BACKGROUND & AIMS:
BACKGROUND:New oral anticoagulants for stroke prevention in atrial fibrillation were developed to be given in fixed doses without the need for the routine monitoring that has hindered usage and acceptance of vitamin K antagonists. A concern has emerged, however, that measurement of drug concentration or anticoagulant activity might be needed to prevent excess drug concentrations, which significantly increase bleeding risk. In the ENGAGE AF-TIMI 48 trial, higher-dose and lower-dose edoxaban were compared with warfarin in patients with atrial fibrillation. Each regimen incorporated a 50% dose reduction in patients with clinical features known to increase edoxaban drug exposure. We aim to assess whether adjustment of edoxaban dose in this trial prevented excess drug concentration and the risk of bleeding events.
METHODS:We analysed data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. We correlated edoxaban dose, plasma concentration, and anti-Factor Xa (FXa) activity and compared efficacy and safety outcomes with warfarin stratified by dose reduction status. Patients with atrial fibrillation and at moderate to high risk of stroke were randomly assigned in a 1:1:1 ratio to receive warfarin, dose adjusted to an international normalised ratio of 2·0-3·0, higher-dose edoxaban (60 mg once daily), or lower-dose edoxaban (30 mg once daily). Randomisation was done with use of a central, 24 h, interactive, computerised response system. International normalised ratio was measured using an encrypted point-of-care device. To maintain masking, sham international normalised ratio values were generated for patients assigned to edoxaban. Edoxaban (or placebo-edoxaban in warfarin group) doses were halved at randomisation or during the trial if patients had creatinine clearance 30-50 mL/min, bodyweight 60 kg or less, or concomitant medication with potent P-glycoprotein interaction. Efficacy outcomes included the primary endpoint of all-cause stroke or systemic embolism, ischaemic stroke, and all-cause mortality. Safety outcomes included the primary safety endpoint of major bleeding, fatal bleeding, intracranial haemorrhage, and gastrointestinal bleeding. This trial is registered with ClinicalTrials.gov, number NCT00781391.
FINDINGS:Between Nov 19, 2008 and Nov 22, 2010, 21 105 patients were recruited. Patients who met clinical criteria for dose reduction at randomisation (n=5356) had higher rates of stroke, bleeding, and death compared with those who did not have a dose reduction (n=15 749). Edoxaban dose ranged from 15 mg to 60 mg, resulting in a two-fold to three fold gradient of mean trough drug exposure (16·0-48·5 ng/mL in 6780 patients with data available) and mean trough anti-FXa activity (0·35-0·85 IU/mL in 2865 patients). Dose reduction decreased mean exposure by 29% (from 48·5 ng/mL [SD 45·8] to 34·6 ng/mL [30·9]) and 35% (from 24·5 ng/mL [22·7] to 16·0 ng/mL [14·5]) and mean anti-FXa activity by 25% (from 0·85 IU/mL [0·76] to 0·64 IU/mL [0·54]) and 20% (from 0·44 IU/mL [0·37] to 0·35 IU/mL [0·28]) in the higher-dose and lower-dose regimens, respectively. Despite the lower anti-FXa activity, dose reduction preserved the efficacy of edoxaban compared with warfarin (stroke or systemic embolic event: higher dose pinteraction=0·85, lower dose pinteraction=0·99) and provided even greater safety (major bleeding: higher dose pinteraction 0·02, lower dose pinteraction=0·002).
INTERPRETATION:These findings validate the strategy that tailoring of the dose of edoxaban on the basis of clinical factors alone achieves the dual goal of preventing excess drug concentrations and helps to optimise an individual patient's risk of ischaemic and bleeding events and show that the therapeutic window for edoxaban is narrower for major bleeding than thromboembolism.
FUNDING:Daiichi-Sankyo Pharma Development.
背景与目标:
背景:开发了用于预防房颤的新型口服抗凝药,以固定剂量给药,而无需进行常规监测,而常规监测已阻碍了维生素K拮抗剂的使用和接受。然而,已经出现了一种担忧,即可能需要测量药物浓度或抗凝活性以防止药物浓度过高,从而显着增加出血风险。在ENGAGE AF-TIMI 48试验中,将房颤患者的高剂量和低剂量的依多沙班与华法林进行了比较。对于具有已知会增加edoxaban药物暴露量的临床特征的患者,每种方案都将剂量减少50%。我们旨在评估在该试验中调整依多沙班剂量是否可以防止药物浓度过高和发生出血事件的风险。
方法:我们分析了来自随机,双盲ENGAGE AF-TIMI 48试验的数据。我们将依多沙班的剂量,血浆浓度和抗Xa因子(FXa)活性相关联,并比较了按剂量减少状态分层的华法林的疗效和安全性结果。心房纤颤且中风至高中风风险的患者以1:1:1:1的比例随机分配接受华法林,剂量调整至国际标准化比例2·0-3·0,大剂量依多沙班(60 mg每天一次)或小剂量的依多沙班(每天一次30毫克)。使用中央的24小时交互式计算机化应答系统进行随机分组。国际标准化比率是使用加密的即时护理设备进行测量的。为保持掩盖效果,为分配给依多沙班的患者提供了假国际标准化比率值。如果患者的肌酐清除率30-50 mL / min,体重60 kg或以下,或同时具有强力P-糖蛋白相互作用的药物,则在随机分组或试验期间,将Edoxaban(或华法林组的安慰剂-edoxaban)剂量减半。疗效结果包括全因中风或全身性栓塞,缺血性中风和全因死亡率的主要终点。安全结局包括主要出血,致命出血,颅内出血和胃肠道出血的主要安全终点。该试验已在ClinicalTrials.gov上注册,编号为NCT00781391。
结果:在2008年11月19日至2010年11月22日之间,共招募了21至105例患者。符合随机降低剂量临床标准的患者(n = 5356)与未降低剂量的患者相比,中风,出血和死亡的发生率更高(n = 15 749)。 Edoxaban剂量范围从15 mg到60 mg,导致平均低谷药物暴露(在6780例患者中16·0-48·5 ng / mL,有可用数据)和平均低谷抗FXa活性的2到3倍梯度(在2865位患者中,0·35-0·85 IU / mL)。减少剂量可使平均暴露量降低29%(从48·5 ng / mL [SD 45·8]降至34·6 ng / mL [30·9])和35%(从24·5 ng / mL [22·7] ]至16·0 ng / mL [14·5])和平均抗FXa活性降低25%(从0·85 IU / mL [0·76]到0·64 IU / mL [0·54])和高剂量和低剂量方案分别为20%(从0·44 IU / mL [0·37]到0·35 IU / mL [0·28])。尽管抗FXa活性较低,但与华法林相比(中风或全身性栓塞事件:降低剂量的FXA活性仍可维持埃多沙班的功效:较高剂量的联用= 0.85,较低剂量的联用= 0.99),并提供更高的安全性(大出血:较高的剂量联射0·02,较低的剂量联射= 0·002)。
解释:这些发现验证了仅根据临床因素调整依多沙班剂量即可达到防止药物过量的双重目标,并有助于优化单个患者局部缺血和出血事件的风险的策略,并显示治疗的窗口是有效的。 edoxaban的主要出血范围比血栓栓塞狭窄。
经费筹措:第一三共制药开发公司。