达比加群酯(商品名为Pradaxa)由德国勃林格殷格翰公司开，于2008年4月在德国和英国率先上市，为近期成功开发的具有多种特点的新型抗凝血药物。
深静脉血栓形成和肺动脉栓塞是人工关节置换术后常见的并发症，严重者甚至可危及患者生命，为此术后需常规使用抗凝血药物。达比加群酯为近期成功开发的具有多种特点的新型抗凝血药物。
达比加群酯(商品名为Pradaxa)由德国勃林格殷格翰公司开，于2008年4月在德国和英国率先上市，这是继华法林之后50年来上市的首个新类别口服抗凝血药物。本品的上市，是抗凝血治疗领域和潜在致死性血栓预防领域的一项重大进展，具有里程碑意义。
达比加群酯是一种新型的合成的直接凝血酶抑制剂，是dabigatran的前体药物，属非肽类的凝血酶抑制剂。口服经胃肠吸收后，在体内转化为具有直接抗凝血活性的dabigatran。dabigatran结合于凝血酶的纤维蛋白特异结合位点，阻止纤维蛋白原裂解为纤维蛋白，从而阻断了凝血瀑布网络的最后步骤及血栓形成。dabigatran可以从纤维蛋白一凝血酶结合体上解离，发挥可逆的抗凝作用。
达比加群酯口服用药后经胃肠道迅速吸收，用药后1h起效，2～3h即达血浆峰浓度，如果与食物同服，其血浆达峰时间后移。达比加群酯口服生物利用度较低，仅6．5%，dabigatran血浆蛋白结合率为25%～30%。药物的平均终末清除半衰期为15h，约80%以原形形式经肾脏排除，其余以葡萄糖醛酸结合以胆汁分泌形式排除体外。肾功能不全(肌酐清除率<50ml／min>可延长其血浆清除时间，并使血浆药物浓度升高。dabigatran的清除不依赖于肝脏细胞色素p450系统，而且不影响从肝脏CYP2C9及CYP3A4酶系统代谢的药物的活性。dabigatran的抗凝强度与血浆浓度成正比，同时服用阿司匹林或其他血小板抑制剂，可增加其出血危险。

达比加群酯是直接凝血酶抑制剂，具有可以口服、强效、无需特殊用药监测、药物相互作用少等特点。体外、体内试验和临床各项研究均提示本品具有良好的疗效及药动学特性，临床应用前景乐观，其成功上市是抗凝血药物研究领域的一项重大突破

深静脉血栓形成和肺动脉栓塞是人工关节置换术后常见的并发症，严重者甚至可危及患者生命，为此术后需常规使用抗凝血药物。达比加群酯为近期成功开发的具有多种特点的新型抗凝血药物。由德国勃林格殷格翰公司开发的达比加群酯(商品名为Pradaxa)于2008年4月在德国和英国率先上市，这是继华法林之后50年来上市的首个新类别口服抗凝血药物。本品的上市，是抗凝血治疗领域和潜在致死性血栓预防领域的一项重大进展，具有里程碑意义。
【药理作用】
凝血酶是细胞外胰岛素样丝氨酸蛋白酶，在凝血过程中具有重要作用，一方面，其能使纤维蛋白原裂解成为纤维蛋白，后者参与构成不溶性血栓基质；另一方面，其能诱导血小板活化和聚集，进而引发一系列次级凝血级联反应。达比加群酯为前药，在体内转化为有活性的达比加群，后者通过直接抑制凝血酶而发挥抗凝血效应。体外，达比加群能有效抑制人凝血酶活性[半数抑制浓度(ICs0)为9.3nmol／L]，其对凝血酶的选择性[抑制常数(kl)为(4.5±0.2)nmol／L]高于凝血因子Xa[Ki为(3760±20)nmol／L]、胰蛋白酶[Kl为(50.3±0.3)nmol／L]、纤维蛋白溶酶[K『为(1695±5O)nmol／L]和激活蛋白C[为(20930±1O)nmol／L]等。
【动物实验】
小鼠静脉血栓形成模型试验嘲显示，达比加群酯抑制血栓形成作用呈剂量和时间依赖性。小鼠麻醉前30分钟服用达比加群酯，能获得最大的抑制血栓形成效应。试验还提示，达比加群酯低剂量组麻醉前2小时给药，也能抑制血栓形成；而高剂量组，即使麻醉前3小时给药仍能显著抑制血栓形成。达比加群酯口服对活化部分凝血活酶时间(aPTT)作用呈剂量和时间依赖性，这种依赖性高剂量组表现尤为明显，剂量越高、给药时间距离麻醉时间越短、aPTT越长。
【临床研究】
2004年11月一2006年3月，在欧洲、澳洲和南非105个研究中心进行的随机双盲RE.MODEL研究，2076例行单侧全膝关节置换术的患者随机分入达比加群酯各剂量组[150mg组(一日1次口服150mg)、220mg组(一日1次口服220mg)]或依诺肝素组(一日1次皮下注射40mg)。达比加群酯各剂量组于术后1-4小时开始服药，依诺肝素组于术前一日晚间开始用药，疗程均为6—10日，随访期为3个月。主要疗效评价终点为总VTE(包括血管造影和症状性VTE)发生率及死亡率的复合终点，安全性评价终点为出血事件发生率。
研究最终对1541例患者的临床数据进行了有效性分析，结果表明：达比加群酯疗效与依诺肝素无显著差异，150mg组、220mg组和依诺肝素组达到主要疗效评价终点的患者比例分别为40.5％(213例，526例)、36.4％(183例／503例)和37.7％(193例／512例)，其中220mg组稍低于其他两组；在预防症状性深静脉血栓形成方面，达比加群酯150mg组和220mg组均优于依诺肝素组，三组深静脉血栓形成的发生率分别为0.4％(3例／696例)、0.1％(1例，675例)和1.2％(8例，685例)。安全性方面，达比加群酯各组出血发生率与依诺肝素组相比无显著差异，三组分别为1.3％(9例／703例)、1.5％(10例/679例)和1.3％(9例/694例)，三组均未出现因大出血死亡的病例。三组因不良反应导致治疗终止的发生率无显著差异，分别为3_7％、3.7％和4.6％。提示在预防全膝关节置换术后VTE发生方面，达比加群酯至少与依诺肝素疗效同等、安全性类似。
【不良反应】
与其他各种抗凝药物类似，达比加群酯用于抗凝治疗过程中也不可避免会出现出血现象。尤其在高剂量应用时，出血发生率更高。Eriksson等率先报道的达比加群酯剂量递增安全性研究即BISTROI研究，314例受试者术后4—8小时开始口服达比加群酯一日2次，每次12.5、25、50、100、150、200和300mg或一日1次150、300mg，结果表明，各组均未见大出血事件，但最高剂量组(一日2次，每次300mg)在接受治疗初始几日内20例受试者中就有2例出现多部位出血。小出血事件的发生具有明显的剂量相关性。其他不良反应，达比加群酯与依诺肝素相比无显著差异。
推荐剂量(150或220mg)下，达比加群酯严重不良反应发生率均为8％。总不良反应发生率均为77％，因严重不良反应导致治疗终止的发生率分别为8％和6％。恶心和呕吐发生率分别为21％-22％和16％-17％；11％-13％的患者出现便秘和发热；6％-7％的患者出现低血压、失眠和水肿；1％-4％的患者出现贫血、眩晕、腹泻、疱疹、头痛，尿潴留、继发性血肿、消化不良和心动过速等症状。
目前，达比加群酯适应证仅为关节置换术后血栓形成的预防，其他适应证包括心房颤动、急性冠状动脉综合征、急性症状性静脉血栓形成和缺血陛脑卒中等，尚处于临床研究中。
总之，达比加群酯是直接凝血酶抑制剂，具有可以口服、强效、无需特殊用药监测、药物相互作用少等特点。体外、体内试验和临床各项研究均提示达比加群酯具有良好的疗效及药动学特性，临床应用前景乐观，其成功上市是抗凝血药物研究领域的一项重大突破。

Benefits

Pradaxa is an anticoagulant direct thrombin inhibitor. It is used for prevention of strokes and systemic embolism in patients with atrial fibrillation (AF). AF affects 1% of people around the world and 10% of people over the age of 80. Around three million patients afflicted with AF suffer from strokes every year as this leads to the formation of blood clots. So far, Warfarin was used to combat strokes but it has many adverse side effects. Pradaxa is a more effective drug with lesser side effects. Pradaxa successfully blocks the activity of thrombin (both free and clot-bound) which is primarily responsible for clot formation. It is also used in preventing blood clots in hip and knee surgery patients. Clinical tests have proved that this blood thinner, unlike warfarin, acts rapidly and displays quick results. Another major difference is that patients using this drug need not make any change in their diet. Clinical tests have proven that those given Pradaxa have a 34% lower risk of stroke or systemic embolism than patients given warfarin.

Side effects
 
Though this blood thinner has fewer side effects as compared to traditional blood thinners like warfarin it should be used only under a doctor’s guidance. There may be some side effects, and as this prescription medication is relatively new, many side effects may not be realized as of yet. Like other blood thinning drugs, Pradaxa too may cause bleeding even resulting in death but such incidents are less. The patient should consult the doctor if he or she observes unusual bruising, coughing up or vomiting blood. It can also cause stomach upset or burning, and stomach pain. People over 75 should use this drug carefully especially if they are already suffering from stomach ulcer and kidney problems. In rare cases it can also cause drug allergy. So far there is no evidence that this medicine can be safely be used on pregnant women. Conclusion Though Pradaxa has arrived like a breath of fresh air in the world of prescription blood thinners, it is not foolproof and has a few drawbacks. It is certainly far better and more effective than warfarin and may eventually replace the drug in the long run. Unlike warfarin, Pradaxa does not necessitate regular blood tests and prothrombin time monitoring, saving the patient needless trouble and not affecting the quality of his life.

FDA批准Pradaxa预防心房颤动患者中风

 2010年10月19日，美国食品药品管理局（FDA）批准Pradaxa胶囊（达比加群酯）用于预防心节律异常（心房颤动）患者中风和血栓的发生。心房颤动是最常见的一种心节律异常，包括心房快速律动和不规则律动。目前在美国患此病的患者超过2,000,000人。
Pradaxa是一种抗凝剂，通过抑制血液中起凝血作用的凝血酶而发挥作用。Pradaxa的安全性和有效性已经一项临床试验得以证实，该试验将Pradaxa与抗凝剂华法林进行了对比和比较。在试验中，与使用华法林的患者相比，使用Pradaxa的患者较少出现中风。
Pradaxa常见的不良反应是出血，包括危及生命的和致死性的出血。另外还有一些胃肠道症状，包括胃部不适（消化不良）、胃痛、恶心、胃灼热、胃气胀。Pradaxa的获批伴随着一项用药指南，目的是使患者知悉使用此药存在出现严重出血的可能性。在对每位患者开具处方时，需向患者提供一份用药指南。

Manufacturer:
Boehringer Ingelheim Pharmaceuticals

Pharmacological Class:
Direct thrombin inhibitor.

Active Ingredient(s):
Dabigatran etexilate mesylate 75mg, 150mg; caps.

Indication(s):
To reduce risk of stroke and systemic embolism in non-valvular atrial fibrillation.

Pharmacology:
By directly inhibiting thrombin, dabigatran and its active metabolites prevent the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited.

Dabigatran prolongs the aPTT, ecarin clotting time (ECT), and TT at therapeutic doses. With a dose of 150mg twice daily, the median peak aPTT is about 2x control; 12 hours after the last dose the median aPTT is 1.5x control. International normalized ratio (INR) is relatively insensitive to the activity of dabigatran. When converting a patient from dabigatran to warfarin, the INR is not likely to be useful until at least 2 days after discontinuing dabigatran.

The capsules should not be opened before administering, as this can increase the bioavailability of the drug by 75%.

Clinical Trials:
A multi-center, randomized parallel-group study compared two blinded doses of dabigatran (110mg twice daily or 150mg twice daily) with open-label warfarin (dosed to target INR of 2 to 3) in patients with non-valvular, persistent, paroxysmal, or permanent atrial fibrillation and one or more additional risk factors (previous stroke, TIA, or systemic embolism; left ventricular ejection fraction <40%; symptomatic heart failure ≥NYHA Class 2; age ≥75years; or age ≥65years with either diabetes, coronary artery disease, or hypertension). The primary objective was to determine if the study drug was non-inferior to warfarin in reducing the occurrence of a composite endpoint, stroke (ischemic and hemorrhagic) and systemic embolism. The study was designed to ensure that dabigatran preserved more than 50% of warfarin’s effect as established by previous warfarin studies in atrial fibrillation. Over 18,000 patients were randomized and followed for a median of 2 years. Compared to warfarin and dabigatran 110mg twice daily, dabigatran 150mg twice daily significantly reduced the primary composite endpoint (stroke and systemic embolism).

Legal Classification:
Rx

Adults:
Swallow whole. CrCl>30mL/min: 150mg twice daily. Renal impairment (CrCl<15–30mL/min): 75mg twice daily; CrCl<15mL/min or on dialysis: not recommended. Converting from warfarin, other anticoagulants: see literature. Take missed dose as soon as possible on same day; skip dose if it cannot be taken at least 6 hours before the next scheduled dose; do not double doses.

Children:
Not recommended.

Contraindication(s):
Active pathological bleeding.

Warnings/Precautions:
Increased risk of serious bleeding. Promptly evaluate signs/symptoms of blood loss (eg, a drop in hemoglobin and/or hematocrit or hypotension). Suspend treatment before invasive therapy or surgery, including dental procedures (see literature); restart promptly. Avoid lapses in therapy. Monitor ecarin clotting time (ECT). Severe renal impairment. Elderly (>75 years). Labor & delivery. Pregnancy (Cat.C). Nursing mothers.

Interaction(s):
Antagonized by P-gp inducers (eg, rifampin); avoid. Increased dabigatran levels with P-gp inhibitors (eg, ketoconazole, amiodarone, quinidine, clopidogrel). May be potentiated by immediate-release verapamil; separate dosing by ≥1 hour. Concomitant NSAIDs, platelet inhibitors, heparin, fibrinolytic therapy: increased risk of bleeding. Switching to or from warfarin: monitor closely.

Adverse Reaction(s):
Gastritis-like symptoms (eg, GERD, esophagitis, erosive gastritis, gastric hemorrhage), bleeding (may be fatal).

How Supplied:
Caps—60