Risks and management of cardioversion and catheter ablation in atrial fibrillation

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Atrial fibrillation is one of the most common arrhythmias that increases in prevalence with age, hypertension,1 alcohol abuse,2 and genetic disposition.3 Together with symptoms such as palpitations and exercise intolerance, atrial fibrillation is associated with stroke and most probably also an increased risk of premature death.4 Currently, anticoagulation with vitamin K antagonists or novel oral anticoagulants (NOACs) is recommended by all guidelines in the prevention of stroke,5 while catheter-based ablation is considered in those not responding to or not tolerating antiarrhythmics.6 The impact of the procedure on outcomes is still controversial,7,8 except in patients with heart failure.9 Catheter-based ablation is also associated with complications,10 among them bleeding and stroke, and extremely rarely death.11 Thus, peri-interventional anticoagulation is an issue addressed in a FAST TRACK entitled ‘Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial’ by Stefan Hohnloser and colleagues from the Klinikum der J.W. Goethe Universität in Frankfurt, Germany.12 This trial, an open-label randomized parallel-group study, assessed safety and efficacy of once-daily edoxaban vs. vitamin K antagonists in 553 patients undergoing catheter ablation. In the ablation population, the primary endpoint was observed in 2.7% on edoxaban and in 1.7% on vitamin K antagonists between the start of ablation and the end of treatment (Figure 1). Incidence rates of combined primary endpoint in ELIMINATE-AF (death, stroke, and International Society on Thrombosis and Haemostasis-defined major bleeding) in the non-vitamin K oral anticoagulant and vitamin K antagonist arms in the modified intent-to-treat peri- and post-ablation study period. Comparison with combined event rates in the three other randomized trials comparing uninterrupted non-vitamin K oral anticoagulant therapy with uninterrupted vitamin K antagonist therapy are shown. For all trials, rates of International Society on Thrombosis and Haemostasis-defined major bleeding events were included. AF, atrial fibrillation; APX, apixaban; DABI, dabigatran; EDX, edoxaban; ISTH, International Society on Thrombosis and Haemostasis; NOAC, non-vitamin K oral anticoagulant; RIV, rivaroxaban; VKA, vitamin K antagonist (from Hohnloser SH, Camm J, Cappato R, Diener H-C, Heidbüchel H, Mont L, Morillo CA, Abozguia K, Grimaldi M, Rauer H, Reimitz P-E, Smolnik R, Mönninghoff C, Kautzner J. Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. See pages 3013–3021). There was one ischaemic and one haemorrhagic stroke, both in patients on edoxaban. Small cerebral microemboli were detected by magnetic resonance imaging in 13.8% on edoxaban compared with 9.6% on vitamin K antagonists. The authors conclude that in spite of a trend to more events with the NOAC, uninterrupted edoxaban therapy represents a alternative to uninterrupted vitamin K antagonist treatment in patients undergoing ablation. In his Editorial, Christopher B. Granger from Duke University Medical Center in Durham, North Carolina, USA discusses the validity of these results for clinical practice.13 Cardioversion of atrial fibrillation bears a certain risk of thrombo-embolic events, even in the presence of anticoagulants.14 It is unclear whether cardioversion causes thrombo-embolic events or is rather a risk marker. In their article entitled ‘Thromboembolic events around the time of cardioversion for atrial fibrillation in patients receiving antiplatelet treatment in the ACTIVE trials’, Jeff S. Healey and colleagues from McMaster University in Canada addressed this issue.15 They studied 962 patients randomized to aspirin or aspirin plus clopidogrel, comparing the thrombo-embolic rate 30 days before until 30 days after cardioversion with the rate thereafter during follow-up. The 30-day thrombo-embolic rate remote from cardioversion was 0.16%, but 0.73% in the peri-cardioversion period (hazard ration 4.1). The 30-day thrombo-embolic rates in the periods immediately before and after cardioversion were 0.47% and 0.96%, respectively (hazard ratio 2.2). Heart failure hospitalization also increased in the peri-cardioversion period, with a hazard ratio of 11.5. Compared with baseline, the thrombo-embolic rate in the 30 days following cardioversion was increased both in patients who received oral anticoagulation or a transoesophogeal echocardiogram prior to cardioversion (hazard ratio 7.9) and in those who did not (hazard ratio 7.9; Figure 2). Of note, the risk was also increased with successful and unsuccessful cardioversion. Thus, thrombo-embolic risk increased in the month before and after cardioversion similar to heart failure hospitalization. Hence, the increased thrombo-embolic risk around cardioversion may not be entirely causal but rather confounded by the overall clinical deterioration of patients requiring cardioversion, a conclusion that is further discussed in a balanced Editorial by Freek W.A. Verheugt from the Onze Lieve Vrouwe Gasthuis in Amsterdam, The Netherlands.16 Incidence of thromboembolism according to time from cardioversion459 hospitalized (A) and 503 non-hospitalized (B) patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate (from McIntyre WF, Connolly SJ, Wang J, Masiero S, Benz AP, Conen D, Wong JA, Beresh H, Healey JS. Thromboembolic events around the time of cardioversion for atrial fibrillation in patients receiving antiplatelet treatment in the ACTIVE trials. See pages 3026–3032). While catheter ablation has emerged as an important treatment option with excellent results in patients with symptomatic atrial fibrillation,17 there are limited data on differences in outcomes in the two genders. In their article ‘Sex-based differences in outcomes, 30-day readmissions, and costs following catheter ablation of atrial fibrillation: the United States Nationwide Readmissions Database 2010–14’ Jim Way Cheung and colleagues from the Weill Cornell Medical College in New York, USA sought to compare in-hospital outcomes and 30-day readmissions of women and men undergoing atrial fibrillation ablation.18 Based on ICD-9-CM codes of the United States Nationwide Readmissions Database, they identified co-morbidities and outcomes in 54 597 patients of whom 38% were female. After adjustment, women had higher rates of any complication, with an odds ratio of 1.39, such as cardiac perforation, bleeding, and/or vascular complications. Thirty-day all-cause readmission rates were also higher for women, with 13.4% compared with 9.4% in men. Surprisingly, despite increased complications and readmissions, total costs for atrial fibrillation ablation were lower for women than for men due to decreased resource utilization. Thus, independent of age, comorbidities and hospital factors, women have higher rates of complications and readmissions following atrial fibrillation ablation. How such disparities in the management of atrial fibrillation would need to be addressed is further discussed in a interesting Editorial by Rashmee Shah from the University of Utah Hospital in SLC, Utah, USA.19 Gout is a highly symptomatic disease and is associated with a higher risk of cardiovascular disease,20 and atrial fibrillation in particular. Allopurinol or febuxostat21 are used to lower uric acid in such patients, but the ability to reduce atrial fibrillation risk is unknown. This issue is discussed in the article ‘Comparative effectiveness of allopurinol and febuxostat for the risk of atrial fibrillation in the elderly: a propensity-matched analysis of Medicare claims data’ by Jasvinder A. Singh and colleagues from the University of Alabama at Birmingham in Alabama, USA.22 They studied a cohort of 23 135 elderly who had received a new prescription for allopurinol or febuxostat, with a baseline period of 365 days without either medication. In 9% of these incidents, allopurinol or febuxostat use ended in incident atrial fibrillation, with crude incidence rates of 8.0 and 10.5 per 100 person-years, respectively. In propensity-matched analyses, febuxostat was associated with a hazard ratio of atrial fibrillation of 1.25. Compared with allopurinol <200 mg/day, febuxostat 80 mg/day was associated with a hazard ratio of 1.62, but not febuxostat 40 mg/day or higher allopurinol doses. Thus, febuxostat is associated with a higher risk of atrial fibrillation compared with allopurinol in older adults, most evident in the first 6 months. The clinical importance of these findings is explored further in an Editorial by Stefano Masi from the University College London in the UK.23 This issue is complemented by various Discussion Forum contributions. In the first one entitled ‘Risk stratification for stroke in atrial fibrillation: incorporating neurologists in the comprehensive management’, Hai-Feng Li from the Qilu Hospital of Shandong University in Beijing, China comment on the recently published article entitled ‘Risk stratification for stroke in atrial fibrillation: a critique’ by Ammar M. Killu and colleagues from the Mayo Clinic in Rochester, USA.24,25 Killu et al. respond to Li and colleagues in a separate response.26 In the second Discussion Forum contribution entitled ‘Central autonomic network and Takotsubo cardiomyopathy: how left insular cortex interact?’ Michiaki Nagai and colleagues from the Hiroshima City Asa Hospital in Hiroshima, Japan comment on the recently published article ‘Altered limbic and autonomic processing supports brain–heart axis in Takotsubo syndrome’ by Christian Templin and colleagues from the University Hospital Zurich in Switzerland.27,28 Templin et al. respond to this contribution in their own manuscript.29 Finally, in a third Discussion Forum, ‘Recommendations for participation in competitive sport in athletes with hypertrophic cardiomyopathy: opening the sacks of Aeolus’, Efstathios D. Pagourelias and colleagues from the University Hospitals Leuven in Belgium comment on the recently published contribution entitled ‘Recommendations for participation in competitive and leisure time sport in athletes with cardiomyopathies, myocarditis, and pericarditis: position statement of the Sport Cardiology Section of the European Association of Preventive Cardiology (EAPC)’ by Sanjay Sharma from the St George’s University of London in the UK, and colleagues.30,31 The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet for help with compilation of this article.