Published online before print June 26, 2006, doi: 10.1161/CIRCULATIONAHA.106.614560
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(Circulation. 2006;114:18-25.)
© 2006 American Heart Association, Inc.
Arrhythmia/Electrophysiology |
Effect of Cardiac Resynchronization on the Incidence of Atrial Fibrillation in Patients With Severe Heart Failure
From the Department of Internal Medicine III (U.C.H., E.E.), University of Cologne, Cologne, Germany; Hospital Reina Sofia (J.M.C.), Cordoba, Spain; Aarhus University Hospital (H.E.), Aarhus, Denmark; Gentofte University Hospital (A.H.), Hellerup, Denmark; Department of Cardiology (J.G.F.C.), Castle Hill Hospital, Kingston-upon-Hull, United Kingdom; and University of Birmingham (N.F.), Edgbaston, United Kingdom.
Correspondence to Uta C. Hoppe, MD, Department of Internal Medicine III, University of Cologne, Kerpener Straße 62, 50937 Cologne, Germany. E-mail uta.hoppe{at}uni-koeln.de
Received November 2, 2005; de novo received January 16, 2006; revision received March 23, 2006; accepted April 24, 2006.
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Abstract |
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Background— Atrial fibrillation/flutter (AF) and heart failure often coexist; however, the effect of cardiac resynchronization therapy (CRT) on the incidence of AF and on the outcome of patients with new-onset AF remains undefined.
Methods and Results— In the CArdiac REsynchronisation in Heart Failure (CARE-HF) trial, 813 patients with moderate or severe heart failure were randomly assigned to pharmacological therapy alone or with the addition of CRT. The incidence of AF was assessed by adverse event reporting and by ECGs during follow-up, and the impact of new-onset AF on the outcome and efficacy of CRT was evaluated. By the end of the study (mean duration of follow-up 29.4 months), AF had been documented in 66 patients in the CRT group compared with 58 who received medical therapy only (16.1% versus 14.4%; hazard ratio 1.05; 95% confidence interval, 0.73 to 1.50; P=0.79). There was no difference in the time until first onset of AF between groups. Mortality was higher in patients who developed AF, but AF was not a predictor in the multivariable model (hazard ratio 1.17; 95% confidence interval, 0.82 to 1.67; P=0.37). In patients with new-onset AF, CRT significantly reduced the risk for all-cause mortality and all other predefined end points and improved ejection fraction and symptoms (no interaction between AF and CRT; all P>0.2).
Conclusions— Although CRT did not reduce the incidence of AF, CRT improved the outcome regardless of whether AF developed.
Key Words: heart failure • cardiac resynchronization • atrial fibrillation • biventricular pacing
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Introduction |
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Atrial fibrillation/flutter (AF) is the most common chronic arrhythmia.1,2 Heart failure and AF often coexist. Both are responsible for increased mortality, more frequent hospitalizations, reduced exercise capacity, decreased quality of life, and substantial healthcare expenditures.3 In addition to merely having risk factors in common, AF and heart failure are believed to directly predispose to each other.4,5 The idea that AF is a predictor of worse prognosis in patients with heart failure is controversial and perhaps reflects the difficulty in measuring left ventricular function and controlling for associated comorbidity.6–11 However, recent studies highlight the adverse effect of new-onset AF in patients with heart failure.9 Thus, increased attention is being paid to medical and mechanical therapies to treat or prevent AF in heart failure.12,13
Clinical Perspective p 25
Cardiac resynchronization therapy (CRT) reduces symptoms, decreases neurohormonal activation, and improves left ventricular function and prognosis in many patients with moderate to severe heart failure caused by systolic dysfunction and cardiac dyssynchrony.14–19 Recently, a small nonrandomized study suggested that biventricular stimulation may reduce the incidence of AF.20 However, a large study of dual-chamber pacing indicated an increased risk of AF, attributing that increased risk to the presence of a right atrial lead.21 Thus, CRT could theoretically increase or decrease the incidence of AF, or opposing effects might lead to no overall effect. To date, the effect of CRT on the induction of AF has not been analyzed in a large randomized population. Accordingly, the purpose of the present study was to evaluate and compare the incidence of AF in patients with moderate to severe systolic heart failure and cardiac dyssynchrony randomized to standard pharmacological therapy alone or the combination of standard medication and atrial-based cardiac resynchronization in the CArdiac REsynchronisation in Heart Failure (CARE-HF) study.14 In addition, we analyzed whether new onset of AF might affect the outcome and benefit of cardiac resynchronization and which patient characteristics were associated with an increased risk for AF. If cardiac resynchronization influences the occurrence or consequences of AF, this might influence patient selection and possibly programming of the device.
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Methods |
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Patient Population
The details of the rationale and design of the CARE-HF trial have been published previously.14,22,23 Patients were eligible for the trial if they were in New York Heart Association (NYHA) class III or IV despite standard pharmacological therapy that included loop diuretics and neuroendocrine antagonists, had a left ventricular ejection fraction
35%, and had a QRS duration of at least 120 ms (patients with a QRS interval of 120 to 149 ms required additional echocardiographic criteria for dyssynchrony22). Participants were randomized to standard pharmacological therapy alone or the combination of standard therapy and atrial-based cardiac resynchronization (Medtronic InSync or InSync III device, Medtronic Bakken Research Center B.V., Maastricht, The Netherlands). Exclusion criteria included conventional indications for a pacemaker or an implantable defibrillator, persistent atrial arrhythmias, and requirement of continuous intravenous therapy. The protocol was approved by the local ethics committee of each participating institution and by appropriate national ethics committees. All patients provided written informed consent.
Definition of AF
At baseline, patients with persistent atrial arrhythmias were excluded from the CARE-HF study. For the purposes of the present analysis, we classified the patients enrolled into groups as those with new-onset AF (that is, patients who developed AF as documented on ECGs during follow-up at 1, 3, 6, 9, 12, and 18 months and every 6 months thereafter, or documented as a serious adverse event or during hospitalization) and those without AF. Additionally, in the CRT group, asymptomatic AF that lasted >10 minutes detected by the device as atrial high-rate episodes (>180 bpm) were evaluated. However, AF detected only by device diagnostics, which would lead to ascertainment bias, was not considered in the comparison of the 2 randomized treatment groups.
End Points
The primary end point of the present analysis was new onset of AF. The secondary end point was planned or unplanned hospitalization related to AF. Although a causal relationship between AF and planned hospitalizations could be established, for unplanned hospitalizations, it cannot be ascertained that AF was the direct cause, ie, AF might have worsened heart failure, or worsening heart failure might have induced AF. Further end points were end points of the main trial: a composite of death due to any cause or an unplanned hospitalization for a major cardiovascular event, unplanned hospitalization for a cardiovascular event, death from any cause, a composite of death from any cause and unplanned hospitalization with worsening heart failure, unplanned hospitalization with worsening heart failure, and, at 18 months, the NYHA class and quality of life as assessed by the patient using the Minnesota Living with Heart Failure questionnaire.22 Death was given a notional NYHA class V for the analysis of changes in functional class. Several echocardiographic and biochemical variables were assessed in core laboratories at baseline and at the 3- and 18-month follow-up visits.22 No data other than NYHA class were imputed for patients who died.
Statistical Analysis
All analyses were conducted according to the intention-to-treat principle. All probability values are considered nominal. The time to AF and AF hospitalization were calculated according to the Kaplan-Meier method and analyzed with the use of Cox proportional hazards models, which included baseline NYHA class as a covariate. Continuous outcomes at 18 months were analyzed with the use of mixed models, which included baseline variables as patient-level covariates and study centers as random effects. Dichotomous outcomes at 18 months were contrasted with generalized linear models, with a logistic link and binomial error. Multivariate relationships were investigated with a Cox proportional hazard model. Two-sided 95% confidence intervals (CIs) were constructed around each point estimate of hazard ratio (HR), and a probability value 0.05 was considered statistically significant. Analyses were conducted with the use of SAS software (version 9.12, SAS Institute, Cary, NC).
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
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Results |
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Incidence of New Onset of AF
By the end of the study,14 AF had been documented in 66 of 409 patients in the cardiac resynchronization group compared with 58 of 404 patients who received medical therapy only (16.1% versus 14.4%; HR 1.05; 95% CI 0.73 to 1.50; P=0.79). In the CRT group, episodes of AF were detected only by device diagnostics in an additional 93 patients (22%), with 20 patients (4.9%) experiencing episodes lasting >48 hours. However, these patients were excluded from further analysis in the AF group to minimize any bias in the comparison of the 2 randomized treatment arms. There was no difference in the time from randomization until first onset of AF in the medical therapy group versus the CRT group (Figure 1).
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The baseline demographic variables of the individual groups with and without AF are presented in Table 1. In the medical therapy group and the resynchronization group, patients with new-onset AF had larger left atrial systolic (P<0.0001 and P=0.0009, respectively) and diastolic (P<0.0001 and P=0.0084, respectively) areas and higher N-terminal pro-brain natriuretic peptide (NT-BNP) levels (P=0.15 and P=0.0118, respectively) than patients who did not develop AF. Patients developing AF more often had a previous history of AF regardless of their treatment allocation (HR 3.75; 95% CI, 2.62 to 5.38; P<0.0001), with no systematic difference observed between the CRT and medical therapy groups.
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In a stepwise Cox constant proportional hazards analysis, we examined the predictive importance of treatment with CRT, age, sex, presence of hypertension, presence of coronary artery disease, ejection fraction, history of AF, NYHA class, left atrial systolic area, use of ß-blockers, use of amiodarone, and (log) NT-BNP for developing AF.24 History of AF, left atrial systolic area, and NT-BNP were associated with a higher risk of new-onset AF in both groups. The HR was 3.29 (95% CI, 2.17 to 4.99; P<0.0001) for history of AF, 1.06 per cm2 (95% CI, 1.03 to 1.09; P=0.0004) for left atrial systolic area, and 1.22 (95% CI, 1.01 to 1.48; P=0.04) for log NT-BNP per log-change in pg/mL.
AF and Hospitalization
In the adverse event reporting in CARE-HF, there were 75 planned and unplanned hospitalizations related to new-onset AF in the control group and 86 in the cardiac resynchronization group, experienced by 44 and 60 patients, respectively. The time to first AF hospitalization was similar in the groups (HR 1.33; 95% CI, 0.90 to 1.97; P=0.15; Figure 2).
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AF and End Points of the Main Trial
In the entire study group, patients who developed AF had a higher death rate; however, new-onset AF was not independently associated with an increased risk of all-cause mortality (HR 1.17; 95% CI, 0.82 to 1.67; P=0.37) when included in the analyses together with treatment and baseline NYHA classification. Death occurred shortly after the onset of AF in 9 patients who died in the medical therapy group and in 4 patients who died in the cardiac resynchronization group, and AF may have contributed to their death. CRT reduced mortality in the trial (HR 0.64; 95% CI, 0.48 to 0.85; P=0.002), and the effect of CRT was not modified by new episodes of AF (P for interaction 0.74; Table 2).
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In the entire population, development of AF was associated with an increased rate of reaching the combined end point of death due to any cause or unplanned hospitalization for a major cardiovascular event (HR 2.00; 95% CI, 1.58 to 2.54; P<0.0001). CRT reduced the incidence of this combined end point (HR 0.63; 95% CI, 0.51 to 0.77; P<0.001) and the incidence of qualifying unplanned hospitalizations (HR 0.61; 95% CI, 0.49 to 0.77; P<0.001) in the trial, and the effect of CRT was not modified by new episodes of AF (Table 2). At 18 months, patients in the cardiac resynchronization group had less severe symptoms (interaction of AF and CRT P=0.30) and a better quality of life regardless of the onset of AF (interaction of AF and CRT P=0.44; Table 2). New onset of AF was associated with a more frequent initiation of digoxin, amiodarone, and warfarin independent of the allocation to pharmacological therapy alone or to the combination of standard medication plus cardiac resynchronization.
Multivariate Effect of History of AF on Death or Unplanned Hospitalization
Using a Cox constant proportional hazards model, we examined the predictive value of history of AF before enrollment on the risk of a combined end point of death or unplanned hospitalization for a cardiovascular event and any modifying effect on response to randomized treatment. In addition to the overall effects of ischemic cause, systolic blood pressure, interventricular mechanical delay, mitral regurgitation, NT-BNP, CRT, and the treatment modifying effects of systolic blood pressure and interventricular mechanical delay, a previous history of AF attenuated the effects of CRT on this primary outcome of the main trial (HR 1.92; 95% CI, 1.05 to 3.51; P=0.03; Table 3).
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Influence of AF on Hemodynamic, Echocardiographic, and Biochemical Variables
At 18 months, left ventricular ejection fraction was greater, left ventricular end-systolic volume index was lower, and left ventricular filling time was shorter in the cardiac resynchronization group with and without AF than in the medical therapy group (Table 4). There was no interaction of AF and cardiac resynchronization on the changes of these variables over time (P>0.05 for all individual variables). AF did not interact with the beneficial effect of cardiac resynchronization on NT-BNP (P for interaction 0.38; Table 4). There was a trend toward an interaction of left atrial size and CRT, which did not reach statistical significance. In addition, heart rate control at 18 months in patients with new-onset AF was better in the CRT group than in the medical therapy group (P for interaction 0.0003).
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Influence of Programmed Variables of the Biventricular Pacemaker
Compared with patients without AF, programmed variables were similar in patients who developed AF. In particular, the programmed atrioventricular delay was not different between groups. There was no significant difference in the median frequency of atrial or ventricular pacing at 3 months in patients without AF (8.0% and 99.8%, respectively) and patients who subsequently developed AF (4.7% and 99.4%, respectively, excluding 14 patients who developed AF in the first 90 days). It is worth noting that, in patients with new-onset AF (after 90 days), the median cumulative percentage of ventricular pacing was similar before development of AF (at 3 months, 99.4%) compared with the first visit after new-onset AF (97.6%; P=0.28).
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Discussion |
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In this analysis of CARE-HF, CRT did not influence the incidence of AF. However, new onset of AF did not diminish the beneficial effects of cardiac resynchronization on the combined primary end point of the main trial or, more fundamentally, on all-cause mortality. There is usually a trigger for the development of AF, including a change in autonomic tone or an increase in atrial wall tension. Because cardiac resynchronization improves ventricular hemodynamic performance, reduces the degree of mitral regurgitation (contributing to a decrease in left atrial overload), and decreases plasma norepinephrine levels,14–19 it has been proposed that CRT might prevent or delay the onset of AF in heart failure patients.25 On the other hand, pacing per se might increase the risk of developing AF. In patients with sick sinus syndrome, the induction of AF increased linearly with the cumulative percentage of pacing of the ventricle not only in patients with single-chamber ventricular pacing (VVI) but also in patients with sequential stimulation (DDD).26 Moreover, in the UK Pace trial, there was a higher risk of AF in the first 18 months with DDD pacing, which was attributed to possible arrhythmogenic effects of the atrial lead.21 When one considers the positive hemodynamic effects together with the potential adverse pacing-related actions of biventricular stimulation, atrial-based cardiac resynchronization might theoretically exert a positive, negative, or neutral effect on the incidence of AF. A small nonrandomized study did suggest a reduction of AF by CRT,20 but we could not confirm this. The time to first onset of AF in patients with medical therapy alone versus patients receiving standard medication plus CRT was similar. This indicated that at least during a follow-up of mean &2.5 years’ duration, resynchronization therapy had no effect on the incidence of AF.
Several factors are known to promote the induction of AF, including age, atrial size, and BNP.24,27 Analysis of data from the CARE-HF population supports these causal relationships. A history of previous AF, a larger left atrial systolic area, and an increased baseline NT-BNP level (a marker for intracardiac pressure overload) were each independently associated with subsequent new onset of AF. However, we did not identify any specific variable that might allow identification of individuals at particular risk for AF depending on treatment allocation.
There is no consensus as to whether AF is an independent risk factor for morbidity and mortality in heart failure or just a marker of more advanced disease. AF can adversely affect cardiac function through loss of atrial systole, increase in ventricular rate, creation of an irregular ventricular rhythm, loss of physiological control of heart rate, and the development of tachycardia-related contractile dysfunction.27–29 Although it remains controversial whether chronic AF is independently associated with a worse outcome,6,7,10,30 most evidence suggests that new-onset AF indicates an adverse prognosis.8,9 However, in patients with advanced heart failure, neither preexisting AF nor new-onset AF appears to have an independent effect on mortality.11,31 The CARE-HF data are consistent with and extend these recent findings. Mortality was higher in patients who developed AF in both treatment groups; however, this was not independent of other, more powerful risk factors in the prognostic model.
Because patients with heart failure who develop AF have a worse outcome, it is of particular interest to know whether outcome might be improved by CRT. The data on the efficacy of cardiac resynchronization in patients with chronic AF are conflicting.32–36 In the present study, we did not prospectively randomize patients with and without preexisting AF but rather evaluated the efficacy of cardiac resynchronization on the outcome of patients who developed AF after randomization. We cannot exclude a weak attenuation of the effects of CRT by new-onset AF, suggested by the observation that a history of AF both attenuated CRT efficacy and was a predictor for new-onset AF during the study. However, if AF developed, most of the benefit of CRT was retained. New-onset AF did not diminish the impact of CRT on the primary or any secondary end points of the main trial. Moreover, the benefits of CRT on cardiac function, functional class, and NT-BNP remained despite the development of AF. Adequate blockade of AV conduction, with ß-blockers and digoxin to produce pharmacological ablation,37 to ensure biventricular stimulation and regular left ventricular contraction, is probably essential to maintaining the efficacy of CRT once AF has developed.
Study Limitations
This study was not designed prospectively to analyze the incidence and importance of AF. The incidence of new-onset AF was assessed by adverse event reporting or presence on ECGs during follow-up or hospitalization. Device diagnostics enabled additional detection of asymptomatic AF in the CRT group. However, similar documentation of asymptomatic AF in the medical therapy group would not have been feasible without device implantation.
Clinical Implications and Conclusions
Cardiac resynchronization does not prevent or increase the induction of AF. Resynchronization therapy significantly improved the outcome of patients similarly, whether or not they developed AF.
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Acknowledgments |
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We thank the CARE-HF study team for their work on the CARE-HF trial, Berthold Stegemann and Sandra Jacobs for their work in data preparation, and Giulia Magrini for analyses of echocardiograms.
Sources of Funding
Dr Cleland has received research grants from Medtronic, Vasomedical, and Abbott. Dr Freemantle has received research grants from Aventis and Amgen.
Disclosures
Dr Cleland has worked as a consultant for Medtronic, Amgen, Menarini, and Pfizer. Dr Freemantle has worked as a consultant for Medtronic and Pfizer. Dr Erdmann has worked as a consultant for Medtronic and Guidant. The remaining authors report no conflicts.
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J. P. Piccini, A. F. Hernandez, D. Dai, K. L. Thomas, W. R. Lewis, C. W. Yancy, E. D. Peterson, G. C. Fonarow, and for the Get With the Guidelines Steering Committee Use of Cardiac Resynchronization Therapy in Patients Hospitalized With Heart Failure Circulation, August 26, 2008; 118(9): 926 - 933. [Abstract] [Full Text] [PDF]
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 J. W H Fung, G. W K Yip, and C.-M. Yu Does atrial fibrillation preclude biventricular pacing? Heart, July 1, 2008; 94(7): 826 - 827. [Full Text] [PDF]
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K Khadjooi, P W Foley, S Chalil, J Anthony, R E A Smith, M P Frenneaux, and F Leyva Long-term effects of cardiac resynchronisation therapy in patients with atrial fibrillation Heart, July 1, 2008; 94(7): 879 - 883. [Abstract] [Full Text] [PDF]
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 S. Buck, M. Rienstra, A. H. Maass, W. Nieuwland, D. J. Van Veldhuisen, and I. C. Van Gelder Cardiac resynchronization therapy in patients with heart failure and atrial fibrillation: importance of new-onset atrial fibrillation and total atrial conduction time Europace, May 1, 2008; 10(5): 558 - 565. [Abstract] [Full Text] [PDF]
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E. Adelstein and S. Saba Cardiac resynchronization therapy and atrial tachyarrhythmias: a question still searching for an answer. J. Am. Coll. Cardiol., February 12, 2008; 51(6): 676 - 677. [Full Text] [PDF]
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 J. G.F. Cleland, A. P. Coletta, A. T. Abdellah, D. Cullington, A. L. Clark, and A. S. Rigby Clinical trials update from the American Heart Association 2007: CORONA, RethinQ, MASCOT, AF-CHF, HART, MASTER, POISE and stem cell therapy Eur J Heart Fail, January 1, 2008; 10(1): 102 - 108. [Abstract] [Full Text] [PDF]
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W.H. W. Tang and G. S. Francis The Year in Heart Failure J. Am. Coll. Cardiol., December 11, 2007; 50(24): 2344 - 2351. [Full Text] [PDF]
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 L. Padeletti, P. Pieragnoli, V. Jentzen, and A. Schuchert The comorbidity of atrial fibrillation and heart failure: a challenge for electrical therapies Eur. Heart J. Suppl., December 1, 2007; 9(suppl_I): I81 - I86. [Abstract] [Full Text] [PDF]
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 H.-R. Neuberger, C. Mewis, D. J. van Veldhuisen, U. Schotten, I. C. van Gelder, M. A. Allessie, and M. Bohm Management of atrial fibrillation in patients with heart failure Eur. Heart J., November 1, 2007; 28(21): 2568 - 2577. [Abstract] [Full Text] [PDF]
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D. Yannopoulos, K. G. Lurie, S. Sakaguchi, S. Milstein, C. Ermis, L. VanHeel, and D. G. Benditt Reduced Atrial Tachyarrhythmia Susceptibility After Upgrade of Conventional Implanted Pulse Generator to Cardiac Resynchronization Therapy in Patients With Heart Failure J. Am. Coll. Cardiol., September 25, 2007; 50(13): 1246 - 1251. [Abstract] [Full Text] [PDF]
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A. R. Leon The Class I Cardiac Resynchronization Therapy Effect? J. Am. Coll. Cardiol., September 25, 2007; 50(13): 1252 - 1253. [Full Text] [PDF]
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S. H. Hohnloser and E. N. Prystowsky CRT-D use in heart failure: too little or too much? Eur. Heart J. Suppl., September 1, 2007; 9(suppl_G): G9 - G16. [Abstract] [Full Text] [PDF]
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J. D. Burkhardt and B. L. Wilkoff Interventional Electrophysiology and Cardiac Resynchronization Therapy: Delivering Electrical Therapies for Heart Failure Circulation, April 24, 2007; 115(16): 2208 - 2220. [Abstract] [Full Text] [PDF]
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 U. C. Hoppe, N. Freemantle, J. G.F. Cleland, M. Marijianowski, and E. Erdmann Effect of Cardiac Resynchronization on Morbidity and Mortality of Diabetic Patients With Severe Heart Failure Diabetes Care, March 1, 2007; 30(3): 722 - 724. [Full Text] [PDF]
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