Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial: a rebuttal

See also Liesenfled K‐H, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, EzekowitzMD, Yusuf S,Wallentin L, Haertter S, Staab A. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial. J Thromb Haemost 2011; 9: 2168–75; and Liesenfeld K‐H, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, Ezekowitz MD, Yusuf S, Wallentin L, Haertter S, Staab A. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with on‐valvular atrial fibrillation from the RE‐LY trial: reply to a rebuttal. This issue, pp 502–4.     

Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial: reply to a rebuttal

See also Liesenfled K‐H, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, EzekowitzMD, Yusuf S,Wallentin L, Haertter S, Staab A. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial. J Thromb Haemost 2011; 9: 2168–75; and Patel JP, Green B, Patel RK, Davies JG, Arya R. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non‐valvular atrial fibrillation from the RE‐LY trial: a rebuttal. This issue, pp 500–2.     

Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I.

BACKGROUND: Dabigatran etexilate (BIBR 1048) is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following total hip replacement. Following oral administration, dabigatran etexilate is rapidly converted to its active form dabigatran (BIBR 953 ZW). OBJECTIVES: To determine the safe therapeutic range of dabigatran etexilate following total hip replacement. METHODS: In a multicenter, open-label, dose-escalating study, 314 patients received oral doses of dabigatran etexilate (12.5, 25, 50, 100, 150, 200 and 300 mg twice daily or 150 and 300 mg once daily) administered 4-8 h after surgery, for 6-10 days. Dose escalation was based on clinical and pharmacokinetic data. The primary safety outcome was major bleeding. The primary efficacy outcome included venographic deep vein thrombosis (DVT), symptomatic DVT and pulmonary embolism, during the treatment period. RESULTS: No major bleeding event was observed in any group, but two patients at the highest dose (300 mg twice daily) suffered bleeding from multiple sites associated with reduced renal clearance and prolonged pharmacodynamic (PD) parameters. A dose-response was demonstrated for minor bleeding events. Of the 289 treated patients, 225 patients had evaluable venograms. The overall incidence of DVT was 12.4% (28/225 patients). There was no consistent relationship between the dose and incidence of DVT, the highest incidence in any group being 20.8% (5/24 patients). The lowest dose (12.5 mg twice daily) showed a high rate of proximal DVT [12.5% (3/24)] and no increase in PD parameters. Peak and trough plasma concentrations, area under the dabigatran plasma concentration-time curve and PD parameters also increased in proportion with the dose. Higher dabigatran plasma concentrations were associated with lower DVT rates. Approximately 20% of the patients had low plasma concentrations after the first dose suggesting further optimization of the preliminary tablet formulation is required. CONCLUSIONS: Dabigatran etexilate demonstrates an acceptable safety profile, with a therapeutic window above 12.5 mg and below 300 mg twice daily. The low number of VTE events within each treatment group indicates a satisfactory antithrombotic potential, although the study was not powered for an efficacy analysis. Additional studies are ongoing to optimize oral absorption and the efficacy/safety balance.     

非瓣膜性心房颤动患者ABCB1和CES1基因多态性对达比加群酯抗凝疗效的影响

目的 探讨ABCB1 SNP rs1045642与CES1 SNP rs2244613基因多态性对非瓣膜性心房颤动患者服用达比加群酯的抗凝疗效的影响.方法 选取2020年5月至2021年6月在郑州大学第五附属医院心内科住院的80例非瓣膜性心房颤动患者作为研究对象.检测患者ABCB1 SNP rs1045642与CES1...     

A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial

BACKGROUND: Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following orthopedic surgery. METHODS: In a multicenter, parallel-group, double-blind study, 1973 patients undergoing total hip or knee replacement were randomized to 6-10 days of oral dabigatran etexilate (50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily), starting 1-4 h after surgery, or subcutaneous enoxaparin (40 mg once daily) starting 12 h prior to surgery. The primary efficacy outcome was the incidence of VTE (detected by bilateral venography or symptomatic events) during treatment. RESULTS: Of the 1949 treated patients, 1464 (75%) patients were evaluable for the efficacy analysis. VTE occurred in 28.5%, 17.4%, 16.6%, 13.1% and 24% of patients assigned to dabigatran etexilate 50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily and enoxaparin, respectively. A significant dose-dependent decrease in VTE occurred with increasing doses of dabigatran etexilate (P < 0.0001). Compared with enoxaparin, VTE was significantly lower in patients receiving 150 mg twice daily [odds ratio (OR) 0.65, P = 0.04], 300 mg once daily (OR 0.61, P = 0.02) and 225 mg twice daily (OR 0.47, P = 0.0007). Compared with enoxaparin, major bleeding was significantly lower with 50 mg twice daily (0.3% vs. 2.0%, P = 0.047) but elevated with higher doses, nearly reaching statistical significance with the 300 mg once-daily dose (4.7%, P = 0.051). CONCLUSIONS: Oral administration of dabigatran etexilate, commenced early in the postoperative period, was effective and safe across a range of doses. Further optimization of the efficacy/safety balance will be addressed in future studies.     

Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis

BACKGROUND: Oral anticoagulant therapies targeted at thrombin are being developed to overcome limitations associated with current standard therapies. OBJECTIVES: This study was undertaken to assess and compare the antithrombotic and anticoagulant effects of the novel, selective and reversible, direct thrombin inhibitor (DTI), dabigatran, and its oral prodrug dabigatran etexilate, to that of unfractionated heparin (UFH), hirudin and melagatran using a rabbit model of venous thrombosis. METHODS: A rabbit model of venous thrombosis consisting of endothelial damage with blood flow reduction was used with minor modifications. RESULTS: All compounds demonstrated a dose-dependent reduction in thrombus formation following i.v. administration with complete or almost complete inhibition at the highest doses. Dabigatran (in the dose range 0.03-0.5 mg kg(-1)) had a 50% effective dose of 0.066 mg kg(-1). By comparison, UFH (5-50 U kg(-1)), hirudin (0.01-0.05 mg kg(-1)) and melagatran (0.01-0.3 mg kg(-1)) had a 50% effective dose of 9.8 U kg(-1), 0.016 mg kg(-1) and 0.058 mg kg(-1), respectively. Similarly, oral dabigatran etexilate (1-20 mg kg(-1)) inhibited thrombus formation in a dose-dependent manner. Maximum inhibition was achieved within 1 h of administration, suggesting a rapid onset of action. For both routes of administration, inhibition of thrombus formation directly correlated with prolongation of the activated partial thromboplastin time. CONCLUSIONS: These findings demonstrate the potent anticoagulant and antithrombotic activity of dabigatran as a selective thrombin inhibitor in a rabbit model of venous thrombosis. Notably, dose-dependent and long-lasting antithrombotic efficacy was observed after application of its oral form dabigatran etexilate, which is currently undergoing phase III clinical development.     

达比加群酯在非瓣膜性房颤患者抗凝治疗中的应用效果

目的探讨达比加群酯在非瓣膜性房颤患者抗凝治疗中的应用效果。方法选取2017年5月至2019年6月入我院治疗的120例非瓣膜性房颤患者,采用信封法将其分为对照组和研究组,每组60例。对照组给予华法林治疗,研究组给予达比加群酯治疗。比较两组的凝血指标、肝肾功能指标、出血事件、栓塞事件及不良反应发生情况。结果治疗后,研究组的TT、APTT、PT长于对照组,INR低于对照组(P<0.05)。治疗后,研究组的Cr、BUN、三酰甘油、转氨酶水平均低于对照组(P<0.05)。研究组的出血事件及栓塞事件的总发生率均低于对照组(P<0.05)。研究组的不良反应总发生率低于对照组(P<0.05)。结论达比加群酯治疗非瓣膜性房颤可调节患者凝血指标水平,不会对肝肾功能造成损伤,且不会增加栓塞事件及出血事件的发生率,不良反应少,应用效果理想,可考虑推广。     

Dabigatran etexilate for thromboembolic prophylaxis in non-valvular atrial fibrillation: the RE-LY study and substudies with commentary

In 2010, dabigatran etexilate, a direct thrombin inhibitor, was the first new oral anticoagulant to be approved for thromboembolic prophylaxis in atrial fibrillation in over 50 years. Dabigatran, unlike warfarin, has a short half-life with a rapid onset of anticoagulant effect, does not require dose adjustment or monitoring, and does not interact with food. The RE-LY trial compared two doses of dabigatran (110 and 150 mg twice daily) with adjusted dose warfarin in patients with non-valvular atrial fibrillation and at least 1 stroke risk factor. Compared with warfarin, dabigatran 150 mg twice daily was superior in reducing the risk of stroke or systemic embolism and was associated with a similar rate of major bleeding, while dabigatran 110 mg twice daily was equally effective in reducing stroke or systemic embolism and was associated with less major bleeding. Despite these favorable results, there remains disagreement regarding the optimal dose and overall safety of dabigatran in certain patient populations including the elderly and those with renal dysfunction.     

Expression of platelet‐bound stromal cell‐derived factor‐1 in patients with non‐valvular atrial fibrillation and ischemic heart disease

Summary. Aims: Blood cell infiltration and inflammation are involved in atrial remodelling during atrial fibrillation (AF) although the exact mechanisms of inflammatory cell recruitment remain poorly understood. Platelet‐bound stromal cell‐derived factor‐1 (SDF‐1) is increased in cases of ischemic myocardium and regulates recruitment of CXCR4⁺ cells on the vascular wall. Whether platelet‐bound SDF‐1 expression is differentially influenced by non‐valvular paroxysmal or permanent atrial fibrillation (AF) in patients with stable angina pectoris (SAP) or acute coronary syndrome (ACS) has not been reported so far. Methods and results: A total of 1291 consecutive patients with coronary artery disease (CAD) undergoing coronary angiography were recruited. Among the patients with SAP, platelet‐bound‐SDF‐1 is increased in patients with paroxysmal AF compared with SR or to persistent/permanent AF (P < 0.05 for both). Platelet‐bound SDF‐1 correlated with plasma SDF‐1 (r = 0.488, P = 0.013) in patients with AF and ACS, which was more pronounced among patients with persistent AF (r = 0.842, P = 0.009). Plasma SDF‐1 was increased in persistent/permanent AF compared with SR. Patients with ACS presented with enhanced platelet‐bound‐SDF‐1 compared with SAP. Interestingly, among patients with ACS, patients with paroxysmal or persistent/permanent AF presented with an impaired platelet‐bound SDF‐1 expression compared with patients with SR. Conclusions: Differential expression of platelet‐bound and plasma SDF‐1 was observed in patients with AF compared with SR which may be involved in progenitor cell mobilization and inflammatory cell recruitment in patients with AF and ischemic heart disease. Further in vivo studies are required to elucidate the role of SDF‐1 in atrial remodeling and the atrial fibrillation course.     

利伐沙班对合并心功能不全的高龄非瓣膜性心房颤动疗效及安全性

目的 分析利伐沙班对合并心功能不全的高龄非瓣膜性心房颤动（non valvular atrial fibrillation,NVAF）患者临床疗效及安全性。方法 随机连续纳入2016年1月至2020年1月间就诊于我院合并心功能不全的高龄NVAF患者182例,随机分为两组,其中91例患者应用利伐沙班抗凝归为观察组,余91例应用华法林抗凝归为对照组。随访记录两组抗凝期间血栓事件、出血等不良反应以及凝血功能和心功能情况。结果 观察组总出血事件显著低于对照组;观察组治疗后N末端B型利钠肽前体（NT proBNP）较对照组显著下降;COX风险模型发现,年龄及华法林是不良事件的危险因素。结论 利伐沙班对于合并心功能不全的高龄NVAF患者疗效不劣于华法林,但安全性显著高于华法林。