**Optimal Anticoagulant Strategy for Periprocedural Management of Atrial Fibrillation Ablation: A Systematic Review and Network Meta-Analysis**

**Tabito Kino 1, Minako Kagimoto 2, Takayuki Yamada 3, Satoshi Ishii 2, Masanari Asai 4, Shunichi Asano 5, Hideto Yano 6, Toshiyuki Ishikawa <sup>7</sup> and Tomoaki Ishigami 7,\***


**Abstract:** This network meta-analysis was performed to rank the safety and efficacy of periprocedural anticoagulant strategies in patients undergoing atrial fibrillation ablation. MEDLINE, EMBASE, CENTRAL, and Web of Science were searched to identify randomized controlled trials comparing anticoagulant regimens in patients undergoing atrial fibrillation ablation up to July 1, 2021. The primary efficacy and safety outcomes were thromboembolic and major bleeding events, respectively, and the net clinical benefit was investigated as the primary-outcome composite. Seventeen studies were included (*n* = 6950). The mean age ranged from 59 to 70 years; 74% of patients were men and 55% had paroxysmal atrial fibrillation. Compared with the uninterrupted vitamin-K antagonist strategy, the odds ratios for the composite of primary safety and efficacy outcomes were 0.61 (95%CI: 0.31–1.17) with uninterrupted direct oral anticoagulants, 0.63 (95%CI: 0.26–1.54) with interrupted direct oral anticoagulants, and 8.02 (95%CI: 2.35–27.45) with interrupted vitamin-K antagonists. Uninterrupted dabigatran significantly reduced the risk of the composite of primary safety and efficacy outcomes (odds ratio, 0.21; 95%CI, 0.08–0.55). Uninterrupted direct oral anticoagulants are preferred alternatives to uninterrupted vitamin-K antagonists. Interrupted direct oral anticoagulants may be feasible as alternatives. Our results support the use of uninterrupted direct oral anticoagulants as the optimal periprocedural anticoagulant strategy for patients undergoing atrial fibrillation ablation.

**Keywords:** periprocedural anticoagulant management; atrial fibrillation ablation; direct oral anticoagulant; vitamin-K antagonist; network meta-analysis

#### **1. Introduction**

Atrial fibrillation (AF) is a cardiac arrhythmia common worldwide [1]. Catheter ablation (CA) is the most effective treatment to prevent AF recurrence [2], and over the last decade, it has resulted in dramatic improvements in safety and efficacy [3–7]. However, periprocedural complications occur in approximately 4–14% of patients undergoing AF ablation, 2–3% of which are potentially life-threatening [8]. Periprocedural stroke or transient ischemic attack (TIA) and cardiac tamponade are the most notable complications [9,10]. As these adverse events are affected by periprocedural anticoagulant management, an

**Citation:** Kino, T.; Kagimoto, M.; Yamada, T.; Ishii, S.; Asai, M.; Asano, S.; Yano, H.; Ishikawa, T.; Ishigami, T. Optimal Anticoagulant Strategy for Periprocedural Management of Atrial Fibrillation Ablation: A Systematic Review and Network Meta-Analysis. *J. Clin. Med.* **2022**, *11*, 1872. https:// doi.org/10.3390/jcm11071872

Academic Editor: Gani Bajraktari

Received: 2 February 2022 Accepted: 25 March 2022 Published: 28 March 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

optimal anticoagulant strategy is essential for the prevention of thromboembolic and bleeding complications.

Compared with vitamin-K antagonists (VKAs), direct oral anticoagulants (DOACs) have been shown to have a favorable risk-benefit profile, as they significantly reduce the incidence of stroke and also carry a similar bleeding risk in the long-term treatment of patients with AF [11]. With respect to CA, many studies have found that DOACs have similar efficacy and safety compared with VKAs [12–19]. These results led to the guideline recommendation of uninterrupted anticoagulants for the perioperative management of patients undergoing AF ablation [8,9]. Conversely, a German survey reported that interrupted and minimally interrupted DOAC was used more frequently than truly uninterrupted DOAC to avoid bleeding complications [20]. Moreover, some meta-analyses including randomized controlled trials (RCTs) have revealed that interrupted DOAC was not inferior to uninterrupted DOAC administration and was preferable to uninterrupted VKA administration [21,22]. Currently, guidelines lack indications based on these RCTs regarding which strategy is preferable for periprocedural anticoagulant management. This was the first study comparing each strategy and regimen with network meta-analysis (NMA) to simultaneously compare multiple treatments in a single analysis by combining direct and indirect evidence within a network of RCTs [23].

This study aimed to synthesize the available evidence from RCTs using NMA to: (1) assess the relative effects of different uninterrupted or interrupted anticoagulant strategies between DOACs and VKAs for reducing thromboembolic or bleeding events in patients undergoing AF ablation; and (2) to rank regimens, uninterrupted or interrupted, and DOAC or VKA administration for effectiveness in preventing thromboembolic or bleeding complications.

#### **2. Materials and Methods**

#### *2.1. Protocol and Registration*

Our report follows the preferred reporting items for systematic reviews and metaanalyses (PRISMA)-NMA extension (Table S1) [24]. The study protocol was registered at PROSPERO (CRD42021268787).

#### *2.2. Eligibility Criteria*

Only studies that met the eligibility criteria were included. The criteria were: (1) only RCTs; (2) uninterrupted or interrupted anticoagulant strategy in the periprocedural period; (3) patients undergoing AF ablation; and (4) publication of efficacy (stroke, TIA, or systemic embolism) and safety (major bleeding) outcomes. We excluded duplicate studies. There were no language or publication date restrictions.

#### *2.3. Search Strategy*

We performed a systematic search of the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science databases up to July 1, 2021. The search used the Population, Intervention, Comparators, Outcomes, and Study design format and included the following terms: atrial fibrillation, ablation, periprocedural anticoagulation, and randomized controlled trial (Table S2). Three independent and blinded reviewers (SI, MA, and SA) separately assessed the search results to select studies based on the eligibility criteria. When a consensus was not reached by the three reviewers, a fourth author (TI) was consulted to reach a decision.

#### *2.4. Outcomes*

The primary efficacy outcome was thromboembolic events, including stroke, TIA, or systemic embolism. The primary safety outcome was major bleeding as defined by the Bleeding Academic Research Consortium (BARC) [25] or the International Society on Thrombosis and Hemostasis (ISTH) [26]. The secondary safety outcome was minor bleeding, and the secondary efficacy outcome was asymptomatic cerebral embolism (ACE). ACE was diagnosed using diffusion-weighted magnetic resonance imaging (MRI). Minor bleeding was defined as any bleeding that did not fulfil the BARC or ISTH criteria. The net clinical benefit was investigated as a composite of the primary safety and efficacy outcomes.

#### *2.5. Data Extraction and Synthesis*

We extracted the following data from the studies: study name, baseline characteristics, anticoagulant regimens, and outcomes. Two reviewers (MK and TY) independently extracted the data. When disagreements between reviewers occurred, a third author (TI) was consulted to reach a decision.

All study regimens were synthesized as follows: uninterrupted DOAC (UI-DOAC), interrupted DOAC (I-DOAC), uninterrupted VKA (UI-VKA), and interrupted VKA (I-VKA) administration. The number of thromboembolic events, major bleeding, composite of primary outcomes, minor bleeding, and ACE were synthesized, and odds ratios (ORs) were estimated. Additionally, all strategies were synthesized per anticoagulant (apixaban, dabigatran, edoxaban, rivaroxaban, and warfarin), and the ORs of the composite of the primary outcomes were estimated in subgroup analyses. The geometry of the network was illustrated using direct comparative treatments.

#### *2.6. Risk of Bias Assessment*

We evaluated the risk of bias using the revised Cochrane risk-of-bias tool for randomized trials (RoB2) [27]. Two reviewers (MK and TY) were involved in the quality assessment; if disagreements occurred, a third author (TI) was consulted to reach a consensus.

#### *2.7. Statistical Analysis*

NMA statistical analyses were performed with frequentist methods using *Netmeta* (version 1.5-0) in R 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria). The ORs and 95% confidence intervals (CIs) were estimated based on a random effects model. Additionally, we calculated the P-score and the surface under the cumulative ranking (SU-CRA) to evaluate and rank the anticoagulant strategies and regimens [28,29]. Both rankings are measured on a scale from 0 (worst) to 1 (best). Common network heterogeneity was evaluated using the *I* <sup>2</sup> measure to locate the source of heterogeneity [30]. Heterogeneity was defined as low, moderate, or high when *I* <sup>2</sup> was 25%, 50%, or 75%, respectively [31]. Inconsistency between direct and indirect evidence was examined globally and locally [32,33]. Begg's rank correlation and Egger's linear regression were performed to assess publication bias among the studies [34,35]. We conducted sensitivity analyses by excluding one study at a time for the four different strategies of the network. Subgroup analysis was performed to evaluate each anticoagulant regimen for the composite of the primary outcomes.

#### **3. Results**

#### *3.1. Study Identification and Study Population Characteristics*

We initially identified 124 studies via the electronic databases, and four additional studies were identified through references. Fifty duplicate studies were removed and 78 were screened. We excluded 57 studies after screening the titles and abstracts, and 21 were retrieved for detailed evaluation, from which four studies were subsequently excluded from the analysis because they did not meet the eligibility criteria (Figure 1). Finally, our meta-analysis included 17 RCTs with 6950 patients undergoing AF ablation [36–52]. They were allocated to I-VKA (*n* = 835) [36,37], UI-VKA (*n* = 2097) [36,38–44], I-DOAC (*n* = 1465) [37,38,45–51], and UI-DOAC (*n* = 2553) groups [39–52]. All approved DOACs (apixaban [40,43,45–51], dabigatran [37,38,41,47,48,51], edoxaban [44,48,49,51,52], and rivaroxaban [39,42,45,47–49,51,52]) were included.

**Figure 1.** Flow diagram of the included studies. The PRISMA flow diagram depicts the phases of the systematic review and shows the number of records identified, screened, included, and excluded. RCT, randomized controlled trial.

The age of the participants ranged from 59 to 70 years (median = 62 years); 74% were men and 55% had paroxysmal AF. Twelve studies (71%) reported mean CHA2DS2-VASc scores ranging from 1.5 to 2.8 (median 2.0). In 15 studies (88%), the median follow-up duration was 30 days (range: 2–90 days). The detailed clinical characteristics of the included studies are summarized in Tables 1 and S3.





**Table 1.** *Cont.*



All studies reported primary efficacy (thromboembolic events) and safety (major bleeding) outcomes, while 14 and 8 studies (82% and 47%, respectively) reported minor bleeding [36–44,46,48–51] and ACE [40,42–45,48,49,52], respectively.

#### *3.2. Risk of Bias Assessment*

We evaluated all studies in five dimensions (Table S4). Concerns were noted for 14 RCTs (82%). All protocols were composed of two interventions after randomization: anticoagulant initiation and AF ablation. Since some deviations occurred before CA, outcomes were analyzed as a modified intention-to-treat population who underwent AF ablation. Some small RCTs did not mention the concealment method. However, none of the studies were classified as having a high bias risk. Therefore, we included all studies in the NMA.

#### *3.3. Structure of the Network*

Figure 2 shows the network of anticoagulant strategies used in the main analysis. We compared four strategies: UI-DOAC, I-DOAC, UI-VKA, and I-VKA, and set UI-VKA as a reference. All direct comparative studies were included, except UI-DOAC vs. I-VKA.

**Figure 2.** Network of treatment comparisons for the overall primary efficacy and safety outcomes. Directly comparable treatments are linked to lines. The nodes are placed and labelled according to the treatments. The thickness of the edges is proportional to the inverse standard error of the treatment effects, aggregated over all studies, including the two respective treatments. The network includes 16 two-armed studies. UI, uninterrupted; I, interrupted; DOAC, direct oral anticoagulant; VKA, vitamin-K antagonist.

#### *3.4. NMA Results for the Primary and Secondary Outcomes*

The results of the NMA for thromboembolic events, major bleeding, and the composite of primary outcomes are presented as forest plots (Figure 3a–c). I-VKA was associated with an increased risk of thromboembolic events compared to UI-VKA (OR [95% CI]: 15.77 [4.16–59.70]), whereas there was no significant difference between UI-DOAC and I-DOAC (OR: 0.97 [0.24–3.87] and OR: 1.31 [0.25–6.86]). Compared to UI-VKA, UI-DOAC significantly decreased the risk of major bleeding (OR: 0.55 [0.31–0.97]). However, I-DOAC and I-VKA did not have a significant effect (OR: 0.53 [0.22–1.23] and OR: 2.70 [0.65–11.18]). In the composite of thromboembolic events and major bleeding, UI-DOAC and I-DOAC were not inferior to UI-VKA (OR: 0.61 [0.31–1.17] and OR: 0.63 [0.26–1.54]), while I-VKA significantly increased the risk of thromboembolic events and major bleeding (OR: 8.02 [2.35–27.45]). Heterogeneity was low for primary outcomes (thromboembolic events, *I* <sup>2</sup> = 0.0%; major bleeding, *I* <sup>2</sup> = 7.8%; and the composite of primary outcomes, *I* <sup>2</sup> = 23.4%).

**Figure 3.** Forest plots for efficacy and safety of anticoagulant strategies compared with UI-VKA. (**a**) The efficacy of thromboembolic events (stroke, TIA, or systemic embolism); (**b**) the safety of major bleeding; (**c**) the efficacy and safety of the composite of the primary outcomes (stroke, TIA, or systemic embolism and major bleeding); (**d**) the safety of minor bleeding; and (**e**) the efficacy of asymptomatic cerebral embolism. TIA, transient ischemic attack; OR, odds ratio; CI, confidence interval; UI, uninterrupted; I, interrupted; DOAC, direct oral anticoagulant; VKA, vitamin-K antagonist.

Regarding the secondary outcomes, the NMA results for minor bleeding and ACE are presented in Figure 3d,e. Both UI-DOAC and I-DOAC carried comparable risks of minor bleeding with UI-VKA (OR: 1.11 [0.87–1.40] and OR: 1.19 [0.79–1.79]), but I-VKA significantly increased the risk (OR: 6.02 [4.19–8.66]). UI-DOAC and I-DOAC were also similar to UI-VKA for the risk of ACE (OR: 1.11 [0.67–1.83] and OR: 1.64 [0.81–3.29]). Heterogeneity was low for secondary outcomes (minor bleeding, *I* <sup>2</sup> = 0.0%; and ACE, *I* <sup>2</sup> = 22.9%).

Table 2 displays the P-score and SUCRA values for the primary and secondary outcomes. There were no ranking mismatches between the P-score and SUCRA. The SUCRA value of DOACs was nearly twice that of UI-VKA in the composite of the primary outcomes (UI-DOAC, 0.82; I-DOAC, 0.77; and UI-VKA, 0.40). In contrast, the secondary outcome SUCRA values were higher for UI-VKA than for DOACs; particularly, the ACE value for I-DOAC was markedly low (UI-DOAC, 0.60; I-DOAC, 0.09; and UI-VKA, 0.82).


**Table 2.** P-score and the SUCRA values for each strategy and outcome.

SUCRA, surface under the cumulative ranking; UI, uninterrupted; I, interrupted; DOAC, direct oral anticoagulant; VKA, vitamin-K antagonist.

Overall, the UI-DOAC strategy was favorable and the I-DOAC strategy was feasible compared with the UI-VKA strategy for the primary and secondary outcomes. However, the I-VKA strategy significantly increased the risk of thromboembolic and bleeding events compared to the UI-VKA strategy.

#### *3.5. Sensitivity Analyses*

We performed sensitivity analyses for the composite of the primary outcomes (Table S5). RE-CIRCUIT and ELIMINATE-AF were the main sources of heterogeneity [41,44]. Moreover, UI-DOAC was associated with a significant reduction in major bleeding; however, this finding was not robust because it was no longer significant when 10 studies were excluded. Overall, this analysis did not suggest that the excluded studies would affect the relative effects and rankings of the anticoagulant strategies.

#### *3.6. Assessment of Inconsistency and Publication Bias*

The inconsistency test did not suggest the presence of inconsistency in the network (Figure S1). Begg's and Egger's tests did not reveal significant publication bias among the included studies (Figure S2).

#### *3.7. Subgroup Analysis*

We conducted a subgroup analysis based on each anticoagulant regimen. The composite of thromboembolic and major bleeding events was analyzed and displayed in a forest plot (Figure 4) and a league table (Table S6); we also calculated the P-score and SUCRA values (Table 3). Four studies were excluded because they had no randomized regimens for each DOAC [47–49,51], and one study included both UI-DOAC arms [52]. The structure of the subgroup network is shown in Figure S3. UI-dabigatran significantly decreased the risk of the composite of the primary outcomes compared with UI-VKA (OR: 0.21 [0.08–0.55]), whereas I-VKA significantly increased the risk (OR: 8.39 [3.43–20.56]). Other anticoagulants had a comparable risk to that of UI-VKA. The P-score and SUCRA values were notably higher for UI-dabigatran and I-dabigatran than for the other anticoagulant regimens (UI-dabigatran, 0.95; and I-dabigatran, 0.82 in SUCRA).

**Table 3.** P-score and the SUCRA values for each strategy and composite of primary outcome.


SUCRA, surface under the cumulative ranking; UI, uninterrupted; I, interrupted; VKA, vitamin-K antagonist.

**Figure 4.** Forest plot for the composite of primary outcomes for each anticoagulant regimen. OR, odds ratio; CI, confidence interval; VKA, vitamin-K antagonist; UI, uninterrupted; I, interrupted; Dab, dabigatran; Api, apixaban; Riv, rivaroxaban; Edo, edoxaban.

#### **4. Discussion**

In this study, we compared uninterrupted or interrupted DOAC administration with uninterrupted or interrupted VKA administration as periprocedural anticoagulant strategies for patients undergoing AF ablation. The main findings were as follows: (1) the risk of thromboembolic events among the strategies was exceedingly rare (UI-DOAC: 0.20%, I-DOAC: 0.20%, and UI-VKA: 0.24%) and not significantly different within strategies, except for the I-VKA strategy (4.79%); (2) ACE occurred with an incidence of 15–21%; (3) major bleeding tended to be halved by DOAC compared with UI-VKA administration; (4) minor bleeding did not differ between DOACs and VKAs, except for I-VKA; and (5) UI-dabigatran significantly reduced the composite of thromboembolic and major bleeding events.

After the COMPARE trial [36], the UI-VKA strategy has been widely adopted as a periprocedural anticoagulant strategy for patients undergoing AF ablation. Meanwhile, there is growing evidence regarding the efficacy and safety of DOACs in patients with AF [53–56]. Recently, worldwide RCTs have revealed that UI-DOAC may be equivalent to UI-VKA [39,41,43,44]. Therefore, the latest guidelines classify the UI-DOAC strategy as a class I recommendation [8,9]. However, I-DOAC is also used as a periprocedural anticoagulant strategy in clinical practice owing to concerns regarding bleeding complications [20]. Although the HRS/EHRA/ECAS/APHRS/SOLAECE 2017 expert consensus statement on CA of AF classified the I-DOAC strategy as a class IIa recommendation [9], RCTs published after 2017 have demonstrated that there were no significant differences between the UI-DOAC and I-DOAC for the prevention of thromboembolic and major bleeding complications [46–51].

Thromboembolism is the most notable complication of CA for AF. The occurrence of periprocedural stroke or TIA was reported to be 0.1–0.6% in the latest guidelines [8]. Herein, both the DOAC and UI-VKA strategies revealed comparable efficacy in preventing thromboembolic events compared with I-VKA, and there were no significant differences among them. Therefore, an uninterrupted anticoagulant strategy is usually favorable, but an interrupted DOAC administration is feasible for the prevention of thromboembolism.

The safety of anticoagulants during periprocedural management must be carefully considered. Our NMA revealed a significant reduction in major bleeding complications with UI-DOAC compared with UI-VKA, consistent with the results of a previous metaanalysis [18]. The mechanism of reduction may be related to the type of anticoagulant (thrombin or factor Xa inhibitor) and a shorter half-life than warfarin. However, a recent meta-analysis showed no significant differences between UI-DOAC and UI-VKA [19]. In the sensitivity analysis, which excluded individual studies, we could not identify the robustness of UI-DOAC for significant reduction of major bleeding without each of the

10 studies in Table S5b. However, the estimated ORs with both DOAC strategies tended to carry a lower risk of major bleeding; thus, they may be safer alternatives to UI-VKA.

The ACE associated with CA for AF is relatively common and reported in 0–12.5% of UI-DOAC, 15.0–35.7% of I-DOAC, and 8.7–18.6% of UI-VKA cases [57–59]. In a previous meta-analysis, UI-DOAC significantly reduced the occurrence of ACE compared to I-DOAC [60]. In our review, similar ACE incidence rates were observed (UI-DOAC, 16.0%; I-DOAC, 20.7%; and UI-VKA, 15.4%), but we were unable to identify a significant reduction with UI-DOAC. Although ACE is classified as a complication of unknown significance in the current guidelines [8], it may be associated with the risk of dementia, cognitive impairment, and future stroke [61,62]. Nakamura et al. reported ACE detected post CA on follow-up MRI disappeared in 79.8% of cases [48]. The remaining 20.2% may develop chronic infarcts due to debris dislodging, air embolism, or small thrombosis [63,64]. The significance of ACE remains unclear, but a continuous anticoagulant strategy is feasible as a periprocedural treatment for ACE prevention.

We set another network with each anticoagulant regimen as a subgroup analysis and found that UI-dabigatran could significantly reduce the composite of the primary outcomes. Since UI-dabigatran did not influence significantly for thromboembolic events in Table S6b, the reduction of major bleeding complications can lead to this result. Although the DOACs included apixaban, dabigatran, edoxaban, and rivaroxaban, dabigatran is a thrombin inhibitor, while the others are factor Xa inhibitors. Dabigatran can extend the activated thromboplastin time, activated coagulation time (ACT), and thrombin time to a greater extent than factor Xa inhibitors [8]. Recent RCTs that compared UI-DOAC and UI-VKA revealed that the total amount of unfractionated heparin (UFH) during AF ablation increased, owing to the use of factor Xa inhibitors (apixaban, 156% [40]; edoxaban, 124% [44]; and rivaroxaban, 133% [39,42]) compared with thrombin inhibitors (dabigatran, 104% [41]), and the mean ACT was lower with factor Xa inhibitors than with thrombin inhibitors (307 vs. 330 s). This previously reported finding [65] may contribute to the increased risk of major bleeding. Martin et al. reported that ACT was strongly correlated with the prothrombin time-international normalized ratio and dabigatran concentration, but not with factor Xa inhibitor concentration [66]. Moreover, only dabigatran was parallel with VKA in the UFH dose–response curves. In contrast, factor Xa inhibitors had a smaller effect on ACT prolongation in response to heparin. The target ACT at 300 s is supported by robust evidence for controlling the thromboembolic and bleeding risks, but this evidence depends on VKA and UFH management [67]. Consequently, dabigatran is the optimal periprocedural anticoagulant for ACT monitoring during AF ablation.

As DOACs have become the practical standard for periprocedural anticoagulant strategies, the management of major bleeding is more important. Idarucizumab, a specific reversal agent for dabigatran, is now available worldwide [68]. In contrast, andexanet alfa, a specific reversal agent for factor Xa inhibitors, is only available in some countries [69]. Therefore, UI-dabigatran allows an option to manage complications if emergency bleeding occurs anywhere in the world.

Although NMA can assess the relative effectiveness of different strategies, our study has limitations. A primary limitation is that this NMA was based on study-level rather than patient-level data, which would considerably weaken the comparison validity. Second, differentiations of bleeding criteria, the usage of protamine and intracardiac echocardiography (ICE), lengths of follow-up, and methods of measuring ACE with MRI may contribute to heterogeneity and potentially affect the interpretation of the results. In particular, the number of participants who underwent MRI was limited in three RCTs. Further studies are needed to determine the significance of the optimal anticoagulant strategy for ACE. Additionally, the usage of protamine after the ablation procedure, and ICE during transseptal puncture, can prevent bleeding events. However, there were few studies to report those applications, and this can influence bleeding outcomes. Since four studies that investigated DOACs were not randomized into individual anticoagulants, a pooled comparison of a specific regimen in NMA could not be performed, and this weakened the interpretation

of the results. Moreover, some regimens lacked data and were dependent on one study because of the limited number of RCTs. As RCTs of I-DOAC were mainly conducted in Japan, their results may involve regional bias.

#### **5. Conclusions**

In patients undergoing AF ablation, both DOAC strategies were associated with a lower incidence of major bleeding and had a similar effect on the prevention of thromboembolic events and minor bleeding compared with the UI-VKA strategy, whereas the I-VKA strategy should generally be avoided. Continuous DOAC and VKA administration was associated with a lower incidence of ACE. Therefore, UI-DOAC is the preferable alternative to UI-VKA. Although further data on the outcomes of patients receiving UI-dabigatran are needed for definitive conclusions, our results support the use of UI-dabigatran as the optimal periprocedural anticoagulant for ACT monitoring during AF ablation.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/jcm11071872/s1, Figure S1: Inconsistency analysis; Figure S2: Comparison adjusted funnel plot; Figure S3: Network of anticoagulant comparisons for the composite of primary outcomes; Table S1: PRISMA network meta-analysis checklist; Table S2: PICOS format and detailed search code; Table S3: Efficacy and safety outcomes in the included studies; Table S4: Assessment of bias in the randomized clinical trials; Table S5: Sensitivity analysis; Table S6: Summary estimates for outcomes with each anticoagulant regimen from network meta-analysis.

**Author Contributions:** Conceptualization, T.K.; methodology, T.Y.; software, T.K.; validation, H.Y. and T.I. (Tomoaki Ishigami); formal analysis, T.K.; investigation, S.I., M.A. and S.A.; resources, T.K.; data curation, M.K. and T.Y.; writing—original draft preparation, T.K.; writing—review and editing, M.K., T.Y., H.Y. and T.I. (Tomoaki Ishigami); visualization, T.K.; supervision, T.I. (Toshiyuki Ishikawa); project administration, T.K. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** All data are incorporated into the article and its online supplementary material.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


## *Article* **Vascular Alterations Preceding Arterial Wall Thickening in Overweight and Obese Children**

**Sung-Ai Kim 1,\*,†, Kyung Hee Park 2,†, Sarah Woo 3, Yoon Myung Kim 4, Hyun Jung Lim <sup>5</sup> and Woo-Jung Park <sup>1</sup>**


**Abstract:** Background: Childhood obesity is linked to adverse cardiovascular outcomes in adulthood. This study aimed to assess the impact of childhood obesity on the vasculature and to investigate whether vascular alteration precedes arterial wall thickening in childhood. Methods: A total of 295 overweight (body mass index [BMI] 85th to 95th percentile, *n* = 30) and obese (BMI ≥ 95th percentile, *n* = 234) children aged 7–17 years and 31 normal-weight controls with similar age and gender were prospectively recruited. We assessed anthropometric data and laboratory findings, and measured the carotid intima–media thickness (IMT), carotid artery (CA) diameter, M-mode-derived arterial stiffness indices, and velocity vector imaging parameters, including the CA area, fractional area change, circumferential strain, and circumferential strain rate (SR). Results: The mean ± standard deviation age of the participants was 10.8 ± 2.1 years; 172 (58%) children were male. Regarding structural properties, there was no difference in the IMT between the three groups. The CA diameter was significantly increased in obese children, whereas the CA area showed a significant increase beginning in the overweight stage. Regarding functional properties, contrary to β stiffness and Young's elastic modulus, which were not different between the three groups, the circumferential SR showed a significant decrease beginning in the overweight stage and was independently associated with BMI z-scores after adjusting for covariates. Conclusion: We have demonstrated that arterial stiffening and arterial enlargement precede arterial wall thickening, and that these vascular alterations begin at the overweight stage in middle childhood or early adolescence.

**Keywords:** obesity; childhood; vascular; stiffness

#### **1. Introduction**

Obesity leads to increased arterial stiffening and increased intima–media thickness (IMT), both of which have been linked to a pathological cascade of cardiovascular (CV) diseases [1]. Recently, childhood obesity has become a public health problem worldwide; its prevalence among children has been increasing due to a sedentary lifestyle and fast-food consumption [2]. As obese children are not only more likely to become obese adults but also have an increased risk of developing hypertension, dyslipidemia, type 2 diabetes mellitus, and future CV disease, childhood obesity will eventually be one of the most serious global health issues [3,4]. Large epidemiological studies have reported that childhood obesity is linked to adverse vascular alterations in adulthood [5–7]. Although the association between obesity and vascular alteration has been extensively investigated in adulthood,

**Citation:** Kim, S.-A.; Park, K.H.; Woo, S.; Kim, Y.M.; Lim, H.J.; Park, W.-J. Vascular Alterations Preceding Arterial Wall Thickening in Overweight and Obese Children. *J. Clin. Med.* **2022**, *11*, 3520. https:// doi.org/10.3390/jcm11123520

Academic Editor: Tomoaki Ishigami

Received: 24 May 2022 Accepted: 17 June 2022 Published: 19 June 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

limited data exist on its impact on the vasculature in childhood. As surrogate markers of vascular alteration, both the IMT and arterial stiffness are known as independent predictors of future CV morbidity and mortality in adults, respectively [8]. However, in childhood, previous studies regarding the impact of obesity on IMT and arterial stiffness have yielded conflicting results, and not all studies have shown higher IMT and arterial stiffness in obese children [9–15]. Using the velocity vector imaging (VVI) technique to assess instantaneous vascular deformation, we previously quantified vascular alterations with aging [16] and demonstrated that the carotid artery (CA) could undergo functional alteration before the IMT increases in patients with hypertension [17]. In this study, we assessed vascular alterations using VVI in overweight and obese children and compared them to normalweight children and sought to determine whether vascular alterations could be observed before arterial wall thickening in overweight and obese children.

#### **2. Materials and Methods**

#### *2.1. Study Subjects*

A total of 295 overweight (*n* = 30) and obese (*n* = 234) children aged 7–17 years (154 boys and 110 girls) and 31 sex- and age-matched normal-weight controls were prospectively recruited for the Intervention for Childhood and Adolescents Obesity via Activity and Nutrition (ICAAN) study through newspapers, broadcasts, posters, websites, and other social networking services. Overweight was defined as a BMI ≥ 85th percentile and <95th percentile for age- and sex-specific BMI according to the 2007 Korean National Growth Charts, while obesity was defined as a BMI ≥ 95th percentile for age and sex or <sup>a</sup> BMI ≥ 25 kg/m2 [18,19]. This study was conducted according to the guidelines of the Declaration of Helsinki, and the study protocol was approved by the local ethics committee. Written informed consent was obtained from all participants and their parents or caregivers.

#### *2.2. Anthropometric Data*

Body weight was measured after a 10 h fast and voiding, with the participants barefoot and wearing indoor and lightweight clothing. Height was measured by a stadiometer (DS-103, DongSahn Jenix, Seoul, Korea) while the participants were barefoot. BMI was calculated (weight [kg]/height [m]2) and converted into percentiles and z-scores based on the age- and sex-specific BMI of the 2007 Korean National Growth Charts [18].

#### *2.3. Laboratory Test*

Venous blood samples were obtained after 12 hours of fasting to determine the fasting plasma glucose (FPG), fasting plasma insulin, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and high-sensitivity C-reactive protein (hsCRP). FPG was measured using ultraviolet assay with hexokinase (Cobas 8000 C702, Roche, Mannheim, Germany). Insulin was measured using electrochemiluminescence immunoassay (Cobas 8000 e802, Roche, Mannheim, Germany). HDL-C and LDL-C were measured using a homogeneous enzymatic colorimetric test (Cobas 8000 C702, Roche, Mannheim, Germany). TG, AST, and ALT were measured using enzymatic assay (Cobas 8000 C702, Roche, Mannheim, Germany). hsCRP was measured using turbidimetric immunoassay (Cobas 8000 C702, Roche, Mannheim, Germany). The homeostasis model assessment for insulin resistance (HOMA-IR) was used to determine insulin sensitivity, and was calculated using the following formula: (FPG Level (mg/dL) × Fasting Plasma Insulin Level (uU/mL))/405. Adiponectin was measured using enzyme-linked immunosorbent assay (VersaMax ELISA Microplate Reader, Molecular Devices, San Jose, CA, USA).

#### *2.4. Carotid Ultrasound and Vascular Parameters*

Carotid ultrasound studies were performed by a single registered vascular technologist (S.H.P) who was blinded to the subject group assignment using a high-resolution B-mode ultrasound (Acuson Sequoia 512, Siemens Acuson, Mountain View, CA, USA) equipped with an 8 MHz linear-array transducer. Data were stored as digital cineloops for subsequent offline analysis, and a single experienced reader (S.A.K.) who was blinded to the subject's clinical status performed all measurements. The mean IMT was calculated as the average of three consecutive manual measurements at the far wall of the CA 1 cm proximal to the carotid bulb of both common carotid arteries (CCA) from leading edge (lumen–intima) to leading edge (media-adventitia) during end diastole. The average end-diastolic diameter (Dd, CA diameter) and peak systolic internal diameters (Ds) were assessed in three cycles as the distance between the intima–lumen interface at the near wall and the lumen–intima interface at the far wall of both CCAs (1 cm proximal to the beginning of the carotid bulb). The M-mode-derived CA stiffness indices were derived according to the following formula: β stiffness was determined as ln (Ps/Pd)/((Ds − Dd)/Dd) [20], where Ps and Pd are systolic and diastolic blood pressures. Young's elastic modulus (YEM) in 102 × kPa/mm was calculated as [[Ps − Pd]/(Ds − Dd)] × (Dd/cIMT) [21]. Transverse images of both CCAs (1 cm proximal to the carotid bulb) were stored using acoustic capture for offline analysis with the VVI workstation (Syngo®, US Workplace, Siemens, Mountain View, CA, USA). VVI fundamentally uses a two-dimensional speckle-tracking method from which the blood–tissue border was traced manually over one frame of a cineloop and wherein the ultrasonic speckles automatically tracked vessel wall motion by dividing it into six segments.

VVI provides instantaneous quantitative measurements of vessel deformation throughout the cardiac cycle, including circumferential vessel area, fractional area change (FAC), circumferential strain and strain rate (SR). CA area was defined as minimal vessel area during the cardiac cycle and FAC was calculated by measuring the percent changes of the CA area [(maximal area) − (minimal area)/(minimal area)] × 100 (%). Circumferential strain (ε) represents the percent change (%) in length along the circumferential axis of CA and circumferential SR represents the temporal derivative of strain and describes the temporal change in strain (dε/dt, 1/s), producing a positive value in systole and a negative value in diastole. All CA measurements on both sides were averaged to obtain the mean values.

#### *2.5. Statistical Analysis*

Data are expressed as the mean ± standard deviation (SD) or as percentages. We compared the means of each continuous variable in the subject groups by one-way factorial analysis of variance with the post hoc test (Tukey). Analysis of covariance using the Bonferroni post hoc test was used to test the differences in the vascular parameters between the three groups while adjusting for covariates, such as age, sex, height, mean blood pressure, low-density lipoprotein (LDL)-cholesterol level, and homeostasis model assessment for insulin resistance (HOMA-IR). Multiple linear regression fit of the circumferential SR on the BMI z-score was generated by considering the effects of other covariates. All statistical analyses were performed using SPSS 24.0 (IBM Corp., Chicago, IL, USA) an open-source statistical package R version 3.6.3 (R Project for Statistical Computing, Vienna, Austria). Statistical significance was defined as *p* < 0.05.

#### **3. Results**

Overall, the mean ± SD age of all participants was 10.8 ± 2.1 years; 172 (58%) children were male. Table 1 presents the baseline characteristics of the study population and statistical differences between the groups.

Obese children had higher blood pressures, HOMA-IR, hsCRP, and LDL cholesterol levels and lower serum adiponectin levels than overweight and normal-weight children. Meanwhile, overweight children had higher levels of HOMA-IR compared to normalweight children, although there were no differences in other variables between the groups.

In the structural evaluation of the CA (Table 2), there was no difference in IMT among the three groups (*p* > 0.05).


**Table 1.** Baseline characteristics.

\* vs. normal < 0.05; \*\* vs. normal, <0.01; † vs. overweight < 0.05; ‡ vs. overweight < 0.01. BMI, body mass index; WC, waist circumference; HC, hip circumference; BP, blood pressure; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HOMA-IR, homeostasis model assessment for insulin resistance; hsCRP, highsensitivity C-reactive protein; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

**Table 2.** Structural and functional characteristics of the carotid artery.


\* vs. normal < 0.05; \*\* vs. normal, <0.01; ‡ vs. overweight < 0.01. IMT, intima–media thickness; CA, carotid artery; YEM, Young's elastic modulus; VVI, velocity vector imaging; FAC, fractional area change; SR, strain rate.

The CA diameter in obese children was distinctly larger than that in normal-weight and overweight children, and there was no difference in the CA diameter between normalweight and overweight children. Meanwhile, the CA area began to increase from the overweight stage. The CA of overweight children was significantly larger than that of normal-weight children but did not differ from obese children. Regarding the functional parameters of vascular elastic properties, M-mode-derived stiffness indices, such as β

stiffness and YEM, were not significantly different among the three groups (*p* > 0.05). Meanwhile, the circumferential SR showed a significant decrease from the overweight stage (0.68 ± 0.24 1/s in normal-weight vs. 0.51 ± 0.21 1/s in overweight children, *p* = 0.002).

Figure 1 shows an example of VVI analysis in normal-weight (A), overweight (B) and obese children (C), respectively. As the BMI level increases, CA area gradually increases and both FAC and circumferential SR decrease in comparison with those of normal-weight children.

**Figure 1.** Velocity vector imaging analysis in normal-weight (**A**), overweight (**B**) and obese children (**C**). The red arrow points to maximal CA area and the black arrow points to minimal CA area during the cardiac cycle. CA area refers to minimal CA area (black arrow) and FAC was calculated by measuring the percent changes of the CA area [(maximal area) − (minimal area)/(minimal area)] × 100 (%). CSR refers to average value of peak CSRs of six segments during the systole. Compared to normalweight children (**A**), overweight (**B**) and obese (**C**) children show an increase in CA area and a decrease in FAC and CSR. CA, carotid artery; FAC, fractional area change; CSR, circumferential strain rate.

In addition, when we compared the M-mode-derived parameters and VVI parameters between the groups after adjusting for age, sex, height, mean blood pressure, LDL cholesterol level, and HOMA-IR, respectively (Figure 2), the CA area and circumferential SR still showed significant changes beginning in the overweight stage in middle childhood or early adolescence.

Additionally, the circumferential SR showed a negative association with the BMI z-score, a linear estimate of obesity; this association remained significant after adjustment of covariates in the multiple linear regression analysis (adjusted R2 = 0.256, *p* < 0.001, Figure 3).

**Figure 2.** Comparison of M-mode-derived parameters and VVI parameters between the groups after adjusting for covariates including age, sex, height, mean blood pressure, LDL cholesterol and HOMA-IR. (**A**) M-mode-derived parameters; (**B**) VVI parameters. \*\* vs. normal, <0.01; ‡ vs. overweight < 0.01. CA, carotid artery; IMT, intima–media thickness; FAC, fractional area change; SR, strain rate; VVI, velocity vector imaging.

**Figure 3.** Multiple linear regression fit of the circumferential SR on the BMI z-score. SR, strain rate; BMI, body mass index.

#### **4. Discussion**

In this study, we demonstrated that even in childhood, arterial stiffening and enlargement, which occur in the overweight stage, precede arterial wall thickening. The circumferential SR, as a sensitive marker of arterial stiffness, significantly decreased in the early stages of obesity and showed a negative linear association with BMI z-score even after adjusting for covariates. Our results emphasize that interventions against childhood obesity should be initiated early to prevent the induction and irreversible progression of obesity-induced vascular complications.

The IMT is an established structural marker of subclinical arteriosclerosis [9,22]. Many studies in adults have demonstrated that obesity is independently associated with an increase in IMT [23–25]. Moreover, large longitudinal cohort studies have shown

that childhood adiposity correlates with an increase in IMT later in adulthood [26,27]. However, some studies have reported the lack of association between BMI and IMT in childhood [9,11,28–33]. In middle childhood (mean age, 10 years; <12 years), BMI is not associated with IMT in obese and normal-weight children [11,28–30], whereas in adolescents (mean age, >12 years), BMI is positively associated with IMT [31–33]. This suggests that arterial wall damage begins later in childhood or in adolescence. Our results are also in line with those of previous reports of children aged 8–12 years that did not show a difference in the IMT between obese and normal-weight subjects [11,28–30]. Moreover, this study including overweight children, who were greater in number than obese children, showed that the IMTs in overweight and obese children were not different to those of normal-weight children, which suggests that the thickening of the arterial wall is limited by time in childhood obesity. In contrast, several studies with similar degree of obesity, age, and gender to this population have reported an increase in IMT in obese children compared with lean children [9,12,34]. These conflicting reports could be due to the differences in exposure duration to obesity, sample size, and racial and/or ethnic characteristics between studies [35,36]. Another possible explanation is that BMI or adiposity itself has no direct association with IMT, and that its effects are instead manifested through CV risk factors, such as age, hypertension, type 2 diabetes mellitus, and other metabolic complications [36,37]. It is also fundamentally linked to exposure duration to obesity.

In this study, we verified that arterial stiffening precedes wall thickening, and that arterial damage begins at the overweight stage in middle childhood or early adolescence. Although longitudinal processes linking obesity to vascular alteration are not fully understood, it is known that long-term exposure to hemodynamic stimuli and metabolic disturbance caused by obesity augments the arterial impedance and afterload of the heart, which eventually leads to an increase in CV morbidity and mortality [38]. In this study, overweight children showed higher insulin resistance than normal-weight children despite the comparable blood pressures and laboratory findings. Although the role of this metabolic disturbance in the process of arteriosclerosis remains unclear, abnormal glucose metabolism is associated with the accumulation of advanced end-glycation products that lead to arterial stiffening [39]. To assess arterial stiffness, we measured the instantaneous vessel deformational parameters (FAC, circumferential strain, and circumferential SR) using VVI as well as conventional M-mode-derived elastic moduli as β stiffness and YEM.

Although the M-mode-derived stiffness indices did not show any difference among the three groups, and the FAC and circumferential strain of overweight children were not significantly different from those of normal-weight children, only circumferential SR has proven its ability to independently confirm early vascular damage that began at the overweight stage and it showed a negative linear association with BMI z-score even after adjusting for covariates. M-mode derived stiffness indices as β-stiffness and YEM are calculated from CA diameter and blood pressures measured at peripheral artery. When interpreting the results, we should consider the facts that pulse pressure amplification may differ with obesity [40] and there is a time difference between the measurements of blood pressures and arterial diameter in pressure-related variables. These limitations may have affected the findings in this study.

Considering that the circumferential SR is the time rate of instantaneous circumferential deformation, it would have been a suitable indicator to reflect subtle vascular changes in these relatively healthy children, although the exact mechanisms cannot be clarified. Additionally, our results revealed the limitations of the M-mode-derived stiffness indices and the superiority of a two-dimensional approach by speckle tracking that enables instantaneous vessel wall motion in the entire circumference of vessel wall.

As a marker of structural change, we demonstrated that vessel area increases as obesity progresses, which is consistent with existing pediatric studies that reported that arterial diameters increase with obesity [41,42]. An increase in arterial diameter might be attributed to the fatiguing effects of tensile stress, which lead to fracture of load-bearing elastin fibers [43,44]. In this study, the CA area, measured by a two-dimensional approach, showed a significant increase from the overweight stage. These results reveal that arterial enlargement and stiffening occur before IMT progression and begin in the overweight stage in childhood. Considering the four large longitudinal cohort studies wherein people who were overweight or obese as children but were non-obese as adults had similar CV outcomes to those of people who were never obese [7], it is plausible that these vascular alterations in childhood are reversible and preventable through early intervention against obesity.

Our investigation has several limitations, including its cross-sectional observational study design, which does not allow causal or temporal inferences. A narrow age range in this population may limit generalizability to later adolescence, wherein the influence of pubertal development, with changes in body shape and adiposity, cannot be overlooked. It is unclear how much the duration of exposure to obesity might affect the degree of structural and functional vascular alterations in this population.

#### **5. Conclusions**

In conclusion, we demonstrated that vascular alterations such as arterial enlargement and arterial stiffening, represented by low circumferential SR, can occur before IMT progression even in the overweight stage in middle childhood or early adolescence. These results emphasize the importance of maintaining a normal body weight in childhood and the necessity of early intervention against childhood obesity to minimize the development of CV disease in adulthood.

**Author Contributions:** Conceptualization, S.-A.K.; data curation, S.-A.K., S.W. and K.H.P.; formal analysis, S.-A.K.; funding acquisition, K.H.P.; investigation, S.-A.K., Y.M.K., H.J.L. and K.H.P.; methodology, S.-A.K.; supervision, K.H.P. and W.-J.P.; validation, S.-A.K. and K.H.P. On behalf of the ICAAN study investigators: writing—original draft preparation, S.-A.K.; writing—review and editing, S.-A.K. and K.H.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Korea Centers for Disease Control and Prevention, grant number 2016-ER6405.

**Institutional Review Board Statement:** The ICAAN study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Hallym University Sacred Heart Hospital's Institutional Review Board (approval number: 2016-I135).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the ICAAN study.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding authors. The data are not publicly available due to privacy concerns.

**Conflicts of Interest:** The authors declare no conflict of interest.

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