Dabigatron( 达比加群 )- 房颤患者抗凝新选？

北京大学第一医院 李建平

Background

Limitations of Warfarin in AF patients:• Interactions with food and drugs

• frequent laboratory monitoring

Alternatives of Warfarin for AF patients: • Combination of Aspirin and Clopidogrel- less effective • Subcutaneous Idraparinux- high risk of bleeding • Ximelagatran- hepatotoxic

About Dabigatran

•Prodrug-Dabigatran etexilate, converted by a serum esterase to Dabigatran

•Dabigatran: a potent, direct, competitive inhibitor of thrombin

•80% of the given dose is excreted by the kidneys

•serum half-life: 12 to 17 hours

Inclusion criteria

1) AF documented as follows: There is ECG documented AF on the day of screening or randomization The patient has had a symptomatic episode of paroxysmal or persistent AF documented by 12-lead ECG within 6 m before randomization2) In addition to documented AF, patients must have one of the following: a. History of previous stroke, TIA, or systemic embolism b. Ejection fraction <40% documented by echocardiogram, radionuclide or contrast angiogram in the last 6 m c. Symptomatic heart failure, New York Heart Association class 2 or higher in the last 6 m d. Age ≥75 y e. Age ≥65 y and one of the following: i) Diabetes mellitus on treatment ii) Documented coronary artery disease (any of: prior myocardial infarction, positive stress test, positive nuclear perfusion study, prior CABG surgery or PCI, angiogram showing ≥75% stenosis in a major coronary artery iii) Hypertension requiring medical treatment

Exclusion Criteria1. History of heart valve disorders (ie, prosthetic valve or hemodynamically relevant valve disease) 2. Severe, disabling stroke within the previous 6 m, or any stroke within the previous 14 d3. Conditions associated with an increased risk of bleeding: a. Major surgery in the previous month b. Planned surgery or intervention in the next 3 m c. History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding d. Gastrointestinal hemorrhage within the past year e. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 d f. Hemorrhagic disorder or bleeding diathesis g. Need for anticoagulant treatment of disorders other than AF h. Fibrinolytic agents within 48 h of study entry i. Uncontrolled hypertension (systolic blood pressure >180 mm Hg and/or diastolic blood pressure >100 mm Hg) j. Recent malignancy or radiation therapy (≤6 m) and not expected to survive 3 y

Exclusion Criteria4. Contraindication to warfarin treatment5. Reversible causes of atrial fibrillation (eg, cardiac surgery, pulmonary embolism, untreated hyperthyroidism). 6. Plan to perform a pulmonary vein ablation or surgery for cure of the AF7. Severe renal impairment (estimated creatinine clearance ≤30 mL/min)8. Active infective endocarditis9. Active liver disease, including but not limited to a. Persistent ALT, AST, Alk Phos >2× ULN b. Known active hepatitis C (positive HCV RNA) c. Active hepatitis B (HBs antigen +, anti HBc IgM+) d. Active hepatitis A10. Women who are pregnant or of childbearing potential who refuse to use a medically acceptable form of contraception throughout the study 11. Anemia (hemoglobin level <100g/L) or thrombocytopenia (platelet count <100 × 109/L) 12. Patients who have developed transaminase elevations upon exposure to ximelagatran. 13. Patients who have received an investigational drug in the past 30 d 14. Patients considered unreliable by the investigator or have a life expectancy less than the expected duration of the trial

Outcomes

•Primary study outcome: stroke or systematic embolism•Secondary outcomes: myocardial infarction, pulmonary embolism, transient ischemic attack, and hospitalization•primary net clinical benefit outcome composite of stroke, systemic embolism, pulmonary embolism, myocardial infarction, death, or major hemorrhage

Study Design: noninferiority

Follow up: 14 days, 1 mon, 3mon, every 3 mons in the first year, Every 4 mons in the second year

Baseline Characteristics

Efficacy Outcome

Primary Outcome

Safety Outcome

Subgroup Analysis

Conclusion

In patients with AF, and have high risk of Stroke, Compared with Warfarin:•110mg bid dabigatran was associated with similar rates of stroke and systemic embolism and lower rates of major heamorrhage;

•160mg bid dabigatran was associated with lower rates of stroke and systemic embolism and similar rates of major heamorrhage;

房颤的抗凝治疗

房颤的分类及治疗策略

类型 持续时间和特征

治疗策略

阵发性 AF 小于 7天 (一般﹤ 24h)

预防复发

持续性 AF 大于 2~7 天 复律 +药物维持窦律或控制心室率 +抗凝

永久性 AF 超过 1年 控制心室率 +抗凝

抗凝

•华法令： INR： 2~3

•阿司匹林： 75~325mg

•80 年代， 6000 余例非瓣膜病房颤，华法令降低脑卒中危险率 68% ，阿司匹林降低 21% 。

非瓣膜病房颤

11526 例，女性占 43% ，平均年龄 71岁随访 25341 人年与未应用华法令患者比较血栓栓塞危险下降 51%还能减少全因死亡的危险颅内出血的绝对危险增加不明显

JAMA, 2003,209:2685-92

非瓣膜病发生血栓栓塞的危险因素

•既往血栓栓塞病史或 TIA病史、高血压、充血性心衰、高龄≥ 75岁尤其女性、糖尿病、冠心病、心房扩大﹥ 50mm、左心室功能下降、 LVEF 40%﹤

•UCG示左心耳血流速度减慢，左房自发显影

谢谢