The CHADS Score Role in Managing Anticoagulation After Surgical Ablation for Atrial Fibrillation

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1 The CHADS Score Role in Managing Anticoagulation After Surgical Ablation for Atrial Fibrillation Niv Ad, MD, Linda Henry, PhD, RN, Karen Schlauch, PhD, Sari D. Holmes, PhD, and Sharon Hunt, MBA Inova Heart and Vascular Institute, Cardiac Surgery Research, Falls Church, Virginia Background. Managing anticoagulation after surgical ablation is challenging, especially when sinus rhythm has been restored and the left atrial appendage has been surgically managed. The study purpose was to examine the applicability of the CHADS 2 in determining anticoagulation strategies after surgical ablation. CHADS 2 is a scoring system (0 to 6) used to indicate a patient s risk for a thromboembolic stroke and used for anticoagulation strategies. One point is given for any of the following conditions: C, congestive heart failure; H, hypertension; A, age 75 years old or greater; D, diabetes mellitus; and S, stroke which receives 2 points. A score of 2 or greater is an indication for a patient to be placed on warfarin unless otherwise contraindicated. Methods. A prospective, longitudinally designed study where CHADS 2 was calculated for all patients (n 385). Clinical data on rhythm, anticoagulation medication, bleeding, and embolic stroke-transient ischemic attack (TIA) was obtained every 3 months. Logistic regression models were used to determine significant predictors of either event. Results. Of the 385 patients, 17% presented with a history of stroke-tia. In a mean follow-up of months, embolic stroke-tia events occurred in 4 patients (4.2 first events per 1,000 patient years) and bleeding events occurred in 69 patients (72.8 first events per 1,000 patient years). There was no significant difference in mean CHADS 2 between the stroke event and nonevent group (0.75 vs 1.46, respectively; p 0.21), but there was a significant difference in CHADS 2 between the major bleed event group and the nonevent group (2.31 vs 1.41, respectively; p < 0.003). The logistic regression model was not predictive of stroke-tia, but was significantly predictive of bleeding events ( , p < 0.02). Conclusions. The number of thromboembolic events after surgical ablation procedure is low and appears unrelated to the CHADS 2. This, together with the higher rate of bleeding, raises questions regarding the applicability of the CHADS 2 for patients after surgical ablation. A randomized study is required to define the risks and anticoagulation strategies for patients after surgical ablation. (Ann Thorac Surg 2010;90: ) 2010 by The Society of Thoracic Surgeons Accepted for publication May 5, Presented at the Poster Session of the Forty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 25 27, Address correspondence to Dr Ad, Inova Heart and Vascular Institute, 3300 Gallows Rd, Falls Church, VA 22042; Niv.ad@inova.org. The number of patients being treated surgically for atrial fibrillation is increasing with over 25,000 procedures being performed concomitantly with other cardiac surgical procedures between the years 2004 and 2006 [1]. There is also a well-recognized increase in the number of patients having ablation surgery as a stand-alone procedure. Multiple nonrandomized studies suggest that patients after the Cox maze III-IV procedure experience very low thromboembolic rates [2 4]. One of the biggest theoretical advantages of surgical ablation over catheter base ablation is the higher success rate and the management of the left atrial appendage. This may in turn lead to higher rates of patients off warfarin after the intervention. Currently the management of anticoagulation is inconsistent and challenging and no guidelines were put in place until recently [5]. In May 2007, the Heart Rhythm Society (HRS) in conjunction with the Society for Thoracic Surgeons, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society developed a consensus statement on catheter and surgical ablation of atrial fibrillation [5]. The purpose of the consensus statement was to provide recommendations for ablation programs to include the monitoring of patients for asymptomatic atrial fibrillation and the continuation of warfarin therapy. Currently, the recommendations suggest patients be followed every 6 months for at least the first 2 years after ablation using an event monitor to screen for recurrent atrial fibrillation-atrial tachycardia-atrial flutter in patients complaining of palpitations, and discontinuing warfarin only after patients had some type of continuous monitor to screen for asymptomatic atrial fibrillationatrial tachycardia or atrial flutter. However, the guidelines recommend the continuation of warfarin whenever 2010 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 1258 AD ET AL Ann Thorac Surg CHADS 2 AND SURGICAL ABLATION 2010;90: a patient s CHADS score is 2 or greater. CHADS 2 is a scoring system (0 to 6) used to indicate a patient s risk for a thromboembolic stroke and used for anticoagulation strategies. One point is given for any of the following conditions: C, congestive heart failure; H, hypertension; A, age 75 years old or greater; D, diabetes mellitus; and S, stroke which receives 2 points. A score 2 or greater is an indication for a patient to be placed on warfarin unless otherwise contraindicated. The HRS guidelines do not address anticoagulation strategies specifically for patients who have undergone surgical ablation and general recommendations are more in line with practice around catheter ablation. Therefore, managing anticoagulation after surgical ablation is challenging, especially when sinus rhythm has been restored and the left atrial appendage has been surgically managed [5]. The purpose of this study was to examine the applicability of the CHADS 2 in determining anticoagulation strategies after surgical ablation when all patients have had their left atrial appendage either removed or over sewn (surgically managed). Patients and Methods This study was a prospective, longitudinally designed study where CHADS 2 was calculated for all patients who presented at our institution for surgical ablation whether as a stand-alone procedure or combined with other cardiac surgery (n 385; full Cox maze III-IV procedure [n 332] and left-sided [n 53]). All patients had their left atrial appendage managed surgically. Follow-up clinical information on heart rhythm, anticoagulation medication, major-minor bleeding incidents, and embolic stroke-transient ischemic attacks (TIAs) was obtained every 3 months through a detailed follow-up to include rehospitalization records. Rhythm status at follow-up time points was verified through electrocardiograms and 24-hour holter obtained from the patients respective cardiologist s office. Neurologic events were verified through follow-up and reports from the patient s respective computed tomographic scan. All patients were discharged on warfarin after surgical ablation unless contraindicated. After discharge, patients warfarin and international normalized ratio (INR) status was managed by their respective cardiologist. This study was approved for exemption and waiver of consent by our Institutional Review Board. Operational Definitions An event was said to have occurred if a patient suffered any of the following incidents. STROKE OR TIA. Defined as a thromboembolic event which was diagnosed through patient reported symptoms, physical examination, and a report from the computed tomographic scan taken at the time of the event. MAJOR BLEEDING EVENT. Defined as the receipt of a blood product for the bleeding, a stroke or death caused by a hemorrhage in the brain, or large hematomas requiring medical intervention. MINOR BLEED. Defined as a patient report of bleeding without the receipt of blood products or any medical intervention beyond hospitalization. Patients were then grouped based on whether they had an event or not (event group versus nonevent group). Our risk analysis was completed using all data after the blanking period, which is defined per the HRS guidelines (ie, the first 3 months after the surgical ablation procedure) [1]. Data Analysis Data were available on 416 patients who have undergone surgical ablation at our institution at the time of this study. However, 31 patients were excluded because of a mechanical valve or if they had other indications for warfarin. An additional 38 patients were excluded from risk analyses due to having survival of less than 3 months (blanking period). Data from 385 patients who had surgical ablation were included in all other analyses. Comparisons between event groups were conducted using Student s t tests. Logistic regression was used to determine whether baseline continuous CHADS 2, rhythm status (sinus or not), and warfarin status (on or off) at 6 months were significant predictors of stroke-tia or bleeding events. An additional multivariate logistic regression analysis was conducted to examine the effect on events from the individual component variables that compose the CHADS 2 (age, diabetes, hypertension, cerebrovascular accident, and congestive heart failure). For all logistic regression analyses, the predictor variables of interest were entered as a group and examined for one-way effects. Kaplan-Meier curves were constructed to examine the time to first bleed, major bleed, and stroke-tia event, as well as the time to discontinuation of warfarin. For all analyses, a 2-sided p value less than 0.05 was used to determine significance. Results Patient Characteristics A total of 385 patients underwent surgical ablation (n 332, Cox maze III-IV; n 53, left atrial ablation only). For all patients in this group the left atrial appendage was either excised or over sewn. The mean age was years. The majority of patients were Caucasian (87%) and males made up 68% of the sample. Clinical characteristics included the following: 63 patients had diabetes, 239 patients had hypertension, 128 patients had congestive heart failure, 58 patients had chronic lung disease, and 25 patients had peripheral vascular disease. In this sample, 64 patients (16.6%) had a history of stroke or TIA. Mean ejection fraction was for this sample. Median CHADS 2 was 1 with a score range of 0 to 5. Concomitant coronary artery bypass grafting was performed on 119 patients (31%) and a concomitant valve procedure was performed on 220 patients (57%). At discharge, 328 patients (85%) were on warfarin, 96 patients

3 Ann Thorac Surg AD ET AL 2010;90: CHADS 2 AND SURGICAL ABLATION 1259 (25%) were on aspirin (alone or in combination), and 7 patients ( 2%) were on Plavix (Bristol-Myers Squibb/ Sanofi Pharmaceuticals Partnership, Bridgewater, NJ). In a mean follow-up of (range, 4.1 to 63.7) months (n 347), 4 patients had 7 thromboembolic events, 3 had a single embolic stroke, and one patient had 4 TIA events (4.2 first events per 1,000 patient years) (Fig 1). The total number of bleeding events was 120, which occurred in 69 patients (72.8 first events per 1,000 patient years). Twenty-two major bleeding events occurred in 16 patients (16.9 first events per 1,000 patient years) with 62% of the major bleeders on warfarin and 37% on aspirin at the time of the first event. In addition, 98 minor bleeding events occurred in 62 patients (65.4 first events per 1,000 patient years) (Fig 1). In the group of patients that experienced a stroke-tia event (n 4), there was a median baseline CHADS 2 of 0.5 (range, 0 to 2) and in 3 patients no atrial arrhythmia was documented by continuous bedside monitoring after the event. Three of the patients had their left atrial appendage over sewn with 3.0 to 4.0 pledgetted sutures and one had their left atrial appendage excised. All of the patients were documented to have closure of their left atrial appendage at the time of their stroke-tia. One patient was on warfarin at the time of event and was documented to be in sinus rhythm as well. The patient who had 4 TIAs was in atrial fibrillation, but not on warfarin at the time of first event. In the group of patients who experienced a major bleed event (n 16), there was a median baseline CHADS 2 of 2 (range, 1 to 4). Ten patients with a major bleed were on warfarin and 6 were on aspirin at the time of the first event. Nine patients were found to be in sinus rhythm at the time of the first major bleed (n 9), of which 5 were on warfarin. Patients who experienced a minor bleed event (n 62) had a median baseline CHADS 2 of 2 (range, 0 to 4). Forty patients with a minor bleed were on warfarin, 16 were on aspirin, and 1 patient was on Plavix at the time of their first event. Forty-five patients were found to be in sinus rhythm at the time of the first minor bleed, of which 31 were on warfarin. There was no significant difference in the mean CHADS 2 between the stroke-tia event and nonevent group (0.75 vs 1.46, respectively; p 0.21). However, there was a difference in the CHADS 2 between the major bleed event group and nonevent group (2.31 vs 1.41, respectively; p 0.003), such that the event group had a significantly higher CHADS 2 as compared with the nonevent group (Fig 2). Logistic regression models were used to determine whether CHADS 2, rhythm, and warfarin status at 6 months were significant predictors of any event. These variables were not predictive of stroke-tia events. Therefore, further logistic regression analyses were not conducted for stroke-tia events. The overall logistic model was significant for all bleeding events ( , p 0.02). Both warfarin status at 6 months (odds ratio [OR] 1.96, confidence interval [CI] 1.03 to 3.74, p 0.05) and CHADS 2 (OR 1.33, CI 1.02 to 1.73, p 0.04) were significant predictors of a bleeding event. Those on warfarin had almost twice the risk of a bleeding event and higher CHADS 2 was related to greater risk of bleeding as well. An additional logistic regression that evaluated the components of the CHADS 2 found significance for the overall model ( , p 0.05). However, the best predictors within the model, age (OR 1.03, CI to 1.06, p 0.08) and diabetes (OR 2.04, CI 0.99 to 4.22, p 0.055), were only marginally significant predictors of all bleeding events. Additionally, the overall logistic model for major bleeding events was significant ( , p 0.03). However, only CHADS 2 was a significant predictor (OR 1.79, p 0.02), such that higher CHADS 2 was associated with greater risk of a major bleed event. An additional logistic regression that evaluated components of the CHADS 2 found a significant model ( , p 0.02) and showed that diabetes (OR 4.07, CI 1.27 to 13.01, p 0.02) and age (OR 1.08, CI 1.01 to 1.16, p 0.04) were significant predictors of major bleeding events. Specifically, for each one year increase in age as well as the presence of diabetes, there was greater risk for a major bleeding event. Kaplan-Meier curves illustrated that survival to stroke- TIA event was greater than survival to bleeding event (Fig 3). In Figure 4, the time to discontinuation of warfarin is plotted concurrently with time to first stroke-tia event Fig 1. Description of rhythm and medication status at the time of first event for bleeding and stroke-tia events. (AF atrial fibrillation; ASA aminosalicylic acid; NSR normal sinus rhythm; TIA transient ischemic attack.)

4 1260 AD ET AL Ann Thorac Surg CHADS 2 AND SURGICAL ABLATION 2010;90: p=0.21 A 5 p<0.003 B 4 4 CHADS Score CHADS Score Event No Event Event No Event Stroke and TIA Major Bleeding Fig 2. Boxplots illustrating differences in stroke-tia (A) and major bleeding event (B) groups on CHADS 2. (TIA transient ischemic attack.) to illustrate that the stroke rate is extremely low, even after most patients have had warfarin discontinued. A Kaplan-Meier curve was also plotted just for patients found to be in sinus rhythm at 6 months (n 229), to show survival to major bleeding events (Fig 5). It should be noted that of these same patients documented to be in sinus rhythm at 6 months, only 1 patient experienced a stroke-tia event at months into follow-up. Also, for patients in sinus rhythm at 6 months, Figure 6 shows that those on warfarin had a greater hazard for any bleeding event as compared with those not on warfarin, though the majority of patients (59%) continued on aspirin and (or) Plavix (log-rank 8.589, p 0.003). Comment Anticoagulation therapy for patients who have experienced atrial fibrillation remains a dilemma for practitioners despite having predictive tools to assist in their decision making. However, little work has been done to determine which patients need continual anticoagulation therapy after restoration of sinus rhythm and management of their left atrial appendage after surgical ablation for atrial fibrillation. Cox and colleagues [2] and Bando and colleagues [3] have explored the impact of surgical ablation on the stroke rate after the procedure, but concluded that more work needs to be done. Our study demonstrated that for patients who have undergone a surgical ablation and had their left atrial appendage managed surgically, the CHADS 2 does not accurately predict who will experience a thromboembolic stroke regardless of rhythm status. In addition, we found that patients who experienced a major bleeding event had a mean CHADS 2 greater than 2 with 62% of the patients on warfarin at the time of their bleed. A recent study found that low risk patients (CHADS 2 0, 1) did not need warfarin after catheter ablation for atrial Stroke/TIA 90 Stroke/TIA Freedom from Event Bleeding Freedom from Event Time to Warfarin Discontinuation Fig 3. Kaplan-Meier curves showing time to first event for all bleeds and stroke-tia events in the total sample followed into the blanking period (n 347). (TIA transient ischemic attack.) Fig 4. Time to first stroke-tia event shown with time to warfarin discontinuation (n 265) using Kaplan-Meier curves. (TIA transient ischemic attack.)

5 Ann Thorac Surg AD ET AL 2010;90: CHADS 2 AND SURGICAL ABLATION 1261 Freedom from Event Fig 5. Kaplan-Meier curve for time to first major bleed event in patients found to be in normal sinus rhythm at 6 months (n 229). fibrillation when an open irrigated tip catheter and aggressive heparin therapy were used [6]. When reviewing the need for warfarin after occlusion of the left atrial appendage with a transcatheter approach, Holmes and Schwartz [7] reported that warfarin was not needed if the risk-to-benefit ratio was calculated as the procedural risk for deployment of the device falls to almost zero over time. However, Whitlock and colleagues [8] argued that left atrial appendage occlusion alone does not eliminate the need for warfarin because the left atrial appendage occlusion does not address the main issue of systemic disorder of coagulation and platelet function. Both of the authors agree though that large randomized trials need to be conducted before any conclusive recommendations may be drawn. Currently work is ongoing investigating left atrial appendage occlusion with a percutaneous device. This study (Protect-AF) is a large study whereby patients with nonvalvular atrial fibrillation are randomized to receive the percutaneous ablation device or to be on long-term warfarin therapy. Thus far, the study has demonstrated that the efficacy of the ablation device is noninferior to that of warfarin therapy providing hope that there may be an alternative therapy for stroke prophylaxis in this cohort of patients [9]. As stated earlier, little work has been done investigating the best anticoagulation treatment strategies after surgical ablation, restoration of sinus rhythm, and left atrial appendage removal. Previous investigations [10 13] have demonstrated that getting complete surgical ligation of the left atrial appendage can be difficult and can actually increase the risk for thromboembolism. A recent study demonstrated that there can be a high rate of unsuccessful surgical occlusion of the left atrial appendage with excision being the more successful method of ablating the left atrial appendage. It is interesting to note, however, that there was no statistical difference in the rate of stroke-tia between the patients who were deemed to have a successful left atrial appendage closure and the group that was thought to have an unsuccessful closure as noted through assessment by a transesophageal echocardiography [14]. All the patients in this study have had their left atrial appendage managed during their surgical ablation procedure. Patients were placed on warfarin therapy unless contraindicated for the first three months after surgery. Once the restoration of sinus rhythm had been established through at least 24 hours of holter monitoring, the necessity of warfarin therapy was reviewed. If there were no other indications for the continuation of warfarin, a recommendation was made for the warfarin to be stopped and aspirin therapy to be started or continued. As we noted, the majority of our patients were off their warfarin therapy by 12 months with no subsequent increase in the thromboembolic stroke-tia events over time. In fact, a bigger problem has been bleeding events for patients who are maintained on warfarin therapy. Our results indicated that warfarin and CHADS 2 are the variables most associated with bleeding events. In addition, age was the most significant predictor from the CHADS 2 component variables so that for every year increase in age there is a 3% increase in risk for bleeding event. This finding is consistent with the current literature studying the effects of age and anticoagulation medications for patients in atrial fibrillation. One of the most current studies found that major bleeding events occurred significantly more often in the very elderly patient on warfarin [15]. These findings then suggest that for patients most at risk for a stroke, but also at the highest risk for a major bleeding episode, need an alternative strategy for anticoagulation. The incongruence of how the CHADS 2 performed in this cohort of patients demonstrates the difficulty in interpreting anticoagulation guidelines or strategies postsurgical ablation. More work needs to be done exploring which patients are best served by continuation of warfarin and who are better served with other anticoagulation strategies. We are encouraged though as some of these questions may be answered when newer anticoag- Cumulative Hazard for Bleeding On Warfarin Off Warfarin Fig 6. Nelson cumulative hazard curves for bleeding events in patients found to be in sinus rhythm at 6 months comparing patients on and off warfarin at 6 months (n 223, log-rank 4.44, p 0.05).

6 1262 AD ET AL Ann Thorac Surg CHADS 2 AND SURGICAL ABLATION 2010;90: ulation drugs become available. A recent study conducted by Connolly and colleagues [15] found that dabigatran, a new oral direct thrombin inhibitor, at a dose of 110 mg twice a day was noninferior to warfarin for strokes, had lower rates of major hemorrhage, and did not require monitoring. Limitations There are several limitations of this study. The first is that we did not collect INRs at the time of a patients stroke-tia or at the time of their reported bleeding event. This can be problematic in that we did not know if a major bleeding event occurred while on warfarin if their INR was supratherapeutic or if the event was a stroke-tia if on warfarin at the time if their INR was subtherapeutic. Already established in the literature is the dilemma of compliance with warfarin therapy and this study only highlights this dilemma [16, 17]. In addition, we did not obtain echocardiographic data on the patients who experienced a stroke-tia in order to report on the function of the left atrium or if smoke was present at the time of their event. Finally, actual rhythm status at the time of an event can be problematic. Though we obtain rhythm verification for the patients self report of rhythm, a recent study on cryptogenic stroke-tia and silent atrial fibrillation indicates that knowing exactly what rhythm the patient is in at the time of the event can be difficult to determine [18]. Conclusions The purpose of this paper was not to debate the best anticoagulation medications but rather to investigate the role of the CHADS 2 in the decision making surrounding anticoagulation after surgical ablation. We found that the number of thromboembolic events after surgical ablation was very low and unrelated to the CHADS 2 or to rhythm status during follow-up. This, together with the higher rate of bleeding events (120 bleeding events in 69 patients), raises questions regarding the applicability of the HRS anticoagulation guidelines for patients after surgical ablation. Furthermore, we believe that continuation of warfarin may have a major negative impact on patients quality of life despite a successful surgical ablation. A large scale randomized study is required to redefine the risks and anticoagulation strategies for this group of patients especially when the left atrial appendage was surgically managed, and measurement of patients quality of life must be taken into account. References 1. Gammie JS, Haddad M, Milford-Beland S, et al. Atrial fibrillation correction surgery: lessons from the Society of Thoracic Surgeons National Cardiac Database. Ann Thorac Surg 2008;85: Cox J, Ad N, Palazzo T. Impact of the maze procedure on the stroke rate in patients with atrial fibrillation. J Thorac Cardiovasc Surg 1999;118: Bando K, Kasegawa H, Okada Y, et al. Impact of preoperative and postoperative atrial fibrillation on outcome after mitral valvuloplasty for nonischemic mitral regurgitation. J Thorac Cardiovasc Surg 2005;129: Itoh A, Kobayashi J, Bando K, et al. The impact of mitral valve surgery combined with maze procedure. Eur J Cardiothorac Surg 2006;29: Calkins H, Brugada J, Packer DL, et al. A report of the Heart Rhythm Society (HRS) Task Force on Catheter Ablation of Atrial Fibrillation developed in partnership with European Heart Rhythm Association (EHRA) and the European Cardiac Arrhythmia (ECAS); in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), and the Society of Thoracic Surgeons (STS). HRS/ EHRA/ECAS Expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for personnel, policy, procedures and follow-up. Europace 2007; 9: Bunch TJ, Crandall BG, Weiss JP, et al. Warfarin is not needed in low risk patients following atrial fibrillation ablation procedures. J Cardiovasc Electrophysiol 2009;20: Holmes DR Jr, Schwartz RS. Left atrial appendage occlusion eliminates the need for warfarin. Circulation 2009;120: Whitlock R, Healey J, Connolly S. Does left atrial appendage occlusion eliminate the need for Warfarin? Left atrial appendage occlusion does not eliminate the need for warfarin? Circulation 2009;120: Holmes D, Reddy V, Turi Z, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomized noninferiority trial. Lancet 2009;374: Johnson W, Ganjoo A, Stone C, Srivyas RC, Howard M. The left atrial appendage: our most lethal human attachment! Surgical Implications. Eur J Cardiothorac Surg 2000;17: García-Fernández MA, Pérez-David E, Quiles J, et al. 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