The Prevalence of Sinus Rhythm in Patients with “Permanent” Atrial Fibrillation PAUL D. ZIEGLER, M.S.,* SCOTT SAKAGUCHI, M.D.,† GRANT R. SIMONS, M.D.,‡ JODI L. KOEHLER, M.S.,* and EDUARDO WARMAN, PH.D.* From the *Cardiac Rhythm Disease Management Division, Medtronic, Inc., Minneapolis, Minnesota; †Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, Minnesota; and ‡Department of Cardiac Electrophysiology, Englewood Hospital and Medical Center, Englewood, New Jersey
Background: The term “permanent” atrial fibrillation (AF) is generally used to describe the rhythm status of patients for whom cardioversion has failed or attempts to restore normal sinus rhythm (NSR) have ceased. However, the rhythm status of such patients is typically assessed by symptoms or intermittent monitoring, and therefore categorization may be imprecise. Methods: We evaluated the presence of NSR among patients who were identified by their physicians as having permanent AF and who underwent prior insertion of a cardiac rhythm management device in the OMNI study. Patients with a dual- or triple-chamber device (pacemaker, implantable cardiac defibrillator, or cardiac resynchronization therapy) and ≥30 days of device data were studied. We tabulated the percentage of follow-up days spent entirely in NSR, entirely in AF, or in both NSR and AF. Results: A total of 69 patients met inclusion criteria and were followed for 767 ± 479 days. More than 73% of patients experienced ≥1 entire day in NSR. On average, 38.2% of days were spent entirely in NSR, 11.8% of days were spent in a combination of NSR and AF, and only 50.0% of days were spent entirely in AF. The median daily AF burden during follow-up was 14.6 [1.1–23.7] hours/day. Conclusions: NSR is common in many device patients thought to have permanent AF, suggesting that continuous arrhythmia monitoring could be useful in identifying permanent AF patients who may benefit from renewed rhythm control efforts. Alternatively, some permanent AF patients undergoing atrioventricular nodal ablation may benefit from dual-chamber devices due to likely periods of NSR. (PACE 2014; 37:674–681) atrial fibrillation, permanent AF, sinus rhythm, monitoring, implantable devices
Introduction The term “permanent” atrial fibrillation (AF) is generally used to describe the rhythm status of patients for whom cardioversion has failed or attempts to restore normal sinus rhythm have ceased.1 However, the rhythm status of such patients is typically assessed by symptoms or intermittent monitoring, and therefore categorization may be imprecise. For example, although it is well established that many episodes of AF are asymptomatic,2–4 previous studies have also demonstrated that symptoms attributed by
Financial disclosures: Paul D. Ziegler, Jodi L. Koehler, and Eduardo Warman are employees and shareholders of Medtronic, Inc. Scott Sakaguchi and Grant R. Simons have no disclosures to report. Address for reprints: Paul D. Ziegler, M.S., Cardiac Rhythm Disease Management Division, Medtronic, Inc., 8200 Coral Sea Street NE, Mailstop MVN41, Mounds View, MN 55112. Fax: 763-526-5725; e-mail: [email protected]
Received October 29, 2013; revised November 21, 2013; accepted November 12, 2013. doi: 10.1111/pace.12354
patients to AF actually correlate with documented atrial arrhythmias in only 20% of cases.2,3 Intermittent monitoring can be used to verify the rhythm status at selected time points, but these snapshots are not representative of the rhythm status between assessments when compared to continuous arrhythmia monitoring.5,6 In patients without implantable devices, it is common for rhythm status to be assessed only intermittently at the time of office visits. In fact, numerous clinical studies have defined permanent or chronic AF as electrocardiogram evidence of AF at two consecutive follow-up visits.7–12 Consequently, physicians may tacitly assume that the entire duration between these clinic visits is spent in AF. We evaluated the prevalence of sinus rhythm among patients who were identified by their physicians as having permanent AF at the time of implantable cardiac rhythm management (CRM) device insertion. Stored diagnostic data downloaded from the CRM devices were analyzed for evidence of sinus rhythm. The purpose of this analysis was to evaluate whether disparity exists between the clinical assessment of rhythm status and a device-based assessment of rhythm status among
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permanent AF patients with dual- or triplechamber implantable CRM devices. Methods This study utilized data from a subset of patients in a postmarket observational study conducted in the United States (NCT00277524, “OMNI Study”) that was designed to gather data on clinical profiles, clinical management, and follow-up practices of patients with CRM devices. The OMNI study enrolled patients at least 18 years of age who received a new or replacement implantable study device within the prior 40 days. Patients were excluded if they were unwilling and unable to comply with the follow-up schedule or were participating in another clinical device trial that required specific treatment or programming. We identified a subset of patients who had been deemed by their physicians to have permanent AF at the time of enrollment in the study. We restricted the present analysis to patients who received a dual- or triple-chamber CRM device (pacemaker or implantable cardioverter defibrillator [ICD]; all devices had an atrial lead and devices may have included a left ventricular lead for cardiac resynchronization therapy [CRT]) with at least 30 days of device data. Baseline data collection consisted of demographics, arrhythmia history, cardiovascular history, and cardiovascular surgery history. The devices employed in this study use AF detection algorithms based on both atrial rate and atrioventricular (AV) conduction pattern informaR , Medtronic, Inc., Minneapolis, tion (PR Logic MN, USA) and have been previously shown to have a very high sensitivity and positive predictive value for the detection of AF.13,14 Although these devices are capable of continuously monitoring rhythm status, the cumulative amount of time spent in AF (AF burden) is aggregated and stored for each calendar day of follow-up. Consequently, our analysis largely focused on this level of data resolution to take advantage of the comprehensive nature of AF diagnostics being reported by the device on a daily basis. We tabulated the percentage of follow-up days spent entirely in sinus rhythm, entirely in AF (>23 hours), or in a combination of both sinus rhythm and AF (up to 23 hours) over the followup period. A threshold of 23 hours was chosen to allow for potential brief periods of transient atrial undersensing due to atrial activity below the sensing threshold and has been previously used in device studies to define a full day of AF.15–17 The average daily AF burden was tabulated for each patient over their respective follow-up duration and the median of these values was computed
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across the entire study population. In this study, 59 patients (85.5%) had their atrial sensitivity programmed to the nominal device setting of 0.30 mV, which optimizes the effectiveness of atrial detection and pacing operations while limiting the possibility of oversensing and crosschamber sensing. In seven patients (10.1%), atrial sensitivity was programmed to 0.15 mV whereas in three patients (4.3%) it was programmed to 0.45 mV. In addition, the atrial rate or interval for AF detection was programmed to the nominal value (175 beats/min or 350 ms) in 84% of patients. Continuous variables are presented as mean ± standard deviation or median (interquartile range, 25th–75th%), as appropriate. Categorical variables are presented as a count and/or percentage. All statistical analyses were performed with SAS version 9.2 (SAS Institute, Cary, NC, USA). Results A total of 2,883 patients who met the main study eligibility criteria were enrolled. Of these, 167 patients were identified as having permanent or chronic AF at the time of enrollment. Among these, 92 (55%) were excluded because they did not have an atrial lead to permit accurate detection of AF (39 ICD patients with a single-chamber device and 53 CRT-defibrillator [CRT-D] patients without an atrial lead implanted). In addition, six patients were excluded because they did not have at least 30 days of device data. The remaining 69 patients comprised our study cohort and were followed for a total of 52,893 patient-days (mean 767 ± 479 days). The mean patient age at implant was 72 ± 10 years, and 70% of patients were male. A history of hypertension was present in 49 patients (71%) while coronary artery disease was present in 40 patients (58%). Additional demographic information for these 69 patients is presented in Table I. Antiarrhythmic drug usage was not collected as part of the OMNI study protocol so this information was not available in the present analysis. Graphical depictions of AF recurrences over the course of follow-up are shown for four representative patients in Figure 1. Patient A had a very low AF burden and never spent an entire day in AF. Patients B and C had intermediate levels of AF burden and spent some days completely in sinus rhythm, some days completely in AF, and some days in a combination of sinus rhythm and AF. Patient D spent every day of follow-up entirely in AF. Distribution of Rhythm States On average, 38.2% of days were spent entirely in sinus rhythm, 11.8% of days were spent in a combination of sinus rhythm and AF, and
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Role of Device Shocks
Table I. Patient Demographics Age at implant (years) Male gender Coronary artery disease Myocardial infarction Dilated cardiomyopathy None Ischemic Nonischemic Hypertension Cerebrovascular accident Diabetes Valvular heart disease History of AV nodal ablation New York Heart Association Classification No heart failure I II III IV Device type ICD CRT-D Pacemaker
72 ± 10 48 (70%) 40 (58%) 28 (41%) 17 (25%) 35 (51%) 17 (25%) 49 (71%) 6 (9%) 20 (29%) 22 (32%) 9 (13%) 8 (15%) 2 (4%) 10 (19%) 27 (52%) 5 (10%) 19 (28%) 35 (51%) 15 (22%)
AV = atrioventricular; CRT-D = cardiac resynchronization therapy defibrillator; ICD = implantable cardioverter defibrillator.
only 50.0% of days were spent entirely in AF. The distribution of these rhythm states for each individual patient is presented in Figure 2. More than 73% of patients experienced at least one entire day in sinus rhythm while 39% of patients spent the majority of their follow-up days entirely in sinus rhythm. Very few patients (7%) spent the majority of their follow-up days in a combination of both sinus rhythm and AF. Fewer than half of patients (49%) spent the majority of their follow-up days entirely in AF, despite being classified as having permanent AF at baseline. AF Burden Assessment The mean and median daily AF burdens for the population during follow-up were 13.0 ± 10.3 hours per day and 14.6 (1.1–23.7) hours per day, respectively. The average daily AF burden values for each of the 69 patients included in this analysis are presented in Figure 3. In total, 44% of the follow-up duration was spent in sinus rhythm. The median AF burden for patients with pacemakers, ICDs, and CRT-D devices was 24.0 (1.1–24.0) hours per day, 7.0 (0.2–21.7) hours per day, and 18.2 (1.7–23.6) hours per day, respectively (P = 0.14).
Of the 69 patients in the study, 54 (78%) were implanted with ICDs that are capable of delivering high-energy shocks. Among these 54 patients, 20 (37%) received one or more shocks (either appropriate or inappropriate) on 41 different days during the follow-up period with a total of 108 shocks being delivered for 74 unique episodes. Conversely, 49 of 69 patients (71%) did not receive device shocks either because they were implanted with a pacemaker or their ICD delivered no shock therapies. Among patients who received any device shock(s), the median AF burden was 10.0 (4.2–19.0) hours per day while the median AF burden among patients not receiving any shocks was 22.0 (0.2–23.9) hours per day (P = 0.29). However, 21 of the 49 patients (43%) who received no device shocks (15 patients with pacemakers and 34 ICD patients who received no shocks) averaged fewer than 12 hours per day in AF. Among the 20 patients who received a shock, the mean and median amount of time spent in sinus rhythm following the first shock was 13.3 ± 9.2 hours per day and 14.6 (3.1–22.9) hours per day, respectively. Patients who received one or more shocks tended to experience a smaller percentage of days completely in AF compared to patients receiving no shocks (26% [11–67%] vs 71% [0–100%], respectively, P = 0.21). Of the 41 patient-days with ICD shocks delivered after the day of implant, eight (20%) converted the patient from a full day of AF on the day preceding shock delivery to a full day of sinus rhythm on the day following shock delivery. An additional seven (17%) shocks converted the patient from a partial day of AF on the day preceding shock delivery to a full day of sinus rhythm on the day following shock delivery. A total of 10 unique patients experienced one or more shocks, which converted a full or partial day of AF on the day before the shock to a full day of sinus rhythm on the day following the shock.
Discussion The main findings of this study are that the vast majority of patients (73%) prospectively identified by their physicians as having permanent AF spent at least one complete day in sinus rhythm and that, collectively, 44% of the total follow-up duration was spent in sinus rhythm. Furthermore, patients tended to spend days either entirely in sinus rhythm (38.2%) or entirely in AF (50.0%), with only 11.8% of days being spent in a combination of AF and sinus rhythm. Device shocks appear to have promoted restoration of sinus rhythm in a minority of patients.
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Figure 1. Representative examples of daily AF recurrences from four patients deemed to have “permanent” AF at baseline are shown. Vertical black lines represent the number of hours spent in AF during each day of follow-up. Despite being classified as having the same type of AF at baseline, these patients exhibit distinctly different amounts of AF during follow-up as quantified by continuous arrhythmia monitoring. AF = atrial fibrillation.
Although numerous prior studies have examined the frequency of newly detected AF among patients thought to be in sinus rhythm,18–22 relatively few studies have explored the presence of sinus rhythm among patients thought to be
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in permanent AF. Gasparini et al. reported that sinus rhythm resumed spontaneously in 10% of heart failure patients with permanent AF who received a CRT device.23 However, in that study, rhythm status was assessed only during infrequent
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Follow-up Days (%)
Days Entirely in Sinus Rhythm Days Partially in AF
Patients *Patient received 1 or more shocks
Days Entirely in AF
Figure 2. Distribution of rhythm states among all patients. White shading represents the proportion of follow-up days spent entirely in sinus rhythm, gray shading represents the proportion of follow-up days spent in both sinus rhythm and AF, and black shading represents the proportion of follow-up days spent entirely in AF. The letters A, B, C, and D refer to the specific patients illustrated in Figure 1. An asterisk (*) indicates that the patient received one or more shocks during follow-up. AF = atrial fibrillation.
outpatient visits. Fragakis et al. demonstrated that 50% of patients with permanent AF could maintain prolonged periods of sinus rhythm when internal cardioversion was followed by a novel continuous bi-atrial pacing protocol.24 Our study is unique in that we were able to utilize the continuous long-term monitoring capabilities available in modern implantable devices to assess rhythm status on a daily basis. Moreover, the retrospective nature of our study protocol did not prescribe overt efforts to convert patients to sinus rhythm. Potential Explanations for the Presence of Sinus Rhythm Patients may be labeled as having permanent AF because cardioversion has failed or because attempts to restore sinus rhythm have ceased. The latter may be due to many causes, including multiple prior cardioversion failures, early recurrence of AF following cardioversion, or intolerance of antiarrhythmic medications that were necessary for a given patient to maintain sinus rhythm. In these cases, it is possible that the patient’s baseline assessment of permanent AF was not entirely accurate because it was based
on symptoms or intermittent rhythm monitoring. Sinus rhythm may have actually been present sporadically prior to implant but went unnoticed because there was a statistically greater chance that these high-burden patients would be found in AF versus sinus rhythm at any given point in time.5 More problematic is the possibility that a diagnosis of permanent AF may reflect a decision to pursue a rate-control strategy in a given patient without a rigorous assessment of their long-term rhythm status. Unfortunately, our database did not distinguish the basis for a patient’s diagnosis of permanent AF. Importantly, the designation of permanent AF as defined in the guidelines1 does not necessarily mean that a patient spends all of their time in AF. Indeed, the fact that patients with a diagnosis of permanent AF received a pacemaker or ICD with an atrial lead may indicate that this possibility was acknowledged in some patients. Nevertheless, the quantity of time in sinus rhythm among patients with a diagnosis of permanent AF is surprising. The fact that 44% of the follow-up was spent in sinus rhythm suggests the possibilities that permanent AF encompasses a broad spectrum of rhythm behavior, that some patient’s AF may be
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SINUS RHYTHM IN PERMANENT ATRIAL FIBRILLATION **
Average Daily AF Burden (Hours/day)
** * *
Median AF Burden = 14.6 hours/day
* Patient received 1 or more shocks
Figure 3. Average daily AF burden among all patients. The average daily AF burden is shown in black for each patient. The median AF burden for the population is shown by the horizontal dashed line. The letters A, B, C, and D refer to the specific patients illustrated in Figure 1. An asterisk (*) indicates that the patient received one or more shocks during follow-up. AF = atrial fibrillation.
misclassified, or that the present classification system of AF is inadequate. Patients with permanent AF may have periods of sinus rhythm due to device therapies or spontaneous conversions. AF may have been terminated either by appropriate shocks for ventricular tachycardia or ventricular fibrillation (VT/VF), or by inappropriate shocks due to AF conducting to the ventricles at a rate faster than VT/VF detection.25 However, device therapies can only be a partial explanation for sinus rhythm episodes. We observed that the majority of patients (49/69, 71%) received no ICD shocks, either because they had a pacemaker or because their ICD delivered no shock therapies. Among these patients, 43% (21/49) spent most of their time in sinus rhythm, averaging less than 12 hours of AF per day. Within our study population, episodes of sinus rhythm showed significant stability and did not necessarily exhibit signs of “early recurrence” of AF as is frequently described in permanent AF.26 On average, most patients either spent entire days in sinus rhythm (38.2% of days) or entirely in AF (50.0% of days). A small percentage of days (11.8%) were spent in a combination of AF and sinus rhythm. Our data suggest that many
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“permanent” AF patients are capable of maintaining sinus rhythm for prolonged periods so that more aggressive external cardioversion may be warranted in patients with significant symptoms in AF despite seeming to have “permanent” AF. Clinical Implications Permanent AF encompasses a broader range of clinical conditions than implied by the word “permanent.” As defined,1 the diagnosis includes patients in whom cardioversion has failed or was not attempted. Within this definition, a significant fraction of permanent AF patients show long periods of sinus rhythm. Once a diagnosis of “permanent AF” is made, rigorous monitoring of the atrial rhythm may be abandoned or minimized. However, an awareness of sinus rhythm among patients diagnosed with permanent AF may have important implications. The AFFIRM sub-study demonstrated that patients who actually achieve rhythm control have lower mortality than patients among whom a rate control strategy is pursued.27 Therefore, perhaps rhythm control should not be abandoned as futile without first verifying the absence of sinus rhythm via a comprehensive monitoring strategy, since interventions such as antiarrhythmic drug therapy may provide utility.
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Even though we observed that patients spent 44% of the time in sinus rhythm, it may be reasonable to expect that an even greater proportion of time in sinus rhythm could be achieved if a deliberate strategy of rhythm control was adopted. The frequent recurrence of AF after cardioversion may prompt a diagnosis of permanent AF and the adoption of a rate control strategy. Some of these patients may have residual symptoms of AF in spite of adequate rate control. A comprehensive monitoring strategy may identify patients with “permanent” AF in whom a continued rhythm control strategy may have symptomatic benefit. The role of CRT in patients with AF remains controversial.28 If the benefit of CRT is determined to be limited to sinus rhythm, then it would be important that a diagnosis of permanent AF should not be allowed to withhold therapy from patients who could benefit from CRT. For patients in whom a rate control strategy has been chosen, awareness of the occasional presence of sinus rhythm may also impact specific aspects of that therapy. For instance, a patient undergoing AV nodal ablation for rate control may be better served by a dual-chamber pacemaker to reduce unnecessary right ventricular pacing if it is likely that the patient will experience intermittent periods of sinus rhythm. It is commonly believed that AF is a progressive disease (i.e., AF begets AF),29 and in this regard, permanent AF is the endstage of this progression. If this is true, this study provides a cross-sectional snapshot of this process. The methodology of this study could serve as a model to prospectively examine the natural history of AF. Limitations Patients were selected for this study if they had been given a diagnosis of permanent AF and received an implantable device that included an atrial lead. There is an inherent selection bias: even though the treating physician deemed the
patient’s AF to be permanent, it is likely that some amount of sinus rhythm was expected. However, the fact that nearly half (45%) of the permanent AF patients enrolled in the OMNI study were implanted with an atrial lead suggests that these results are applicable to a considerable portion of permanent AF patients. In any event, the patients were deemed to fit the definition of permanent AF. This definition is broad and the clinical implications are demonstrated in the broad range of AF patterns observed in the study population. It is possible that antiarrhythmic medications may have been initiated or preexisting medications may have been prescribed at higher dosages in some defibrillator patients in order to reduce the incidence of VT/VF and possible defibrillator shock. Some of these medications could contribute to the conversion to sinus rhythm or maintenance of sinus rhythm in some patients. Since these patients were deemed to have permanent AF, it may be presumed that antiarrhythmic medications were not prescribed to reduce AF, but it was not possible to examine the contributing effect of antiarrhythmic medication. Detailed antiarrhythmic medication information was not available as the OMNI study database was designed to examine CRM device utilization and not comprehensive arrhythmia management. Conclusions The prevalence of sinus rhythm in patients identified as having permanent AF is greater than previously realized. This may be due to imprecise assessments of rhythm status at baseline and/or new interventions performed after device implantation. Irrespective of the root cause, these findings suggest that continuous arrhythmia monitoring may be useful in identifying patients with apparent permanent AF who may benefit from renewed efforts at rhythm control or from selection of dual-chamber devices after AV nodal ablation.
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