# Early and late bleeding events according to Valve Academic Research Consortium 3 criteria following transcatheter aortic valve implantation

Maxime Nolf, Dominique Boulmier, Guillaume Leurent, Jacques Tomasi, Florent Le Bars, Abdelkader Bakhti, Sam Sharobeem, Léo Lemarchand, Gwenaelle Sost, Marielle Le Guellec, et al.

► To cite this version:

Maxime Nolf, Dominique Boulmier, Guillaume Leurent, Jacques Tomasi, Florent Le Bars, et al. "Early and late bleeding events according to Valve Academic Research Consortium 3 criteria following transcatheter aortic valve implantation." Archives of cardiovascular diseases, 2025, 118 (4), pp.248-259. 10.1016/j.acvd.2024.12.009. hal-04975587

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https://hal.science/hal-04975587v1

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Clinical Research

# Early and late bleeding events according to Valve Academic Research Consortium 3 criteria following transcatheter aortic valve implantation☆

<figure><img src="image_3.png" /></figure>

Maxime Nolfª, Dominique Boulmierª, Guillaume Leurentª, Jacques Tomasiᵇ, Florent Le Barsᵇ, Abdelkader Bakhtiª, Sam Sharobeemª, Léo Lemarchandª, Gwenaelle Sostᶜ, Marielle Le Guellecª, Hervé Le Bretonª, Vincent Auffretª,\*

## INFO ARTICLE

**Historique de l'article :**
Reçu le 13 septembre 2024
Reçu sous la forme révisée
le 15 décembre 2024
Accepté le 24 décembre 2024
Disponible sur Internet le 30 January 2025

**Keywords :**
Transcatheter aortic valve implantation
Bleeding
VARC-3
VARC-2
Mortality

## ABSTRACT

**Background.** – Transcatheter aortic valve implantation may be associated with significant haemorrhagic complications.

**Aims.** – To evaluate the timing, incidence, predictors and clinical impact of bleeding events after transcatheter aortic valve implantation, according to the updated Valve Academic Research Consortium (VARC)-3 criteria, compared with the VARC-2 criteria.

**Methods.** – A retrospective observational study involving 487 consecutive patients who underwent transcatheter aortic valve implantation between July 2017 and May 2019 was performed. Bleeding events were classified according to the VARC-2 and VARC-3 definitions.

**Results.** – Bleeding events occurred in 17.6% of patients, with early bleeding (in-hospital) in 12.5% and late bleeding (occurring after discharge) in 6.1%. The primary vascular access site was the most common source of early bleeding, whereas gastrointestinal bleeding was predominant in late events. Significant predictors of early VARC-3-defined bleeding included active cancer, previous implantable cardioverter-defibrillator, history of mitral valve surgery, a non-transfemoral approach and occurrence of an in-hospital major vascular complication or new-onset atrial fibrillation. Late bleeding was independently associated with a history of myocardial infarction and treatment with vitamin K antagonists at discharge. Early bleeding events were not associated with increased late all-cause mortality. No significant difference was observed based on the VARC-2 and VARC-3 bleeding definitions.

**Conclusions.** – Bleeding events occurred in one sixth of patients undergoing transcatheter aortic valve implantation without significant difference in their incidence between the VARC-2 and VARC-3 classifications. Early bleeding events were not associated with poorer long-term survival, regardless of the classification used. Larger studies with greater statistical power, including more contemporary patients, are needed to confirm these findings.

© 2025 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## 1. Abbreviations

AF atrial fibrillation

CI confidence interval

DAPT dual antiplatelet therapy

ICD implantable cardioverter-defibrillator

NOAC non-vitamin K antagonist oral anticoagulant

OR odds ratio

sHR subhazard ratio

TAVI transcatheter aortic valve implantation

VARC Valve Academic Research Consortium

VKA vitamin K antagonist

<footnote>ª Service de cardiologie, LTSI Inserm U1099, centre d'investigation clinique (CIC) Inserm 1414, CHU de Rennes, université de Rennes 1, 2, rue Henri-Le-Guilloux, 35000 Rennes, France</footnote>

<footnote>ᵇ Service de chirurgie thoracique et cardio-vasculaire, LTSI Inserm U1099, CHU de Rennes, université de Rennes 1, 35000 Rennes, France</footnote>

<footnote>ᶜ Service de gériatrie, CHU de Rennes, 35000 Rennes, France</footnote>

<footnote>☆ X post (Tweet): What are the incidence, timing, predictors and impact of VARC-3-defined bleeding events following transcatheter aortic valve implantation?</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>Adresse e-mail : vincent.auffret@chu-rennes.fr (V. Auffret).</footnote>
## 2. Background

Introduced in 2002, transcatheter aortic valve implantation (TAVI) has emerged as a revolutionary alternative to surgical aortic valve replacement for the treatment of severe symptomatic aortic stenosis in high- and intermediate-risk patients [1,2]. Recent trials have demonstrated the non-inferiority of TAVI compared with surgery in low-risk patients [3,4], with long-term follow-up data even suggesting a trend towards superiority of TAVI in this setting [5].

Literature reports that haemorrhagic complications occur in approximately 2.4 to 41.7% of TAVI cases, with variation based on the criteria used to define bleeding and the populations studied [1,6,7]. The risk of bleeding arises from a combination of procedural factors, medical treatments and patient characteristics, such as advanced age, female sex, history of bleeding and chronic kidney disease. In the context of TAVI, the definition of bleeding has been highly heterogeneous, depending on the timing (early or late) and severity of events, albeit a strong correlation with increased short- and long-term mortality has repeatedly been reported [8]. Early bleeding is one of the most common complications after TAVI. A meta-analysis of 3519 patients reported rates of major and life-threatening bleeding at 30 days of 22.3 and 15.5%, respectively [9].

To reduce the incidence of haemorrhagic complications, several strategies have been implemented, including minimizing the use of non-femoral access, adopting ultrasound-guided puncture techniques and utilizing smaller-diameter introducer sheaths. The use of contemporary closure systems such as the suture-based Proglide® (Abbott Vascular, Santa Clara, CA, USA) or the plug-based Manta® (Teleflex Incorporated, Wayne, PA, USA), as opposed to more historical ones, such as the Prostar XL® (Abbott Vascular, Santa Clara, CA, USA), has also proven effective [10]. Additionally, for late bleeding, discontinuing dual antiplatelet therapy (DAPT) has shown benefits [11,12]. However, despite these advances, which have enabled the procedure to be performed in lower-risk patients with a longer life expectancy, the risk of bleeding remains significant, even in low-risk patients, with bleeding incidence reported to be as high as 7.7% at 1 year [3].

In an effort to standardize outcomes reporting, the Valve Academic Research Consortium (VARC)-2 [8] classification for TAVI-related bleeding has been used for about a decade, and is well-established, although it differs significantly from the commonly used Bleeding Academic Research Consortium classification for all types of bleeding severity [13]. The VARC has since introduced updated definitions for relevant clinical endpoints in TAVI, with the VARC-3 bleeding definition shifting from a simple severity grading to a more granular and descriptive classification [14]. However, this new bleeding definition has been relatively understudied. The largest study to date included patients from as early as 2007, with a high rate of non-transfemoral access and periprocedural bleeding, which may not reflect current TAVI practice [15]. Therefore, the objectives of this study were to evaluate the incidence, predictors and clinical impact of early and late bleeding events after TAVI according to the VARC-3 criteria, and to compare their prognostic significance with the VARC-2 criteria.

## 3. Methods

### 3.1. Study population and procedures

A retrospective observational single-centre study was conducted at the University Hospital of Rennes (France). The 487 patients who underwent TAVI between July 2017 and May 2019 were included in the present analysis. Details regarding the preprocedural workup have been described previously [16]. TAVI indication,

valve type and approach were decided by the local heart team in accordance with the preoperative assessment. The transfemoral approach was used as the first-line access, whereas alternative accesses were performed among patients with unfavourable peripheral anatomy. In such cases, transarterial (transcarotid and transaxillary) alternative accesses were performed whenever possible, with transthoracic accesses (transapical and transaortic) being limited to patients without other options. Among patients with an indication for oral anticoagulant therapy at baseline, the treatment was withdrawn for 48 hours before the procedure, and restarted within 24 hours of the procedure in the absence of contraindication. Procedural anticoagulation was based on a 50 IU/kg bolus of unfractionated heparin. All patients gave written informed consent for the procedures and anonymous collection of their data, which were gathered prospectively in an electronic database as part of the national registry [17].

### 3.2. Data collection and clinical endpoints

Follow-up was conducted during on-site clinical visits, by reviewing the records of referring cardiologists, general practitioners and other hospitals in case of rehospitalization or through telephone contact at 30 days, 1 year and yearly after TAVI. The median follow-up duration of the study population was 44.3 (interquartile range 20.8–60) months. Late bleeding events at follow-up could be ascertained for all but eight patients (1.6%; five in-hospital deaths and three patients lost to follow-up). The evaluation of late bleeding events was thus performed among 479 patients. TAVI outcomes and adverse events were defined according to the VARC definitions used at the time of the procedure.

### 3.3. Bleeding event definitions

Bleeding events were defined according to the VARC-2 and VARC-3 definitions (Table A.1) [8,14]. As defined previously by Avvedimento et al. [15], any significant procedural blood loss > 3 g/dL haemoglobin, even in the absence of an obvious source of bleeding, was considered as a VARC-3 bleeding event. Haemoglobin decrease from baseline to the lowest value within the first 48 hours after the procedure was calculated to identify any significant procedural blood loss. Early bleeding was defined as any bleeding event occurring during the index hospitalization, whereas bleeding was classified as late when occurring after discharge. Data regarding bleeding location and antithrombotic therapy at the time of bleeding were recorded. Finally, to evaluate bleeding severity, the number of red blood cell transfusions, timing with respect to index procedure and indications were collected, for the index hospitalization and any subsequent hospitalization.

### 3.4. Statistical analysis

Continuous variables are presented as medians (interquartile ranges), as all were non-normally distributed, and were compared using the Mann-Whitney U test. Categorical variables are summarized as numbers (percentages), and were compared using the $\chi^2$ test or Fisher's exact test, as appropriate. Cumulative incidence of all-cause mortality was summarized using Kaplan-Meier estimates, and the log-rank test was used to compare groups. Predictors of early bleeding events were analysed in univariate and multivariable logistic regressions, reporting adjusted odds ratios (ORs) with their 95% confidence intervals (CIs). Late bleeding predictors were evaluated using competing-risk models, with all-cause mortality as a competing event, reporting adjusted subhazard ratios (SHRs) with their 95% CIs. Cumulative incidence function plots were constructed to present the cumulative probability of late bleeding in the presence of competing events. All-cause mortality was
<table><caption>**Table 1**
Baseline characteristics of the population according to the occurrence of early Valve Academic Research Consortium 3 (VARC-3)-defined bleeding events.</caption><thead><tr><th></th><th>Total (n = 487)</th><th>No early bleeding (n = 426)</th><th>Early bleeding (n = 61)</th><th>P</th></tr></thead><tbody><tr><td>Age (years)</td><td>83 (79–86)</td><td>83 (79–86)</td><td>83 (79.5–85)</td><td>0.82</td></tr><tr><td>Female sex</td><td>210 (43.1)</td><td>186 (43.7)</td><td>24 (39.3)</td><td>0.58</td></tr><tr><td>BMI (kg/m²)</td><td>25.9 (23.5–29.4)</td><td>25.75 (23.75–29.25)</td><td>26.8 (23.5–31.4)</td><td>0.11</td></tr><tr><td>Active cancer</td><td>3 (0.6)</td><td>1 (0.2)</td><td>2 (3.3)</td><td>0.043</td></tr><tr><td>Diabetes mellitus</td><td>103 (21.1)</td><td>86 (20.2)</td><td>17 (27.9)</td><td>0.18</td></tr><tr><td>Previous heart failure</td><td>174 (36)</td><td>146 (34.6)</td><td>28 (45.9)</td><td>0.09</td></tr><tr><td>Atrial fibrillation</td><td>189 (38.8)</td><td>165 (38.7)</td><td>24 (39.3)</td><td>0.52</td></tr><tr><td>Previous permanent pacemaker</td><td>39 (8.0)</td><td>32 (7.5)</td><td>7 (11.5)</td><td>0.31</td></tr><tr><td>Previous ICD</td><td>3 (0.6)</td><td>1 (0.2)</td><td>2 (3.3)</td><td>0.043</td></tr><tr><td>Coronary artery disease</td><td>242 (49.7)</td><td>208 (48.8)</td><td>34 (55.7)</td><td>0.34</td></tr><tr><td>Previous MI</td><td>9 (1.8)</td><td>9 (2.1)</td><td>0 (0.0)</td><td>0.61</td></tr><tr><td>Previous CABG</td><td>34 (7.0)</td><td>32 (7.5)</td><td>2 (3.3)</td><td>0.17</td></tr><tr><td>Previous mitral valve surgery</td><td>5 (1.0)</td><td>2 (0.5)</td><td>3 (4.9)</td><td>0.016</td></tr><tr><td>Previous aortic valve surgery</td><td>20 (4.1)</td><td>18 (4.2)</td><td>2 (3.3)</td><td>0.77</td></tr><tr><td>Carotid vascular disease</td><td>41 (8.5)</td><td>39 (9.2)</td><td>2 (8.5)</td><td>0.14</td></tr><tr><td>Peripheral artery disease</td><td>105 (21.6)</td><td>93 (21.8)</td><td>12 (19.1)</td><td>0.74</td></tr><tr><td>Previous stroke</td><td>66 (13.6)</td><td>55 (12.9)</td><td>11 (18.0)</td><td>0.32</td></tr><tr><td>COPD</td><td>131 (26.9)</td><td>114 (26.8)</td><td>17 (27.9)</td><td>0.88</td></tr><tr><td>Chronic kidney disease</td><td></td><td></td><td></td><td></td></tr><tr><td>Stage 3</td><td>133 (27.3)</td><td>112 (26.3)</td><td>21 (34.4)</td><td>0.60</td></tr><tr><td>Stage 4–5</td><td>12 (2.5)</td><td>11 (2.6)</td><td>1 (1.6)</td><td></td></tr><tr><td>Dialysis</td><td>7 (1.4)</td><td>6 (1.4)</td><td>1 (1.6)</td><td></td></tr><tr><td>NYHA class 3–4</td><td>197 (40.5)</td><td>175 (40.4)</td><td>25 (41.0)</td><td>1.00</td></tr><tr><td>Haemoglobin (g/dL)</td><td>12.2 (11.3–13.1)</td><td>12 (11–13.1)</td><td>12.2 (11.4–13.1)</td><td>0.30</td></tr><tr><td>Platelets (g/L)</td><td>200 (160–241)</td><td>202 (161–243)</td><td>200 (154–239)</td><td>0.48</td></tr><tr><td>LVEF (%)</td><td>60 (50–60)</td><td>60 (56–60)</td><td>60 (50–61)</td><td>0.98</td></tr><tr><td>Mean gradient (mmHg)</td><td>50 (42–61)</td><td>50 (42–61)</td><td>54 (46–60)</td><td>0.24</td></tr><tr><td>Aortic valve area (cm²)</td><td>0.7 (0.6–0.8)</td><td>0.7 (0.6–0.8)</td><td>0.7 (0.6–0.8)</td><td>0.57</td></tr><tr><td>sPAP (mmHg)</td><td>44.5 (33–55)</td><td>42 (33–55)</td><td>45 (35–54)</td><td>0.45</td></tr><tr><td>Baseline antithrombotic regimen</td><td></td><td></td><td></td><td></td></tr><tr><td>ASA</td><td>230 (48.1)</td><td>199 (47.7)</td><td>31 (50.8)</td><td>0.68</td></tr><tr><td>Clopidogrel</td><td>68 (14.2)</td><td>60 (14.4)</td><td>8 (13.1)</td><td>0.85</td></tr><tr><td>Anticoagulant</td><td>187 (38.4)</td><td>163 (39.3)</td><td>24 (39.3)</td><td>0.89</td></tr><tr><td>VKA</td><td>90 (18.8)</td><td>74 (17.7)</td><td>16 (26.2)</td><td>0.12</td></tr><tr><td>NOAC</td><td>97 (20.3)</td><td>89 (21.3)</td><td>8 (13.1)</td><td>0.17</td></tr><tr><td>SAPT</td><td>178 (37.6)</td><td>151 (36.7)</td><td>27 (44.3)</td><td>0.41</td></tr><tr><td>DAPT</td><td>32 (6.8)</td><td>30 (7.3)</td><td>2 (3.3)</td><td></td></tr><tr><td>Anticoagulant only</td><td>144 (30.4)</td><td>128 (31.1)</td><td>16 (26.2)</td><td></td></tr><tr><td>Anticoagulant + SAPT</td><td>33 (7.0)</td><td>26 (6.3)</td><td>7 (11.5)</td><td></td></tr><tr><td>Triple therapy</td><td>8 (1.7)</td><td>7 (1.7)</td><td>1 (1.6)</td><td></td></tr><tr><td>No treatment</td><td>78 (16.5)</td><td>70 (13.1)</td><td>8.5 (13.1)</td><td></td></tr></tbody></table>

Continuous variables are presented as median (interquartile range); categorical variables are presented as number (percentage). ASA: acetylsalicylic acid; BMI: body mass index; CABG: coronary artery bypass surgery; COPD: chronic obstructive pulmonary disease; DAPT: dual antiplatelet therapy; ICD: implantable cardioverter-defibrillator; LVEF: left ventricular ejection fraction; MI: myocardial infarction; NOAC: non-vitamin K antagonist oral anticoagulant; NYHA: New York Heart Association; SAPT: single antiplatelet therapy; sPAP: systolic pulmonary artery pressure; VKA: vitamin K antagonist.

analysed using Cox proportional hazard models, reporting adjusted hazard ratios with their 95% CIs. Proportional hazard assumption was checked using Schoenfeld residuals, and by examining the log-log plot of survival. Variables demonstrating significant departure from this assumption were introduced into the model as time-varying covariates. For each model, all variables with a univariate P value < 0.1 were included in the multivariable analysis. All tests were two-sided at the 0.05 significance level. Statistical analyses were conducted using Stata Statistical Software, release 13 (Stata-Corp, College Station, TX, USA) and the Statistical Package for Social Sciences, version 25 (SPSS Inc., IBM, Armonk, NY, USA).

## 4. Results

A total of 487 consecutive patients who underwent TAVI were included in the study. The median age was 83 (79–86) years, and 43.1% were women. The transfemoral approach was used in 396 patients (81.3%), whereas the transcarotid, transaxillary, transapical and transaortic accesses were used in 14.8%, 1.6%, 1.0% and 1.2% of patients, respectively. Balloon-expandable valves were used in 73.6% of patients. Baseline clinical and echocardiographic characteristics of the study population according to the occurrence of early and late VARC-3-defined bleeding are summarized in

Tables 1 and 2, respectively. Procedural and in-hospital outcomes of the study population according to the occurrence of early and late VARC-3-defined bleeding are shown in Tables 3 and 4, respectively. A total of 86 patients (17.6%) experienced at least one early or late VARC-3-defined bleeding event.

### 4.1. Incidence, site and severity of bleeding events

The incidence and severity of bleeding events according to time of occurrence are highlighted in Fig. 1.

#### 4.1.1. Early bleeding

A total of 61 patients (12.5%) experienced at least one early VARC-3-defined bleeding event, including 42 patients (10.6%) treated by transfemoral TAVI (Appendix A; Fig. A.1). The incidence of early bleeding events was identical when applying the VARC-3 definition compared with VARC-2. The frequency and location of bleeding events based on their timing are highlighted in Fig. 2. The primary vascular access was the most common bleeding site (n = 49, 10.1%). Early bleeding events occurred in 10.6% of transfemoral TAVI recipients, compared with 12.5%, 18.1%, 40.0% and 50.0% with the transaxillary, transcarotid, transapical and transaortic routes, respectively (P = 0.008).
<table><caption>**Table 2**
Baseline characteristics of the population according to the occurrence of late Valve Academic Research Consortium 3 (VARC-3)-defined bleeding events.</caption><thead><tr><th></th><th>Total (n = 479)</th><th>No late bleeding (n = 449)</th><th>Late bleeding (n = 30)</th><th>P</th></tr></thead><tbody><tr><td>Age (years)</td><td>83 (79–86)</td><td>83 (79–85)</td><td>82 (79–86)</td><td>0.93</td></tr><tr><td>Female sex</td><td>208 (43.4)</td><td>198 (44.1)</td><td>10 (33.3)</td><td>0.26</td></tr><tr><td>BMI (kg/m<sup>2</sup>)</td><td>25.9 (23.5–29.4)</td><td>25.8 (23.4–29.4)</td><td>26.9 (23.65–28.77)</td><td>0.95</td></tr><tr><td>Active cancer</td><td>3 (0.6)</td><td>2 (0.4)</td><td>1 (3.3)</td><td>0.18</td></tr><tr><td>Diabetes mellitus</td><td>102 (21.3)</td><td>95 (21.2)</td><td>7 (23.3)</td><td>0.82</td></tr><tr><td>Previous heart failure</td><td>172 (36.3)</td><td>159 (35.7)</td><td>13 (43.3)</td><td>0.44</td></tr><tr><td>Atrial fibrillation</td><td>187 (39.0)</td><td>170 (37.9)</td><td>17 (56.7)</td><td>0.05</td></tr><tr><td>Previous permanent pacemaker</td><td>38 (7.9)</td><td>38 (8.5)</td><td>0 (0.0)</td><td>0.16</td></tr><tr><td>Coronary artery disease</td><td>238 (49.7)</td><td>226 (50.3)</td><td>12 (40.0)</td><td>0.35</td></tr><tr><td>Previous MI</td><td>9 (1.9)</td><td>7 (1.6)</td><td>2 (6.7)</td><td>0.10</td></tr><tr><td>Previous CABG</td><td>33 (6.9)</td><td>33 (7.3)</td><td>0 (0.0)</td><td>0.16</td></tr><tr><td>Previous mitral valve surgery</td><td>5 (1.0)</td><td>5 (1.1)</td><td>0 (0.0)</td><td>0.72</td></tr><tr><td>Previous aortic valve surgery</td><td>20 (4.2)</td><td>20 (4.5)</td><td>0 (0.0)</td><td>0.39</td></tr><tr><td>Peripheral artery disease</td><td>103 (21.5)</td><td>96 (21.4)</td><td>7 (23.3)</td><td>0.82</td></tr><tr><td>Previous stroke</td><td>66 (13.8)</td><td>62 (13.8)</td><td>4 (13.3)</td><td>0.60</td></tr><tr><td>COPD</td><td>128 (26.7)</td><td>119 (26.5)</td><td>9 (30.0)</td><td>0.83</td></tr><tr><td>Chronic kidney disease</td><td></td><td></td><td></td><td></td></tr><tr><td>Stage 3</td><td>131 (27.3)</td><td>118 (26.3)</td><td>13 (43.3)</td><td>0.16</td></tr><tr><td>Stage 4–5</td><td>11 (2.3)</td><td>11 (2.4)</td><td>0 (0.0)</td><td></td></tr><tr><td>Dialysis</td><td>7 (1.5)</td><td>7 (1.6)</td><td>0 (0.0)</td><td></td></tr><tr><td>NYHA class 3–4</td><td>197 (41.1)</td><td>184 (41.0)</td><td>13 (43.3)</td><td>0.85</td></tr><tr><td>Haemoglobin (g/dL)</td><td>12.2 (11.3–13.0)</td><td>12.2 (11.1–13.1)</td><td>13 (12.2–13.8)</td><td>0.12</td></tr><tr><td>Platelets (g/L)</td><td>200 (160–242)</td><td>201 (160–243)</td><td>205 (203–242)</td><td>0.37</td></tr><tr><td>LVEF (%)</td><td>60 (50–60)</td><td>60 (50–60)</td><td>60 (58.5–68)</td><td>0.82</td></tr><tr><td>Mean gradient (mmHg)</td><td>50 (42–61)</td><td>50 (42–61)</td><td>49.5 (43.5–60.25)</td><td>0.90</td></tr><tr><td>Aortic valve area (cm<sup>2</sup>)</td><td>0.7 (0.6–0.8)</td><td>0.7 (0.6–0.8)</td><td>0.75 (0.61–0.84)</td><td>0.48</td></tr><tr><td>sPAP (mmHg)</td><td>45 (33–55)</td><td>45 (33–55)</td><td>42.5 (31.25–55)</td><td>0.85</td></tr><tr><td>Baseline antithrombotic regimen</td><td></td><td></td><td></td><td></td></tr><tr><td>ASA</td><td>226 (48.1)</td><td>217 (49.3)</td><td>9 (30.0)</td><td>0.57</td></tr><tr><td>Clopidogrel</td><td>65 (13.8)</td><td>60 (13.6)</td><td>5 (16.7)</td><td>0.78</td></tr><tr><td>Anticoagulant</td><td>184 (38.4)</td><td>166 (37.0)</td><td>18 (60.0)</td><td>0.019</td></tr><tr><td>VKA</td><td>88 (18.7)</td><td>77 (17.5)</td><td>11 (36.7)</td><td>0.015</td></tr><tr><td>NOAC</td><td>96 (20.4)</td><td>90 (20.4)</td><td>6 (20.0)</td><td>0.59</td></tr><tr><td>SAPT</td><td>177 (38.1)</td><td>171 (39.3)</td><td>6 (20.0)</td><td>0.12</td></tr><tr><td>DAPT</td><td>30 (6.5)</td><td>28 (6.4)</td><td>2 (6.7)</td><td></td></tr><tr><td>Anticoagulant only</td><td>143 (30.8)</td><td>128 (29.4)</td><td>15 (50.0)</td><td></td></tr><tr><td>Anticoagulant + SAPT</td><td>31 (6.7)</td><td>29 (6.7)</td><td>2 (6.7)</td><td></td></tr><tr><td>Triple therapy</td><td>8 (1.7)</td><td>7 (1.6)</td><td>1 (3.3)</td><td></td></tr><tr><td>No treatment</td><td>76 (16.3)</td><td>72 (16.6)</td><td>4 (13.3)</td><td></td></tr></tbody></table>

Continuous variables are presented as median (interquartile range); categorical variables are presented as number (percentage). ASA: acetylsalicylic acid; BMI: body mass index; CABG: coronary artery bypass surgery; COPD: chronic obstructive pulmonary disease; DAPT: dual antiplatelet therapy; LVEF: left ventricular ejection fraction; MI: myocardial infarction; NOAC: non-vitamin K antagonist oral anticoagulant; NYHA: New York Heart Association; SAPT: single antiplatelet therapy; sPAP: systolic pulmonary artery pressure; VKA: vitamin K antagonist.

Regarding the severity of bleeding, the number of type 1 events was the same according to both VARC-3 and VARC-2 criteria, with no fatal bleeding events. However, type 3 bleeding according to VARC-3 was more common (3.1%) than life-threatening bleeding (1.2%) according to VARC-2.

### 4.1.2. Late bleeding

A total of 30 patients (6.1%) experienced at least one late VARC-3-defined bleeding event at a median follow-up of 645 (172–1305) days, five (16.7%) of whom had already had an early bleeding event. Only two patients (0.4%) presented a second late bleeding event during follow-up. The 1- and 5-year estimates for late VARC-3-defined bleeding events were 2.43% (95% CI 1.35–4.35%) and 9.65% (95% CI 6.55–14.09%), respectively. The incidence of late bleeding events was identical when applying the VARC-3 definition compared with VARC-2 (Fig. 1). Gastrointestinal bleeding was the most common site of late bleeding (n = 18, 3.7%).

Regarding the severity of bleeding, one event was fatal. Akin to early bleeding events, type 3 bleeding according to VARC-3 was more frequent than life-threatening bleeding according to VARC-2. In contrast, there were fewer VARC-3 type 1 bleeding events (1.2%) than VARC-2 minor bleeding events (2.7%).

## 4.2. Factors associated with bleeding events

### 4.2.1. Early bleeding

Factors associated with early VARC-3-defined bleeding in the univariate analysis were active cancer (OR 14.3, 95% CI 1.27–159.8; P = 0.03), history of heart failure (OR 1.60, 95% CI 0.93–2.76; P = 0.09), previous implantable cardioverter-defibrillator (ICD) (OR 14.3, 95% CI 1.27–159.8; P = 0.03), history of mitral valve surgery (OR 10.97, 95% CI 1.79–67.0; P = 0.01), a non-transfemoral approach (OR 2.22, 95% CI 1.22–4.05; P = 0.009), a temporary pacemaker left in place at the end of the procedure (OR 1.72, 95% CI 0.99–2.98; P = 0.054), a major vascular complication (OR 34.1, 95% CI 13.0–89.8; P < 0.001) and new-onset atrial fibrillation (AF) (OR 4.16, 95% CI 1.76–9.83; P = 0.001). Fig. 3A depicts multivariable predictors of early VARC-3-defined bleeding events, which included active cancer (OR 36.2, 95% CI 3.14–417.4; P = 0.004), previous ICD (OR 18.9, 95% CI 1.20–296.5; P = 0.036), history of mitral valve surgery (OR 18.5, 95% CI 2.53–135.7; P = 0.004), a non-transfemoral approach (OR 2.82, 95% CI 1.33–5.95; P = 0.007), a major vascular complication (OR 44.4, 95% CI 15.8–124.3; P < 0.001) and new-onset AF (OR 3.26, 95% CI 1.12–9.50; P = 0.03).

### 4.2.2. Late bleeding

Variables associated with late VARC-3-defined bleeding complications in the univariate analysis included active cancer (sHR
<table><caption>**Table 3**
Procedural and discharge characteristics of the population according to the occurrence of early Valve Academic Research Consortium 3 (VARC-3)-defined bleeding events.</caption><thead><tr><th></th><th>Total (n = 487)</th><th>No early bleeding (n = 426)</th><th>Early bleeding (n = 61)</th><th>P</th></tr></thead><tbody><tr><td>Procedural characteristics</td><td></td><td></td><td></td><td></td></tr><tr><td>Transfemoral approach</td><td>391 (81.3)</td><td>354 (83.1)</td><td>42 (68.9)</td><td>0.012</td></tr><tr><td>Balloon-expandable valve</td><td>357 (73.6)</td><td>315 (74.3)</td><td>42 (68.9)</td><td>0.44</td></tr><tr><td>Valve size (mm)</td><td></td><td></td><td></td><td></td></tr><tr><td>23</td><td>163 (33.7)</td><td>145 (34.1)</td><td>19 (31.1)</td><td>0.20</td></tr><tr><td>25</td><td>2 (0.4)</td><td>2 (0.5)</td><td>0 (0.0)</td><td></td></tr><tr><td>26</td><td>188 (38.7)</td><td>170 (40.0)</td><td>18 (29.5)</td><td></td></tr><tr><td>27</td><td>3 (0.6)</td><td>3 (0.7)</td><td>0 (0.0)</td><td></td></tr><tr><td>29</td><td>116 (23.9)</td><td>95 (22.4)</td><td>21 (34.4)</td><td></td></tr><tr><td>34</td><td>13 (2.7)</td><td>10 (2.4)</td><td>3 (4.9)</td><td></td></tr><tr><td>Sheath size (Fr)</td><td></td><td></td><td></td><td></td></tr><tr><td>14</td><td>367 (75.4)</td><td>324 (76.1)</td><td>43 (70.5)</td><td>0.37</td></tr><tr><td>16</td><td>112 (23.0)</td><td>94 (20.1)</td><td>18 (29.5)</td><td></td></tr><tr><td>18</td><td>4 (0.8)</td><td>4 (0.9)</td><td>0 (0.0)</td><td></td></tr><tr><td>19</td><td>4 (0.8)</td><td>4 (0.9)</td><td>0 (0.0)</td><td></td></tr><tr><td>Access closure device</td><td></td><td></td><td></td><td></td></tr><tr><td>Proglide</td><td>54 (11.3)</td><td>51 (12.3)</td><td>3 (4.9)</td><td>0.045</td></tr><tr><td>Prostar</td><td>329 (69.0)</td><td>289 (69.5)</td><td>40 (65.5)</td><td></td></tr><tr><td>Surgical closure<sup>a</sup></td><td>94 (19.7)</td><td>76 (18.3)</td><td>18 (29.5)</td><td></td></tr><tr><td>Temporary pacemaker left in place at end of procedure</td><td>164 (34.5)</td><td>137 (32.9)</td><td>27 (45.8)</td><td>0.06</td></tr><tr><td>Procedural complications</td><td></td><td></td><td></td><td></td></tr><tr><td>Death</td><td>2 (0.4)</td><td>2 (0.5)</td><td>0 (0.0)</td><td>0.77</td></tr><tr><td>Surgical conversion</td><td></td><td></td><td></td><td></td></tr><tr><td>Cardiac surgery</td><td>3 (0.6)</td><td>1 (0.2)</td><td>2 (3.3)</td><td>&lt; 0.001</td></tr><tr><td>Vascular surgery</td><td>10 (2.1)</td><td>2 (0.5)</td><td>8 (13.1)</td><td>&lt; 0.001</td></tr><tr><td>In-hospital complications and discharge data</td><td></td><td></td><td></td><td></td></tr><tr><td>Death</td><td>5 (1.0)</td><td>5 (1.2)</td><td>0 (0.0)</td><td>0.63</td></tr><tr><td>Major vascular complication</td><td>26 (5.3)</td><td>6 (1.4)</td><td>20 (32.8)</td><td>&lt; 0.001</td></tr><tr><td>Stroke</td><td>12 (2.5)</td><td>11 (2.6)</td><td>1 (1.6)</td><td>0.73</td></tr><tr><td>MI</td><td>1 (0.2)</td><td>0 (0.0)</td><td>1 (0.2)</td><td>0.71</td></tr><tr><td>Acute kidney injury</td><td>16 (3.3)</td><td>10 (2.3)</td><td>6 (9.8)</td><td>0.09</td></tr><tr><td>Permanent pacemaker implantation</td><td>68 (14.0)</td><td>63 (14.8)</td><td>5 (8.2)</td><td>0.18</td></tr><tr><td>Hospitalization length (days)</td><td>5 (4–7)</td><td>5 (4–7)</td><td>4 (4–7)</td><td>0.55</td></tr><tr><td>≥ Mild paravalvular leak</td><td>90 (18.6)</td><td>78 (18.4)</td><td>12 (19.4)</td><td>0.86</td></tr><tr><td>New-onset AF<sup>b</sup></td><td>18/292 (6.2)</td><td>12/256 (4.7)</td><td>6/36 (16.7)</td><td>0.014</td></tr><tr><td>Discharge antithrombotic regimen</td><td></td><td></td><td></td><td></td></tr><tr><td>ASA</td><td>383 (79.0)</td><td>342 (80.7)</td><td>41 (67.2)</td><td>0.19</td></tr><tr><td>Clopidogrel</td><td>276 (56.9)</td><td>246 (58.0)</td><td>30 (49.2)</td><td>0.21</td></tr><tr><td>Anticoagulant</td><td>204 (42.1)</td><td>176 (41.5)</td><td>28 (45.9)</td><td>0.58</td></tr><tr><td>VKA</td><td>92 (19.4)</td><td>74 (17.9)</td><td>18 (29.5)</td><td>0.038</td></tr><tr><td>NOAC</td><td>106 (22.4)</td><td>96 (23.2)</td><td>10 (16.7)</td><td>0.32</td></tr><tr><td>SAPT</td><td>27 (5.7)</td><td>21 (5.1)</td><td>6 (10.0)</td><td>0.12</td></tr><tr><td>DAPT</td><td>240 (51.1)</td><td>214/52.2</td><td>26 (43.3)</td><td></td></tr><tr><td>Anticoagulant only</td><td>74 (15.7)</td><td>58 (14.1)</td><td>16 (26.7)</td><td></td></tr><tr><td>Anticoagulant + SAPT</td><td>115 (24.5)</td><td>104 (25.4)</td><td>11 (18.3)</td><td></td></tr><tr><td>Triple therapy</td><td>13 (2.8)</td><td>12 (2.9)</td><td>1 (1.7)</td><td></td></tr><tr><td>No treatment</td><td>1 (0.2)</td><td>1 (0.2)</td><td>0 (0.0)</td><td></td></tr></tbody></table>

Continuous variables are presented as median (interquartile range); categorical variables are presented as number (percentage). AF: atrial fibrillation; ASA: acetylsalicylic acid; DAPT: dual antiplatelet therapy; Fr: French; MI: myocardial infarction; NOAC: non-vitamin K antagonist oral anticoagulant; SAPT: single antiplatelet therapy; VKA: vitamin K antagonist.

<sup>a</sup> Surgical closure was performed in 12 patients undergoing transfemoral TAVI (3.0%); this was planned in two cases (0.5%) and was the result of a percutaneous vascular closure device failure or a vascular complication in 10 patients (2.5%).

<sup>b</sup> Among patients without known previous AF.

5.27, 95% CI 0.81–34.3; P=0.08), history of myocardial infarction (sHR 4.39, 95% CI 1.10–17.5; P=0.04), treatment with vitamin K antagonists (VKAs) at discharge (sHR 2.61, 95% CI 1.23–5.51; P=0.01) and the aortic mean gradient at discharge (sHR 0.92, 95% CI 0.84–1.01; P=0.08).

Factors associated with late VARC-3-defined bleeding events in the multivariable analysis are shown in Fig. 3B, and included history of myocardial infarction (sHR 5.84, 95% CI 1.41–24.2; P=0.02) and treatment with VKAs at discharge (sHR 2.87, 95% CI 1.34–6.18; P=0.007). The cumulative incidences of late VARC-3-defined bleeding complications according to treatment by VKAs or non-VKA oral anticoagulants (NOACs) at discharge are highlighted in Fig. 4. Unlike patients receiving VKAs, patients treated with NOACs did not experience a higher risk of late bleeding (sHR 0.58, 95% CI 0.20–1.66; P=0.31).

### 4.3. Impact of bleeding events

Thirty-day mortality was low, with only seven patients dying within a month of the procedure (1.4%, 95% CI 0.7%–3.0%). At 1 and 5 years, mortality was 5.5% (95% CI 3.8–7.9%) and 55.2% (95% CI 49.8–60.7%), respectively. Fig. 5 demonstrates the Kaplan-Meier estimates of all-cause mortality according to the occurrence of early bleeding events defined by the VARC-2 and VARC-3 definitions. There was no difference in late all-cause mortality according to the occurrence of VARC-2-defined early bleeding (log-rank P=0.24). A gradual increase in late mortality was observed with the severity of bleeding events according to VARC-3 criteria; however, the discrimination of type 3 events appeared lower than that of VARC-2 life-threatening bleeding, and there was no significant difference in late mortality
<table><caption>**Table 4**
Procedural and discharge characteristics of the population according to the occurrence of late Valve Academic Research Consortium 3 (VARC-3)-defined bleeding events.</caption><thead><tr><th></th><th>Total (n = 479)</th><th>No early bleeding (n = 449)</th><th>Early bleeding (n = 30)</th><th>P</th></tr></thead><tbody><tr><td>Procedural characteristics</td><td></td><td></td><td></td><td></td></tr><tr><td>Transfemoral approach</td><td>390 (81.4)</td><td>364 (81.1)</td><td>26 (86.7)</td><td>0.34</td></tr><tr><td>Balloon-expandable valve</td><td>349 (73.0)</td><td>330 (73.8)</td><td>19 (63.3)</td><td>0.29</td></tr><tr><td>Valve size (mm)</td><td></td><td></td><td></td><td></td></tr><tr><td>23</td><td>162 (33.9)</td><td>156 (34.8)</td><td>6 (20.0)</td><td>0.28</td></tr><tr><td>25</td><td>2 (0.4)</td><td>2 (0.4)</td><td>0 (0.0)</td><td></td></tr><tr><td>26</td><td>185 (38.7)</td><td>172 (38.4)</td><td>13 (43.3)</td><td></td></tr><tr><td>27</td><td>3 (0.6)</td><td>2 (0.4)</td><td>1 (3.3)</td><td></td></tr><tr><td>29</td><td>113 (23.6)</td><td>104 (23.2)</td><td>9 (30.0)</td><td></td></tr><tr><td>34</td><td>13 (2.7)</td><td>12 (2.7)</td><td>1 (3.3)</td><td></td></tr><tr><td>Sheath size (Fr)</td><td></td><td></td><td></td><td></td></tr><tr><td>14</td><td>362 (75.6)</td><td>344 (76.6)</td><td>18 (60.0)</td><td>0.09</td></tr><tr><td>16</td><td>109 (22.8)</td><td>98 (21.8)</td><td>11 (36.7)</td><td></td></tr><tr><td>18</td><td>4 (0.8)</td><td>4 (0.9)</td><td>0 (0.0)</td><td></td></tr><tr><td>19</td><td>4 (0.8)</td><td>3 (0.7)</td><td>1 (3.3)</td><td></td></tr><tr><td>Access closure device</td><td></td><td></td><td></td><td></td></tr><tr><td>Proglide</td><td>50 (10.7)</td><td>48 (10.9)</td><td>2 (6.7)</td><td>0.48</td></tr><tr><td>Prostar</td><td>328 (69.9)</td><td>304 (69.2)</td><td>24 (80)</td><td></td></tr><tr><td>Surgical closure<sup>a</sup></td><td>91 (19.4)</td><td>87 (19.8)</td><td>4 (13.3)</td><td></td></tr><tr><td>Temporary pacemaker left in place at end of procedure</td><td>162 (34.7)</td><td>156 (36.2)</td><td>4 (16.3)</td><td>0.010</td></tr><tr><td>Procedural complications</td><td></td><td></td><td></td><td></td></tr><tr><td>Death</td><td>2 (0.4)</td><td>2 (0.4)</td><td>0 (0.0)</td><td>0.88</td></tr><tr><td>Surgical conversion</td><td></td><td></td><td></td><td></td></tr><tr><td>Cardiac surgery</td><td>3 (0.6)</td><td>3 (0.7)</td><td>0 (0.0)</td><td>0.49</td></tr><tr><td>Vascular surgery</td><td>10 (2.1)</td><td>9 (2.0)</td><td>1 (3.3)</td><td></td></tr><tr><td>In-hospital complications and discharge data</td><td></td><td></td><td></td><td></td></tr><tr><td>Death</td><td>5 (1.0)</td><td>5 (1.1)</td><td>0 (0.0)</td><td>0.72</td></tr><tr><td>Early bleeding</td><td>61 (12.7)</td><td>56 (12.5)</td><td>5 (16.7)</td><td>0.57</td></tr><tr><td>Major vascular complication</td><td>26 (5.4)</td><td>24 (5.3)</td><td>2 (6.7)</td><td>0.50</td></tr><tr><td>Stroke</td><td>12 (2.5)</td><td>12 (2.7)</td><td>0 (0.0)</td><td>0.63</td></tr><tr><td>MI</td><td>1 (0.2)</td><td>1 (0.2)</td><td>0 (0.0)</td><td>0.94</td></tr><tr><td>Acute kidney injury</td><td>16 (3.3)</td><td>15 (3.3)</td><td>1 (3.3)</td><td>0.74</td></tr><tr><td>Permanent pacemaker implantation</td><td>67 (14.0)</td><td>61 (13.3)</td><td>6 (20.0)</td><td>0.29</td></tr><tr><td>Hospitalization length (days)</td><td>5 (4–7)</td><td>5 (4–7)</td><td>4.5 (4–7)</td><td>0.92</td></tr><tr><td>≥ Mild paravalvular leak</td><td>90 (16.7)</td><td>85 (19.0)</td><td>5 (16.1)</td><td>0.82</td></tr><tr><td>New-onset AF<sup>b</sup></td><td>21 (4.5)</td><td>20 (4.6)</td><td>1 (3.4)</td><td>0.62</td></tr><tr><td>Discharge antithrombotic regimen</td><td></td><td></td><td></td><td></td></tr><tr><td>ASA</td><td>376 (78.8)</td><td>354 (79.2)</td><td>22 (73.3)</td><td>0.49</td></tr><tr><td>Clopidogrel</td><td>270 (56.6)</td><td>258 (57.7)</td><td>12 (40.0)</td><td>0.09</td></tr><tr><td>Anticoagulant</td><td>201 (42.1)</td><td>184 (41.2)</td><td>17 (56.7)</td><td>0.13</td></tr><tr><td>VKA</td><td>91 (19.5)</td><td>18.3 (11)</td><td>11 (36.7)</td><td>0.019</td></tr><tr><td>NOAC</td><td>104 (22.3)</td><td>98 (22.5)</td><td>6 (20.0)</td><td>0.83</td></tr><tr><td>SAPT</td><td>27 (5.8)</td><td>25 (5.8)</td><td>2 (6.7)</td><td>0.38</td></tr><tr><td>DAPT</td><td>235 (50.9)</td><td>224 (51.9)</td><td>11 (36.7)</td><td></td></tr><tr><td>Anticoagulant only</td><td>74 (16.0)</td><td>67 (15.5)</td><td>7 (23.3)</td><td></td></tr><tr><td>Anticoagulant + SAPT</td><td>112 (24.2)</td><td>102 (23.6)</td><td>10 (33.3)</td><td></td></tr><tr><td>Triple therapy</td><td>13 (2.8)</td><td>13 (3.0)</td><td>0 (0.0)</td><td></td></tr><tr><td>No treatment</td><td>1 (0.2)</td><td>1 (0.2)</td><td>0 (0.0)</td><td></td></tr></tbody></table>

Continuous variables are presented as median (interquartile range); categorical variables are presented as number (percentage). AF: atrial fibrillation; ASA: acetylsalicylic acid; DAPT: dual antiplatelet therapy; Fr: French; MI: myocardial infarction; NOAC: non-vitamin K antagonist oral anticoagulant; SAPT: single antiplatelet therapy; VKA: vitamin K antagonist.

according to VARC-3-defined bleeding events overall (log-rank $P=0.26$).

After adjustment for potential confounders, early bleeding events were not associated with an increased risk of late mortality, regardless of the definition used for their classification (Table 5).

## 5. Discussion

VARC-3-defined bleeding events after TAVI were relatively common, occurring in 17.6% of patients. The most frequently identified sites for early and late bleeding events were the vascular access site and the gastrointestinal tract, respectively. Independent predictors of early bleeding included the presence of active cancer, a history of ICD, a history of mitral valve surgery, the use of non-transfemoral access and the occurrence of a major vascular complication or new-onset AF during hospitalization. For late bleeding events, the

predictors were the prescription of VKAs at discharge and a history of myocardial infarction.

### 5.1. Incidence and impact of early bleeding events

The reduction in the risk of bleeding events is considered one of the key mechanisms explaining the survival benefit observed with TAVI over time [18]. Early bleeding is generally attributed to periprocedural complications [19]. Our results are in line with these previous findings, with 10.1% of patients experiencing early bleeding at the primary access site in the present study. Moreover, major vascular complications and new-onset AF, which may prompt the introduction of an oral anticoagulant therapy, were significant predictors of early bleeding. The choice of the primary vascular access is also crucial for mitigating bleeding risk, especially in patients with a complex femoral access or who are not

<footnote>a Surgical closure was performed in 12 patients undergoing transfemoral TAVI (3.0%); this was planned in two cases (0.5%) and was the result of a percutaneous vascular closure device failure or a vascular complication in 10 patients (2.5%).</footnote>

<footnote>b Among patients without known previous AF.</footnote>
<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Incidence and severity of early and late bleeding events defined according to VARC-2 and VARC-3 criteria. VARC: Valve Academic Research Consortium.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Frequency and location of Valve Academic Research Consortium 3 (VARC-3) bleeding events according to time of occurrence.</figcaption></figure>

eligible for the transfemoral approach, as demonstrated by a significant increase in bleeding complications associated with the use of a non-transfemoral approach (largely confined to transthoracic approaches).

Our study found a lower incidence of early bleeding events (12.5%) compared with Avvedimento et al. [15], who reported a 27.1% incidence of VARC-3-defined early bleeding events among 2384 TAVI recipients treated between 2007 and 2022. This
<figure><img src="image_6.png" /><figcaption>**Fig. 3.** A–B. Multivariable predictors of early and late bleeding according to Valve Academic Research Consortium 3 (VARC-3) criteria. A. Multivariable predictors of early bleeding events. B. Multivariable predictors of late bleeding events. AF: atrial fibrillation; CI: confidence interval; ICD: implantable cardioverter-defibrillator; MI: myocardial infarction; MV: mitral valve; TF: transfemoral; VKA: vitamin K antagonist.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**Fig. 4.** A, B. Cumulative incidence of late Valve Academic Research Consortium 3 (VARC-3)-defined bleeding events according to treatment by vitamin K antagonist (VKA) or non-vitamin K antagonist oral anticoagulant (NOAC) at discharge. A. According to treatment by VKA at discharge. B. According to treatment by NOAC at discharge. sHR: subhazard ratio.</figcaption></figure>

<table><caption>**Table 5**

Impact of early bleeding events on all-cause mortality at follow-up according to VARC-2 and VARC-3 criteria.</caption><thead><tr><th></th><th>n (%)</th><th>HR (95% CI)</th><th>P</th></tr></thead><tbody><tr><td>VARC-3</td><td></td><td></td><td></td></tr><tr><td>No bleeding</td><td>220 (51.6)</td><td>-</td><td>-</td></tr><tr><td>Type 1</td><td>12 (36.4)</td><td>0.70 (0.39–1.25)</td><td>0.23</td></tr><tr><td>Type 2</td><td>8 (61.5)</td><td>1.27 (0.62–2.60)</td><td>0.51</td></tr><tr><td>Type 3</td><td>10 (66.7)</td><td>1.23 (0.61–2.45)</td><td>0.56</td></tr><tr><td>VARC-2</td><td></td><td></td><td></td></tr><tr><td>No bleeding</td><td>220 (51.6)</td><td>-</td><td>-</td></tr><tr><td>Minor</td><td>12 (36.4)</td><td>0.70 (0.39–1.25)</td><td>0.23</td></tr><tr><td>Major</td><td>15 (68.2)</td><td>1.24 (0.71–2.16)</td><td>0.45</td></tr><tr><td>Life-threatening</td><td>3 (50.0)</td><td>1.30 (0.40–4.26)</td><td>0.67</td></tr></tbody></table>

Models were adjusted for sex, previous atrial fibrillation, type of previous stroke, chronic obstructive pulmonary disease, baseline New York Heart Association class 3 or 4, stroke during index hospitalization and acute kidney injury during index hospitalization; stroke during index hospitalization and acute kidney injury during index hospitalization were included as time-varying covariates. CI: confidence interval; HR: hazard ratio; VARC: Valve Academic Research Consortium.
<figure><img src="image_8.png" /><figcaption>**Fig. 5.** Kaplan-Meier estimates of mortality according to the presence of early bleeding events. VARC: Valve Academic Research Consortium.</figcaption></figure>

difference may be explained by the increased expertise of operators and centres, the widespread adoption of the transfemoral approach, along with a reduction in sheath sizes, and improved haemostasis at the access site over time. Indeed, in the study by Avvedimento et al. [15], 35% of patients were treated via a non-transfemoral access. Additionally, because of the retrospective nature of our study, some early type 2 bleeding events according to the VARC-3 criteria may have gone undetected, particularly in patients in whom only a single postoperative haemoglobin concentration was measured. Another potential explanation for this difference may be the omission of a clopidogrel loading dose before TAVI in the present series, which probably contributed to reduce the early bleeding risk. However, Avvedimento et al. reported a higher incidence of VARC-3 compared with VARC-2 bleeding events, mainly driven by non-overt procedural blood loss, which accounted for one third of early bleeding events [15]. Furthermore, the authors also demonstrated a major decrease in early bleeding rates defined using either the VARC-2 or VARC-3 classification, starting in 2018, with rates of VARC-3 events nearing those of VARC-2 events at approximately 10–15% afterwards; this was related to a substantial decrease in non-overt procedural blood loss. Therefore, our results and this previous report are mostly in line, and question the relevance of introducing these periprocedural non-overt blood losses in the VARC-3 definition, especially for bleeding events that have no therapeutic impact later on (no transfusion or adjustment in antithrombotic therapy). Indeed, while Stortecky et al. [20] reported a refined predictive ability associated with the addition of the amount of periprocedural blood loss to the VARC-2 criteria among 489 TAVI recipients treated between 2007 and 2012, neither Avvedimento et al. [15] nor the present study demonstrated an improved prediction of all-cause mortality with the VARC-3 classification. Consequently, further large-scale studies are required to better delineate the prognostic impact of each component of the VARC-3 classification, especially non-overt procedural blood loss.

## 5.2. Predictive factors for bleeding events

Several important factors, both patient and procedure related, were associated with an increased risk of early bleeding events. These include the presence of active cancer, a history of ICD, previous mitral valve surgery, a non-transfemoral access and the

occurrence of a major vascular complication or new-onset AF during hospitalization.

One of the primary predictors of bleeding is the use of a non-transfemoral approach. The transfemoral approach is now considered the standard access method; however, 5–20% of patients are not eligible for this approach, depending on the habits and practices of each centre [21]. Historically, alternative approaches required transthoracic access (transapical and transthoracic), but several studies have shown the superiority of the transfemoral approach [22,23]. New approaches have since emerged (e.g., transcarotid or transaxillary), showing similar results to the femoral approach [24]. Although these findings are based on retrospective studies, there is accumulating evidence of the safety and efficacy of these newer alternative accesses. Although the femoral approach remains the standard and least invasive option, it remains of the utmost importance to conduct a thorough anatomical preprocedural evaluation. This ensures the selection of the access route with the lowest risk based on each patient's unique anatomy.

Patients who developed new-onset AF during hospitalization experienced more bleeding events, which can be explained, in part, by the fact that long-term anticoagulation was initiated in 50% of these patients.

These findings align with the present literature, which reports that new-onset AF following TAVI occurs in 4.9 to 8.2% of patients. The occurrence of new-onset AF has also been associated with an increased risk of bleeding and a higher incidence of stroke. In the literature, the initiation of anticoagulant therapy for patients who develops new-onset AF varies between 30 and 50%, which remains relatively low, and is consistent with our study [25,26]. This highlights the importance of exercising caution in managing antithrombotic therapy, particularly in avoiding the combination of anticoagulants and antiplatelet agents whenever possible, and in carefully evaluating the balance between bleeding and ischaemic risks.

## 5.3. Incidence and predictors of late bleeding events

A total of 30 patients experienced a late bleeding event, amounting to 6.1% of the study population, with 1- and 5-year estimates of 2.43% (95% CI 1.35–4.35%) and 9.65% (95% CI 6.55–14.09%),
respectively. These findings are similar to those of Avvedimento et al., who reported a 7.2% incidence of late bleeding events [15]. Using the Bleeding Academic Research Consortium classification, Yamamoto et al. also found a 7.4% incidence of late bleeding events over a 3-year follow-up among 2518 TAVI recipients included in a Japanese multicentre registry [27,28]. Furthermore, type 4 (i.e., fatal) VARC-3 bleeding events were scarce in the present study, which is consistent with previous findings, including a low ~1% rate observed in a recent series encompassing 297 TAVI recipients receiving oral anticoagulation therapy [29].

The incidence of late bleeding events is less dependent on procedural factors, with the patient's risk profile and discharge antithrombotic regimen playing a critical role in determining long-term bleeding risk. During the recruitment period, the reference antithrombotic strategy was DAPT. Evidence from randomized studies has highlighted the increased bleeding risk associated with DAPT compared with single antiplatelet therapy, without showing significant protection against ischaemic events [30]. Similarly, the use of an antiplatelet agent in addition to oral anticoagulation therapy leads to a higher rate of bleeding complications, without any advantage in preventing long-term thromboembolic events. The POPular-TAVI trial [31] showed that adding clopidogrel to oral anti-coagulation therapy (either NOAC or VKA) for 3 months after TAVI significantly increased non-procedural bleeding (34.6 vs. 21.7%; P=0.01), whereas the composite endpoint of cardiovascular death, stroke or myocardial infarction was similar between the groups. Akin to previous studies, a majority of patients in the present study were discharged on DAPT, whereas a significant proportion received combinations of oral anticoagulation therapy and antiplatelet agents. Such combinations were probably more commonly prescribed in patients with a history of myocardial infarction, which may explain its significant association with late bleeding in the present study. Lower rates of late bleeding events may be expected in future studies more accurately reflecting current guidelines regarding antithrombotic therapy after TAVI.

We observed an increase in late bleeding events among patients discharged on a VKA, which was not observed among those on a NOAC. More recently, a Spanish study found opposite results, with a higher incidence of late bleeding events in patients on a NOAC [29]. Data from the ATLANTIS [32] first stratum and the ENVISAGE-TAVI AF [33] randomized trials reported the non-inferiority of apixaban and edoxaban, respectively, compared with a VKA regarding composite endpoints, mainly including ischaemic and thromboembolic events. Yet, although there was no difference between NOACs and VKAs in terms of the risk of the primary safety endpoint of major, disabling or life-threatening bleeding in the ATLANTIS trial, the ENVISAGE-TAVI AF trial failed to demonstrate the non-inferiority

of edoxaban to VKA regarding major bleeding. In fact, a higher rate of major bleeding was observed in patients on edoxaban compared with their VKA counterparts. In contrast, a large-scale French trial found that long-term mortality and major bleeding events were lower with a NOAC compared with a VKA [34]. These findings add to seminal pivotal trials comparing NOACs with VKAs for thromboembolic prevention in patients with AF, supporting the former as the first-line treatment option.

### 5.4. Study limitations

First, this was a retrospective study, which inherently carries the biases associated with such studies, especially the risk of under-reporting certain outcomes without any therapeutic consequence subsequently. Second, because of its observational nature, the presence of unmeasured confounding factors that could influence the study's conclusions cannot be excluded. Furthermore, competitive bias arising from the fact that death prevents the occurrence of late bleeding is a common limitation of such observational studies. Third, the study population was based on the experience of a single centre, so the results may not be generalizable. Fourth, a lack of statistical power resulting from the moderate size of the study may have prevented us from identifying some predictors of bleeding events, and a type II error cannot be excluded in the analysis of the prognostic impact of early bleeding events. Finally, as already alluded to in the Discussion section, some characteristics of the present work (e.g., low rates of Proglide vascular closure system, a majority of patients discharged on DAPT, etc.) suggest that our cohort is unlikely to reflect the most contemporary practice of TAVI. Therefore, lower rates of both early and late bleeding events may be expected among patients treated more recently.

## 6. Conclusions

Bleeding events occurred in 17.6% of patients undergoing TAVI, without significant difference between VARC-2- and VARC-3-defined events. Procedural factors and postprocedural complications had a prominent role in the occurrence of early bleeding, whereas late bleeding was associated with the prescription of VKA at discharge and a history of myocardial infarction. Although a lack of statistical power cannot be excluded, early bleeding events were not associated with an increased risk of late mortality, regardless of the classification used, and the VARC-3 criteria did not seem to provide a refined prognostic assessment above and beyond the VARC-2 definition (Central Illustration).
<figure><img src="image_9.png" /></figure>

487 patients with severe symptomatic AS undergoing TAVI (2017-2019)

<figure><img src="image_10.png" /></figure>

BEV 74%

<figure><img src="image_11.png" /></figure>

SEV 26%

Median FU: 44.3 months

(IQR: 20.8-60 months)

Incidence of VARC-3 bleeding

<figure><img src="image_12.png" /></figure>

Most frequent bleeding site

<figure><img src="image_13.png" /></figure>

Multivariable predictors of bleeding

Early bleeding

Active cancer

Previous ICD

Previous MV surgery

Non-TF approach

New-onset AF

Major vascular complication

Late bleeding

Previous MI

VKA at discharge

Bleeding severity

Early bleeding events

<figure><img src="image_14.png" /></figure>

Late bleeding events

<figure><img src="image_15.png" /></figure>

Early bleeding impact on late mortality

VARC-2 bleeding classification

<figure><img src="image_16.png" /></figure>

Time from procedure (days)

Number at risk

<table><tr><td>426</td><td>390</td><td>302</td><td>248</td><td>186</td><td>97</td><td>20</td></tr><tr><td>33</td><td>32</td><td>24</td><td>20</td><td>16</td><td>9</td><td>3</td></tr><tr><td>22</td><td>22</td><td>19</td><td>15</td><td>13</td><td>6</td><td>2</td></tr><tr><td>6</td><td>5</td><td>5</td><td>4</td><td>4</td><td>1</td><td>1</td></tr></table>

VARC-3 bleeding classification

<figure><img src="image_17.png" /></figure>

Time from procedure (days)

Number at risk

<table><tr><td>426</td><td>390</td><td>302</td><td>248</td><td>186</td><td>97</td><td>20</td></tr><tr><td>33</td><td>32</td><td>24</td><td>20</td><td>16</td><td>9</td><td>3</td></tr><tr><td>13</td><td>13</td><td>10</td><td>9</td><td>2</td><td>2</td><td>1</td></tr><tr><td>15</td><td>14</td><td>13</td><td>9</td><td>7</td><td>5</td><td>1</td></tr></table>

**Central Illustration.** Incidence, location, predictors and prognostic impact of bleeding events after transcatheter aortic valve implantation (TAVI). Incidence, location and predictors of VARC-3 bleeding events (top). Severity and prognostic impact of bleeding events according to the VARC-2 and VARC-3 classifications (bottom). AF: atrial fibrillation; AS: aortic stenosis; BEV: balloon-expandable valve; FU: follow-up; ICD: implantable cardioverter-defibrillator; IQR: interquartile range; MI: myocardial infarction; MV: mitral valve; SEV: self-expandable valve; TF: transfemoral; VARC: Valve Academic Research Consortium; VKA: vitamin K antagonist.

Funding

None.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.acvd.2024.12.009.

Disclosure of interest

V.A. has received lecture fees from Edwards Lifesciences, Med-
tronic and Bouchara-Recordati, and consulting fees from Boston
Scientific and Medtronic.

G.L. has received lecture, proctor and consultant fees from Abbott.

All the other authors declare that they have no competing inter-
est.
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