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Management of Patients Receiving Warfarin during Invasive Procedures and the Adverse Effects of Warfarin
J Arrhythmia
Vol 26 No 2 2010
Original Article
Management of Patients Receiving Warfarin during Invasive Procedures and the Adverse Effects of Warfarin Norikazu Watanabe MD, Kaoru Tanno MD, Haruyuki Ito MD, Tatsuya Onuki MD, Fumito Miyoshi MD, Yoshino Minoura MD, Mitsuharu Kawamura MD, Taku Asano MD, Takashi Katagiri MD, Youichi Kobayashi MD Division of Cardiology, Department of Internal Medicine, Showa University School of Medicine
Aim: The aim of this study was to assess the frequency and characteristics of complications in patients on anticoagulant therapy who were to undergo invasive procedure. Methods and Results: We sent a questionnaire to 2758 doctors who were on the mailing list of the Japanese Society of Cardiac Pacing and Electrophysiology in August 2004. We received 614 questionnaires (response rate, 22.3%). Out of the 614 doctors, 19 (3.1%) reported that their patients had embolic events upon the interruption of warfarin therapy during dental extraction. In patients undergoing invasive procedures such as surgery, endoscopy, pacemaker implantation, and catheterization, 168 (27.4%) of the 614 doctors reported embolic events after the interruption of warfarin therapy. Further, 255 (41.5%) of the 614 doctors reported bleeding episodes when warfarin therapy was continued during the invasive procedures. Conclusion: Several complications of different types were reported to occur in patients receiving warfarin therapy who underwent elective invasive procedures, regardless of whether warfarin administration was interrupted or continued at the time of the invasive procedure. Therefore, it is necessary to make careful decisions about the management of patients on warfarin therapy who will be undergoing invasive procedures. (J Arrhythmia 2010; 26: 96–102)
Key words: Warfarin, Atrial fibrillation, Invasive procedure
Introductions Many doctors encounter a difficult situation when they have to perform elective procedure or minor surgery on patients receiving warfarin-sodium therapy. Cessation of anticoagulant therapy in the perioperative period may expose the patients to increased risk of thromboembolic events, while
continuing anticoagulant therapy may increase the risk of bleeding. There are limited guidelines or randomized controlled trials that provide information about perioperative management of patients on warfarin therapy. The aim of this study was to assess the frequency and characteristics of complications in patients receiving anticoagulant therapy who were to undergo invasive procedures.
Received 20, May, 2009: accepted 11, May, 2010. Address for Correspondence: Kaoru Tanno MD, Division of Cardiology, Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai Shinagawa-Ku Tokyo 142-8666, Japan. TEL: 03-3784-8539 FAX: 03-3784-8622 E-mail: k-tanno@med. showa-u.ac.jp
96
Watanabe N
Anticoagulant therapy during invasive procedures
(%) 80
75.7% 67.1%
70 60 50 40 17.1% 30 20
(n=614)
9.9% 7.2%
10
8.6% 5.2% 0.2%
0
continuation (n=61)
dose reduction (n=44)
(%) 100 90 80 70 60 50 40 30 20 10 3.1% (n=19) 0 experience (%) B 90 80 76.5% A
cancellation discontinuation others of tooth gradually (n=53) discontinuation extraction (n=32) suddenly (n=1) (n=412)
Figure 1 Technique for the management of patients on warfarin who were to undergo dental extraction. Warfarin administration was continued by 17.1% of doctors and discontinued by 75.7% in patients who were to undergo dental extraction.
Methods We sent a questionnaire to 2758 doctors who were on the mailing list of the Japanese Society of Cardiac Pacing and Electrophysiology (JASPE) in August 2004. The doctors were instructed to return completed questionnaires anonymously in an enclosed stamped addressed envelope. Through the questionnaire, we collected information about the international normalized ratios (INR) of the pathological conditions (valvular disease, atrial fibrillation (AF), and cerebral infarction), the characteristics of patients on warfarin therapy, including patient responses to dental extraction, surgery, endoscopy, pacemaker implantation, and catheterization, and the adverse effects of warfarin use. Results We received 614 questionnaires (response rate, 22.3%) from 277 doctors aged in their 50s (45.1%), 162 (26.4%) in 40s, and 132 (21.5%) in 60s. The number of patients prescribed with warfarin per month was <10 (23.5%), 10–20 (16.9%), and 20–30 (15.3%). Further, 93.3%, 92.8%, and 82.4% of doctors prescribed warfarin to patients with AF, patients who had undergone replacement of heart
70 60 50 40 30 20
95.4% (n=586)
inexperience N=19 multiple answers allowed
23.5% 11.8%
10 0 brain infarction (n=13)
vascular myocardial occlusion infarction of extremities (n=4) (n=2)
5.9% others (n=1)
Figure 2 Thrombosis in dental extraction Out of the 614 doctors, 19 (3.1%) reported that their patients had an embolic event due to discontinuation of warfarin therapy. Among these patients, 13, 4, and 2 developed brain infarction, myocardial infarction, and vascular occlusion of the extremities, respectively.
valves, and patients with cerebrovascular disease, respectively. Dental extraction
For patients who underwent dental extraction, 17.1% of doctors administered the same dosage or decreased the dose of warfarin continuously, and 75.7% of doctors interrupted warfarin therapy during the extraction procedure (Figure 1). Among doctors who administered the same or a decreased dose of warfarin, 29.5%, 30.9%, and 13.8% reported INR values in the range of 1.0–1.3, 1.3–1.5, and 1.5–2.0, respectively. Out of the 614 doctors, 19 (3.1%) reported that their patients had embolic events when warfarin therapy was interrupted. Among the 19 embolic events, 13 were brain infarction, 4 were myocardial infarction, and 2 were vascular occlusion of the extremities (Figure 2). No bleeding episodes were reported in patients for whom warfarin therapy was continued.
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J Arrhythmia
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Invasive procedures
The reasons for interruption of warfarin therapy were surgery (92.5%), endoscopy (78.7%), pacemaker implantation (66.6%), and catheterization (33.4%). Among the 614 doctors, 168 (27.4%) reported that their patients had embolic events when warfarin therapy was interrupted. The types of embolic events were 161 cerebral infarctions, 41 vascular occlusions of the extremities, 9 pulmonary infarctions, 3 myocardial infarctions, and 15 others (Figure 3-A). Among the patients who developed cerebral infarctions, 90% had PT-INR values of <1:5 at the time of the event. In patients for whom warfarin therapy was continued, 255 (41.5%) of the 614 doctors reported bleeding episodes. Among the 614 doctors, 251 (40.9%) reported subcutaneous bleedings, 28 (4.6%) reported cerebral hemorrhage, and 21 (3.4%) reported intraperitoneal hemorrhage (Figure 3-B). Fifty percent of patients with cerebral hemorrhage had PT-INR values of >2:5 at the time of the event. Pacemaker implantation
When treating patients with atrial fibrillation, 23.0% doctors continued warfarin therapy and 62.4% discontinued the therapy (other, 6.0%, no answer, 8.6%) during pacemaker implantation. When treating patients with valvular diseases, 31.1% doctors continued warfarin therapy and 51.7% discontinued the therapy (other, 8.2%, no answer, 9.0%) during pacemaker implantation. Further, 35.7% and 51.5% of doctors discontinued warfarin therapy and performed heparin exchange in patients with atrial fibrillation and valvular diseases, respectively, during pacemaker implantation.
A) (%) 30
26.2%
thrombosis
25
N=168 multiple answers allowed
20 15 10
6.7%
5 0
0.5%
1.5%
brain myocardial vascular pulmonary infarction infarction occlusion infarction of extremities (n=9) (n=161) (n=3) (n=41)
B) (%) 50
bleeding
2.4% others (n=15)
N=255 multiple answers allowed 40.9%
40 30 20 10 0
4.6%
3.4%
cerebral intraperitoneal subcutaneous hemorrhage hemorrhage. bleeding (n=28) (n=251) (n=21)
6.7% others (n=41)
Figure 3 A) Thrombosis in invasive procedures Out of the 614 doctors, 168 (27.4%) reported that their patients had embolic events due to warfarin discontinuation in invasive procedures. The types of embolic events were 161 cerebral infarctions, 41 vascular occlusions of the extremities, 3 myocardial infarctions, and 9 pulmonary infarctions. B) Bleeding in invasive procedures Out of the 614 doctors, 255 (41.5%) reported episodes of bleeding due to warfarin continuation; 251 (40.9%) were subcutaneous bleeds, 28 (4.6%) were cerebral hemorrhages, and 21 (3.4%) were intraperitoneal hemorrhages.
Catheterization
In patients with atrial fibrillation, 40.0% of doctors continued warfarin therapy and 41.5% discontinued the therapy during catheterization. In patients with valvular disease, 46.9% of doctors continued warfarin therapy and 32.4% discontinued the therapy during catheterization. Further, 40.3% and 54.5% of doctors performed heparin exchange after interrupting warfarin administration during catheterization in patients who received treatment for atrial fibrillation and valvular diseases, respectively. Radiofrequency ablation of pulmonary vein
Of the 614 doctors, 135 (22%) reported that they performed radiofrequency ablation for pulmonary vein (RFPV). Among these 135 doctors, 78 (57.7%) and 46 (34.1%) administered warfarin before and after RFPV, respectively. Further, 52 (38.5%) doc-
98
tors continued to administer warfarin during RFPV and 77 (57.0%) discontinued warfarin administration during the procedure (Figure 4-A). Among doctors who administered the same or decreased dosage of warfarin, 59.6% and 28.8% reported PT-INR values in the range of 1.5–2.0 and 2.0–2.5, respectively, in patients for whom warfarin was continued during RFPV (Figure 4-B). Among doctors who discontinued warfarin during RFPV, 67.3% performed heparin exchange and 31.1% did not perform the exchange (Figure 5). Further, 36.5% and 28.5% of doctors administered warfarin for 3 and 6 months to patients who developed paroxysmal atrial fibrillation after RFPV, respectively, and 82.5% administered permanent warfarin therapy to patients who developed persistent or permanent atrial fibrillation after RFPV (Figure 6).
Watanabe N
A)
Anticoagulant therapy during invasive procedures
(N=135)
(%) 60
57.0%
(%) 50 discontinuation of warfarin prescription during RFPV 77/135 (57.0%)
50 38.5%
40
45.5%
40
30 20
30
∗Warfain :W
10 0 B)
continuation N=52
discontinuation N=77
19.5%
20
15.6%
(%) 70 10
59.6%
60
6.4%
5.2%
5.2%
2.6%
50 0
40
Currnt day Sudden Gradual Currnt day Sudden Gradual antiplatelet W stop W stop W stop W stop W stop W stop (n=2)
28.8%
30 20 10 0
(n=5) (n=15) (n=4)
3.8%
1.9%
(n=12) (n=35) (n=4)
5.9% +
1.0~1.5 1.5~2.0 2.0~2.5 2.5~3.0 (n=1) (n=31) (n=15) (n=2)
others (n=3)
PT-INR Figure 4 A) Warfarin prescription during RFPV Out of 135 patients, 78 (57.7%) were prescribed warfarin before and 46 (34.1%) after RFPV. During RFPV, warfarin therapy was continued in 52 (38.5%) and discontinued in 77 (57.0%) patients. B) PT-INR of patients who were prescribed continuation of warfarin therapy during RFPV.
Discussion Since we administered questionnaires to doctors who prescribed warfarin, the number of embolic or bleeding events reported in this study does not reflect the actual number of patients who experienced thromboembolism or bleeding at the time of the elective invasive procedure. However, it was noteworthy that approximately one-third of the doctors who prescribed warfarin reported that their patients who underwent invasive procedures experienced these problems. The incidence of thromboembolism or bleeding determined in this study may be higher than that reported in previous papers1) because we used the questionnaire method to collect the data. Dental extraction
Several studies have addressed the issue of management of patients on anticoagulants who need dental extractions2–5) and various protocols have been suggested. One approach is to replace warfarin
No heparin infusion 31.1% Heparin infusion change
67.3%
Figure 5 Discontinuation of warfarin therapy during RFPV Heparin exchange was performed by 67.3% of doctors and was not performed by 31.1% in patients in whom warfarin therapy was discontinued during RFPV.
with heparin before dental extraction, and resume warfarin administration after the procedure.6) This method requires hospitalization and careful monitoring of anticoagulation, however, because warfarin reaches the therapeutic level after several days, the patients are at a risk of developing postoperative thromboembolism.7) The second approach is to stop anticoagulant treatment 2–3 days before dental extraction, and this method has been widely applied to manage patients on warfarin therapy. Although this approach has an advantage of low risk of hemorrhage, the risk of thromboembolism is high. The third approach involves continuation of anticoagulant treatment. This approach does not appear to increase postoperative bleeding and it is not associated with thromboembolism. Many guidelines have recommended this approach;7–10) however, it has not yet become a standard procedure. We found that for patients on warfarin therapy who undergo dental extractions, only 17.1% of doctors prescribed the same or a decreased dosage of warfarin, whereas the majority (75.7%) of doctors instructed the patients to discontinue warfarin. Further, 19 (3.1%) of 614 doctors reported that their patients had embolic events due to warfarin discontinuation.
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Vol 26 No 2 2010
(%) 100 (n=137)
90 paroxysmal atrial fibrillation
82.5%
80 no paroxysmal atrial fibrillation
70 60 50 40
36.5% 28.5%
30 20
15.3% 10.9%
10 2.2%
2.2%
6.6% 0.7%
3.6%
5.8% 5.1%
0 One month 3 months 6 months 12 months permanent others
Figure 6 Warfarin dosing period after RFPV After RFPV, 36.5% and 28.5% of doctors administered warfarin therapy for 3 and 6 months to patients who developed paroxysmal atrial fibrillation, respectively, and 82.5% of them administered uninterrupted warfarin therapy to patients who developed persistent or permanent atrial fibrillation.
According to the Japanese Circulation Society Guidelines (2004), the continuation of warfarin around the time of dental extraction was recommended for patients of class IIa. However, we found that more than 80% of doctors interrupted warfarin at the time of dental extraction. Adherence to the guidelines was generally poor for dental procedures. Invasive procedures
We found that most doctors recommended the interruption of warfarin therapy for patients undergoing surgery (92.5%), endoscopy (78.7%), pacemaker implantation (66.6%), and catheterization (33.4%). Out of the 614 doctors, 168 (27.4%) reported that patients who underwent invasive procedures had embolic events on warfarin discontinuation. Cerebral infarction was the most frequent type of embolic event, and 90% of patients had a PTINR value of <1:5 when the embolic event occurred. Further, 41.5% of doctors reported bleeding episodes when warfarin therapy was continued. However, they reported that the incidence of cerebral hemorrhage was lower than that of cerebral infarction, and 50% of patients had PT-INR values of >2:5 when cerebral hemorrhage occurred. For patients at a high
100
risk for thromboembolism, many experts recommend the bridging therapy. This therapy involves warfarin discontinuation and maintenance of heparin dose for therapeutic anticoagulation before the procedure; pausing heparin administration during the operation; and resuming heparin treatment after the procedure until the INR reaches to a desired therapeutic level. However, there is limited data which the doctors can use to identify patients who are at a sufficiently high risk of thromboembolism and to weigh the risk of heparin treatment beforehand.11) Chaudari12) reported low frequency of acute gastrointestinal hemorrhage associated with endoscopic procedures in patients who received warfarin treatment. Kumada13) reported a high incidence of cerebral infarction after warfarin discontinuation before undergoing endoscopic procedures. The Guidelines of the Japan Gastroenterological Endoscopy Society regarding anticoagulation and antiplatelet therapy indicate that warfarin should be discontinued 3–4 days before endoscopic procedures and that the PT-INR at this time should be <1:5. Heparin infusions are therefore required for high-risk patients.14) The number of patients undergoing device implantation and taking warfarin is increasing steadily. The guidelines recommend bridging therapy for such patients.8) However, several papers reported that hematoma was prevalent in patients receiving bridging therapy.15,16) Further, it has been reported that it is possible to implant a pacemaker in patients on warfarin therapy without the interruption of warfarin therapy.17) In this study, we found that approximately one-third of the doctors continued warfarin therapy throughout the perioperative periods of pacemaker implantation. This value is similar to that reported by Krahn,18) but higher than that reported by de Bono.19) This approach is supported by a number of case studies that report a very low incidence of complications in patients with an INR >1:5 who undergo implantation.20,21) Hence, pacemaker implantation can be considered safe even when continuing oral anticoagulation therapy by experienced doctors. There is growing evidence that uninterrupted warfarin therapy is safe for certain procedures such as dental extraction and pacemaker implantation. In addition, cardiac catheterization may not require interruption of warfarin therapy. Although 33% of doctors discontinue warfarin at cauterization, there are no evidence-based guidelines that provide information about perioperative anticoagulation practices in such patients.22)
Watanabe N
RFPV is an effective treatment for drug-refractory atrial fibrillation. The risk of thromboembolic events at the time of RFPV is a matter of concern, and it is important to achieve periprocedural anticoagulation to prevent these complications. However, anticoagulation may increase the risk of bleeding and hemorrhagic complications in the periprocedural period. The best anticoagulation procedure is not known. Most centers discontinue warfarin at least 3–5 days before ablation and apply the bridging strategy to warfarin therapy after ablation.23–25) These strategies are consistent with the recommendations made by the 2007 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation.26) Study Limitations This study has several limitations. Firstly, we administered the questionnaire to doctors who prescribed warfarin. Therefore, the number of embolic or bleeding events in this paper does not reflect the actual number of patients who had thromboembolism or bleeding. Secondly, the present guidelines are different from those formulated at the time when the questionnaire was administered. Further, we did not test the specific hypothesis in this study. The main purpose was to understand the effects of warfarin usage during invasive procedures in patients at risk of thromboembolism. Conclusion Several complications of different types occurred in patients on warfarin therapy who underwent invasive procedures, regardless of whether warfarin was interrupted or continued during the invasive procedure. Therefore, it is necessary to make careful decisions about the management of patients on warfarin therapy who are required to undergo invasive procedures. Acknowledgement We greatly appreciate the co-operation of the members of the Japanese Society of Cardiac Pacing and Electrophysiology.
References 1) Garcia DA, Regan S, Henault LE, et al: Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med 2008; 168: 63–9 2) Devani P, Lavery KM, Howell CJ: Dental extractions in patients on warfarin: Is alteration of anticoagulant regime necessary? Br J Oral Maxillofac Surg. 1998;
Anticoagulant therapy during invasive procedures
36: 107–111 3) Al-Mubarak S, Al-Ali N, Rass MA, et al: Evaluation of dental extractions, suturing and INR on postoperative bleeding of patients maintained on oral anticoagulant therapy. Br Dent J. 2007; 203: E15 4) Evans IL, Sayers MS, Gibbons AJ, et al: Can warfarin be continued during dental extraction? Results of a randomized controlled trial. Br J Oral Maxillofac Surg. 2002; 40: 248–252 5) Muthukrishnan A, Bishop K: An assessment of the management of patients on warfarin by general dental practitioners in South West Wales. Br Dent J. 2003; 195: 567–570 6) Madura JA, Rookstool M, Wease G: The management of patients on chronic Coumadin therapy undergoing subsequent surgical procedures. Am Surg. 1994; 60: 542– 546 7) Douketis JD, Berger PB, Dunn AS, et al: The perioperative management of antithrombotic therapy. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). CHEST 2008; 133: 299–339S 8) Perry MO: Anticoagulation: A surgical perspective. Am J Surg. 1988; 155: 268–276 9) Guidelines for management of anticoagulant and antiplatelet therapy in cardiovascular disease (JCS 2004). Cir J 2004; 68: Suppl. IV 10) Hirsh J, Fuster V, Ansell J, et al: American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy. Circulation 2003; 107: 1692–1711 11) Jaffer AK, Brotman DJ, Bash LD, et al: Variations in perioperative warfarin management: Outcomes and practice patterns at nine hospitals. The American Journal of Medicine 2010; 123: 141–150 12) Chaudrai CP, Palmer KR: Acute gastrointestinal hemorrhage in anticoagulated patients treated with anticoagulant drugs. Gut 1995; 36: 483–484 13) Kuwada SK, Balm R, Gostout CJ: The role of withdrawing chronic anticoagulation because of acute GI bleeding. Amm J Gastroenterol 1996; 91: 1116–1119 14) Ogoshi K: The management of anticoagulation and antiplatelet therapy for endoscopic procedures. Gastroenterol Endosc 2005; 47: 2691–2695 15) Wiegand UK, Lejeune D, Boguschewski F, et al: Pocket hematoma after pacemaker or implantable Cardioverter defibrillator surgery: Influence of patient morbidity, operation strategy, and perioperative antiplatelet/anticoagulation therapy. Chest 2004; 126: 1177–1186 16) Klug D, Balde M, Pavin D, et al: Risk factors related to infections of implanted pacemakers and cardioverterdefibrillators: Results of a large prospective study. Circulation 2007; 116: 1349–1355 17) Goldstein DJ, Losquadro W, Spontnitz HM: Outpatient pacemaker procedures in orally anticoagulated patients. Pacing Clin Electrophysiol 1998; 21: 1730–1734 18) Krahn AD, Healey JS, Simpson CS, et al: Anticoagulation of patients on chronic warfarin undergoing arrhythmia device surgery: Wide variability of perioperative bridging in Canada. Heart Rhythm 2009; 6: 1276–1279 19) de Bono J, Nazir S, Ruparelia N, et al: Perioperative
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management of anticoagulation during device implantation—The UK perspective. Pacing Clin Electrophysiol 2010; 33: 389–393 al-Khadra AS: Implantation of pacemakers and implantable cardioverter defibrillators in orally anticoagulated patients. Pacing Clin Electrophysiol 2003; 26: 511–514 Giudici MC, Paul DL, Bontu P, et al: Pacemakers and implantable cardioverter defibrillator implantation without reversal of warfarin therapy. Pacing Clin Electrophysiol 2004; 27: 358–360 Jessup DB, Coletti AT, Muhlenstein JB, et al: Elective coronary angiography and percutaneous coronary intervension during uninterrupted warfarin therapy. Catheter Cardiovasc Interv 2003; 60: 180–184 Ren JF, Marchlinski FE, Callans DJ, et al: Increased intensity of anticoagulation may reduce risk of thrombus during atrial fibrillation ablation procedures in patients
with spontaneous echo contrast. J Cardiovasc Electrophysiol 2005; 16: 474–477 24) Pappone C, Santinelli V: How to perform encircling ablation of the left atrium. Heart Rhythm 2005; 3: 1105– 1109 25) Oral H, Chugh A, Ozyadin M, et al: Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation for atrial fibrillation. Circulation 2006; 114: 759–765 26) Calkins H, Brugada J Packer DL, et al: HRS/EHRS/ ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendation for personal, policy, procedures and follow-up. A report of the Heart Rhythm Society Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2007; 4: 816–861
Vol 26 No 2 2010
Original Article
Management of Patients Receiving Warfarin during Invasive Procedures and the Adverse Effects of Warfarin Norikazu Watanabe MD, Kaoru Tanno MD, Haruyuki Ito MD, Tatsuya Onuki MD, Fumito Miyoshi MD, Yoshino Minoura MD, Mitsuharu Kawamura MD, Taku Asano MD, Takashi Katagiri MD, Youichi Kobayashi MD Division of Cardiology, Department of Internal Medicine, Showa University School of Medicine
Aim: The aim of this study was to assess the frequency and characteristics of complications in patients on anticoagulant therapy who were to undergo invasive procedure. Methods and Results: We sent a questionnaire to 2758 doctors who were on the mailing list of the Japanese Society of Cardiac Pacing and Electrophysiology in August 2004. We received 614 questionnaires (response rate, 22.3%). Out of the 614 doctors, 19 (3.1%) reported that their patients had embolic events upon the interruption of warfarin therapy during dental extraction. In patients undergoing invasive procedures such as surgery, endoscopy, pacemaker implantation, and catheterization, 168 (27.4%) of the 614 doctors reported embolic events after the interruption of warfarin therapy. Further, 255 (41.5%) of the 614 doctors reported bleeding episodes when warfarin therapy was continued during the invasive procedures. Conclusion: Several complications of different types were reported to occur in patients receiving warfarin therapy who underwent elective invasive procedures, regardless of whether warfarin administration was interrupted or continued at the time of the invasive procedure. Therefore, it is necessary to make careful decisions about the management of patients on warfarin therapy who will be undergoing invasive procedures. (J Arrhythmia 2010; 26: 96–102)
Key words: Warfarin, Atrial fibrillation, Invasive procedure
Introductions Many doctors encounter a difficult situation when they have to perform elective procedure or minor surgery on patients receiving warfarin-sodium therapy. Cessation of anticoagulant therapy in the perioperative period may expose the patients to increased risk of thromboembolic events, while
continuing anticoagulant therapy may increase the risk of bleeding. There are limited guidelines or randomized controlled trials that provide information about perioperative management of patients on warfarin therapy. The aim of this study was to assess the frequency and characteristics of complications in patients receiving anticoagulant therapy who were to undergo invasive procedures.
Received 20, May, 2009: accepted 11, May, 2010. Address for Correspondence: Kaoru Tanno MD, Division of Cardiology, Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai Shinagawa-Ku Tokyo 142-8666, Japan. TEL: 03-3784-8539 FAX: 03-3784-8622 E-mail: k-tanno@med. showa-u.ac.jp
96
Watanabe N
Anticoagulant therapy during invasive procedures
(%) 80
75.7% 67.1%
70 60 50 40 17.1% 30 20
(n=614)
9.9% 7.2%
10
8.6% 5.2% 0.2%
0
continuation (n=61)
dose reduction (n=44)
(%) 100 90 80 70 60 50 40 30 20 10 3.1% (n=19) 0 experience (%) B 90 80 76.5% A
cancellation discontinuation others of tooth gradually (n=53) discontinuation extraction (n=32) suddenly (n=1) (n=412)
Figure 1 Technique for the management of patients on warfarin who were to undergo dental extraction. Warfarin administration was continued by 17.1% of doctors and discontinued by 75.7% in patients who were to undergo dental extraction.
Methods We sent a questionnaire to 2758 doctors who were on the mailing list of the Japanese Society of Cardiac Pacing and Electrophysiology (JASPE) in August 2004. The doctors were instructed to return completed questionnaires anonymously in an enclosed stamped addressed envelope. Through the questionnaire, we collected information about the international normalized ratios (INR) of the pathological conditions (valvular disease, atrial fibrillation (AF), and cerebral infarction), the characteristics of patients on warfarin therapy, including patient responses to dental extraction, surgery, endoscopy, pacemaker implantation, and catheterization, and the adverse effects of warfarin use. Results We received 614 questionnaires (response rate, 22.3%) from 277 doctors aged in their 50s (45.1%), 162 (26.4%) in 40s, and 132 (21.5%) in 60s. The number of patients prescribed with warfarin per month was <10 (23.5%), 10–20 (16.9%), and 20–30 (15.3%). Further, 93.3%, 92.8%, and 82.4% of doctors prescribed warfarin to patients with AF, patients who had undergone replacement of heart
70 60 50 40 30 20
95.4% (n=586)
inexperience N=19 multiple answers allowed
23.5% 11.8%
10 0 brain infarction (n=13)
vascular myocardial occlusion infarction of extremities (n=4) (n=2)
5.9% others (n=1)
Figure 2 Thrombosis in dental extraction Out of the 614 doctors, 19 (3.1%) reported that their patients had an embolic event due to discontinuation of warfarin therapy. Among these patients, 13, 4, and 2 developed brain infarction, myocardial infarction, and vascular occlusion of the extremities, respectively.
valves, and patients with cerebrovascular disease, respectively. Dental extraction
For patients who underwent dental extraction, 17.1% of doctors administered the same dosage or decreased the dose of warfarin continuously, and 75.7% of doctors interrupted warfarin therapy during the extraction procedure (Figure 1). Among doctors who administered the same or a decreased dose of warfarin, 29.5%, 30.9%, and 13.8% reported INR values in the range of 1.0–1.3, 1.3–1.5, and 1.5–2.0, respectively. Out of the 614 doctors, 19 (3.1%) reported that their patients had embolic events when warfarin therapy was interrupted. Among the 19 embolic events, 13 were brain infarction, 4 were myocardial infarction, and 2 were vascular occlusion of the extremities (Figure 2). No bleeding episodes were reported in patients for whom warfarin therapy was continued.
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Invasive procedures
The reasons for interruption of warfarin therapy were surgery (92.5%), endoscopy (78.7%), pacemaker implantation (66.6%), and catheterization (33.4%). Among the 614 doctors, 168 (27.4%) reported that their patients had embolic events when warfarin therapy was interrupted. The types of embolic events were 161 cerebral infarctions, 41 vascular occlusions of the extremities, 9 pulmonary infarctions, 3 myocardial infarctions, and 15 others (Figure 3-A). Among the patients who developed cerebral infarctions, 90% had PT-INR values of <1:5 at the time of the event. In patients for whom warfarin therapy was continued, 255 (41.5%) of the 614 doctors reported bleeding episodes. Among the 614 doctors, 251 (40.9%) reported subcutaneous bleedings, 28 (4.6%) reported cerebral hemorrhage, and 21 (3.4%) reported intraperitoneal hemorrhage (Figure 3-B). Fifty percent of patients with cerebral hemorrhage had PT-INR values of >2:5 at the time of the event. Pacemaker implantation
When treating patients with atrial fibrillation, 23.0% doctors continued warfarin therapy and 62.4% discontinued the therapy (other, 6.0%, no answer, 8.6%) during pacemaker implantation. When treating patients with valvular diseases, 31.1% doctors continued warfarin therapy and 51.7% discontinued the therapy (other, 8.2%, no answer, 9.0%) during pacemaker implantation. Further, 35.7% and 51.5% of doctors discontinued warfarin therapy and performed heparin exchange in patients with atrial fibrillation and valvular diseases, respectively, during pacemaker implantation.
A) (%) 30
26.2%
thrombosis
25
N=168 multiple answers allowed
20 15 10
6.7%
5 0
0.5%
1.5%
brain myocardial vascular pulmonary infarction infarction occlusion infarction of extremities (n=9) (n=161) (n=3) (n=41)
B) (%) 50
bleeding
2.4% others (n=15)
N=255 multiple answers allowed 40.9%
40 30 20 10 0
4.6%
3.4%
cerebral intraperitoneal subcutaneous hemorrhage hemorrhage. bleeding (n=28) (n=251) (n=21)
6.7% others (n=41)
Figure 3 A) Thrombosis in invasive procedures Out of the 614 doctors, 168 (27.4%) reported that their patients had embolic events due to warfarin discontinuation in invasive procedures. The types of embolic events were 161 cerebral infarctions, 41 vascular occlusions of the extremities, 3 myocardial infarctions, and 9 pulmonary infarctions. B) Bleeding in invasive procedures Out of the 614 doctors, 255 (41.5%) reported episodes of bleeding due to warfarin continuation; 251 (40.9%) were subcutaneous bleeds, 28 (4.6%) were cerebral hemorrhages, and 21 (3.4%) were intraperitoneal hemorrhages.
Catheterization
In patients with atrial fibrillation, 40.0% of doctors continued warfarin therapy and 41.5% discontinued the therapy during catheterization. In patients with valvular disease, 46.9% of doctors continued warfarin therapy and 32.4% discontinued the therapy during catheterization. Further, 40.3% and 54.5% of doctors performed heparin exchange after interrupting warfarin administration during catheterization in patients who received treatment for atrial fibrillation and valvular diseases, respectively. Radiofrequency ablation of pulmonary vein
Of the 614 doctors, 135 (22%) reported that they performed radiofrequency ablation for pulmonary vein (RFPV). Among these 135 doctors, 78 (57.7%) and 46 (34.1%) administered warfarin before and after RFPV, respectively. Further, 52 (38.5%) doc-
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tors continued to administer warfarin during RFPV and 77 (57.0%) discontinued warfarin administration during the procedure (Figure 4-A). Among doctors who administered the same or decreased dosage of warfarin, 59.6% and 28.8% reported PT-INR values in the range of 1.5–2.0 and 2.0–2.5, respectively, in patients for whom warfarin was continued during RFPV (Figure 4-B). Among doctors who discontinued warfarin during RFPV, 67.3% performed heparin exchange and 31.1% did not perform the exchange (Figure 5). Further, 36.5% and 28.5% of doctors administered warfarin for 3 and 6 months to patients who developed paroxysmal atrial fibrillation after RFPV, respectively, and 82.5% administered permanent warfarin therapy to patients who developed persistent or permanent atrial fibrillation after RFPV (Figure 6).
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A)
Anticoagulant therapy during invasive procedures
(N=135)
(%) 60
57.0%
(%) 50 discontinuation of warfarin prescription during RFPV 77/135 (57.0%)
50 38.5%
40
45.5%
40
30 20
30
∗Warfain :W
10 0 B)
continuation N=52
discontinuation N=77
19.5%
20
15.6%
(%) 70 10
59.6%
60
6.4%
5.2%
5.2%
2.6%
50 0
40
Currnt day Sudden Gradual Currnt day Sudden Gradual antiplatelet W stop W stop W stop W stop W stop W stop (n=2)
28.8%
30 20 10 0
(n=5) (n=15) (n=4)
3.8%
1.9%
(n=12) (n=35) (n=4)
5.9% +
1.0~1.5 1.5~2.0 2.0~2.5 2.5~3.0 (n=1) (n=31) (n=15) (n=2)
others (n=3)
PT-INR Figure 4 A) Warfarin prescription during RFPV Out of 135 patients, 78 (57.7%) were prescribed warfarin before and 46 (34.1%) after RFPV. During RFPV, warfarin therapy was continued in 52 (38.5%) and discontinued in 77 (57.0%) patients. B) PT-INR of patients who were prescribed continuation of warfarin therapy during RFPV.
Discussion Since we administered questionnaires to doctors who prescribed warfarin, the number of embolic or bleeding events reported in this study does not reflect the actual number of patients who experienced thromboembolism or bleeding at the time of the elective invasive procedure. However, it was noteworthy that approximately one-third of the doctors who prescribed warfarin reported that their patients who underwent invasive procedures experienced these problems. The incidence of thromboembolism or bleeding determined in this study may be higher than that reported in previous papers1) because we used the questionnaire method to collect the data. Dental extraction
Several studies have addressed the issue of management of patients on anticoagulants who need dental extractions2–5) and various protocols have been suggested. One approach is to replace warfarin
No heparin infusion 31.1% Heparin infusion change
67.3%
Figure 5 Discontinuation of warfarin therapy during RFPV Heparin exchange was performed by 67.3% of doctors and was not performed by 31.1% in patients in whom warfarin therapy was discontinued during RFPV.
with heparin before dental extraction, and resume warfarin administration after the procedure.6) This method requires hospitalization and careful monitoring of anticoagulation, however, because warfarin reaches the therapeutic level after several days, the patients are at a risk of developing postoperative thromboembolism.7) The second approach is to stop anticoagulant treatment 2–3 days before dental extraction, and this method has been widely applied to manage patients on warfarin therapy. Although this approach has an advantage of low risk of hemorrhage, the risk of thromboembolism is high. The third approach involves continuation of anticoagulant treatment. This approach does not appear to increase postoperative bleeding and it is not associated with thromboembolism. Many guidelines have recommended this approach;7–10) however, it has not yet become a standard procedure. We found that for patients on warfarin therapy who undergo dental extractions, only 17.1% of doctors prescribed the same or a decreased dosage of warfarin, whereas the majority (75.7%) of doctors instructed the patients to discontinue warfarin. Further, 19 (3.1%) of 614 doctors reported that their patients had embolic events due to warfarin discontinuation.
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(%) 100 (n=137)
90 paroxysmal atrial fibrillation
82.5%
80 no paroxysmal atrial fibrillation
70 60 50 40
36.5% 28.5%
30 20
15.3% 10.9%
10 2.2%
2.2%
6.6% 0.7%
3.6%
5.8% 5.1%
0 One month 3 months 6 months 12 months permanent others
Figure 6 Warfarin dosing period after RFPV After RFPV, 36.5% and 28.5% of doctors administered warfarin therapy for 3 and 6 months to patients who developed paroxysmal atrial fibrillation, respectively, and 82.5% of them administered uninterrupted warfarin therapy to patients who developed persistent or permanent atrial fibrillation.
According to the Japanese Circulation Society Guidelines (2004), the continuation of warfarin around the time of dental extraction was recommended for patients of class IIa. However, we found that more than 80% of doctors interrupted warfarin at the time of dental extraction. Adherence to the guidelines was generally poor for dental procedures. Invasive procedures
We found that most doctors recommended the interruption of warfarin therapy for patients undergoing surgery (92.5%), endoscopy (78.7%), pacemaker implantation (66.6%), and catheterization (33.4%). Out of the 614 doctors, 168 (27.4%) reported that patients who underwent invasive procedures had embolic events on warfarin discontinuation. Cerebral infarction was the most frequent type of embolic event, and 90% of patients had a PTINR value of <1:5 when the embolic event occurred. Further, 41.5% of doctors reported bleeding episodes when warfarin therapy was continued. However, they reported that the incidence of cerebral hemorrhage was lower than that of cerebral infarction, and 50% of patients had PT-INR values of >2:5 when cerebral hemorrhage occurred. For patients at a high
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risk for thromboembolism, many experts recommend the bridging therapy. This therapy involves warfarin discontinuation and maintenance of heparin dose for therapeutic anticoagulation before the procedure; pausing heparin administration during the operation; and resuming heparin treatment after the procedure until the INR reaches to a desired therapeutic level. However, there is limited data which the doctors can use to identify patients who are at a sufficiently high risk of thromboembolism and to weigh the risk of heparin treatment beforehand.11) Chaudari12) reported low frequency of acute gastrointestinal hemorrhage associated with endoscopic procedures in patients who received warfarin treatment. Kumada13) reported a high incidence of cerebral infarction after warfarin discontinuation before undergoing endoscopic procedures. The Guidelines of the Japan Gastroenterological Endoscopy Society regarding anticoagulation and antiplatelet therapy indicate that warfarin should be discontinued 3–4 days before endoscopic procedures and that the PT-INR at this time should be <1:5. Heparin infusions are therefore required for high-risk patients.14) The number of patients undergoing device implantation and taking warfarin is increasing steadily. The guidelines recommend bridging therapy for such patients.8) However, several papers reported that hematoma was prevalent in patients receiving bridging therapy.15,16) Further, it has been reported that it is possible to implant a pacemaker in patients on warfarin therapy without the interruption of warfarin therapy.17) In this study, we found that approximately one-third of the doctors continued warfarin therapy throughout the perioperative periods of pacemaker implantation. This value is similar to that reported by Krahn,18) but higher than that reported by de Bono.19) This approach is supported by a number of case studies that report a very low incidence of complications in patients with an INR >1:5 who undergo implantation.20,21) Hence, pacemaker implantation can be considered safe even when continuing oral anticoagulation therapy by experienced doctors. There is growing evidence that uninterrupted warfarin therapy is safe for certain procedures such as dental extraction and pacemaker implantation. In addition, cardiac catheterization may not require interruption of warfarin therapy. Although 33% of doctors discontinue warfarin at cauterization, there are no evidence-based guidelines that provide information about perioperative anticoagulation practices in such patients.22)
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RFPV is an effective treatment for drug-refractory atrial fibrillation. The risk of thromboembolic events at the time of RFPV is a matter of concern, and it is important to achieve periprocedural anticoagulation to prevent these complications. However, anticoagulation may increase the risk of bleeding and hemorrhagic complications in the periprocedural period. The best anticoagulation procedure is not known. Most centers discontinue warfarin at least 3–5 days before ablation and apply the bridging strategy to warfarin therapy after ablation.23–25) These strategies are consistent with the recommendations made by the 2007 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation.26) Study Limitations This study has several limitations. Firstly, we administered the questionnaire to doctors who prescribed warfarin. Therefore, the number of embolic or bleeding events in this paper does not reflect the actual number of patients who had thromboembolism or bleeding. Secondly, the present guidelines are different from those formulated at the time when the questionnaire was administered. Further, we did not test the specific hypothesis in this study. The main purpose was to understand the effects of warfarin usage during invasive procedures in patients at risk of thromboembolism. Conclusion Several complications of different types occurred in patients on warfarin therapy who underwent invasive procedures, regardless of whether warfarin was interrupted or continued during the invasive procedure. Therefore, it is necessary to make careful decisions about the management of patients on warfarin therapy who are required to undergo invasive procedures. Acknowledgement We greatly appreciate the co-operation of the members of the Japanese Society of Cardiac Pacing and Electrophysiology.
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