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Abstract
Objective To investigate whether catheter ablation of atrial fibrillation (AF) reduces stroke rate or mortality.
Methods An international multicentre registry was compiled from seven centres in the UK and Australia for consecutive patients undergoing catheter ablation of AF. Long-term outcomes were compared with (1) a cohort with AF treated medically in the Euro Heart Survey, and (2) a hypothetical cohort without AF, age and gender matched to the general population. Analysis of stroke and death was carried out after the first procedure (including peri-procedural events) regardless of success, on an intention-to-treat basis.
Results 1273 patients, aged 58±11 years, 56% paroxysmal AF, CHADS2 score 0.7±0.9, underwent 1.8±0.9 procedures. Major complications occurred in 5.4% of procedures, including stroke/TIA in 0.7%. Freedom from AF following the last procedure was 85% (76% off antiarrhythmic drugs) for paroxysmal AF, and 72% (60% off antiarrhythmic drugs) for persistent AF. During 3.1 (1.0–9.6) years from the first procedure, freedom from AF predicted stroke-free survival on multivariate analysis (HR=0.30, CI 0.16 to 0.55, p<0.001). Rates of stroke and death were significantly lower in this cohort (both 0.5% per patient-year) compared with those treated medically in the Euro Heart Survey (2.8% and 5.3%, respectively; p<0.0001). Rates of stroke and death were no different from those of the general population (0.4% and 1.0%, respectively).
Conclusion Restoration of sinus rhythm by catheter ablation of AF is associated with lower rates of stroke and death compared with patients treated medically.
- AF
- catheter ablation
- outcome
- mortality
- stroke
- atrial fibrillation
- arrhythmias
- radiofrequency ablation (RFA)
- ventricular tachycardia
- ventricular fibrillation
- ECG
- stroke
- ICD
- atrial arrhythmias
- radiofrequency catheter ablation
- sudden cardiac death
- pacing
- electrophysiology
- atrial flutter
- EBM
- invasive electrophysiology
- arrhythmic right ventricular dysplasia
- WPW syndrome
- implantable cardioverter defibrillator (ICD)
- sudden cardiac death
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- AF
- catheter ablation
- outcome
- mortality
- stroke
- atrial fibrillation
- arrhythmias
- radiofrequency ablation (RFA)
- ventricular tachycardia
- ventricular fibrillation
- ECG
- stroke
- ICD
- atrial arrhythmias
- radiofrequency catheter ablation
- sudden cardiac death
- pacing
- electrophysiology
- atrial flutter
- EBM
- invasive electrophysiology
- arrhythmic right ventricular dysplasia
- WPW syndrome
- implantable cardioverter defibrillator (ICD)
- sudden cardiac death
Introduction
The association between atrial fibrillation (AF) and increased risk of stroke and death is well known, but poorly understood.1 Although the AFFIRM study showed no benefit of a predominantly medical rhythm control strategy over rate control,2 a post hoc analysis suggested that maintenance of sinus rhythm was associated with reduced mortality, but that this was negated if antiarrhythmic drugs (AADs) were used.3 This relationship has been demonstrated subsequently in some studies,4 5 but not others.6 Hence it remains unclear whether AF is a risk marker that should be ameliorated, or a risk factor that might be eliminated.
Catheter ablation is now successful in maintaining freedom from AF long term in the majority of patients without the need for AADs,7–12 raising the possibility that it might reduce rates of stroke and death. Several single-centre registries 7–9 11–13 and two large multicentre registries10 14 have demonstrated low rates of stroke and death after catheter ablation of AF. Data from one large multicentre registry suggested that risk of stroke and death after catheter ablation of AF is reduced compared with patients treated medically, and is the same as that of the general population.10
Since randomised data to confirm this effect remain some years away, we sought to investigate the impact of catheter ablation of AF on long-term outcomes by compiling an international multicentre registry. Outcomes were compared with (1) a real-world cohort of patients with AF treated medically in the Euro Heart Survey on AF, and (2) a hypothetical cohort of the general population without AF, age and gender matched to registry patients using UK national statistics.
Methods
A multicentre registry was compiled from a collaborative group in the UK and Australia. Independent prospective registries were held for consecutive patients undergoing catheter ablation of AF (paroxysmal or persistent), including baseline demographics, procedural data, complications and follow-up. The peri-procedural management, procedural techniques and follow-up varied between centres, although there were certain commonalities.
Peri-procedural management and anticoagulation
All patients underwent trans-oesophageal echocardiography before the procedure to rule out intracardiac thrombus. Patients were anticoagulated peri-procedurally, and continued to receive warfarin for at least 3 months after the procedure. Subsequent advice about anticoagulation was guided by thromboembolic risk rather than freedom from AF, according to guidelines.15
Catheter ablation procedures
All procedures included pulmonary vein isolation as a procedural end point. A majority of patients underwent wide-area circumferential ablation guided by a 3D mapping system, although a variety of techniques were used including segmental ostial isolation, cryo-balloon ablation (Arctic Front, Medtronic, California, USA) and robotic ablation with the Hansen robot (Hansen Medical Inc, Mount View, California, USA). Lesions were also not limited to pulmonary vein isolation, and included targeting of fractionated electrograms and linear ablation, particularly for persistent AF.
Patient follow-up
A 3-month blanking period was observed as recurrences during this period, termed early recurrence of AF, often settle spontaneously.16–18 Where possible, patients were managed medically during this period and repeat intervention avoided. Patients were followed up at 3 and 6 months, with a period of ambulatory monitoring. Patients with persistent AF/atrial tachycardia or symptomatic paroxysmal AF at 3 months or after were offered a repeat procedure. Follow-up after 6 months varied between institutions and included clinic visits, telephone appointments, follow-up with local cardiologists and open access to arrhythmia nurse specialists. Attempts were made to contact patients to update follow-up, but where this was not possible the final follow-up was taken from the point of last patient contact.
As catheter ablation of AF carries a small procedural risk, to discern any long-term impact on outcomes a minimum period within which to derive benefit must be allowed. Therefore, registry data were included for consecutive cases up to 1 year before data analysis for this study began. Analyses of rates of stroke and death were carried out after the first procedure in an intention-to-treat fashion. Subsequent analysis aimed to answer the following questions:
Did restoring sinus rhythm impact on rates of stroke and death?
Was catheter ablation as a strategy, regardless of success, associated with lower rates of stroke and death than patients treated medically?
Were rates of stroke and death with catheter ablation of AF as a treatment strategy, regardless of success, any different to the general population without AF?
What is the risk of stroke during follow-up after catheter ablation of AF in those who stopped oral anticoagulant therapy (OAT)?
Impact of restoration of sinus rhythm
Success was defined as freedom from documented AF/atrial tachycardia lasting ≥ 30 s after the 3 month blanking period according to current guidelines,15 and is reported following the final procedure. The rates of stroke and death in those in whom sinus rhythm was restored were compared with those in patients where AF recurred.
Outcomes after catheter ablation compared with medical treatment for AF
Published data describing risk of stroke in anticoagulated patients were insufficient to allow patient matching. Therefore, patients were compared with a large published cohort of patients managed medically (>97%) in the real world, in the Euro Heart Survey on AF.19 20 Analysis included all patients, regardless of success, and included adverse procedural events.
Outcomes after catheter ablation of AF compared with outcomes for the general population
Rates of stroke and death in our cohort were compared with a hypothetical cohort with an equal number of patient-years of follow-up, age and gender matched to the general population. Mortality rates were taken from UK national statistics.21 22 Analysis included all patients, regardless of success, and included adverse procedural events.
Stroke after catheter ablation of AF without warfarin
Rates of stroke during follow-up (excluding procedural events) in those who stopped OAT was broken down by CHADS2 and CHA2DS2 VASc scores, and compared with expected rates.23 24 Rates of major bleeding complications were also gathered.
Statistics
Continuous variables are reported as mean±SD, or median (range) if not normally distributed. Continuous data were compared by Student t test if normally distributed or χ2 test if not normally distributed. Categorical data were compared by χ2 test. Kaplan–Meier curves were used to analyse freedom from AF and stroke-free survival. Groups were compared using the log-rank test. Multivariate analysis of predictors of stroke or death was by Cox regression and included the following factors: freedom from AF, hypertension, gender, cardiac failure, persistent AF and continuing use of AADs as categorical covariates, and age as a continuous covariate. Variables were then removed stepwise from the model when the p value exceeded 0.10, and variables with p<0.05 in the final model were considered to be significant predictors of stroke and death. Analysis was performed using SPSS V.16 (SPSS Inc).
Results
Patients and procedures
A total of 1273 patients were included, their demographics are shown in table 1. In total 2261 procedures were performed, with a mean of 1.7±0.8 for paroxysmal AF and 1.9±0.9 for persistent AF (p<0.0001). Over the long term, 584 patients (46%) had one procedure, 464 (36%) had two procedures, 169 (13%) had three procedures, 39 (3%) had four procedures, 16 (1%) had five procedures, and one had six procedures.
Patient demographics and stroke risk factors
The procedural complications are shown in table 2. There were no procedural deaths, although two patients died within 30 days of their procedure. One patient had a procedural stroke, and died 5 days later from a myocardial infarction owing to in-stent thrombosis (on a background of ischaemic heart disease and previous coronary stents). The second had a history of ischaemic heart disease and severe left ventricular systolic dysfunction, had a tamponade drained at the time of the procedure and despite being well initially, died from a combination of hospital-acquired pneumonia and cardiac failure at 10 days.
Procedural complications
Follow-up and freedom from AF
Patients were followed up for 3.1 (1.0–9.6) years from their first procedure, and 2.2 (0.2–8.9) years from their last procedure. This gave a total of 4189 patient-years of follow-up for analysis. Kaplan–Meier analysis of AF fee survival is shown in figure 1. After the final procedure, freedom from AF (or other atrial tachyarrhythmia) was achieved in 85% for paroxysmal AF (76% off AADs), and 72% for persistent AF (60% off AADs).
Freedom from atrial fibrillation (AF). Kaplan–Meier curve showing freedom from AF following the last procedure for patients with paroxysmal AF (PAF) and persistent AF. Comparison of curves was by the log-rank test. The number in brackets is the proportion free from AF and not receiving antiarrhythmic drugs (AADs).
Freedom from AF and survival
Freedom from AF was associated with lower rates of stroke and death, which was highly significant on univariate analysis (p<0.0001; figure 2). Freedom from AF remained a significant predictor of stroke-free survival on multivariate analysis (figure 3) with an HR of 0.33 (95% CI 0.17 to 0.67). After stepwise removal from the model of covariates with p>0.10, the variables remaining were freedom from AF (HR=0.30, 95% CI 0.16 to 0.55, p<0.001), female gender (HR=0.37, 95% CI 0.15 to 0.89, p=0.027) and age (HR=1.03 per year of age, 95% CI 1.00 to 1.07, p=0.051).
Maintenance of sinus rhythm and stroke-free survival. Kaplan–Meier curve showing stroke-free survival for patients who remained free from atrial fibrillation (AF) compared with those with recurrent AF. Comparison of curves was by the log-rank test. The number at the bottom is the number of patients still followed up at each time point.
Multivariate analysis of factors predicting stroke and death. Multivariate analysis was carried out using Cox regression. Figures show HRs with 95% CIs, p values are shown to the right. AAD denotes continuing antiarrhythmic drug use. AF, atrial fibrillation.
Rates of stroke and death compared with the Euro Heart Survey
The Euro Heart Survey enrolled 5333 patients with AF, >97% of whom were managed medically.20 Patients in the Euro Heart Survey were slightly older at 65±12 years compared with 58±11 years in our cohort, and with a higher CHADS2 score at 1.6±1.2 (18% scored 0, 33% scored 1, 27% scored 2, 13% scored 3, 9% scored ≥4) compared with 0.7±0.9 in our patients (breakdown is shown in table 1). Follow-up data were reported for 4192 patients at 1 year, with the outcomes compared with this cohort in figure 4.19 There were 117 ischaemic strokes or transient ischaemic attacks (TIAs) (2.8% per patient-year) in the Euro Heart Survey compared with 20 in this cohort (0.5% per patient-year; p<0.0001). There were 221 deaths (5.3% per patient-year) in the Euro Heart Survey compared with 23 in this cohort (0.5% per patient-year; p<0.0001).
Outcome after catheter ablation of atrial fibrillation (AF) compared with medical treatment in the Euro Heart Survey and controls without AF in the general population. Bars show rates of stroke, death, or a composite of both as a percentage of patients per 100 years of patient follow-up for the study cohort, for the Euro Heart Survey on AF and for a hypothetical cohort matched to the study cohort for age and gender from UK national statistics. *Denotes a significant difference between the Euro Heart Survey cohort and the other two groups.
Rates of stroke and death compared with the general population
The rates of stroke and death in a population matched to this cohort for age and gender were 0.4% and 1.0% per year, respectively. There was no difference between this cohort and the general population for stroke. There was a slightly lower mortality in the ablation cohort (p<0.05) than in the general population. Overall, the rates of stroke and death were no different in the ablation cohort from those in the general public.
Rates of stroke during follow-up when OAT had been stopped
Of 1273 patients, 464 (36%) continued with OAT. Of the 809 in whom OAT was stopped, 690 patients (85%) took an antiplatelet drug. Patients were much more likely to have their OAT stopped if they were free from AF (69% continued with OAT in those with recurrent AF vs 29% in those free from AF, p<0.0001), despite a very small, albeit statistically significant, difference in CHADS2 scores (0.9±0.9 in those with recurrent AF vs 0.7±0.9 in those who remained free from AF, p<0.0001). In those who stopped warfarin, four strokes or TIAs occurred during follow-up (excluding those within 30 days of a procedure). The number of TIAs or strokes broken down by CHADS2 and CHA2DS2VASc scores is shown in table 3,23 24 with expected event rates taken from the studies defining these algorithms.23 24
Strokes and transient ischaemic attack (TIA) during follow-up while not receiving warfarin
Bleeding events
Ten major bleeds occurred in those who continued with OAT (0.4% a year), including five intracerebral haemorrhages (0.2% a year), two of which were fatal (0.1% a year). In those who stopped OAT, two major bleeds occurred (0.1% a year), one of which was an intracerebral haemorrhage, and neither of which were fatal (both patients were taking an antiplatelet drug).
Discussion
Freedom from AF predicted stroke-free survival within the cohort, and was the strongest predictor of those studied in our multivariate analysis. An ablation strategy was associated with low rates of stroke and death over the long term. In particular, rates of stroke and death were substantially lower than in patients with AF managed medically in the Euro Heart Survey on AF, and were comparable with those of the general population. In patients who had stopped OAT, rates of stroke were very low, both in those assessed as low or medium risk and, in a limited number of patient follow-up years, in those at high risk.
Freedom from AF as a predictor of stroke-free survival
Although the AFFIRM study showed no benefit in pursuing a predominantly pharmacological rhythm control strategy over rate control,2 a post hoc analysis showed that achieving sinus rhythm was associated with a halving of mortality, although this effect was effectively negated if continuing antiarrhythmic therapy was used.3 This relationship between sinus rhythm and mortality has been demonstrated subsequently in some studies,4 5 but not others.6 The potential for antiarrhythmic agents to increase mortality has been documented in several high-profile trials such as CAST,25 SWORD26 and SPAF.27 A recent trial showing reduced cardiovascular death in patients with AF taking dronedarone suggests that rhythm control with certain drugs may still provide a survival benefit.28
Freedom from AF was found to be a powerful predictor of stroke-free survival in this cohort, with an approximate two-thirds reduction in events. Although it remains possible that AF is a risk marker of more serious cardiac disease, rather than a causative factor, freedom from AF remained the strongest predictor of stroke-free survival on multivariate analysis. Increasing age and a male gender were also shown to be associated with increased risk. Despite women in the general population having a lower stroke rate than men,22 female gender is associated with a higher stroke risk in AF.24 The lower risk associated with female gender in this cohort suggests that restoring sinus rhythm may be particularly beneficial for reducing stroke risk for women. Cardiac failure and AAD use were both associated with a higher hazard ratio, although these did not reach statistical significance. This relationship between survival and freedom from AF after ablation is compatible with the findings of a smaller single-centre study.9
Rates of stroke and death compared with medical treatment
Since there is a small procedural risk with catheter ablation of AF, and since patients often need repeat procedures to achieve and maintain sinus rhythm, the rates of stroke and death included all procedural events and those during follow-up in order to portray accurately the long-term event rate with a catheter ablation strategy. The rates of stroke and death were low (0.5% a year each) during an average follow-up of >3 years. Outcomes were compared with patients treated medically in the Euro Heart Survey on AF.20 This was a ‘real-world’ cohort, meaning that a range of treatments were employed, including rate control and rhythm control, although >97% were managed medically.20 OAT in the Euro Heart Survey was based on thromboembolic risk, and 72% of those deemed high risk were anticoagulated.29 Accepting a small difference in baseline risk between cohorts, there was an eightfold higher rate of these events in those treated medically.
This difference in outcome between those managed medically and those undergoing catheter ablation is consistent with the results from smaller registries, and one large recent multicentre registry.8 10 11 13 These studies reported mortalities ranging from 0.4% to 2.4% a year following catheter ablation of AF compared with 2.9%–9.4% for patients with AF treated medically (with similar rates of stroke where it was reported). The rates of stroke and death in this cohort (and those of our comparator group, the Euro Heart Survey on AF) were comparable to these rates reported by others. The consistency of these findings suggests that lower rates of stroke and death are found with a catheter ablation strategy than with medical treatment of AF.
Rates of stroke and death compared with the general population
The rates of stroke and death were compared with a hypothetical cohort matched for age and gender from UK national statistics. The event rate was no different between our cohort and the general population, a finding consistent with other large registries.8 10 These data suggest that elimination of AF may normalise risk of stroke and death.
Rates of stroke when OAT had been stopped
The stroke rate during follow-up was analysed independently of procedural events, so as to better inform the doctor assessing risk and benefit of anticoagulation after catheter ablation of AF. The rate of stroke while not receiving OAT was low at 0.2% a year overall. The majority of patients were low or medium risk (ie, CHADS2 score 0 or 1, respectively), although there were 150 patient-years of follow-up in patients conventionally deemed high risk (ie, CHADS2 ≥2) without a single event. Similarly, using the more sensitive CHA2DS2 VASc system, there were >200 patient-years of follow-up for scores of 0, 1, 2 and 3, all with very low event rates. Other large registries have reported similarly low rates of stroke after catheter ablation of AF.7 14
The rates of embolic stroke while not receiving OAT were similar to the rates of intracerebral haemorrhage while continuing with OAT (0.2%). This suggests that conventional risk stratification systems such as CHADS2 and CHA2DS2 VASc may be too sensitive to apply to populations after successful catheter ablation of AF. However, the risk/benefit ratio of OAT in this setting cannot be re-appraised until it has been prospectively evaluated.
Limitations
The independent prospective registries which comprise this study were all dependent on doctors' record keeping, and hence events may have been missed through error. However, the rates of thromboembolic stroke, intracerebral haemorrhage and death are all in keeping with other studies in this setting. Furthermore, the impact of freedom from AF on stroke-free survival cannot be attributed to such error.
It is recognised that the retrospective nature of registries makes them prone to bias. The patients in the cohort were a selected population. Those with serious concurrent illness and other high-risk groups, such as those with thrombus in the left atrial appendage, were excluded. Furthermore, all patients were seen by arrhythmia specialists, and this was not necessarily the case in the Euro Heart Survey.
Conclusion
These data, taken in conjunction with those of other recent multicentre registries, suggest that an ablation strategy is associated with lower rates of stroke and death compared with patients with AF treated medically and, furthermore, that this risk is no different from that of the general population. Therefore, by extension, this suggests that AF is not simply a risk marker but is responsible for an increased risk of stroke and death, and that elimination of AF normalises that risk. These data highlight the urgent need for (1) randomised controlled trials to confirm these findings, and (2) prospective evaluation of the risk/benefit ratio of OAT after successful catheter ablation of AF.
References
Footnotes
Funding RJH is supported by a British Heart Foundation grant (PG/08/130). This work was facilitated by Barts and The London NHS Trust NIHR Biomedical Research Unit.
Competing interests None.
Ethics approval This was retrospective analysis of registry data.
Provenance and peer review Not commissioned; externally peer reviewed.