August Issue - Novel oral anticoagulants in patients with non-valvular atrial fibrillation undergoing catheter ablation
Riccardo Cappato, MD
Riccardo Cappato is Head of the Arrhythmia and Electrophysiology Research Centre at the Humanitas Gavazzeni Hospital, Bergamo, and the Istituto Clinico Humanitas in Rozzano, Milan, Italy. Dr Cappato’s clinical focus is the treatment of supraventricular and ventricular arrhythmias with transcatheter radiofrequency ablation. He is a fellow of the European Society of Cardiology and the Heart Rhythm Society, and is the current President of the European Cardiac Arrhythmia Society and co-director of the Europe AF Congress. He is also the co-inventor of the Subcutaneous ICD system. Dr Cappato was the Principal Investigator of the X-VeRT and VENTURE AF studies, investigating the use of periprocedural rivaroxaban in patients with non-valvular atrial fibrillation undergoing cardioversion and ablation, respectively. He has published more than 300 peer-reviewed manuscripts and book chapters, and serves on the editorial boards of several cardiology journals.
Welcome to the August 2015 edition of the Thrombosis Adviser newsletter.
Dear Thrombosis Adviser user,
To restore normal sinus rhythm, patients with non-valvular atrial fibrillation (AF) routinely undergo an ablation procedure, which is recommended as an alternative to antiarrhythmic therapy and/or cardioversion. A variety of ablation approaches exist, the most commonly employed of which uses a catheter-directed energy source to destroy the cardiac tissue responsible for the arrhythmia. The European Society of Cardiology (ESC) recommends catheter ablation as the first-line therapy in selected patients with symptomatic AF if they are receiving antiarrhythmic drug therapy but would instead prefer rhythm control. Catheter ablation is successful in correcting AF in up to 80% of patients.
Like electrical cardioversion, catheter ablation carries a recognized risk of thromboembolic events. This is because the procedure may dislodge pre-existing intracardiac thrombi, cause an air embolism, or lead to thrombus formation on the catheter or ablation lesions. Anticoagulation therapy is therefore required before, during and for a period after the procedure (as defined by guidelines), and may be continued indefinitely in patients with ongoing risk factors for stroke (CHADS2 ≥1 or CHA2DS2-VASc ≥ 2). Guidelines recommend uninterrupted vitamin K antagonist (VKA) therapy, for example with warfarin, dosed to an international normalized ratio (INR) of 2.0–2.5. However, VKAs may be difficult to manage because of variable pharmacokinetics and drug interactions, and the need to monitor the INR and maintain it in the desired range via dose adjustments. Because of these drawbacks, the fixed-dose novel oral anticoagulants (OACs) are increasingly used instead of VKAs for stroke prevention in patients with non-valvular AF (as well as in other settings, such as the prevention and treatment of venous thromboembolism), and their use in patients undergoing ablation is therefore also of interest.
Although limited evidence exists to support the use of novel OACs for catheter ablation, several small, non-randomized, observational studies and meta-analyses (e.g. Providência et al. 2014, Lakkireddy et al. 2014, Di Biase et al. 2015, Aryal et al. 2014, Phan et al. 2015) have suggested a similar safety and efficacy profile for the direct Factor Xa inhibitors rivaroxaban and apixaban, and the direct thrombin inhibitor dabigatran, compared to warfarin. In a subanalysis of the large, randomized ROCKET AF study, a relatively small group of patients undergoing catheter ablation or cardioversion had similar outcomes when receiving either rivaroxaban or warfarin. As a result, the use of rivaroxaban was further investigated in VENTURE AF in patients undergoing catheter ablation. VENTURE AF is currently the only completed prospective, randomized clinical study of a novel OAC in this setting, and despite this being an exploratory study with a small number of patients, it was felt that clinically important and relevant information could be obtained.
A total of 248 patients were randomized to receive either uninterrupted rivaroxaban 20 mg once daily or uninterrupted VKA (INR 2.0–3.0). Catheter ablation could be performed after 1–7 days of anticoagulation if the patient had no evidence of intracardiac thrombus on a transesophageal or intracardiac echocardiogram, or if sufficient anticoagulation was documented for 3 weeks before randomization. All other patients received anticoagulation for 4–5 weeks before undergoing ablation; patients with sufficient anticoagulation documented for 3 weeks before randomization could also elect to undergo ablation at a later date, i.e. after receiving an additional 4–5 weeks of anticoagulation. Unfractionated heparin was administered during the ablation procedure to achieve an activated clotting time of 300–400 seconds (preferred target 300–325 seconds). The primary endpoint was the incidence of major bleeding events during the follow-up period of 30 (±5) days after ablation, during which patients continued on the assigned anticoagulation therapy.
The results of VENTURE AF showed that patients undergoing catheter ablation for non-valvular AF had similar safety outcomes with uninterrupted oral rivaroxaban and uninterrupted standard VKA therapy. The incidence of major bleeding events was very low in both treatment groups, and remained consistent throughout the study period regardless of the definition of bleeding used. Only two thromboembolic events occurred (one ischaemic stroke and one vascular death), both in the VKA arm. Non-major bleeding events and other procedure-attributable events also occurred with similar and low incidences between the treatment arms. Although this was a small, open-label study, the prospectively obtained results support retrospectively analysed data from ROCKET AF and real world evidence demonstrating similar safety and effectiveness for rivaroxaban and VKA in the setting of catheter ablation for non-valvular AF.
VENTURE AF provides important results that are relevant to real world anticoagulation practice and guideline-recommended treatment patterns. Importantly, it also defines some potential treatment modalities. How should rivaroxaban be used in the setting of ablation? As in patients with non-valvular AF, the recommended dose is an oral 20 mg tablet taken once daily with a meal, preferably in the evening. This applies to patients with creatinine clearance >50 ml/min – patients with creatinine clearance ≤50 ml/min were not studied in VENTURE AF. Rivaroxaban should be administered to patients for a minimum of 3 weeks prior to ablation or for a shorter period of 1–7 days in patients with documented absence of intracardiac thrombus. Periprocedural intravenous heparin should be administered and dosed to an accepted target range in line with clinical practice (300–400 seconds; 300–325 seconds was the preferred target in VENTURE AF). Patients can then receive their first post-ablation dose of rivaroxaban ≥6 hours, and no later than 12 hours, after haemostasis is re-established, with anticoagulation continued for at least 4 weeks and for as long as judged clinically necessary – this may be life-long in patients with ongoing risk factors for stroke (CHA2DS2-VASc ≥ 2).
The results of VENTURE-AF complement those of the international, multicentre X-VeRT study, which was the first prospective study of a novel OAC in patients with non-valvular AF in the setting of elective cardioversion. In this study, rivaroxaban had a similar safety and efficacy profile to VKA, but provided practical advantages in terms of improving the numbers of patients with adequate anticoagulation and allowing patients to undergo the procedure after a shorter period of anticoagulant treatment when cardioversion was delayed. Because both X-VeRT and VENTURE AF were designed to reflect real world treatment decisions, the results should provide physicians with confidence that the use of rivaroxaban is feasible and well tolerated in patients with non-valvular AF undergoing procedures to restore sinus rhythm.
In patients undergoing catheter ablation for non-valvular AF, uninterrupted oral rivaroxaban has a similar safety profile to that of uninterrupted VKA therapy, with overall low incidences of thromboembolic, major bleeding and other procedure-attributable events. The VENTURE AF study therefore indicates that rivaroxaban provides clinicians with an additional therapeutic option for patients with non-valvular AF undergoing catheter ablation.
Preparation Date: July 2015