/$ -see front matter 2010 Heart Rhythm Society. All rights reserved. doi: /j.hrthm

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1 Continuing warfarin therapy is superior to interrupting warfarin with or without bridging anticoagulation therapy in patients undergoing pacemaker and defibrillator implantation Imdad Ahmed, MD, Elie Gertner, MD, William B. Nelson, MD, PhD,* Chad M. House, BS, RDCS, Ranjan Dahiya, MD,* Christopher P. Anderson, MPH, David G. Benditt, MD, FHRS, Dennis W.X. Zhu, MD* From the *Section of Cardiology and Department of Medicine, Regions Hospital and the University of Minnesota Medical School, Saint Paul, Minnesota, Regions Hospital, Saint Paul, Minnesota, and Cardiac Arrhythmia and Syncope Center, University of Minnesota Medical School, Minneapolis, Minnesota. BACKGROUND Current guidelines recommend stopping oral anticoagulation and starting bridging anticoagulation with intravenous heparin or subcutaneous enoxaparin when implanting a pacemaker or defibrillator in patients at moderate or high risk for thromboembolic events. A limited body of literature suggests that device surgery without cessation of oral anticoagulation may be feasible. OBJECTIVE The purpose of this study was to evaluate the safety of device surgery in orally anticoagulated patients without interrupting warfarin therapy. METHODS We performed a retrospective study of 459 consecutive patients on chronic warfarin therapy who underwent device surgery from April 2004 to September Warfarin was continued in 222 patients during the perioperative period. Warfarin was temporarily held and bridging therapy administered in 123 patients. Warfarin was temporarily held without bridging therapy in 114 patients. RESULTS There were no significant differences with regard to age, sex, or risk factors for thromboembolism in the three groups. Patients who continued taking warfarin had a lower incidence of pocket hematoma (P.004) and a shorter hospital stay (P.0001) than did patients in the bridging group. Holding warfarin without bridging is associated with a higher incidence of transient ischemic attacks (P.01). CONCLUSION Temporarily interrupting anticoagulation is associated with increased thromboembolic events, whereas cessation of warfarin with bridging anticoagulation is associated with a higher rate of pocket hematoma and a longer hospital stay. Continuing warfarin with a therapeutic international normalized ratio appears to be a safe and cost-effective approach when implanting a pacemaker or defibrillator in patients with moderate to high thromboembolic risk. KEYWORDS Anticoagulation; Defibrillator; Implantation; Pacemaker; Warfarin ABBREVIATIONS INR international normalized ratio; TIA transient ischemic attack (Heart Rhythm 2010;7: ) 2010 Heart Rhythm Society. All rights reserved. Drs. Zhu and Ahmed were supported in part by Discovery Grants from the HealthPartners Research Foundation, Minneapolis, Minnesota. Address reprint requests and correspondence: Dr. Dennis W. Zhu, Cardiology 11102H, Regions Hospital, 640 Jackson Street, Saint Paul, Minnesota address: dennis.w.zhu@healthpartners.com. (Received December 9, 2009; accepted February 9, 2010.) Introduction Many patients undergoing pacemaker or defibrillator implantation are on chronic warfarin therapy. Because of concern about bleeding, device implantation in anticoagulated patients often is postponed until the international normalized ratio (INR) is reduced toward baseline value by withholding warfarin with or without administration of coagulation factors (fresh frozen plasma) or vitamin K. Several days then may be needed to reestablish therapeutic anticoagulation after the procedure. Although the period of subtherapeutic anticoagulation is short, it could expose patients to potential thromboembolic complications. 1 therapy with intravenous heparin or subcutaneous low-molecular-weight heparin is often used to minimize the time before and after the procedure during which anticoagulation is subtherapeutic in patients with moderate to high risk of thromboembolic events. 2 However, problems associated with bridging therapy include an increased incidence of pocket hematoma and other bleeding complications, higher costs, and complexity of procedure scheduling. 3 6 A limited body of literature has suggested that pacemaker and defibrillator implantation without cessation of oral anticoagulation is feasible; 7 10 however, the safety of this approach in a large number of patients in whom INR is maintained in the therapeutic range during device implantation is not well established. Given the lack of consensus among implanting physicians on the perioperative management of anticoagulation, 11 we compared three different strategies (continuation of warfarin therapy, cessation of warfarin with bridging therapy, cessation of warfarin with no bridging /$ -see front matter 2010 Heart Rhythm Society. All rights reserved. doi: /j.hrthm

2 746 Heart Rhythm, Vol 7, No 6, June 2010 therapy) in patients receiving chronic warfarin undergoing device surgery at our institution. Methods Study cohort Between April 2004 and September 2008, 1,750 consecutive patients underwent antiarrhythmic device surgery (pacemaker or defibrillator implantation, generator replacement, or lead revision) at Regions Hospital, a major teaching affiliate of the University of Minnesota Medical School. At admission, 459 (26%) patients were being treated with warfarin. At the discretion of the attending clinicians, one of three strategies for perioperative management of anticoagulation was followed: Continued warfarin group. Warfarin therapy was continued to maintain INR in the therapeutic range ( ) during the entire perioperative period. group. Warfarin was discontinued 3 to 5 days prior to the surgery or the INR was normalized by coagulation factors or vitamin K. Patients received bridging therapy when INR was expected to be subtherapeutic. Intravenous heparin was discontinued 4 to 6 hours prior to the procedure and restarted without bolus administration 12 hours after the procedure. The last dose of subcutaneous enoxaparin (1 mg/kg q12h) was given 12 to 18 hours prior to the procedure and restarted 24 hours after the procedure. Warfarin was reinstituted in the evening of the day of surgery. therapy was discontinued when INR reached the therapeutic range. Anticoagulation withheld group. Warfarin was discontinued 3 to 5 days prior to the procedure or the INR was normalized by coagulation factors or vitamin K. Device procedure was performed when INR was 1.5. Warfarin was restarted in the evening of the day of surgery. Patients did not receive bridging therapy perioperatively. Any prior antiplatelet therapy was routinely continued throughout the perioperative period. The study protocol was approved by the Regions Hospital Institutional Review Board. Implantation An ipsilateral subclavian venogram was performed. The initial subclavian venous puncture was made using a micropuncture introducer set (Cook Medical, Bloomington, IN, USA) with a 21-gauge needle, then a small introducer upsized the initial inch guidewire to a standard inch introducer wire, 12 with the intention of reducing the incidence of pneumothorax and the severity of bleeding in case of inadvertent arterial punctures. A generator pocket was formed between the deep fascia and the pectoral muscles. A pressure dressing was routinely applied to the wound postoperatively and left in place overnight. Three electrophysiologists (EP1, EP2, EP3) performed the device procedures. Outpatients were discharged within 24 hours of the procedure unless they experienced complications or were assigned to bridging therapy. All patients were followed in the device clinic at Regions Hospital 1 and 8 weeks postimplantation. Definition of hemorrhagic and thromboembolic complications: A pocket hematoma was defined as a palpable tense swelling causing severe pain that required prolonged hospitalization ( 1 day longer than the scheduled hospitalization) and/or discontinuation of anticoagulation and/or surgical evacuation and/or blood transfusion. Direct procedure-related bleeding events, including hemothorax, pericardial effusion, and tamponade, were documented by chest X-ray film or echocardiography as indicated. Other major perioperative bleeding events were documented. Thromboembolic events were defined as transient ischemic attack (TIA), stroke, deep vein thrombosis, and pulmonary embolism. Statistical analysis All statistical analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC, USA). Fisher s exact test was used to test the association between primary outcomes and categorical predictors. The incidence of complications was compared between continued warfarin and bridging and between continued warfarin and anticoagulation withheld groups, respectively. Distribution of continuous covariates among treatment groups was tested by one-way analysis of variance. Differences between treatment groups in proportions of dichotomous covariates were analyzed via logistic regression. Differences in length of stay between treatment groups were determined by log rank test on Kaplan-Meier estimates. Threshold of significance for all statistical tests was set at All tests performed were two-sided. Results Patient characteristics: A total of 459 consecutive patients on chronic warfarin therapy were evaluated retrospectively. Of these patients, 222 continued taking warfarin during the perioperative period. Warfarin was temporarily held and bridging therapy administered in 123 patients: 66% on subcutaneous enoxaparin and 34% on intravenous heparin. Warfarin was temporarily held without bridging therapy in 114 patients. Patient characteristics, type of procedures, and proportion of patients operated by each electrophysiologist in the three groups are listed in Table 1. There was no significant difference with regard to age, sex, platelet count, serum creatinine, and thromboembolic risk factors among the three groups, except the prevalence of diabetes mellitus was higher in the bridging group (P.016). There was a lower concurrent use of aspirin in the continued warfarin group (P.001). Clopidogrel use and type of procedures did not differ among the three groups. EP1 performed more procedures in the continued warfarin group, whereas EP2 and EP3 operated on a higher proportion of patients in the bridging group. The indications for warfarin therapy are listed in Table 2. The anticoagulation withheld group had a

3 Ahmed et al Continuing Warfarin During Device Surgery 747 Table 1 Patient characteristics, type of procedures, and proportion of patients operated on by the three electrophysiologists Continued warfarin Anticoagulation withheld (n 114) P value Mean age (95% CI) 71.5 (70.0, 73.1) 70.9 (68.8, 73.0) 73.3 (71.1, 75.6).253 Mean body mass index (95% CI) 28.7 (28.2, 29.3) 28.1 (27.4, 28.7) 28.8 (27.9, 29.7).297 Mean creatinine (95% CI) 1.16 (1.09, 1.23) 1.18 (1.04, 1.32) 1.17 (1.06, 1.28).964 Mean platelet (K) (95% CI) (233.3, 256.1) (221.3, 247.5) (220.6, 246.1).341 Male (%) Aspirin (%) Clopidogrel (%) Coronary artery disease (%) Congestive heart failure (%) Diabetes mellitus (%) Hypertension (%) History of cerebrovascular accident (%) CHADS2 score New implant (%) Replacement/revision(%) EP1 (%) EP2 (%) EP3 (%) CI confidence interval; EP electrophysiologist. higher proportion of patients with atrial fibrillation and a lower proportion of patients with a mechanical (s). Perioperative INR Mean INR on the morning of the procedure and the associated complications that occurred within 8 weeks postoperatively in the three groups are listed in Table 3. Mean INR was (range ) in the continued warfarin group. Among 222 patients, 214 (96%) had INR between 2.0 to 3.5 perioperatively. Mean INR was and for bridging and anticoagulation withheld groups, respectively. Hemorrhagic complications Pocket hematomas occurred in 10 patients: 1 (0.45%) in the continued warfarin group, 7 (5.7%) in the bridging group, and 2 (1.75%) in the anticoagulation withheld group. The incidence of pocket hematoma was significantly higher in patients on bridging therapy than in patients who continued taking warfarin (P.004). The former group had a 16-fold increase in pocket hematoma formation (odds ratio 16.2, 95% confidence Table 2 Indications Indications for anticoagulation Continued warfarin Atrial fibrillation (%) P.32 Mechanical heart (%) Deep vein thrombosis/ pulmonary embolism (%) Left ventricular thrombus (%) 1 3 P.13 Anticoagulation withheld (n 114) 94 P P P.25 0 interval ) compared with the latter group. The incidence of pocket hematoma for the three individual electrophysiologists was 4.3%, 7.7%, and 5.3% in the bridging group and 0.6%, 0%, and 0% in the continued warfarin group, respectively. The rate of hematoma was not significantly different between patients who continued taking warfarin and those in whom anticoagulation was withheld. No patient had hemothorax, pericardial tamponade, other major perioperative bleedings, or procedure-related death. Thromboembolic complications TIA was reported in five patients within 3 days postoperatively: 4 (3.5%) had anticoagulation withheld, one (0.8%) received bridging therapy, and none were on continued warfarin. The incidence of TIAs was significantly higher in patients who had anticoagulation withheld than in patients on continued warfarin (P.01). No patient developed perioperative stroke, deep vein thrombosis, or pulmonary embolism. The type of complication in each patient, along with indication for anticoagulation, CHADS2 score, operating electrophysiologist, type of device surgery, concurrent antiplatelet therapy, type of bridging therapy, if used, and INR are listed in Table 3 INR level and perioperative hemorrhagic and thromboembolic complications in all patients Outcome Continued warfarin Anticoagulation withheld (n 114) Hematoma 1 (0.45%) 7 (5.7%) P (1.75%) P.26 Transient ischemic attack 0 1 (0.8%) P.35 4 (3.5%) P.01 Mean INR ( SD) INR range INR international normalized ratio.

4 748 Heart Rhythm, Vol 7, No 6, June 2010 Table 4 Clinical details of 15 patients with complications Group Age (years)/sex Indication for anticoagulation EP Device surgery Antiplatelet agent therapy INR Complication Warfarin continued Anticoagulation withheld 88/M AF (4) 1 Pacemaker generator Aspirin, clopidogrel 3.2 Hematoma 75/M DVT 1 ICD Aspirin IV heparin 1.4 Hematoma 75/M Left ventricular 2 ICD Aspirin IV heparin 1.3 Hematoma thrombus 84/F AF (4) 1 Pacemaker Aspirin, clopidogrel SQ enoxaparin 1.7 Hematoma 75/M AF (5) 2 Pacemaker Aspirin IV heparin 1.3 Hematoma 61/M Mechanical mitral 2 Pacemaker Aspirin IV heparin 1.5 Hematoma 68/M Mechanical mitral 1 Pacemaker Aspirin SQ enoxaparin 1.2 TIA 51/F Mechanical mitral 3 ICD generator Aspirin IV heparin 1.3 Hematoma 64/M AF (3) 3 Pacemaker Aspirin IV heparin 1.1 Hematoma 77/M AF (5) 1 ICD Aspirin 1.3 TIA 69/M AF (3) 2 Pacemaker Aspirin 1.2 TIA generator 75/M AF (4) 2 Pacemaker Aspirin 1.2 TIA 79/M AF (3) 1 ICD Aspirin, clopidogrel 1.5 Hematoma 63/M AF (3) 3 Pacemaker Aspirin 1.4 TIA 85/M AF (4) 2 ICD generator Aspirin, clopidogrel 1.6 Hematoma Patient received fresh frozen plasma and vitamin K after INR value was obtained. Repeat INR was not drawn before the procedure. CHADS2 score in patients with atrial fibrillation is given in parentheses. AF atrial fibrillation; DVT deep vein thrombosis; EP Electrophysiologist; ICD implantable cardioverter-defibrillator; INR international normalized ratio; IV intravenous; SQ subcutaneous; TIA transient ischemic attack. Table 4. The indication(s) for anticoagulation was atrial fibrillation with a CHADS2 score from 3 to 5 in the four patients who developed TIAs in the anticoagulation withheld group. Postprocedural days of hospital stay Table 5 lists the length of hospitalization of patients in the three groups after device surgery. A log rank test of homogeneity over strata showed postprocedure hospital stay was significantly longer in patients who were on bridging therapy than in those on continued warfarin (P.0001). No difference in length of postprocedural stay was found between patients on continued warfarin and those in whom anticoagulation was withheld (P.92). Discussion Main findings This study compared three different strategies for the management of perioperative anticoagulation in patients undergoing pacemaker or defibrillator surgery. Continuing warfarin therapy with a therapeutic INR during device procedure appears to be safe and, in terms of perioperative complications, Table 5 Group Length of postoperative hospital stay No. of days (mean SD) Continued warfarin P.0001 Anticoagulation withheld (n 114) P.93 seems to be superior to temporarily holding warfarin with or without bridging therapy. therapy was associated with a higher incidence of bleeding complications and a longer hospital stay. Patients in whom anticoagulation was withheld had a higher risk of TIAs. Previous studies A number of reports have addressed the feasibility of device procedures without cessation of warfarin therapy Goldstein et al 7 implanted 37 pacemakers in patients on continued warfarin therapy without significant bleeding or thromboembolic complications. Al-Khadra 8 and Giudici et al 9 made similar observations. Tolosana et al 10 reported a low incidence of hematoma in a small prospective study in which patients on continued oral anticoagulant acenocoumarol therapy were compared to patients who received bridging therapy. Additional experience exists in abstract format. Belott 13 reported his 11-year experience with patients undergoing device surgery on continued warfarin therapy. Colley et al 14 demonstrated a lower bleeding risk with maintaining warfarin compared to bridging with heparin. Similar findings were reported by other investigators However, it is not clear how many patients in these studies actually had INR in the therapeutic range at the time of the procedure. None of the recent ACC/AHA guidelines mentioned device surgery with continuation of warfarin therapy. 2,18,19 Our study demonstrates that the bleeding risk was low in a large cohort of patients who underwent device surgery with a therapeutic INR ( ).

5 Ahmed et al Continuing Warfarin During Device Surgery 749 Recently updated guidelines from the American College of Chest Physicians have recommended use of bridging anticoagulation with therapeutic dose of subcutaneous lowmolecular-weight heparin or intravenous heparin in patients with mechanical heart s, atrial fibrillation, or venous thromboembolism who are at moderate or high risk for thromboembolic events. 2 However, a substantial risk of pocket hematoma related to bridging therapy has been reported in patients undergoing device surgery. 3 6 Michaud et al 4 reported up to 10-fold greater risk of pocket hematoma after device implantation in patients who received intravenous heparin than in patients who did not receive bridging therapy. The risk was similar whether heparin therapy was initiated 6 hours or 24 hours after surgery. Robinson et al 5 showed that omission of low-molecular-weight heparin the night before procedure did not decrease hematoma rate, but omission of postprocedural low-molecular-weight heparin dramatically reduced the occurrence of hematoma. The incidence of hematoma in the bridging subset of our study was comparable to the rate reported in those studies. Our study also demonstrates that bridging therapy is associated with a longer hospital study after the procedure. This finding is expected, as a patient on bridging therapy with intravenous heparin must be kept in the hospital until INR reaches the therapeutic range. Although subcutaneous low-molecular-weight heparin could be self-administered, many of our patients were unable to do so and required transfer to a transitional facility. In addition, patients who developed a pocket hematoma stayed in the hospital longer for observation, transfusion, or surgical evacuation. 20 A systematic review of perioperative anticoagulation suggests that risk of stroke for patients in whom warfarin is withheld may be substantially higher than would be predicted based on annual thromboembolic rates of patients with atrial fibrillation or a mechanical heart. 21 The finding of 3.5% incidence of TIA in patients with anticoagulation withheld group suggests that interrupting anticoagulation perioperatively, even in the short term, may not be an acceptable alternative in patients with moderate to high risk for thromboembolic events. Study limitations Our data were derived from a single large-center registry. This observational study was nonrandomized, and data were analyzed retrospectively. Differences in techniques may have existed among the three implanting electrophysiologists, and we cannot exclude the possibility of patient selection bias. These limitations should be considering when interpreting the findings of this study, which may reflect the real world of current common practice. Conclusion Implantation of pacemakers and defibrillators in patients on continued warfarin therapy with therapeutic INR appears to be safe and cost effective compared to bridging therapy or temporarily withholding of anticoagulation. These findings need to be confirmed by multicenter, prospective, randomized, controlled studies. 22 References 1. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Eng J Med 1997;336: Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic therapy. Chest 2008;133:299S 399S. 3. 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: Michaud GF, Pelosi F Jr, Noble MD, Knight BP, Morady F, Strickberger SA. A randomized trial comparing heparin initiation 6 h or 24 h after pacemaker or defibrillator implantation. J Am Coll Cardiol 2000;35: Robinson M, Healey JS, Eikelboom J, et al. Postoperative low-molecular-weight heparin bridging is associated with an increase in wound hematoma following surgery for pacemakers and implantable defibrillators. Pacing Clin Electrophysiol 2009;32: Cheng M, Hua W, Chen K, et al. Perioperative anticoagulation for patients with mechanic heart (s) undertaking pacemaker implantation. Europace 2009; 11: Goldstein DJ, Losquadro W, Spotnitz HM. Outpatient pacemaker surgery in orally anticoagulated patients. Pacing Clin Electrophysiol 1998;21: Al-Khadra AS. Implantation of pacemakers and implantable cardioverter defibrillators in orally anticoagulated patients. Pacing Clin Electrophysiol 2003;26: Giudici MC, Barold SS, Paul DL, Bontu P. Pacemaker and implantable cardioverter defibrillator implantation without reversal of warfarin therapy. Pacing Clin Electrophysiol 2004;27: Tolosana JM, Berne P, Mont L, et al. Preparation for pacemaker or implantable cardiac defibrillator implants in patients with high risk of thrombo-embolic events: oral anticoagulation or bridging with intravenous heparin? A prospective randomized trial. Eur Heart J 2009;30: Krahn AD, Healey JS, Simpson CS, Essebag V, Sivakumaran S, Birnie DH. Anticoagulation of patients on chronic warfarin undergoing arrhythmia device surgery: wide variability of perioperative bridging in Canada. Heart Rhythm 2009;6: Schneider PA. Endovascular Skills: Guidewire and Catheter Skills for Endovascular Surgery. Third Edition. 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ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;48:e1 e Fuster V, Rydén LE, Cannom DS, et al. 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 (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48: Zhu DWX. 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