Differences in activated clotting time and total unfractionated heparin dose during pulmonary vein isolation in patients on different anticoagulation therapy

Abstract Background Periprocedural pulmonary vein isolation (PVI) anticoagulation requires balancing between bleeding and thromboembolic risk. Intraprocedural anticoagulation is monitored by activated clotting time (ACT) with target value >300 s, and there are no guidelines specifying an initial unfractionated heparin (UFH) dose. Methods We aimed to assess differences in ACT values and UFH dosage during PVI in patients on different oral anticoagulants. We conducted an international, multi‐center, registry‐based study. Consecutive patients with atrial fibrillation (AF) undergoing PVI, on uninterrupted anticoagulation therapy, were analyzed. Before transseptal puncture, UFH bolus of 100 IU/kg was administered regardless of the anticoagulation drug. Results Total of 873 patients were included (median age 61 years, IQR 53–66; female 30%). There were 248, 248, 189, 188 patients on warfarin, dabigatran, rivaroxaban, and apixaban, respectively. Mean initial ACT was 257 ± 50 s, mean overall ACT 295 ± 45 s and total UFH dose 158 ± 60 IU/kg. Patients who were receiving warfarin and dabigatran compared to patients receiving rivaroxaban and apixaban had: (i) significantly higher initial ACT values (262 ± 57 and 270 ± 48 vs. 248 ± 42 and 241 ± 44 s, p < .001), (ii) significantly higher ACT throughout PVI (309 ± 46 and 306 ± 44 vs. 282 ± 37 and 272 ± 42 s, p < .001), and (iii) needed lower UFH dose during PVI (140 ± 39 and 157 ± 71 vs. 171 ± 52 and 172 ± 70 IU/kg). Conclusion There are significant differences in ACT values and UFH dose during PVI in patients receiving different anticoagulants. Patients on warfarin and dabigatran had higher initial and overall ACT values and needed lower UFH dose to achieve adequate anticoagulation during PVI than patients on rivaroxaban and apixaban.


| INTRODUCTION
Pulmonary vein isolation (PVI) is a well-established therapeutic option for patients with atrial fibrillation (AF). 1,2 Although currently performed on a routine basis, PVI is associated with a nonnegligible complication rates. 3,4 Periprocedural PVI anticoagulation strategy always represents a balance between the risk of bleeding (vascular access site complications and pericardial effusion/tamponade) and the risk of thromboembolic incidents, in particular cerebrovascular events which incidence could reach up to 1%. [1][2][3][4][5][6] Effective intraprocedural anticoagulation is essential to minimize the risk of thromboembolism during the PVI and is monitored throughout the procedure by activated clotting time (ACT). 1,[7][8][9] It has been observed that thrombi could form on the transseptal sheath and/or the catheter even before the transseptal puncture. 7 Early unfractionated heparin (UFH) administration significantly reduces the risk for thrombus formation. 7,8 However, the use of high UFH loading doses may come with a higher bleeding risk, suggesting that there exists a potential for overshooting with the initial UFH bolus. 1,4,10,11 The EHRA/HRS consensus statement recognizes the need of higher initial doses of UFH in patients on DOACs than on vitamin K antagonist (VKA), as well as the requirement for more frequent ACT measurements. 1 Similarly, it has been recognized by the EHRA Practical guide on the use of DOACs, that larger doses of UFH might be required to achieve target ACT values in patients on DOACs than on VKA. 12 In addition, recent studies showed great variability in UFH loading dosage and periprocedural anticoagulation strategies. 1,4,[8][9][10][11][12] Thus, the aim of the current study is to assess differences in ACT values and total UFH dosage during PVI in patients on different oral anticoagulation therapies. We aimed to evaluate the differences in the initial and overall ACT during the procedure as well as doses of the initial UFH bolus required to achieve ACT >300 s in patients receiving different oral anticoagulation therapy.

| METHODS
We performed an international, multi-center, registry-based cohort analysis. Total of nine electrophysiology centers from four countries (Table 1) were actively participating in the prospective Southeast-Central European PVI (SECE-PVI) registry. Consecutive patients with paroxysmal, persistent and long-standing persistent AF enrolled in the SECE-PVI registry, in the period between April 2016 and July 2019, were analyzed. Patients with moderate and severely decreased renal function (creatinine clearance rate < 50 ml/min), those with anticoagulation therapy started just before or after PVI and in whom the ACT measurements were not done or not recorded properly were excluded from the study. Additionally, patients with left atrial appendage thrombus have not undergone PVI, and thus could not be included in the registry or the study itself. Baseline demographic characteristics, medical history with chronic medication usage and all procedural data were collected. Baseline laboratory data included hemoglobin, platelet count, international normalized ratio (INR) and serum creatinine.
All included patients gave written informed consent for participating in the SECE-PVI registry. The hospital's Ethics Committee gave its approval for the study, which was conducted in accordance with the current version of Declaration of Helsinki.

| Anticoagulation therapy and ACT measurement
In each group, last dose of warfarin or DOAC was given in the evening before the procedure. When PVI was performed in the afternoon, morning dose of warfarin or DOAC was administered in the morning  (13) 3.6 (9) 3.7 (7) 3.7 (7) 0.65 COPD 1.9 (17) 2.4 (6) 1.6 (4)

| Statistical analysis
The distribution of variables was tested using Kolmogorov-Smirnov

| DISCUSSION
The main findings of this multi-center, registry-based cohort study are as follows: (1)  The requirement for higher initial doses of UFH during PVI in patients receiving DOACs has been previously reported. 11,[15][16][17][18] Recently, the study by Payne et al. 10 showed that the patients receiv-