Safety of Expedited Anticoagulation in Patients Undergoing Transesophageal Echocardiographic-guided Cardioversion

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1 The American Journal of Medicine (2006) 119, CLINICAL RESEARCH STUDY Safety of Expedited Anticoagulation in Patients Undergoing Transesophageal Echocardiographic-guided Cardioversion Lambert A. Wu, MD, a Krishnaswamy Chandrasekaran, MD, a Paul A. Friedman, MD, a Naser M. Ammash, MD, a Gautam Ramakrishna, MD, a Chari Y. T. Hart, MD, a Brenda S. Moon, RN, a Regina M. Herges, BS, b A. Gabriela Rosales, MS, b Joseph F. Malouf, MD a a Division of Cardiovascular Diseases and b Division of Biostatistics, Mayo Clinic, Rochester, Minn. ABSTRACT BACKGROUND: In patients undergoing transesophageal echocardiography-guided cardioversion, we evaluated the use and safety of an expedited in-hospital anticoagulation regimen that incorporates shorterthan-standard durations of precardioversion intravenous unfractionated heparin and postcardioversion bridging therapy with a low-molecular-weight heparin. METHODS: Adult patients who underwent successful transesophageal echocardiography-guided cardioversion for atrial fibrillation or atrial flutter between May 2000 and August 2003 were classified into 2 groups by duration of intravenous unfractionated heparin therapy ( 24hor 24 h) before transesophageal echocardiography and cardioversion. Safety end points evaluated included all-cause death, stroke or other thromboembolic events, and major bleeding complications within 1 month after successful cardioversion. RESULTS: The study population of 386 patients included 199 (52%) who received expedited intravenous unfractionated heparin ( 24 h; minimum duration, 4 h) and 193 patients (50%) who were discharged on low-molecular-weight heparin therapy. The adverse event rates at 1-month follow-up were not significantly different between the 2 unfractionated heparin patient groups, and the rate of stroke among patients dismissed on low-molecular-weight heparin was less than 1%. No adverse events occurred among patients who received intravenous unfractionated heparin for less than 12 hours and who were dismissed on low-molecular-weight heparin bridging therapy. CONCLUSIONS: The use of an expedited heparin anticoagulation regimen in patients with atrial fibrillation or atrial flutter undergoing transesophageal echocardiography-guided cardioversion appears to be safe. Cardioversion can be performed as early as a few hours after initiation of intravenous unfractionated heparin, and bridging therapy with a low-molecular-weight heparin can be used after cardioversion until the international normalized ratio is therapeutic Elsevier Inc. All rights reserved. KEYWORDS: Cardioversion; Low-molecular-weight heparin; Transesophageal echocardiography Requests for reprints should be addressed to Joseph F. Malouf, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN address: maalouf.youssef@mayo.edu. The minimum safe duration of intravenous unfractionated heparin before transesophageal echocardiography-guided cardioversion of atrial fibrillation or flutter remains unresolved and has ranged from 1 to 4 days in the published reports. 1-4 Moreover, recent studies have reported safe transesophageal echocardiography-guided cardioversion using low-molecular-weight heparin in lieu of intravenous intravenous unfractionated heparin. 5,6 Here, we report a single-center experience with the use and safety of an expedited in-hospital anticoagulation regimen that incorporates 24 hours of precardioversion intravenous unfractionated heparin and, after successful cardioversion, bridging therapy with low-molecular-weight heparin in lieu of intravenous unfractionated heparin in patients with subtherapeutic international normalized ratios (INRs) /$ -see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.amjmed

2 Wu et al Expedited Pericardioversion Anticoagulation 143 METHODS We retrospectively identified all adult patients who underwent successful transesophageal echocardiography-guided cardioversion of atrial fibrillation or atrial flutter between May 2000 and August Successful cardioversion was defined as sinus rhythm, documented in the clinical record or by electrocardiography, upon discharge from the hospital. For inclusion in the study, eligible patients had to fulfill all of the following conditions: 1) atrial fibrillation or atrial flutter for more than 48 hours or for an unknown duration, 2) initiation of intravenous unfractionated heparin before transesophageal echocardiography-guided cardioversion, and 3) either no warfarin treatment or, if on warfarin, a subtherapeutic INR at initiation of intravenous unfractionated heparin therapy. Patients who underwent cardioversion for postoperative atrial fibrillation or atrial flutter and patients who did not give authorization for their medical records to be used were excluded. Study patients were classified into two groups on the basis of CLINICAL SIGNIFICANCE duration of intravenous unfractionated heparin therapy before transesophageal echocardiography-guided cardioversion; Group 1 (standard) received intravenous unfractionated heparin for 24 hours or more and Group 2 (expedited) received unfractionated heparin for 24 hours. To determine the safety of transesophageal echocardiographyguided cardioversion in patients who received only a few hours of precardioversion intravenous unfractionated heparin, Group 2 patients were further stratified into three groups by duration of unfractionated heparin administration: Group 2a, 4 h; Group 2b, 4hto 12 h; and Group 2c, 12 h to 24 h. Follow-up data were obtained by review of the patient s medical records or by mailed questionnaire. The study was approved by the Mayo Foundation Institutional Review Board, and all patients provided informed consent. Therapeutic anticoagulation, in practice, may be achieved very rapidly after initiation of intravenous unfractionated heparin. For patients undergoing transesophageal echocardiography-guided cardioversion of atrial fibrillation, shorter-than-standard duration of precardioversion intravenous heparin administration in not associated with increased risk of postcardioversion embolism. Low-molecular-weight heparin bridging therapy after successful cardioversion is not associated with a significant increase in adverse events compared with the standard approach. Anticoagulation Protocol A weight-based intravenous heparin-dosing nomogram was used to determine heparin dose for each patient. Warfarin therapy was initiated concurrently with intravenous unfractionated heparin therapy. After cardioversion, patients with a subtherapeutic INR received either intravenous unfractionated heparin or low-molecular-weight heparin until the INR was therapeutic. 2,3 The treating physician chose the mode of postcardioversion bridging heparin therapy (unfractionated heparin or low-molecular-weight heparin). Warfarin treatment was continued for at least 1 month after cardioversion. Patients who were discharged home on an low-molecular-weight heparin regimen received either ardeparin (130 units/kg, twice daily), dalteparin (200 units/ kg, as a single daily dose for patients weighing 90 kg and in two divided doses for patients weighing 90 kg), or enoxaparin (1 mg/ kg, twice daily). The dose of lowmolecular-weight heparin was adjusted for patients with renal failure. Study End Points To compare the safety of the different anticoagulation regimens, adverse event rates were determined for each patient group. Safety outcome measures included all-cause deaths, strokes (embolic or hemorrhagic), transient ischemic attacks, peripheral embolic events, and major bleeding complications occurring within 1 month after transesophageal echocardiographyguided cardioversion. Major bleeding complications included intracerebral hemorrhage, a decrease ( 2 mg/dl) in the hemoglobin concentration from baseline, transfusion of red blood cells, or bleeding resulting in death. Statistical Analysis The median and interquartile range are reported for continuous variables, and the number and percentage are reported for categorical variables. Continuous data were compared among the 4 groups with the Kruskal-Wallis test, and the Wilcoxon rank sum test was used for comparisons between 2 groups. Categorical data were compared across groups with the chi-squared test. Because of few events, we were unable to estimate the univariate and multivariate associations of the study end points with clinical, precardioversion intravenous unfractionated heparin anticoagulation, and cardioversion variables. P values.05 were considered statistically significant. RESULTS During the study period, 386 patients fulfilled all inclusion criteria. Two-thirds of patients were in atrial fibrillation, and cardioversion was performed with biphasic waveforms in 90% of patients (Table 1). At the time of cardioversion, 165 patients (43%) were not receiving warfarin and 221 patients (57%) were receiving subtherapeutic doses of the drug. One hundred ninety-nine patients (52%) received intravenous

3 144 The American Journal of Medicine, Vol 119, No 2, February 2006 Table 1 Anticoagulation and cardioversion data Variable All (n 386) Group 1 (n 187) Patients* Group 2a (n 39) Group 2b (n 26) Group 2c (n 134) P value Prestudy anticoagulation INR pre-tee 1.1 (1.0,1.3) 1.1 (1.0,1.3) 1.2 (1.0,1.6) 1.1 (1.0,1.4) 1.1 (1.0,1.2).17 Warfarin 221 (57) 122 (65) 15 (38) 8 (31) 76 (57).001 Clopidogrel 15 (4) 13 (7) 1 (3) 0 1 (0.7).02 Aspirin 215 (56) 109 (58) 20 (51) 11 (42) 75 (56).44 TEE findings LA or LAA SEC 168 (52) 84 (55) 16 (52) 9 (41) 59 (50).63 (n 323) (n 153) (n 31) (n 22) (n 117) Peak LAA v, cm/s 40 (27,55) 39 (25,54) 40 (32,57) 49 (30,69) 39 (25,53).29 (n 287) (n 126) (n 31) (n 20) (n 110) Peak LAA v 20 cm/s 134 (36) 74 (41) 12 (31) 8 (31) 40 (30).18 (n 376) (n 179) (n 132) LVEF, % 55 (40,60) 55 (40,60) 60 (45,60) 60 (50,60) 55 (35,60).34 (n 378) (n 181) (n 38) (n 133) Mode of electrical cardioversion.86 Monophasic 36 (9) 17 (9) 4 (10) 1 (4) 14 (10) Biphasic 346 (90) 167 (89) 35 (90) 25 (96) 119 (89) Via ICD 4 (1) 3 (2) (1) LMWH therapy on dismissal 193 (50) 76 (41) 28 (72) 17 (65) 72 (54).001 ICD implantable cardioverter-defibrillator; INR international normalized ratio; LA left atrium; LAA left atrial appendage; LAA v LAA velocity; LMWH low-molecular-weight heparin; LVEF left ventricular ejection fraction; SEC spontaneous echocontrast; TEE transesophageal echocardiography; UFH unfractionated heparin. *Values are median (interquartile range) or number of patients (percentage). Patient subgroups defined by duration of intravenous UFH before cardioversion. Group 1, UFH 24 h; Group 2a, UFH 4 h; Group 2b, 4hto 12 h; and Group 2c, 12 h to 24 h. unfractionated heparin for 24 hours (Group 2). The duration of pre-transesophageal echocardiography intravenous unfractionated heparin was 12 hours in 65 patients (17%). A total of 193 patients (50%) were discharged on lowmolecular-weight heparin therapy (153 with dalteparin, 31 with enoxaparin, 7 with ardeparin, and 2 not specified). Most patients (367, 95%) had a follow-up visit at 1 month. Baseline clinical characteristics, including age, prevalence of atrial fibrillation or atrial flutter, and history of hypertension, coronary artery disease, congestive heart failure, cerebrovascular accident/transient ischemic attack, or diabetes mellitus, were not significantly different between Groups 1 and 2. No difference was seen at the time of cardioversion in echocardiographic surrogates of increased risk of thromboembolism (mean of peak left atrial appendage-emptying velocities, peak left atrial appendage velocity 20 cm/s, or presence of left atrial or left atrial appendage spontaneous echocontrast activity) (Table 1). 2-5 Group 1 patients, however, had greater use of warfarin and clopidogrel. Significantly more patients in Groups 2a and 2b were dismissed on low-molecular-weight heparin bridging therapy (P.001). Compared with patients not receiving lowmolecular-weight heparin, those receiving low-molecularweight heparin were relatively younger, had a lower prevalence of coronary artery disease, and had relatively better left ventricular and left atrial appendage contractility before cardioversion (Table 2). Nonetheless, their median age was 71 years, and 28% had severely diminished left atrial appendage contractility (peak left atrial appendage velocity 20 cm/s). At 1-month follow-up, there were no significant differences in the safety outcome measures between the patient groups (Table 3). No adverse events occurred among the 45 patients who received intravenous unfractionated heparin for 12 hours (Groups 2a and 2b) and who were dismissed on bridging therapy with low-molecular-weight heparin. DISCUSSION In the present report, shorter-than-standard duration of precardioversion intravenous unfractionated heparin was not associated with a significant increase in risk of postcardioversion embolism. Moreover, no adverse events occurred among patients who received intravenous unfractionated heparin for 12 hours and who were dismissed on lowmolecular-weight heparin bridging therapy. Heres et al 7 showed that the onset of action of unfractionated heparin after a large intravenous bolus was almost immediate, and Raschke et al 8 found that in 86% of patients a therapeutic threshold was achieved on the first activated partial thromboplastin time (aptt) measured 6

4 Wu et al Expedited Pericardioversion Anticoagulation 145 Table 2 Clinical, anticoagulation, and cardioversion data by LMWH therapy Patients* Variable No LMWH (n 193) LMWH on dismissal (n 193) P value Clinical history Age, y 74 (65,82) 71 (61,78).01 AF 136 (70) 126 (65).28 Atrial flutter 58 (30) 67 (35).33 Hypertension 113 (59) 101 (52).24 CHF 66 (34) 51 (26).08 CVA/TIA 31 (16) 28 (15).70 Diabetes mellitus 46 (24) 31 (16).06 CAD 73 (38) 50 (26).01 Prestudy anticoagulation Warfarin 119 (62) 102 (53).08 Clopidogrel 11 (6) 4 (2).07 Aspirin 108 (56) 107 (55).92 TEE findings LA or LAA SEC 86 (53)(n 161) 82 (51)(n 162).61 Peak LAA v, cm/s 36 (24,52)(n 138) 42 (30,56)(n 149).03 Peak LAA v 20 cm/s 81 (43)(n 190) 53 (28)(n 186).004 LVEF, % 50 (35,60)(n 187) 55 (45,60)(n 191).02 Mode of electrical cardioversion.94 Monophasic 17 (9) 19 (10) Biphasic 174 (90) 172 (89) Via ICD 2 (1) 2 (1) AF atrial fibrillation; CAD coronary artery disease; CHF congestive heart failure; CVA cerebrovascular accident; ICD implantable cardioverter-defibrillator; LA left atrium; LAA left atrial appendage; LAA v LAA velocity; LMWH low-molecular-weight heparin; LVEF left ventricular ejection fraction; SEC spontaneous echocontrast; TEE transesophageal echocardiography; TIA transient ischemic attack. *Values are median (interquartile range) or number of patients (percentage). P values determined with the 2 test unless otherwise noted. P value determined with the Wilcoxon rank sum test. hours after initiation of a weight-based dose of intravenous heparin. Transesophageal echocardiography-guided cardioversion can therefore be safely performed within hours of initiation of intravenous unfractionated heparin and possibly immediately after a large bolus injection, provided therapeutic aptt levels have been achieved. Two reports 5,6 showed that use of the low-molecularweight heparin enoxaparin both before and after transesophageal echocardiography-guided cardioversion is as safe as conventional therapy with intravenous unfractionated heparin. However, patients were a select low-risk group in one study 5 and cardioversion was performed 1 to Table 3 Outcomes within 1 month after cardioversion by patient group and by LMWH therapy Event Patients* P value All (n 386) Group 1 (n 187) Group 2a (n 39) Group 2b (n 26) Group 2c (n 134) Death 2 (0.5) 2 (1.1) Stroke or systemic embolism 1 (0.3) (0.7).60 Major bleeding 2 (0.5) 1 (0.5) (0.7).92 No LMWH (n 193) LMWH on dismissal (n 193) Death 2 (1) 0.16 Stroke or systemic embolism 0 1 (0.5).32 Major bleeding 1 (0.5) 1 (0.5).99 LMWH low-molecular-weight heparin; UFH unfractionated heparin. *Values are number of events (percentage). Patient subgroups defined by duration of intravenous UFH before cardioversion. Group 1, UFH 24 h; Group 2a, UFH 4 h; Group 2b, 4hto 12 h; and Group 2c, 12 h to 24 h. Deaths not related to cardioversion. Six days postcardioversion; INR, 2.8. One day postcardioversion; INR, 2.

5 146 The American Journal of Medicine, Vol 119, No 2, February days after a thrombus-negative transesophageal echocardiography in the other. 6 Low-molecular-weight heparin provides rapid and reliable anticoagulation levels that do not need to be checked Moreover, because low-molecular-weight heparin is given subcutaneously, it can be self-administered. With these evolving anticoagulation regimens, transesophageal echocardiography-guided cardioversion should become an entirely outpatient procedure with potential for substantial cost savings. 12 Although low-molecular-weight heparin therapy in the present study may have been prescribed preferentially to patients at lower risk for postcardioversion embolism, our data support an expedited anticoagulation approach. The vast majority of patients in our study underwent biphasic waveform cardioversion. Whether the lower energy levels associated with biphasic waveform cardioversion decrease the severity of atrial stunning, and consequently the risk of postcardioversion embolism, remains to be determined. Study Limitations The present study had several limitations. The study was retrospective and underpowered for the groups of patients who received 4 hours and 12 hours of intravenous unfractionated heparin. Postcardioversion warfarin and low-molecularweight heparin therapy were not monitored in all patients. All decisions about individual patient treatment were made at the discretion of the treating physician, thus potentially introducing a treatment bias. Nonetheless, the study population is representative of normal practice in a high-volume referral center, and high-risk patients were not excluded. CONCLUSION Our results indicate that expedited pericardioversion heparin anticoagulation therapy in patients with atrial fibrillation or atrial flutter undergoing transesophageal echocardiography-guided cardioversion is probably safe. Brief pre-transesophageal echocardiography intravenous unfractionated heparin therapy can be used to rapidly achieve a therapeutic aptt, and outpatient low-molecular-weight heparin bridging therapy can be given until the INR is therapeutic. References 1. Manning WJ, Silverman DI, Gordon SP, Krumholz HM, Douglas PS. Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med. 1993;328: Silverman DI, Manning WJ. Role of echocardiography in patients undergoing elective cardioversion of atrial fibrillation. Circulation. 1998;98: Klein AL, Grimm RA, Murray RD, et al, Assessment of Cardioversion Using Transesophageal Echocardiography Investigators. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med. 2001;344: Klein AL, Murray RD, Grimm RA. Role of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation. J Am Coll Cardiol. 2001;37: Roijer A, Eskilsson J, Olsson B. Transoesophageal echocardiographyguided cardioversion of atrial fibrillation or flutter: selection of a low-risk group for immediate cardioversion. Eur Heart J. 2000;21: Stellbrink C, Nixdorff U, Hofmann T, et al, ACE (Anticoagulation in Cardioversion using Enoxaparin) Study Group. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of throboembolic complications in cardioversion of nonvalvular atrial fibrillation: the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial. Circulation Mar 2;109: Epub 2004 Feb Heres EK, Speight K, Benckart D, Marquez J, Gravlee GP. The clinical onset of heparin is rapid. Anesth Analg. 2001;92: Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a standard care nomogram: a randomized controlled trial. Ann Intern Med. 1993;119: Weitz JI. Low-molecular-weight heparins. N Engl J Med. 1997;337: Erratum in: N Engl J Med. 1997;337: Levine M, Gent M, Hirsh J, et al. A comparison of low-molecularweight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334: Koopman MM, Prandoni P, Piovella F, et al, The Tasman Study Group.Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med. 1996;334: Erratum in: N Engl J Med. 1997;337: Murray RD, Deitcher SR, Shah A, et al. Potential clinical efficacy and cost benefit of a transesophageal echocardiography-guided low-molecular-weight heparin (enoxaparin) approach to antithrombotic therapy in patients undergoing immediate cardioversion from atrial fibrillation. J Am Soc Echocardiogr. 2001;14: