Atrial Fibrillation Ablation and Reduction of Stroke Events
2019; Lippincott Williams & Wilkins; Volume: 50; Issue: 10 Linguagem: Inglês
10.1161/strokeaha.119.026890
ISSN1524-4628
AutoresSérgio Barra, Kumar Narayanan, Serge Bovéda, João Primo, Helena Gonçalves, Jakub Baran, Sharad Agarwal, Éloi Marijon, Rui Providência,
Tópico(s)Cardiac electrophysiology and arrhythmias
ResumoHomeStrokeVol. 50, No. 10Atrial Fibrillation Ablation and Reduction of Stroke Events Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBAtrial Fibrillation Ablation and Reduction of Stroke EventsUnderstanding the Paradoxical Lack of Evidence Sérgio Barra, MD, Kumar Narayanan, MD, PhD, Serge Boveda, MD, PhD, João Primo, MD, Helena Gonçalves, MD, Jakub Baran, MD, PhD, Sharad Agarwal, MD, Eloi Marijon, MD, PhD and Rui Providência, MD, PhD Sérgio BarraSérgio Barra Correspondence to Sergio Barra, MD, Cardiology Department, Hospital da Luz Arrabida, V. N. Gaia, Portugal. Email E-mail Address: [email protected] From the Cardiology Department, Hospital da Luz Arrabida, V.N. Gaia, Portugal (S. Barra) Cardiology Department, V.N. Gaia Hospital Center, Portugal (S. Barra, J.P., H.G.) Cardiology Department, Royal Papworth Hospital, Cambridge, United Kingdom (S. Barra, S.A.) , Kumar NarayananKumar Narayanan Department of Cardiovascular Epidemiology, Paris Cardiovascular Research Center, Paris, France (K.N., E.M.) Cardiology Department, MaxCure Hospitals, Hyderabad, India (K.N.) , Serge BovedaSerge Boveda Cardiology Department, Institute Pasteur, Toulouse, France (S. Boveda) , João PrimoJoão Primo Cardiology Department, V.N. Gaia Hospital Center, Portugal (S. Barra, J.P., H.G.) , Helena GonçalvesHelena Gonçalves Cardiology Department, V.N. Gaia Hospital Center, Portugal (S. Barra, J.P., H.G.) , Jakub BaranJakub Baran Division of Clinical Electrophysiology, Department of Cardiology, Centre of Postgraduate Medical Education, Grochowski Hospital, Warsaw, Poland (J.B.) , Sharad AgarwalSharad Agarwal Cardiology Department, Royal Papworth Hospital, Cambridge, United Kingdom (S. Barra, S.A.) , Eloi MarijonEloi Marijon Department of Cardiovascular Epidemiology, Paris Cardiovascular Research Center, Paris, France (K.N., E.M.) Cardiology Department, European Georges Pompidou Hospital, Paris, France (E.M.) Paris Descartes University, Paris, France (E.M.) and Rui ProvidênciaRui Providência Institute of Health Informatics Research, University College of London, United Kingdom (R.P.) Cardiology Department, Barts Health Center, London, United Kingdom (R.P.). Originally published12 Sep 2019https://doi.org/10.1161/STROKEAHA.119.026890Stroke. 2019;50:2970–2976is corrected byCorrection to: Atrial Fibrillation Ablation and Reduction of Stroke Events: Understanding the Paradoxical Lack of EvidenceOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: September 23, 2019: Previous Version of Record September 12, 2019: Ahead of Print Atrial fibrillation (AF) is the most prevalent chronic arrhythmia and a major cause of stroke and mortality. It is thought to confer an overall 5-fold increased risk of a cerebrovascular event, causing ≈one-third of all ischemic strokes. Half of the 2 to 3 fold higher risk of mortality among AF patients is related to AF itself, not only via fatal progression of heart failure, the most frequent mode, but also sudden death and embolic events.1,2 Importantly, AF patients who suffer a cardioembolic stroke have a worse outcome compared with stroke patients without AF.Anticoagulation has been shown to reduce the risk of a cerebrovascular event in AF patients. However, despite adequate anticoagulation, some patients remain at risk of stroke. Whether successful catheter ablation can reduce this risk remains unclear. Although there has not been any convincing evidence thus far that AF ablation leads to a reduction in the risk of stroke, no randomized study was powered to address this question. In this review article, we discuss the AF-stroke association, as well as the apparent lack of evidence supporting the use of ablation for the specific reduction of this end point.AF-Stroke NexusAlthough the notion of thrombus formation caused by stasis of blood (mostly in the left atrial appendage [LAA]), with subsequent embolism to the brain, has been the generally accepted explanation for the increased risk of stroke in AF, fact is that the exact pathogenesis of stroke in AF patients remains unclear and much more complex, especially when considering the lack of temporality between AF episodes and stroke as observed in patients with implantable loop recorders, and the increased risk of noncardioembolic stroke which has also been reported in AF patients. Mechanisms such as large-artery atherosclerosis, endothelial dysfunction or cerebral small-vessel occlusion, commonly seen in patients with AF, may also contribute to an increased risk of stroke among AF patients, confounding the association to some extent.Recent attention has centered on the atrial cardiopathy hypothesis: this was elegantly described by Kamel et al3 in their updated model of thromboembolic stroke. Briefly, the authors emphasized the importance of an abnormal atrial tissue substrate, or atrial cardiopathy, characterized by progressive chamber dilatation with ensuing fibrosis and impaired myocyte function, which subsequently results in AF and thromboembolism. The arrhythmia itself further increases the risk of thromboembolism and leads to additional adverse structural remodeling of the atrium, thereby worsening the atrial cardiopathy and further increasing the risk of stroke. However, the atrial cardiopathy as a cause of cardioembolic stroke appears to be independent of AF itself. Electrocardiographic markers of atrial dysfunction, such as an abnormally increased P-wave terminal force in lead V1, associate much more strongly with embolic, rather than with lacunar stroke due to small-vessel occlusion, regardless of the presence of AF.4Stroke Reduction by Catheter Ablation of AFIn the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management)5 and RACE (Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation)6 trials, stroke rates did not differ significantly in the rate versus rhythm control groups. However, in both trials, cessation of anticoagulation therapy was allowed 4 weeks after documentation of sinus rhythm, which may have led to increased risk of stroke and mortality in patients in the rhythm control arm. Moreover, they exposed the relative inefficiency of antiarrhythmic drugs in maintaining sinus rhythm (eg, <40% AF-free survival in the RACE trial). Therefore, their results can hardly be extrapolated to the current era of AF treatment when the more effective catheter-based treatment of AF has become common.Maintenance of sinus rhythm is beneficial in patients with AF, with a substudy of the AFFIRM trial showing that both oral anticoagulation and sinus rhythm were independently associated with a better survival and a 60% reduction in stroke risk.7 Because ablation is superior to antiarrhythmic drug therapy for maintaining sinus rhythm and reducing the burden of AF, it would seem logical that this approach could reduce stroke risk to some extent. Multiple studies have assessed whether catheter ablation can reduce the risk of stroke or mortality, and 2 recent meta-analyses8,9 pooled available data to provide further insight. With regard to the outcome of stroke, a reduction was noted only in observational studies,10,11 but the limitations of observational design need to be borne in mind. Patients in whom sinus rhythm can be maintained with ablation are inherently less prone to stroke given their more favorable profile and less advanced atrial cardiopathy. No stroke reduction was noted in the pooled analysis of randomized trials.Since the publication of the 2 aforementioned meta-analyses,8,9 there has been only one additional randomized trial addressing the question of whether AF ablation can impact on hard outcomes.12 This was the largest ever randomized study on this topic, the CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy in Atrial Fibrillation).12 With CABANA included, there were a total of 20 randomized studies comparing patients receiving ablation versus those treated medically and providing outcome data including stroke or mortality.12–31 Except for the study by Di Biase et al,31 all provided data on the risk of stroke. These 19 studies12–30 enrolled 4722 patients (2485 receiving ablation versus 2237 on optimal medical therapy alone; Table). The overall risk of stroke was very low and very similar in both the interventional and medical therapy groups (0.85% risk in the former versus 1.0% in the latter). It may appear paradoxical that available evidence does not lend support to the concept of reduction in stroke events by AF ablation, which may be logically expected, as mentioned earlier. In the following sections, we put this seeming lack of evidence in perspective and discuss possible reasons why it may be difficult for AF ablation to have a demonstrable impact with respect to this end point.Table. Randomized Studies Comparing Catheter Ablation vs Medical Treatment Alone and Providing Data on the Risk of StrokeAuthor, ReferenceSample Size (Patients)No. of EventsAblationNo AblationAblationNo AblationStrokeDeathStrokeDeathKrittayaphong et al1315150000Wazni et al1433370000Stabile et al1568690111Oral et al1677690100Forleo et al1735350000Jais et al1853590022Wilber et al19106610100Pappone et al2099991000MacDonald et al2122191000Cosedis Nielsen et al221461482314Jones et al2326260100Packer et al24163826100Mont et al2598480000Morillo et al2666610000Hummel et al27132721100Hunter et al2826240000Marrouche et al291791847241246Prabhu et al3033330000Packer et al121108109635876724852237219123120AF Ablation Procedure and Anticoagulation ProtocolIn its most typical form, AF ablation procedures involve access to the left atrium through 1 or 2 transseptal punctures and the electrical isolation of the pulmonary veins with radiofrequency energy, cryoablation, or alternative sources of energy. In specific patients, more extensive ablation might be required, such as the ablation of complex fractionated atrial electrograms or ganglionated plexi or the performance of ablation lines. However, the effectiveness of these approaches in improving the outcome of the procedure remains a matter of dispute.The anticoagulation protocol typically involves a minimum of 1 month of effective anticoagulation with either warfarin or one of the new oral anticoagulants before the ablation, plus at least 2 months after it. The decision to discontinue anticoagulation beyond 2 months postablation should not be based on the perceived outcome of the procedure but rather on the patient's stroke risk profile. However, despite these precautions, the occurrence of an embolic stroke remains one of the most feared complications of an AF ablation. This could manifest as symptomatic or asymptomatic stroke or, most frequently, cerebral microembolism. The risk of silent embolism, as detected by cerebral magnetic resonance imaging, can occur in up to 20% to 30% of patients even with uninterrupted anticoagulation therapy.32,33 The risk may be higher in older patients, those with persistent AF (compared with paroxysmal), or submitted to electrical cardioversion or more extensive ablation.Impact of Stroke on AF-Related MortalityIn a subanalysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy), only ≈7% of deaths among AF patients on anticoagulation were due to stroke or peripheral embolism, with most deaths resulting from other cardiac causes or noncardiovascular conditions.2 Similar findings were noted in a large observational study of patients diagnosed with AF in a 4-hospital institution.34 Likewise, in a more comprehensive analysis of contemporary AF trials, most follow-up deaths were seen to be cardiac-related, whereas nonhemorrhagic stroke and systemic embolism represented only 5.7% of the total mortality.35 Perhaps unsurprisingly, stroke or peripheral embolism also represents only a small percentage of in-hospital deaths among hospitalized patients with AF.36Approximately half of deaths reported in AF patients are cardiovascular in nature, whereas one-third die of noncardiovascular causes and the remaining die from stroke or hemorrhage (around 6% each) or other less prevalent causes. Thus, the apparent survival benefit of AF ablation in specific groups of patients, as seen in AATAC (Ablation vs Amiodarone for Treatment of Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted ICD/CRTD) and CASTLE-AF trials (Catheter Ablation Versus Standard Conventional Therapy in Patients With Left Ventricular Dysfunction and Atrial Fibrillation), and as suggested by some subanalyses of CABANA, is likely the result of a reduction in heart failure-related death or the interruption of potentially deleterious antiarrhythmic drug therapy rather than a reduction in stroke-related mortality. This notion is supported by the recent CAMERA-MRI study (Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction), which demonstrated that restoration of sinus rhythm with catheter ablation results in significant improvements in ventricular function in persistent AF patients with idiopathic cardiomyopathy.30 Successful AF ablation may indeed lead to improvements in left ventricular function, particularly when sinus rhythm is maintained.37Low Number of Stroke Events in Contemporary AF PopulationsIn all 19 randomized studies providing data on the risk of stroke in AF ablation patients versus those treated medically, only 44 stroke events were reported. The CASTLE-AF29 and CABANA12 trials accounted for 29 stroke events, with the remaining 18 trials reporting only 15 strokes in total. Contrarily, the risk of death during follow-up in these 19 trials was ≈5× higher, at 3.7% and 5.4% in ablation and medical therapy groups, respectively, translating into a much lower number needed to treat. The overall risk of death would increase to 3.8% and 5.9%, respectively, if we included data from the study by Di Biase et al,31 which reported mortality data but not stroke. In CABANA, the number of deaths was ≈20× and 10× higher than the number of disabling strokes in the ablation and control groups, respectively.12Most patients considered for AF ablation have a low annual stroke risk regardless of whether they are actually ablated, provided they are appropriately anticoagulated if indicated. Freedman et al38 showed that AF patients on anticoagulation have a stroke risk similar to that of non-AF patients, and the residual stroke risk likely reflects the occurrence of noncardioembolic stroke that may be expected in individuals of similar age, sex, and comorbidity without AF rather than anticoagulant treatment failure. Conversely, this finding did not apply for overall death in their study, as AF was associated with a direct mortality risk that was only partially reduced by anticoagulant therapy.38 These results again help explain the more noticeable effect of catheter ablation on mortality risk compared with an apparently limited effect on the risk of stroke. If adequate anticoagulation already reduces AF-related stroke to a large extent, it would be quite difficult to prove a further incremental benefit of catheter ablation in the reduction of residual stroke risk. For instance, if catheter ablation reduced stroke risk by 50%, which would be quite commendable, the number needed to treat to prevent 1 stroke event would still be very high based on a baseline overall absolute risk of only 1.0% in medically treated patients, as seen in randomized data. This helps explain why no randomized study to date was powered to show any meaningful effect of AF ablation on stroke rates, and even pooled data lacks statistical power. Furthermore, it shows how a different metric, such as the number needed to treat, can sometimes provide a more realistic estimate of how useful an intervention can be compared with relative measures of risk. The very low incidence of stroke in randomized studies is, in fact, quite reassuring, although caution is required when extrapolating to real-world patients. Nevertheless, although outcome data in randomized trials is not always representative of real-world data, some studies have shown that the rates of stroke in real-world patients are actually consistent with those seen in landmark trials such as ROCKET-AF and RE-LY.39,40Cardioembolic Versus Noncardioembolic StrokeIs AF always a culprit for stroke in patients with AF?41 This subject has been addressed by different investigators,41,42 although most clinical trials on the risk of stroke in AF have not distinguished between the different stroke mechanisms. It has been estimated that between one-sixth and one-third of classifiable cerebral infarcts in AF patients are unrelated to AF and have characteristics suggestive of a noncardioembolic mechanism.42,43 Large-vessel atheromatosis, in particular that affecting the carotid arteries, and cerebral small-vessel disease may be the cause of stroke, although the distinction between the different pathophysiologic mechanisms of stroke remains a difficult task. The proportion of cardioembolic stroke is significantly lower in patients on anticoagulation, whereas the proportion of noncardioembolic stroke is lower in those taking aspirin.42 Most importantly, and as mentioned before, cardioembolic stroke rates are sharply reduced by adjusted-dose warfarin—a reduction in excess of 80% compared with aspirin.38 A recent study has shown that a 1% increase in anticoagulant use associates with a 0.8% decrease in the weekly rate of AF-related stroke.43 Essentially, stroke rates in adequately anticoagulated AF patients are similar to those of patients without AF38—the residual stroke risk is mainly due to noncardioembolic stroke, for which the effectiveness of oral anticoagulation has been disputed.Although successful catheter ablation may, in theory, reduce the risk of cardioembolic stroke by preventing thrombus formation due to stasis of blood in the context of AF, there is no obvious pathophysiologic mechanism through which AF ablation could reduce the risk of noncardioembolic stroke. Considering that most patients submitted to AF ablation have a CHA2DS2-VASc score between 0 and 3, their estimated annual risk of stroke off anticoagulation would vary between 0.2% and 3.2%. The risk of cardioembolic stroke, corresponding to between two-thirds and five-sixths of that number, can be drastically reduced with consistent anticoagulation, leaving a residual annual stroke risk of up to 0.5% to 0.6% consisting mostly of noncardioembolic events. Lifestyle modification, including aggressive treatment of vascular risk factors and concomitant comorbidities, such as hypertension, sleep apnea, diabetes mellitus, dyslipidemia, and obesity, is thus more likely to impact on the residual risk of stroke rather than catheter ablation.Cardioembolic Stroke in Appropriately Anticoagulated PatientsAF patients on adequate anticoagulation have a stroke risk, which is similar to that of non-AF patients.38 However, the potential for stroke still remains, as described above. Although it is reasonable to speculate that most of these events represent noncardioembolic stroke events, the detection of LAA thrombus in a nonnegligible percentage of appropriately anticoagulated patients suggests the potential for cardioembolic stroke, albeit very low, still persists. Several studies have shown that AF patients on adequate anticoagulation not infrequently develop LAA thrombus, as detected through transesophageal echocardiography.44–46 The probability of LAA thrombus formation is higher in patients in persistent AF, with higher CHA2DS2-VASc scores, increased left atrial size, reduced LAA flow velocity, and decreased left ventricular systolic function.44–46 However, in patients without any risk factor, the incidence of LAA thrombus approaches zero.46 It is, therefore, recommendable that LAA thrombus is excluded in patients with clinical features associated with increased cardioembolic risk and that the decision to anticoagulate post-AF ablation takes into account not only the CHA2DS2-VASc score of the patient but also left atrial size and function.Asymptomatic Cerebral EmboliGenerally speaking, randomized studies accounted for neither asymptomatic stroke nor cerebral microembolism, which may represent the majority of cerebrovascular events in AF patients. Contrary to the strategy of anticoagulation cessation in AFFIRM5 and RACE,6 most AF patients undergoing ablation continue their anticoagulation indefinitely according to their CHA2DS2-VASc score. Asymptomatic embolic signals, as detected by transcranial Doppler, have been shown to predict stroke risk in acute stroke, symptomatic carotid stenosis, and postoperatively after carotid endarterectomy.47 Although the incidence of cerebral microembolic signals during endocardial ablation procedures has been previously examined,48 whether AF ablation reduces the long-term risk of cerebral microembolism has never been assessed before, but given the possible association between AF and increased risk of dementia,49 such a study could provide important insights. There is an increasing body of evidence associating AF with cognitive decline or dementia, possibly the result of recurrent asymptomatic cerebral thromboembolism. Notwithstanding, any potential impact on long-term silent thromboembolism must be weighed against the procedural risk of stroke and asymptomatic thromboembolism, the latter of which occurs in a substantial percentage of patients32,33 and is mostly related to procedural parameters, such as the activated clotting time value and performance of electrical cardioversion.50 The long-term implications of an accumulated burden of neurological injury from intracardiac interventions, such as catheter ablation, are unknown.Recurrences of AF Following Catheter AblationAF recurrence rates of up to 54.5% were reported in AF trials (eg, 36.9% in CASTLE-AF and 52% in CABANA), which means that although catheter ablation was fairly successful in reducing AF burden, many patients were still experiencing AF. Importantly, as most AF episodes are asymptomatic, intermittent monitoring alone is inadequate in assessing AF burden, and estimates of AF control in randomized trials which did not use continuous monitoring likely overestimate the efficacy of ablation or antiarrhythmic drug therapy. Research has shown that even short episodes of atrial arrhythmia associate with increased stroke risk, and thus very high AF-free survival rates may be required to significantly reduce the risk of stroke.Adverse Atrial RemodelingAlthough AF ablation may significantly reduce AF burden, thereby theoretically preventing some cardioembolic events, it does not fully reverse the process of reverse remodeling nor does it satisfactorily control the systemic risk factors associated with noncardioembolic stroke. It is possible that the atrial cardiopathy per se plays a bigger role in the pathophysiology of AF-related stroke than AF itself (AF thereby being merely a marker of that condition). Atrial structural and electrical remodeling are associated with not only increased automaticity and triggered activity and subsequently recurrent arrhythmia but also increased risk of thromboembolism. Preablation atrial fibrosis associates with increased risk of both arrhythmia and stroke. In fact, more severe left atrial late gadolinium enhancement associates with increased risk of major adverse cardiovascular and cerebrovascular events, driven primarily by increased risk of stroke or transient ischemic attack.51Final RemarksSummarizing, current randomized data do not demonstrate a clinically impactful reduction in stroke risk through AF ablation. The reasons for this are manifold. First, absolute stroke rates are very low in appropriately anticoagulated contemporary AF populations; hence, even large relative reductions in stroke risk would still translate into a tiny net benefit. Second, residual stroke risk may largely relate to noncardioembolic stroke wherein AF ablation cannot be expected to show benefit. Third, even occasional, short, potentially silent AF recurrences postsuccessful AF ablation may still matter as far as stroke risk is concerned. Lastly, adverse atrial remodeling (atrial cardiopathy) is likely a dominant factor in stroke risk, relatively unimpacted by ablation. A relatively unexplored area is the issue of silent cerebral microembolism with attendant cognitive impairment, and further research should focus on whether AF ablation has any long-term impact in this regard. In conclusion, it appears unlikely that a randomized trial can be adequately powered to show meaningful reductions in stroke risk by AF ablation, considering low absolute event rates, although the ongoing EAST trial (Early Treatment of Atrial Fibrillation for Stroke Prevention, https://www.clinicaltrials.gov. Unique identifier: NCT01288352) may provide some needed clarity in this area. Thus, pragmatic discussions on the long-term value of AF ablation should move away from a stroke centric approach and rather focus on the potential reduction of cardiovascular mortality and hospitalization (for which there is increasingly encouraging evidence). With the ready availability of reliable anticoagulation with new oral anticoagulants, interventions beyond stroke-reduction measures are clearly warranted to meaningfully reduce total mortality in this population (Figure).Download figureDownload PowerPointFigure. Treatment options for different stages of the atrial cardiopathy. LAAO indicates left atrial appendage occlusion; and OAC, oral anticoagulation. *Risk factors: arterial hypertension, diabetes mellitus, obesity, sleep apnea, any other conditions associated with endothelial dysfunction.DisclosuresDr Barra reports grants from Biosense and Biotronik outside the submitted work. Dr Marijon reports personal fees from BMS, Bayer, and Boehringer Ingelheim; grants from Abbott; and personal fees from Biosense during the conduct of the study. The other authors report no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart AssociationCorrespondence to Sergio Barra, MD, Cardiology Department, Hospital da Luz Arrabida, V. N. Gaia, Portugal. Email [email protected]comReferences1. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study.Circulation. 1998; 98:946–952. doi: 10.1161/01.cir.98.10.946LinkGoogle Scholar2. Marijon E, Le Heuzey JY, Connolly S, Yang S, Pogue J, Brueckmann M, et al; RE-LY Investigators. 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