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Pre-Operative Continued Oral Anticoagulation Impact on Early Outcomes after Transcatheter Aortic Valve Implantation

Open AccessPublished:March 20, 2021DOI:https://doi.org/10.1016/j.amjcard.2021.03.022
      Considering that there is a lack of evidence and guideline-based recommendations on the best preoperative oral anticoagulation management (OAC) for transcatheter aortic valve implantation (TAVI), this cohort study aimed to evaluate bleeding, access site complications, and early safety in patients undergoing TAVI on continued OAC therapy vs no-OAC therapy. Three-hundred forty-four patients submitted to a TAVI procedure (66.3% no-OAC vs 33.7% OAC) were consecutively enrolled. Primary endpoint was defined as in-hospital VARC-2 life-threatening or disabling bleeding. Secondary endpoints were in-hospital VARC-2 major vascular complications and VARC-2 early safety at 30 days. Propensity score matching analysis was performed to reduce potential distribution bias, resulting in 2 well-balanced groups (92 patients in each arm). In the overall cohort, mean age, median EuroScore II, and STS-score were 78.7±7.6 years, 2.9% (1.7-5.9), and 2.3% (1.6-3.6), respectively. Despite being older (78 ± 8 vs 80 ± 6, p = 0.004) and having higher STS score (2.1 vs 2.6, p = 0.001), patients on OAC had similar incidence of in-hospital VARC-2 life-threatening or disabling bleeding (1.3% vs. 0.9%, p = 0.711), major vascular complications (4.8% vs 5.2%, p = 0.888), and VARC-2 early safety at 30 days (10.1% vs 12.1%, p = 0.575). No significant differences in the main outcomes were observed when propensity score matching was applied. In conclusion, the management of patients on OAC submitted to a TAVI procedure is challenging and requires balancing the risk of bleeding with the risk of thromboembolic events. The present study suggests that continued OAC was not associated with increased in-hospital VARC-2 life-threatening or disabling bleeding, major vascular complications, and VARC-2 early safety at 30 days.
      Antithrombotic or anticoagulation therapy following transcatheter aortic valve implantation (TAVI) has been recently investigated in the POPular TAVI trial cohorts A and B, respectively.
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      • Timmers L
      • Kelder JC
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      • Baan J
      • Ten Berg JM
      Aspirin with or without clopidogrel after transcatheter aortic-valve implantation.
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      • Hermanides RS
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      • Dubois CLF
      • Frambach P
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      • Van Der Heyden JAS
      • Toušek P
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      • Buysschaert I
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      • Ferdinande B
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      • Roosen J
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      • Timmers L
      • Kelder JC
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      • Ten Berg JM
      Anticoagulation with or without clopidogrel after transcatheter aortic-valve implantation.
      Results have suggested the superiority of single antiplatelet therapy (aspirin) in patients without indication for oral anticoagulation (OAC), and OAC alone in those with an OAC indication. These trials, however, focused on post-TAVI management and did not investigate the optimal perioperative regimen. Current European guidelines recommend vitamin K antagonists (VKA) discontinuation 5 days prior to elective cardiac surgery, aiming an INR (international normalized ratio) value <1.5 on the procedure day. Preoperative direct OAC (DOAC) discontinuation is recommended at least 48-96 hours before the procedure. However, no specific recommendation on how to manage these medications on the TAVI context has been provided.
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      2017 EACTS Guidelines on perioperative medication in adult cardiac surgery.
      Trying to clarify this issue, a retrospective study showed that, in patients with atrial fibrillation submitted to transfemoral TAVI, the lowest rates of early safety (with lower values indicating superior safety) and 1-year mortality were observed in the continued DOAC group compared to continued or interrupted VKA. Continued VKA had similar incidence of bleeding and access site complication than interrupted VKA.
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      • Linke A
      Continued versus interrupted oral anticoagulation during transfemoral transcatheter aortic valve implantation and impact of postoperative anticoagulant management on outcome in patients with atrial fibrillation.
      These results are in line with the previous ones in which several DOAC regimens [dabigatran
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      RE-LY Steering Committee and Investigators
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ; edoxaban
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      ENGAGE AF-TIMI 48 Investigators
      Edoxaban versus warfarin in patients with atrial fibrillation.
      ; apixaban
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      • Lewis BS
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      ARISTOTLE Committees and Investigators
      Apixaban versus warfarin in patients with atrial fibrillation.
      ; rivaroxaban
      • Patel MR
      • Mahaffey KW
      • Garg J
      • Pan G
      • Singer DE
      • Hacke W
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      • Hankey GJ
      • Piccini JP
      • Becker RC
      • Nessel CC
      • Paolini JF
      • Berkowitz SD
      • Fox KA
      • Califf RM
      ROCKET AF Investigators
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ] were compared to warfarin in patients with atrial fibrillation. Considering the lack of evidence and guideline-based recommendations on the best pre-TAVI OAC management, this study aims to evaluate the impact of continued OAC. For that, we compared patients receiving continued OAC with those not receiving any OAC therapy in terms of bleeding, vascular complications, and early safety.

      Methods

      From January 2019 to July 2020, 344 patients submitted to TAVI in a single center were consecutively enrolled. Patients were analyzed according to the perioperative OAC regimen. Group 1 (no-OAC): patients who were not on OAC at the time of the index procedure. Group 2 (OAC): patients who were on OAC (either VKA or DOAC) at the time of the index procedure. This comparison was possible since, as a local institutional routine, TAVI procedures are systematically performed without interruption of the ongoing antithrombotic or OAC regimen. Patients on VKA therapy were kept on VKA therapy during the whole periprocedural phase with an INR target range between 2 and 3, while patients on DOAC remained receiving the therapy during the whole procedural period, without skipping doses. TAVI indication was driven by the institutional heart team and patients provided written informed consent before the procedure. All patients undergoing TAVI in our institution are included in the nationwide Swiss TAVI Registry approved by local ethic committees.
      • Wenaweser P
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      • Tueller D
      • Nietlispach F
      • Falk V
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      • Jeger R
      • Reuthebuch O
      • Carrel T
      • Räber L
      • Amann FW
      • Ferrari E
      • Toggweiler S
      • Noble S
      • Roffi M
      • Gruenenfelder J
      • Jüni P
      • Windecker S
      • Huber C.
      Short-term clinical outcomes among patients undergoing transcatheter aortic valve implantation in Switzerland: the Swiss TAVR registry.
      ,
      • Stortecky S
      • Franzone A
      • Heg D
      • Tueller D
      • Noble S
      • Pilgrim T
      • Jeger R
      • Toggweiler S
      • Ferrari E
      • Nietlispach F
      • Taramasso M
      • Maisano F
      • Grünenfelder J
      • Muller O
      • Huber C
      • Roffi M
      • Carrel T
      • Wenaweser P
      • Windecker S.
      Temporal trends in adoption and outcomes of transcatheter aortic valve implantation: a SwissTAVR Registry analysis.
      During TAVI, intravenous heparin was administered, adjusted to baseline activated clotting time, aiming to reach an activated clotting time above 250 seconds in both groups. Decision about anesthetic approach and the access route were taken based on patient and devices characteristics, local expertise, and operator discretion. Cerebral embolic protection, using the Sentinel system (Boston Scientific, Marlborough, MA, USA), was routinely used. First choice access site was percutaneous transfemoral, performed through ultrasound-guided puncture. Second choice access was left subclavian artery and the third left carotid artery or transapical, performed by open surgical dissection. In the case of transfemoral route, closure devices, Perclose/ProGlide system (Abbott Vascular, CA, USA) or Manta (Essential Medical Inc, Exton, PA), were used. TAVIs were performed using CE-approved devices. The Medtronic platform (Medtronic Inc., Minneapolis, MN, USA) has an integrated InLine Sheath (14F for the Evolut R 23, 26, 29 mm, and 16F for Evolut Pro and Evolut R 34 mm). The Edwards Sapien platform (Edwards Lifesciences, Irvine, CA, USA) was introduced through a 14F or16F eSheath, which has a dynamic expansion mechanism (14F for 20, 23, 26 mm, and 16F for 29 mm). The Portico (Abbott Vascular, Santa Clara, CCA, USA) previous generation was introduced sheathless, while the new FlexNav system has an integrated 14 or15F sheath (14F for 23, 25 mm, and 15F for 27, 29 mm). The Acurate-Neo (Boston Scientific Corporation, Natick, MA, USA) was introduced through a 14F iSLEEVE expandable introducer. The Lotus Edge (Boston Scientific Corporation, Natick, MA, USA) and the Allegra (New Valve Technology, Hechingen, Germany) platforms were used with an 18F sheath.
      Baseline characteristics, procedural data, and outcomes were prospectively collected and adjudicated according to the Valve Academic Research Consortium updated criteria (VARC-2).
      • Mack MJ
      • Leon MB
      • Thourani VH
      • Makkar R
      • Kodali SK
      • Russo M
      • Kapadia SR
      • Malaisrie SC
      • Cohen DJ
      • Pibarot P
      • Leipsic J
      • Hahn RT
      • Blanke P
      • Williams MR
      • McCabe JM
      • Brown DL
      • Babaliaros V
      • Goldman S
      • Szeto WY
      • Genereux P
      • Pershad A
      • Pocock SJ
      • Alu MC
      • Webb JG
      • Smith CR
      PARTNER 3 Investigators
      Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients.
      Primary endpoint was defined as in-hospital VARC-2 life-threatening or disabling bleeding. Secondary endpoints were in-hospital VARC-2 major vascular complications, and VARC-2 early safety at 30 days (a composite of all-cause mortality, all-stroke, life-threatening bleeding, acute kidney injury stage 2 or 3, coronary artery obstruction requiring intervention, major vascular complication, and valve-related dysfunction requiring repeat procedure). Preoperative CHA2DS2-VASc and HAS-BLED scores were calculated as recommended by current guidelines.
      • Kappetein AP
      • Head SJ
      • Généreux P
      • Piazza N
      • van Mieghem NM
      • Blackstone EH
      • Brott TG
      • Cohen DJ
      • Cutlip DE
      • van Es GA
      • Hahn RT
      • Kirtane AJ
      • Krucoff MW
      • Kodali S
      • Mack MJ
      • Mehran R
      • Rodés-Cabau J
      • Vranckx P
      • Webb JG
      • Windecker S
      • Serruys PW
      • Leon MB.
      Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document.
      Sudden cardiac death was defined as unexpected death from a presumptively cardiac cause that occurs in a short time period, generally within 1 hour of symptom onset or without prior symptoms.
      • Lilly SM
      • Deshmukh AJ
      • Epstein AE
      • Ricciardi MJ
      • Shreenivas S
      • Velagapudi P
      • Wyman JF.
      2020 ACC expert consensus decision pathway on management of conduction disturbances in patients undergoing transcatheter aortic valve replacement.
      Descriptive data were expressed as mean ± standard deviation (SD) or median and interquartile range (IQR). Statistical analyses were performed using the statistical package SPSS 25.0 software (IBM Corporation, Armonk, New York). Categorical variables were analyzed using Chi-square test, and continuous variables using Student's t-test or Mann-Whitney U test, according to the distribution pattern. A two-sided p-value lower than 0.05 was considered significant for all analyses. In order to reduce bias, a propensity score matching analysis was performed. Variables related to the primary endpoint or with an unequal distribution between groups (p<0.2) were included in a 1:1 nearest neighbor model. The caliper width was equal to 0.15 of the standard deviation of the logit of the propensity score. The effectiveness of balancing was analyzed with propensity score histograms, estimating the reduction in the standardized percentage bias and performing Chi-square and t-test between groups.

      Results

      Among the overall 344 evaluated patients, 116 (33.7%) underwent TAVI receiving continued OAC therapy, while 228 (66.3%) did not receive any OAC therapy. Applying propensity score matching, two well-balanced groups, with 92 patients in each one, were generated. Baseline characteristics and echocardiographic parameters for the overall cohort are presented in Table 1, and for the propensity score-matched cohort in Table 2. Before propensity score matching, patients in the OAC group were older, had higher EuroScore II and STS-score, and also higher previous permanent pacemaker prevalence, but lower previous acute myocardial infarction prevalence. As expected, patients on OAC had significantly higher CHA2DS2Vasc score (3.8 ± 1.3 vs 4.4 ± 1.2, p < 0.001) with similar HAS-BLED score (2.4 ± 1 vs 2.6 ± 0.98, p = 0.303).
      Table 1Baseline characteristics and echocardiographic parameters before propensity score matching
      VariableAll (n = 344)OACp value
      No (n = 228)Yes (n = 116)
      Age (years)78.7 ± 7.678 ± 8.180.4 ± 6.10.004
      Men214 (62.2%)149 (65.4%)65 (56%)0.092
      Body mass index (Kg/m2)26.4 ± 426.4 ± 4.726.5 ± 4.70.921
      EuroScore II (%)2.9 (1.7-5.9)2.7 (1.55-5)3.4 (2.4-7.2)0.001
      STS-score (%)2.3 (1.6-3.6)2.1 (1.5-3.3)2.6 (2.0-3.8)0.001
      CHA2DS2-Vasc score ≥3311 (90.4%)199 (87.3%)112 (96.6%)0.006
      HAS-BLED score ≥3157 (45.6%)100 (43.9%)57 (49.1%)0.353
      NYHA 3/4185 (53.8%)114 (50%)71 (61.2%)0.214
      Coronary artery disease170 (49.4%)117 (51.3%)53 (45.7%)0.324
      Previous myocardial infarction51 (14.8%)41 (18%)10 (8.6%)0.021
      Previous coronary artery bypass grafting35 (10.2%)22 (9.6%)13 (11.2%)0.651
      Previous percutaneous coronary intervention103 (29.9%)76 (33.3%)27 (23.3%)0.054
      Previous pacemaker30 (8.7%)10 (4.4%)20 (17.2%)<0.001
      Arterial hypertension248 (72.1%)164 (71.9%)84 (72.4%)0.925
      Diabetes Mellitus87 (25.3%)57 (25%)30 (25.9%)0.827
      Previous stroke30 (8.7%)18 (7.9%)12 (10.3%)0.446
      Peripheral artery disease40 (11.6%)25 (11%)15 (12.9%)0.591
      Chronic obstructive lung disease47 (13.7%)29 (12.7%)18 (15.5%)0.475
      Active smoker121 (35.2%)89 (39%)32 (27.6%)0.036
      Chronic kidney disease125 (36.3%)77 (33.8%)48 (41.4%)0.165
      Indication0.058
       Native valve330 (95.9%)221 (96.9%)109 (94%)
       Valve-in-valve14 (4.1%)7 (3.1%)7 (6%)
      Echocardiographic variables
      Aortic valve main disease0.107
       Regurgitation10 (2.9%)9 (3.9%)1 (0.9%)
       Stenosis334 (97.1%)219 (96%)115 (99.1%)
      Bicuspid aortic valve25 (7.3%)19 (8.3%)6 (5.2%)0.286
      Left ventricular ejection fraction (%)54.4 ± 1354.8 ± 1253.5 ± 130.378
      Mean aortic valve gradient (mm Hg)44.5 ± 1645 ± 1544 ± 170.06
      Peak aortic valve gradient (mm Hg)69.9 ± 2470 ± 2369.7 ± 250.928
      Variables are expressed as numbers (%), mean (±SD) or median (IQR). NYHA = new york heart association.
      Table 2Baseline characteristics and echocardiographic parameters after propensity score matching
      VariableOACp value
      No (n = 92)Yes (n = 92)
      Age (years)80.4 ± 7.580.6 ± 6.50.873
      Men58 (63.1%)53 (57.6%)0.451
      Body mass index (Kg/m2)26.6 ± 4.727.3 ± 4.80.329
      EuroScore II (%)3.2 (2.2-5.7)4.1 (2.4-7.4)0.439
      STS-score (%)2.5 (1.8-3.7)2.6 (1.9-3.6)0.739
      CHA2DS2-Vasc score ≥382 (89.1%)88 (95.7%)0.095
      HAS-BLED score ≥344 (47.8%)42 (45.7%)0.768
      NYHA 3/454 (58.7%)54 (58.7%)0.868
      Coronary artery disease44 (47.8%)44 (47.8%)1.0
      Previous myocardial infarction9 (9.8%)8 (8.7%)0.799
      Previous coronary artery bypass grafting10 (10.9%)8 (8.7%)0.620
      Previous percutaneous coronary intervention19 (20.7%)23 (25%)0.482
      Previous pacemaker7 (7.6%)7 (7.6%)1.0
      Arterial hypertension63 (68.5%)66 (71.7%)0.629
      Diabetes Mellitus14 (15.2%)23 (25%)0.090
      Previous stroke9 (9.8%)8 (8.7%)0.799
      Peripheral artery disease9 (9.8%)11 (11.9%)0.636
      Chronic obstructive lung disease16 (17.4%)15 (16.3%)0.844
      Active smoker30 (32.6%)24 (26.1%)0.331
      Chronic kidney disease35 (38%)38 (41.3%)0.651
      Indication0.515
       Native valve86 (93.5%)88 (95.6%)
       Valve-in-valve6 (6.5%)4 (4.4%)
      Echocardiographic variables
      Aortic valve main disease0.055
       Regurgitation6 (6.5%)1 (1.1%)
       Stenosis86 (93.5%)91 (98.9%)
      Bicuspid aortic valve7 (7.6%)6 (6.5%)0.774
      Left ventricular ejection fraction (%)54 ± 1253 ± 120.444
      Mean aortic valve gradient (mm Hg)43 ± 1344 ± 180.638
      Peak aortic valve gradient (mm Hg)65 ± 2070 ± 270.174
      Variables are expressed as numbers (%), mean (±SD) or median (IQR). NYHA = new york heart association.
      Preoperative OAC or antithrombotic regimes are presented in supplementary Table 1. The main reasons for preoperative OAC indication were: atrial fibrillation (n = 107/116, 92.2%), left ventricle thrombus (n = 2/116, 1.7%), prior thromboembolism (n = 5/116, 4.3%), mechanical mitral valve (n = 1/116, 0.8%), and prior thrombus in the aortic valve (n = 1/116, 0.8%). DOAC were taken by 87 patients (87/116, 75%) and warfarin by 29 patients (29/116, 25%).
      Type of transcatheter heart valve used and other periprocedural features are presented in Table 3. Baseline and post-procedural laboratory values are displayed in supplementary Table 2. In patients on VKA, INR value was on target on the day before (2.3 ± 0.5) and after the intervention (2.4 ± 0.67).
      Table 3Procedural characteristics
      VariableOverallp valuePropensity Score Matchingp value
      OACOAC
      All (n = 344)No (n = 228)Yes (n = 116)No (n = 92)Yes (n = 92)
      Conscious sedation318 (92.4%)211 (92.5%)107 (92.2%)0.48085 (92.4%)86 (93.5%)0.563
      Vascular access0.5310.361
       Right Transfemoral283 (82.2%)186 (81.5%)97 (83.6%)78 (84.8%)81 (88.1%)
       Left Transfemoral46 (13.3%)33 (14.5%)13 (11.2%)12 (13.1%)7 (7.6%)
       Left subclavian artery12 (3.5%)6 (2.6%)6 (5.2%)2 (2.2%)4 (4.3%)
       Transapical2 (0.5%)2 (0.9%)---
       Left carotid artery1 (0.3%)1 (0.4%)---
      TAVI device0.8260.503
       Portico116 (33.7%)79 (34.6%)37 (31.9%)30 (32.6%)30 (32.6%)
       Sapien 3/Ultra112 (32.5%)75 (32.9%)37 (31.9%)23 (25%)30 (32.6%)
       Evolut R/PRO80 (23.2%)51 (22.3%)29 (25%)30 (32.6%)20 (21.7%)
       Acurate-neo25 (7.3%)16 (7%)9 (7.8%)5 (5.4%)8 (8.7%)
       Other11 (3.2%)7 (3.1%)4 (3.5%)4 (4.3%)4 (4.3%)
      Pre-dilatation141 (40.9%)96 (42.1%)45 (38.8%)0.50936 (39.1%)37 (40.2%)0.880
      Post-dilatation45 (13%)27 (11.8%)18 (15.5%)0.1476 (6.5%)14 (15.2%)0.058
      Procedure time (min)54 (44-68)53 (44-67)55 (43-69)0.97452 (43-67)53 (43-67)0.713
      Contrast dye (mL)88 (70-122)88 (73-120)87 (67-125)0.64894 (71- 121)86 (65- 124)0.489
      Variables are expressed as numbers (%), mean (± SD) or median (IQR).
      In-hospital clinical and echocardiographic outcomes are summarized in Table 4. In the overall cohort, the primary outcome in-hospital VARC-2 life-threatening or disabling bleeding was not increased in the OAC group (1.3% no-OAC vs 0.9% OAC, p = 0.711) (Figure 1), as well as the secondary outcomes in-hospital VARC-2 major vascular complications (4.8% no-OAC vs 5.2% OAC, p = 0.888) and VARC-2 early safety at 30-days (10.1% no-OAC vs 12.1% OAC, p = 0.575). The overall rates of VARC-2 all-stroke (1.3% no-OAC vs 2.5% OAC, p = 0.398) and any red blood cell transfusion were also not statistically different between groups (1.8% no-OAC vs 2.6% OAC, p = 0.605). Similar results were observed in the propensity score-matched cohort, with a VARC-2 early safety at 30-days of 10.9% in the no-OAC and 14.1% in the OAC group (p = 0.504) (Table 4). Since only 4 events were reported for the primary endpoint, a multivariate analysis could not be performed.
      Table 4In-hospital outcomes
      VariableOverallp valuePropensity Score Matchingp value
      OACOAC
      All (n = 344)No (n = 228)Yes (n = 116)No (n = 92)Yes (n = 92)
      VARC-2 all-bleeding46 (13.3%)27 (11.8%)19 (16.3%)0.33813 (14.1%)17 (18.5%)0.425
       Minor19 (5.5%)9 (3.9%)10 (8.6%)0.0735 (5.4%)8 (8.7%)0.388
       Major23 (6.7%)15 (6.6%)8 (6.9%)0.9117 (7.6%)8 (8.7%)0.788
       Life-threatening or disabling4 (1.2%)3 (1.3%)1 (0.9%)0.7111 (1.1%)1 (1.1%)1.0
      VARC-2 vascular complications75 (21.8%)48 (21%)27 (23.2%)0.89217 (18.5%)20 (21.7%)0.581
       Minor58 (16.9%)37 (16.2%)21 (18.1%)0.66113 (14.1%)15 (16.3%)0.681
       Major17 (4.9%)11 (4.8%)6 (5.2%)0.8884 (4.4%)5 (5.4%)0.733
      VARC-2 all-stroke6 (1.7%)3 (1.3%)3 (2.5%)0.3983 (3.2%)3 (3.2%)0.549
       Disabling-----
       Non-disabling stroke5 (1.4%)3 (1.3%)2 (1.7%)3 (3.2%)2 (2.2%)
       TIA1 (0.3%)-1 (0.9%)-1 (1.1%)
      VARC-2 myocardial infarction2 (0.6%)2 (0.9%)-0.3122 (2.2%)-0.155
      Second valve implant5 (1.4%)2 (0.9%)3 (2.6%)0.211-3 (3.2%)0.081
      Surgical conversion1 (0.3%)1 (0.4%)-0.4751 (1.1%)-0.316
      Any red packed blood cells7 (2%)4 (1.8%)3 (2.6%)0.6052 (2.2%)3 (3.2%)0.650
      New permanent pacemaker51 (14.8%)37 (16.2%)14 (12.1%)0.30516 (17.4%)11 (11.9%)0.298
      New atrial fibrillation11 (3.2%)10 (4.4%)1 (0.9%)0.0791 (1.1%)1 (1.1%)1.0
      Delirium14 (4%)11 (4.8%)3 (2.6%)0.3216 (6.5%)3 (3.2%)0.305
      All-cause mortality6 (1.7%)1 (0.4%)5 (4.3%)0.011 (1.1%)4 (4.3%)0.174
      Hospital length of stay (days)5 (4-7)5 (4-7)6 (4-7)0.7416 (4-8)6 (4-7)0.243
      Echocardiographic variables
      Left ventricular ejection fraction (%)55.5 ± 11.555.3 ± 1155.8 ± 110.68355.1 ± 11.556.1 ± 10.90.565
      Residual mean gradient (mmHg)8 ± 3.98.2 ± 3.97.7 ± 3.80.3307.9 ± 3.77.8 ± 3.90.905
      Residual peak gradient (mmHg)15 ± 6.915.9 ± 714.3 ± 6.50.07615.5 ± 7.114.5 ± 6.70.407
      Residual aortic regurgitation ≤Mild320 (93%)216 (94.7%)105 (90.5%)0.16586 (93.4%)83 (90.2%)0.117
      Variables are expressed as numbers (%), mean (SD) or median (IQR). TIA = transient ischemic attack.
      Figure 1
      Figure 1VARC-2 bleeding comparing no-OAC to OAC.
      In the overall cohort, 30-day all-cause mortality was numerically higher in the OAC group (0.9% no-OAC vs 4.3% OAC, p = 0.033). However, when propensity score matching was applied, the difference in 30-day all-cause mortality lost statistical significance (1.1% no-OAC vs 4.3% OAC, p = 0.174). Death's specific reasons are presented in supplementary Table 3. On the last contact [median follow-up 80 days (36-262 days)], survival rate was similar between the groups [96.9% no-OAC vs 94% OAC, p = 0.188]. Kaplan Meier survival curves are presented in Supplementary Figures 1 and 2.

      Discussion

      In the last decade, TAVI has evolved from a procedure of exception, reserved for inoperable and high-risk patients, to a well-established intervention, even in low-risk populations. Herein, we reported early outcomes after TAVI according to the perioperative OAC regimen. The main differential of the present article lies in the discussion about perioperative TAVI OAC management, a controversial topic that lacks guideline-based recommendations. This issue is especially relevant once the 2 main trials recently published on TAVI antithrombotic or anticoagulant therapy focused only on post-procedural management.
      • Brouwer J
      • Nijenhuis VJ
      • Delewi R
      • Hermanides RS
      • Holvoet W
      • Dubois CLF
      • Frambach P
      • De Bruyne B
      • van Houwelingen GK
      • Van Der Heyden JAS
      • Toušek P
      • van der Kley F
      • Buysschaert I
      • Schotborgh CE
      • Ferdinande B
      • van der Harst P
      • Roosen J
      • Peper J
      • Thielen FWF
      • Veenstra L
      • Chan Pin Yin DRPP
      • Swaans MJ
      • Rensing BJWM
      • van 't Hof AWJ
      • Timmers L
      • Kelder JC
      • Stella PR
      • Baan J
      • Ten Berg JM
      Aspirin with or without clopidogrel after transcatheter aortic-valve implantation.
      ,
      • Nijenhuis VJ
      • Brouwer J
      • Delewi R
      • Hermanides RS
      • Holvoet W
      • Dubois CLF
      • Frambach P
      • De Bruyne B
      • van Houwelingen GK
      • Van Der Heyden JAS
      • Toušek P
      • van der Kley F
      • Buysschaert I
      • Schotborgh CE
      • Ferdinande B
      • van der Harst P
      • Roosen J
      • Peper J
      • Thielen FWF
      • Veenstra L
      • Chan Pin Yin DRPP
      • Swaans MJ
      • Rensing BJWM
      • van 't Hof AWJ
      • Timmers L
      • Kelder JC
      • Stella PR
      • Baan J
      • Ten Berg JM
      Anticoagulation with or without clopidogrel after transcatheter aortic-valve implantation.
      Furthermore, guidelines recommend preoperative VKA or DOAC interruption
      • Sousa-Uva M
      • Head SJ
      • Milojevic M
      • Collet JP
      • Landoni G
      • Castella M
      • Dunning J
      • Gudbjartsson T
      • Linker NJ
      • Sandoval E
      • Thielmann M
      • Jeppsson A
      • Landmesser U
      2017 EACTS Guidelines on perioperative medication in adult cardiac surgery.
      and current TAVI trials have been, usually, performed adopting the interrupted OAC strategy.
      • Kirchhof P
      • Benussi S
      • Kotecha D
      • Ahlsson A
      • Atar D
      • Casadei B
      • Castella M
      • Diener HC
      • Heidbuchel H
      • Hendriks J
      • Hindricks G
      • Manolis AS
      • Oldgren J
      • Popescu BA
      • Schotten U
      • Van Putte B
      • Vardas P
      ESC Scientific Document Group
      2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      One of the first evidences supporting the safety of continued OAC in patients with atrial fibrillation submitted to transfemoral TAVI was published in 2019 by Mangner et al. In this study, the lowest rates of VARC-2 early safety (13.2% DOAC vs 19.7% continued VKA vs 23.1% interrupted VKA, p = 0.029) and 1-year all-cause mortality (8.8% DOAC vs 13.7% continued VKA vs. 20.1% interrupted VKA, p = 0.015) were observed in the continued DOAC group. Continued VKA regimen had similar outcomes compared to interrupted VKA in terms of all procedural bleeding (38.8% continued VKA vs. 34.8% interrupted VKA, p = 0.097) and access site complications (40.5% continued VKA vs 32.1% interrupted VKA, p = 0.661).
      • Mangner N
      • Crusius L
      • Haussig S
      • Woitek FJ
      • Kiefer P
      • Stachel G
      • Leontyev S
      • Schlotter F
      • Spindler A
      • Höllriegel R
      • Hommel J
      • Thiele H
      • Borger MA
      • Holzhey D
      • Linke A
      Continued versus interrupted oral anticoagulation during transfemoral transcatheter aortic valve implantation and impact of postoperative anticoagulant management on outcome in patients with atrial fibrillation.
      Similarly to Mangner's study, our results supported the safety of the continued OAC strategy. Our VARC-2 early safety in patients receiving continued OAC (12.1%) was at least comparable to that presented by Mangner, whereas our in-hospital VARC-2 all-bleeding rate (16.3%) was even lower (27.5% in continued DOAC and 38.8% in continued VKA). On the other hand, while in the present study the majority of patients on continued OAC were receiving DOAC (75%), in Mangner's study the DOAC therapy had a lower prevalence (60%). Furthermore, we included also, even in a minority, non-transfemoral routes and patients receiving OAC due to reasons other than atrial fibrillation. Besides these points, the main difference between Mangner's and our study is that, while the former compared continued versus interrupted OAC strategies only in patients previously receiving OAC, we compared continued OAC in patients with indication and previously receiving OAC to those not previously receiving any OAC therapy. Thus, if the continued OAC strategy had been associated with worse outcomes, our study would be more likely to detect a difference in bleeding rates since it compared ongoing OAC with a lower bleeding risk control group. Therefore, this study helps to answer the question: in a patient receiving continued OAC, should we expect worse outcomes after TAVI compared to those not receiving any OAC therapy?
      In this same line, a letter from Brinker et al. reported that in patients on continued (186 patients) or interrupted (185 patients) OAC regimen submitted to transfemoral TAVI, the rates of periprocedural major or life-threatening bleeding (10.2% vs 10.8%, p = 0.85), major vascular complications (8.6% vs 10.3, p = 0.58), periprocedural stroke (0.6% vs 3.2%, p = 0.06), and 1-year mortality (9.38% vs 9.83%, p = 0.897) did not have statistical difference.
      • Brinkert M
      • Keller LS
      • Moriyama N
      • Cuculi F
      • Bossard M
      • Lehnick D
      • Kobza R
      • Laine M
      • Nietlispach F
      • Toggweiler S.
      Safety and efficacy of transcatheter aortic valve replacement with continuation of oral anticoagulation.
      These same authors recently published an update on the previous analysis with 584 patients receiving continued and 733 interrupted OAC. At 30 days, major or life-threatening bleedings (11.3% vs 14.3%, p = 0.39) and major vascular complications rates (11.0% vs 12.3%, p = 0.52) were similar, but packed red blood cell transfusion was less frequent in the continued group (13.7% vs 17.7%, p = 0.001).
      • Brinkert M
      • Mangner N
      • Moriyama N
      • Keller LS
      • Hagemeyer D
      • Crusius L
      • Lehnick D
      • Kobza R
      • Abdel-Wahab M
      • Laine M
      • Stortecky S
      • Pilgrim T
      • Nietlispach F
      • Ruschitzka F
      • Thiele H
      • Linke A
      • Toggweiler S
      Safety and efficacy of transcatheter aortic valve replacement with continuation of vitamin k antagonists or direct oral anticoagulants.
      Two meta-analyses comparing continuous OAC versus heparin bridging in patients undergoing cardiac implantable electronic devices had suggested that OAC maintenance did not increase procedural adverse events. In the first, continued VKA was associated with significant lower postoperative bleeding risk [odds ratio (OR) 0.25, 95% Confidence Interval (CI) 0.17-0.36, p<0.001] and no difference in thromboembolic events (OR 1.86, 95% CI 0.29-12.17, p = 0.57).
      • Sant'anna RT
      • Leiria TL
      • Nascimento T
      • Sant'anna JR
      • Kalil RA
      • Lima GG
      • Verma A
      • Healey JS
      • Birnie DH
      • Essebag V
      Meta-analysis of continuous oral anticoagulants versus heparin bridging in patients undergoing CIED surgery: reappraisal after the BRUISE study.
      In the second, uninterrupted OAC was associated with significantly lower bleeding risk (OR 0.31, 95% CI 0.18-0.53, p < 0.0001) and no difference in thromboembolic risk (OR 0.82, 95% CI 0.32-2.09, p = 0.65).
      • Yang X
      • Wang Z
      • Zhang Y
      • Yin X
      • Hou Y.
      The safety and efficacy of antithrombotic therapy in patients undergoing cardiac rhythm device implantation: a meta-analysis.
      Supplementary Table 4 presents TAVI outcomes observed in the present study in the context of current literature.
      • Brouwer J
      • Nijenhuis VJ
      • Delewi R
      • Hermanides RS
      • Holvoet W
      • Dubois CLF
      • Frambach P
      • De Bruyne B
      • van Houwelingen GK
      • Van Der Heyden JAS
      • Toušek P
      • van der Kley F
      • Buysschaert I
      • Schotborgh CE
      • Ferdinande B
      • van der Harst P
      • Roosen J
      • Peper J
      • Thielen FWF
      • Veenstra L
      • Chan Pin Yin DRPP
      • Swaans MJ
      • Rensing BJWM
      • van 't Hof AWJ
      • Timmers L
      • Kelder JC
      • Stella PR
      • Baan J
      • Ten Berg JM
      Aspirin with or without clopidogrel after transcatheter aortic-valve implantation.
      ,
      • Nijenhuis VJ
      • Brouwer J
      • Delewi R
      • Hermanides RS
      • Holvoet W
      • Dubois CLF
      • Frambach P
      • De Bruyne B
      • van Houwelingen GK
      • Van Der Heyden JAS
      • Toušek P
      • van der Kley F
      • Buysschaert I
      • Schotborgh CE
      • Ferdinande B
      • van der Harst P
      • Roosen J
      • Peper J
      • Thielen FWF
      • Veenstra L
      • Chan Pin Yin DRPP
      • Swaans MJ
      • Rensing BJWM
      • van 't Hof AWJ
      • Timmers L
      • Kelder JC
      • Stella PR
      • Baan J
      • Ten Berg JM
      Anticoagulation with or without clopidogrel after transcatheter aortic-valve implantation.
      ,
      • Mangner N
      • Crusius L
      • Haussig S
      • Woitek FJ
      • Kiefer P
      • Stachel G
      • Leontyev S
      • Schlotter F
      • Spindler A
      • Höllriegel R
      • Hommel J
      • Thiele H
      • Borger MA
      • Holzhey D
      • Linke A
      Continued versus interrupted oral anticoagulation during transfemoral transcatheter aortic valve implantation and impact of postoperative anticoagulant management on outcome in patients with atrial fibrillation.
      ,
      • Kirchhof P
      • Benussi S
      • Kotecha D
      • Ahlsson A
      • Atar D
      • Casadei B
      • Castella M
      • Diener HC
      • Heidbuchel H
      • Hendriks J
      • Hindricks G
      • Manolis AS
      • Oldgren J
      • Popescu BA
      • Schotten U
      • Van Putte B
      • Vardas P
      ESC Scientific Document Group
      2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      ,
      • Popma JJ
      • Deeb GM
      • Yakubov SJ
      • Mumtaz M
      • Gada H
      • O'Hair D
      • Bajwa T
      • Heiser JC
      • Merhi W
      • Kleiman NS
      • Askew J
      • Sorajja P
      • Rovin J
      • Chetcuti SJ
      • Adams DH
      • Teirstein PS
      • Zorn 3rd, GL
      • Forrest JK
      • Tchétché D
      • Resar J
      • Walton A
      • Piazza N
      • Ramlawi B
      • Robinson N
      • Petrossian G
      • Gleason TG
      • Oh JK
      • Boulware MJ
      • Qiao H
      • Mugglin AS
      • Reardon MJ
      Evolut Low Risk Trial Investigators
      Transcatheter aortic-valve replacement with a self-expanding valve in low-risk patients.
      ,
      • Dangas GD
      • Tijssen JGP
      • Wöhrle J
      • Søndergaard L
      • Gilard M
      • Möllmann H
      • Makkar RR
      • Herrmann HC
      • Giustino G
      • Baldus S
      • De Backer O
      • Guimarães AHC
      • Gullestad L
      • Kini A
      • von Lewinski D
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      • Volkl AA
      • Zazula A
      • van Amsterdam RGM
      • Mehran R
      • Windecker S
      GALILEO Investigators
      A controlled trial of rivaroxaban after transcatheter aortic-valve replacement.
      Although the present study had not observed differences in both, primary and secondary outcomes, patients on OAC presented a higher 30-day mortality rate (0.9% no-OAC vs 4.3% OAC, p = 0.033). Nonetheless, only 1 of the 5 deaths observed in the OAC group could be associated or worsened by anticoagulation (intraprocedural cardiac tamponade). It is relevant to highlight that when propensity score matching was performed, OAC was not associated with higher 30-day mortality rate (p = 0.174).
      Since DOAC has largely replaced VKA to prevent thrombotic events in atrial fibrillation, which is present in a significant number of patients undergoing TAVI (16%–59%),
      • Tarantini G
      • Mojoli M
      • Urena M
      • Vahanian A.
      Atrial fibrillation in patients undergoing transcatheter aortic valve implantation: epidemiology, timing, predictors, and outcome.
      we performed also an analysis comparing DOAC to VKA. In this analysis, there's no significant difference in terms of main outcomes between the 2 regimens (Supplementary Table 5).
      We would like to highlight that, the present analysis reflects a single-center, non-randomized, but prospectively acquired experience. Hence, all the inherent limitations of such design need to be taken into account. Besides, this study focused on short-term results. Properly designed trials with long-term follow-up are required to confirm the best pre- and post-TAVI anticoagulant management. The low number of observed events limits the statistical power of the logistic regression model. Therefore, even though continued OAC had not been associated with increased outcomes, it should be noted that we had a very low number of events, which may difficult a more generalized or definitive conclusion. Lastly, however DOAC comprised different active ingredients, with a predominance of rivaroxaban, clinical trials evaluating the safety and efficacy of DOACs have indicated a class rather than a specific drug effect.
      In conclusion, the management of patients on OAC submitted to a TAVI procedure is challenging and requires balancing the risk of bleeding with the risk of thromboembolic events. The present study suggests that continued OAC was not associated with increased in-hospital VARC-2 life-threatening or disabling bleeding, major vascular complications, and VARC-2 early safety at 30 days.

      Authors Contribution

      Ana Paula Tagliari: Conceptualization; Data curation; Formal analysis; Writing − Original Draft; Daniel Perez-Camargo: Conceptualization; Data curation; Formal analysis; Writing − Original Draft; Enrico Ferrari: Formal analysis; Supervision; Validation; Writing - Review & Editing; Philipp K. Haager: Formal analysis; Supervision; Validation; Writing - Review & Editing; Lucas Jörg: Supervision; Validation; Marco Gennari: Supervision; Validation; Mi Chen: Supervision; Validation; Mara Gavazzoni: Supervision; Validation; Ahmed Aziz Khattab: Supervision; Validation; Stefan Blöchlinger: Supervision; Validation; Francesco Maisano: Supervision; Validation; Maurizio Taramasso: Conceptualization; Formal analysis; Supervision; Writing - Review & Editing.

      Acknowledgment

      The authors thank Malik Riva and Leonora Kodzadziku for supporting TAVI procedures.

      Disclosures

      Ana Paula Tagliari reports a relationship with CAPES - Brazil that includes: funding grants. Enrico Ferrari reports a relationship with Consultant for Edwards Lifesciences and received Grants and Research Support from Edwards Lifesciences, Medtronic and Somahlution that includes: consulting or advisory and funding grants. Marco Gennari reports a relationship with Consultant for Medtronic. that includes: consulting or advisory. Mara Gavazzoni reports a relationship with Consultant for Biotronik and Abbott. that includes: consulting or advisory. Francesco Maisano reports a relationship with Abbott, Medtronic, Edwards Lifesciences, Biotronik, Boston Scientific Corporation, NVT, Terumo, SwissVortex, Perifect, Xeltis, Transseptal solutions, Cardiovalve, Magenta, CardioGard, SwissVortex, 4 Tech that includes: consulting or advisory, funding grants, and speaking and lecture fees. Maurizio Taramasso reports a relationship with Abbott Vascular, Boston Scientific, 4 Tech, Edwards Lifesciences, CoreMedic, SwissVortex, Mitraltech and Somahlution that includes: consulting or advisory, funding grants, and speaking and lecture fees. APT has received a Research Grant from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (Capes) - Finance Code 001. EF is consultant for Edwards Lifesciences and received Grants and Research Support from Edwards Lifesciences, Medtronic and Somahlution. M Gennari is consultant for Medtronic. M Gavazzoni is consultant for Biotronik and Abbott. FM received Research Support and/or Grant from Abbott, Medtronic, Edwards Lifesciences, Biotronik, Boston Scientific Corporation, NVT, Terumo; Consulting fees and/or Honoraria from Abbott, Medtronic, Edwards Lifesciences, SwissVortex, Perifect, Xeltis, Transseptal solutions, Cardiovalve, Magenta; has Royalty Income/IP Rights Edwards Lifesciences and is Shareholder of CardioGard, Magenta, SwissVortex, Transseptal Solutions, 4 Tech, Perifect. MT is consultant for Abbott Vascular, Boston Scientific, and 4 Tech; and has received Consulting fees from Edwards Lifesciences, CoreMedic, SwissVortex, and Mitraltech.

      Appendix. Supplementary materials

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