦定组(n=44)。经冠状动脉插入指引导丝或小直径球囊导管预扩张,使冠状动脉恢复前向血流≥TIMI 1级后,对照组不予冠脉内注射比伐芦定,正常进行PPCI常规操作;比伐芦定组经指引导管或微导管一次性冠脉内推注50%静脉负荷剂量的比伐芦定,此后按照PPCI常规正常操作。主要观察终点为PPCI术终靶血管校正的TIMI血流帧数(CTFC);次要观察终点为患者30 d内不良心脑血管事件(MACCE)发生率(包括死亡、再次心肌梗死、靶血管血运重建、脑卒中)、支架内血栓及出血学术研究会(BARC)定义的出血事件。结果两组患者靶血管PPCI术后,最终CTFC比较,差异无统计学意义(P>0.05);两组术后30 d内,MACCE事件发生率、支架内血栓及出血事件发生率比较,差异无统计学意义(P>0.05)。结论比伐芦定组与对照组比较,在改善冠脉血流方面无显著作用;冠脉内应用比伐芦定对术后30 d的临床缺血及出血事件均无明显影响。     

比伐卢定在体外膜氧合抗凝中的有效性和安全性的Meta分析

目的 评价比伐卢定在体外膜氧合(ECMO)抗凝中的有效性和安全性.方法 计算机检索CNKI、PubMed等数据库在2020年9月之前公开发表的相关文献,并对获得文献进行严格的筛选和质量评价,提取相关数据,采用Rev Man 5.3软件进行统计分析.结果 纳入九个研究,共计551人,其中比伐卢定组215人,肝素组336人...     

The Use of Bivalirudin for Cardiopulmonary Bypass Anticoagulation in Pediatric Heparin‐Induced Thrombocytopenia Patients

Infants with heparin‐induced thrombocytopenia (HIT) represent a challenging and high‐risk group of patients when they require cardiopulmonary bypass (CPB). Bivalirudin offers many potential pharmacologic advantages over other nonheparin anticoagulants for such patients. We describe our protocol for the use of bivalirudin in a 5‐month‐old infant undergoing stage 2 Norwood for hypoplastic left heart syndrome. The patient was a 5‐ month‐old, 6‐kg infant who developed HIT after a bowel resection complicating initial Norwood stage 1. After sternotomy and dissection had been redone, the child received an initial dose of bivalirudin of 1.0 mg/kg and 0.5 mg/kg 5 min later. The CPB circuit was primed with 50 mg/kg bivalirudn/400 cc volume. With the initiation of CPB, a continuous infusion of 2.5 mg/kg bivalirudin was begun. Activated clotting time (ACT) was targeted for over 400 s, with an examination prior to bypass and each 15 min thereafter. Bivalirudin was discontinued with separation from bypass and during modified ultrafiltration (MUF). The ACT was 286 s after the initial 1 mg/kg bolus and 597 s after the second 0.5 mg/kg bolus and initiation of CPB. At a rate of 2.5 mg/kg/min, ACT ranged between 461 and 597 s. At the completion of MUF, the ACT was 316 s. The ACT was 214 s 20 min after MUF. No clots were noted in the CPB circuit, and good hemostasis was achieved within 10 min after MUF was completed. Incision to closure time was 160 min; time from completion of MUF to sternal closure was 30 min. Post‐MUF, 60 cc of processed cell saver blood was reinfused, and no clotting factors were required. Chest tube output was 10, 10, 3, and 4 ccs, respectively, at hours 1–4 post operation. Bivalirudin provides effective anticoagulation in infants requiring CPB in the presence of HIT. Bivalirudin's efficacy is effectively monitored by ACT, and, after CPB, its short half‐life and ability to be ultrafiltered facilitate the ability to achieve hemostasis in a timely fashion.     

Point-of-care ecarin clotting time versus activated clotting time in correlation with bivalirudin concentration

INTRODUCTION: A thrombin inhibitor management (TIM) point-of-care test based upon the ecarin clotting time (ECT) has been developed. The ECT has been suggested to more accurately reflect the anti-coagulant effect of direct thrombin inhibitors compared with the activated clotting time (ACT). We sought to examine the correlation of the TIM-ECT test with bivalirudin concentration in patients undergoing percutaneous coronary intervention (PCI), and to compare the performance of this test with the current standard (i.e., ACT). MATERIALS AND METHODS: In a multicenter study, blood samples were obtained at six pre-defined time-points in 170 consecutive patients undergoing PCI using bivalirudin. For each sample, the TIM-ECT (citrated and non-citrated), ACT, and bivalirudin concentration was determined. RESULTS: Considering samples from all time-points (n=784), the correlations of TIM-ECT citrated, TIM-ECT non-citrated, and ACT with bivalirudin concentration were 0.96, 0.93, and 0.90, respectively. For samples collected at therapeutic levels of bivalirudin (n=353), the correlations of TIM-ECT citrated, TIM-ECT non-citrated, and ACT with bivalirudin concentration were lower, and showed a greater disparity between methods, with correlation coefficients of 0.75, 0.59, and 0.37, respectively. Prediction models based on the measured bivalirudin concentration were developed for TIM-ECT and ACT, and the coefficients of determination (r(2)) of actual versus predicted TIM-ECT and ACT were 0.91 and 0.81, respectively. CONCLUSIONS: In this PCI population, the TIM-ECT point-of-care test and ACT demonstrated a strong correlation with bivalirudin concentration. The TIM-ECT test had a higher correlation with bivalirudin concentration at therapeutic levels of the drug, and for individual samples appears to more consistently reflect the bivalirudin concentration compared with the ACT.     

抗凝药比伐卢定在冠状动脉介入领域中的应用进展

比伐卢定(bivalirudin)是一种新型直接凝血酶抑制剂,2000年被美国食品药品监督管理局批准应用于临床。比伐卢定是水蛭素的衍生物,通过抑制凝血酶的活性位点而起效,国外将其与其他常用抗凝药进行了比较研究,认为比伐卢定可以作为普通肝素和糖蛋白GPⅡb/Ⅲa受体阻滞剂的替代药物用于手术过程中的抗凝治疗。现综述比伐卢定的药理学特点及其在经皮冠状动脉介入治疗、肝素诱导的血小板减少症及对血小板功能的影响等方面的临床研究进展。     

比伐卢定对急性冠脉综合征患者介入术后出血影响的临床分析

目的评价国产注射用比伐卢定和普通肝素在急性冠状动脉综合征(ACS)患者冠状动脉介入术(PCI)后的出血风险。方法择期行PCI的ACS患者95例,随机分为肝素组(n=46)和比伐卢定组(n=49),其中肝素组脱落5例,比伐卢定组脱落3例,2组各剔除6例。2组分别采用国产注射用比伐卢定和肝素抗凝。于用药前和停药后1 h测定凝血酶原时间(PT)、凝血酶时间(TT)、纤维蛋白原(Fib),并比较试验期间各项凝血指标的变化。PCI术后随访30 d比较2组患者出血事件发生率和主要心血管不良事件(MACE)发生率。结果 2组患者基线资料相当,比伐卢定组和肝素组用药前和停药后1 h凝血指标无显著性差异(P>0.05)。PCI术后30 d内2组出血事件发生率、MACE发生率及不良反应比较差异无统计学意义(P均>0.05)。结论与常规肝素抗凝相比,比伐卢定在PCI术中抗凝效果安全稳定。     

国产比伐卢定用于冠状动脉介入治疗术中抗凝的疗效和安全性评价

目的:评估国产比伐卢定应用于择期冠状动脉介入治疗术(PCI)中抗凝治疗的疗效及安全性.方法:采用随机、单盲、多中心临床试验设计,随机将接受择期PCI的患者分为比伐卢定组和肝素组,在PCI术中分别采用比伐卢定或普通肝素抗凝治疗,主要疗效评价指标为术中测定激活的全血凝固时间(ACT)、手术成功率(靶病变术后狭窄程度小于20%并24 h内无冠状动脉事件发生)及30天无心血管事件生存率,主要安全性评价指标为轻度及重度出血.结果:共有218例患者入选,实际入组完成试验207例,比伐卢定组(n=105)和肝素组(n=102).用药后5 min除肝素组2例需要追加剂量外,其余两组患者PCI术中均能维持ACT>225 s,两组差异无统计学意义(P>0.05);比伐卢定组和肝素组PCI手术成功率和30天无心脏事件生存率均分别为100%和98.04%(P>0.05),差异无统计学意义.比伐卢定组和肝素组24 h内轻度出血的发生率分别为0.95%和6.86%(P<0.05)、30天内轻度出血发生率分别为1.9%和8.8%(P<0.05),肝素组有1例发生严重消化道出血.结论:国产比伐卢定能安全有效地应用于择期PCI术中抗凝治疗,疗效不劣于肝素且出血副作用低于肝素.