Impact of the type of transcatheter heart valve on the incidence of early subclinical leaflet thrombosis

Impact of the type of transcatheter heart valve on the incidence of early subclinical leaflet... Abstract OBJECTIVES The aim of this study was to investigate whether balloon-expandable and self-expandable transcatheter heart valves (THVs) differ in terms of the incidence of early subclinical leaflet thrombosis (LT). METHODS Electrocardiographic-gated cardiac dual-source computed tomography angiography was performed at a median of 5 days after transcatheter aortic valve implantation and assessed for evidence of LT. RESULTS Of the 629 consecutive patients, 538 (86%) received a balloon-expandable THV and 91 (14%) a self-expandable THV. LT was documented in 77 (14%) patients with a balloon-expandable valve and in 16 (18%) with a self-expandable valve (P = 0.42). Similarly, LT was not significantly related to THV size (P = 0.62). Corresponding to a lower rate of atrial fibrillation in the group with LT [25 (27%) vs 222 (41%), P = 0.01], anticoagulation at the time of computed tomography angiography was less frequent in this group [21 (23%) vs 183 (34%), P = 0.03]. Among the other potentially relevant covariables, there was no significant difference in the clinical baseline and the procedural characteristics between patients with and without LT (age 82 ± 6 years vs 82 ± 6 years, P = 0.51; ejection fraction 49 ± 10% vs 50 ± 10%, P = 0.47). In multivariate logistic regression analysis, including potentially relevant covariables, valve type was not significantly associated with LT (P = 0.36). In the univariate and multivariate analyses, only the lack of anticoagulation at the time of computed tomography angiography was predictive of thrombus formation [0.563 (0.335–0.944), P = 0.03; 0.576 (0.343–0.970), P = 0.04]. CONCLUSIONS In this large retrospective study of 629 patients, the type and the size of THV was not predictive of early LT. Transcatheter aortic valve implantation, Transcatheter heart valve, Thrombosis, Computed tomography angiography INTRODUCTION Transcatheter aortic valve implantation (TAVI) is a well-established treatment option for severe aortic stenosis in patients with increased perioperative risk [1]. Recently, we [2] and others [3, 4] reported the findings of an early post-procedural electrocardiographic-gated cardiac dual-source computed tomography angiography (CTA) to be highly suspicious of leaflet thrombosis (LT). Early subclinical LT was diagnosed in up to 13% of patients and is considered a new entity post-TAVI [2–5]. CTA has emerged as the preferred diagnostic procedure, because echocardiography provides insufficient resolution due to prosthesis-related shadowing [6]. Various types of transcatheter heart valves (THVs) have been developed and are currently in clinical use. It is unclear whether the risk of LT differs between the use of balloon-expandable and self-expandable THV types or in specific patient subsets. Such information may be clinically important to guide the choice of THV as well as pre- and post-TAVI patient management. Therefore, we sought to evaluate the potential risk factors for LT associated with the different types of THVs in a large cohort of unselected, consecutive patients who underwent TAVI with a variety of commercially available THVs. PATIENTS AND METHODS This retrospective study was approved by the institutional review board and complies with the Declaration of Helsinki. Routine predischarge CTAs are scheduled in our institution to all patients without contraindications who undergo TAVI to exclude stent-related complications including stent malpositioning, contained ruptures and others. Patients who had undergone TAVI between May 2012 and December 2016 were candidates for inclusion into this study. For the current comparison between balloon-expandable and self-expandable valves, we excluded mechanically-expandable LOTUS valve and valve types implanted at low numbers (<10). Clinical, echocardiographic and CTA data were recorded prospectively in our institutional database. Transcatheter heart valve implantation procedure A multidisciplinary, institutional heart team assessed patient eligibility for TAVI, feasibility of the procedure and decided on the preferred access route, valve type and size. The preinterventional CTA-planimetric area measurements were performed as described previously [7]. The implantation procedure was performed under general anaesthesia using a combination of fluoroscopy and transoesophageal echocardiography for guidance. Periprocedural and post-procedural antithrombotic regimen For peri-interventional antithrombotic treatment, prior to the procedure, all patients were loaded with either 400 mg effervescent of aspirin (until May 2014) or a combination of 400 mg effervescent acetylsalicylic acid and 600 mg clopidogrel (from May 2014 onwards). All patients received peri-interventional heparin, in general 5000 IU, with adjustments for high and low body weights. As of Day 1 postimplantation, antithrombotic regimen consisted of acetylsalicylic acid monotherapy (100 mg daily, until May 2014). Subsequently, dual-antiplatelet therapy with acetylsalicylic acid (100 mg daily) and clopidogrel (75 mg daily) was given. In patients on oral anticoagulation, treatment was paused prior to the procedure for 24 h for novel oral anticoagulants or until an international normalized ratio <2 was reached in patients on vitamin K antagonists. No bridging with heparin was performed prior to intervention. On Day 1 following procedure, anticoagulation was readministered combined with single-antiplatelet therapy (clopidogrel 75 mg). Patients were considered on anticoagulation at the time of CTA if international normalized ratio was >1.8 (in case of vitamin K antagonist treatment) or if novel oral anticoagulant therapy was readministered at least 24 h before CTA. In case of heparin-bridging therapy combined with the start of a vitamin K antagonist postimplantation, patients were considered to be on anticoagulation if the prothrombin time was greater than 60 s. As described previously, patients diagnosed with LT received empirical anticoagulation therapy for at least 3 months until May 2015 and thereafter were switched back to usual care [8]. Postinterventional echocardiographic assessment Within 24 h after implantation, the first transthoracic echocardiography was performed with a final transthoracic echocardiography evaluation prior to discharge. All echocardiographic assessments were performed by experienced cardiologists using a Philips IE33 system (Philips, Leiden, Netherlands). Prosthesis function and grading of paravalvular leakage (PVL) were assessed based on the recommendations of the Valve Academic Research Consortium (VARC; deliberately extending the grading scale by one class: 0 = none, 1 = trace, 2 = mild, 3= moderate and 4 = severe PVL) [9]. According to the VARC-2 criteria [10], a mean pressure gradient of >20 mmHg was defined as the presence of haemodymamic valve deterioration, and a mild valve stenosis was determined by a mean pressure gradient between 20 mmHg and 40 mmHg or a peak velocity of 3–4 m/s. Computed tomography angiography data acquisition and image analysis Patients underwent routine CTA prior to discharge. Reasons for not performing this have been published in detail previously [2]. CTA examinations were performed with a second-generation dual-source CT scanner (Somatom Definition Flash, Siemens Healthcare, Forchheim, Germany) with a temporal resolution of 75 ms. The protocol for the CTA included the injection of a total of 40 ml iodinated contrast agent (Imeron400®, Bracco, Konstanz, Germany) at 4 ml/s, followed by a saline bolus chaser of 40 ml at 4 ml/s. Seven seconds after the attenuation of a region of interest placed in the left atrium reached 70 HU (bolus-tracking technique), data acquisition was initiated. To deliberately cover the entire cardiac cycle, a cardiac-CTA electrocardiographic-gated dose modulation was omitted, and the tube voltage and tube current time product were adapted for each patient using FASTCARE© (Siemens Healthcare). All CTA data were reconstructed at either 5% or 50 ms steps throughout the cardiac cycle with a section thickness of 1 mm and an increment of 0.8 mm using a stent-specific convolution kernel (B46f). Image analyses were performed with a dedicated post-processing workstation (Syngo Multimodality Workplace, Siemens Healthcare) using multiplanar reformations. Prosthesis leaflets were dynamically assessed for LT criteria throughout the cardiac cycle by 2 radiologists/cardiologists in consensus. Diagnostic criteria for LT were previously described [2]. In brief, we defined LT as a hypo-attenuated thickening with or without reduced leaflet mobility of one or more leaflet segments, detectable in at least 2 different projections and 2 different time reconstruction intervals. Statistical analysis All statistical analyses were performed using the SPSS software (SPSS version 23.0, SPSS, Chicago, IL, USA). Continuous variables were reported as mean and standard deviation. The Kolmorogov–Smirnoff test was used to test the variables for normal distribution. Non-normal distributed continuous variables were tested with the Mann–Whitney U-test and normal distributed continuous variables were tested by the Student’s t-test. Categorical data were reported as frequencies and percentages. Differences between the groups for categorical variables were tested with the χ2 test or the Fisher’s exact test where appropriate. We primarily assessed the association of 2 groups of TVH types with the incidence of LT and secondarily that of the strata of valve size. For this purpose, we calculated the univariate and multivariate logistic regression models. As independent covariables, the multivariate models comprised variables with a difference between patients with and without LT at a P-value <0.1 in the univariate analyses. Because anticoagulation and atrial fibrillations were closely associated, we only included anticoagulation in these models. The results were presented as odds ratio with 95% confidence interval. The P-values of <0.05 were considered statistically significant. The performance of the logisitic regression model was evaluated with respect to discrimination and calibration. Regarding discrimination, we used the C-statistics estimating the area under the curve derived from receiver operator characteristic curve analysis. The Hosmer–Lemeshow test was applied to evaluate the calibration of models. For this purpose, we used the classification into 9 groups of the distribution of the model-based predicted LT probabilities. RESULTS Study cohort A total of 1210 patients received a THV between May 2012 and December 2016 at our institution. Of these patients, 660 (55%) underwent routine CTA at a median period of 5 (interquartile range 5.6) days post-procedure (Fig. 1). We grouped 390 (60%) SAPIEN 3 THVs plus 148 (22%) SAPIEN XT THVs (both Edwards Lifesciences, Irvine, CA, USA) to the balloon-expandable cohort and 56 (9%) Evolut R THVs plus 35 (5%) CoreValve THVs (both Medtronic, Minneapolis, MN, USA) to the self-expandable cohort. Twenty-one (3%) Lotus THVs (Boston Scientific, Natick, MA, USA), 6 (<1%) Portico THVs (St. Jude Medical, Minneapolis, MN, USA) and 4 (<1%) Symetis THVs (Symetis SA, Ecublens, Switzerland) were not included in this analysis. Valve sizes were categorized according to the valve diameter as small (≤ 23 mm), medium (25–27 mm) and large (29–31 mm). Baseline and procedural characteristics are presented in Table 1. Table 1: Baseline and procedural characteristics of the entire study population and of patients without and with leaflet thrombosis   All patients (n = 629)  Without LT (n = 536)  With LT (n = 93)  P-Value  Age (years)  82.0 ± 5.6  81.9 ± 5.5  82.4 ± 6.0  0.51  Female  333 (53)  277 (52)  56 (60)  0.13  BMI (kg/m2)  27.1 ± 5.0  27.1 ± 5.2  27.0 ± 3.7  0.47  Logistic EuroSCORE (%)  14.4 ± 10.9  14.6 ± 11.2  13.7 ± 9.5  0.85  History of stroke  98 (16)  85 (16)  13 (14)  0.65  Diabetes  173 (28)  150 (28)  23 (25)  0.52  Hypertonus  575 (91)  486 (91)  59 (96)  0.11  Creatinine clearance (ml/min)  53.8 ± 20.2  53.8 ± 20.9  54.0 ± 20.2  0.61  Previous heart surgery  74 (11.8)  63 (12)  11 (12)  0.98  Atrial fibrillation  247 (39)  222 (41)  25 (27)  0.01  CHA2DS2-VASc score  5.7 ± 1.2  5.6 ± 1.2  5.8 ± 1.2  0.65  AC at CT (>24 h)   Any oral AC  204 (32)  183 (34)  21 (23)  0.03   Vitamin K antagonist  124 (20)  112 (21)  12 (13)  0.07   Novel oral AC  80 (13)  71 (13)  9 (10)  0.34  Coronary artery disease  397 (63)  336 (63)  61 (66)  0.59  History of myocardial infarction  103 (16)  92 (17)  11 (12)  0.20  History of smoking  115 (18)  97 (18)  18 (19)  0.77  LVEF (%)  49.5 ± 9.5  49.6 ± 9.9  49.3 ± 9.5  0.47  Annulus size (CTA) (mm)  24.1 ± 2.3  24.2 ± 2.3  23.9 ± 1.9  0.26  Mitral insufficiency   0  50 (8)  37 (7)  13 (14.0)  0.19   1  429 (68)  370 (69)  59 (63.4)   2  130 (21)  111 (208)  19 (20.4)   3  20 (3)  18 (3)  2 (2.2)  Access route   Transfemoral  619 (98)  529 (99)  90 (97)  0.17   Transapical  10 (2)  7 (1)  3 (3)    Valve type   Ballon-expandable (SAPIEN 3/SAPIEN XT)  538 (86)  461 (86)  77 (83)  0.42   Self-expandable (CoreValve/Evolut R)  91 (14)  75 (14)  16 (17)    Prosthesis size   Small (23 mm)  180 (29)  153 (28)  27 (29)  0.62   Medium (25–27 mm)  296 (47)  249 (47)  47 (51)   Large (29–31 mm)  153 (24)  134 (25)  19 (20)  Post-dilatation  101 (16)  83 (16)  18 (19)  0.35  PVL at the time of CTA   None/trace  461 (73)  389 (72)  72 (77)  0.37   Mild  160 (25)  139 (26)  21 (23)   Moderate  8 (1)  8 (2)  0 (0)  MPG after implantation (mmHg)  11.4 ± 5.0  11.3 ± 5.0  12.3 ± 5.2  0.14    All patients (n = 629)  Without LT (n = 536)  With LT (n = 93)  P-Value  Age (years)  82.0 ± 5.6  81.9 ± 5.5  82.4 ± 6.0  0.51  Female  333 (53)  277 (52)  56 (60)  0.13  BMI (kg/m2)  27.1 ± 5.0  27.1 ± 5.2  27.0 ± 3.7  0.47  Logistic EuroSCORE (%)  14.4 ± 10.9  14.6 ± 11.2  13.7 ± 9.5  0.85  History of stroke  98 (16)  85 (16)  13 (14)  0.65  Diabetes  173 (28)  150 (28)  23 (25)  0.52  Hypertonus  575 (91)  486 (91)  59 (96)  0.11  Creatinine clearance (ml/min)  53.8 ± 20.2  53.8 ± 20.9  54.0 ± 20.2  0.61  Previous heart surgery  74 (11.8)  63 (12)  11 (12)  0.98  Atrial fibrillation  247 (39)  222 (41)  25 (27)  0.01  CHA2DS2-VASc score  5.7 ± 1.2  5.6 ± 1.2  5.8 ± 1.2  0.65  AC at CT (>24 h)   Any oral AC  204 (32)  183 (34)  21 (23)  0.03   Vitamin K antagonist  124 (20)  112 (21)  12 (13)  0.07   Novel oral AC  80 (13)  71 (13)  9 (10)  0.34  Coronary artery disease  397 (63)  336 (63)  61 (66)  0.59  History of myocardial infarction  103 (16)  92 (17)  11 (12)  0.20  History of smoking  115 (18)  97 (18)  18 (19)  0.77  LVEF (%)  49.5 ± 9.5  49.6 ± 9.9  49.3 ± 9.5  0.47  Annulus size (CTA) (mm)  24.1 ± 2.3  24.2 ± 2.3  23.9 ± 1.9  0.26  Mitral insufficiency   0  50 (8)  37 (7)  13 (14.0)  0.19   1  429 (68)  370 (69)  59 (63.4)   2  130 (21)  111 (208)  19 (20.4)   3  20 (3)  18 (3)  2 (2.2)  Access route   Transfemoral  619 (98)  529 (99)  90 (97)  0.17   Transapical  10 (2)  7 (1)  3 (3)    Valve type   Ballon-expandable (SAPIEN 3/SAPIEN XT)  538 (86)  461 (86)  77 (83)  0.42   Self-expandable (CoreValve/Evolut R)  91 (14)  75 (14)  16 (17)    Prosthesis size   Small (23 mm)  180 (29)  153 (28)  27 (29)  0.62   Medium (25–27 mm)  296 (47)  249 (47)  47 (51)   Large (29–31 mm)  153 (24)  134 (25)  19 (20)  Post-dilatation  101 (16)  83 (16)  18 (19)  0.35  PVL at the time of CTA   None/trace  461 (73)  389 (72)  72 (77)  0.37   Mild  160 (25)  139 (26)  21 (23)   Moderate  8 (1)  8 (2)  0 (0)  MPG after implantation (mmHg)  11.4 ± 5.0  11.3 ± 5.0  12.3 ± 5.2  0.14  Values are expressed as mean ± SD, median (interquartile range) or n (%). AC: anticoagulation; BMI: body mass index; CTA: computed tomography angiography; LVEF: left ventricular ejection fraction; LT: leaflet thrombosis; MPG: mean pressure gradient; PVL: paravalvular leakage; SD: standard deviation. Figure 1: View largeDownload slide Study design and enrolment. CTA denotes electrocardiography-gated cardiac dual-source computed tomography and TAVI. CTA: computed tomography angiography; TAVI: transcatheter aortic valve implantation. Figure 1: View largeDownload slide Study design and enrolment. CTA denotes electrocardiography-gated cardiac dual-source computed tomography and TAVI. CTA: computed tomography angiography; TAVI: transcatheter aortic valve implantation. In 93 (15%) of the 629 patients, LT was diagnosed based on CTA imaging. Eight patients of the overall cohort experienced stroke during in-hospital stay (all within the first 48 h after procedure), 1 patient in the LT group and 7 patients without LT (P = 0.66). None of the patients with LT showed clinical symptoms of aggravated heart failure during the in-hospital stay. Association of leaflet thrombosis with the type of transcatheter heart valve and clinical or procedural characteristics There was no significant difference in the incidence of LT between the 2 groups of THV types (P = 0.42). LT was found in 14% (77 of 538) of the balloon-expandable group and in 18% (16 of 91) of the self-expandable group (Fig. 2, Table 1). Similarly, we did not find a significant association with the THV sizes (P = 0.62). LT occurred in 15% (27 of 180), 16% (47 of 296) or 12% (19 of 153) of small-sized, medium-sized or large sized TVHs, respectively (Table 1). Figure 2: View largeDownload slide Electrocardiography-gated cardiac dual-source computed tomography angiography after transcatheter aortic valve implantation revealing leaflet thrombosis (arrows in A–D) in different valve types. Computed tomography angiography showing the axial and the sagittal oblique reconstructions of a 87-year-old man with an implanted SAPIEN 3 prosthesis (A, B) and of a 89-year-old woman with an implanted Evolut R prosthesis (C, D). Figure 2: View largeDownload slide Electrocardiography-gated cardiac dual-source computed tomography angiography after transcatheter aortic valve implantation revealing leaflet thrombosis (arrows in A–D) in different valve types. Computed tomography angiography showing the axial and the sagittal oblique reconstructions of a 87-year-old man with an implanted SAPIEN 3 prosthesis (A, B) and of a 89-year-old woman with an implanted Evolut R prosthesis (C, D). Corresponding to a lower rate of atrial fibrillation in the group with LT [25 (27%) vs 222 (41%), P = 0.01], anticoagulation at the time of CTA was less frequent in this group [21 (23%) vs 183 (34%), P = 0.03] (Table 1). Among other potentially relevant covariables, there were no significant differences in the clinical baseline and the procedural characteristics between patients with or without LT. Patients with LT were essentially of the same age (82.4 ± 6.0 vs 81.9 ± 5.5, P = 0.51) and had comparable perioperative risk (log. EuroSCORE 13.7 ± 9.5 vs 14.6 ± 11.2; P = 0.85), annulus size (23.9 ± 1.9 mm vs 24.2 ± 2.3 mm; P = 0.26) and left ventricular ejection fraction (49.3 ± 9.5% vs 49.6 ± 9.9%; P = 0.47). Post-procedurally, there was no difference in the prevalence and degree of PVL or predischarge echocardiographic mean pressure gradient between patients with or without LT [mild PVL 21 (22.6%) vs 139 (25.9%), P = 0.37; 12.3 ± 5.2 mmHg vs 11.3 ± 5.0 mmHg, P = 0.14, respectively; Table 1]. Predictors of leaflet thrombosis Neither in univariate nor in multivariate analyses did we find a significant association of LT with the valve type. The same was true for strata of the valve sizes. Anticoagulation at the time of CTA was protective of LT in the univariate [odds ratio 0.563 (0.335–0.944), P = 0.03] and in the multivariate [odds ratio 0.576 (0.343–0.970), P = 0.04] analyses (Table 2). The area under the curve of our multivariate regression model confirmed poor but statistically significant prediction of LT. Comparing the area under the curves of each single variable, only anticoagulation was a significant predictor (Table 2, Supplementary Material, Table S1). Table 2: Results from univariable and multivariable logistic regression analyses for LT   Univariate   Multivariatea     P-value  Odds ratio (95% CI)  P-value  Odds ratio (95% CI)  Valve type   Ballon-expandable (SAPIEN 3/SAPIEN XT)  Reference  Reference  Reference  Reference   Self-expandable (CoreValve/Evolut R)  0.42  1.277 (0.707–2.307)  0.36  1.333 (0.720–2.469)  Prosthesis size   Small (23 mm)  0.62  Reference  0.57  Reference   Medium (25–27 mm)  0.80  1.070 (0.640–1.789)  0.76  1.082 (0.645–1.817)   Large (29–31 mm)  0.50  0.803 (0.427–1.510)  0.48  0.788 (0.409–1.518)  Anticoagulation at CTA  0.03  0.563 (0.335–0.944)  0.04  0.576 (0.343–0.970)    Univariate   Multivariatea     P-value  Odds ratio (95% CI)  P-value  Odds ratio (95% CI)  Valve type   Ballon-expandable (SAPIEN 3/SAPIEN XT)  Reference  Reference  Reference  Reference   Self-expandable (CoreValve/Evolut R)  0.42  1.277 (0.707–2.307)  0.36  1.333 (0.720–2.469)  Prosthesis size   Small (23 mm)  0.62  Reference  0.57  Reference   Medium (25–27 mm)  0.80  1.070 (0.640–1.789)  0.76  1.082 (0.645–1.817)   Large (29–31 mm)  0.50  0.803 (0.427–1.510)  0.48  0.788 (0.409–1.518)  Anticoagulation at CTA  0.03  0.563 (0.335–0.944)  0.04  0.576 (0.343–0.970)  a C-statistics estimating the AUC of the multivariate logistic regression model: 0.573 [CI (0.534–0.612), P = 0.02, for comparison with the AUC of 0.5]. P = 0.91 in the Hosmer–Lemeshow test. The AUC of anticoagulation alone was 0.558 [CI (0.518–0.597), P = 0.02, for comparison with the AUC of 0.5]. AUC: area under the curve; CI: confidence interval; CTA: computed tomography angiography; LT: leaflet thrombosis. DISCUSSION In this large series of 629 patients undergoing post-TAVI CTA, early LT was found in 15% of the patients. It was not significantly associated with the type or the size of TVH. Among other clinical and procedural characteristics, we identified the lack of anticoagulation at the time of CTA as an independent predictor for the development of LT. LT has recently been identified both shortly after implantation and 1–3 months after the procedure and may be present in up to 40% of patients undergoing TAVI [2–5]. Diagnosis relies on CTA because standard transthoracic echocardiography is limited by stent-related shadowing. Identification of the risk factors for the development of LT is of clinical relevance for the guidance of post-TAVI surveillance and management including a more selective use of post-TAVI CTA [6]. A number of trials have been conducted to identify the specific clinical or procedural risk factors for the development of LT [2–5, 11]. In line with our study, Hansson et al. [4] reported the lack of anticoagulation therapy as an independent predictor for LT. Chakravarty et al. [5] also described the lack of anticoagulation as independent predictors (besides increased age and low ejection fraction). A previous study of our group failed to reveal a significant association of anticoagulation with the development of LT [2]. This inconsistency might be explained by a large difference in the size of both cohorts (156 vs 629 patients). Current guidelines recommend dual antiplatelet therapy after TAVI even in the case of a diagnosis of LT based on a number of studies that failed to show an increased rate of adverse events in these patients [2, 3, 5, 12–14]. However, anticoagulation should be considered in patients with an increase in transvalvular gradients or clinical symptoms as discussed in previous studies [2–5, 8]. Chakravarty et al. [5] reported that antiplatelet therapy, be it dual (aspirin and P2Y12 inhibitor) or single (aspirin or P2Y12 inhibitor), had no impact on the occurrence of LT. Both in the study of Chakravarty et al. [4, 5] and in our study cohort, the size of THV was not predictive of LT, whereas Hansson et al. [4, 5] found a larger valve size to be an independent predictor of LT. Indeed, we found numerically fewer LTs in larger THV. Reported incidences of LT after bioprosthetic aortic valve implantation vary considerably between studies ranging from 4% to 40% [2–5, 13, 15]. Apart from the design issues with THVs addressed in this study, it is still unclear whether there are differences in the risk of LT between the surgically implanted valves and the THVs. Chakravarty et al. [5, 13] revealed a significant difference with more LTs after TAVI, while Sondergaard et al. [5, 13] found similar rates in both groups. A systematic prospective analysis with post-interventional and post-surgical CTA is currently missing. Limitations Although our study is based on one of the largest cohorts undergoing systematic CTA after TAVI, the number of patients with LT was low. Furthermore, we had to exclude various valve types implanted at low frequency to enable a meaningful statistical analysis. Post-TAVI CTAs were performed in only 55% of the patients for a number of reasons including chronic kidney disease. This might have caused a selection bias due to the inclusion of healthier patients with lower mean Society of thoracic Surgeons (STS) score and EuroSCORE in the study. A higher rate of post-TAVI CTA might have allowed for the identification of potential predictors of LT. CONCLUSIONS The findings of our study show that LT is not related to specific THV types or sizes. Similarly, our study suggests that there is no other procedural issue or specific patient subset that is associated with a relevant increase in the risk of LT. Thus, the underlying mechanism for LT remains obscure and appears to be related to factors that normally are not assessed in patients undergoing TAVI. In this respect, it is important to note that we did not assay platelet function and other parameters of haemostasis systematically. Thus, we cannot exclude an impact of concomitant antithrombotic treatment. This needs to be addressed in further prospective studies. As shown in our and previous studies, oral anticoagulation reduces the risk for thrombus formation. Thus, further studies are needed to evaluate the clinical benefit of systematic anticoagulation after TAVI. SUPPLEMENTARY MATERIAL Supplementary material is available at EJCTS online. Conflict of interest: Philipp Blanke provides core laboratory services for Edwards Lifesciences, Medtronic, Neovasc, Tedyne and Aegis, for which he does not receive direct financial compensation, and is a consultant to Edwards Lifesciences, Neovasc, Tendyne and Circle Cardiovascular Imaging. Gregor Pache is a consultant to Edwards Lifesciences Inc. REFERENCES 1 Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JPIII, Guyton RA et al.   2014 AHA/ACC Guideline for the management of patients with valvular heart disease. J Thorac Cardiovasc Surg  2014; 148: e1– 132. Google Scholar CrossRef Search ADS PubMed  2 Pache G, Schoechlin S, Blanke P, Dorfs S, Jander N, Arepalli CD et al.   Early hypo-attenuated leaflet thickening in balloon-expandable transcatheter aortic heart valves. Eur Heart J  2016; 37: 2263– 71. 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Usefulness of phenprocoumon for the treatment of obstructing thrombus in bioprostheses in the aortic valve position. Am J Cardiol  2012; 109: 257– 62. Google Scholar CrossRef Search ADS PubMed  7 Blanke P, Schoepf UJ, Leipsic JA. CT in transcatheter aortic valve replacement. Radiology  2013; 269: 650– 69. Google Scholar CrossRef Search ADS PubMed  8 Ruile P, Jander N, Blanke P, Schoechlin S, Reinöhl J, Gick M et al.   Course of early subclinical leaflet thrombosis after transcatheter aortic valve implantation with or without oral anticoagulation. Clin Res Cardiol  2017; 106: 85– 96. Google Scholar CrossRef Search ADS PubMed  9 Zoghbi WA, Chambers JB, Dumesnil JG, Foster E, Gottdiener JS, Grayburn PA et al.   Recommendations for evaluation of prosthetic valves with echocardiography and Doppler ultrasound. J Am Soc Echocardiogr  2009; 22: 975– 1014. Google Scholar CrossRef Search ADS PubMed  10 Kappetein AP, Head SJ, Généreux P, Piazza N, van Mieghem NM, Blackstone EH et al.   Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. Eur Heart J  2012; 33: 2403– 18. Google Scholar CrossRef Search ADS PubMed  11 Leetmaa T, Hansson NC, Leipsic J, Jensen K, Poulsen SH, Andersen HR et al.   Early aortic transcatheter heart valve thrombosis: diagnostic value of contrast-enhanced multidetector computed tomography. Circ Cardiovasc Interv  2015; 8: e001596. Google Scholar CrossRef Search ADS PubMed  12 Hansson NC, Grove EL, Andersen HR, Leipsic J, Mathiassen ON, Jensen JM et al.   Transcatheter aortic valve thrombosis: incidence, predisposing factors, and clinical implications. J Am Coll Cardiol  2016; 68: 2059– 69. Google Scholar CrossRef Search ADS PubMed  13 Sondergaard L, De Backer O, Kofoed KF, Jilaihawi H, Fuchs A, Chakravarty T et al.   Natural history of subclinical leaflet thrombosis affecting motion in bioprosthetic aortic valves. Eur Heart J  2017; 38: 2201– 7. Google Scholar CrossRef Search ADS PubMed  14 Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ et al.   2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J  2017; 38: 2739– 86. Google Scholar CrossRef Search ADS PubMed  15 Vollema EM, Kong WKF, Katsanos S, Kamperidis V, van Rosendael PJ, van der Kley F et al.   Transcatheter aortic valve thrombosis: the relation between hypo-attenuated leaflet thickening, abnormal valve haemodynamics, and stroke. Eur Heart J  2017; 38: 1207– 17. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. 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Abstract

Abstract OBJECTIVES The aim of this study was to investigate whether balloon-expandable and self-expandable transcatheter heart valves (THVs) differ in terms of the incidence of early subclinical leaflet thrombosis (LT). METHODS Electrocardiographic-gated cardiac dual-source computed tomography angiography was performed at a median of 5 days after transcatheter aortic valve implantation and assessed for evidence of LT. RESULTS Of the 629 consecutive patients, 538 (86%) received a balloon-expandable THV and 91 (14%) a self-expandable THV. LT was documented in 77 (14%) patients with a balloon-expandable valve and in 16 (18%) with a self-expandable valve (P = 0.42). Similarly, LT was not significantly related to THV size (P = 0.62). Corresponding to a lower rate of atrial fibrillation in the group with LT [25 (27%) vs 222 (41%), P = 0.01], anticoagulation at the time of computed tomography angiography was less frequent in this group [21 (23%) vs 183 (34%), P = 0.03]. Among the other potentially relevant covariables, there was no significant difference in the clinical baseline and the procedural characteristics between patients with and without LT (age 82 ± 6 years vs 82 ± 6 years, P = 0.51; ejection fraction 49 ± 10% vs 50 ± 10%, P = 0.47). In multivariate logistic regression analysis, including potentially relevant covariables, valve type was not significantly associated with LT (P = 0.36). In the univariate and multivariate analyses, only the lack of anticoagulation at the time of computed tomography angiography was predictive of thrombus formation [0.563 (0.335–0.944), P = 0.03; 0.576 (0.343–0.970), P = 0.04]. CONCLUSIONS In this large retrospective study of 629 patients, the type and the size of THV was not predictive of early LT. Transcatheter aortic valve implantation, Transcatheter heart valve, Thrombosis, Computed tomography angiography INTRODUCTION Transcatheter aortic valve implantation (TAVI) is a well-established treatment option for severe aortic stenosis in patients with increased perioperative risk [1]. Recently, we [2] and others [3, 4] reported the findings of an early post-procedural electrocardiographic-gated cardiac dual-source computed tomography angiography (CTA) to be highly suspicious of leaflet thrombosis (LT). Early subclinical LT was diagnosed in up to 13% of patients and is considered a new entity post-TAVI [2–5]. CTA has emerged as the preferred diagnostic procedure, because echocardiography provides insufficient resolution due to prosthesis-related shadowing [6]. Various types of transcatheter heart valves (THVs) have been developed and are currently in clinical use. It is unclear whether the risk of LT differs between the use of balloon-expandable and self-expandable THV types or in specific patient subsets. Such information may be clinically important to guide the choice of THV as well as pre- and post-TAVI patient management. Therefore, we sought to evaluate the potential risk factors for LT associated with the different types of THVs in a large cohort of unselected, consecutive patients who underwent TAVI with a variety of commercially available THVs. PATIENTS AND METHODS This retrospective study was approved by the institutional review board and complies with the Declaration of Helsinki. Routine predischarge CTAs are scheduled in our institution to all patients without contraindications who undergo TAVI to exclude stent-related complications including stent malpositioning, contained ruptures and others. Patients who had undergone TAVI between May 2012 and December 2016 were candidates for inclusion into this study. For the current comparison between balloon-expandable and self-expandable valves, we excluded mechanically-expandable LOTUS valve and valve types implanted at low numbers (<10). Clinical, echocardiographic and CTA data were recorded prospectively in our institutional database. Transcatheter heart valve implantation procedure A multidisciplinary, institutional heart team assessed patient eligibility for TAVI, feasibility of the procedure and decided on the preferred access route, valve type and size. The preinterventional CTA-planimetric area measurements were performed as described previously [7]. The implantation procedure was performed under general anaesthesia using a combination of fluoroscopy and transoesophageal echocardiography for guidance. Periprocedural and post-procedural antithrombotic regimen For peri-interventional antithrombotic treatment, prior to the procedure, all patients were loaded with either 400 mg effervescent of aspirin (until May 2014) or a combination of 400 mg effervescent acetylsalicylic acid and 600 mg clopidogrel (from May 2014 onwards). All patients received peri-interventional heparin, in general 5000 IU, with adjustments for high and low body weights. As of Day 1 postimplantation, antithrombotic regimen consisted of acetylsalicylic acid monotherapy (100 mg daily, until May 2014). Subsequently, dual-antiplatelet therapy with acetylsalicylic acid (100 mg daily) and clopidogrel (75 mg daily) was given. In patients on oral anticoagulation, treatment was paused prior to the procedure for 24 h for novel oral anticoagulants or until an international normalized ratio <2 was reached in patients on vitamin K antagonists. No bridging with heparin was performed prior to intervention. On Day 1 following procedure, anticoagulation was readministered combined with single-antiplatelet therapy (clopidogrel 75 mg). Patients were considered on anticoagulation at the time of CTA if international normalized ratio was >1.8 (in case of vitamin K antagonist treatment) or if novel oral anticoagulant therapy was readministered at least 24 h before CTA. In case of heparin-bridging therapy combined with the start of a vitamin K antagonist postimplantation, patients were considered to be on anticoagulation if the prothrombin time was greater than 60 s. As described previously, patients diagnosed with LT received empirical anticoagulation therapy for at least 3 months until May 2015 and thereafter were switched back to usual care [8]. Postinterventional echocardiographic assessment Within 24 h after implantation, the first transthoracic echocardiography was performed with a final transthoracic echocardiography evaluation prior to discharge. All echocardiographic assessments were performed by experienced cardiologists using a Philips IE33 system (Philips, Leiden, Netherlands). Prosthesis function and grading of paravalvular leakage (PVL) were assessed based on the recommendations of the Valve Academic Research Consortium (VARC; deliberately extending the grading scale by one class: 0 = none, 1 = trace, 2 = mild, 3= moderate and 4 = severe PVL) [9]. According to the VARC-2 criteria [10], a mean pressure gradient of >20 mmHg was defined as the presence of haemodymamic valve deterioration, and a mild valve stenosis was determined by a mean pressure gradient between 20 mmHg and 40 mmHg or a peak velocity of 3–4 m/s. Computed tomography angiography data acquisition and image analysis Patients underwent routine CTA prior to discharge. Reasons for not performing this have been published in detail previously [2]. CTA examinations were performed with a second-generation dual-source CT scanner (Somatom Definition Flash, Siemens Healthcare, Forchheim, Germany) with a temporal resolution of 75 ms. The protocol for the CTA included the injection of a total of 40 ml iodinated contrast agent (Imeron400®, Bracco, Konstanz, Germany) at 4 ml/s, followed by a saline bolus chaser of 40 ml at 4 ml/s. Seven seconds after the attenuation of a region of interest placed in the left atrium reached 70 HU (bolus-tracking technique), data acquisition was initiated. To deliberately cover the entire cardiac cycle, a cardiac-CTA electrocardiographic-gated dose modulation was omitted, and the tube voltage and tube current time product were adapted for each patient using FASTCARE© (Siemens Healthcare). All CTA data were reconstructed at either 5% or 50 ms steps throughout the cardiac cycle with a section thickness of 1 mm and an increment of 0.8 mm using a stent-specific convolution kernel (B46f). Image analyses were performed with a dedicated post-processing workstation (Syngo Multimodality Workplace, Siemens Healthcare) using multiplanar reformations. Prosthesis leaflets were dynamically assessed for LT criteria throughout the cardiac cycle by 2 radiologists/cardiologists in consensus. Diagnostic criteria for LT were previously described [2]. In brief, we defined LT as a hypo-attenuated thickening with or without reduced leaflet mobility of one or more leaflet segments, detectable in at least 2 different projections and 2 different time reconstruction intervals. Statistical analysis All statistical analyses were performed using the SPSS software (SPSS version 23.0, SPSS, Chicago, IL, USA). Continuous variables were reported as mean and standard deviation. The Kolmorogov–Smirnoff test was used to test the variables for normal distribution. Non-normal distributed continuous variables were tested with the Mann–Whitney U-test and normal distributed continuous variables were tested by the Student’s t-test. Categorical data were reported as frequencies and percentages. Differences between the groups for categorical variables were tested with the χ2 test or the Fisher’s exact test where appropriate. We primarily assessed the association of 2 groups of TVH types with the incidence of LT and secondarily that of the strata of valve size. For this purpose, we calculated the univariate and multivariate logistic regression models. As independent covariables, the multivariate models comprised variables with a difference between patients with and without LT at a P-value <0.1 in the univariate analyses. Because anticoagulation and atrial fibrillations were closely associated, we only included anticoagulation in these models. The results were presented as odds ratio with 95% confidence interval. The P-values of <0.05 were considered statistically significant. The performance of the logisitic regression model was evaluated with respect to discrimination and calibration. Regarding discrimination, we used the C-statistics estimating the area under the curve derived from receiver operator characteristic curve analysis. The Hosmer–Lemeshow test was applied to evaluate the calibration of models. For this purpose, we used the classification into 9 groups of the distribution of the model-based predicted LT probabilities. RESULTS Study cohort A total of 1210 patients received a THV between May 2012 and December 2016 at our institution. Of these patients, 660 (55%) underwent routine CTA at a median period of 5 (interquartile range 5.6) days post-procedure (Fig. 1). We grouped 390 (60%) SAPIEN 3 THVs plus 148 (22%) SAPIEN XT THVs (both Edwards Lifesciences, Irvine, CA, USA) to the balloon-expandable cohort and 56 (9%) Evolut R THVs plus 35 (5%) CoreValve THVs (both Medtronic, Minneapolis, MN, USA) to the self-expandable cohort. Twenty-one (3%) Lotus THVs (Boston Scientific, Natick, MA, USA), 6 (<1%) Portico THVs (St. Jude Medical, Minneapolis, MN, USA) and 4 (<1%) Symetis THVs (Symetis SA, Ecublens, Switzerland) were not included in this analysis. Valve sizes were categorized according to the valve diameter as small (≤ 23 mm), medium (25–27 mm) and large (29–31 mm). Baseline and procedural characteristics are presented in Table 1. Table 1: Baseline and procedural characteristics of the entire study population and of patients without and with leaflet thrombosis   All patients (n = 629)  Without LT (n = 536)  With LT (n = 93)  P-Value  Age (years)  82.0 ± 5.6  81.9 ± 5.5  82.4 ± 6.0  0.51  Female  333 (53)  277 (52)  56 (60)  0.13  BMI (kg/m2)  27.1 ± 5.0  27.1 ± 5.2  27.0 ± 3.7  0.47  Logistic EuroSCORE (%)  14.4 ± 10.9  14.6 ± 11.2  13.7 ± 9.5  0.85  History of stroke  98 (16)  85 (16)  13 (14)  0.65  Diabetes  173 (28)  150 (28)  23 (25)  0.52  Hypertonus  575 (91)  486 (91)  59 (96)  0.11  Creatinine clearance (ml/min)  53.8 ± 20.2  53.8 ± 20.9  54.0 ± 20.2  0.61  Previous heart surgery  74 (11.8)  63 (12)  11 (12)  0.98  Atrial fibrillation  247 (39)  222 (41)  25 (27)  0.01  CHA2DS2-VASc score  5.7 ± 1.2  5.6 ± 1.2  5.8 ± 1.2  0.65  AC at CT (>24 h)   Any oral AC  204 (32)  183 (34)  21 (23)  0.03   Vitamin K antagonist  124 (20)  112 (21)  12 (13)  0.07   Novel oral AC  80 (13)  71 (13)  9 (10)  0.34  Coronary artery disease  397 (63)  336 (63)  61 (66)  0.59  History of myocardial infarction  103 (16)  92 (17)  11 (12)  0.20  History of smoking  115 (18)  97 (18)  18 (19)  0.77  LVEF (%)  49.5 ± 9.5  49.6 ± 9.9  49.3 ± 9.5  0.47  Annulus size (CTA) (mm)  24.1 ± 2.3  24.2 ± 2.3  23.9 ± 1.9  0.26  Mitral insufficiency   0  50 (8)  37 (7)  13 (14.0)  0.19   1  429 (68)  370 (69)  59 (63.4)   2  130 (21)  111 (208)  19 (20.4)   3  20 (3)  18 (3)  2 (2.2)  Access route   Transfemoral  619 (98)  529 (99)  90 (97)  0.17   Transapical  10 (2)  7 (1)  3 (3)    Valve type   Ballon-expandable (SAPIEN 3/SAPIEN XT)  538 (86)  461 (86)  77 (83)  0.42   Self-expandable (CoreValve/Evolut R)  91 (14)  75 (14)  16 (17)    Prosthesis size   Small (23 mm)  180 (29)  153 (28)  27 (29)  0.62   Medium (25–27 mm)  296 (47)  249 (47)  47 (51)   Large (29–31 mm)  153 (24)  134 (25)  19 (20)  Post-dilatation  101 (16)  83 (16)  18 (19)  0.35  PVL at the time of CTA   None/trace  461 (73)  389 (72)  72 (77)  0.37   Mild  160 (25)  139 (26)  21 (23)   Moderate  8 (1)  8 (2)  0 (0)  MPG after implantation (mmHg)  11.4 ± 5.0  11.3 ± 5.0  12.3 ± 5.2  0.14    All patients (n = 629)  Without LT (n = 536)  With LT (n = 93)  P-Value  Age (years)  82.0 ± 5.6  81.9 ± 5.5  82.4 ± 6.0  0.51  Female  333 (53)  277 (52)  56 (60)  0.13  BMI (kg/m2)  27.1 ± 5.0  27.1 ± 5.2  27.0 ± 3.7  0.47  Logistic EuroSCORE (%)  14.4 ± 10.9  14.6 ± 11.2  13.7 ± 9.5  0.85  History of stroke  98 (16)  85 (16)  13 (14)  0.65  Diabetes  173 (28)  150 (28)  23 (25)  0.52  Hypertonus  575 (91)  486 (91)  59 (96)  0.11  Creatinine clearance (ml/min)  53.8 ± 20.2  53.8 ± 20.9  54.0 ± 20.2  0.61  Previous heart surgery  74 (11.8)  63 (12)  11 (12)  0.98  Atrial fibrillation  247 (39)  222 (41)  25 (27)  0.01  CHA2DS2-VASc score  5.7 ± 1.2  5.6 ± 1.2  5.8 ± 1.2  0.65  AC at CT (>24 h)   Any oral AC  204 (32)  183 (34)  21 (23)  0.03   Vitamin K antagonist  124 (20)  112 (21)  12 (13)  0.07   Novel oral AC  80 (13)  71 (13)  9 (10)  0.34  Coronary artery disease  397 (63)  336 (63)  61 (66)  0.59  History of myocardial infarction  103 (16)  92 (17)  11 (12)  0.20  History of smoking  115 (18)  97 (18)  18 (19)  0.77  LVEF (%)  49.5 ± 9.5  49.6 ± 9.9  49.3 ± 9.5  0.47  Annulus size (CTA) (mm)  24.1 ± 2.3  24.2 ± 2.3  23.9 ± 1.9  0.26  Mitral insufficiency   0  50 (8)  37 (7)  13 (14.0)  0.19   1  429 (68)  370 (69)  59 (63.4)   2  130 (21)  111 (208)  19 (20.4)   3  20 (3)  18 (3)  2 (2.2)  Access route   Transfemoral  619 (98)  529 (99)  90 (97)  0.17   Transapical  10 (2)  7 (1)  3 (3)    Valve type   Ballon-expandable (SAPIEN 3/SAPIEN XT)  538 (86)  461 (86)  77 (83)  0.42   Self-expandable (CoreValve/Evolut R)  91 (14)  75 (14)  16 (17)    Prosthesis size   Small (23 mm)  180 (29)  153 (28)  27 (29)  0.62   Medium (25–27 mm)  296 (47)  249 (47)  47 (51)   Large (29–31 mm)  153 (24)  134 (25)  19 (20)  Post-dilatation  101 (16)  83 (16)  18 (19)  0.35  PVL at the time of CTA   None/trace  461 (73)  389 (72)  72 (77)  0.37   Mild  160 (25)  139 (26)  21 (23)   Moderate  8 (1)  8 (2)  0 (0)  MPG after implantation (mmHg)  11.4 ± 5.0  11.3 ± 5.0  12.3 ± 5.2  0.14  Values are expressed as mean ± SD, median (interquartile range) or n (%). AC: anticoagulation; BMI: body mass index; CTA: computed tomography angiography; LVEF: left ventricular ejection fraction; LT: leaflet thrombosis; MPG: mean pressure gradient; PVL: paravalvular leakage; SD: standard deviation. Figure 1: View largeDownload slide Study design and enrolment. CTA denotes electrocardiography-gated cardiac dual-source computed tomography and TAVI. CTA: computed tomography angiography; TAVI: transcatheter aortic valve implantation. Figure 1: View largeDownload slide Study design and enrolment. CTA denotes electrocardiography-gated cardiac dual-source computed tomography and TAVI. CTA: computed tomography angiography; TAVI: transcatheter aortic valve implantation. In 93 (15%) of the 629 patients, LT was diagnosed based on CTA imaging. Eight patients of the overall cohort experienced stroke during in-hospital stay (all within the first 48 h after procedure), 1 patient in the LT group and 7 patients without LT (P = 0.66). None of the patients with LT showed clinical symptoms of aggravated heart failure during the in-hospital stay. Association of leaflet thrombosis with the type of transcatheter heart valve and clinical or procedural characteristics There was no significant difference in the incidence of LT between the 2 groups of THV types (P = 0.42). LT was found in 14% (77 of 538) of the balloon-expandable group and in 18% (16 of 91) of the self-expandable group (Fig. 2, Table 1). Similarly, we did not find a significant association with the THV sizes (P = 0.62). LT occurred in 15% (27 of 180), 16% (47 of 296) or 12% (19 of 153) of small-sized, medium-sized or large sized TVHs, respectively (Table 1). Figure 2: View largeDownload slide Electrocardiography-gated cardiac dual-source computed tomography angiography after transcatheter aortic valve implantation revealing leaflet thrombosis (arrows in A–D) in different valve types. Computed tomography angiography showing the axial and the sagittal oblique reconstructions of a 87-year-old man with an implanted SAPIEN 3 prosthesis (A, B) and of a 89-year-old woman with an implanted Evolut R prosthesis (C, D). Figure 2: View largeDownload slide Electrocardiography-gated cardiac dual-source computed tomography angiography after transcatheter aortic valve implantation revealing leaflet thrombosis (arrows in A–D) in different valve types. Computed tomography angiography showing the axial and the sagittal oblique reconstructions of a 87-year-old man with an implanted SAPIEN 3 prosthesis (A, B) and of a 89-year-old woman with an implanted Evolut R prosthesis (C, D). Corresponding to a lower rate of atrial fibrillation in the group with LT [25 (27%) vs 222 (41%), P = 0.01], anticoagulation at the time of CTA was less frequent in this group [21 (23%) vs 183 (34%), P = 0.03] (Table 1). Among other potentially relevant covariables, there were no significant differences in the clinical baseline and the procedural characteristics between patients with or without LT. Patients with LT were essentially of the same age (82.4 ± 6.0 vs 81.9 ± 5.5, P = 0.51) and had comparable perioperative risk (log. EuroSCORE 13.7 ± 9.5 vs 14.6 ± 11.2; P = 0.85), annulus size (23.9 ± 1.9 mm vs 24.2 ± 2.3 mm; P = 0.26) and left ventricular ejection fraction (49.3 ± 9.5% vs 49.6 ± 9.9%; P = 0.47). Post-procedurally, there was no difference in the prevalence and degree of PVL or predischarge echocardiographic mean pressure gradient between patients with or without LT [mild PVL 21 (22.6%) vs 139 (25.9%), P = 0.37; 12.3 ± 5.2 mmHg vs 11.3 ± 5.0 mmHg, P = 0.14, respectively; Table 1]. Predictors of leaflet thrombosis Neither in univariate nor in multivariate analyses did we find a significant association of LT with the valve type. The same was true for strata of the valve sizes. Anticoagulation at the time of CTA was protective of LT in the univariate [odds ratio 0.563 (0.335–0.944), P = 0.03] and in the multivariate [odds ratio 0.576 (0.343–0.970), P = 0.04] analyses (Table 2). The area under the curve of our multivariate regression model confirmed poor but statistically significant prediction of LT. Comparing the area under the curves of each single variable, only anticoagulation was a significant predictor (Table 2, Supplementary Material, Table S1). Table 2: Results from univariable and multivariable logistic regression analyses for LT   Univariate   Multivariatea     P-value  Odds ratio (95% CI)  P-value  Odds ratio (95% CI)  Valve type   Ballon-expandable (SAPIEN 3/SAPIEN XT)  Reference  Reference  Reference  Reference   Self-expandable (CoreValve/Evolut R)  0.42  1.277 (0.707–2.307)  0.36  1.333 (0.720–2.469)  Prosthesis size   Small (23 mm)  0.62  Reference  0.57  Reference   Medium (25–27 mm)  0.80  1.070 (0.640–1.789)  0.76  1.082 (0.645–1.817)   Large (29–31 mm)  0.50  0.803 (0.427–1.510)  0.48  0.788 (0.409–1.518)  Anticoagulation at CTA  0.03  0.563 (0.335–0.944)  0.04  0.576 (0.343–0.970)    Univariate   Multivariatea     P-value  Odds ratio (95% CI)  P-value  Odds ratio (95% CI)  Valve type   Ballon-expandable (SAPIEN 3/SAPIEN XT)  Reference  Reference  Reference  Reference   Self-expandable (CoreValve/Evolut R)  0.42  1.277 (0.707–2.307)  0.36  1.333 (0.720–2.469)  Prosthesis size   Small (23 mm)  0.62  Reference  0.57  Reference   Medium (25–27 mm)  0.80  1.070 (0.640–1.789)  0.76  1.082 (0.645–1.817)   Large (29–31 mm)  0.50  0.803 (0.427–1.510)  0.48  0.788 (0.409–1.518)  Anticoagulation at CTA  0.03  0.563 (0.335–0.944)  0.04  0.576 (0.343–0.970)  a C-statistics estimating the AUC of the multivariate logistic regression model: 0.573 [CI (0.534–0.612), P = 0.02, for comparison with the AUC of 0.5]. P = 0.91 in the Hosmer–Lemeshow test. The AUC of anticoagulation alone was 0.558 [CI (0.518–0.597), P = 0.02, for comparison with the AUC of 0.5]. AUC: area under the curve; CI: confidence interval; CTA: computed tomography angiography; LT: leaflet thrombosis. DISCUSSION In this large series of 629 patients undergoing post-TAVI CTA, early LT was found in 15% of the patients. It was not significantly associated with the type or the size of TVH. Among other clinical and procedural characteristics, we identified the lack of anticoagulation at the time of CTA as an independent predictor for the development of LT. LT has recently been identified both shortly after implantation and 1–3 months after the procedure and may be present in up to 40% of patients undergoing TAVI [2–5]. Diagnosis relies on CTA because standard transthoracic echocardiography is limited by stent-related shadowing. Identification of the risk factors for the development of LT is of clinical relevance for the guidance of post-TAVI surveillance and management including a more selective use of post-TAVI CTA [6]. A number of trials have been conducted to identify the specific clinical or procedural risk factors for the development of LT [2–5, 11]. In line with our study, Hansson et al. [4] reported the lack of anticoagulation therapy as an independent predictor for LT. Chakravarty et al. [5] also described the lack of anticoagulation as independent predictors (besides increased age and low ejection fraction). A previous study of our group failed to reveal a significant association of anticoagulation with the development of LT [2]. This inconsistency might be explained by a large difference in the size of both cohorts (156 vs 629 patients). Current guidelines recommend dual antiplatelet therapy after TAVI even in the case of a diagnosis of LT based on a number of studies that failed to show an increased rate of adverse events in these patients [2, 3, 5, 12–14]. However, anticoagulation should be considered in patients with an increase in transvalvular gradients or clinical symptoms as discussed in previous studies [2–5, 8]. Chakravarty et al. [5] reported that antiplatelet therapy, be it dual (aspirin and P2Y12 inhibitor) or single (aspirin or P2Y12 inhibitor), had no impact on the occurrence of LT. Both in the study of Chakravarty et al. [4, 5] and in our study cohort, the size of THV was not predictive of LT, whereas Hansson et al. [4, 5] found a larger valve size to be an independent predictor of LT. Indeed, we found numerically fewer LTs in larger THV. Reported incidences of LT after bioprosthetic aortic valve implantation vary considerably between studies ranging from 4% to 40% [2–5, 13, 15]. Apart from the design issues with THVs addressed in this study, it is still unclear whether there are differences in the risk of LT between the surgically implanted valves and the THVs. Chakravarty et al. [5, 13] revealed a significant difference with more LTs after TAVI, while Sondergaard et al. [5, 13] found similar rates in both groups. A systematic prospective analysis with post-interventional and post-surgical CTA is currently missing. Limitations Although our study is based on one of the largest cohorts undergoing systematic CTA after TAVI, the number of patients with LT was low. Furthermore, we had to exclude various valve types implanted at low frequency to enable a meaningful statistical analysis. Post-TAVI CTAs were performed in only 55% of the patients for a number of reasons including chronic kidney disease. This might have caused a selection bias due to the inclusion of healthier patients with lower mean Society of thoracic Surgeons (STS) score and EuroSCORE in the study. A higher rate of post-TAVI CTA might have allowed for the identification of potential predictors of LT. CONCLUSIONS The findings of our study show that LT is not related to specific THV types or sizes. Similarly, our study suggests that there is no other procedural issue or specific patient subset that is associated with a relevant increase in the risk of LT. Thus, the underlying mechanism for LT remains obscure and appears to be related to factors that normally are not assessed in patients undergoing TAVI. In this respect, it is important to note that we did not assay platelet function and other parameters of haemostasis systematically. Thus, we cannot exclude an impact of concomitant antithrombotic treatment. This needs to be addressed in further prospective studies. As shown in our and previous studies, oral anticoagulation reduces the risk for thrombus formation. Thus, further studies are needed to evaluate the clinical benefit of systematic anticoagulation after TAVI. SUPPLEMENTARY MATERIAL Supplementary material is available at EJCTS online. Conflict of interest: Philipp Blanke provides core laboratory services for Edwards Lifesciences, Medtronic, Neovasc, Tedyne and Aegis, for which he does not receive direct financial compensation, and is a consultant to Edwards Lifesciences, Neovasc, Tendyne and Circle Cardiovascular Imaging. Gregor Pache is a consultant to Edwards Lifesciences Inc. REFERENCES 1 Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JPIII, Guyton RA et al.   2014 AHA/ACC Guideline for the management of patients with valvular heart disease. J Thorac Cardiovasc Surg  2014; 148: e1– 132. Google Scholar CrossRef Search ADS PubMed  2 Pache G, Schoechlin S, Blanke P, Dorfs S, Jander N, Arepalli CD et al.   Early hypo-attenuated leaflet thickening in balloon-expandable transcatheter aortic heart valves. Eur Heart J  2016; 37: 2263– 71. Google Scholar CrossRef Search ADS PubMed  3 Makkar RR, Fontana G, Jilaihawi H, Chakravarty T, Kofoed KF, de Backer O et al.   Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med  2015; 373: 2015– 24. Google Scholar CrossRef Search ADS PubMed  4 Hansson NC, Grove EL, Andersen HR, Leipsic J, Mathiassen ON, Jensen JM et al.   Transcatheter aortic heart valve thrombosis: incidence, predisposing factors, and clinical implications. J Am Coll Cardiol  2016; 68: 2059– 69. Google Scholar CrossRef Search ADS PubMed  5 Chakravarty T, Søndergaard L, Friedman J, De Backer O, Berman D, Kofoed KF et al.   Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet  2017; 389: 2383– 92. Google Scholar CrossRef Search ADS PubMed  6 Jander N, Kienzle R-P, Kayser G, Neumann F-J, Gohlke-Baerwolf C, Minners J. 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Google Scholar CrossRef Search ADS PubMed  10 Kappetein AP, Head SJ, Généreux P, Piazza N, van Mieghem NM, Blackstone EH et al.   Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. Eur Heart J  2012; 33: 2403– 18. Google Scholar CrossRef Search ADS PubMed  11 Leetmaa T, Hansson NC, Leipsic J, Jensen K, Poulsen SH, Andersen HR et al.   Early aortic transcatheter heart valve thrombosis: diagnostic value of contrast-enhanced multidetector computed tomography. Circ Cardiovasc Interv  2015; 8: e001596. Google Scholar CrossRef Search ADS PubMed  12 Hansson NC, Grove EL, Andersen HR, Leipsic J, Mathiassen ON, Jensen JM et al.   Transcatheter aortic valve thrombosis: incidence, predisposing factors, and clinical implications. J Am Coll Cardiol  2016; 68: 2059– 69. Google Scholar CrossRef Search ADS PubMed  13 Sondergaard L, De Backer O, Kofoed KF, Jilaihawi H, Fuchs A, Chakravarty T et al.   Natural history of subclinical leaflet thrombosis affecting motion in bioprosthetic aortic valves. Eur Heart J  2017; 38: 2201– 7. Google Scholar CrossRef Search ADS PubMed  14 Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ et al.   2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J  2017; 38: 2739– 86. Google Scholar CrossRef Search ADS PubMed  15 Vollema EM, Kong WKF, Katsanos S, Kamperidis V, van Rosendael PJ, van der Kley F et al.   Transcatheter aortic valve thrombosis: the relation between hypo-attenuated leaflet thickening, abnormal valve haemodynamics, and stroke. Eur Heart J  2017; 38: 1207– 17. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

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European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Apr 1, 2018

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