Atrial Fibrillation in Patients Undergoing Liver TransplantationdA Single-Center Experience A. Vannuccia, R. Rathora, N. Vachharajanib, W. Chapmanb, and I. Kangrgaa,* Departments of aAnesthesiology and bSurgery, Washington University School of Medicine, St Louis, Missouri
ABSTRACT Background. As the prevalence of atrial fibrillation rises with age and older patients increasingly receive transplants, the perioperative management of this common arrhythmia and its impact on outcomes in liver transplantation is of relevance. Methods. Retrospective review of 757 recipients of liver transplantation from January 2002 through December 2011. Results. Nineteen recipients (2.5%) had documented pre-transplantation atrial fibrillation. Sixteen patients underwent liver and 3 a combined liver-kidney transplantation. Three patients died within 30 days (84.2% 1-month survival) and another 3 within 1 year of transplantation (68.4% 1-year survival). Compared with patients without atrial fibrillation, the relative risk of death in the atrial fibrillation group was 5.29 at 1 month (P ¼ .0034; 95% confidence interval [CI], 1.73e16.18) and 3.28 at 1 year (P ¼ .0008; 95% CI, 1.63e6.59). Time to extubation and intensive care unit (ICU) and hospital readmissions were not different from the control cohort. Rapid ventricular response requiring treatment occurred in 4 patients during surgery and 7 after surgery, resulting in 3 ICU and 3 hospital readmissions. Conclusions. The results suggest that patients with atrial fibrillation may be at increased risk of mortality after liver transplantation. Optimization of medical therapy may decrease ICU and hospital readmission due to rapid ventricular response.
P
ATIENTS 50 years are the fastest growing age group of liver transplant (LT) recipients [1]. More than 70% (4,473) of 6,341 patients who received LT in the United States in 2011 were 50 years old and almost 12% (745) were 65 years oldda 2-fold increase from 2001 (6.5%, 339 of 5,195 patients) [1]. Although elderly patients have good perioperative outcomes, this cohort also has an increased risk of cardiovascular comorbidities, primarily hypertension, coronary artery disease, and arrhythmias [2,3]. If these trends continue, more LT candidates will be at risk of atrial fibrillation (AF) [4e7]. AF is the most common sustained cardiac arrhythmia in Europe and the United States, with a prevalence of 1%e2% in the general population [4,8,9]. AF prevalence increases with age, ranging from 0.5% in the 6th decade to almost 9% in octogenarians [10]. Similar trends have been reported in other parts of the world [11]. AF has been reported as a complication of LT [12e16], and a recent retrospective study suggests that patients with
preexisting AF may have worse patient and graft survivals after LT [17]. We report our institutional experience with 19 patients with a preoperative diagnosis of AF who received either liver or combined liver-kidney transplants. METHODS Selection and Description of Participants This was a retrospective cohort study evaluating the outcomes of adult LT recipients with documented pre-transplantation AF. After Institutional Review Board approval, we reviewed the records of patients who underwent LT at our institution from January 1, 2002, to December 31, 2011. We included patients who presented with a documented preoperative diagnosis of AF.
*Address correspondence to Ivan Kangrga, MD, PhD, 660 S Euclid Ave, Box 8054, St Louis, MO 63110. E-mail: kangrgai@ anest.wustl.edu
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2014.02.020
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
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Transplantation Proceedings, 46, 1432e1437 (2014)
ATRIAL FIBRILLATION IN LIVER TRANSPLANT RECIPIENTS The classification of AF is based on the temporal pattern of occurrence, as summarized in the 2011 updated guidelines for management of patients with AF [4]. AF that self-terminates within 7 days is designated as paroxysmal, and when sustained beyond 7 days it is designated as persistent. Persistent AF that continues for >1 year, if cardioversion has failed or has been deemed to be unadvisable, is classified as permanent [4].
Patient Management All LT candidates were evaluated and managed by a dedicated multidisciplinary team that included 4 LT surgeons and 6 anesthesiologists. In all cases surgery was performed with balanced general anesthesia and the use of the piggyback technique with a portacaval shunt. In combined liver-kidney transplantations, the LT was completed first. All organs were harvested from brain-dead donors. All patients were monitored with the use of an arterial line and a pulmonary artery catheter except for 1 in whom transesophageal echocardiography was used.
Data Collection and Analysis Data were collected from electronic and paper medical records. Patient characteristics included age at the time of transplantation, sex, diagnosis, Model for End-Stage Liver Disease (MELD) score, and body mass index (BMI). The CHADS2 index [18] was calculated based on the data collected at presentation for transplantation. Risk factors for AF, including coronary artery disease, mitral regurgitation, mitral stenosis, left atrial enlargement, chronic obstructive pulmonary disease, and obstructive sleep apnea, were reviewed [19]. Pharmacologic and interventional treatments for AF were identified. Intraoperative hemodynamic data, including the initial rate and rhythm, baseline cardiac index, maximum and minimum heart rate, intraoperative rhythm change and interventions, were obtained from the anesthetic record. Serial blood tests obtained during transplant included arterial blood gas, complete blood cell count, prothrombin time, partial thromboplastin time, fibrinogen, thromboelastogram, and Ddimers. Postoperative management data, including time to extubation, intensive care unit (ICU) and hospital length of stay, 30-day and 1year patient and graft survivals, postoperative rhythm change, and 30-day readmission for AF, were collected. Where indicated, parameters are represented as median or mean SD. Relative risk ratio was calculated to compare the risk of death in the AF versus non-AF groups.
RESULTS Patients
Out of 757 patients who had liver or combined liver-kidney transplantation from 2002 to 2011, 19 (2.5%) had documented pre-transplantation AF. The mean age was 57.9 6.8 years. Thirteen patients were male (68.4%), and 6 (31.6%) were female. Five patients (26.3%) were obese (BMI > 30 kg/m2). The average MELD score was 23.5 10.1. Indications for LT were alcoholic cirrhosis (31.6%), hepatitis C (10.5%), alcoholic cirrhosis in conjunction with hepatitis C (26.3%), cryptogenic cirrhosis (10.5%), nonalcoholic steatohepatitis (10.5%), amyloidosis (5.3%), and
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a-1 antitrypsin deficiency (5.3%). Four patients (21.1%) also had a diagnosis of hepatocellular carcinoma. Three patients underwent combined liver-kidney transplantation. Patients with AF were not statistically different from other LT recipients at our institution regarding sex, BMI, MELD score, cold ischemia time, warm ischemia time, donor age, diabetes mellitus, creatinine >2 mg/dL, retransplantation, and donation after cardiac death. There was a small but statistically significant difference in age between the 2 groups (P < .05): Patients with AF were older (57.9 6.8 y) than all LT recipients (53.4 9.9 y). Atrial Fibrillation Risk Factors and Treatment
Table 1 summarizes types, risk factors, and preoperative management of AF in the study group. Eight patients had a CHADS2 score [18] of 2. Of those, 4 were on aspirin and/or warfarin. None of the nineteen patients had documented stroke or transient ischemic attack. Five patients had a history of coronary artery disease. Coronary reserve was assessed in all patients with the use of either nuclear or dobutamine stress testing as part of the transplantation evaluation. Four patients had positive Table 1. Atrial Fibrillation (AF) Preoperative Type, Risk Factors, and Treatment, n AF type Paroxysmal Persistent Permanent CHADS2 score 0 1 2 Preoperative management Antiarrhythmic Beta-blocker Digoxin Amiodarone Anticoagulant Aspirin Warfarin Intervention Cardioversion Ablation Pacemaker Preoperative echocardiography Mitral regurgitation Mitral stenosis Left atrial enlargement Diastolic dysfunction Stress test Negative Positive
9 3 7 7 4 8 11* 8 4 5 5† 3 3 6 3 1 3 13‡ 2 13 9x 15 4
*Three patients on beta-blocker and amiodarone; 3 patients on beta-blocker and digoxin. † One patient on aspirin and warfarin. ‡ Twelve patients with mild mitral regurgitation; 1 patient with mild-moderate mitral regurgitation. x Assessment of diastolic function unavailable in 5 patients.
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Table 2. Intraoperative Hemodynamics and Interventions, n Initial rhythm NSR AF Paced Intraoperative rhythm change AF to NSR NSR to atrial flutter AF to paced NSR to AF to NSR NSR to paced to NSR Intraoperative interventions Antiarrhythmic Beta-blocker Amiodarone Calcium channel blocker Cardioversion
Table 3. Postoperative Management and Outcomes, n
10 8 1 1 1 1 1 1 4* 4 1 1 1
Abbreviations: AF, atrial fibrillation; NSR, normal sinus rhythm. *One patient received beta-blocker and calcium channel blocker. One patient received beta-blocker and amidoarone.
stress tests but no significant disease according to coronary angiography. One patient had previous multiple coronary stents with recommendations for medical management. One patient had mitral stenosis, treated with the use of commissurotomy w30 years before. Calculated valve area on transthoracic echo was 1.65 cm2 according to planimetry and 1.25 cm2 according to pressure halftime, corresponding to mild or moderate mitral stenosis, respectively. Eleven patients were treated with 1 antiarrhythmic agents (Table 1). No patients were on calcium channel blockers or statins. Three patients had ventricular pacemakers placed to prevent bradycardia induced by the antiarrhythmic treatment. Intraoperative Course
On presentation to transplantation, 8 patients (42.1%) were in AF (6 permanent and 2 persistent), 10 (52.6%) were in sinus rhythm, and 1 (5.3%) was paced (Table 2). All patients with AF presented with adequate rate control (heart rates 100 beats/min). Intraoperative rhythm change occurred in 3 patients: One patient with permanent AF converted to normal sinus rhythm (NSR) after treatment of rapid ventricular rate with esmolol and diltiazem, and 2 patients with paroxysmal AF presented in NSR and developed atrial flutter or AF. The latter patient required esmolol, amiodarone, and eventually cardioversion to restore NSR. Three patients were paced during surgery: One patient was paced continuously and 2 others required intermittent ventricular pacing via the implanted pacemaker owing to bradycardia. Ten patients received antifibrinolytics (6 aminocaproic acid, 4 tranexamic acid) based on clinical presentation and point-of-care tests. Compared with the control group, AF patients received more cryoprecipitate during surgery (1.1 2.2 compared with 0.5 1.0; P ¼ .02). Transfusion of red blood cells, fresh
Extubation Postoperative day 0 Postoperative day 1 Postoperative day >1 Mean SD (d) Median length of stay (d) ICU Hospital Postoperative troponin elevation Postoperative rhythm change NSR to AF Atrial flutter to AF NSR to AF to NSR AF treatment Antiarrhythmic Beta-blocker Digoxin Amiodarone Calcium channel blocker Anticoagulant Aspirin Warfarin Interventional cardioversion Readmission for AF with rapid ventricular rate ICU Hospital Rhythm at discharge NSR AF Paced Survival 30 d, n (%) 1 y, n (%)
10 6 3* 0.9 1.7 2 8 10† 3 1 1 12‡ 7 5 4 1 15x 12 6 1 3 3 9 7 2 16 (84.2%) 13 (68.4%)
Abbreviations: ICU, intensive care unit; other abbreviations as in Table 2. *One patient never extubated: tracheostomy done on postoperative day 13. † Postoperative troponin not available in 1 patient. ‡ One patient on beta-blocker and amiodarone; 3 patients on beta-blocker and digoxin; 1 patient on amiodarone and digoxin. x Three patients on aspirin and warfarin.
frozen plasma, and platelets was similar between groups (P values .96, .76, and .74, respectively). Postoperative Course
Ten patients were extubated on the day of transplantation: 6 in the operating room and 4 in the ICU (Table 3). Another 6 patients were extubated within 24 hours. The median ICU stay for both AF and control groups was 2 days (AF interquartile range [IQR], 2e6 days; control IQR, 1e4 days). In the AF group, 3 patients had prolonged ICU stays owing to pulmonary edema and rapid ventricular rate, multiorgan failure, and respiratory failure. Median hospital stay was not different between the 2 groups: 8 versus 7 days in AF and control, respectively. Troponin I levels were checked after surgery in all LT recipients routinely, and 10 patients had elevated levels. Nine peaked within 48 hours after surgery and 1 on postoperative day (POD) 5. Because there were no associated clinical symptoms or electrocardiographic (ECG) or
ATRIAL FIBRILLATION IN LIVER TRANSPLANT RECIPIENTS
echocardiographic (ECHO) evidence of myocardial ischemia, patients were managed medically. Five patients had a postoperative rhythm change before discharge; 3 required readmission to the ICU because of recurrence of AF with rapid ventricular rate within 1 week after transplantation. All 3 patients eventually converted to NSR. Three patients were readmitted to the hospital for AF with rapid ventricular response within 3 weeks after transplantation. In each case, adequate rate control was achieved and maintained by increasing the dose of beta-blockers or digoxin. At the time of discharge, more patients were on an antiplatelet agent, coumarin, and digoxin than at admission. Three patients (15.8%) died within 30 days after transplantation. One patient was readmitted to the hospital on POD 15 for septic shock. An exploratory laparotomy revealed hepatic artery thrombosis and hepatojejunostomy breakdown. Autopsy was declined. One patient expired on POD 16 in the emergency department with pulseless electrical activity. Autopsy showed acute myocardial infarction. One patient had a cardiac arrest after discharge and died on POD 17. Thirty-day survival in the AF group was significantly lower than in the non-AF group (84.2% vs 97.1%; P ¼ .0065). The relative risk of death at 1 month in the AF versus non-AF group was 5.29 (P ¼ .0034; 95% confidence interval [CI], 1.73e16.18). Another 3 patients died within 1 year of transplant, resulting in overall 68.4% 1-year survival. Two patients died from liver failure 8 and 11 months after transplant. One patient died on POD 70 without leaving the hospital. A complicated postoperative course included several episodes of AF and rapid ventricular rate, sepsis, and multiorgan failure. Serial transthoracic echocardiography consistently confirmed preoperatively diagnosed mild-to-moderate mitral stenosis and preserved systolic function. Unexpectedly, the autopsy revealed severe mitral stenosis. Additional findings of extensive liver necrosis, secondary to a low-flow state, and diffuse alveolar damage, were consistent with a contributory role of unrecognized severe mitral stenosis in the demise of this patient. The 1-year survival in the AF group was significantly lower than in the non-AF group (68.4% vs 90.4%; P ¼ .011). The relative risk of death at 1 year in the AF versus non-AF group was 3.28 (P ¼ .0008; 95% CI, 1.63e6.59). DISCUSSION
In cardiac surgery, preoperative AF is considered to be an independent risk factor for early and late postoperative mortality [20]. Diastolic dysfunction, a condition that may be associated with AF [21,22], has been identified as an independent predictor of heart failure and worse outcomes after LT [23], but the direct link between AF and LT outcomes has not been clearly established. A recent retrospective study was the first to suggest that patients with AF undergoing LT are at increased risk for perioperative
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cardiac events [17]. The present study attempted to assess the impact of preoperative AF on perioperative management and LT outcomes in a large American transplant center. We compared the AF group to all non-AF patients undergoing transplantation in our center; the 2 groups did not appear to differ except for a small difference in age, with AF patients being older. In our institution, AF has not been considered to be an absolute contraindication for LT. The prevalence of AF in our cohort (2.5%) was similar to that in general population in the USA [4]. In contrast, a recent retrospective study of patients on the LT waiting list [24] reported lower prevalence of AF, hypothesizing a protective effect of cirrhosis. Our results, as well as those recently reported by Bargehr et al [17], do not support that hypothesis. The principal finding of the present study is a higher mortality of AF recipients at 1 month and 1 year after LT. We can not draw firm conclusions whether AF is an independent risk factor or a marker of overall poor physical status. Based on clinical presentation, it appears that 3 of the 6 deceased patients died of cardiac causes. Two cardiac mortalities occurred within 30 days of transplant. The third cardiac mortality occurred on POD 70; autopsy supported the role of severe mitral stenosis in that patient’s death. Ten patients had increased postoperative troponin levels. Myocardial infarction was ruled out based on clinical presentation and noninvasive tests (ECG, ECHO), and patients were managed medically. Five of the 10 patients died, 2 within 30 days and 3 within 1 year. These data suggest that postoperative troponin release in LT recipients may have a prognostic value. This hypothesis is consistent with findings in noncardiac surgery, where increased postoperative release of troponin is an independent prognostic factor of all-cause 1-year mortality [25]. There was no difference between the AF and non-AF patients in time to extubation, ICU and hospital stay, or readmissions. It is interesting to note that 3 out of 7 patients who developed post-LT rapid ventricular response were readmitted to the hospital within 30 days after surgery. Management of AF was optimized with titration of rate-controlling agents. It is possible that the pretransplantation antiarrhythmic regimens became subtherapeutic due to increased metabolism as a result of improved liver function. This suggests that inadequate ventricular rate control is a significant post-LT complication in patients with AF that requires additional interventions, including hospital readmission. The intraoperative AF management goal was rate control; conversion to NSR was undesirable because of the potential for embolic complications. However, 1 of the 8 patients who presented to transplantation in AF converted to NSR during surgery after the rapid ventricular rate was treated with diltiazem and esmolol infusion. No embolic complications were evident clinically. The rhythm reverted to AF after surgery. In retrospect, it may be argued that administration of esmolol was a suboptimal choice, because beta-blockers are
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associated with higher rate of conversion to NSR [26]. Alternatives to beta-blockers include digoxin and amiodarone. Digoxin does not require dose adjustment in liver impairment unless renal dysfunction is present, but its toxicity is potentiated by electrolyte imbalance. Concerns regarding amiodarone in patients with end-stage liver disease (ESLD) are prolonged QT interval, ventricular arrhythmias [27e29], and rare acute severe hepatic necrosis [15]. Although amiodarone’s limited negative effect on inotropy and systemic vascular resistance render it an attractive choice for intraoperative management of AF, in our study it was used only once during surgery to treat rapid ventricular response in a patient with paroxysmal AF. Another unresolved issue in managing ESLD patients with AF is the absence of evidence-based guidelines for the assessment and management of anticoagulation in this patient group [4]. The CHADS2 score is used to stratify the annual risk of stroke in patients with nonvalvular AF and to guide antithrombotic therapy [18]. Current recommendation for antithrombotic therapy in patients with CHADS2 score of 0 is no treatment or aspirin; in those with score of 1, aspirin or warfarin (goal of international normalized ratio [INR] 2-3); and in patients with CHADS2 score of 2 or those with mitral stenosis, warfarin (goal INR 2-3) [4]. Eight patients in our study had a CHADS2 score of 2, but only 3 patients were on warfarin. The preoperative INRs were below the suggested protected range in 3 patients [4]. An alternative to warfarin, dabigatran etexilate, a direct thrombin inhibitor, was included in the 2011 American Heart Association guidelines but not available during the study period. Recent North American and European guidelines recommend avoiding dabigatran in patients with advanced liver disease [30,31]. Interpretation of INR in ESLD patients on warfarin can be complicated. INR prolongation can be due to either drug effect or liver synthetic dysfunction, and it is recognized that prolonged INR in ESLD may be associated with preserved coagulation or even hypercoagulability [32]. This latter concept suggests that patients with ESLD often do not receive antithrombotic therapy per general guidelines owing to a perceived increased risk of bleeding [26]. This is also evident in our patients that were possibly undertreated; despite the recommendations for universal treatment of patients with AF with aspirin, 4 patients with CHADS2 score of 1 were on no prophylaxis. In these 4 patients, coagulopathy due to deteriorating liver function was cited as the reason for withholding treatment. Despite the varying approaches to managing anticoagulation, none of the 19 patients in our study had a clinically evident thromboembolic event. At discharge, more patients were on aspirin and/or warfarin then before surgery. The decision to implement an antithrombotic regimen per guidelines [4] was likely in part motivated by the recovery of liver metabolic function. Ten patients received intraoperative antifibrinolytics based on clinical presentation and laboratory-confirmed fibrinolysis. Interestingly, 8 of these 10 patients had
VANNUCCI, RATHOR, VACHHARAJANI ET AL
elevated postoperative troponin levels. The safety of prophylactic intraoperative use of antifibrinolytics in patients with AF is unknown. Although our numbers are too small to make any conclusions, patients with AF are at increased risk for forming intracardiac thrombi, and we think that antifibrinolytics should be used only therapeutically, based on point-of-care testing, and not prophylactically. The main limitations of the present study are its retrospective nature and the small number of AF patients. Furthermore, the patient data spanned a decade during which time the preoperative evaluation criteria for and intraoperative management of LT as well as therapeutic approaches to treating AF evolved. The 2 main findings of this retrospective analysis are the association of AF with increased post-LT mortality and with post-LT rapid ventricular response. The latter occurred in approximately one-third of the patients and resulted in ICU and hospital readmissions and additional diagnostic and pharmacologic interventions. To confirm the association of AF with decreased post-LT survival and identify best practices in managing patients with AF presenting for LT, more data and multicenter approaches are needed. REFERENCES [1] Organ Procurement and Transplantation Network. Scientific Registry of Transplant Recipients annual data report 2012. Available at: http://optn.transplant.hrsa.gov/latestData/rptData.asp. [2] Aloia TA, Knight R, Gaber AO, Ghobrial RM, Goss JA. Analysis of liver transplant outcomes for United Network for Organ Sharing recipients 60 years old or older identifies multiple model for end-stage liver disease-independent prognostic factors. Liver Transpl 2010;16:950e9. [3] Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statisticsd2012 update: a report from the American Heart Association. Circulation 2012;125:e2e220. [4] Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:e269e367. [5] Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001;285:2370e5. [6] Piccini JP, Hammill BG, Sinner MF, Jensen PN, Hernandez AF, Heckbert SR, et al. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007. Circ Cardiovasc Qual Outcomes 2012;5:85e93. [7] Rich MW. Epidemiology of atrial fibrillation. J Interv Card Electrophysiol 2009;25:3e8. [8] Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31: 2369e429. [9] Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and
ATRIAL FIBRILLATION IN LIVER TRANSPLANT RECIPIENTS implications on the projections for future prevalence. Circulation 2006;114:119e25. [10] Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82(8A): 2Ne9N. [11] Lip GY, Brechin CM, Lane DA. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. Chest 2012;142(6):1489e98. [12] Fouad TR, Abdel-Razek WM, Burak KW, Bain VG, Lee SS. Prediction of cardiac complications after liver transplantation. Transplantation 2009;87:763e70. [13] Sakai T, Planinsic RM, Hilmi IA, Marsh JW. Complications associated with percutaneous placement of venous return cannula for venovenous bypass in adult orthotopic liver transplantation. Liver Transpl 2007;13:961e5. [14] Chung M, Muntyan I. Atrial fibrillation during veno-venous bypass for orthotopic liver transplantation. J Clin Anesth 2011;23: 428e9. [15] von Vital JM, Karachristos A, Singhal A, Thomas R, Jain A. Acute amiodarone hepatotoxicity after liver transplantation. Transplantation 2011;91(8):e62e4. [16] Huang CJ, Chen CL, Wang CS, Cheng KW, Chen KH, Wang CC, et al. Rhabdomyolysis after liver transplantation: a case report. Transplant Proc 2008;40:2821e2. [17] Bargehr J, Trejo-Gutierrez JF, Rosser BG, Patel T, Yataco ML, Pungpapong S, et al. Liver transplantation in patients with atrial fibrillation. Transplant Proc 2013;45:2302e6. [18] Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864e70. [19] Indik JH, Alpert JS. The patient with atrial fibrillation. Am J Med 2009;122:415e8. [20] Saxena A, Dinh D, Dimitriou J, Reid C, Smith J, Shardey G, et al. Preoperative atrial fibrillation is an independent risk factor for mid-term mortality after concomitant aortic valve replacement and coronary artery bypass graft surgery. Interact Cardiovasc Thorac Surg 2013;16:488e94. [21] Rosenberg MA, Manning WJ. Diastolic dysfunction and risk of atrial fibrillation: a mechanistic appraisal. Circulation 2012;126: 2353e62.
1437 [22] Kosiuk J, Breithardt O, Bode K, Kornej J, Arya A, Gaspar T, et al. Left ventricular diastolic dysfunction and thromboembolic risk in atrial fibrillation: diastolic dysfunction and thromboembolic risk in AF. Int J Cardiol; 2013. [23] Dowsley TF, Bayne DB, Langnas AN, Dumitru I, Windle JR, Porter TR, et al. Diastolic dysfunction in patients with end-stage liver disease is associated with development of heart failure early after liver transplantation. Transplantation 2012;94: 646e51. [24] Zamirian M, Sarmadi T, Aghasadeghi K, Kazemi MB. Liver cirrhosis prevents atrial fibrillation: A reality or just an illusion? J Cardiovasc Dis Res 2012;3:109e12. [25] Levy M, Heels-Ansdell D, Hiralal R, Bhandari M, Guyatt G, Yusuf S, et al. Prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurement after noncardiac surgery: a systematic review and meta-analysis. Anesthesiology 2011;114:796e806. [26] Rosenman MB, Simon TA, Teal E, McGuire P, Nisi D, Jackson JD. Perceived or actual barriers to warfarin use in atrial fibrillation based on electronic medical records. Am J Ther 2012;19: 330e7. [27] di Micoli A, Zambruni A, Bracci E, Benazzi B, Zappoli P, Berzigotti A, et al. “Torsade de pointes” during amiodarone infusion in a cirrhotic woman with a prolonged QT interval. Dig Liver Dis 2009;41:535e8. [28] Zimetbaum P. Amiodarone for atrial fibrillation. N Engl J Med 2007;356:935e41. [29] Bernardi M, Maggioli C, Dibra V, Zaccherini G. QT interval prolongation in liver cirrhosis: innocent bystander or serious threat? Expert Rev Gastroenterol Hepatol 2012;6:57e66. [30] Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes 3rd NA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011;57:223e42. [31] de Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, et al. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on ThrombosiseTask Force on Anticoagulants in Heart Disease position paper. J Am Coll Cardiol 2012;59:1413e25. [32] Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011;365:147e56.
ABSTRACT Background. As the prevalence of atrial fibrillation rises with age and older patients increasingly receive transplants, the perioperative management of this common arrhythmia and its impact on outcomes in liver transplantation is of relevance. Methods. Retrospective review of 757 recipients of liver transplantation from January 2002 through December 2011. Results. Nineteen recipients (2.5%) had documented pre-transplantation atrial fibrillation. Sixteen patients underwent liver and 3 a combined liver-kidney transplantation. Three patients died within 30 days (84.2% 1-month survival) and another 3 within 1 year of transplantation (68.4% 1-year survival). Compared with patients without atrial fibrillation, the relative risk of death in the atrial fibrillation group was 5.29 at 1 month (P ¼ .0034; 95% confidence interval [CI], 1.73e16.18) and 3.28 at 1 year (P ¼ .0008; 95% CI, 1.63e6.59). Time to extubation and intensive care unit (ICU) and hospital readmissions were not different from the control cohort. Rapid ventricular response requiring treatment occurred in 4 patients during surgery and 7 after surgery, resulting in 3 ICU and 3 hospital readmissions. Conclusions. The results suggest that patients with atrial fibrillation may be at increased risk of mortality after liver transplantation. Optimization of medical therapy may decrease ICU and hospital readmission due to rapid ventricular response.
P
ATIENTS 50 years are the fastest growing age group of liver transplant (LT) recipients [1]. More than 70% (4,473) of 6,341 patients who received LT in the United States in 2011 were 50 years old and almost 12% (745) were 65 years oldda 2-fold increase from 2001 (6.5%, 339 of 5,195 patients) [1]. Although elderly patients have good perioperative outcomes, this cohort also has an increased risk of cardiovascular comorbidities, primarily hypertension, coronary artery disease, and arrhythmias [2,3]. If these trends continue, more LT candidates will be at risk of atrial fibrillation (AF) [4e7]. AF is the most common sustained cardiac arrhythmia in Europe and the United States, with a prevalence of 1%e2% in the general population [4,8,9]. AF prevalence increases with age, ranging from 0.5% in the 6th decade to almost 9% in octogenarians [10]. Similar trends have been reported in other parts of the world [11]. AF has been reported as a complication of LT [12e16], and a recent retrospective study suggests that patients with
preexisting AF may have worse patient and graft survivals after LT [17]. We report our institutional experience with 19 patients with a preoperative diagnosis of AF who received either liver or combined liver-kidney transplants. METHODS Selection and Description of Participants This was a retrospective cohort study evaluating the outcomes of adult LT recipients with documented pre-transplantation AF. After Institutional Review Board approval, we reviewed the records of patients who underwent LT at our institution from January 1, 2002, to December 31, 2011. We included patients who presented with a documented preoperative diagnosis of AF.
*Address correspondence to Ivan Kangrga, MD, PhD, 660 S Euclid Ave, Box 8054, St Louis, MO 63110. E-mail: kangrgai@ anest.wustl.edu
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2014.02.020
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
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Transplantation Proceedings, 46, 1432e1437 (2014)
ATRIAL FIBRILLATION IN LIVER TRANSPLANT RECIPIENTS The classification of AF is based on the temporal pattern of occurrence, as summarized in the 2011 updated guidelines for management of patients with AF [4]. AF that self-terminates within 7 days is designated as paroxysmal, and when sustained beyond 7 days it is designated as persistent. Persistent AF that continues for >1 year, if cardioversion has failed or has been deemed to be unadvisable, is classified as permanent [4].
Patient Management All LT candidates were evaluated and managed by a dedicated multidisciplinary team that included 4 LT surgeons and 6 anesthesiologists. In all cases surgery was performed with balanced general anesthesia and the use of the piggyback technique with a portacaval shunt. In combined liver-kidney transplantations, the LT was completed first. All organs were harvested from brain-dead donors. All patients were monitored with the use of an arterial line and a pulmonary artery catheter except for 1 in whom transesophageal echocardiography was used.
Data Collection and Analysis Data were collected from electronic and paper medical records. Patient characteristics included age at the time of transplantation, sex, diagnosis, Model for End-Stage Liver Disease (MELD) score, and body mass index (BMI). The CHADS2 index [18] was calculated based on the data collected at presentation for transplantation. Risk factors for AF, including coronary artery disease, mitral regurgitation, mitral stenosis, left atrial enlargement, chronic obstructive pulmonary disease, and obstructive sleep apnea, were reviewed [19]. Pharmacologic and interventional treatments for AF were identified. Intraoperative hemodynamic data, including the initial rate and rhythm, baseline cardiac index, maximum and minimum heart rate, intraoperative rhythm change and interventions, were obtained from the anesthetic record. Serial blood tests obtained during transplant included arterial blood gas, complete blood cell count, prothrombin time, partial thromboplastin time, fibrinogen, thromboelastogram, and Ddimers. Postoperative management data, including time to extubation, intensive care unit (ICU) and hospital length of stay, 30-day and 1year patient and graft survivals, postoperative rhythm change, and 30-day readmission for AF, were collected. Where indicated, parameters are represented as median or mean SD. Relative risk ratio was calculated to compare the risk of death in the AF versus non-AF groups.
RESULTS Patients
Out of 757 patients who had liver or combined liver-kidney transplantation from 2002 to 2011, 19 (2.5%) had documented pre-transplantation AF. The mean age was 57.9 6.8 years. Thirteen patients were male (68.4%), and 6 (31.6%) were female. Five patients (26.3%) were obese (BMI > 30 kg/m2). The average MELD score was 23.5 10.1. Indications for LT were alcoholic cirrhosis (31.6%), hepatitis C (10.5%), alcoholic cirrhosis in conjunction with hepatitis C (26.3%), cryptogenic cirrhosis (10.5%), nonalcoholic steatohepatitis (10.5%), amyloidosis (5.3%), and
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a-1 antitrypsin deficiency (5.3%). Four patients (21.1%) also had a diagnosis of hepatocellular carcinoma. Three patients underwent combined liver-kidney transplantation. Patients with AF were not statistically different from other LT recipients at our institution regarding sex, BMI, MELD score, cold ischemia time, warm ischemia time, donor age, diabetes mellitus, creatinine >2 mg/dL, retransplantation, and donation after cardiac death. There was a small but statistically significant difference in age between the 2 groups (P < .05): Patients with AF were older (57.9 6.8 y) than all LT recipients (53.4 9.9 y). Atrial Fibrillation Risk Factors and Treatment
Table 1 summarizes types, risk factors, and preoperative management of AF in the study group. Eight patients had a CHADS2 score [18] of 2. Of those, 4 were on aspirin and/or warfarin. None of the nineteen patients had documented stroke or transient ischemic attack. Five patients had a history of coronary artery disease. Coronary reserve was assessed in all patients with the use of either nuclear or dobutamine stress testing as part of the transplantation evaluation. Four patients had positive Table 1. Atrial Fibrillation (AF) Preoperative Type, Risk Factors, and Treatment, n AF type Paroxysmal Persistent Permanent CHADS2 score 0 1 2 Preoperative management Antiarrhythmic Beta-blocker Digoxin Amiodarone Anticoagulant Aspirin Warfarin Intervention Cardioversion Ablation Pacemaker Preoperative echocardiography Mitral regurgitation Mitral stenosis Left atrial enlargement Diastolic dysfunction Stress test Negative Positive
9 3 7 7 4 8 11* 8 4 5 5† 3 3 6 3 1 3 13‡ 2 13 9x 15 4
*Three patients on beta-blocker and amiodarone; 3 patients on beta-blocker and digoxin. † One patient on aspirin and warfarin. ‡ Twelve patients with mild mitral regurgitation; 1 patient with mild-moderate mitral regurgitation. x Assessment of diastolic function unavailable in 5 patients.
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Table 2. Intraoperative Hemodynamics and Interventions, n Initial rhythm NSR AF Paced Intraoperative rhythm change AF to NSR NSR to atrial flutter AF to paced NSR to AF to NSR NSR to paced to NSR Intraoperative interventions Antiarrhythmic Beta-blocker Amiodarone Calcium channel blocker Cardioversion
Table 3. Postoperative Management and Outcomes, n
10 8 1 1 1 1 1 1 4* 4 1 1 1
Abbreviations: AF, atrial fibrillation; NSR, normal sinus rhythm. *One patient received beta-blocker and calcium channel blocker. One patient received beta-blocker and amidoarone.
stress tests but no significant disease according to coronary angiography. One patient had previous multiple coronary stents with recommendations for medical management. One patient had mitral stenosis, treated with the use of commissurotomy w30 years before. Calculated valve area on transthoracic echo was 1.65 cm2 according to planimetry and 1.25 cm2 according to pressure halftime, corresponding to mild or moderate mitral stenosis, respectively. Eleven patients were treated with 1 antiarrhythmic agents (Table 1). No patients were on calcium channel blockers or statins. Three patients had ventricular pacemakers placed to prevent bradycardia induced by the antiarrhythmic treatment. Intraoperative Course
On presentation to transplantation, 8 patients (42.1%) were in AF (6 permanent and 2 persistent), 10 (52.6%) were in sinus rhythm, and 1 (5.3%) was paced (Table 2). All patients with AF presented with adequate rate control (heart rates 100 beats/min). Intraoperative rhythm change occurred in 3 patients: One patient with permanent AF converted to normal sinus rhythm (NSR) after treatment of rapid ventricular rate with esmolol and diltiazem, and 2 patients with paroxysmal AF presented in NSR and developed atrial flutter or AF. The latter patient required esmolol, amiodarone, and eventually cardioversion to restore NSR. Three patients were paced during surgery: One patient was paced continuously and 2 others required intermittent ventricular pacing via the implanted pacemaker owing to bradycardia. Ten patients received antifibrinolytics (6 aminocaproic acid, 4 tranexamic acid) based on clinical presentation and point-of-care tests. Compared with the control group, AF patients received more cryoprecipitate during surgery (1.1 2.2 compared with 0.5 1.0; P ¼ .02). Transfusion of red blood cells, fresh
Extubation Postoperative day 0 Postoperative day 1 Postoperative day >1 Mean SD (d) Median length of stay (d) ICU Hospital Postoperative troponin elevation Postoperative rhythm change NSR to AF Atrial flutter to AF NSR to AF to NSR AF treatment Antiarrhythmic Beta-blocker Digoxin Amiodarone Calcium channel blocker Anticoagulant Aspirin Warfarin Interventional cardioversion Readmission for AF with rapid ventricular rate ICU Hospital Rhythm at discharge NSR AF Paced Survival 30 d, n (%) 1 y, n (%)
10 6 3* 0.9 1.7 2 8 10† 3 1 1 12‡ 7 5 4 1 15x 12 6 1 3 3 9 7 2 16 (84.2%) 13 (68.4%)
Abbreviations: ICU, intensive care unit; other abbreviations as in Table 2. *One patient never extubated: tracheostomy done on postoperative day 13. † Postoperative troponin not available in 1 patient. ‡ One patient on beta-blocker and amiodarone; 3 patients on beta-blocker and digoxin; 1 patient on amiodarone and digoxin. x Three patients on aspirin and warfarin.
frozen plasma, and platelets was similar between groups (P values .96, .76, and .74, respectively). Postoperative Course
Ten patients were extubated on the day of transplantation: 6 in the operating room and 4 in the ICU (Table 3). Another 6 patients were extubated within 24 hours. The median ICU stay for both AF and control groups was 2 days (AF interquartile range [IQR], 2e6 days; control IQR, 1e4 days). In the AF group, 3 patients had prolonged ICU stays owing to pulmonary edema and rapid ventricular rate, multiorgan failure, and respiratory failure. Median hospital stay was not different between the 2 groups: 8 versus 7 days in AF and control, respectively. Troponin I levels were checked after surgery in all LT recipients routinely, and 10 patients had elevated levels. Nine peaked within 48 hours after surgery and 1 on postoperative day (POD) 5. Because there were no associated clinical symptoms or electrocardiographic (ECG) or
ATRIAL FIBRILLATION IN LIVER TRANSPLANT RECIPIENTS
echocardiographic (ECHO) evidence of myocardial ischemia, patients were managed medically. Five patients had a postoperative rhythm change before discharge; 3 required readmission to the ICU because of recurrence of AF with rapid ventricular rate within 1 week after transplantation. All 3 patients eventually converted to NSR. Three patients were readmitted to the hospital for AF with rapid ventricular response within 3 weeks after transplantation. In each case, adequate rate control was achieved and maintained by increasing the dose of beta-blockers or digoxin. At the time of discharge, more patients were on an antiplatelet agent, coumarin, and digoxin than at admission. Three patients (15.8%) died within 30 days after transplantation. One patient was readmitted to the hospital on POD 15 for septic shock. An exploratory laparotomy revealed hepatic artery thrombosis and hepatojejunostomy breakdown. Autopsy was declined. One patient expired on POD 16 in the emergency department with pulseless electrical activity. Autopsy showed acute myocardial infarction. One patient had a cardiac arrest after discharge and died on POD 17. Thirty-day survival in the AF group was significantly lower than in the non-AF group (84.2% vs 97.1%; P ¼ .0065). The relative risk of death at 1 month in the AF versus non-AF group was 5.29 (P ¼ .0034; 95% confidence interval [CI], 1.73e16.18). Another 3 patients died within 1 year of transplant, resulting in overall 68.4% 1-year survival. Two patients died from liver failure 8 and 11 months after transplant. One patient died on POD 70 without leaving the hospital. A complicated postoperative course included several episodes of AF and rapid ventricular rate, sepsis, and multiorgan failure. Serial transthoracic echocardiography consistently confirmed preoperatively diagnosed mild-to-moderate mitral stenosis and preserved systolic function. Unexpectedly, the autopsy revealed severe mitral stenosis. Additional findings of extensive liver necrosis, secondary to a low-flow state, and diffuse alveolar damage, were consistent with a contributory role of unrecognized severe mitral stenosis in the demise of this patient. The 1-year survival in the AF group was significantly lower than in the non-AF group (68.4% vs 90.4%; P ¼ .011). The relative risk of death at 1 year in the AF versus non-AF group was 3.28 (P ¼ .0008; 95% CI, 1.63e6.59). DISCUSSION
In cardiac surgery, preoperative AF is considered to be an independent risk factor for early and late postoperative mortality [20]. Diastolic dysfunction, a condition that may be associated with AF [21,22], has been identified as an independent predictor of heart failure and worse outcomes after LT [23], but the direct link between AF and LT outcomes has not been clearly established. A recent retrospective study was the first to suggest that patients with AF undergoing LT are at increased risk for perioperative
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cardiac events [17]. The present study attempted to assess the impact of preoperative AF on perioperative management and LT outcomes in a large American transplant center. We compared the AF group to all non-AF patients undergoing transplantation in our center; the 2 groups did not appear to differ except for a small difference in age, with AF patients being older. In our institution, AF has not been considered to be an absolute contraindication for LT. The prevalence of AF in our cohort (2.5%) was similar to that in general population in the USA [4]. In contrast, a recent retrospective study of patients on the LT waiting list [24] reported lower prevalence of AF, hypothesizing a protective effect of cirrhosis. Our results, as well as those recently reported by Bargehr et al [17], do not support that hypothesis. The principal finding of the present study is a higher mortality of AF recipients at 1 month and 1 year after LT. We can not draw firm conclusions whether AF is an independent risk factor or a marker of overall poor physical status. Based on clinical presentation, it appears that 3 of the 6 deceased patients died of cardiac causes. Two cardiac mortalities occurred within 30 days of transplant. The third cardiac mortality occurred on POD 70; autopsy supported the role of severe mitral stenosis in that patient’s death. Ten patients had increased postoperative troponin levels. Myocardial infarction was ruled out based on clinical presentation and noninvasive tests (ECG, ECHO), and patients were managed medically. Five of the 10 patients died, 2 within 30 days and 3 within 1 year. These data suggest that postoperative troponin release in LT recipients may have a prognostic value. This hypothesis is consistent with findings in noncardiac surgery, where increased postoperative release of troponin is an independent prognostic factor of all-cause 1-year mortality [25]. There was no difference between the AF and non-AF patients in time to extubation, ICU and hospital stay, or readmissions. It is interesting to note that 3 out of 7 patients who developed post-LT rapid ventricular response were readmitted to the hospital within 30 days after surgery. Management of AF was optimized with titration of rate-controlling agents. It is possible that the pretransplantation antiarrhythmic regimens became subtherapeutic due to increased metabolism as a result of improved liver function. This suggests that inadequate ventricular rate control is a significant post-LT complication in patients with AF that requires additional interventions, including hospital readmission. The intraoperative AF management goal was rate control; conversion to NSR was undesirable because of the potential for embolic complications. However, 1 of the 8 patients who presented to transplantation in AF converted to NSR during surgery after the rapid ventricular rate was treated with diltiazem and esmolol infusion. No embolic complications were evident clinically. The rhythm reverted to AF after surgery. In retrospect, it may be argued that administration of esmolol was a suboptimal choice, because beta-blockers are
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associated with higher rate of conversion to NSR [26]. Alternatives to beta-blockers include digoxin and amiodarone. Digoxin does not require dose adjustment in liver impairment unless renal dysfunction is present, but its toxicity is potentiated by electrolyte imbalance. Concerns regarding amiodarone in patients with end-stage liver disease (ESLD) are prolonged QT interval, ventricular arrhythmias [27e29], and rare acute severe hepatic necrosis [15]. Although amiodarone’s limited negative effect on inotropy and systemic vascular resistance render it an attractive choice for intraoperative management of AF, in our study it was used only once during surgery to treat rapid ventricular response in a patient with paroxysmal AF. Another unresolved issue in managing ESLD patients with AF is the absence of evidence-based guidelines for the assessment and management of anticoagulation in this patient group [4]. The CHADS2 score is used to stratify the annual risk of stroke in patients with nonvalvular AF and to guide antithrombotic therapy [18]. Current recommendation for antithrombotic therapy in patients with CHADS2 score of 0 is no treatment or aspirin; in those with score of 1, aspirin or warfarin (goal of international normalized ratio [INR] 2-3); and in patients with CHADS2 score of 2 or those with mitral stenosis, warfarin (goal INR 2-3) [4]. Eight patients in our study had a CHADS2 score of 2, but only 3 patients were on warfarin. The preoperative INRs were below the suggested protected range in 3 patients [4]. An alternative to warfarin, dabigatran etexilate, a direct thrombin inhibitor, was included in the 2011 American Heart Association guidelines but not available during the study period. Recent North American and European guidelines recommend avoiding dabigatran in patients with advanced liver disease [30,31]. Interpretation of INR in ESLD patients on warfarin can be complicated. INR prolongation can be due to either drug effect or liver synthetic dysfunction, and it is recognized that prolonged INR in ESLD may be associated with preserved coagulation or even hypercoagulability [32]. This latter concept suggests that patients with ESLD often do not receive antithrombotic therapy per general guidelines owing to a perceived increased risk of bleeding [26]. This is also evident in our patients that were possibly undertreated; despite the recommendations for universal treatment of patients with AF with aspirin, 4 patients with CHADS2 score of 1 were on no prophylaxis. In these 4 patients, coagulopathy due to deteriorating liver function was cited as the reason for withholding treatment. Despite the varying approaches to managing anticoagulation, none of the 19 patients in our study had a clinically evident thromboembolic event. At discharge, more patients were on aspirin and/or warfarin then before surgery. The decision to implement an antithrombotic regimen per guidelines [4] was likely in part motivated by the recovery of liver metabolic function. Ten patients received intraoperative antifibrinolytics based on clinical presentation and laboratory-confirmed fibrinolysis. Interestingly, 8 of these 10 patients had
VANNUCCI, RATHOR, VACHHARAJANI ET AL
elevated postoperative troponin levels. The safety of prophylactic intraoperative use of antifibrinolytics in patients with AF is unknown. Although our numbers are too small to make any conclusions, patients with AF are at increased risk for forming intracardiac thrombi, and we think that antifibrinolytics should be used only therapeutically, based on point-of-care testing, and not prophylactically. The main limitations of the present study are its retrospective nature and the small number of AF patients. Furthermore, the patient data spanned a decade during which time the preoperative evaluation criteria for and intraoperative management of LT as well as therapeutic approaches to treating AF evolved. The 2 main findings of this retrospective analysis are the association of AF with increased post-LT mortality and with post-LT rapid ventricular response. The latter occurred in approximately one-third of the patients and resulted in ICU and hospital readmissions and additional diagnostic and pharmacologic interventions. To confirm the association of AF with decreased post-LT survival and identify best practices in managing patients with AF presenting for LT, more data and multicenter approaches are needed. REFERENCES [1] Organ Procurement and Transplantation Network. Scientific Registry of Transplant Recipients annual data report 2012. Available at: http://optn.transplant.hrsa.gov/latestData/rptData.asp. [2] Aloia TA, Knight R, Gaber AO, Ghobrial RM, Goss JA. Analysis of liver transplant outcomes for United Network for Organ Sharing recipients 60 years old or older identifies multiple model for end-stage liver disease-independent prognostic factors. Liver Transpl 2010;16:950e9. [3] Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statisticsd2012 update: a report from the American Heart Association. Circulation 2012;125:e2e220. [4] Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:e269e367. [5] Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001;285:2370e5. [6] Piccini JP, Hammill BG, Sinner MF, Jensen PN, Hernandez AF, Heckbert SR, et al. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993-2007. Circ Cardiovasc Qual Outcomes 2012;5:85e93. [7] Rich MW. Epidemiology of atrial fibrillation. J Interv Card Electrophysiol 2009;25:3e8. [8] Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31: 2369e429. [9] Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and
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1437 [22] Kosiuk J, Breithardt O, Bode K, Kornej J, Arya A, Gaspar T, et al. Left ventricular diastolic dysfunction and thromboembolic risk in atrial fibrillation: diastolic dysfunction and thromboembolic risk in AF. Int J Cardiol; 2013. [23] Dowsley TF, Bayne DB, Langnas AN, Dumitru I, Windle JR, Porter TR, et al. Diastolic dysfunction in patients with end-stage liver disease is associated with development of heart failure early after liver transplantation. Transplantation 2012;94: 646e51. [24] Zamirian M, Sarmadi T, Aghasadeghi K, Kazemi MB. Liver cirrhosis prevents atrial fibrillation: A reality or just an illusion? J Cardiovasc Dis Res 2012;3:109e12. [25] Levy M, Heels-Ansdell D, Hiralal R, Bhandari M, Guyatt G, Yusuf S, et al. Prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurement after noncardiac surgery: a systematic review and meta-analysis. Anesthesiology 2011;114:796e806. [26] Rosenman MB, Simon TA, Teal E, McGuire P, Nisi D, Jackson JD. Perceived or actual barriers to warfarin use in atrial fibrillation based on electronic medical records. Am J Ther 2012;19: 330e7. [27] di Micoli A, Zambruni A, Bracci E, Benazzi B, Zappoli P, Berzigotti A, et al. “Torsade de pointes” during amiodarone infusion in a cirrhotic woman with a prolonged QT interval. Dig Liver Dis 2009;41:535e8. [28] Zimetbaum P. Amiodarone for atrial fibrillation. N Engl J Med 2007;356:935e41. [29] Bernardi M, Maggioli C, Dibra V, Zaccherini G. QT interval prolongation in liver cirrhosis: innocent bystander or serious threat? Expert Rev Gastroenterol Hepatol 2012;6:57e66. [30] Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes 3rd NA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011;57:223e42. [31] de Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, et al. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on ThrombosiseTask Force on Anticoagulants in Heart Disease position paper. J Am Coll Cardiol 2012;59:1413e25. [32] Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011;365:147e56.
