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The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAVI registry
CARREV-01727; No of Pages 7 Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Cardiovascular Revascularization Medicine
The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAVI registry☆,☆☆ Kensuke Takagi a,⁎, Toru Naganuma b, Norio Tada c, Futoshi Yamanaka d, Motoharu Araki e, Shinichi Shirai f, Akihiro Higashimori g, Yusuke Watanabe h, Masanori Yamamoto i, Kentaro Hayashida j a
Department of Cardiology, Ogaki Municipal Hospital, Gifu, Japan Department of Cardiology, New Tokyo Hospital, Chiba, Japan Department of Cardiology, Sendai Kousei Hospital, Sendai, Japan d Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan e Department of Cardiology, Saiseikai Yokohama City Eastern Hospital, Yokohama, Japan f Department of Cardiology, Kokura Memorial Hospital, Kokura, Japan g Department of Cardiology, Kishiwada Tokushukai Hospital, Osaka, Japan h Department of Cardiology, Teikyo University School of Medicine, Tokyo, Japan i Department of Cardiology, Toyohashi Heart Canter, Toyohashi, Japan j Department of Cardiology, Keio University School of Medicine, Tokyo, Japan b c
a r t i c l e
i n f o
Article history: Received 10 August 2019 Received in revised form 1 October 2019 Accepted 9 October 2019 Available online xxxx Keywords: Transcatheter aortic valve replacement Cerebrovascular event Ischemic stroke Indexed aortic valve area
a b s t r a c t Background: Cerebrovascular events (CVEs) are not uncommon complications of transcatheter aortic valve replacement (TAVR). Our study aimed to determine the predictors of peri-procedural and sub-acute CVEs following TAVR. Methods: Using the Japanese multicenter registry, we evaluated 1613 patients undergoing TAVR between October-2013 and July-2016. Occurrences of 24-hour and 1- to 30-day CVEs were evaluated to clarify the predictors of CVEs following TAVR. Results: The mean age was 84.4 years and mean Society of Thoracic Surgeons score was 8.3%. Overall 24-hour and 30-day CVE rates were 1.2% and 2.7%, respectively. A multivariate analysis demonstrated that independent predictor of 24-hour CVEs was index aortic valve area (iAVA) [adjusted OR (adjusted-OR), 0.001; 95% CI, 0.001–0.13; p = .005]. The receiver operator curve derived cut-off value of iAVA for the prediction of 24-hour CVEs was 0.40 cm2/m2. In contrast, independent predictors of 1- to 30-day CVEs were paroxysmal atrial fibrillation (PAF; adjusted-OR, 3.35; 95% CI, 1.36–8.27; p = .009) and iAVA after TAVR (adjusted-OR, 0.11; 95% CI, 0.02–0.66; p = .02). Consequently, independent predictors of 30-day CVEs were prior stroke (adjusted-OR, 2.18; 95% CI, 1.07–4.45; p = .03), PAF (adjusted-OR, 2.18; 95% CI, 1.05–4.56; p = .04), and prior coronary artery disease (adjusted-OR, 1.88; 95% CI, 1.01–3.48; p = .05). Conclusions: Within 24 h, small iAVA impacted the increased risk of CVEs, whereas PAF and iAVA after TAVR impacted the increased risk of 1- to 30-day CVEs following TAVR. The mechanism of CVEs might differ according to onset. © 2019 Elsevier Inc. All rights reserved.
1. Introduction
☆ Funding: The OCEAN-TAVI registry is supported by Edwards Lifesciences, Japan. ☆☆ Disclosures: Dr. Tada, Dr. Naganuma, Dr. Araki, Dr. Shirai, Dr. Takagi, Dr. Watanabe, Dr. Yamamoto, Dr. Saito, and Dr. Hayashida are clinical proctors for Edwards Lifesciences. Dr. Naganuma, Dr. Watanabe, Dr. Yamamoto, and Dr. Saito are clinical proctors for Medtronic. The other authors have no conflicts of interest to declare. ⁎ Corresponding author at: Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Japan. E-mail address: [email protected] (K. Takagi).
The popularity of transcatheter aortic valve replacement (TAVR) for the treatment of severe aortic stenosis (AS) has increased due to advances in transcatheter heart valve technology and treatment strategies [1–4]. Cerebrovascular events (CVEs) are not uncommon complications following TAVR; however, recent studies have suggested a decrease in 30-day CVEs to rates of 1% to 3% over time [5–9]. Thirty-day CVEs are known to be associated with multiple comorbidities [10–12]. However, there are little data available to clarify the predictors of peri-procedural CVEs, including not only mechanical interactions between the calcified
https://doi.org/10.1016/j.carrev.2019.10.013 1553-8389/© 2019 Elsevier Inc. All rights reserved.
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native valve and the device but also hemodynamic instability driven by serious complications. Therefore, in the present study, we evaluated the predictors of peri-procedural CVEs after TAVR using comprehensive data such as computed tomographic, echocardiographic, procedural, and pharmacotherapeutic variables of a large Japanese cohort from high-volume centers.
2. Methods 2.1. Study population and design The Optimized transCathEter vAlvular interventioN-Transcatheter Aortic Valve Implantation (OCEAN-TAVI) registry is an ongoing, prospective, multicenter registry that was initiated to observe and document the procedural results and post-procedural clinical outcomes of TAVR [13–15]. We evaluated 1613 consecutive high-risk patients with symptomatic, severe AS who underwent TAVR with the SAPIEN XT or SAPIEN 3 balloon-expandable prosthesis (Edwards Lifesciences, Irvine, CA, USA) or the CoreValve Revalving System self-expandable prosthesis (Medtronic, Minneapolis, MN, USA) between October 2013 and July 2016 at 14 Japanese high-volume institutions. The inclusion criteria were presence of symptomatic and degenerative AS, mean gradient N40 mm Hg or jet velocity N 4.0 m/s, or aortic valve area (AVA) b1.0 cm2 (or effective orifice area index b0.6 cm2/m2). Patients for whom TAVR was deemed the best treatment option were selected based on clinical consensus by a multidisciplinary team comprising cardiac surgeons, interventional cardiologists, anesthetists, and imaging specialists. The primary exclusion criterion was failed surgical bioprosthesis. The medical ethics committee approved this study at each hospital. This trial is registered with the University Hospital Medical Information Network as number UMIN000020423. The TAVR procedure was performed using conventional techniques via transfemoral, transiliac, transapical, trans-subclavian, and transaortic approaches according to the experience at each center. Prosthesis size was determined based on pre-procedural echocardiographic and computed tomographic findings. The implanted valves included the SAPIEN XT and SAPIEN 3 devices in sizes of 20 mm, 23 mm, 26 mm, and 29 mm (Edwards Lifesciences) and the CoreValve device in sizes of 26 mm and 29 mm (Medtronic). An antithrombotic regimen was used
at the discretion of the operator. Heparin was administered to achieve an activated clotting time N 250 s. 2.2. Post-procedural care All patients were observed in the intensive care unit for at least 24 h after the index procedure. Dual-antiplatelet therapy was continued for 3 to 6 months; thereafter, aspirin was continued indefinitely. For patients who needed anticoagulant therapy or who were at high risk for bleeding, the use antiplatelets, anticoagulant therapy, or both was at the discretion of the attending physician. 2.3. Endpoint definitions Procedure success, device success (DS), and other procedural complications during TAVR were evaluated according to the Valve Academic Research Consortium (VARC)-2 criteria [16]. 2.4. Study endpoint In the case of a suspected neurologic event based on clinical evaluation by the local heart team, systematic consultation of an on-site neurologist was performed. CVEs included transient ischemic attack (TIA) and clinical stroke (ischemic or hemorrhagic), which were defined according to VARC-2 criteria. Disabling stroke was defined using a modified Rankin Scale according to VARC-2 criteria [16]. Furthermore, we evaluated the predictors of CVEs according to the following time periods after TAVR: 24 h, 1- to 30 days, and 30 days. 2.5. Statistical analysis Continuous variables are expressed as mean ± SD. Comparisons of clinical, echocardiographic, angiographic, computed tomographic, and procedural variables were performed using the Student's t-test, Wilcoxon rank-sum test (continuous variables), or chi-square test (categorical variables) for 24-hour, 1- to 30-day, and 30-day CVEs. Receiveroperating characteristic (ROC) analysis and Youden index were used to confirm the optimal cut-off values of the iAVA for the prediction of 24-hour CVEs.
The occurrence of CVEs
% (number)
2.7
1.4
1.2 (23) (20)
OVERALL N-1613
3.3
(15)
3.1
(17)
(43)
1.8 1.5 (8) (7)
1.8 1.6 1.4 (9) (8) 0.8 (5)
2013-14 N-452 24 hours
2015 N-555 1-30 days
(11)
1 (6)
2016 N-606
30 days
Fig. 1. The incidence of 24-hour, 1-to-30 days, 30-days cerebrovascular event according to transcatheter aortic valve replacement year. CVE, cerebrovascular event. TAVR, transcatheter aortic valve replacement.
Please cite this article as: K. Takagi, T. Naganuma, N. Tada, et al., The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAV..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.013
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Table 1 Baseline patient characteristics. Patients, n
Overall n = 1613
24-hour CVEs n = 20
No 24-hour CVEs n = 1593
p value
1–30-day CVEs n = 23
No 1–30-day CVEs n = 1593
p value
Patient clinical characteristics Age, years Female, n Height, cm Weight, kg Body mass index, kg/m2 Body mass index N30 kg/m2, n Body surface area, m2 NYHA class, III or IV Clinical frail score ≥ 5 MMSE PAD, n Prior heart failure, n Coronary artery disease, n Prior MI, n Prior ischemic stroke, n Prior PCI Prior CABG, n Dyslipidemia, n Diabetes mellitus, n Hypertension, n COPD, n Active smoking CKD, n All AF, n Paroxysmal AF, n none Aspirin P2Y12 inhibitor Dual antiplatelet therapy Vitamin K antagonists Direct oral anticoagulants Anticoagulant and single antiplatelet therapy Triple therapy Unknown Statin Logistic EuroSCORE, % Logistic EuroSCORE II, % STS score, %
84.4 ± 5.1 1136 (70.4) 149.8 ± 9.0 49.8 ± 10.1 22.1 ± 3.6 38 (2.4) 1.42 ± 0.17 816 (50.6) 450 (28.3) 25.0 ± 5.1 246 (15.3) 1313 (81.4) 474 (39.4) 116 (7.2) 205 (12.7) 431 (26.7) 120 (7.5) 688 (42.7) 430 (26.7) 1268 (78.6) 297 (18.4) 44 (2.7) 975 (60.4) 337 (20.9) 187 (11.6) 19 (1.2) 174 (11.0) 68 (4.3) 983 (62.1) 30 (1.9) 40 (2.5) 241 (15.2) 29 (1.8) 29 (1.8) 678 (42.0) 17.0 ± 13.1 5.5 ± 6.4 8.3 ± 7.0
83.1 ± 6.5 12 (60.0) 151.9 ± 8.5 49.9 ± 11.0 21.5 ± 3.4 0 (0) 1.44 ± 0.18 12 (60.0) 6 (31.6) 21.5 ± 6.7 6 (30.0) 18 (90.0) 10 (50.0) 2 (10.0) 5 (25.0) 5 (25.0) 1 (5.0) 10 (50.0) 5 (25.0) 14 (70.0) 3 (15.0) 2 (10.0) 11 (55.0) 4 (20.0) 3 (15.0) 3 (15.0) 6 (30.0) 0 (0) 6 (30.0) 0 (0) 3 (15.0) 2 (10.0) 0 (0) 0 (0) 11 (55.0) 18.6 ± 16.7 7.3 ± 9.1 11.7 ± 15.6
84.4 ± 5.1 1124 (70.6) 149.7 ± 9.0 49.8 ± 10.1 22.1 ± 3.6 38 (2.4) 1.42 ± 0.17 804 (50.5) 444 (28.3) 25.0 ± 5.1 240 (15.1) 1295 (81.3) 464 (29.1) 114 (7.2) 200 (12.6) 426 (26.7) 119 (7.5) 678 (42.6) 425 (26.7) 1254 (78.7) 294 (18.5) 42 (2.6) 964 (60.5) 333 (20.9) 184 (11.6) 16 (1.0) 168 (10.7) 68 (4.3) 977 (62.5) 30 (1.9) 37 (2.4) 239 (15.3) 29 (1.9) 29 (1.8) 667 (41.9) 17.0 ± 13.1 5.5 ± 6.3 8.3 ± 6.8
0.27 0.33 0.29 0.97 0.41 1.00 0.67 0.70 0.80 0.02 0.11 0.56 0.05 0.65 0.16 1.00 1.00 0.51 1.00 0.41 1.00 0.10 0.65 1.00 0.50 0.001
84.4 ± 5.1 1120 (70.4) 149.8 ± 9.0 49.8 ± 10.1 22.1 ± 3.6 38 (2.4) 1.42 ± 0.17 805 (50.6) 443 (28.3) 24.9 ± 5.1 243 (15.3) 1296 (81.5) 465 (29.2) 115 (7.2) 199 (12.5) 428 (26.9) 116 (7.3) 676 (42.5) 423 (26.6) 1248 (78.5) 296 (18.6) 43 (2.7) 960 (60.4) 329 (20.7) 180 (11.3) 18 (1.1) 172 (10.8) 66 (4.2) 976 (61.4) 29 (1.8) 39 (2.5) 236 (14.8) 29 (1.8) 25 (1.6) 664 (41.8) 17.0 ± 13.1 5.5 ± 6.3 8.3 ± 6.9
0.67 1.00 0.77 0.39 0.47 1.00 0.44 0.96 0.82 0.31 1.00 0.41 0.36 1.00 0.06 0.16 0.09 0.40 0.64 0.45 0.10 0.47 0.68 0.12 0.01
0.26 0.59 0.21 0.35
83.9 ± 4.8 16 (69.6) 150.3 ± 8.0 51.6 ± 11.7 22.7 ± 3.8 0 (0) 1.45 ± 0.18 11 (47.8) 7 (30.4) 26.4 ± 3.4 3 (13.0) 17 (73.9) 9 (39.1) 1 (4.3) 6 (26.1) 3 (13.0) 4 (17.4) 12 (52.2) 7 (30.4) 20 (87.0) 1 (4.3) 1 (4.3) 15 (65.2) 8 (34.8) 7 (30.4) 1 (4.3) 2 (8.7) 2 (8.7) 7 (30.4) 1 (4.3) 1 (4.3) 5 (21.7) 0 (0) 4 (17.4) 14 (60.9) 19.0 ± 15.7 7.5 ± 8.9 9.3 ± 9.9
Echocardiographic data LVEF, % Left atrial diameter, mm AVA, cm2 Indexed AVA cm2/m2 Peak velocity, m/s Mean gradient, mm Hg AR ≥ moderate, n MR ≥ moderate, n
62.2 ± 12.6 42.0 ± 6.9 0.6 ± 0.2 0.4 ± 0.1 4.6 ± 0.8 50.5 ± 18.0 155 (9.6) 162 (10.0)
62.7 ± 11.4 39.9 ± 6.5 0.5 ± 0.2 0.4 (0.37) ± 0.1 5.0 ± 1.1 60.0 ± 26.2 4 (20.0) 3 (15.0)
62.2 ± 12.6 42.0 ± 6.9 0.6 ± 0.2 0.4 (0.44) ± 0.1 4.6 ± 0.8 50.4 ± 17.9 151 (9.5) 159 (10.0)
0.93 0.26 0.02 0.006 0.03 0.12 0.12 0.44
58.3 ± 12.9 43.7 ± 6.1 0.7 ± 0.2 0.5 ± 0.1 4.4 ± 0.6 46.2 ± 14.6 3 (13.0) 3 (13.0)
62.2 ± 12.5 42.0 ± 6.9 0.6 ± 0.2 0.4 ± 0.1 4.6 ± 0.8 50.6 ± 18.1 152 (9.6) 159 (10.0)
0.14 0.24 0.20 0.25 0.35 0.25 0.48 0.50
Computed tomographic data Annulus area, mm2 Annulus minimum diameter, mm Annulus maximum diameter, mm Annulus mean diameter, mm Sinotubular junction diameter, mm
394.5 ± 67.3 19.6 ± 2.0 25.3 ± 2.3 22.5 ± 1.9 25.1 ± 2.8
412.5 ± 70.7 20.1 ± 2.1 25.9 ± 2.5 23.0 ± 2.2 23.3 ± 3.0
394.3 ± 67.3 19.6 ± 2.0 25.3 ± 2.3 22.5 ± 1.9 25.1 ± 2.8
0.23 0.25 0.28 0.24 0.01
389.8 ± 77.7 19.2 ± 2.3 25.5 ± 2.4 22.3 ± 2.1 25.3 ± 2.7
394.6 ± 67.2 19.6 ± 2.0 25.3 ± 2.3 22.5 ± 1.9 25.1 ± 2.8
0.74 0.29 0.76 0.72 0.72
Laboratory data Hemoglobin, g/dL Low-density lipoprotein, mg/dL High-density lipoprotein, mg/dL eGFR, mL/min/1.73m2 Albumin, mg/dL Brain-type natriuretic peptidea, pg/ml C-reactive proteina, mg/dL
11.2 ± 1.6 100.7 ± 29.4 53.2 ± 15.2 52.0 ± 20.3 3.8 ± 0.5 468.0 ± 648.0 0.5 ± 1.9
11.3 ± 1.7 96.1 ± 28.2 52.1 ± 14.5 57.6 ± 26.5 3.8 ± 0.6 780.1 ± 954.7 0.5 ± 1.3
11.2 ± 1.6 100.8 ± 29.4 53.2 ± 15.2 51.9 ± 20.2 3.8 ± 0.5 463.7 ± 642.5 0.5 ± 1.9
0.80 0.48 0.74 0.21 0.75 0.17 0.98
11.3 ± 1.9 99.6 ± 30.3 52.8 ± 17.0 49.0 ± 24.2 3.7 ± 0.6 590.9 ± 1548.1 1.0 ± 2.9
11.2 ± 1.6 100.7 ± 29.4 53.2 ± 15.2 52.0 ± 20.3 3.8 ± 0.5 466.2 ± 627.0 0.5 ± 1.9
0.71 0.86 0.89 0.14 0.74 0.72 0.29
0.001
0.09 0.46 0.14 0.50
Values are numbers (%) or mean ± SD. CVE, cerebrovascular event; NYHA, New York Heart Association; PAD, peripheral artery disease; MI, myocardial infarction; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; AF, atrial fibrillation; EuroSCORE, European System for Cardiac Operative Risk Evaluation; STS, Society of Thoracic Surgeons Predictive Risk of Mortality; LVEF, left ventricle ejection fraction; AVA, aortic valve area; AR, aortic regurgitation; MR, mitral regurgitation; eGFR, estimated glomerular filtration rate. a 1403 and 1560 of the 1613 patients with available clinical record about Brain-type natriuretic peptide and C-reactive protein, respectively.
A multivariate logistic regression analysis using purposeful selection of covariates [17] was performed to determine the independent predictors of 24-hour, 1-to 30-day, and 30-day CVEs following TAVR using
predictors associated with each CVE (p b .2) and those judged to be of clinical importance by previously published literature. To avoid overfitting the number of independent variables entered into the final
Please cite this article as: K. Takagi, T. Naganuma, N. Tada, et al., The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAV..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.013
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Table 2 Procedural characteristics and clinical outcome. Patients, n
Overall n = 1613
24-hour CVEs n = 20
No 24-hour CVEs n = 1593
p value
1–30-day CVEs n = 23
No 1–30-day CVEs n = 1593
p value
Procedural variables SAPIEN-XT, n SAPIEN-3, n CoreValve, n Pre dilatation, n Post dilatation, n Local anesthesia, n Trans-femoral approach, n Percutaneous approach, n Urgency, n PCPS during TAVR Coronary protection Contrast media volume, ml Procedure time, min Fluoroscopy time, min
1328 (82.3) 141 (8.7) 144 (8.9) 1245 (77.2) 348 (21.6) 199 (12.3) 1283 (79.5) 710 (44.0) 64 (4.1) 43 (2.7) 158 (9.8) 123.3 ± 60.1 88.5 ± 47.7 21.4 ± 9.9
17 (85.0) 2 (10.0) 1 (5.0) 17 (85.0) 3 (15.0) 3 (15.0) 17 (85.0) 7 (35.0) 1 (5.0) 2 (10.0) 1 (5.0) 139.0 ± 69.2 118.3 ± 68.1 25.0 ± 7.6
1311 (82.3) 139 (8.7) 143 (9.0) 1228 (77.1) 345 (21.7) 196 (12.3) 1266 (79.5) 703 (44.1) 63 (4.0) 41 (2.6) 157 (9.9) 123.1 ± 60.0 88.2 ± 47.3 21.3 ± 9.9
0.82
1308 (82.3) 141 (8.9) 141 (8.9) 1236 (77.1) 343 (21.6) 199 (12.5) 1266 (79.6) 701 (44.0) 63 (4.0) 42 (2.6) 157 (9.9) 123.3 ± 59.9 88.4 ± 47.7 21.4 ± 9.9
0.28
0.30 0.59 0.73 0.78 0.78 0.56 0.10 0.71 0.24 0.06 0.10
20 (87.0) 0 (0) 3 (13.0) 19 (82.6) 5 (21.7) 0 (0) 17 (73.9) 9 (39.1) 1 (4.3) 1 (2.3) 1 (4.3) 125.7 ± 69.8 96.8 ± 45.8 22.7 ± 12.6
0.80 1.00 0.10 0.45 0.68 0.61 0.47 0.72 0.85 0.40 0.51
Post-procedural variables ICU stay, day (median, IQR) Hospital stay after TAVR, Day (median, IQR)
1.0 (1.0–3.0) 10.0 (7.0–16.0)
3.0 (1.0–6.5) 28.5 (12.8–45.5)
1.0 (1.0–3.0) 10.0 (7.0–16.0)
0.009 b0.001
2.0 (1.0–4.0) 15.0 (9.0–31.0)
1.0 (1.0–3.0) 10.0 (7.0–16.0)
0.13 0.02
VARC-2 complication Peri-procedural MI, n Coronary obstruction, n Life-threatening bleeding, n AKI STAGE 1–3, n Device success, n Severe PPM, n
8 (0.5) 13 (0.8) 94 (5.8) 150 (9.3) 1516 (94.0) 12 (0.8)
0 (0) 0 (0) 3 (15.0) 7 (35.0) 14 (73.7) 0 (0)
8 (0.5) 13 (0.8) 91 (5.7) 143 (9.0) 1452 (94.0) 12 (0.8)
1.00 1.00 0.11 0.001 0.005 1.00
0 (0) 0 (0) 5 (21.7) 5 (21.7) 19 (82.6) 1 (4.3)
8 (0.5) 13 (0.8) 89 (5.6) 145 (9.21) 1447 (94.0) 11 (0.7)
1.00 1.00 0.009 0.06 0.05 0.16
64.0 ± 11.6 1.7 ± 0.4 1.2 ± 0.3 2.2 ± 0.4 10.2 ± 3.9
63.6 ± 13.4 1.7 ± 0.5 1.1 ± 0.3 2.3 ± 0.6 11.8 ± 5.8
64.0 ± 11.6 1.7 ± 0.4 1.2 ± 0.3 2.2 ± 0.4 10.2 ± 3.9
0.90 0.70 0.40 0.35 0.25
58.3 ± 12.9 1.5 ± 0.4 1.0 ± 0.2 2.1 ± 0.4 9.7 ± 4.4
62.2 ± 12.5 1.7 ± 0.4 1.2 ± 0.3 2.2 ± 0.4 10.3 ± 3.9
0.25 0.07 0.001 0.24 0.49
129 (8.0) 21 (1.3) 26 (1.6) 20 (1.2) 16 (1.0) 48 (3.0)
3 (15.0) 2 (10.0) 1 (5.0) 2 (10.0) 1 (5.0) 2 (10.0)
126 (7.9) 19 (1.2) 25 (1.6) 18 (1.1) 15 (0.9) 46 (2.9)
0.21 0.03 0.28 0.01 0.19 0.23
1 (4.3) 0 (0) 0 (0) 1 (4.3) 1 (6.3) 1 (4.3)
128 (8.1) 21 (1.3) 26 (1.6) 19 (1.2) 15 (0.9) 47 (3.0)
1.00 1.00 1.00 0.26 0.21 0.50
Echocardiographic data LVEF, % Post AVA,CM2 Post index AVA, CM2/M2 Post peak velocity, m/s Post mean gradient, mm Hg Other procedural complication Pacemaker implantation, n 2 valve implantation, n Cardiac tamponade, n Rates of any cardiac surgery, n Post AR ≥ MODERATE, n New onset AFa, n
Value are numbers (%) or mean ± SD. CVE, cerebrovascular event; PCPS; percutaneous cardiopulmonary support; VARC, Valve academic research consortium; TAVI, Transcatheter aortic valve implantation; ICU, Intensive care unit; AKI, acute kidney injury; Other abbreviations as in Table 1. a 1299 of the 1613 patients with available clinical record about new onset AF.
multivariate model, the number of independent variables was limited to a maximum of 1 for every 8 to 10 events. Results were reported as odds ratios (OR) with associated 95% confidence intervals (CI) and p values. Analyses were conducted using SPSS version 21.0 (IBM SPSS Inc., Chicago, IL, USA). 3. Results During the study period, 1613 consecutive patients with severe AS were treated with the SAPIEN XT valve (n = 1328), SAPIEN 3 valve (n = 141), or CoreValve (n = 144). Within 30 days, 43 patients had CVEs (TIA, 4; ischemic stroke, 35; hemorrhagic stroke, 4). Of these, 33 CVEs were classified as disabling stroke. CVEs occurred within 24 h for 20 patients (TIA, 4; ischemic stroke, 16). Rates of 24-hour and 30-day CVEs were 1.5% and 3.3% in 2013–2014, 1.4% and 3.1% in 2015, and 0.8% and 1.8% in 2016, respectively (Fig. 1). The median clinical follow-up occurred on day 289 (interquartile range, 105–409 days). During the follow-up period, 159 patients died. Baseline clinical, echocardiographic, computed tomographic, laboratory, and procedural variables of patients according to 24-hour and 1- to 30-day CVEs are shown in Tables 1 and 2. The narrow sinotubular junction (STJ) diameter, small indexed AVA (iAVA), higher peak velocity, and coronary artery disease (CAD) were more frequently observed in patients with 24-hour CVEs. The inability to achieve device success,
acute kidney injury (AKI), conversion to cardiac surgery, and second valve implantation were the post-TAVR incidents that occurred more frequently in patients with 24-hour CVEs and resulted in longer procedure times, intensive care unit stays, and hospital stays following TAVR. However, paroxysmal atrial fibrillation was more frequently observed in patients with 1- to 30-day CVEs. Peri-procedural complications did not increase the incidence risk of 1- to 30-day CVEs. A multivariate analysis demonstrated that the independent predictor of 24-hour CVEs was small iAVA alone. The ROC-derived cut-off value of the iAVA for the prediction of peri-procedural CVEs in the study population were found to be 0.40 cm2/m2 and the area under the curve was 0.67 (Fig. 2). Fluoroscopic time had a trend to be longer in patients with smaller iAVA (b0.40 cm 2 ) compared to those with larger iAVA (22.0 ± 10.2 vs. 21.0 ± 9.7, p = .06). With the cut-off value, the independent predictor of 24-hour CVEs was iAVA b 0.40 cm 2 /m (adjusted OR, 3.96; 95% CI, 1.49–10.47; p = .006). In contrast, the independent predictors of 1- to 30-day CVEs were paroxysmal atrial fibrillation (PAF; adjusted OR, 3.35; 95% CI, 1.36–8.27; p = .009) and iAVA post TAVR (adjusted OR, 0.11; 95% CI, 0.02–0.66; p = .02) (Table 3). Consequently, the independent predictors of 30-day CVEs were prior ischemic stroke (adjusted OR, 2.18; 95% CI, 1.07–4.45; p = .03), PAF (adjusted OR, 2.18; 95% CI, 1.05–4.56; p = .04), and prior coronary artery disease (prior CAD, adjusted OR, 1.88; 95% CI, 1.01–3.48; p = .048) (Table 4).
Please cite this article as: K. Takagi, T. Naganuma, N. Tada, et al., The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAV..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.013
K. Takagi et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
Index aorc valve area 0.40 cm2/m2
5
The occurrence of 24-hour CVEs
Sensivity
% (number) The occurrence of CVEs
2.5
Sensivity: 0.70 Specificity: 0.62
2.2 (14)
2 1.5 1
0.6 (6) 0.5 0 iAVA<0.4
n=630
iAVA<0.4
n=971
1-Specificity Adjusted OR: 3.96, 95%CI (1.49-10.47), p=0.006
AUC 0.67 (0.55-0.79)
*missing data in 12 paents Fig. 2. Receiver-operating characteristic analysis to confirm the optimal cut-off values of the iAVA for the prediction of 24-hour CVEs. iAVA, index aortic valve area. AUC, area under the curve. CVE, cerebrovascular event.
Table 3 Univariate and multivariate regression analysis for the association between 24-hour (n = 20) and 1–30-day CVEs (n = 23) and clinical findings. Factors for predicting
Univariate analysis
Multivariate analysis
Univariate analysis
24-hour CVEs
Pre procedural parameters Age (per 1 year increase) Gender (female) Body surface area (per 1.0 m2 increase) Body mass index, kg/m2 PAD Prior ischemic stroke Prior CAD Prior CABG Dyslipidemia Diabetes mellitus Hypertension CKD eGFR (per 1 ml/min/1.73 m2 increase) Paroxysmal atrial fibrillation Logistic EuroSCORE (per 1% increase) STS score (per 1% increase) Procedural year (per 1 year increase) Indexed AVA (per 1.0 cm2/m2 increase) Indexed AVA ≤0.40 cm2/m2 Peak velocity, m/s AR ≥ moderate Annulus area, mm2 Sinotubular junction diameter, mm Valve type General anesthesia PCPS during TAVR Predilatation Postdilatation Approach route (transapical) Post procedural parameters Post indexed AVA (per 1.0 cm2/m2 increase) All acute kidney injury (stage1–3) Conversion to cardiac surgery New onset atrial fibrillation
Multivariate analysis
1–30-day CVEs
OR
95% CI
p value
0.96 0.63 1.74 0.95 2.41 2.32 2.43 0.65 1.35 0.92 0.63 0.80 1.01 1.35 1.01 1.04 0.74 0.002
0.89–1.03 0.25–1.54 0.13–22.87 0.83–1.08 0.92–6.34 0.83–6.45 1.01–5.89 0.09–4.91 0.56–3.26 0.33–2.54 0.24–1.65 0.33–1.94 0.99–1.03 0.39–4.65 0.98–1.04 1.00–1.07 0.43–1.28 0.00–0.17
0.27 0.31 0.67 0.41 0.070 0.11 0.05 0.68 0.51 0.87 0.35 0.62 0.21 0.64 0.59 0.04 0.28 0.01
1.82 2.39 1.00 0.78 0.99 0.80 4.21 1.68 0.64 0.51
1.07–3.12 0.79–7.23 1.00–1.01 0.65–0.93 0.60–1.66 0.23–2.74 0.95–18.73 0.49–5.78 0.19–2.19 0.12–2.20
– – – –
– – – –
OR
OR
95% CI
p value
0.98 0.96 2.56 1.04 0.83 2.47 1.56 2.68 1.48 1.21 1.83 1.23 0.99 3.42 1.01 1.02 0.75 7.34
0.91–1.06 0.39–2.35 0.24–27.43 0.93–1.16 0.25–2.82 0.96–6.33 0.67–3.62 0.90–7.99 0.65–3.36 0.49–2.95 0.54–6.18 0.52–2.92 0.97–1.01 1.39–8.43 0.98–1.04 0.97–1.06 0.45–1.26 0.25–219.59
0.67 0.93 0.44 0.47 0.83 0.06 0.31 0.08 0.36 0.68 0.33 0.64 0.49 0.01 0.47 0.50 0.28 0.25
0.03 0.12 0.23 0.01 0.99 0.72 0.06 0.41 0.48 0.37
0.77 1.42 0.99 1.03 0.62 NA 1.68 1.41 1.01 1.64
0.45–1.32 0.42–4.83 0.99–1.01 0.89–1.20 0.27–1.40 NA 0.22–12.72 0.48–4.17 0.37–2.74 0.64–4.19
0.35 0.58 0.74 0.72 0.25 NA 0.62 0.53 0.99 0.30
– – – –
0.11 2.77 3.76 1.29
0.02–0.6 1.01–7.57 0.48–29.32 0.17–9.77
0.02 0.05 0.21 0.80
2.56
3.96
95% CI
0.91–7.16
1.49–10.47
p value
0.070
OR
95% CI
p value
3.35
1.36–8.27
0.010
0.11
0.02–0.66
0.020
0.006
OR, odds ratio; CI, confidence interval; other abbreviations as in Tables 1 and 2. TAVR, transcatheter aortic valve replacement.
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K. Takagi et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
4. Discussion Corresponding with previous reports [5–9], the OCEAN-TAVI registry demonstrated that the rates of 24-hour and 30-day CVEs were approximately 1.2% and 2.7% and decreased annually. This trend can be potentially explained by the learning curve [18,19] and the emergence of new valve systems [20]. This study clarified that the peri-procedural complications had a certain influence on the increased risk of peri-procedural CVEs (24 h), but not sub-acute CVEs (1- to 30-day CVEs). More specifically, patients who needed conversion to cardiac surgery, second valve implantation, and mechanical support using percutaneous cardiopulmonary support were at increased risk for CVEs because of low perfusion of the cerebral blood flow caused by hemodynamic instability during TAVR [10,21]. Furthermore, this study showed that one-third of the patients with peri-procedural CVEs were affected by AKI—a finding in agreement with previous reports [12,22]. This finding might imply that the mechanisms of development of both CVEs and AKI are caused by microembolisms and hypotension caused by TAVR. Notably, our study showed that small iAVA and prior stroke were frequently seen in patients with peri-procedural CVEs, whereas PAF and iAVA after TAVR were frequently seen in patients with subacute CVEs, implying that the mechanism of CVEs differs according to the onset. The mechanisms of periprocedural and sub-acute CVEs could be summarized as follows. Patients with a narrow aortic complex were at higher risk for embolic debris (comprising aortic wall and leaflet remnants and thrombi) during the delivery of the transcatheter prosthesis Table 4 Univariate and multivariate regression analysis for the association between 30-day CVEs (n = 43) and clinical findings. Factors for predicting
Univariate analysis
Multivariate analysis
30-day CVEs OR Age (per 1 year increase) Gender (female) Body surface area (per 1.0 m2 increase) Body mass index, kg/m2 PAD Prior ischemic stroke Prior CAD Dyslipidemia Diabetes mellitus Hypertension CKD eGFR (per 1 ml/min/1.73m2 increase) Paroxysmal atrial fibrillation Active smoking Logistic EuroSCORE (per 1% increase) STS score (per 1% increase) Procedural year (per 1 year increase) Indexed AVA (per 1.0 cm2/m2 increase) Peak velocity, m/s AR ≥ moderate Annulus area, mm2 Sinotubular junction diameter, mm SAPIEN XT General anesthesia PCPS during TAVR Predilatation Postdilatation Approach route (transapical)
95% CI
p OR value
0.97 0.92–1.03 1.29 0.68–2.42 2.2 0.37–12.6
0.28 0.44 0.39
1.00 1.49 2.44 1.94 1.42 1.07 1.03 1.00 1.00
0.92–1.09 0.70–3.14 1.21–4.91 1.05–3.58 0.78–2.61 0.54–2.10 0.49–2.17 0.54–1.86 0.99–1.02
0.98 0.30 0.01 0.03 0.26 0.85 0.94 1.00 0.73
2.38 1.15–4.92 2.80 0.83–9.41 1.01 0.99–1.03
0.02 0.10 0.36
1.03 1.00–1.06 0.74 0.51–1.08
0.05 0.12
0.20 0.001–3.20 0.25 1.17 1.87 1.00 0.91
0.80–1.72 0.82–4.27 1.00–1.01 0.81–1.02
0.41 0.14 0.57 0.10
1.33 0.53 2.87 1.54 0.83 1.05
0.56–3.19 0.16–1.72 0.85–9.66 0.68–3.48 0.38–1.80 0.48–2.30
0.52 0.29 0.09 0.30 0.63 0.90
95% CI
p value
2.18 1.07–4.45 0.030 1.88 1.01–3.48 0.046
2.18 1.05–4.56 0.040
0.19 0.01–3.24 0.25
OR, odds ratio; CI, confidence interval; other abbreviations as in Tables 1 and 2. TAVR, transcatheter aortic valve replacement.
[23,24]. Patients diagnosed with AS and a small iAVA usually demonstrated a higher peak velocity and mean pressure gradient, as well as a greater degree of annular degeneration and attenuated plaques, which caused a stroke in patients with AS who underwent TAVR [25]. Therefore, it is reasonable that the difficulty of crossing the aortic valve with a retrograde approach, delivering the transcatheter prosthesis and multiple device repositioning in those with small iAVA required time and aggressive maneuvers, resulting in an increased risk of peri-procedural CVEs, as demonstrated by transcranial Doppler studies (11). These findings are in line with the PARTNER trial, which showed a higher rate of stroke in patients with small aortic annuli and small iAVA [26,27]. In this study, prior ischemic stroke was related to acute CVEs, and prior stroke and prior CAD were associated with an increased risk of 30-days CVEs. The potential mechanism of CVEs might be caused by hemodynamic instability due to decreased LV function and significant CAD, not CAD itself. Furthermore, patients with advanced atherosclerosis, such as those presenting with ischemic stroke, CAD, and CABG, usually had severe atherosclerosis in the aortic arch, resulting in an independent association with the development of acute CVEs [21,27,28]. The presence of PAF, regardless of new onset, had an impact on the occurrence of sub-acute CVEs. Although a previous systemic review showed that new-onset atrial fibrillation (NOAF) was a predictor of stroke [11], our data did not show such a relationship. Instead, PAF or combined PAF and NOAF increased the risk of subacute CVEs, but not acute CVEs. This is because the occurrence of NOAF in our cohort was only 3.5%, and it is possible that this number was underestimated [29,30] because it is sometimes difficult to distinguish between undetected PAF and NOAF. In any case, our findings support the need for continuous rhythm monitoring during hospitalization before and after TAVR to detect otherwise silent episodes of AF. Therefore, we should start prompt anticoagulant therapy when AF is detected because the presence of AF itself increases the risk of CVEs [12,21]. Interestingly, this study showed that iAVA after TAVR was associated with an increased risk of sub-acute CVEs. This is because patients with small iAVA usually had a severe calcified valve, retaining small iAVA after TAVR and were at high risk by nature. In addition, a underexpanded valve with small iAVA after TAVR and valve malapposition (leading to delayed prosthesis endothelialization) might increase the risk of pathogenesis of subclinical leaflet thrombus [31,32]. However, further studies are necessary to clarify the impact of iAVA after TAVR on the development of CVEs. The strength of our report was the use comprehensive data to identify reliable predictors of peri-procedural and sub-acute CVEs in daily practice. This study clarified that small iAVA (b0.40 cm2/m2) and prior stroke were associated with an increased risk of peri-procedural CVEs following TAVR. There is controversy regarding the indication for protection devices with TAVR. However, our study demonstrated the ideal candidates who would obtain benefits from such protection devices. On the other hand, the findings that prior ischemic stroke and PAF were identified as predictors of the 30-day CVEs raises the ongoing debate on what is the optimal antithrombotic regimen in patients postTAVR regardless of whether they are in sinus rhythm or AF. Several ongoing studies may help define these important questions. 5. Study limitations The main limitation of this study was its retrospective, observational design. Furthermore, the majority of patients were treated using the SAPIEN XT device, and the rate of 30-day CVEs exceeded 2.7%. Because newer devices, such as the SAPIEN 3 and Evolute R, could reduce the occurrence of CVEs following TAVR due to the smaller catheter size, our data should be carefully interpreted. However, we believe the predictors of acute CVEs such as small iAVA and prior stroke are universal and applicable even in new devices with smaller catheter size because the mechanism of acute CVEs is logical and reasonable. Again,
Please cite this article as: K. Takagi, T. Naganuma, N. Tada, et al., The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAV..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.013
K. Takagi et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
considering limited number of symptomatic CVEs and no assessment using magnetic resource imaging in this study, our data should be carefully interpreted. Finally, access type and anesthesia type is not fully evaluated because of limited number. Registries and trials dedicated to stroke following TAVR with new prosthesis devices, a larger patient cohort, and longer follow-up will be required to clarify the risk factors for 24-hour and 1- to 30-day CVEs.
[12]
[13]
[14]
6. Conclusions Within 24 h, small iAVA (b0.4 cm2/m2) were associated with an increased risk of CVEs, whereas PAF and iAVA after TAVR were associated with an increased risk of 1- to 30-day CVEs following TAVR. The mechanism of CVEs might differe according to the onset.
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Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAVI registry☆,☆☆ Kensuke Takagi a,⁎, Toru Naganuma b, Norio Tada c, Futoshi Yamanaka d, Motoharu Araki e, Shinichi Shirai f, Akihiro Higashimori g, Yusuke Watanabe h, Masanori Yamamoto i, Kentaro Hayashida j a
Department of Cardiology, Ogaki Municipal Hospital, Gifu, Japan Department of Cardiology, New Tokyo Hospital, Chiba, Japan Department of Cardiology, Sendai Kousei Hospital, Sendai, Japan d Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan e Department of Cardiology, Saiseikai Yokohama City Eastern Hospital, Yokohama, Japan f Department of Cardiology, Kokura Memorial Hospital, Kokura, Japan g Department of Cardiology, Kishiwada Tokushukai Hospital, Osaka, Japan h Department of Cardiology, Teikyo University School of Medicine, Tokyo, Japan i Department of Cardiology, Toyohashi Heart Canter, Toyohashi, Japan j Department of Cardiology, Keio University School of Medicine, Tokyo, Japan b c
a r t i c l e
i n f o
Article history: Received 10 August 2019 Received in revised form 1 October 2019 Accepted 9 October 2019 Available online xxxx Keywords: Transcatheter aortic valve replacement Cerebrovascular event Ischemic stroke Indexed aortic valve area
a b s t r a c t Background: Cerebrovascular events (CVEs) are not uncommon complications of transcatheter aortic valve replacement (TAVR). Our study aimed to determine the predictors of peri-procedural and sub-acute CVEs following TAVR. Methods: Using the Japanese multicenter registry, we evaluated 1613 patients undergoing TAVR between October-2013 and July-2016. Occurrences of 24-hour and 1- to 30-day CVEs were evaluated to clarify the predictors of CVEs following TAVR. Results: The mean age was 84.4 years and mean Society of Thoracic Surgeons score was 8.3%. Overall 24-hour and 30-day CVE rates were 1.2% and 2.7%, respectively. A multivariate analysis demonstrated that independent predictor of 24-hour CVEs was index aortic valve area (iAVA) [adjusted OR (adjusted-OR), 0.001; 95% CI, 0.001–0.13; p = .005]. The receiver operator curve derived cut-off value of iAVA for the prediction of 24-hour CVEs was 0.40 cm2/m2. In contrast, independent predictors of 1- to 30-day CVEs were paroxysmal atrial fibrillation (PAF; adjusted-OR, 3.35; 95% CI, 1.36–8.27; p = .009) and iAVA after TAVR (adjusted-OR, 0.11; 95% CI, 0.02–0.66; p = .02). Consequently, independent predictors of 30-day CVEs were prior stroke (adjusted-OR, 2.18; 95% CI, 1.07–4.45; p = .03), PAF (adjusted-OR, 2.18; 95% CI, 1.05–4.56; p = .04), and prior coronary artery disease (adjusted-OR, 1.88; 95% CI, 1.01–3.48; p = .05). Conclusions: Within 24 h, small iAVA impacted the increased risk of CVEs, whereas PAF and iAVA after TAVR impacted the increased risk of 1- to 30-day CVEs following TAVR. The mechanism of CVEs might differ according to onset. © 2019 Elsevier Inc. All rights reserved.
1. Introduction
☆ Funding: The OCEAN-TAVI registry is supported by Edwards Lifesciences, Japan. ☆☆ Disclosures: Dr. Tada, Dr. Naganuma, Dr. Araki, Dr. Shirai, Dr. Takagi, Dr. Watanabe, Dr. Yamamoto, Dr. Saito, and Dr. Hayashida are clinical proctors for Edwards Lifesciences. Dr. Naganuma, Dr. Watanabe, Dr. Yamamoto, and Dr. Saito are clinical proctors for Medtronic. The other authors have no conflicts of interest to declare. ⁎ Corresponding author at: Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Japan. E-mail address: [email protected] (K. Takagi).
The popularity of transcatheter aortic valve replacement (TAVR) for the treatment of severe aortic stenosis (AS) has increased due to advances in transcatheter heart valve technology and treatment strategies [1–4]. Cerebrovascular events (CVEs) are not uncommon complications following TAVR; however, recent studies have suggested a decrease in 30-day CVEs to rates of 1% to 3% over time [5–9]. Thirty-day CVEs are known to be associated with multiple comorbidities [10–12]. However, there are little data available to clarify the predictors of peri-procedural CVEs, including not only mechanical interactions between the calcified
https://doi.org/10.1016/j.carrev.2019.10.013 1553-8389/© 2019 Elsevier Inc. All rights reserved.
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native valve and the device but also hemodynamic instability driven by serious complications. Therefore, in the present study, we evaluated the predictors of peri-procedural CVEs after TAVR using comprehensive data such as computed tomographic, echocardiographic, procedural, and pharmacotherapeutic variables of a large Japanese cohort from high-volume centers.
2. Methods 2.1. Study population and design The Optimized transCathEter vAlvular interventioN-Transcatheter Aortic Valve Implantation (OCEAN-TAVI) registry is an ongoing, prospective, multicenter registry that was initiated to observe and document the procedural results and post-procedural clinical outcomes of TAVR [13–15]. We evaluated 1613 consecutive high-risk patients with symptomatic, severe AS who underwent TAVR with the SAPIEN XT or SAPIEN 3 balloon-expandable prosthesis (Edwards Lifesciences, Irvine, CA, USA) or the CoreValve Revalving System self-expandable prosthesis (Medtronic, Minneapolis, MN, USA) between October 2013 and July 2016 at 14 Japanese high-volume institutions. The inclusion criteria were presence of symptomatic and degenerative AS, mean gradient N40 mm Hg or jet velocity N 4.0 m/s, or aortic valve area (AVA) b1.0 cm2 (or effective orifice area index b0.6 cm2/m2). Patients for whom TAVR was deemed the best treatment option were selected based on clinical consensus by a multidisciplinary team comprising cardiac surgeons, interventional cardiologists, anesthetists, and imaging specialists. The primary exclusion criterion was failed surgical bioprosthesis. The medical ethics committee approved this study at each hospital. This trial is registered with the University Hospital Medical Information Network as number UMIN000020423. The TAVR procedure was performed using conventional techniques via transfemoral, transiliac, transapical, trans-subclavian, and transaortic approaches according to the experience at each center. Prosthesis size was determined based on pre-procedural echocardiographic and computed tomographic findings. The implanted valves included the SAPIEN XT and SAPIEN 3 devices in sizes of 20 mm, 23 mm, 26 mm, and 29 mm (Edwards Lifesciences) and the CoreValve device in sizes of 26 mm and 29 mm (Medtronic). An antithrombotic regimen was used
at the discretion of the operator. Heparin was administered to achieve an activated clotting time N 250 s. 2.2. Post-procedural care All patients were observed in the intensive care unit for at least 24 h after the index procedure. Dual-antiplatelet therapy was continued for 3 to 6 months; thereafter, aspirin was continued indefinitely. For patients who needed anticoagulant therapy or who were at high risk for bleeding, the use antiplatelets, anticoagulant therapy, or both was at the discretion of the attending physician. 2.3. Endpoint definitions Procedure success, device success (DS), and other procedural complications during TAVR were evaluated according to the Valve Academic Research Consortium (VARC)-2 criteria [16]. 2.4. Study endpoint In the case of a suspected neurologic event based on clinical evaluation by the local heart team, systematic consultation of an on-site neurologist was performed. CVEs included transient ischemic attack (TIA) and clinical stroke (ischemic or hemorrhagic), which were defined according to VARC-2 criteria. Disabling stroke was defined using a modified Rankin Scale according to VARC-2 criteria [16]. Furthermore, we evaluated the predictors of CVEs according to the following time periods after TAVR: 24 h, 1- to 30 days, and 30 days. 2.5. Statistical analysis Continuous variables are expressed as mean ± SD. Comparisons of clinical, echocardiographic, angiographic, computed tomographic, and procedural variables were performed using the Student's t-test, Wilcoxon rank-sum test (continuous variables), or chi-square test (categorical variables) for 24-hour, 1- to 30-day, and 30-day CVEs. Receiveroperating characteristic (ROC) analysis and Youden index were used to confirm the optimal cut-off values of the iAVA for the prediction of 24-hour CVEs.
The occurrence of CVEs
% (number)
2.7
1.4
1.2 (23) (20)
OVERALL N-1613
3.3
(15)
3.1
(17)
(43)
1.8 1.5 (8) (7)
1.8 1.6 1.4 (9) (8) 0.8 (5)
2013-14 N-452 24 hours
2015 N-555 1-30 days
(11)
1 (6)
2016 N-606
30 days
Fig. 1. The incidence of 24-hour, 1-to-30 days, 30-days cerebrovascular event according to transcatheter aortic valve replacement year. CVE, cerebrovascular event. TAVR, transcatheter aortic valve replacement.
Please cite this article as: K. Takagi, T. Naganuma, N. Tada, et al., The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAV..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.013
K. Takagi et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
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Table 1 Baseline patient characteristics. Patients, n
Overall n = 1613
24-hour CVEs n = 20
No 24-hour CVEs n = 1593
p value
1–30-day CVEs n = 23
No 1–30-day CVEs n = 1593
p value
Patient clinical characteristics Age, years Female, n Height, cm Weight, kg Body mass index, kg/m2 Body mass index N30 kg/m2, n Body surface area, m2 NYHA class, III or IV Clinical frail score ≥ 5 MMSE PAD, n Prior heart failure, n Coronary artery disease, n Prior MI, n Prior ischemic stroke, n Prior PCI Prior CABG, n Dyslipidemia, n Diabetes mellitus, n Hypertension, n COPD, n Active smoking CKD, n All AF, n Paroxysmal AF, n none Aspirin P2Y12 inhibitor Dual antiplatelet therapy Vitamin K antagonists Direct oral anticoagulants Anticoagulant and single antiplatelet therapy Triple therapy Unknown Statin Logistic EuroSCORE, % Logistic EuroSCORE II, % STS score, %
84.4 ± 5.1 1136 (70.4) 149.8 ± 9.0 49.8 ± 10.1 22.1 ± 3.6 38 (2.4) 1.42 ± 0.17 816 (50.6) 450 (28.3) 25.0 ± 5.1 246 (15.3) 1313 (81.4) 474 (39.4) 116 (7.2) 205 (12.7) 431 (26.7) 120 (7.5) 688 (42.7) 430 (26.7) 1268 (78.6) 297 (18.4) 44 (2.7) 975 (60.4) 337 (20.9) 187 (11.6) 19 (1.2) 174 (11.0) 68 (4.3) 983 (62.1) 30 (1.9) 40 (2.5) 241 (15.2) 29 (1.8) 29 (1.8) 678 (42.0) 17.0 ± 13.1 5.5 ± 6.4 8.3 ± 7.0
83.1 ± 6.5 12 (60.0) 151.9 ± 8.5 49.9 ± 11.0 21.5 ± 3.4 0 (0) 1.44 ± 0.18 12 (60.0) 6 (31.6) 21.5 ± 6.7 6 (30.0) 18 (90.0) 10 (50.0) 2 (10.0) 5 (25.0) 5 (25.0) 1 (5.0) 10 (50.0) 5 (25.0) 14 (70.0) 3 (15.0) 2 (10.0) 11 (55.0) 4 (20.0) 3 (15.0) 3 (15.0) 6 (30.0) 0 (0) 6 (30.0) 0 (0) 3 (15.0) 2 (10.0) 0 (0) 0 (0) 11 (55.0) 18.6 ± 16.7 7.3 ± 9.1 11.7 ± 15.6
84.4 ± 5.1 1124 (70.6) 149.7 ± 9.0 49.8 ± 10.1 22.1 ± 3.6 38 (2.4) 1.42 ± 0.17 804 (50.5) 444 (28.3) 25.0 ± 5.1 240 (15.1) 1295 (81.3) 464 (29.1) 114 (7.2) 200 (12.6) 426 (26.7) 119 (7.5) 678 (42.6) 425 (26.7) 1254 (78.7) 294 (18.5) 42 (2.6) 964 (60.5) 333 (20.9) 184 (11.6) 16 (1.0) 168 (10.7) 68 (4.3) 977 (62.5) 30 (1.9) 37 (2.4) 239 (15.3) 29 (1.9) 29 (1.8) 667 (41.9) 17.0 ± 13.1 5.5 ± 6.3 8.3 ± 6.8
0.27 0.33 0.29 0.97 0.41 1.00 0.67 0.70 0.80 0.02 0.11 0.56 0.05 0.65 0.16 1.00 1.00 0.51 1.00 0.41 1.00 0.10 0.65 1.00 0.50 0.001
84.4 ± 5.1 1120 (70.4) 149.8 ± 9.0 49.8 ± 10.1 22.1 ± 3.6 38 (2.4) 1.42 ± 0.17 805 (50.6) 443 (28.3) 24.9 ± 5.1 243 (15.3) 1296 (81.5) 465 (29.2) 115 (7.2) 199 (12.5) 428 (26.9) 116 (7.3) 676 (42.5) 423 (26.6) 1248 (78.5) 296 (18.6) 43 (2.7) 960 (60.4) 329 (20.7) 180 (11.3) 18 (1.1) 172 (10.8) 66 (4.2) 976 (61.4) 29 (1.8) 39 (2.5) 236 (14.8) 29 (1.8) 25 (1.6) 664 (41.8) 17.0 ± 13.1 5.5 ± 6.3 8.3 ± 6.9
0.67 1.00 0.77 0.39 0.47 1.00 0.44 0.96 0.82 0.31 1.00 0.41 0.36 1.00 0.06 0.16 0.09 0.40 0.64 0.45 0.10 0.47 0.68 0.12 0.01
0.26 0.59 0.21 0.35
83.9 ± 4.8 16 (69.6) 150.3 ± 8.0 51.6 ± 11.7 22.7 ± 3.8 0 (0) 1.45 ± 0.18 11 (47.8) 7 (30.4) 26.4 ± 3.4 3 (13.0) 17 (73.9) 9 (39.1) 1 (4.3) 6 (26.1) 3 (13.0) 4 (17.4) 12 (52.2) 7 (30.4) 20 (87.0) 1 (4.3) 1 (4.3) 15 (65.2) 8 (34.8) 7 (30.4) 1 (4.3) 2 (8.7) 2 (8.7) 7 (30.4) 1 (4.3) 1 (4.3) 5 (21.7) 0 (0) 4 (17.4) 14 (60.9) 19.0 ± 15.7 7.5 ± 8.9 9.3 ± 9.9
Echocardiographic data LVEF, % Left atrial diameter, mm AVA, cm2 Indexed AVA cm2/m2 Peak velocity, m/s Mean gradient, mm Hg AR ≥ moderate, n MR ≥ moderate, n
62.2 ± 12.6 42.0 ± 6.9 0.6 ± 0.2 0.4 ± 0.1 4.6 ± 0.8 50.5 ± 18.0 155 (9.6) 162 (10.0)
62.7 ± 11.4 39.9 ± 6.5 0.5 ± 0.2 0.4 (0.37) ± 0.1 5.0 ± 1.1 60.0 ± 26.2 4 (20.0) 3 (15.0)
62.2 ± 12.6 42.0 ± 6.9 0.6 ± 0.2 0.4 (0.44) ± 0.1 4.6 ± 0.8 50.4 ± 17.9 151 (9.5) 159 (10.0)
0.93 0.26 0.02 0.006 0.03 0.12 0.12 0.44
58.3 ± 12.9 43.7 ± 6.1 0.7 ± 0.2 0.5 ± 0.1 4.4 ± 0.6 46.2 ± 14.6 3 (13.0) 3 (13.0)
62.2 ± 12.5 42.0 ± 6.9 0.6 ± 0.2 0.4 ± 0.1 4.6 ± 0.8 50.6 ± 18.1 152 (9.6) 159 (10.0)
0.14 0.24 0.20 0.25 0.35 0.25 0.48 0.50
Computed tomographic data Annulus area, mm2 Annulus minimum diameter, mm Annulus maximum diameter, mm Annulus mean diameter, mm Sinotubular junction diameter, mm
394.5 ± 67.3 19.6 ± 2.0 25.3 ± 2.3 22.5 ± 1.9 25.1 ± 2.8
412.5 ± 70.7 20.1 ± 2.1 25.9 ± 2.5 23.0 ± 2.2 23.3 ± 3.0
394.3 ± 67.3 19.6 ± 2.0 25.3 ± 2.3 22.5 ± 1.9 25.1 ± 2.8
0.23 0.25 0.28 0.24 0.01
389.8 ± 77.7 19.2 ± 2.3 25.5 ± 2.4 22.3 ± 2.1 25.3 ± 2.7
394.6 ± 67.2 19.6 ± 2.0 25.3 ± 2.3 22.5 ± 1.9 25.1 ± 2.8
0.74 0.29 0.76 0.72 0.72
Laboratory data Hemoglobin, g/dL Low-density lipoprotein, mg/dL High-density lipoprotein, mg/dL eGFR, mL/min/1.73m2 Albumin, mg/dL Brain-type natriuretic peptidea, pg/ml C-reactive proteina, mg/dL
11.2 ± 1.6 100.7 ± 29.4 53.2 ± 15.2 52.0 ± 20.3 3.8 ± 0.5 468.0 ± 648.0 0.5 ± 1.9
11.3 ± 1.7 96.1 ± 28.2 52.1 ± 14.5 57.6 ± 26.5 3.8 ± 0.6 780.1 ± 954.7 0.5 ± 1.3
11.2 ± 1.6 100.8 ± 29.4 53.2 ± 15.2 51.9 ± 20.2 3.8 ± 0.5 463.7 ± 642.5 0.5 ± 1.9
0.80 0.48 0.74 0.21 0.75 0.17 0.98
11.3 ± 1.9 99.6 ± 30.3 52.8 ± 17.0 49.0 ± 24.2 3.7 ± 0.6 590.9 ± 1548.1 1.0 ± 2.9
11.2 ± 1.6 100.7 ± 29.4 53.2 ± 15.2 52.0 ± 20.3 3.8 ± 0.5 466.2 ± 627.0 0.5 ± 1.9
0.71 0.86 0.89 0.14 0.74 0.72 0.29
0.001
0.09 0.46 0.14 0.50
Values are numbers (%) or mean ± SD. CVE, cerebrovascular event; NYHA, New York Heart Association; PAD, peripheral artery disease; MI, myocardial infarction; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; AF, atrial fibrillation; EuroSCORE, European System for Cardiac Operative Risk Evaluation; STS, Society of Thoracic Surgeons Predictive Risk of Mortality; LVEF, left ventricle ejection fraction; AVA, aortic valve area; AR, aortic regurgitation; MR, mitral regurgitation; eGFR, estimated glomerular filtration rate. a 1403 and 1560 of the 1613 patients with available clinical record about Brain-type natriuretic peptide and C-reactive protein, respectively.
A multivariate logistic regression analysis using purposeful selection of covariates [17] was performed to determine the independent predictors of 24-hour, 1-to 30-day, and 30-day CVEs following TAVR using
predictors associated with each CVE (p b .2) and those judged to be of clinical importance by previously published literature. To avoid overfitting the number of independent variables entered into the final
Please cite this article as: K. Takagi, T. Naganuma, N. Tada, et al., The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAV..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.013
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Table 2 Procedural characteristics and clinical outcome. Patients, n
Overall n = 1613
24-hour CVEs n = 20
No 24-hour CVEs n = 1593
p value
1–30-day CVEs n = 23
No 1–30-day CVEs n = 1593
p value
Procedural variables SAPIEN-XT, n SAPIEN-3, n CoreValve, n Pre dilatation, n Post dilatation, n Local anesthesia, n Trans-femoral approach, n Percutaneous approach, n Urgency, n PCPS during TAVR Coronary protection Contrast media volume, ml Procedure time, min Fluoroscopy time, min
1328 (82.3) 141 (8.7) 144 (8.9) 1245 (77.2) 348 (21.6) 199 (12.3) 1283 (79.5) 710 (44.0) 64 (4.1) 43 (2.7) 158 (9.8) 123.3 ± 60.1 88.5 ± 47.7 21.4 ± 9.9
17 (85.0) 2 (10.0) 1 (5.0) 17 (85.0) 3 (15.0) 3 (15.0) 17 (85.0) 7 (35.0) 1 (5.0) 2 (10.0) 1 (5.0) 139.0 ± 69.2 118.3 ± 68.1 25.0 ± 7.6
1311 (82.3) 139 (8.7) 143 (9.0) 1228 (77.1) 345 (21.7) 196 (12.3) 1266 (79.5) 703 (44.1) 63 (4.0) 41 (2.6) 157 (9.9) 123.1 ± 60.0 88.2 ± 47.3 21.3 ± 9.9
0.82
1308 (82.3) 141 (8.9) 141 (8.9) 1236 (77.1) 343 (21.6) 199 (12.5) 1266 (79.6) 701 (44.0) 63 (4.0) 42 (2.6) 157 (9.9) 123.3 ± 59.9 88.4 ± 47.7 21.4 ± 9.9
0.28
0.30 0.59 0.73 0.78 0.78 0.56 0.10 0.71 0.24 0.06 0.10
20 (87.0) 0 (0) 3 (13.0) 19 (82.6) 5 (21.7) 0 (0) 17 (73.9) 9 (39.1) 1 (4.3) 1 (2.3) 1 (4.3) 125.7 ± 69.8 96.8 ± 45.8 22.7 ± 12.6
0.80 1.00 0.10 0.45 0.68 0.61 0.47 0.72 0.85 0.40 0.51
Post-procedural variables ICU stay, day (median, IQR) Hospital stay after TAVR, Day (median, IQR)
1.0 (1.0–3.0) 10.0 (7.0–16.0)
3.0 (1.0–6.5) 28.5 (12.8–45.5)
1.0 (1.0–3.0) 10.0 (7.0–16.0)
0.009 b0.001
2.0 (1.0–4.0) 15.0 (9.0–31.0)
1.0 (1.0–3.0) 10.0 (7.0–16.0)
0.13 0.02
VARC-2 complication Peri-procedural MI, n Coronary obstruction, n Life-threatening bleeding, n AKI STAGE 1–3, n Device success, n Severe PPM, n
8 (0.5) 13 (0.8) 94 (5.8) 150 (9.3) 1516 (94.0) 12 (0.8)
0 (0) 0 (0) 3 (15.0) 7 (35.0) 14 (73.7) 0 (0)
8 (0.5) 13 (0.8) 91 (5.7) 143 (9.0) 1452 (94.0) 12 (0.8)
1.00 1.00 0.11 0.001 0.005 1.00
0 (0) 0 (0) 5 (21.7) 5 (21.7) 19 (82.6) 1 (4.3)
8 (0.5) 13 (0.8) 89 (5.6) 145 (9.21) 1447 (94.0) 11 (0.7)
1.00 1.00 0.009 0.06 0.05 0.16
64.0 ± 11.6 1.7 ± 0.4 1.2 ± 0.3 2.2 ± 0.4 10.2 ± 3.9
63.6 ± 13.4 1.7 ± 0.5 1.1 ± 0.3 2.3 ± 0.6 11.8 ± 5.8
64.0 ± 11.6 1.7 ± 0.4 1.2 ± 0.3 2.2 ± 0.4 10.2 ± 3.9
0.90 0.70 0.40 0.35 0.25
58.3 ± 12.9 1.5 ± 0.4 1.0 ± 0.2 2.1 ± 0.4 9.7 ± 4.4
62.2 ± 12.5 1.7 ± 0.4 1.2 ± 0.3 2.2 ± 0.4 10.3 ± 3.9
0.25 0.07 0.001 0.24 0.49
129 (8.0) 21 (1.3) 26 (1.6) 20 (1.2) 16 (1.0) 48 (3.0)
3 (15.0) 2 (10.0) 1 (5.0) 2 (10.0) 1 (5.0) 2 (10.0)
126 (7.9) 19 (1.2) 25 (1.6) 18 (1.1) 15 (0.9) 46 (2.9)
0.21 0.03 0.28 0.01 0.19 0.23
1 (4.3) 0 (0) 0 (0) 1 (4.3) 1 (6.3) 1 (4.3)
128 (8.1) 21 (1.3) 26 (1.6) 19 (1.2) 15 (0.9) 47 (3.0)
1.00 1.00 1.00 0.26 0.21 0.50
Echocardiographic data LVEF, % Post AVA,CM2 Post index AVA, CM2/M2 Post peak velocity, m/s Post mean gradient, mm Hg Other procedural complication Pacemaker implantation, n 2 valve implantation, n Cardiac tamponade, n Rates of any cardiac surgery, n Post AR ≥ MODERATE, n New onset AFa, n
Value are numbers (%) or mean ± SD. CVE, cerebrovascular event; PCPS; percutaneous cardiopulmonary support; VARC, Valve academic research consortium; TAVI, Transcatheter aortic valve implantation; ICU, Intensive care unit; AKI, acute kidney injury; Other abbreviations as in Table 1. a 1299 of the 1613 patients with available clinical record about new onset AF.
multivariate model, the number of independent variables was limited to a maximum of 1 for every 8 to 10 events. Results were reported as odds ratios (OR) with associated 95% confidence intervals (CI) and p values. Analyses were conducted using SPSS version 21.0 (IBM SPSS Inc., Chicago, IL, USA). 3. Results During the study period, 1613 consecutive patients with severe AS were treated with the SAPIEN XT valve (n = 1328), SAPIEN 3 valve (n = 141), or CoreValve (n = 144). Within 30 days, 43 patients had CVEs (TIA, 4; ischemic stroke, 35; hemorrhagic stroke, 4). Of these, 33 CVEs were classified as disabling stroke. CVEs occurred within 24 h for 20 patients (TIA, 4; ischemic stroke, 16). Rates of 24-hour and 30-day CVEs were 1.5% and 3.3% in 2013–2014, 1.4% and 3.1% in 2015, and 0.8% and 1.8% in 2016, respectively (Fig. 1). The median clinical follow-up occurred on day 289 (interquartile range, 105–409 days). During the follow-up period, 159 patients died. Baseline clinical, echocardiographic, computed tomographic, laboratory, and procedural variables of patients according to 24-hour and 1- to 30-day CVEs are shown in Tables 1 and 2. The narrow sinotubular junction (STJ) diameter, small indexed AVA (iAVA), higher peak velocity, and coronary artery disease (CAD) were more frequently observed in patients with 24-hour CVEs. The inability to achieve device success,
acute kidney injury (AKI), conversion to cardiac surgery, and second valve implantation were the post-TAVR incidents that occurred more frequently in patients with 24-hour CVEs and resulted in longer procedure times, intensive care unit stays, and hospital stays following TAVR. However, paroxysmal atrial fibrillation was more frequently observed in patients with 1- to 30-day CVEs. Peri-procedural complications did not increase the incidence risk of 1- to 30-day CVEs. A multivariate analysis demonstrated that the independent predictor of 24-hour CVEs was small iAVA alone. The ROC-derived cut-off value of the iAVA for the prediction of peri-procedural CVEs in the study population were found to be 0.40 cm2/m2 and the area under the curve was 0.67 (Fig. 2). Fluoroscopic time had a trend to be longer in patients with smaller iAVA (b0.40 cm 2 ) compared to those with larger iAVA (22.0 ± 10.2 vs. 21.0 ± 9.7, p = .06). With the cut-off value, the independent predictor of 24-hour CVEs was iAVA b 0.40 cm 2 /m (adjusted OR, 3.96; 95% CI, 1.49–10.47; p = .006). In contrast, the independent predictors of 1- to 30-day CVEs were paroxysmal atrial fibrillation (PAF; adjusted OR, 3.35; 95% CI, 1.36–8.27; p = .009) and iAVA post TAVR (adjusted OR, 0.11; 95% CI, 0.02–0.66; p = .02) (Table 3). Consequently, the independent predictors of 30-day CVEs were prior ischemic stroke (adjusted OR, 2.18; 95% CI, 1.07–4.45; p = .03), PAF (adjusted OR, 2.18; 95% CI, 1.05–4.56; p = .04), and prior coronary artery disease (prior CAD, adjusted OR, 1.88; 95% CI, 1.01–3.48; p = .048) (Table 4).
Please cite this article as: K. Takagi, T. Naganuma, N. Tada, et al., The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAV..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.013
K. Takagi et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
Index aorc valve area 0.40 cm2/m2
5
The occurrence of 24-hour CVEs
Sensivity
% (number) The occurrence of CVEs
2.5
Sensivity: 0.70 Specificity: 0.62
2.2 (14)
2 1.5 1
0.6 (6) 0.5 0 iAVA<0.4
n=630
iAVA<0.4
n=971
1-Specificity Adjusted OR: 3.96, 95%CI (1.49-10.47), p=0.006
AUC 0.67 (0.55-0.79)
*missing data in 12 paents Fig. 2. Receiver-operating characteristic analysis to confirm the optimal cut-off values of the iAVA for the prediction of 24-hour CVEs. iAVA, index aortic valve area. AUC, area under the curve. CVE, cerebrovascular event.
Table 3 Univariate and multivariate regression analysis for the association between 24-hour (n = 20) and 1–30-day CVEs (n = 23) and clinical findings. Factors for predicting
Univariate analysis
Multivariate analysis
Univariate analysis
24-hour CVEs
Pre procedural parameters Age (per 1 year increase) Gender (female) Body surface area (per 1.0 m2 increase) Body mass index, kg/m2 PAD Prior ischemic stroke Prior CAD Prior CABG Dyslipidemia Diabetes mellitus Hypertension CKD eGFR (per 1 ml/min/1.73 m2 increase) Paroxysmal atrial fibrillation Logistic EuroSCORE (per 1% increase) STS score (per 1% increase) Procedural year (per 1 year increase) Indexed AVA (per 1.0 cm2/m2 increase) Indexed AVA ≤0.40 cm2/m2 Peak velocity, m/s AR ≥ moderate Annulus area, mm2 Sinotubular junction diameter, mm Valve type General anesthesia PCPS during TAVR Predilatation Postdilatation Approach route (transapical) Post procedural parameters Post indexed AVA (per 1.0 cm2/m2 increase) All acute kidney injury (stage1–3) Conversion to cardiac surgery New onset atrial fibrillation
Multivariate analysis
1–30-day CVEs
OR
95% CI
p value
0.96 0.63 1.74 0.95 2.41 2.32 2.43 0.65 1.35 0.92 0.63 0.80 1.01 1.35 1.01 1.04 0.74 0.002
0.89–1.03 0.25–1.54 0.13–22.87 0.83–1.08 0.92–6.34 0.83–6.45 1.01–5.89 0.09–4.91 0.56–3.26 0.33–2.54 0.24–1.65 0.33–1.94 0.99–1.03 0.39–4.65 0.98–1.04 1.00–1.07 0.43–1.28 0.00–0.17
0.27 0.31 0.67 0.41 0.070 0.11 0.05 0.68 0.51 0.87 0.35 0.62 0.21 0.64 0.59 0.04 0.28 0.01
1.82 2.39 1.00 0.78 0.99 0.80 4.21 1.68 0.64 0.51
1.07–3.12 0.79–7.23 1.00–1.01 0.65–0.93 0.60–1.66 0.23–2.74 0.95–18.73 0.49–5.78 0.19–2.19 0.12–2.20
– – – –
– – – –
OR
OR
95% CI
p value
0.98 0.96 2.56 1.04 0.83 2.47 1.56 2.68 1.48 1.21 1.83 1.23 0.99 3.42 1.01 1.02 0.75 7.34
0.91–1.06 0.39–2.35 0.24–27.43 0.93–1.16 0.25–2.82 0.96–6.33 0.67–3.62 0.90–7.99 0.65–3.36 0.49–2.95 0.54–6.18 0.52–2.92 0.97–1.01 1.39–8.43 0.98–1.04 0.97–1.06 0.45–1.26 0.25–219.59
0.67 0.93 0.44 0.47 0.83 0.06 0.31 0.08 0.36 0.68 0.33 0.64 0.49 0.01 0.47 0.50 0.28 0.25
0.03 0.12 0.23 0.01 0.99 0.72 0.06 0.41 0.48 0.37
0.77 1.42 0.99 1.03 0.62 NA 1.68 1.41 1.01 1.64
0.45–1.32 0.42–4.83 0.99–1.01 0.89–1.20 0.27–1.40 NA 0.22–12.72 0.48–4.17 0.37–2.74 0.64–4.19
0.35 0.58 0.74 0.72 0.25 NA 0.62 0.53 0.99 0.30
– – – –
0.11 2.77 3.76 1.29
0.02–0.6 1.01–7.57 0.48–29.32 0.17–9.77
0.02 0.05 0.21 0.80
2.56
3.96
95% CI
0.91–7.16
1.49–10.47
p value
0.070
OR
95% CI
p value
3.35
1.36–8.27
0.010
0.11
0.02–0.66
0.020
0.006
OR, odds ratio; CI, confidence interval; other abbreviations as in Tables 1 and 2. TAVR, transcatheter aortic valve replacement.
Please cite this article as: K. Takagi, T. Naganuma, N. Tada, et al., The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAV..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.013
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K. Takagi et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
4. Discussion Corresponding with previous reports [5–9], the OCEAN-TAVI registry demonstrated that the rates of 24-hour and 30-day CVEs were approximately 1.2% and 2.7% and decreased annually. This trend can be potentially explained by the learning curve [18,19] and the emergence of new valve systems [20]. This study clarified that the peri-procedural complications had a certain influence on the increased risk of peri-procedural CVEs (24 h), but not sub-acute CVEs (1- to 30-day CVEs). More specifically, patients who needed conversion to cardiac surgery, second valve implantation, and mechanical support using percutaneous cardiopulmonary support were at increased risk for CVEs because of low perfusion of the cerebral blood flow caused by hemodynamic instability during TAVR [10,21]. Furthermore, this study showed that one-third of the patients with peri-procedural CVEs were affected by AKI—a finding in agreement with previous reports [12,22]. This finding might imply that the mechanisms of development of both CVEs and AKI are caused by microembolisms and hypotension caused by TAVR. Notably, our study showed that small iAVA and prior stroke were frequently seen in patients with peri-procedural CVEs, whereas PAF and iAVA after TAVR were frequently seen in patients with subacute CVEs, implying that the mechanism of CVEs differs according to the onset. The mechanisms of periprocedural and sub-acute CVEs could be summarized as follows. Patients with a narrow aortic complex were at higher risk for embolic debris (comprising aortic wall and leaflet remnants and thrombi) during the delivery of the transcatheter prosthesis Table 4 Univariate and multivariate regression analysis for the association between 30-day CVEs (n = 43) and clinical findings. Factors for predicting
Univariate analysis
Multivariate analysis
30-day CVEs OR Age (per 1 year increase) Gender (female) Body surface area (per 1.0 m2 increase) Body mass index, kg/m2 PAD Prior ischemic stroke Prior CAD Dyslipidemia Diabetes mellitus Hypertension CKD eGFR (per 1 ml/min/1.73m2 increase) Paroxysmal atrial fibrillation Active smoking Logistic EuroSCORE (per 1% increase) STS score (per 1% increase) Procedural year (per 1 year increase) Indexed AVA (per 1.0 cm2/m2 increase) Peak velocity, m/s AR ≥ moderate Annulus area, mm2 Sinotubular junction diameter, mm SAPIEN XT General anesthesia PCPS during TAVR Predilatation Postdilatation Approach route (transapical)
95% CI
p OR value
0.97 0.92–1.03 1.29 0.68–2.42 2.2 0.37–12.6
0.28 0.44 0.39
1.00 1.49 2.44 1.94 1.42 1.07 1.03 1.00 1.00
0.92–1.09 0.70–3.14 1.21–4.91 1.05–3.58 0.78–2.61 0.54–2.10 0.49–2.17 0.54–1.86 0.99–1.02
0.98 0.30 0.01 0.03 0.26 0.85 0.94 1.00 0.73
2.38 1.15–4.92 2.80 0.83–9.41 1.01 0.99–1.03
0.02 0.10 0.36
1.03 1.00–1.06 0.74 0.51–1.08
0.05 0.12
0.20 0.001–3.20 0.25 1.17 1.87 1.00 0.91
0.80–1.72 0.82–4.27 1.00–1.01 0.81–1.02
0.41 0.14 0.57 0.10
1.33 0.53 2.87 1.54 0.83 1.05
0.56–3.19 0.16–1.72 0.85–9.66 0.68–3.48 0.38–1.80 0.48–2.30
0.52 0.29 0.09 0.30 0.63 0.90
95% CI
p value
2.18 1.07–4.45 0.030 1.88 1.01–3.48 0.046
2.18 1.05–4.56 0.040
0.19 0.01–3.24 0.25
OR, odds ratio; CI, confidence interval; other abbreviations as in Tables 1 and 2. TAVR, transcatheter aortic valve replacement.
[23,24]. Patients diagnosed with AS and a small iAVA usually demonstrated a higher peak velocity and mean pressure gradient, as well as a greater degree of annular degeneration and attenuated plaques, which caused a stroke in patients with AS who underwent TAVR [25]. Therefore, it is reasonable that the difficulty of crossing the aortic valve with a retrograde approach, delivering the transcatheter prosthesis and multiple device repositioning in those with small iAVA required time and aggressive maneuvers, resulting in an increased risk of peri-procedural CVEs, as demonstrated by transcranial Doppler studies (11). These findings are in line with the PARTNER trial, which showed a higher rate of stroke in patients with small aortic annuli and small iAVA [26,27]. In this study, prior ischemic stroke was related to acute CVEs, and prior stroke and prior CAD were associated with an increased risk of 30-days CVEs. The potential mechanism of CVEs might be caused by hemodynamic instability due to decreased LV function and significant CAD, not CAD itself. Furthermore, patients with advanced atherosclerosis, such as those presenting with ischemic stroke, CAD, and CABG, usually had severe atherosclerosis in the aortic arch, resulting in an independent association with the development of acute CVEs [21,27,28]. The presence of PAF, regardless of new onset, had an impact on the occurrence of sub-acute CVEs. Although a previous systemic review showed that new-onset atrial fibrillation (NOAF) was a predictor of stroke [11], our data did not show such a relationship. Instead, PAF or combined PAF and NOAF increased the risk of subacute CVEs, but not acute CVEs. This is because the occurrence of NOAF in our cohort was only 3.5%, and it is possible that this number was underestimated [29,30] because it is sometimes difficult to distinguish between undetected PAF and NOAF. In any case, our findings support the need for continuous rhythm monitoring during hospitalization before and after TAVR to detect otherwise silent episodes of AF. Therefore, we should start prompt anticoagulant therapy when AF is detected because the presence of AF itself increases the risk of CVEs [12,21]. Interestingly, this study showed that iAVA after TAVR was associated with an increased risk of sub-acute CVEs. This is because patients with small iAVA usually had a severe calcified valve, retaining small iAVA after TAVR and were at high risk by nature. In addition, a underexpanded valve with small iAVA after TAVR and valve malapposition (leading to delayed prosthesis endothelialization) might increase the risk of pathogenesis of subclinical leaflet thrombus [31,32]. However, further studies are necessary to clarify the impact of iAVA after TAVR on the development of CVEs. The strength of our report was the use comprehensive data to identify reliable predictors of peri-procedural and sub-acute CVEs in daily practice. This study clarified that small iAVA (b0.40 cm2/m2) and prior stroke were associated with an increased risk of peri-procedural CVEs following TAVR. There is controversy regarding the indication for protection devices with TAVR. However, our study demonstrated the ideal candidates who would obtain benefits from such protection devices. On the other hand, the findings that prior ischemic stroke and PAF were identified as predictors of the 30-day CVEs raises the ongoing debate on what is the optimal antithrombotic regimen in patients postTAVR regardless of whether they are in sinus rhythm or AF. Several ongoing studies may help define these important questions. 5. Study limitations The main limitation of this study was its retrospective, observational design. Furthermore, the majority of patients were treated using the SAPIEN XT device, and the rate of 30-day CVEs exceeded 2.7%. Because newer devices, such as the SAPIEN 3 and Evolute R, could reduce the occurrence of CVEs following TAVR due to the smaller catheter size, our data should be carefully interpreted. However, we believe the predictors of acute CVEs such as small iAVA and prior stroke are universal and applicable even in new devices with smaller catheter size because the mechanism of acute CVEs is logical and reasonable. Again,
Please cite this article as: K. Takagi, T. Naganuma, N. Tada, et al., The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAV..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.013
K. Takagi et al. / Cardiovascular Revascularization Medicine xxx (xxxx) xxx
considering limited number of symptomatic CVEs and no assessment using magnetic resource imaging in this study, our data should be carefully interpreted. Finally, access type and anesthesia type is not fully evaluated because of limited number. Registries and trials dedicated to stroke following TAVR with new prosthesis devices, a larger patient cohort, and longer follow-up will be required to clarify the risk factors for 24-hour and 1- to 30-day CVEs.
[12]
[13]
[14]
6. Conclusions Within 24 h, small iAVA (b0.4 cm2/m2) were associated with an increased risk of CVEs, whereas PAF and iAVA after TAVR were associated with an increased risk of 1- to 30-day CVEs following TAVR. The mechanism of CVEs might differe according to the onset.
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Please cite this article as: K. Takagi, T. Naganuma, N. Tada, et al., The predictors of peri-procedural and sub-acute cerebrovascular events following TAVR from OCEAN-TAV..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2019.10.013