非瓣膜病房颤或房扑患者应用不同起始剂量华法林对INR达标速度的影响
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摘要
目的:观察我国非瓣膜病房颤(NVAF)或房扑(AFL)患者应用不同起始剂量国产华法林时,在不同时间国际标准化比值(INR)的达标率,比较INR首次达标时间、INR达稳定时间及出血并发症的发生率等,以进一步了解国人应用国产华法林的最佳起始剂量,为临床进一步合理应用华法林提供更多证据。
方法:入选2008年3月至2009年3月具有华法林抗凝适应证的NVAF或AFL患者共85例,随机分入起始剂量3.125mg组(第一组)28例,起始5mg,2天后改为3.125mg组(第二组)25例和起始5mg治疗组(第三组)32例。每日16时服用华法林钠(上海医药有限公司信谊制药总厂,国药准字H31022123),行AF经导管射频消融术(RFCA)的患者术后回病房后即服,次日起每日16时服。本组中AF术后患者2～4小时起以及其它血栓高危患者同时给予达肝素钠(5000～7500U,皮下注射,每12小时1次)4-7天,直至INR达到抗凝效果即1.6以上停用。于治疗第3、4、5、7、9天早晨8~10时测定INR,根据INR调整华法林剂量,每次增减量为0.625～1.25mg,直到INR稳定于1.8～3.0之间(服用同一剂量华法林,间隔一周INR稳定)。如INR>3.0时,暂停当日药物,每日监测INR,待INR<3.0时,华法林减量继续服用。如果连续2次INR在治疗范围,改为每周2次,1周后如果INR稳定,即可过渡到每周1次,如连续2次INR值稳定在目标范围之内,视为达到稳定,此时应用的华法林剂量为维持剂量,此后仍要每个月监测1次INR。INR达稳定后如再次超过目标范围,需复查INR,并寻找INR波动原因,如饮食结构改变、合并用药增减以及是否漏服药物等,确认后可适当增减剂量0.625～1.25mg,并重新按隔日测一次INR开始调整华法林剂量。随访1个月,观察三组在不同时间INR的达标率,三组患者INR首次达标时间,达稳定INR所需时间,发生INR增高(INR>3.0)次数,主要出血/血栓栓塞事件的差异等。
结果:入选85例患者有1例患者于RFCA后第4天出现黑便、血红蛋白下降而终止应用华法林,当时INR为1.41,考虑非华法林所致,实际入选84例。三组基线特征(包括年龄、性别、身高、体重、联合用药、伴随疾病、服药前INR值等基线情况)无统计学差异。三组在第3天和第9天达标率无显著差异,第4、5和7天时第三组比第一、二组达标率明显增高(P<0.05),第二组比第一组达标率略高,但无统计学差异(P>0.05)。三组达标时间分别为8.2±2.4天;7.6±3.1天及6.2±2.1天,稳定时间分别为15.5±2.8天;14.8±3.1天及13.0±2.0天,第三组比第一、二组提早达标并稳定(P<0.05),第一、二组间无统计学差异(P>0.05)。第一组和第三组各有一例轻微出血(牙龈或结膜下少量出血),经停药及减量后无继续出血。三组均无明显出血及血栓栓塞事件,INR增高发生率亦无显著差异(P>0.05)。
结论:对于中国NVAF或AFL患者,以5mg为初始剂量应用国产华法林能使INR安全、迅速、有效地达标并稳定。服药前3天可不必监测INR,于第4天起测INR,如达标则根据INR值减量至2.5～3.125mg,以后隔日测INR;如未达标,于第5、7天再测INR,此时如果达标,华法林则根据INR值减量至2.5～3.75mg。如果1周内仍未达标,表明该患者应用华法林的维持量应较大,达标后应维持达标剂量而不应减量,达标后监测时间可逐渐延长,但至少应每月监测一次。
Objective: To investigate the effect of different initial warfarin dosages on the time of target international normalized ratio (INR) and the safety during dose adjustment in patients with nonvalvular atrial fibrillation (NVAF) or atrial flutter (AFL).
Methods: 85 patients with NVAF or AFL who had the indication of anticoagulation therapy were randomly assigned to three groups according to different initial warfarin dosages, 3.125 mg/d (Group 1), 3.125mg/d after 5 mg/d for tow days (Group 2) and 5 mg/d (Group 3). Baseline data collected included demographic characteristics (age, sex, height, weight), conjoined medication, assident diseases, and the INR before taking warfarin. Warfarin should be administered at 16:00 daily except for the patients following an AF radiofrequency current catheter ablation (RFCA) who should take warfarin come back ward. Low-molecular-weight heparin (LMWH 5000～7500U every 12 hours by subcutaneous injection) can be restarted 2-4 hours postoperatively along with warfarin and the combination continued for 4 to 7 days until the INR increase to the desired range (>1.6). If patients are considered to be at high risk of postoperative bleeding, LMWH can be delayed for 24 hours or longer. The INR was measured on the 3rd、4th、5th、7th and 9th day before 10:00 am, the dose of warfarin was adjusted according to INR, until INR was stabilized between 1.8 and 3.0 for at least one week at the same dose of warfarin. When the INR is above the therapeutic range 3.0 but less than 5.0, the patient has not developed clinically significant bleeding, the next dose of warfarin can be omitted and resumed (at a lower dose) when the INR approaches the desired range (<3.0). The INR is usually checked every other day until the therapeutic range has been reached and sustained for 2 times, then 2 times weekly for 1 week, then less often, according to the stability of the results. Once the INR becomes stable, the frequency of testing can be reduced to intervals as long as 4 weeks. Some patients on long-term warfarin therapy experience unexpected fluctuations in dose-response due to changes in diet, concurrent medication changes or poor compliance. When dose adjustments are confirmed and required, frequent monitoring is resumed. Follow up one month, to observe the INR change with different warfarin dose in patients with NVAF or AFL,and to compare the time that INR stabilized at target range,the ratio within stabilized target range at different days, and the incidence of bleeding episodes during the dose adjustment.
Results: One patient occured dark stools and decrease of Hb as to terminate to take warfarin. It’s independence of warfarin because INR was 1.41. Actually 84 patients were selected. There was no significant difference on baseline data collected included demographic characteristics (age, sex, body height weight) , conjoined medication, assident disease , and the INR before taking warfarin in the 3 groups (P>0.05). Compared with group 1 and group2, the INR change in group3 was more quickly, the ratios of INR within target range on day 4, 5and day 7 were the highest (P<0.05) and the ratios in the group 2 was higher than group 1, but there was no significant statistic difference in group 1 and 2 (P>0.05). The mean time achieving the target INR was 8.2±2.4 days, 7.6±3.1 days and 6.2±2.1 days and reach a stabilized target INR was 15.5±2.8, 14.8±3.1 and 13.0±2.0 respectively in Group 1, 2 and 3. Compared with group 1 and group 2, the mean time achieving and reaching the stabilized target INR in group 3 was the shortest (P<0.05) and the INR in group 2 is shorter than group1, but no significant statistic difference (P>0.05). There was no significant difference on the incidence of exorbitant INR in three groups. There were not thromboembolism and important hemorrhage complication in 3 groups (P>0.05).
Conclusions: In Chinese patients with NVAF or AFL who had the indication of anticoagulation therapy,an initial warfarin dosage of 5 mg/d treatment may reach the stabilized INR range quickly, safety and efficiently without increasing the bleeding complication.It’s not necessary to measure INR in the first 3 days. If INR reaches target range at 4th day,warfarin should be decreased to 2.5～3.125mg according to INR, and INR should be mearsured every other day. If INR is lower than target, INR should be measured at the 5th day and the 7th day until the therapeutic range has been reached, and then warfarin should be decreased to 2.5～3.75mg according to INR. It’s indicated that the maintenance dose of warfarin is higher if INR not yet reach target range at the 4th day. It’s not ought to decease dose of warfarin after INR reach target range. Once the INR becomes stable, the frequency of testing can be reduced to intervals as long as 4 weeks.
方法:入选2008年3月至2009年3月具有华法林抗凝适应证的NVAF或AFL患者共85例,随机分入起始剂量3.125mg组(第一组)28例,起始5mg,2天后改为3.125mg组(第二组)25例和起始5mg治疗组(第三组)32例。每日16时服用华法林钠(上海医药有限公司信谊制药总厂,国药准字H31022123),行AF经导管射频消融术(RFCA)的患者术后回病房后即服,次日起每日16时服。本组中AF术后患者2～4小时起以及其它血栓高危患者同时给予达肝素钠(5000～7500U,皮下注射,每12小时1次)4-7天,直至INR达到抗凝效果即1.6以上停用。于治疗第3、4、5、7、9天早晨8~10时测定INR,根据INR调整华法林剂量,每次增减量为0.625～1.25mg,直到INR稳定于1.8～3.0之间(服用同一剂量华法林,间隔一周INR稳定)。如INR>3.0时,暂停当日药物,每日监测INR,待INR<3.0时,华法林减量继续服用。如果连续2次INR在治疗范围,改为每周2次,1周后如果INR稳定,即可过渡到每周1次,如连续2次INR值稳定在目标范围之内,视为达到稳定,此时应用的华法林剂量为维持剂量,此后仍要每个月监测1次INR。INR达稳定后如再次超过目标范围,需复查INR,并寻找INR波动原因,如饮食结构改变、合并用药增减以及是否漏服药物等,确认后可适当增减剂量0.625～1.25mg,并重新按隔日测一次INR开始调整华法林剂量。随访1个月,观察三组在不同时间INR的达标率,三组患者INR首次达标时间,达稳定INR所需时间,发生INR增高(INR>3.0)次数,主要出血/血栓栓塞事件的差异等。
结果:入选85例患者有1例患者于RFCA后第4天出现黑便、血红蛋白下降而终止应用华法林,当时INR为1.41,考虑非华法林所致,实际入选84例。三组基线特征(包括年龄、性别、身高、体重、联合用药、伴随疾病、服药前INR值等基线情况)无统计学差异。三组在第3天和第9天达标率无显著差异,第4、5和7天时第三组比第一、二组达标率明显增高(P<0.05),第二组比第一组达标率略高,但无统计学差异(P>0.05)。三组达标时间分别为8.2±2.4天;7.6±3.1天及6.2±2.1天,稳定时间分别为15.5±2.8天;14.8±3.1天及13.0±2.0天,第三组比第一、二组提早达标并稳定(P<0.05),第一、二组间无统计学差异(P>0.05)。第一组和第三组各有一例轻微出血(牙龈或结膜下少量出血),经停药及减量后无继续出血。三组均无明显出血及血栓栓塞事件,INR增高发生率亦无显著差异(P>0.05)。
结论:对于中国NVAF或AFL患者,以5mg为初始剂量应用国产华法林能使INR安全、迅速、有效地达标并稳定。服药前3天可不必监测INR,于第4天起测INR,如达标则根据INR值减量至2.5～3.125mg,以后隔日测INR;如未达标,于第5、7天再测INR,此时如果达标,华法林则根据INR值减量至2.5～3.75mg。如果1周内仍未达标,表明该患者应用华法林的维持量应较大,达标后应维持达标剂量而不应减量,达标后监测时间可逐渐延长,但至少应每月监测一次。
Objective: To investigate the effect of different initial warfarin dosages on the time of target international normalized ratio (INR) and the safety during dose adjustment in patients with nonvalvular atrial fibrillation (NVAF) or atrial flutter (AFL).
Methods: 85 patients with NVAF or AFL who had the indication of anticoagulation therapy were randomly assigned to three groups according to different initial warfarin dosages, 3.125 mg/d (Group 1), 3.125mg/d after 5 mg/d for tow days (Group 2) and 5 mg/d (Group 3). Baseline data collected included demographic characteristics (age, sex, height, weight), conjoined medication, assident diseases, and the INR before taking warfarin. Warfarin should be administered at 16:00 daily except for the patients following an AF radiofrequency current catheter ablation (RFCA) who should take warfarin come back ward. Low-molecular-weight heparin (LMWH 5000～7500U every 12 hours by subcutaneous injection) can be restarted 2-4 hours postoperatively along with warfarin and the combination continued for 4 to 7 days until the INR increase to the desired range (>1.6). If patients are considered to be at high risk of postoperative bleeding, LMWH can be delayed for 24 hours or longer. The INR was measured on the 3rd、4th、5th、7th and 9th day before 10:00 am, the dose of warfarin was adjusted according to INR, until INR was stabilized between 1.8 and 3.0 for at least one week at the same dose of warfarin. When the INR is above the therapeutic range 3.0 but less than 5.0, the patient has not developed clinically significant bleeding, the next dose of warfarin can be omitted and resumed (at a lower dose) when the INR approaches the desired range (<3.0). The INR is usually checked every other day until the therapeutic range has been reached and sustained for 2 times, then 2 times weekly for 1 week, then less often, according to the stability of the results. Once the INR becomes stable, the frequency of testing can be reduced to intervals as long as 4 weeks. Some patients on long-term warfarin therapy experience unexpected fluctuations in dose-response due to changes in diet, concurrent medication changes or poor compliance. When dose adjustments are confirmed and required, frequent monitoring is resumed. Follow up one month, to observe the INR change with different warfarin dose in patients with NVAF or AFL,and to compare the time that INR stabilized at target range,the ratio within stabilized target range at different days, and the incidence of bleeding episodes during the dose adjustment.
Results: One patient occured dark stools and decrease of Hb as to terminate to take warfarin. It’s independence of warfarin because INR was 1.41. Actually 84 patients were selected. There was no significant difference on baseline data collected included demographic characteristics (age, sex, body height weight) , conjoined medication, assident disease , and the INR before taking warfarin in the 3 groups (P>0.05). Compared with group 1 and group2, the INR change in group3 was more quickly, the ratios of INR within target range on day 4, 5and day 7 were the highest (P<0.05) and the ratios in the group 2 was higher than group 1, but there was no significant statistic difference in group 1 and 2 (P>0.05). The mean time achieving the target INR was 8.2±2.4 days, 7.6±3.1 days and 6.2±2.1 days and reach a stabilized target INR was 15.5±2.8, 14.8±3.1 and 13.0±2.0 respectively in Group 1, 2 and 3. Compared with group 1 and group 2, the mean time achieving and reaching the stabilized target INR in group 3 was the shortest (P<0.05) and the INR in group 2 is shorter than group1, but no significant statistic difference (P>0.05). There was no significant difference on the incidence of exorbitant INR in three groups. There were not thromboembolism and important hemorrhage complication in 3 groups (P>0.05).
Conclusions: In Chinese patients with NVAF or AFL who had the indication of anticoagulation therapy,an initial warfarin dosage of 5 mg/d treatment may reach the stabilized INR range quickly, safety and efficiently without increasing the bleeding complication.It’s not necessary to measure INR in the first 3 days. If INR reaches target range at 4th day,warfarin should be decreased to 2.5～3.125mg according to INR, and INR should be mearsured every other day. If INR is lower than target, INR should be measured at the 5th day and the 7th day until the therapeutic range has been reached, and then warfarin should be decreased to 2.5～3.75mg according to INR. It’s indicated that the maintenance dose of warfarin is higher if INR not yet reach target range at the 4th day. It’s not ought to decease dose of warfarin after INR reach target range. Once the INR becomes stable, the frequency of testing can be reduced to intervals as long as 4 weeks.
引文
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38. Murphy SA. Regulation of coagulation in major orthopaedic surgery reducing the risk of DVT and PE (RECORD3 ). Cardiosource 2007
1. Ezekowitz MD, Levine JA. Preventing stroke in patients with atrial fibrillation. JAMA 1999; 281: 1830-1835
2. Wolf PA, Abbott RD, Kannel VCB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991 Vol; 22(8): 983-988
3.胡大一,孙艺红,周自强等.中国人非瓣膜性心房颤动脑卒中危险因素的病例对照研究.中华内科杂志2003; 42: 157-161
4.马长生,周玉杰,马煜等.北京地区非瓣膜病心房颤动患者缺血性脑卒中的发生率及影响因素的随访研究.中华心血管病杂志2002; 30(3): 165-167
5. Peterson P,Boysen G,Gotfriedsen J,et a1. PIacebo-controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK Study. Lancet 1989; 1: 175-179
6. Stroke prevention in atrial fibrillation investigators. Stroke prevention in atrial fibrillation study: final results. Circu1ation 1991Aug; 84(2): 527-539
7. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigator. The effect of low-dose warfarin on the risk of stroke in patients with non-rheumatic atrial fibrillation. N Engl J Med 1990 Nov; 323(22): 1505-15l1
8. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with non-reumatic atrial fibrillation. N Engl J Med 1992 Nov; 327(20): 1406-1412
9. Connoly SJ, Laupacis A, Gent M , et a1. Canadian Atrial Fibril1ation Anticoagulation (CAFA) Study. J Am Coil Cardiol 1991Aug; 18(2): 349-355
10. Carlvan Walmven MD, Robert G, Hart MD. Oral anticoagulants vs Aspirin in nonvalvular atrial fibrilation an individual patient meta-analysis. JAMA 2002 Nov; 288(19): 2441-2448
11. Fuster V, Ryden LE, Cannom Ds, et a1. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation -executive summary:a report of the American College of Cardiology /American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines. Eur Heart J 2006; 27(16):1979-2030
12. Oral H, Chugh A, Ozaydin M, et al. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation 2006 Aug; 114: 759–765
13. Yamaguchi T. Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation.A multicenter, prospective, randomized trial. Stroke 2000 Apr; 31: 817-821
14. Hylek EM, Skates sJ, Sheehan MA, et a1. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996 Aug; 335(2): 540-546
15.心房颤动抗栓研究协作组.华法林对非瓣膜病心房颤动抗栓的安全性和有效性研究[J].中华内科杂志2006; 45: 800-803
16. HiYshJ, Valentin F, Ansell J, et a1. American Heart Association/American College of Cardiology foundation guide to warfarin therapy. J Am Call Cardiol 2003; 107(9): 1692-1711
17. Kovacs MJ, Rodger M, Anderson DR, et al. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Ann Intern Med 2003 May 6; 138(9): 714-719
18. Monkman K, Lazo-Langner A, Michael J, et al. A 10 mg warfarin initiation nomogram is safe and effective in outpatients starting oral anticoagulant therapy for venous thromboembolism. Thromb Research 2009
19. GanGG, TehA, GohKY, et a1.Racial background is a determinant factor in the maintenance dosage of warfarin. Int J Hematol 2003; 78(1): 84-86
20.朱平辉,马长生,何华等.非瓣膜病房颤用华法林抗凝治疗的最佳初始剂量研究.中国医刊2008; 43(1):36-37
21.杨帆,杜昕,刘晓惠.华法林应用初期INR变化的分析.广西医学2005; 27(12): 1914-1916
22. Kovacs MJ, Anderson DA, Wells PS. Prospective assessment of a nomogram for the initiation of oral anticoagulation therapy for outpatient treatment of ve-nous thromboembolism. Pathophysiol Haemost Thromb 2002; 32: 131-133
23. Harrison L, Johnston M, Massicotte MP, Crowther M, Moffat K, Hirsh J. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997; 126: 133-136
24. Tait DC, Sefcick A. A warfarin induction regiment for out-patient an- ticoagulation in patients with atrial fibrillation.Br J Haematology 1998 Jun; 101(3): 450-454
2.中华医学会心血管病分会.中国部分地区心房颤动住院病例回顾性调查[J].中华心血管病杂志2003 Aug ; 31(12): 913-916
3. Wolf PA, Abbott RD, Kannel VCB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22(8): 983-988
4.胡大一,孙艺红,周自强等.中国人非瓣膜性心房颤动脑卒中危险因素的病例对照研究.中华内科杂志2003; 42: 157-161
5.马长生,周玉杰,马煜等.北京地区非瓣膜病心房颤动患者缺血性脑卒中的发生率及影响因素的随访研究.中华心血管病杂志2002; 30(3): 165-167
6. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002 Dec; 347: 1825-1833
7. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002 Dec; 347: 1834-1840
8. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation-pharmacological intervention in atrial fibrillation (PIAF): a ran- domised trial. Lancet 2000 Nov; 356(9244): 1789-1794
9. Carlsson J, Miketic S, Windeler JJ, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation. The Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003; 41: 1690-1696
10. Sherman DG, Kim SG, Boop BS, et al. Occurrence and characteristics of stroke events in the atrial fibrillation follow-up investigation of sinus rhythm management (AFFIRM) study. Arch Intern Med 2005 May; 165(10): 1185-1191
11. Hagens VE, Vermeulen KM, TenVergert EM, Rate control is more cost-effective than rhythm control for patients with persistent atrial fibrillation - results from the rate control versus electrical cardioversion (RACE) study. Eur Heart J 2004 Jun; 25(17): 1542-1549
12. Peterson P, Boysen G, Gotfriedsen J, et a1. PIacebo-controlled, randomized trialof warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK Study. Lancet 1989 Jan; 1(8631): 175-179
13. Stroke Prevention in Atrial Fibrillation Investigators. Stroke prevention in atrial fibrillation study: final results. Circu1ation 1991 Aug ; 84(2): 527-539
14. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigator. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990 Nov; 323(22): 1505-15l1
15. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with non-reumatic atrial fibrillation. N Engl J Med 1992 Nov; 327(20): 1406-1412
16. Connoly SJ, Laupacis A, Gent M, et a1. Canadian atrial fibril1ation an- ticoagulation (CAFA) Study. J Am Coil Cardiol 1991 Aug; 18(2): 349-355
17. Carlvan Walmven MD, Robert G, Hart MD. Oral anticoagulants vs aspirin in nonvalvular atrial fibrilation an individual patient meta-analysis. JAMA 2002 Nov; 288(19): 2441-2448
18. Hugh Calkins MD, FHRS; Josep Brugada MD, FESC; Douglas L. Packer MD, FHRS, et al. HRS/EHRA/ECAS Expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. Heart Rhythm 2007 Vol; 4(6): 1-46
19. Natale A, Raviele A, Arentz T, et a1. Venice chart intemational consensus document on atrial fibrillation ablation.Journal of cardiovascular electrophy- siology 2007 May; 18(5): 560-580
20. Fuster V, Ryden LE, Cannom Ds, et a1. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology /American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for practice guidelines. Eur Heart J 2006; 27(16): 1979-2030
21.周京敏,刘少稳,聂振宁等.持续性与阵发性心房颤动导管射频消融肺静脉电隔离的抗凝治疗.中国心脏起搏与心电生理杂志2007; 21(2): 116-119
22. Maleki K, Mohammadi R, Hart D, et al. Intracardiac ultrasound detection of thrombus on transseptal sheath: incidence, treatment, and prevention[J]. Cardiovasc Electrophysiol. 2005 Jun; 16(6): 561-565
23. Ren JF MD, Marchlinski FE, Callans DJ, et al. Increased intensity ofanticoagulation may reduce risk of thrombus during atrial fibrillation ablation procedures in patients with spontaneous echo contrast. Journal of Cardiovascular Electrophysiology 2005 May; 16(5): 474–477
24. Wazni OM, Rossillo A, Marrouche NF et al. Embolic events and char formation during pulmonary vein isolation in patients with atrial fibrillation: impact of different anticoagulation regimens and importance of intracardiac echo Imaging . Journal of Cardiovascular Electrophysiology 2005 Jun; 16(6):576–581
25.刘少稳,杨延宗,高连君等.心房颤动导管射频消融电隔离前后的抗凝治疗.中国心脏起搏与心电生理杂志2004; 18(6): 432-435
26. Oral H, Chugh A, Ozaydin M, et al. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation 2006 Aug; 114: 759–765
27. Israel CW, Gronereid G, Ehrlich JR, et a1. Long-term risk of recurrent atrial fibrillation as documented by an implantable monitoring device: implications for optimal patient. Care J Am Coll Cardiol 2004 Jan; 43(1): 47-52
28. Stelbrink C, Nixdorff U, Hofmann T, et a1. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation the anticoagulation in cardioversion using enoxaparin (ACE) trial. Circulation 2004 Feb; 109: 997-1003
29. Yamaguchi T. Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation.A multicenter, prospective, randomized trial. Stroke 2000 Apr; 31: 817-821
30. Hylek EM, Skates SJ, Sheehan MA, et a1. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996 Aug; 335(8): 540-546
31.心房颤动抗栓研究协作组.华法林对非瓣膜病心房颤动抗栓的安全性和有效性研究[J].中华内科杂志2006 Oct; 45(10): 800-803
32. HiYshJ, Valentin F, Ansell J, et a1. American Heart Association/American College of Cardiology foundation guide to warfarin therapy. J Am Call Cardiol 2003; 107(9): 1692-1711
33. GanGG, TehA, GohKY, et a1. Racial background is a determinant factor in the maintenance dosage of warfarin. Int J Hematol 2003; 78(1): 84-86
34. Jones M, McEwan P, Morgan CL, et a1. Evaluation of the pattern of treatment,level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 2005; 91: 472-477
35. Tait DC, Sefcick A. A warfarin induction regiment for out-patient an- ticoagulation in patients with atrial fibrillation. British Journal of Haematology 1998 Jun; 101(3): 450-454
36.杨帆,杜昕,刘晓惠.华法林应用初期INR变化的分析.广西医学2005; 27(12): 1914-1916
37.朱平辉,马长生,何华等.非瓣膜病房颤用华法林抗凝治疗的最佳初始剂量研究.中国医刊2008; 43(1): 36-37
38. Murphy SA. Regulation of coagulation in major orthopaedic surgery reducing the risk of DVT and PE (RECORD3 ). Cardiosource 2007
1. Ezekowitz MD, Levine JA. Preventing stroke in patients with atrial fibrillation. JAMA 1999; 281: 1830-1835
2. Wolf PA, Abbott RD, Kannel VCB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991 Vol; 22(8): 983-988
3.胡大一,孙艺红,周自强等.中国人非瓣膜性心房颤动脑卒中危险因素的病例对照研究.中华内科杂志2003; 42: 157-161
4.马长生,周玉杰,马煜等.北京地区非瓣膜病心房颤动患者缺血性脑卒中的发生率及影响因素的随访研究.中华心血管病杂志2002; 30(3): 165-167
5. Peterson P,Boysen G,Gotfriedsen J,et a1. PIacebo-controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK Study. Lancet 1989; 1: 175-179
6. Stroke prevention in atrial fibrillation investigators. Stroke prevention in atrial fibrillation study: final results. Circu1ation 1991Aug; 84(2): 527-539
7. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigator. The effect of low-dose warfarin on the risk of stroke in patients with non-rheumatic atrial fibrillation. N Engl J Med 1990 Nov; 323(22): 1505-15l1
8. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with non-reumatic atrial fibrillation. N Engl J Med 1992 Nov; 327(20): 1406-1412
9. Connoly SJ, Laupacis A, Gent M , et a1. Canadian Atrial Fibril1ation Anticoagulation (CAFA) Study. J Am Coil Cardiol 1991Aug; 18(2): 349-355
10. Carlvan Walmven MD, Robert G, Hart MD. Oral anticoagulants vs Aspirin in nonvalvular atrial fibrilation an individual patient meta-analysis. JAMA 2002 Nov; 288(19): 2441-2448
11. Fuster V, Ryden LE, Cannom Ds, et a1. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation -executive summary:a report of the American College of Cardiology /American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines. Eur Heart J 2006; 27(16):1979-2030
12. Oral H, Chugh A, Ozaydin M, et al. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation 2006 Aug; 114: 759–765
13. Yamaguchi T. Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation.A multicenter, prospective, randomized trial. Stroke 2000 Apr; 31: 817-821
14. Hylek EM, Skates sJ, Sheehan MA, et a1. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996 Aug; 335(2): 540-546
15.心房颤动抗栓研究协作组.华法林对非瓣膜病心房颤动抗栓的安全性和有效性研究[J].中华内科杂志2006; 45: 800-803
16. HiYshJ, Valentin F, Ansell J, et a1. American Heart Association/American College of Cardiology foundation guide to warfarin therapy. J Am Call Cardiol 2003; 107(9): 1692-1711
17. Kovacs MJ, Rodger M, Anderson DR, et al. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Ann Intern Med 2003 May 6; 138(9): 714-719
18. Monkman K, Lazo-Langner A, Michael J, et al. A 10 mg warfarin initiation nomogram is safe and effective in outpatients starting oral anticoagulant therapy for venous thromboembolism. Thromb Research 2009
19. GanGG, TehA, GohKY, et a1.Racial background is a determinant factor in the maintenance dosage of warfarin. Int J Hematol 2003; 78(1): 84-86
20.朱平辉,马长生,何华等.非瓣膜病房颤用华法林抗凝治疗的最佳初始剂量研究.中国医刊2008; 43(1):36-37
21.杨帆,杜昕,刘晓惠.华法林应用初期INR变化的分析.广西医学2005; 27(12): 1914-1916
22. Kovacs MJ, Anderson DA, Wells PS. Prospective assessment of a nomogram for the initiation of oral anticoagulation therapy for outpatient treatment of ve-nous thromboembolism. Pathophysiol Haemost Thromb 2002; 32: 131-133
23. Harrison L, Johnston M, Massicotte MP, Crowther M, Moffat K, Hirsh J. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997; 126: 133-136
24. Tait DC, Sefcick A. A warfarin induction regiment for out-patient an- ticoagulation in patients with atrial fibrillation.Br J Haematology 1998 Jun; 101(3): 450-454