Adequate Initial Heparin Dosage for Atrial Fibrillation Ablation in Patients Receiving Non-Vitamin K Antagonist Oral Anticoagulants

The present study was conducted at a single-centre, Okayama Heart Clinic (Okayama, Japan), and it included patients who underwent their first AF ablation between September 2013 and December 2014. Patients with previous AF ablation and decreased renal function (creatinine clearance rate <30 mL/min) were excluded.

We analysed 360 patients (age 64 ± 10 years; 274 men and 86 women; 224 with paroxysmal AF and 136 with non-paroxysmal AF). Patients were classified into a control (warfarin) group and three NOAC groups: dabigatran, rivaroxaban and apixaban. Each group included 90 consecutive patients. On the basis of the Heart Rhythm Society’s scientific statement described above, 100 U/kg of an initial bolus heparin dose in patients receiving warfarin anticoagulation therapy was used in the control group [4]. The primary and second endpoints were set as the ACT measured 15 min after the initial bolus heparin administration (15-min ACT) and thromboembolic complications. A preliminary test to determine the range of the heparin dosage in the NOAC groups indicated that 100 U/kg did not provide >50 % of patients with 15-min ACTs >300 s. Therefore, for each NOAC group, the dosage of the initial heparin bolus administration was randomly assigned, i.e. 110, 120 and 130 U/kg, as stated below. The anticoagulant regimens in the three groups are shown in Fig. 1. The selection and dosages of NOAC were left to the physician’s discretion, considering the patient’s characteristics (including renal function) and the drug manufacturer’s directions [8]. Dabigatran and apixaban were administered twice a day in the morning and evening. Rivaroxaban was administered once a day in the morning.

After the completion of AF ablation, heparin was discontinued. Protamine was administered intravenously (20 or 30 mg, 2800–3600 anti-heparin IU) just after removal of all sheaths to reverse heparin, depending on whether the ACT was 300–350 s or >350 s, respectively). When bleeding at the puncture site did not stop after the initial administration of protamine sulfate, additional doses of it (10–20 mg, 1400–2800 anti-heparin IU) were administered, depending on the bleeding status. Haemostasis at the catheter insertion site was confirmed 3 h after completion of the AF ablation, which was the removal of all devices and sheaths from the vessels, then a single dose of each NOAC was administered.

Data obtained from 120 days of anticoagulation therapy (from 30 days before to 90 days after) were analysed. The examination procedure complied with the rules of the Declaration of Helsinki [9], and the study was approved by the Institutional Ethics Committee for Human Research of Okayama Heart Clinic. Written informed consent was obtained from all patients.

Details of the present AF ablation procedure have been published elsewhere [10]. In brief, for electrical mapping and ablation, five venous accesses were obtained as follows. Two standard electrophysiology catheters were positioned: a 4-French (F) catheter (Japan Lifeline Co., Ltd, Tokyo, Japan) at the His bundle region via a femoral vein and a 6-F catheter in the coronary sinus via the right intrajugular vein. Three catheters were positioned in the LA by use of the Brockenbrough technique, which requires two decapolar ring catheters (Japan Lifeline Co., Ltd) and an open irrigated ablation catheter (CoolFlex™, St Jude Medical, Inc.; CoolPath Duo™, St Jude Medical, Inc.; or Safire BLU™, St Jude Medical, Inc.).

PVAI was performed in all patients by use of an open irrigated ablation catheter inserted via the transseptal sheath with an electroanatomic integration mapping system (Ensite-NavX System, St Jude Medical, Inc.). The temperature of the oesophagus was continuously monitored by a catheter with a temperature sensor (SensiTherm™, St Jude Medical, Inc.) during the ablation.

The endpoint of PVAI was defined as [1] the elimination of PV potentials recorded by the two ring catheters within the ipsilateral PVs and the lack of LA capture during intra-PV, isthmus and PV atrium pacing at least 30 min after isolation; and [2] no recurrence of PV spikes within all of the PVs after intravenous administration of 20–40 mg of adenosine triphosphate during sinus rhythm or coronary sinus pacing. Acute success of the ablation was defined as satisfaction of the endpoint criterion noted above.

In patients with paroxysmal AF, only PVAI was performed. In patients with persistent and long-standing persistent AF, additional ablation was performed in combination with PVAI. After PVAI, an LA roof line was created first, and ablation of complex fractionated atrial electrograms in the right atrium, LA and coronary sinus, and linear ablation, were also performed at the operator’s discretion. Further ablation of the superior vena cava and cavotricuspid isthmus was also performed. If the AF did not terminate, direct current cardioversion was performed to achieve normal sinus rhythm.

In each group, when AF ablation was performed in the afternoon, heparin (5000 U) was administered subcutaneously in the morning on the day of the AF ablation procedure.

Before transseptal catheterization, a bolus of heparin (100 U/kg) was administered in the warfarin group as the control. For each NOAC, a bolus of intravenous heparin, in which the dosage was randomly assigned, i.e. 110, 120 and 130 U/kg, was administered. After bolus heparin administration, a continuous heparinized saline infusion was administered via a peripheral vein to maintain the ACT within 300–350 s to avoid thrombus formation. The ACT was measured in 30-min intervals.

After the procedure, anticoagulation therapy was continued for at least 3 months after AF ablation in all groups (Fig. 1). All patients were followed monthly at our centre for at least 90 days after AF ablation.

Cerebrovascular accidents and transient ischaemic attacks were considered thromboembolic complications after intracranial haemorrhage was ruled out. Pulmonary embolism and deep venous embolism were also defined as thromboembolic complications. Cardiac tamponade, pericardial effusion and bleeding were considered bleeding complications. Cardiac tamponade was defined by characteristic clinical features with a considerable pericardial effusion that required drainage. Pericardial effusion was defined as an effusion determined in the pericardial space by routine follow-up echocardiography without any haemodynamic disturbance. Major bleeding was defined as bleeding requiring blood transfusion, haematomas requiring surgical intervention and cardiac tamponade requiring drainage. Late cardiac tamponades were those occurring >48 h after the procedure. Minor bleeding complications included small haematomas and pericardial effusions not requiring drainage (non-tamponade). The primary safety outcome was a composite of bleeding and thromboembolic complications. Miscellaneous non-anticoagulation-related events were also recorded.

We used SPSS version 17 for statistical analysis. Data were expressed as mean ± standard deviation. For comparison of two groups, a student’s t test and Chi squared test were used for continuous and categorical variables, respectively. For multiple comparisons of continuous variables, including ACT levels among the warfarin control and three NOAC groups, we used one-way analysis of variance (ANOVA) or a Kruskal–Wallis test, and Scheffe’s F test or a Mann–Whitney U test with Bonferroni correction as post hoc tests to compare two groups in multiple groups, when appropriate. Chi squared tests with m × n contingency tables and two-tailed tests for categorical variables were used to evaluate the differences among the three NOAC groups. Differences at P < 0.05 were considered significant.