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Anticoagulation management in patients with mechanical heart valves having pacemaker or defibrillator insertion
Thrombosis Research 131 (2013) 300–303
Contents lists available at SciVerse ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Anticoagulation management in patients with mechanical heart valves having pacemaker or defibrillator insertion S. Schulman a, b, e,⁎, J. Schoenberg b, S. Divakara Menon c, A.C. Spyropoulos a, b, J.S. Healey d, J.W. Eikelboom a, b, d a
Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON, Canada Department of Medicine, Thrombosis Service, McMaster University, Hamilton, ON, Canada Arrhythmia Services, McMaster University, Hamilton, ON, Canada d Population Health Research Institute, McMaster University, Hamilton, ON, Canada e Karolinska Institute, Stockholm, Sweden b c
a r t i c l e
i n f o
Article history: Received 31 October 2012 Received in revised form 4 January 2013 Accepted 8 January 2013 Available online 29 January 2013 Keywords: Pacemaker Defibrillator Mechanical heart valve Mitral Aortic Anticoagulation
a b s t r a c t Background: In patients with a high risk for stroke and having invasive procedures with a high risk for bleeding it is unclear how anticoagulant therapy should be managed. Methods: We reviewed data from all patients with mechanical heart valves, who had elective insertion or replacement of pacemaker or implantable cardioverter defibrillator (ICD) during the past 8 years at our hospital. Data on anticoagulant treatment, pocket hematoma and thromboembolic complications were captured. Results: Of the 111 patients reviewed, 68 (61%) had a mechanical valve in the mitral position with or without other valves replaced and 43 (39%) had a mechanical valve only in the aortic position. Fifty-nine (53%) were undergoing replacement for their device. Six patients received a tapered warfarin regimen and 102 received preoperative bridging anticoagulation of whom 12 also received postoperative bridging. One stroke occurred 40 days after pacemaker replacement in a patient with mitral mechanical valve and without postoperative bridging. Six patients (5.5%) developed pocket hematoma without a significant association to postoperative bridging, type of mechanical valve or to type of device. Predictors for pocket hematoma appeared to be replacement surgery (odds ratio 12.5; 95% confidence interval [CI], 0.69-228) and an international normalized ratio of 1.5 or higher on the day of surgery (odds ratio 8.4; 95% CI, 0.96-68.1). Conclusion: We found a low risk for stroke in the absence of postoperative bridging. For patients with device replacement surgery reversal of the anticoagulant effect at the time of procedure might reduce the risk for pocket hematoma, but this requires prospective evaluation including the risk of thromboembolism. © 2013 Elsevier Ltd. All rights reserved.
Introduction Surgical procedures necessitating interruption of anticoagulant treatment require decisions on management that involve an assessment of the risk of thromboembolism versus the risk of bleeding. Despite the high frequency of invasive procedures in patients on anticoagulant therapy, estimated at 10% annually in North America, the quality of the evidence to guide decision-making is low [1]. There are no randomized studies to inform the clinician of when to use bridging anticoagulation versus only withholding oral anticoagulation temporarily. The epitome of the dilemma is in patients at high risk of thromboembolic complications having a procedure associated with a high risk of bleeding. Patients with mechanical heart valves are considered at high risk of thromboembolic events, particularly when the prosthetic valve is in the mitral position, where the blood flow is sluggish across the valve [2]. Insertion of pacemaker⁎ Corresponding author at: Thrombosis Service, HHS-General Hospital, 237 Barton Street East, Hamilton, ON, Canada L8L 2X2. Tel.: +1 905 5270271x44479; fax: +1 905 5211551. E-mail address: [email protected] (S. Schulman). 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.01.012
or implantable cardioverter defibrillator (ICD) devices is considered as a procedure associated with a high-risk for bleeding [1]. The dissection of infraclavicular layers without suturing explains the high risk of development of a pocket hematoma, and the risk is accentuated if a rapidly acting anticoagulant is introduced early after the procedure [3]. Although pocket hematoma is not a life-threatening complication, it is associated with an increased risk for infection that may require removal of the device, and an incremental cost of almost $7,000 [4]. Guidelines recommend stopping warfarin for 5 days before surgery [1] and recommence treatment in the evening following the procedure. This will leave the patient without effective anticoagulation for at least a week if no bridging anticoagulation is provided, or for at least 4 days if bridging is not given postoperatively. Although avoidance of postoperative anticoagulant can be expected to minimize the risk of pocket hematoma, it is unclear what consequences this strategy would have for patients at high risk of thromboembolism. The aim of this study was to review outcomes of all patients with mechanical mitral (it should thus say mechanical mitral heart valves) heart valves undergoing elective insertion or replacement of a pacemaker
S. Schulman et al. / Thrombosis Research 131 (2013) 300–303
or ICD at our institution. We report rates of stroke, systemic embolism and pocket hematoma according to different perioperative anticoagulation regimens. For comparison we also reviewed patients with mechanical aortic valves and the same surgery. A secondary objective was to assess the risk factors for development of pocket hematoma in these patients. Materials and Methods Consecutive patients with mechanical heart valves undergoing elective implantation of pacemaker or ICD during the period June 2004 to December 2011 were included. All patients were on chronic anticoagulation with warfarin; no other coumarin derivates were used. There were no exclusion criteria. All patients planned for device implantation and treated with anticoagulant drugs are identified by the Arrhythmia Service and referred preoperatively to the Thrombosis Service, both located at Hamilton Health Sciences-General Hospital. Since June 2004 all patients referred to Thrombosis Service for perioperative management for any invasive procedure have been entered into a computerized database. The Arrhythmia Service performs a follow-up at 2–3 weeks and then at regular intervals after implantation of a pacemaker or ICD. Occurrence of pocket hematoma or other complications is documented in the discharge note, in the clinic notes at follow-up or in telephone contact notes. There was no formal protocol for perioperative anticoagulant management during this period but the physicians at the Thrombosis Service routinely used low-molecular-weight heparin (LMWH), enoxaparin 1 mg/kg twice daily subcutaneously for bridging anticoagulation. For patients with a calculated creatinine clearance between 30 and 40–50 mL/min the LMWH was only given once daily and in case of a clearance below 30 mL/min unfractionated heparin (UFH) was used instead. For patients with previous heparin-induced thrombocytopenia we used fondaparinux. The timing of the last dose of LMWH or heparin before surgery and the decision to use post-operative bridging anticoagulation was at the discretion of the physician. Warfarin was stopped for 5 days before the surgery or for 6–7 days if the INR at the preoperative visit, which occurred 1 week before surgery, was higher than 3.0. In that case the number of days with preoperative bridging anticoagulation was also reduced to avoid unnecessary overlap. Local hemostatic agents are not used routinely for device implantation at our center. The cardiologists involved have performed 500–4000 device implantations each. We defined the subset of mechanical mitral valves as those with any type of artificial valve in that position and irrespective of additional mechanical valves in other positions. The subset of mechanical aortic valves was defined as any type of artificial valve in that position in the absence of an additional mechanical mitral valve. A pocket hematoma was defined as a palpable swelling of the device pocket exceeding the size of the generator and that required interruption of anticoagulation and/or additional Arrhythmia Service clinic visits. One of the authors (JS) reviewed all paper and electronic medical records for the included patients for the period from the preoperative visit at the Thrombosis Service until the 3-month follow-up at Arrhythmia Service and extracted data on patient characteristics, perioperative anticoagulation, surgical procedure, adverse events, and laboratory results. An additional author (SS) verified the occurrence of pocket hematoma. The Research Ethics Board approved the study as a retrospective chart review and waived the requirement for informed consent. Statistical Analyses A two-sided Mann–Whitney test was used for comparison of continuous variables with a skewed distribution (age, weight, CrCl) and Chi-square test or Fisher's exact test was used for categorical data.
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Results Overall 111 patients with mechanical heart valves and pacemaker/ ICD implantation were managed by us during the study period and included in the analysis. The patients were distributed evenly over the study period. The characteristics of the patients are shown in Table 1. The creatinine clearance was lower among patients with mechanical mitral valves compared to those with aortic valves (P= 0.036) and the proportion of females was lower among those with only mechanical aortic valves (Pb 0.001). Atrial fibrillation was present in 28% of the patients with similar proportion in the two groups. The characteristics of the surgery and the perioperative anticoagulant treatment are shown in Table 2. One patient with mechanical aortic valve was lost from follow-up regarding complications. None of the differences between the patients with mitral versus aortic mechanical valves or between the patients who did or did not receive postoperative bridging anticoagulation were statistically significant. The incidence of pocket hematoma did not appear to be increased in patients who received postoperative bridging anticoagulation (1 of 12; 8%) compared with those who received no bridging (5 of 99; 5%), but post-operative bridging was only used for a small number of patients (mitral valves 10; aortic valves 2). One patient with mechanical mitral valve was admitted with an ischemic stroke 45 days after her pacemaker replacement; she did not receive postoperative bridging anticoagulation. The INR was 2.4 on the day of admission with stroke. The only variables that seemed to be predictive of development of pocket hematoma were repeat pacemaker/ICD replacement surgery (odds ratio 12.5; 95% confidence interval [CI], 0.69 to 228) and an INR of 1.5 or higher on the day of the procedure (odds ratio 8.4; 95% CI, 0.96-68.1) (Table 3). In view of the small numbers of pocket hematomas (n = 6), tapered warfarin (n = 6), residual high INR (n = 14), last dose of LMWH in proximity to the surgery (n = 6), and postoperative bridging (n = 12) an adjusted analysis did not contribute additional information. Discussion The overall risk for pocket hematoma in our series of patients with mechanical heart valves and device implantation was relatively low
Table 1 Baseline characteristics of the patients according to postoperative anticoagulation strategy. Characteristic⁎ Mechanical mitral valves N Age –years Sex –females Body weight – kg Creatinine clearance – mL/min† Indication for anticoagulation Mechanical mitral valve alone Idem and atrial fibrillation Mechanical mitral and aortic valve Idem and atrial fibrillation Mechanical mitral, aortic and tricuspid valve Mechanical aortic valves N Age –years Sex –females Body weight – kg Creatinine clearance – mL/min† Indication for anticoagulation Mechanical aortic valve alone Idem and atrial fibrillation
No postop bridging
Postop bridging
All patients
58 71 28 77 62
(13) (48%) (26) (44)
10 70 (13) 6 (60%) 65 (18) 41 (39)
68 71 34 73 59
26 (45%) 11 (19%) 12 (21%) 7 (12%) 2 (4%)
6 (60%) 1 (10%) 1 (10%) 1 (10%) 1 (10%)
32 (47%) 12 (18%) 13 (19%) 8 (12%) 3 (4%)
41 70 (18) 5 (12%) 79 (24) 74 (41)
2 55 0 95 123
43 68 (20) 5 (12%) 80 (23) 75 (44)
30 (73%) 11 (27%)
2 (100%) 0
32 (74%) 11 (26%)
(12) (50%) (26) (47)
⁎ Results are median (interquartile range) or, for proportions, no. and (%). None of the differences between the two strategies are statistically significant. † Estimated with the Cockroft-Gault method.
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Table 2 Characteristics of the procedures and anticoagulant treatment. Mechanical mitral valves
Mechanical aortic valves
Characteristic⁎
No postop bridging
Postop bridging
All patients
No postop bridging
Postop bridging
All patients
N Pacemaker Defibrillator Left ventricle lead insertion/removal First insertion Repeat insertion Tapered warfarin, no bridging INR at time of procedure, median (range) Preoperative bridging anticoagulation Bridging with LMWH Bridging with UFH Bridging with fondaparinux Last preop dose LMWH/UFH 12 h Last preop dose LMWH/UFH 24 h Warfarin resumed Day 0 postop Warfarin resumed Day 1 postop Postop bridging started – days, median (range) Pocket hematoma
58 33 (57%) 23 (40%) 2 (3%) 23 (40%) 33 (57%) 3 (5%) 1.2 (1.0-2.1) 53 (91%) 49 (84%) 3 (5%) 1 (2%) 2 (4%) 49† (84%) 25 (32%) 33 (57%) NA 4 (7%)
10 6 (60%) 3 (30%) 1 (10%) 5 (50%) 4 (40%) NA 1.2 (1.0-1.9) 9 (90%) 7 (70%) 1 (10%) 1 (10%) 0 8‡ (80%) 6 (60%) 3 (30%) 1.5 (1–4) 1 (10%)
68 40 (59%) 25 (37%) 3 (4%) 28 (41%) 37 (54%) 3 (4%) 1.2 (1.0-2.1) 62 (91%) 56 (82%) 4 (6%) 2 (3%) 2 (3%) 57 (84%) 31 (46%) 36 (53%) NA 5 (7%)
41 22 (54%) 18 (44%) 1 (2%) 18 (44%) 22 (54%) 3 (7%) 1.2 (1.0-1.7) 38 (93%) 37 (90%) 1 (2%) 0 (0%) 3 (7%) 34 (83%) 13 (32%) 28 (68%) NA 1 (2%)
2 1 (50%) 0 1 (5%) 0 1 (50%) NA 1.1 (1.1-1.1) 2 (100%) 2 (100%) 0 (0%) 1 (50%) 1 (50%) 1 (50%) 2 (100%) 0 2 (1–3) 0
43 23 (53%) 18 (42%) 2 (5%) 18 (42%) 23 (53%) 3 (7%) 1.2 (1.0-1.7) 40 (93%) 39 (91%) 1 (2%) 1 (2%) 4 (9%) 35 (81%) 15 (35%) 27 (63%) NA 1 (2%)
INR - international normalized ratio; LMWH - low-molecular-weight heparin; UFH - unfractionated heparin. ⁎ Results are median (range) or, for proportions, number and (%). † Two additional patients were preadmitted with intravenous infusion of heparin, and two additional patients’ last dose was 72 h preop. ‡ One patient had the last dose 48 h before surgery.
(5.5%) but not negligible. We could not identify postoperative bridging anticoagulation as a risk factor but this strategy was only used in a minority (11%) of the patients. On the other hand, replacement compared with first ever pacemaker or ICD implantation and incomplete reversal of vitamin K antagonist therapy (INR ≥ 1.5) seemed to predict the development of pocket hematoma. Among the patients without postoperative bridging anticoagulation we observed only one stroke (1%), which occurred late after the surgery and the causality can be questioned. In a series of 556 patients with mechanical heart valves and any kind of invasive procedure Daniels et al. found a 3-month incidence of ischemic events of 0.9% and of major bleeding events of 3.6% [5]. They also failed to identify any association between postoperative bridging anticoagulation and either ischemic or bleeding complications. Conversely, in another study on 109 patients with mechanical heart valves undergoing pacemaker implantation Cheng et al. found an increased risk for pocket hematoma among patients with postoperative heparin treatment and also when warfarin was discontinued less than 3 days
Table 3 Characteristics of patients and treatment among those with or without pocket hematoma. Characteristic⁎
No pocket hematoma
Pocket hematoma
N Age –years Sex –females Body weight – kg Creatinine clearance – mL/min† Hypertension Diabetes mellitus Congestive heart failure Atrial fibrillation Pacemaker (vs. defibrillator) Repeat insertion INR at time of procedure INR ≥ 1.5 Preoperative bridging Postoperative bridging Warfarin resumption Day 0 (vs. Day 1) postop
104§ 68 (±11) 37 (36%) 78 (±18) 70 (±34) 49 (47%) 21 (20) 39 (38%) 45 (43%) 59 (57%) 53 (51%) 1.2 (±0.23) 11 (11%) 96 (92%) 11 (11%) 42 (40%)
6 70 (±10) 2 (33%) 66 (±12) 59 (±34) 3 (50%) 2 (33%) 3 (50%) 2 (33%) 2 (33%) 6 (100%) 1.4 (±0.35) 3 (50%) 5 (83%) 1 (17%) 4 (67%)
P-value
0.80 1.0 0.12 0.43 1.0 0.60 0.67 1.0 0.40 0.029 0.15 0.028 0.41 0.51 0.23
INR - international normalized ratio. ⁎ Results are mean (±standard deviation) or, for proportions, no. and (%). § Information on postoperative bleeding was missing for one patient.
before the procedure [6]. Others and we have previously reported incidences of pocket hematoma of 17-25% when postoperative LMWH was given to patients with any indication for warfarin therapy [3,7–11], but lower incidences despite postoperative heparin have been described (4%-10.7%) [12–15] and also a very high of 32% in patients with mechanical valves and heparin started 3 h after wound closure [16]. Thus, most of the evidence is supporting an increased risk of this complication with postoperative bridging anticoagulation. A reduced postoperative dose of LMWH (enoxaparin 1 mg/kg once daily) seemed to reduce the risk for hematoma (4.5%) [17]. A similar strategy with 70% of therapeutic dose LMWH for high thromboembolic risk-patients and only a prophylactic dose for moderate-low risk-patients for unselected invasive procedures also seemed effective and safe [18]. To our knowledge, replacement surgery for pacemakers or defibrillators has previously not been identified as a risk factor for pocket hematoma. Tischenko et al. found on the contrary a lower risk for pocket hematoma after replacement surgery than after a new implant [9]. It is, however, plausible that replacement surgery would carry a higher risk of hematoma formation since the dissection occurs in fibrous tissue with capillary bleeding as opposed to the new insertion in an avascular plane between muscle and skin. Almost all the replacements in our patients (95%) were into the old pocket. We did not identify an increased risk for ICD compared with pacemaker insertions or replacements, even though they are larger than pacemakers, but sometimes the pocket for a pacemaker is also widened to improve the position of the device. The increased risk for pocket hematoma with a residual warfarin effect, as seen in this study, is biologically plausible. Higher INR was also an independent predictor for pocket hematoma in our previous study of patients with mixed indications for anticoagulation [3]. Nevertheless, it seems to be a weak risk factor, since several studies of patients with device implantation and uninterrupted treatment with vitamin K antagonist reported a relatively low incidence of pocket hematoma of 0–8.0% [7,9,10,12,14,15,19–22]. Furthermore, the effect of INR was not statistically significant when analyzed in our material as a continuous variable. Dual antiplatelet therapy, which has been reported as a risk factor for bleeding complications after device therapy [11], was not used by any patient in our material. The thromboembolic events are rare and when they occur more than a month after the surgery the influence of other risk factors, e.g. poor management of anticoagulation with warfarin or thrombogenic effects from infection or subsequent procedures may confound the picture. It
S. Schulman et al. / Thrombosis Research 131 (2013) 300–303
is therefore more difficult to identify periprocedural risk factors for thromboembolism than for bleeding. In a retrospective analysis of over 3000 patients with device implantations Wiegand et al. reported 23 thromboembolic complications (0.7%) [13]. They could not identify any association between the dose of heparin and risk of stroke whereas there was a reduction of venous thromboembolism with high-dose heparin. In another retrospective analysis Ahmed et al. identified 4 events of transient ischemic attacks shortly after device implantation in 114 patients (3.5%), for whom anticoagulation was withheld [15]. In the study on mechanical valves by Cheng et al. 87 patients did not receive heparin after the device implantation and one of those, who also did not receive preoperative heparin and had subtherapeutic INR for several days, developed an embolic stroke 3 days after surgery [6]. When pooled with our data there were 2 strokes among 186 patients without postoperative bridging (1.1%). The International Society on Thrombosis and Haemostasis recommended recently that only events up to 30 days after surgery should be included in the analysis of safety and efficacy in bridging studies [23]. In that case the pooled event rate is 0.5%. This is similar to the incidence of 0.9% during a mean follow-up of 30 days as recently reported in a systematic review of 34 studies with over 7000 patients, who had interruption of a vitamin K antagonist and bridging anticoagulation with heparin for various procedures [24]. In conclusion, despite the perceived high risk of stroke or systemic embolism in patients with mechanical heart valves, the risk after device implantation is low and any evidence supporting the use of postoperative bridging anticoagulation to further reduce this risk is lacking. Conflict of Interest Statement The authors have no conflicts of interest in relation to this article. References [1] Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e326S–50S. [2] Hering D, Piper C, Bergemann R, Hillenbach C, Dahm M, Huth C, et al. Thromboembolic and bleeding complications following St. Jude medical valve replacement. Results of the German experience with low-intensity anticoagulation study Chest 2005;127:53–9. [3] Robinson M, Healey JS, Eikelboom J, Schulman S, Morillo CA, Nair GM, 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;32:378–82. [4] Reynolds MR, Cohen DJ, Kugelmass AD, Brown PP, Becker ER, Culler SD, et al. The frequency and incremental cost of major complications among medicare beneficiaries receiving implantable cardioverter-defibrillators. J Am Coll Cardiol 2006;47:2493–7. [5] Daniels PR, McBane RD, Litin SC, Ward SA, Hodge DO, Dowling NF, et al. Peri-procedural anticoagulation management of mechanical prosthetic heart valve patients. Thromb Res 2009;124:300–5. [6] Cheng M, Hua W, Chen K, Pu J, Ren X, Zhao X, et al. Perioperative anticoagulation for patients with mechanic heart valve(s) undertaking pacemaker implantation. Europace 2009;11:1183–7.
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[7] Michaud GF, Pelosi Jr F, 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;35:1915–8. [8] Milic DJ, Perisic ZD, Zivic SS, Stanojkovic ZA, Stojkovic AM, Karanovic ND, et al. Prevention of pocket related complications with fibrin sealant in patients undergoing pacemaker implantation who are receiving anticoagulant treatment. Europace 2005;7:374–9. [9] Tischenko A, Gula LJ, Yee R, Klein GJ, Skanes AC, Krahn AD. Implantation of cardiac rhythm devices without interruption of oral anticoagulation compared with perioperative bridging with low-molecular weight heparin. Am Heart J 2009;158: 252–6. [10] Cano O, Munoz B, Tejada D, Osca J, Sancho-Tello MJ, Olague J, et al. Evaluation of a new standardized protocol for the perioperative management of chronically anticoagulated patients receiving implantable cardiac arrhythmia devices. Heart Rhythm 2012;9:361–7. [11] Tompkins C, Cheng A, Dalal D, Brinker JA, Leng CT, Marine JE, et al. Dual antiplatelet therapy and heparin "bridging" significantly increase the risk of bleeding complications after pacemaker or implantable cardioverter-defibrillator device implantation. J Am Coll Cardiol 2010;55:2376–82. [12] Tolosana JM, Berne P, Mont L, Heras M, Berruezo A, Monteagudo J, 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;30:1880–4. [13] Wiegand UK, LeJeune D, Boguschewski F, Bonnemeier H, Eberhardt F, Schunkert H, et al. Pocket hematoma after pacemaker or implantable cardioverter defibrillator surgery: influence of patient morbidity, operation strategy, and perioperative antiplatelet/anticoagulation therapy. Chest 2004;126:1177–86. [14] Cheng A, Nazarian S, Brinker JA, Tompkins C, Spragg DD, Leng CT, et al. Continuation of warfarin during pacemaker or implantable cardioverter-defibrillator implantation: a randomized clinical trial. Heart Rhythm 2011;8:536–40. [15] Ahmed I, Gertner E, Nelson WB, House CM, Dahiya R, Anderson CP, et al. Continuing warfarin therapy is superior to interrupting warfarin with or without bridging anticoagulation therapy in patients undergoing pacemaker and defibrillator implantation. Heart Rhythm 2010;7:745–9. [16] Marquie C, De Geeter G, Klug D, Kouakam C, Brigadeau F, Jabourek O, et al. Post-operative use of heparin increases morbidity of pacemaker implantation. Europace 2006;8:283–7. [17] Hammerstingl C, Omran H. Perioperative bridging of chronic oral anticoagulation in patients undergoing pacemaker implantation–a study in 200 patients. Europace 2011;13:1304–10. [18] Pengo V, Cucchini U, Denas G, Erba N, Guazzaloca G, La Rosa L, et al. Standardized low-molecular-weight heparin bridging regimen in outpatients on oral anticoagulants undergoing invasive procedure or surgery: an inception cohort management study. Circulation 2009;119:2920–7. [19] al-Khadra AS. Implantation of pacemakers and implantable cardioverter defibrillators in orally anticoagulated patients. Pacing Clin Electrophysiol 2003;26:511–4. [20] Denman RA, Walters DL, Twidale N, Masterson ML. The implantation of permanent pacemakers and automatic implantable cardiac defibrillators in patients on warfarin. CSANZ 47 Annual Scientific Meeting; 1999 [www.csanz.edu.au/abstracts/47abstracts/ 041.doc.htm.]. [21] Giudici MC, Barold SS, Paul DL, Bontu P. Pacemaker and implantable cardioverter defibrillator implantation without reversal of warfarin therapy. Pacing Clin Electrophysiol 2004;27:358–60. [22] Goldstein DJ, Losquadro W, Spotnitz HM. Outpatient pacemaker procedures in orally anticoagulated patients. Pacing Clin Electrophysiol 1998;21:1730–4. [23] Spyropoulos AC, Douketis JD, Gerotziafas G, Kaatz S, Ortel TL, Schulman S. Periprocedural antithrombotic and bridging therapy: recommendations for standardized reporting in patients with arterial indications for chronic oral anticoagulant therapy. J Thromb Haemost 2012;10:692–4. [24] Siegal D, Yudin J, Kaatz S, Douketis JD, Lim W, Spyropoulos AC. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates. Circulation 2012;126:1630–9.
Contents lists available at SciVerse ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Anticoagulation management in patients with mechanical heart valves having pacemaker or defibrillator insertion S. Schulman a, b, e,⁎, J. Schoenberg b, S. Divakara Menon c, A.C. Spyropoulos a, b, J.S. Healey d, J.W. Eikelboom a, b, d a
Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON, Canada Department of Medicine, Thrombosis Service, McMaster University, Hamilton, ON, Canada Arrhythmia Services, McMaster University, Hamilton, ON, Canada d Population Health Research Institute, McMaster University, Hamilton, ON, Canada e Karolinska Institute, Stockholm, Sweden b c
a r t i c l e
i n f o
Article history: Received 31 October 2012 Received in revised form 4 January 2013 Accepted 8 January 2013 Available online 29 January 2013 Keywords: Pacemaker Defibrillator Mechanical heart valve Mitral Aortic Anticoagulation
a b s t r a c t Background: In patients with a high risk for stroke and having invasive procedures with a high risk for bleeding it is unclear how anticoagulant therapy should be managed. Methods: We reviewed data from all patients with mechanical heart valves, who had elective insertion or replacement of pacemaker or implantable cardioverter defibrillator (ICD) during the past 8 years at our hospital. Data on anticoagulant treatment, pocket hematoma and thromboembolic complications were captured. Results: Of the 111 patients reviewed, 68 (61%) had a mechanical valve in the mitral position with or without other valves replaced and 43 (39%) had a mechanical valve only in the aortic position. Fifty-nine (53%) were undergoing replacement for their device. Six patients received a tapered warfarin regimen and 102 received preoperative bridging anticoagulation of whom 12 also received postoperative bridging. One stroke occurred 40 days after pacemaker replacement in a patient with mitral mechanical valve and without postoperative bridging. Six patients (5.5%) developed pocket hematoma without a significant association to postoperative bridging, type of mechanical valve or to type of device. Predictors for pocket hematoma appeared to be replacement surgery (odds ratio 12.5; 95% confidence interval [CI], 0.69-228) and an international normalized ratio of 1.5 or higher on the day of surgery (odds ratio 8.4; 95% CI, 0.96-68.1). Conclusion: We found a low risk for stroke in the absence of postoperative bridging. For patients with device replacement surgery reversal of the anticoagulant effect at the time of procedure might reduce the risk for pocket hematoma, but this requires prospective evaluation including the risk of thromboembolism. © 2013 Elsevier Ltd. All rights reserved.
Introduction Surgical procedures necessitating interruption of anticoagulant treatment require decisions on management that involve an assessment of the risk of thromboembolism versus the risk of bleeding. Despite the high frequency of invasive procedures in patients on anticoagulant therapy, estimated at 10% annually in North America, the quality of the evidence to guide decision-making is low [1]. There are no randomized studies to inform the clinician of when to use bridging anticoagulation versus only withholding oral anticoagulation temporarily. The epitome of the dilemma is in patients at high risk of thromboembolic complications having a procedure associated with a high risk of bleeding. Patients with mechanical heart valves are considered at high risk of thromboembolic events, particularly when the prosthetic valve is in the mitral position, where the blood flow is sluggish across the valve [2]. Insertion of pacemaker⁎ Corresponding author at: Thrombosis Service, HHS-General Hospital, 237 Barton Street East, Hamilton, ON, Canada L8L 2X2. Tel.: +1 905 5270271x44479; fax: +1 905 5211551. E-mail address: [email protected] (S. Schulman). 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.01.012
or implantable cardioverter defibrillator (ICD) devices is considered as a procedure associated with a high-risk for bleeding [1]. The dissection of infraclavicular layers without suturing explains the high risk of development of a pocket hematoma, and the risk is accentuated if a rapidly acting anticoagulant is introduced early after the procedure [3]. Although pocket hematoma is not a life-threatening complication, it is associated with an increased risk for infection that may require removal of the device, and an incremental cost of almost $7,000 [4]. Guidelines recommend stopping warfarin for 5 days before surgery [1] and recommence treatment in the evening following the procedure. This will leave the patient without effective anticoagulation for at least a week if no bridging anticoagulation is provided, or for at least 4 days if bridging is not given postoperatively. Although avoidance of postoperative anticoagulant can be expected to minimize the risk of pocket hematoma, it is unclear what consequences this strategy would have for patients at high risk of thromboembolism. The aim of this study was to review outcomes of all patients with mechanical mitral (it should thus say mechanical mitral heart valves) heart valves undergoing elective insertion or replacement of a pacemaker
S. Schulman et al. / Thrombosis Research 131 (2013) 300–303
or ICD at our institution. We report rates of stroke, systemic embolism and pocket hematoma according to different perioperative anticoagulation regimens. For comparison we also reviewed patients with mechanical aortic valves and the same surgery. A secondary objective was to assess the risk factors for development of pocket hematoma in these patients. Materials and Methods Consecutive patients with mechanical heart valves undergoing elective implantation of pacemaker or ICD during the period June 2004 to December 2011 were included. All patients were on chronic anticoagulation with warfarin; no other coumarin derivates were used. There were no exclusion criteria. All patients planned for device implantation and treated with anticoagulant drugs are identified by the Arrhythmia Service and referred preoperatively to the Thrombosis Service, both located at Hamilton Health Sciences-General Hospital. Since June 2004 all patients referred to Thrombosis Service for perioperative management for any invasive procedure have been entered into a computerized database. The Arrhythmia Service performs a follow-up at 2–3 weeks and then at regular intervals after implantation of a pacemaker or ICD. Occurrence of pocket hematoma or other complications is documented in the discharge note, in the clinic notes at follow-up or in telephone contact notes. There was no formal protocol for perioperative anticoagulant management during this period but the physicians at the Thrombosis Service routinely used low-molecular-weight heparin (LMWH), enoxaparin 1 mg/kg twice daily subcutaneously for bridging anticoagulation. For patients with a calculated creatinine clearance between 30 and 40–50 mL/min the LMWH was only given once daily and in case of a clearance below 30 mL/min unfractionated heparin (UFH) was used instead. For patients with previous heparin-induced thrombocytopenia we used fondaparinux. The timing of the last dose of LMWH or heparin before surgery and the decision to use post-operative bridging anticoagulation was at the discretion of the physician. Warfarin was stopped for 5 days before the surgery or for 6–7 days if the INR at the preoperative visit, which occurred 1 week before surgery, was higher than 3.0. In that case the number of days with preoperative bridging anticoagulation was also reduced to avoid unnecessary overlap. Local hemostatic agents are not used routinely for device implantation at our center. The cardiologists involved have performed 500–4000 device implantations each. We defined the subset of mechanical mitral valves as those with any type of artificial valve in that position and irrespective of additional mechanical valves in other positions. The subset of mechanical aortic valves was defined as any type of artificial valve in that position in the absence of an additional mechanical mitral valve. A pocket hematoma was defined as a palpable swelling of the device pocket exceeding the size of the generator and that required interruption of anticoagulation and/or additional Arrhythmia Service clinic visits. One of the authors (JS) reviewed all paper and electronic medical records for the included patients for the period from the preoperative visit at the Thrombosis Service until the 3-month follow-up at Arrhythmia Service and extracted data on patient characteristics, perioperative anticoagulation, surgical procedure, adverse events, and laboratory results. An additional author (SS) verified the occurrence of pocket hematoma. The Research Ethics Board approved the study as a retrospective chart review and waived the requirement for informed consent. Statistical Analyses A two-sided Mann–Whitney test was used for comparison of continuous variables with a skewed distribution (age, weight, CrCl) and Chi-square test or Fisher's exact test was used for categorical data.
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Results Overall 111 patients with mechanical heart valves and pacemaker/ ICD implantation were managed by us during the study period and included in the analysis. The patients were distributed evenly over the study period. The characteristics of the patients are shown in Table 1. The creatinine clearance was lower among patients with mechanical mitral valves compared to those with aortic valves (P= 0.036) and the proportion of females was lower among those with only mechanical aortic valves (Pb 0.001). Atrial fibrillation was present in 28% of the patients with similar proportion in the two groups. The characteristics of the surgery and the perioperative anticoagulant treatment are shown in Table 2. One patient with mechanical aortic valve was lost from follow-up regarding complications. None of the differences between the patients with mitral versus aortic mechanical valves or between the patients who did or did not receive postoperative bridging anticoagulation were statistically significant. The incidence of pocket hematoma did not appear to be increased in patients who received postoperative bridging anticoagulation (1 of 12; 8%) compared with those who received no bridging (5 of 99; 5%), but post-operative bridging was only used for a small number of patients (mitral valves 10; aortic valves 2). One patient with mechanical mitral valve was admitted with an ischemic stroke 45 days after her pacemaker replacement; she did not receive postoperative bridging anticoagulation. The INR was 2.4 on the day of admission with stroke. The only variables that seemed to be predictive of development of pocket hematoma were repeat pacemaker/ICD replacement surgery (odds ratio 12.5; 95% confidence interval [CI], 0.69 to 228) and an INR of 1.5 or higher on the day of the procedure (odds ratio 8.4; 95% CI, 0.96-68.1) (Table 3). In view of the small numbers of pocket hematomas (n = 6), tapered warfarin (n = 6), residual high INR (n = 14), last dose of LMWH in proximity to the surgery (n = 6), and postoperative bridging (n = 12) an adjusted analysis did not contribute additional information. Discussion The overall risk for pocket hematoma in our series of patients with mechanical heart valves and device implantation was relatively low
Table 1 Baseline characteristics of the patients according to postoperative anticoagulation strategy. Characteristic⁎ Mechanical mitral valves N Age –years Sex –females Body weight – kg Creatinine clearance – mL/min† Indication for anticoagulation Mechanical mitral valve alone Idem and atrial fibrillation Mechanical mitral and aortic valve Idem and atrial fibrillation Mechanical mitral, aortic and tricuspid valve Mechanical aortic valves N Age –years Sex –females Body weight – kg Creatinine clearance – mL/min† Indication for anticoagulation Mechanical aortic valve alone Idem and atrial fibrillation
No postop bridging
Postop bridging
All patients
58 71 28 77 62
(13) (48%) (26) (44)
10 70 (13) 6 (60%) 65 (18) 41 (39)
68 71 34 73 59
26 (45%) 11 (19%) 12 (21%) 7 (12%) 2 (4%)
6 (60%) 1 (10%) 1 (10%) 1 (10%) 1 (10%)
32 (47%) 12 (18%) 13 (19%) 8 (12%) 3 (4%)
41 70 (18) 5 (12%) 79 (24) 74 (41)
2 55 0 95 123
43 68 (20) 5 (12%) 80 (23) 75 (44)
30 (73%) 11 (27%)
2 (100%) 0
32 (74%) 11 (26%)
(12) (50%) (26) (47)
⁎ Results are median (interquartile range) or, for proportions, no. and (%). None of the differences between the two strategies are statistically significant. † Estimated with the Cockroft-Gault method.
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Table 2 Characteristics of the procedures and anticoagulant treatment. Mechanical mitral valves
Mechanical aortic valves
Characteristic⁎
No postop bridging
Postop bridging
All patients
No postop bridging
Postop bridging
All patients
N Pacemaker Defibrillator Left ventricle lead insertion/removal First insertion Repeat insertion Tapered warfarin, no bridging INR at time of procedure, median (range) Preoperative bridging anticoagulation Bridging with LMWH Bridging with UFH Bridging with fondaparinux Last preop dose LMWH/UFH 12 h Last preop dose LMWH/UFH 24 h Warfarin resumed Day 0 postop Warfarin resumed Day 1 postop Postop bridging started – days, median (range) Pocket hematoma
58 33 (57%) 23 (40%) 2 (3%) 23 (40%) 33 (57%) 3 (5%) 1.2 (1.0-2.1) 53 (91%) 49 (84%) 3 (5%) 1 (2%) 2 (4%) 49† (84%) 25 (32%) 33 (57%) NA 4 (7%)
10 6 (60%) 3 (30%) 1 (10%) 5 (50%) 4 (40%) NA 1.2 (1.0-1.9) 9 (90%) 7 (70%) 1 (10%) 1 (10%) 0 8‡ (80%) 6 (60%) 3 (30%) 1.5 (1–4) 1 (10%)
68 40 (59%) 25 (37%) 3 (4%) 28 (41%) 37 (54%) 3 (4%) 1.2 (1.0-2.1) 62 (91%) 56 (82%) 4 (6%) 2 (3%) 2 (3%) 57 (84%) 31 (46%) 36 (53%) NA 5 (7%)
41 22 (54%) 18 (44%) 1 (2%) 18 (44%) 22 (54%) 3 (7%) 1.2 (1.0-1.7) 38 (93%) 37 (90%) 1 (2%) 0 (0%) 3 (7%) 34 (83%) 13 (32%) 28 (68%) NA 1 (2%)
2 1 (50%) 0 1 (5%) 0 1 (50%) NA 1.1 (1.1-1.1) 2 (100%) 2 (100%) 0 (0%) 1 (50%) 1 (50%) 1 (50%) 2 (100%) 0 2 (1–3) 0
43 23 (53%) 18 (42%) 2 (5%) 18 (42%) 23 (53%) 3 (7%) 1.2 (1.0-1.7) 40 (93%) 39 (91%) 1 (2%) 1 (2%) 4 (9%) 35 (81%) 15 (35%) 27 (63%) NA 1 (2%)
INR - international normalized ratio; LMWH - low-molecular-weight heparin; UFH - unfractionated heparin. ⁎ Results are median (range) or, for proportions, number and (%). † Two additional patients were preadmitted with intravenous infusion of heparin, and two additional patients’ last dose was 72 h preop. ‡ One patient had the last dose 48 h before surgery.
(5.5%) but not negligible. We could not identify postoperative bridging anticoagulation as a risk factor but this strategy was only used in a minority (11%) of the patients. On the other hand, replacement compared with first ever pacemaker or ICD implantation and incomplete reversal of vitamin K antagonist therapy (INR ≥ 1.5) seemed to predict the development of pocket hematoma. Among the patients without postoperative bridging anticoagulation we observed only one stroke (1%), which occurred late after the surgery and the causality can be questioned. In a series of 556 patients with mechanical heart valves and any kind of invasive procedure Daniels et al. found a 3-month incidence of ischemic events of 0.9% and of major bleeding events of 3.6% [5]. They also failed to identify any association between postoperative bridging anticoagulation and either ischemic or bleeding complications. Conversely, in another study on 109 patients with mechanical heart valves undergoing pacemaker implantation Cheng et al. found an increased risk for pocket hematoma among patients with postoperative heparin treatment and also when warfarin was discontinued less than 3 days
Table 3 Characteristics of patients and treatment among those with or without pocket hematoma. Characteristic⁎
No pocket hematoma
Pocket hematoma
N Age –years Sex –females Body weight – kg Creatinine clearance – mL/min† Hypertension Diabetes mellitus Congestive heart failure Atrial fibrillation Pacemaker (vs. defibrillator) Repeat insertion INR at time of procedure INR ≥ 1.5 Preoperative bridging Postoperative bridging Warfarin resumption Day 0 (vs. Day 1) postop
104§ 68 (±11) 37 (36%) 78 (±18) 70 (±34) 49 (47%) 21 (20) 39 (38%) 45 (43%) 59 (57%) 53 (51%) 1.2 (±0.23) 11 (11%) 96 (92%) 11 (11%) 42 (40%)
6 70 (±10) 2 (33%) 66 (±12) 59 (±34) 3 (50%) 2 (33%) 3 (50%) 2 (33%) 2 (33%) 6 (100%) 1.4 (±0.35) 3 (50%) 5 (83%) 1 (17%) 4 (67%)
P-value
0.80 1.0 0.12 0.43 1.0 0.60 0.67 1.0 0.40 0.029 0.15 0.028 0.41 0.51 0.23
INR - international normalized ratio. ⁎ Results are mean (±standard deviation) or, for proportions, no. and (%). § Information on postoperative bleeding was missing for one patient.
before the procedure [6]. Others and we have previously reported incidences of pocket hematoma of 17-25% when postoperative LMWH was given to patients with any indication for warfarin therapy [3,7–11], but lower incidences despite postoperative heparin have been described (4%-10.7%) [12–15] and also a very high of 32% in patients with mechanical valves and heparin started 3 h after wound closure [16]. Thus, most of the evidence is supporting an increased risk of this complication with postoperative bridging anticoagulation. A reduced postoperative dose of LMWH (enoxaparin 1 mg/kg once daily) seemed to reduce the risk for hematoma (4.5%) [17]. A similar strategy with 70% of therapeutic dose LMWH for high thromboembolic risk-patients and only a prophylactic dose for moderate-low risk-patients for unselected invasive procedures also seemed effective and safe [18]. To our knowledge, replacement surgery for pacemakers or defibrillators has previously not been identified as a risk factor for pocket hematoma. Tischenko et al. found on the contrary a lower risk for pocket hematoma after replacement surgery than after a new implant [9]. It is, however, plausible that replacement surgery would carry a higher risk of hematoma formation since the dissection occurs in fibrous tissue with capillary bleeding as opposed to the new insertion in an avascular plane between muscle and skin. Almost all the replacements in our patients (95%) were into the old pocket. We did not identify an increased risk for ICD compared with pacemaker insertions or replacements, even though they are larger than pacemakers, but sometimes the pocket for a pacemaker is also widened to improve the position of the device. The increased risk for pocket hematoma with a residual warfarin effect, as seen in this study, is biologically plausible. Higher INR was also an independent predictor for pocket hematoma in our previous study of patients with mixed indications for anticoagulation [3]. Nevertheless, it seems to be a weak risk factor, since several studies of patients with device implantation and uninterrupted treatment with vitamin K antagonist reported a relatively low incidence of pocket hematoma of 0–8.0% [7,9,10,12,14,15,19–22]. Furthermore, the effect of INR was not statistically significant when analyzed in our material as a continuous variable. Dual antiplatelet therapy, which has been reported as a risk factor for bleeding complications after device therapy [11], was not used by any patient in our material. The thromboembolic events are rare and when they occur more than a month after the surgery the influence of other risk factors, e.g. poor management of anticoagulation with warfarin or thrombogenic effects from infection or subsequent procedures may confound the picture. It
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is therefore more difficult to identify periprocedural risk factors for thromboembolism than for bleeding. In a retrospective analysis of over 3000 patients with device implantations Wiegand et al. reported 23 thromboembolic complications (0.7%) [13]. They could not identify any association between the dose of heparin and risk of stroke whereas there was a reduction of venous thromboembolism with high-dose heparin. In another retrospective analysis Ahmed et al. identified 4 events of transient ischemic attacks shortly after device implantation in 114 patients (3.5%), for whom anticoagulation was withheld [15]. In the study on mechanical valves by Cheng et al. 87 patients did not receive heparin after the device implantation and one of those, who also did not receive preoperative heparin and had subtherapeutic INR for several days, developed an embolic stroke 3 days after surgery [6]. When pooled with our data there were 2 strokes among 186 patients without postoperative bridging (1.1%). The International Society on Thrombosis and Haemostasis recommended recently that only events up to 30 days after surgery should be included in the analysis of safety and efficacy in bridging studies [23]. In that case the pooled event rate is 0.5%. This is similar to the incidence of 0.9% during a mean follow-up of 30 days as recently reported in a systematic review of 34 studies with over 7000 patients, who had interruption of a vitamin K antagonist and bridging anticoagulation with heparin for various procedures [24]. In conclusion, despite the perceived high risk of stroke or systemic embolism in patients with mechanical heart valves, the risk after device implantation is low and any evidence supporting the use of postoperative bridging anticoagulation to further reduce this risk is lacking. Conflict of Interest Statement The authors have no conflicts of interest in relation to this article. References [1] Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e326S–50S. [2] Hering D, Piper C, Bergemann R, Hillenbach C, Dahm M, Huth C, et al. Thromboembolic and bleeding complications following St. Jude medical valve replacement. Results of the German experience with low-intensity anticoagulation study Chest 2005;127:53–9. [3] Robinson M, Healey JS, Eikelboom J, Schulman S, Morillo CA, Nair GM, 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;32:378–82. [4] Reynolds MR, Cohen DJ, Kugelmass AD, Brown PP, Becker ER, Culler SD, et al. The frequency and incremental cost of major complications among medicare beneficiaries receiving implantable cardioverter-defibrillators. J Am Coll Cardiol 2006;47:2493–7. [5] Daniels PR, McBane RD, Litin SC, Ward SA, Hodge DO, Dowling NF, et al. Peri-procedural anticoagulation management of mechanical prosthetic heart valve patients. Thromb Res 2009;124:300–5. [6] Cheng M, Hua W, Chen K, Pu J, Ren X, Zhao X, et al. Perioperative anticoagulation for patients with mechanic heart valve(s) undertaking pacemaker implantation. Europace 2009;11:1183–7.
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