- Email: [email protected]
Leaflet thrombosis following transcatheter aortic valve implantation
Accepted Manuscript Leaflet thrombosis following transcatheter aortic valve implantation M. Marwan, N. Mekkhala, M. Göller, J. Röther, D. Bittner, A. Schuhbaeck, M. Hell, G. Muschiol, J. Kolwelter, R. Feyrer, C. Schlundt, S. Achenbach, M. Arnold PII:
S1934-5925(17)30241-1
DOI:
10.1016/j.jcct.2017.11.002
Reference:
JCCT 1032
To appear in:
Journal of Cardiovascular Computed Tomograph
Received Date: 19 March 2017 Revised Date:
29 October 2017
Accepted Date: 7 November 2017
Please cite this article as: Marwan M, Mekkhala N, Göller M, Röther J, Bittner D, Schuhbaeck A, Hell M, Muschiol G, Kolwelter J, Feyrer R, Schlundt C, Achenbach S, Arnold M, Leaflet thrombosis following transcatheter aortic valve implantation, Journal of Cardiovascular Computed Tomograph (2017), doi: 10.1016/j.jcct.2017.11.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Leaflet Thrombosis Following Transcatheter Aortic Valve Implantation Marwan M1, Mekkhala N1, Göller M1, Röther J1, Bittner D1,2, Schuhbaeck A1, Hell M1, Muschiol G1, Kolwelter J, Feyrer R3, Schlundt C1, Achenbach S1 , Arnold M1
Department of Internal Medicine 2 (Cardiology), University of Erlangen, Germany
2
Division of Cardiovascular Imaging, Massachusetts General Hospital, Boston, USA
3
Department of Cardiosurgery, University of Erlangen, Germany
M AN U
SC
RI PT
1
Conflict of interest:
Stephan Achenbach has received research grants from Siemens Healthcare and Abbott
TE D
Vascular
Mohamed Marwan has received speaker honoraria from Siemens Healthcare and Edwards Lifesciences
AC C
EP
Martin Arnold is a consultant for St. Jude Medical and Edwards Lifesciences
*Corresponding author:
Mohamed Marwan, MD, Department of Internal Medicine 2 (Cardiology), University of Erlangen, Ulmenweg 18, D-91054 Erlangen, Germany. Phone: +49-9131-85-35000. E-mail: mohamed.marwan @uk-erlangen.de
1
ACCEPTED MANUSCRIPT Abstract Background:
RI PT
Transcatheter aortic valve implantation (TAVI) is increasingly being offered to high-risk patients with symptomatic aortic valve stenosis. Recent reports have suggested a high incidence of subclinical leaflet thrombosis following bioprosthestic aortic valve replacement. We report the frequency and clinical presentation of leaflet thrombosis identified by cardiac CT in patients referred for follow-up contrast enhanced CT angiography following TAVI. Methods:
M AN U
SC
91 consecutive patients referred for follow-up contrast-enhanced CT angiography following TAVI were screened for inclusion in this analysis. Out of these, 13 patients were excluded. All CT examinations were performed using a 2nd or a 3rd generation dual-source system (Somatom Definition Flash/Force, Forchheim, Germany). In all patients, retrospectively ECGgated spiral acquisition with tube modulation was performed to allow for assessment of leaflet motion. All prostheses were analyzed for presence of leaflet thrombosis defined as hypo-attenuated leaflet thickening with or without leaflet restriction. Post-procedural antithrombotic regimen as well as symptom status was documented in all patients. Results:
EP
TE D
78 consecutive patients (35 males, 81±4 years) were analyzed. TAVI had been performed in all patients (76 transfemoral access, 2 transapical access) with either balloon-expandable prostheses (4 Sapien XT, 64 Sapien 3) or self-expandable prostheses (5 SJM Portico, 5 Symetis Acurate). Follow-up CT angiography was performed at a median of 4 months following index procedure (Interquartile range 1 month). Leaflet thrombosis was detected in 18 patients (23%, 14 Sapien 3, 1 Sapien XT, 2 SJM Portico, 1 Symetis Acurate). In patients with leaflet thickening on CT, only 11% were on either oral anticoagulation or new oral anticoagulants versus 50% for patients with no leaflet thickening (p 0.002). In patients with leaflet thrombosis, 3 leaflets were affected in 5 patients, 2 leaflets in 5 patients and in 8 patient only 1 leaflet was affected. Clinical symptoms (angina, dyspnea or both) were reported in 2/18 patients with leaflet thrombosis (11%) and in both patients a significant increase of the mean echocardiographic gradient over the prosthesis was documented. The peak
AC C
and mean echocardiographic gradients obtained at the day of CT examination was significantly higher in symptomatic patients versus asymptomatic patients (peak 46±7 vs. 23±11 mmHg, mean 29± 7 vs. 12 ±6 mmHg, p=0.01 and 0.002, respectively). Follow-up CT was available for 4 patients with complete resolution of the hypo-attenuated leaflet thickening following treatment. Conclusion:
Leaflet thrombosis following TAVI is a relatively frequent finding in patients referred for contrast enhanced CT angiography following TAVI. In the majority of patients it follows a subclinical course and is substantially more frequent in individuals who are not on oral anticoagulation. However, in patients with relevant increase in prosthetic gradients, symptomatic presentations are possible.
2
ACCEPTED MANUSCRIPT Keywords
EP
TE D
M AN U
Dual source computed tomography Transcatheter aortic valve implantation Transcatheter aortic valve replacement Multiplanar reconstruction Valve Academic Research Consortium
AC C
DSCT TAVI TAVR MPR VARC
SC
Abbreviations
RI PT
Transcatheter aortic valve replacement / implantation (TAVR / TAVI) Computed Tomography Leaflet thrombosis
3
ACCEPTED MANUSCRIPT
Introduction Aortic valve stenosis is a common cause of morbidity and mortality in the aging population. In patients with symptomatic high grade aortic stenosis, prognosis is very poor when left 1, 2
Transcatheter aortic valve implantation (TAVI)/ transcatheter aortic valve
RI PT
untreated.
replacement (TAVR) has emerged as an accepted alternative for conventional surgery in patients with aortic valve stenosis deemed at high operative risk. 3, 4
Pre-procedural imaging is essential not only for correct sizing of the prosthesis, but also for
SC
adequate procedural planning regarding the access route (transfemoral vs. apical, aortic or subclavian access). For this purpose, contrast enhanced computed tomography (CT) imaging
M AN U
- owing to its high and isotropic spatial resolution as well as fast volume coverage – offers valuable information regarding aortic root dimensions as well as aortic and iliac artery anatomy and is recommended prior to TAVI/TAVR procedures. 4
Furthermore, post-interventional imaging using CT provides valuable information regarding prosthesis position, function as well as leaflet anatomy. Recently, reports from multi-center data have been published showing subclinical leaflet thrombosis following bioprosthestic 6
We report the incidence and clinical presentation of leaflet
TE D
aortic valve replacement.5,
thrombosis in patients referred for follow-up contrast enhanced CT angiography following
EP
TAVI.
AC C
Material and Methods
Study design and patient population This is a single-center, retrospective analysis. 91 consecutive patients referred for contrast enhanced CT imaging between October 2014 and June 2016 within a median of 4 months following transcatheter aortic valve implantation (TAVI)/ transcatheter aortic valve replacement (TAVR) were screened for inclusion in this study. Out of 91 patients, 78 patients were included in this analysis. CT exams were performed as a part of routine imaging following TAVI in 65 patients. In 13 patients, CT was performed either for further clarification of an increase in the echocardiographic gradient over the prosthesis or due to clinical
4
ACCEPTED MANUSCRIPT symptoms. All patients gave an informed written consent. Due to the retrospective nature of the study, approval was waived by IRB.
DSCT data acquisition and image reconstruction CT data sets were acquired with either a second or third generation dual-source CT system
RI PT
(Somatom Definition Flash/ Somatom Force, Siemens Healthcare, Forchheim, Germany) using a retrospectively ECG-triggered spiral acquisition mode, extending from the pulmonary artery bifurcation to the caudal end of the heart. Scan parameters were as follows: tube voltage 120 kV, tube current time product 350-450 mAs, 2x128x0.6/2x192x0.6 mm
SC
collimation, 330ms/250 ms rotation time, for 2nd and 3rd generation systems, respectively. ECG dose modulation was performed with full radiation exposure between 40-70% of the
M AN U
peak R-wave to R-wave and a dose reduction to 20% outside this window. CT angiography was performed using 10ml of contrast agent (Imeron 350, Bracco Imaging, Konstanz, Germany) for assessing the contrast agent transit time and 50 ml at a flow rate of 5ml/sec followed by a 50 ml saline chaser at the same flow rate for the following angiography. For each patient, a multiphase reconstruction every 10% of the cardiac cycle was rendered using a small field of view (FOV) data set to allow for 4 dimensional functional assessment of
TE D
the prosthesis. All reconstructions were rendered using a medium soft convolution kernel (Siemens B26 f, Siemens Bv40 for 2nd and 3rd generation system, respectively) with a slice thickness of 1.5 mm and slice increment of 1 mm. For image data acquired using third
EP
generation system, reconstructions were performed using a newly introduced iterative reconstruction algorithm (Admire®, Siemens, Forchheim, Germany) at a strength level of 2.
AC C
Moreover, for each patient, a diastolic reconstruction was rendered using thin slice thickness of 0.75/0.5 mm and an increment of 0.4/0.3 mm for 2nd versus 3rd generation system, respectively.
CT analysis of leaflet morphology and motion: Data sets were displayed on a dedicated workstation (MMWP, Siemens Healthcare, Forchheim, Germany). Window settings for interpretation of the image data were adjusted individually according to reader’s discretion. Multiphase reconstructions were used for primary analysis. Using multiplanar reconstruction (MPR), views similar to echocardiographic short-axis view and parasternal long-axis view 5
ACCEPTED MANUSCRIPT were simulated in CT to allow for assessment of leaflet motion. Moreover, a double-oblique coronal view of the aortic valve prosthesis was also rendered for further analysis. Assessment of leaflet thickening and restriction was performed visually by a cardiologist with 10 years of experience in cardiac CT. Furthermore, maximal leaflet thickening was assessed visually in the short-axis view with the measurements performed in a long axis view
RI PT
orthogonal to the leaflet to avoid overestimation. (figure 1) Possible leaflet thrombosis was defined as previously reported by Pache et al.5 as hypo-attenuated thickening with or without restriction of one or more leaflets identifiable in at least two different MPR projections and two different reconstruction time intervals.
SC
Using diastolic reconstructions, the location of the affected cusp was defined according to former native cusp position as right, left, or non-coronary cusp. The number of the affected
Post-procedural echocardiography:
M AN U
cusps as well as the maximum thickness of the affected cusps were assessed. (figure 2)
Examinations were performed by experienced cardiologists using either a Vivid 7 system (General Electric Medical Systems, Milwaukee, WI, USA) or a Philips IE33-system (Philips,
TE D
Leiden, the Netherlands). Transthoracic echocardiographic data were collected at the time of discharge. The mean pressure gradient was calculated according to the Bernoulli formula. For patients with CT diagnosed leaflet thickening, echocardiographic maximal and mean
Clinical status:
EP
gradients were obtained on the same day of the CT examination.
AC C
All patients included in the study were referred either from the institution’s outpatient clinic or inpatient ward. All patients underwent a structured interview to assess clinical status. Symptomatic patients were defined as patients with new-onset/worsening dyspnea or angina. Patients with stable symptoms existing since index intervention or with improved symptoms were deemed as asymptomatic.
Anticoagulation and antiplatelet regimen: Patients with no indication for oral anticoagulation received a standard dual antiplatelet therapy with acetyl salicylic acid and clopidogrel for 3-6 months, whereas patients on oral anticoagulation were kept on the pre-procedural medication (phenprocoumon or NOAC). 6
ACCEPTED MANUSCRIPT Statistical analyses Continuous data are presented as mean ± standard deviation. Categorical variables are shown in proportions. Mean values were compared using a two sided paired t-test. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 21.0.
RI PT
(Armonk, NY: IBM Corp IBM®). Categorical variables were compared using Fisher’s exact test.
Results
SC
Study population
Between October 2014 to June 2016, 279 consecutive TAVI/TAVR procedures were
M AN U
performed in our institution. Out of these, 15 procedures were Valve-in-Valve. 91 consecutive patients referred for contrast-enhanced CT imaging of the aortic valve prosthesis following TAVI/TAVR were screened for inclusion in this analysis. Out of these, 13 patients were excluded (2 patients valve-in -valve TAVI had been performed due severe bioprosthetic aortic regurgitation, in 9 patients valve-in-valve TAVI had been performed due
TE D
to severe bioprosthetic aortic stenosis, 1 patient was referred for suspicion of prosthesis endocarditis and 1 patient was examined for assessment of prosthesis/left main coronary artery anatomy). The remaining 78 patients were included in this analysis. Baseline clinical characteristics are displayed in table 1. The mean age was 81±4 years, mean ejection
EP
fraction was 53±10%, mean pre-procedural aortic valve area 0.7±0.2 cm2 and mean pre-
AC C
procedural aortic valve gradient was 40 ± 15 mmHg.
CT analysis of the prosthetic leaflets: CT was performed at a median of 4 months following the index procedure (interquartile range 1 month). Out of 78 patients, 18 (23%) showed leaflet thickening in CT. Mean age, ejection fraction, aortic valve area derived by the continuity equation, mean echocardiographic gradient at baseline as well as
time interval between TAVI to CT
examination was not significantly different between patients with and without leaflet thickening. Out of 18 patients with leaflet thickening on CT, only 2 patients were on oral anticoagulation at the time of CT (one patient on oral phenprocoumon, however not in therapeutic range [INR < 2.0], 1 patient on NOAC with mild diffuse leaflet thickening). 7
ACCEPTED MANUSCRIPT Patients without leaflet thickening were significantly more frequently on oral anticoagulation with either phenprocoumon or new oral anticoagulants compared to patients with leaflet thickening on follow-up (31% phenprocoumon, 19% NOAC vs. 5.5% phenprocoumon, 5.5% NOAC, respectively, p = 0.002). Out of the 18 patients with leaflet thickening on CT, only 2 patients (11%) were symptomatic (1 patient with angina pectoris
RI PT
and dyspnea, 1 patient with dyspnea). The peak and mean echocardiographic gradients obtained at the day of the CT examination were significantly higher in symptomatic patients as compared to asymptomatic patients (46±7 vs. 23±11 mmHg, 29± 7 vs. 12 ±6 mmHg,
SC
p=0.01 and 0.002, respectively).
Assessment of leaflet mobility:
M AN U
For the 18 patients with leaflet thickening, 9 patients had at least one leaflet with visually restricted mobility. Out of these 9 patients, 8 patients had only 1 leaflet with restricted mobility (right coronary cusp in 4 patients, non-coronary cusp in 3 patients and left coronary cusp in 1 patient). In 1 patient, 2 leaflets were affected (right coronary cusp and noncoronary cusp). Maximal leaflet thickening was significantly higher in patients showing
respectively, p>0.0001).
Aortic valve prostheses:
TE D
leaflet thickening (mean 4.2 ± 1 mm vs 2.5 ± 1mm for leaflets with vs. without restriction,
EP
Out of 78 patients, 2 patients had been intervened through a transapical access, while the remaining 76 patients had been treated through a transfemoral access. For the 18 patients
AC C
with leaflet thickening, the spectrum of implanted prostheses was as follows: 1 Sapien XT; 14 Sapien 3 (Edwards Lifesciences, Irvine, CA, USA); 2 Portico (St. Jude Medical, Inc., St. Paul, MN, USA); 1 Symetis Acurate neo (Symetis AG, Ecublens Switzerland). For the 60 patients without leaflet thickening, the spectrum of implanted prostheses was as follows: 3 Sapien XT; 50 Sapien 3; 3 Portico; 4 Symetis Acurate neo. All prostheses had been implanted successfully with ‘Device Success’ as defined by the Valve Academic Research Consortium (VARC). 7
Additional Follow-up CT angiography
8
ACCEPTED MANUSCRIPT In 11 of the 18 patients, oral anticoagulation with phenprocoumon was recommended. Out of these 11 patients, follow-up CT was performed in 5 patients within 1-3 months showing no residual leaflet thickening. For the remaining 6 patients; 4 patients received no follow-up CT and in 2 patients no therapeutic anticoagulation was achieved and follow-up CT showed residual leaflet thickening.
RI PT
In 5 of the 18 patients with leaflet thickening no oral anticoagulation was recommended and no control CT was performed. For the remaining 2 patients with leaflet thickening, in one patient NOAC with Apixaban was recommended and in the other patient - on oral anticoagulation with phenprocoumon due to atrial fibrillation - better adjustment of INR
was
recommended.
Both
symptomatic
patients
SC
therapeutic
received
oral
anticoagulation with disappearance of the thrombotic material and symptom improvement
M AN U
on follow-up. (figure 3)
Outcome data:
In all patients with leaflet thrombosis, no neurological or thromboembolic events occurred till the time of presentation for follow-up CT. 12 months follow-up data was available for all but 3 patients in the thrombosis group. For the 15 patients with 12 months data, no neurological or thromboembolic
TE D
events were documented. In one patient non-ST-segment elevation myocardial infarction was diagnosed and the patient was hospitalized. In another patient, acute myeloid leukemia was diagnosed. All patients with leaflet thrombosis were reported as such to the treating physician and oral anticoagulation was recommended, however, the final management was left to the discretion of
AC C
EP
the referring physician.
Discussion
In this retrospective analysis, leaflet thrombosis was found to be a relatively frequent finding in patients referred for contrast-enhanced CT angiography following TAVI (23%). Leaflet thickening followed a subclinical course in the majority of patients. In the current literature, several studies have reported on the incidence of leaflet thrombosis following bioprosthetic transcatheter heart valves in different study populations. 5, 6, 8-10 Leteema et al. reported an incidence of 4% (5 patients) of 140 patients who received a Sapien XT prosthesis and were diagnosed on follow-up CT acquisitions performed 1-3 months after implantation.8 Out of 5 patients with leaflet thrombosis, only 1 patient was symptomatic with heart failure. Of note, 9
ACCEPTED MANUSCRIPT CT acquisitions were performed using ECG-triggered axial prospective acquisition mode at a single time point in the cardiac cycle. In another multicenter study including 156 consecutive patients, Pache et al. reported on early hypoattenuated leaflet thickening in follow up CT acquisitions performed on a median of 5 days following TAVI exclusively using Sapien 3 transcatheter heart valve.5 In their cohort, leaflet thrombosis was found in 10.3% of patients
RI PT
(16/165). On multivariable analysis, no baseline or procedural variables were shown to be associated with leaflet thrombosis. Furthermore, neither peri-interventional antithrombotic regimen nor antithrombotic medication at the time of CT was found to be associated with leaflet thrombosis. Moreover, all patients with leaflet thrombosis were clinically inapparent
SC
and full anticoagulation led to complete resolution of leaflet hypoattenuation. Makkar et al reported on possible subclinical leaflet thrombosis in patients arising from different cohorts
bioprostheses).
6
M AN U
(clinical trial for TAVR and 2 registries including transcatheter and surgical aortic valve In their analysis, reduced leaflet motion was observed in 40% (22 of 55
patients) out of the clinical trial and in 13% (17 of 132 patients) in the 2 registries. CT acquisitions had been performed at 30 days in the trial and at a median of 87 days in the registries. Patients with reduced leaflet motion had a subclinical course and all patients
TE D
receiving oral anticoagulation showed recovery of leaflet motion. More recently, the phenomenon of leaflet thrombosis have been analyzed in larger cohorts. Hansson et al. included 405 consecutive patients treated with balloon-expandable prosthesis (Sapien XT and Sapien 3). 10 In their analysis the prevalence of leaflet thrombosis in patients referred for
EP
CT imaging 1-3 months after implantation was reported to be 7% (28/405) with 5% of patients being symptomatic. In a multivariable setting, the absence of post-implantation oral
AC C
anticoagulation as well as larger transcatheter heart valve (29 mm) were the only 2 factors that independently predicted leaflet thrombosis. These data support observations from our cohort were patients without leaflet thickening were significantly more frequently on oral anticoagulation with either phenprocoumon or new oral anticoagulants compared to patients with leaflet thickening on follow-up (31% phenprocoumon, 19% NOAC vs. 5.5% phenprocoumon, 5.5% NOAC, respectively, p = 0.002). Moreover, Chavartaky et al. recently reported on patients enrolled in the Resolve and Savory registries.
9
Out of 890 patients
treated with both surgical and transcatheter heart valves, leaflet thrombosis was observed in 4% of 138 patients treated with surgical valves versus 13% of 752 patients treated with transcatheter heart valves (p=0.001). Median time till CT acquisitions was 83 days. Similar to 10
ACCEPTED MANUSCRIPT previous observations, leaflet thickening occurred more frequently in patients treated with dual antiplatelet regimen (15%) versus patients on oral anticoagulation (4%, p<0.0001). Interestingly, in this cohort of 890 patients, the incidence of transient ischemic attacks and not stroke was found to be significantly higher compared to patients without thrombosis. In our all-comer cohort referred for follow-up contrast-enhanced CT acquisitions after TAVI,
RI PT
incidence of leaflet thickening as a manifestation of leaflet thrombosis was found in 23% of patients (18/78) receiving both self-expandable and balloon-expandable prostheses. The higher incidence of leaflet thickening compared to the data from Pache et al., could be explained by the longer interval between implantation and CT acquisitions (median 5 days
SC
vs. 4 months, respectively) and the different types of prostheses included in the analysis. Leteema et al. who reported an incidence of only 4% included only balloon-expandable
M AN U
Sapient XT prostheses and had a substantially shorter follow-up interval than we did. Furthermore acquisitions were performed using prospective ECG-triggered acquisition at one time point in the cardiac cycle which could influence the diagnostic accuracy to detect leaflet thickening especially in subtle findings. Also differences in geometrical configuration of the prostheses used for implantation might potentially play a role in triggering leaflet
TE D
thickening.
The incidence of leaflet thrombosis after TAVI in our cohort is closer to data reported from registry data (23% vs. 13%), this is probably due to the fact that similar to registry data our patients resemble a ‘real life’ all-comer cohort. Importantly, similar to other published
EP
studies, all patients receiving effective anticoagulation showed resolution of leaflet thickening. In our cohort out of 18 patients with leaflet thickening, two patients presented
AC C
with symptoms (angina/dyspnea) with an echocardiographic correlate of increased gradient (post-implantation mean echocardiographic gradient 6 and 10 mmHg vs. 28 and 29 mmHg at the time of CT, respectively). Similar to patients with a subclinical course, oral anticoagulation led to symptom resolution with recovery of the echocardiographic gradient. Interestingly, in 2 patients receiving insufficient oral anticoagulation, leaflet thickening could be observed. So far, recommendations for optimal antiplatelet and anticoagulant therapy following implantation of transcatheter heart valves are based on expert consensus, with lack of randomized data supporting these recommendations. 11, 12 Furthermore, the duration of oral anticoagulant treatment in patients with identified leaflet thrombosis is still unclear and is most commonly tailored to patients according to individual considerations. 11
ACCEPTED MANUSCRIPT The mechanism behind leaflet thickening following implantation of transcatheter heart valves remains unclear. Due to lack of histological evidence, similar to previously published studies, the finding of leaflet thrombosis can only be assumed supported by the fact that resolution occurs following oral anticoagulation. Several theories have been speculated for the increased prothrombotic activity following
RI PT
TAVI/TAVR including possible coagulant activity of the remnant native valve, the intraannular design of the prostheses causing dead-water areas favoring thrombosis, high shear stress at the metal struts potentially causing blood trauma and increased procoagulant activity and an increased on-clopidogrel platelet activity in the elderly. 5, 13-17 Further studies
SC
are needed to clarify the mechanism behind this finding as well as its optimal medical management.
M AN U
Among non-invasive imaging modalities, CT - owing to its superior spatial resolution - has emerged as the modality of choice for visualizing leaflet thickening following TAVI/TAVR. The majority of studies addressing this phenomenon reported the use of retrospective ECGtriggered acquisitions providing functional assessment of the prosthesis.
5, 6, 9, 10, 18
These
acquisitions - although deemed with higher radiation exposure - are necessary to allow for
TE D
assessment of leaflet restriction and mobility. Furthermore different kernels for image reconstruction have been proposed. In our study as well as the studies reported by Makkar et al. and Chakravarty et al., a medium smooth reconstruction kernel has been used for image analysis.6, 9 In other studies, e.g in the study by Pache et al., a sharp reconstruction
EP
kernel has been proposed for image analysis. 5 Whether the use of different reconstruction kernels would influence the diagnosis of leaflet thickening remains unknown, however,
AC C
owing to the non-calcified nature of this phenomenon, an influence of reconstruction kernel on diagnosing leaflet thickening would probably be minimal. More importantly, a standardized approach for assessment of leaflet thickening/thrombosis is crucial for structured reporting. In this context, Jilaihawi et al. recently proposed a systematic CT methodology for assessment of leaflet thrombosis/reduced leaflet motion. 18 Some limitations need to be acknowledged. We included a relatively small patient population in this study. Furthermore, we included consecutive all-comer patients referred for follow-up CT after TAVI. Indication for CT imaging included routine follow-up imaging as well as symptom-triggered acquisitions which may have led to selection bias. Also, of all patients treated by TAVI in our institution, a significant number were lost to CT-follow-up. 12
ACCEPTED MANUSCRIPT In conclusion, leaflet thickening following implantation of transcatherter heart valves deemed as leaflet thrombosis is relatively frequent. It is substantially more frequent in individuals who are not on oral anticoagulation. However, in patients with relevant increase in prosthetic gradients, symptomatic presentations are possible with improvement on oral
AC C
EP
TE D
M AN U
SC
RI PT
anticoagulation.
13
ACCEPTED MANUSCRIPT References
AC C
EP
TE D
M AN U
SC
RI PT
1. Kapadia SR, Goel SS, Svensson L, Roselli E, Savage RM, Wallace L, Sola S, Schoenhagen P, Shishehbor MH, Christofferson R, Halley C, Rodriguez LL, Stewart W, Kalahasti V, Tuzcu EM. Characterization and outcome of patients with severe symptomatic aortic stenosis referred for percutaneous aortic valve replacement. J Thorac Cardiovasc Surg 2009;137(6):1430-5. 2. Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Bärwolf C, Levang OW, Tornos P, Vanoverschelde JL, Vermeer F, Boersma E, Ravaud P, Vahanian A. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003;24(13):1231-43. 3. Holmes DR, Mack MJ, Kaul S, Agnihotri A, Alexander KP, Bailey SR, Calhoon JH, Carabello BA, Desai MY, Edwards FH, Francis GS, Gardner TJ, Kappetein AP, Linderbaum JA, Mukherjee C, Mukherjee D, Otto CM, Ruiz CE, Sacco RL, Smith D, Thomas JD. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol 2012;59(13):1200-54. 4. Achenbach S, Delgado V, Hausleiter J, Schoenhagen P, Min JK, Leipsic JA. SCCT expert consensus document on computed tomography imaging before transcatheter aortic valve implantation (TAVI)/transcatheter aortic valve replacement (TAVR). J Cardiovasc Comput Tomogr 2012;6(6):366-80. 5. Pache G, Schoechlin S, Blanke P, Dorfs S, Jander N, Arepalli CD, Gick M, Buettner HJ, Leipsic J, Langer M, Neumann FJ, Ruile P. Early hypo-attenuated leaflet thickening in balloon-expandable transcatheter aortic heart valves. Eur Heart J 2015. 6. Makkar RR, Fontana G, Jilaihawi H, Chakravarty T, Kofoed KF, de Backer O, Asch FM, Ruiz CE, Olsen NT, Trento A, Friedman J, Berman D, Cheng W, Kashif M, Jelnin V, Kliger CA, Guo H, Pichard AD, Weissman NJ, Kapadia S, Manasse E, Bhatt DL, Leon MB, Sondergaard L. Possible Subclinical Leaflet Thrombosis in Bioprosthetic Aortic Valves. N Engl J Med 2015;373(21):2015-24. 7. Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, Krucoff MW, Mack M, Mehran R, Miller C, Morel MA, Petersen J, Popma JJ, Takkenberg JJ, Vahanian A, van Es GA, Vranckx P, Webb JG, Windecker S, Serruys PW. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium. Eur Heart J 2011;32(2):205-17. 8. Leetmaa T, Hansson NC, Leipsic J, Jensen K, Poulsen SH, Andersen HR, Jensen JM, Webb J, Blanke P, Tang M, Norgaard BL. Early aortic transcatheter heart valve thrombosis: diagnostic value of contrast-enhanced multidetector computed tomography. Circ Cardiovasc Interv 2015;8(4). 9. Chakravarty T, Sondergaard L, Friedman J, De Backer O, Berman D, Kofoed KF, Jilaihawi H, Shiota T, Abramowitz Y, Jorgensen TH, Rami T, Israr S, Fontana G, de Knegt M, Fuchs A, Lyden P, Trento A, Bhatt DL, Leon MB, Makkar RR, Resolve, Investigators S. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet 2017;389(10087):2383-2392. 10. Hansson NC, Grove EL, Andersen HR, Leipsic J, Mathiassen ON, Jensen JM, Jensen KT, Blanke P, Leetmaa T, Tang M, Krusell LR, Klaaborg KE, Christiansen EH, Terp K, Terkelsen CJ, Poulsen SH, Webb J, Botker HE, Norgaard BL. Transcatheter Aortic Valve Thrombosis: Incidence, Predisposing Factors, and Clinical Implications. J Am Coll Cardiol 2016;68(19):2059-2069. 14
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
11. Holmes DR, Jr., Mack MJ, Kaul S, Agnihotri A, Alexander KP, Bailey SR, Calhoon JH, Carabello BA, Desai MY, Edwards FH, Francis GS, Gardner TJ, Kappetein AP, Linderbaum JA, Mukherjee C, Mukherjee D, Otto CM, Ruiz CE, Sacco RL, Smith D, Thomas JD, Harrington RA, Bhatt DL, Ferrari VA, Fisher JD, Garcia MJ, Gardner TJ, Gentile F, Gilson MF, Hernandez AF, Jacobs AK, Kaul S, Linderbaum JA, Moliterno DJ, Weitz HH, American Heart A, American Society of E, European Association for Cardio-Thoracic S, Heart Failure Society of A, Mended H, Society of Cardiovascular A, Society of Cardiovascular Computed T, Society for Cardiovascular Magnetic R. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement: developed in collabration with the American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Thorac Cardiovasc Surg 2012;144(3):e29-84. 12. Joint Task Force on the Management of Valvular Heart Disease of the European Society of C, European Association for Cardio-Thoracic S, Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33(19):2451-96. 13. Blanke P, Schoepf UJ, Leipsic JA. CT in transcatheter aortic valve replacement. Radiology 2013;269(3):650-69. 14. Cordoba-Soriano JG, Puri R, Amat-Santos I, Ribeiro HB, Abdul-Jawad Altisent O, del Trigo M, Paradis JM, Dumont E, Urena M, Rodes-Cabau J. Valve thrombosis following transcatheter aortic valve implantation: a systematic review. Rev Esp Cardiol (Engl Ed) 2015;68(3):198-204. 15. Hochholzer W, Trenk D, Fromm MF, Valina CM, Stratz C, Bestehorn HP, Buttner HJ, Neumann FJ. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol 2010;55(22):2427-34. 16. Huck V, Schneider MF, Gorzelanny C, Schneider SW. The various states of von Willebrand factor and their function in physiology and pathophysiology. Thromb Haemost 2014;111(4):598-609. 17. Mylotte D, Andalib A, Theriault-Lauzier P, Dorfmeister M, Girgis M, Alharbi W, Chetrit M, Galatas C, Mamane S, Sebag I, Buithieu J, Bilodeau L, de Varennes B, Lachapelle K, Lange R, Martucci G, Virmani R, Piazza N. Transcatheter heart valve failure: a systematic review. Eur Heart J 2015;36(21):1306-27. 18. Jilaihawi H, Asch FM, Manasse E, Ruiz CE, Jelnin V, Kashif M, Kawamori H, Maeno Y, Kazuno Y, Takahashi N, Olson R, Alkhatib J, Berman D, Friedman J, Gellada N, Chakravarty T, Makkar RR. Systematic CT Methodology for the Evaluation of Subclinical Leaflet Thrombosis. JACC Cardiovasc Imaging 2017;10(4):461-470.
15
ACCEPTED MANUSCRIPT
0.7±0.2²
0.6±0.3 cm²
0.5
66±23 mmHg 39±14 mmHg 6% 30% 2%
64±29 mmHg 42±19 mmHg 7% 40% 13%
0.7 0.6 0.89 0.48 0.07
15% 2% 14%
13% 7% 20%
0.85 0.33 0.58
14% 2% 2% 75% 21% 19% 64%
7% 7% 20% 73% 46% 20% 40%
0.48 0.33 0.01 0.87 0.06 0.93 0.1
48%
20% 5±4 months 11% Phenprocoumon or NOAC Sapien XT (n=1) Sapien 3 (n=14) Portico (n=2) Symetis Acurate neo (n=1) 5% (1/18)
0.06 0.5 0.002
TE D
M AN U
RI PT
Patients with leaflet thrombosis (n=18) 81±4 67% 53%±10
EP
Age Male sex Ejection fraction (mean ±SD) Aortic Valve Area (mean±SD) Pre-procedural Echocardiographic Gradient Max Mean Previous MI Previous PCI Peripheral Arterial Disease COPD Carotid Stenosis >50% Chronic renal Insufficiency Previous Pacemaker Previous ICD Previous Stroke Hypertension Diabetes mellitus Dyslipidemia Pulmonary Hypertension Atrial fibrillation Time to CT imaging Peri-interventional medication Implanted Prosthesis
Patients without leaflet thrombosis (n=60) 81±4 42% 53%±10
SC
Table 1: Baseline clinical characteristics:
AC C
5±8 months 50% phenprocoumon or NOAC Sapien XT (n=3) Sapien 3 (n=50) Portico (n=3) Symetis Acurate neo (n=4) 15% (9/60)
Post-Procedural Angiographic Aortic Regurgitation ≥2
16
P 0.99 0.5 0.98
0.26
RI PT
ACCEPTED MANUSCRIPT
TE D
M AN U
SC
Figure 1: Multiplanar reconstruction of the aortic valve prosthesis (Sapien 3) in a patient with leaflet thickening affecting both right coronary and left coronary cusps (a). Reference lines were aligned orthogonally on the affected leaflet (a, b) to avoid overestimation of the maximal leaflet thickening (c).
AC C
Figure 3:
EP
Figure 2: Multiplanar reconstruction simulating a short-axis view of the aortic valve prostheses in 3 patients with leaflet thickening. Cusp affection is assigned according to former native cusp. (a) right coronary cusp, (b) right and left coronary cusp, (c) right, left and acoronary cusp affection.
17
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Figure 3: 73 year old patient with ischemic cardiomyopathy, status post TAVI 12/2014. CT was performed on follow-up 8 months following intervention. (a) Multiplanar reconstruction simulating echocardiographic parasternal long axis view showing leaflet thickening of the aortic valve prosthesis (Sapien 3). (B) Patient received oral anticoagulation and the CT was performed 1 month later showing resolution of the leaflet thickening.
18
S1934-5925(17)30241-1
DOI:
10.1016/j.jcct.2017.11.002
Reference:
JCCT 1032
To appear in:
Journal of Cardiovascular Computed Tomograph
Received Date: 19 March 2017 Revised Date:
29 October 2017
Accepted Date: 7 November 2017
Please cite this article as: Marwan M, Mekkhala N, Göller M, Röther J, Bittner D, Schuhbaeck A, Hell M, Muschiol G, Kolwelter J, Feyrer R, Schlundt C, Achenbach S, Arnold M, Leaflet thrombosis following transcatheter aortic valve implantation, Journal of Cardiovascular Computed Tomograph (2017), doi: 10.1016/j.jcct.2017.11.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Leaflet Thrombosis Following Transcatheter Aortic Valve Implantation Marwan M1, Mekkhala N1, Göller M1, Röther J1, Bittner D1,2, Schuhbaeck A1, Hell M1, Muschiol G1, Kolwelter J, Feyrer R3, Schlundt C1, Achenbach S1 , Arnold M1
Department of Internal Medicine 2 (Cardiology), University of Erlangen, Germany
2
Division of Cardiovascular Imaging, Massachusetts General Hospital, Boston, USA
3
Department of Cardiosurgery, University of Erlangen, Germany
M AN U
SC
RI PT
1
Conflict of interest:
Stephan Achenbach has received research grants from Siemens Healthcare and Abbott
TE D
Vascular
Mohamed Marwan has received speaker honoraria from Siemens Healthcare and Edwards Lifesciences
AC C
EP
Martin Arnold is a consultant for St. Jude Medical and Edwards Lifesciences
*Corresponding author:
Mohamed Marwan, MD, Department of Internal Medicine 2 (Cardiology), University of Erlangen, Ulmenweg 18, D-91054 Erlangen, Germany. Phone: +49-9131-85-35000. E-mail: mohamed.marwan @uk-erlangen.de
1
ACCEPTED MANUSCRIPT Abstract Background:
RI PT
Transcatheter aortic valve implantation (TAVI) is increasingly being offered to high-risk patients with symptomatic aortic valve stenosis. Recent reports have suggested a high incidence of subclinical leaflet thrombosis following bioprosthestic aortic valve replacement. We report the frequency and clinical presentation of leaflet thrombosis identified by cardiac CT in patients referred for follow-up contrast enhanced CT angiography following TAVI. Methods:
M AN U
SC
91 consecutive patients referred for follow-up contrast-enhanced CT angiography following TAVI were screened for inclusion in this analysis. Out of these, 13 patients were excluded. All CT examinations were performed using a 2nd or a 3rd generation dual-source system (Somatom Definition Flash/Force, Forchheim, Germany). In all patients, retrospectively ECGgated spiral acquisition with tube modulation was performed to allow for assessment of leaflet motion. All prostheses were analyzed for presence of leaflet thrombosis defined as hypo-attenuated leaflet thickening with or without leaflet restriction. Post-procedural antithrombotic regimen as well as symptom status was documented in all patients. Results:
EP
TE D
78 consecutive patients (35 males, 81±4 years) were analyzed. TAVI had been performed in all patients (76 transfemoral access, 2 transapical access) with either balloon-expandable prostheses (4 Sapien XT, 64 Sapien 3) or self-expandable prostheses (5 SJM Portico, 5 Symetis Acurate). Follow-up CT angiography was performed at a median of 4 months following index procedure (Interquartile range 1 month). Leaflet thrombosis was detected in 18 patients (23%, 14 Sapien 3, 1 Sapien XT, 2 SJM Portico, 1 Symetis Acurate). In patients with leaflet thickening on CT, only 11% were on either oral anticoagulation or new oral anticoagulants versus 50% for patients with no leaflet thickening (p 0.002). In patients with leaflet thrombosis, 3 leaflets were affected in 5 patients, 2 leaflets in 5 patients and in 8 patient only 1 leaflet was affected. Clinical symptoms (angina, dyspnea or both) were reported in 2/18 patients with leaflet thrombosis (11%) and in both patients a significant increase of the mean echocardiographic gradient over the prosthesis was documented. The peak
AC C
and mean echocardiographic gradients obtained at the day of CT examination was significantly higher in symptomatic patients versus asymptomatic patients (peak 46±7 vs. 23±11 mmHg, mean 29± 7 vs. 12 ±6 mmHg, p=0.01 and 0.002, respectively). Follow-up CT was available for 4 patients with complete resolution of the hypo-attenuated leaflet thickening following treatment. Conclusion:
Leaflet thrombosis following TAVI is a relatively frequent finding in patients referred for contrast enhanced CT angiography following TAVI. In the majority of patients it follows a subclinical course and is substantially more frequent in individuals who are not on oral anticoagulation. However, in patients with relevant increase in prosthetic gradients, symptomatic presentations are possible.
2
ACCEPTED MANUSCRIPT Keywords
EP
TE D
M AN U
Dual source computed tomography Transcatheter aortic valve implantation Transcatheter aortic valve replacement Multiplanar reconstruction Valve Academic Research Consortium
AC C
DSCT TAVI TAVR MPR VARC
SC
Abbreviations
RI PT
Transcatheter aortic valve replacement / implantation (TAVR / TAVI) Computed Tomography Leaflet thrombosis
3
ACCEPTED MANUSCRIPT
Introduction Aortic valve stenosis is a common cause of morbidity and mortality in the aging population. In patients with symptomatic high grade aortic stenosis, prognosis is very poor when left 1, 2
Transcatheter aortic valve implantation (TAVI)/ transcatheter aortic valve
RI PT
untreated.
replacement (TAVR) has emerged as an accepted alternative for conventional surgery in patients with aortic valve stenosis deemed at high operative risk. 3, 4
Pre-procedural imaging is essential not only for correct sizing of the prosthesis, but also for
SC
adequate procedural planning regarding the access route (transfemoral vs. apical, aortic or subclavian access). For this purpose, contrast enhanced computed tomography (CT) imaging
M AN U
- owing to its high and isotropic spatial resolution as well as fast volume coverage – offers valuable information regarding aortic root dimensions as well as aortic and iliac artery anatomy and is recommended prior to TAVI/TAVR procedures. 4
Furthermore, post-interventional imaging using CT provides valuable information regarding prosthesis position, function as well as leaflet anatomy. Recently, reports from multi-center data have been published showing subclinical leaflet thrombosis following bioprosthestic 6
We report the incidence and clinical presentation of leaflet
TE D
aortic valve replacement.5,
thrombosis in patients referred for follow-up contrast enhanced CT angiography following
EP
TAVI.
AC C
Material and Methods
Study design and patient population This is a single-center, retrospective analysis. 91 consecutive patients referred for contrast enhanced CT imaging between October 2014 and June 2016 within a median of 4 months following transcatheter aortic valve implantation (TAVI)/ transcatheter aortic valve replacement (TAVR) were screened for inclusion in this study. Out of 91 patients, 78 patients were included in this analysis. CT exams were performed as a part of routine imaging following TAVI in 65 patients. In 13 patients, CT was performed either for further clarification of an increase in the echocardiographic gradient over the prosthesis or due to clinical
4
ACCEPTED MANUSCRIPT symptoms. All patients gave an informed written consent. Due to the retrospective nature of the study, approval was waived by IRB.
DSCT data acquisition and image reconstruction CT data sets were acquired with either a second or third generation dual-source CT system
RI PT
(Somatom Definition Flash/ Somatom Force, Siemens Healthcare, Forchheim, Germany) using a retrospectively ECG-triggered spiral acquisition mode, extending from the pulmonary artery bifurcation to the caudal end of the heart. Scan parameters were as follows: tube voltage 120 kV, tube current time product 350-450 mAs, 2x128x0.6/2x192x0.6 mm
SC
collimation, 330ms/250 ms rotation time, for 2nd and 3rd generation systems, respectively. ECG dose modulation was performed with full radiation exposure between 40-70% of the
M AN U
peak R-wave to R-wave and a dose reduction to 20% outside this window. CT angiography was performed using 10ml of contrast agent (Imeron 350, Bracco Imaging, Konstanz, Germany) for assessing the contrast agent transit time and 50 ml at a flow rate of 5ml/sec followed by a 50 ml saline chaser at the same flow rate for the following angiography. For each patient, a multiphase reconstruction every 10% of the cardiac cycle was rendered using a small field of view (FOV) data set to allow for 4 dimensional functional assessment of
TE D
the prosthesis. All reconstructions were rendered using a medium soft convolution kernel (Siemens B26 f, Siemens Bv40 for 2nd and 3rd generation system, respectively) with a slice thickness of 1.5 mm and slice increment of 1 mm. For image data acquired using third
EP
generation system, reconstructions were performed using a newly introduced iterative reconstruction algorithm (Admire®, Siemens, Forchheim, Germany) at a strength level of 2.
AC C
Moreover, for each patient, a diastolic reconstruction was rendered using thin slice thickness of 0.75/0.5 mm and an increment of 0.4/0.3 mm for 2nd versus 3rd generation system, respectively.
CT analysis of leaflet morphology and motion: Data sets were displayed on a dedicated workstation (MMWP, Siemens Healthcare, Forchheim, Germany). Window settings for interpretation of the image data were adjusted individually according to reader’s discretion. Multiphase reconstructions were used for primary analysis. Using multiplanar reconstruction (MPR), views similar to echocardiographic short-axis view and parasternal long-axis view 5
ACCEPTED MANUSCRIPT were simulated in CT to allow for assessment of leaflet motion. Moreover, a double-oblique coronal view of the aortic valve prosthesis was also rendered for further analysis. Assessment of leaflet thickening and restriction was performed visually by a cardiologist with 10 years of experience in cardiac CT. Furthermore, maximal leaflet thickening was assessed visually in the short-axis view with the measurements performed in a long axis view
RI PT
orthogonal to the leaflet to avoid overestimation. (figure 1) Possible leaflet thrombosis was defined as previously reported by Pache et al.5 as hypo-attenuated thickening with or without restriction of one or more leaflets identifiable in at least two different MPR projections and two different reconstruction time intervals.
SC
Using diastolic reconstructions, the location of the affected cusp was defined according to former native cusp position as right, left, or non-coronary cusp. The number of the affected
Post-procedural echocardiography:
M AN U
cusps as well as the maximum thickness of the affected cusps were assessed. (figure 2)
Examinations were performed by experienced cardiologists using either a Vivid 7 system (General Electric Medical Systems, Milwaukee, WI, USA) or a Philips IE33-system (Philips,
TE D
Leiden, the Netherlands). Transthoracic echocardiographic data were collected at the time of discharge. The mean pressure gradient was calculated according to the Bernoulli formula. For patients with CT diagnosed leaflet thickening, echocardiographic maximal and mean
Clinical status:
EP
gradients were obtained on the same day of the CT examination.
AC C
All patients included in the study were referred either from the institution’s outpatient clinic or inpatient ward. All patients underwent a structured interview to assess clinical status. Symptomatic patients were defined as patients with new-onset/worsening dyspnea or angina. Patients with stable symptoms existing since index intervention or with improved symptoms were deemed as asymptomatic.
Anticoagulation and antiplatelet regimen: Patients with no indication for oral anticoagulation received a standard dual antiplatelet therapy with acetyl salicylic acid and clopidogrel for 3-6 months, whereas patients on oral anticoagulation were kept on the pre-procedural medication (phenprocoumon or NOAC). 6
ACCEPTED MANUSCRIPT Statistical analyses Continuous data are presented as mean ± standard deviation. Categorical variables are shown in proportions. Mean values were compared using a two sided paired t-test. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 21.0.
RI PT
(Armonk, NY: IBM Corp IBM®). Categorical variables were compared using Fisher’s exact test.
Results
SC
Study population
Between October 2014 to June 2016, 279 consecutive TAVI/TAVR procedures were
M AN U
performed in our institution. Out of these, 15 procedures were Valve-in-Valve. 91 consecutive patients referred for contrast-enhanced CT imaging of the aortic valve prosthesis following TAVI/TAVR were screened for inclusion in this analysis. Out of these, 13 patients were excluded (2 patients valve-in -valve TAVI had been performed due severe bioprosthetic aortic regurgitation, in 9 patients valve-in-valve TAVI had been performed due
TE D
to severe bioprosthetic aortic stenosis, 1 patient was referred for suspicion of prosthesis endocarditis and 1 patient was examined for assessment of prosthesis/left main coronary artery anatomy). The remaining 78 patients were included in this analysis. Baseline clinical characteristics are displayed in table 1. The mean age was 81±4 years, mean ejection
EP
fraction was 53±10%, mean pre-procedural aortic valve area 0.7±0.2 cm2 and mean pre-
AC C
procedural aortic valve gradient was 40 ± 15 mmHg.
CT analysis of the prosthetic leaflets: CT was performed at a median of 4 months following the index procedure (interquartile range 1 month). Out of 78 patients, 18 (23%) showed leaflet thickening in CT. Mean age, ejection fraction, aortic valve area derived by the continuity equation, mean echocardiographic gradient at baseline as well as
time interval between TAVI to CT
examination was not significantly different between patients with and without leaflet thickening. Out of 18 patients with leaflet thickening on CT, only 2 patients were on oral anticoagulation at the time of CT (one patient on oral phenprocoumon, however not in therapeutic range [INR < 2.0], 1 patient on NOAC with mild diffuse leaflet thickening). 7
ACCEPTED MANUSCRIPT Patients without leaflet thickening were significantly more frequently on oral anticoagulation with either phenprocoumon or new oral anticoagulants compared to patients with leaflet thickening on follow-up (31% phenprocoumon, 19% NOAC vs. 5.5% phenprocoumon, 5.5% NOAC, respectively, p = 0.002). Out of the 18 patients with leaflet thickening on CT, only 2 patients (11%) were symptomatic (1 patient with angina pectoris
RI PT
and dyspnea, 1 patient with dyspnea). The peak and mean echocardiographic gradients obtained at the day of the CT examination were significantly higher in symptomatic patients as compared to asymptomatic patients (46±7 vs. 23±11 mmHg, 29± 7 vs. 12 ±6 mmHg,
SC
p=0.01 and 0.002, respectively).
Assessment of leaflet mobility:
M AN U
For the 18 patients with leaflet thickening, 9 patients had at least one leaflet with visually restricted mobility. Out of these 9 patients, 8 patients had only 1 leaflet with restricted mobility (right coronary cusp in 4 patients, non-coronary cusp in 3 patients and left coronary cusp in 1 patient). In 1 patient, 2 leaflets were affected (right coronary cusp and noncoronary cusp). Maximal leaflet thickening was significantly higher in patients showing
respectively, p>0.0001).
Aortic valve prostheses:
TE D
leaflet thickening (mean 4.2 ± 1 mm vs 2.5 ± 1mm for leaflets with vs. without restriction,
EP
Out of 78 patients, 2 patients had been intervened through a transapical access, while the remaining 76 patients had been treated through a transfemoral access. For the 18 patients
AC C
with leaflet thickening, the spectrum of implanted prostheses was as follows: 1 Sapien XT; 14 Sapien 3 (Edwards Lifesciences, Irvine, CA, USA); 2 Portico (St. Jude Medical, Inc., St. Paul, MN, USA); 1 Symetis Acurate neo (Symetis AG, Ecublens Switzerland). For the 60 patients without leaflet thickening, the spectrum of implanted prostheses was as follows: 3 Sapien XT; 50 Sapien 3; 3 Portico; 4 Symetis Acurate neo. All prostheses had been implanted successfully with ‘Device Success’ as defined by the Valve Academic Research Consortium (VARC). 7
Additional Follow-up CT angiography
8
ACCEPTED MANUSCRIPT In 11 of the 18 patients, oral anticoagulation with phenprocoumon was recommended. Out of these 11 patients, follow-up CT was performed in 5 patients within 1-3 months showing no residual leaflet thickening. For the remaining 6 patients; 4 patients received no follow-up CT and in 2 patients no therapeutic anticoagulation was achieved and follow-up CT showed residual leaflet thickening.
RI PT
In 5 of the 18 patients with leaflet thickening no oral anticoagulation was recommended and no control CT was performed. For the remaining 2 patients with leaflet thickening, in one patient NOAC with Apixaban was recommended and in the other patient - on oral anticoagulation with phenprocoumon due to atrial fibrillation - better adjustment of INR
was
recommended.
Both
symptomatic
patients
SC
therapeutic
received
oral
anticoagulation with disappearance of the thrombotic material and symptom improvement
M AN U
on follow-up. (figure 3)
Outcome data:
In all patients with leaflet thrombosis, no neurological or thromboembolic events occurred till the time of presentation for follow-up CT. 12 months follow-up data was available for all but 3 patients in the thrombosis group. For the 15 patients with 12 months data, no neurological or thromboembolic
TE D
events were documented. In one patient non-ST-segment elevation myocardial infarction was diagnosed and the patient was hospitalized. In another patient, acute myeloid leukemia was diagnosed. All patients with leaflet thrombosis were reported as such to the treating physician and oral anticoagulation was recommended, however, the final management was left to the discretion of
AC C
EP
the referring physician.
Discussion
In this retrospective analysis, leaflet thrombosis was found to be a relatively frequent finding in patients referred for contrast-enhanced CT angiography following TAVI (23%). Leaflet thickening followed a subclinical course in the majority of patients. In the current literature, several studies have reported on the incidence of leaflet thrombosis following bioprosthetic transcatheter heart valves in different study populations. 5, 6, 8-10 Leteema et al. reported an incidence of 4% (5 patients) of 140 patients who received a Sapien XT prosthesis and were diagnosed on follow-up CT acquisitions performed 1-3 months after implantation.8 Out of 5 patients with leaflet thrombosis, only 1 patient was symptomatic with heart failure. Of note, 9
ACCEPTED MANUSCRIPT CT acquisitions were performed using ECG-triggered axial prospective acquisition mode at a single time point in the cardiac cycle. In another multicenter study including 156 consecutive patients, Pache et al. reported on early hypoattenuated leaflet thickening in follow up CT acquisitions performed on a median of 5 days following TAVI exclusively using Sapien 3 transcatheter heart valve.5 In their cohort, leaflet thrombosis was found in 10.3% of patients
RI PT
(16/165). On multivariable analysis, no baseline or procedural variables were shown to be associated with leaflet thrombosis. Furthermore, neither peri-interventional antithrombotic regimen nor antithrombotic medication at the time of CT was found to be associated with leaflet thrombosis. Moreover, all patients with leaflet thrombosis were clinically inapparent
SC
and full anticoagulation led to complete resolution of leaflet hypoattenuation. Makkar et al reported on possible subclinical leaflet thrombosis in patients arising from different cohorts
bioprostheses).
6
M AN U
(clinical trial for TAVR and 2 registries including transcatheter and surgical aortic valve In their analysis, reduced leaflet motion was observed in 40% (22 of 55
patients) out of the clinical trial and in 13% (17 of 132 patients) in the 2 registries. CT acquisitions had been performed at 30 days in the trial and at a median of 87 days in the registries. Patients with reduced leaflet motion had a subclinical course and all patients
TE D
receiving oral anticoagulation showed recovery of leaflet motion. More recently, the phenomenon of leaflet thrombosis have been analyzed in larger cohorts. Hansson et al. included 405 consecutive patients treated with balloon-expandable prosthesis (Sapien XT and Sapien 3). 10 In their analysis the prevalence of leaflet thrombosis in patients referred for
EP
CT imaging 1-3 months after implantation was reported to be 7% (28/405) with 5% of patients being symptomatic. In a multivariable setting, the absence of post-implantation oral
AC C
anticoagulation as well as larger transcatheter heart valve (29 mm) were the only 2 factors that independently predicted leaflet thrombosis. These data support observations from our cohort were patients without leaflet thickening were significantly more frequently on oral anticoagulation with either phenprocoumon or new oral anticoagulants compared to patients with leaflet thickening on follow-up (31% phenprocoumon, 19% NOAC vs. 5.5% phenprocoumon, 5.5% NOAC, respectively, p = 0.002). Moreover, Chavartaky et al. recently reported on patients enrolled in the Resolve and Savory registries.
9
Out of 890 patients
treated with both surgical and transcatheter heart valves, leaflet thrombosis was observed in 4% of 138 patients treated with surgical valves versus 13% of 752 patients treated with transcatheter heart valves (p=0.001). Median time till CT acquisitions was 83 days. Similar to 10
ACCEPTED MANUSCRIPT previous observations, leaflet thickening occurred more frequently in patients treated with dual antiplatelet regimen (15%) versus patients on oral anticoagulation (4%, p<0.0001). Interestingly, in this cohort of 890 patients, the incidence of transient ischemic attacks and not stroke was found to be significantly higher compared to patients without thrombosis. In our all-comer cohort referred for follow-up contrast-enhanced CT acquisitions after TAVI,
RI PT
incidence of leaflet thickening as a manifestation of leaflet thrombosis was found in 23% of patients (18/78) receiving both self-expandable and balloon-expandable prostheses. The higher incidence of leaflet thickening compared to the data from Pache et al., could be explained by the longer interval between implantation and CT acquisitions (median 5 days
SC
vs. 4 months, respectively) and the different types of prostheses included in the analysis. Leteema et al. who reported an incidence of only 4% included only balloon-expandable
M AN U
Sapient XT prostheses and had a substantially shorter follow-up interval than we did. Furthermore acquisitions were performed using prospective ECG-triggered acquisition at one time point in the cardiac cycle which could influence the diagnostic accuracy to detect leaflet thickening especially in subtle findings. Also differences in geometrical configuration of the prostheses used for implantation might potentially play a role in triggering leaflet
TE D
thickening.
The incidence of leaflet thrombosis after TAVI in our cohort is closer to data reported from registry data (23% vs. 13%), this is probably due to the fact that similar to registry data our patients resemble a ‘real life’ all-comer cohort. Importantly, similar to other published
EP
studies, all patients receiving effective anticoagulation showed resolution of leaflet thickening. In our cohort out of 18 patients with leaflet thickening, two patients presented
AC C
with symptoms (angina/dyspnea) with an echocardiographic correlate of increased gradient (post-implantation mean echocardiographic gradient 6 and 10 mmHg vs. 28 and 29 mmHg at the time of CT, respectively). Similar to patients with a subclinical course, oral anticoagulation led to symptom resolution with recovery of the echocardiographic gradient. Interestingly, in 2 patients receiving insufficient oral anticoagulation, leaflet thickening could be observed. So far, recommendations for optimal antiplatelet and anticoagulant therapy following implantation of transcatheter heart valves are based on expert consensus, with lack of randomized data supporting these recommendations. 11, 12 Furthermore, the duration of oral anticoagulant treatment in patients with identified leaflet thrombosis is still unclear and is most commonly tailored to patients according to individual considerations. 11
ACCEPTED MANUSCRIPT The mechanism behind leaflet thickening following implantation of transcatheter heart valves remains unclear. Due to lack of histological evidence, similar to previously published studies, the finding of leaflet thrombosis can only be assumed supported by the fact that resolution occurs following oral anticoagulation. Several theories have been speculated for the increased prothrombotic activity following
RI PT
TAVI/TAVR including possible coagulant activity of the remnant native valve, the intraannular design of the prostheses causing dead-water areas favoring thrombosis, high shear stress at the metal struts potentially causing blood trauma and increased procoagulant activity and an increased on-clopidogrel platelet activity in the elderly. 5, 13-17 Further studies
SC
are needed to clarify the mechanism behind this finding as well as its optimal medical management.
M AN U
Among non-invasive imaging modalities, CT - owing to its superior spatial resolution - has emerged as the modality of choice for visualizing leaflet thickening following TAVI/TAVR. The majority of studies addressing this phenomenon reported the use of retrospective ECGtriggered acquisitions providing functional assessment of the prosthesis.
5, 6, 9, 10, 18
These
acquisitions - although deemed with higher radiation exposure - are necessary to allow for
TE D
assessment of leaflet restriction and mobility. Furthermore different kernels for image reconstruction have been proposed. In our study as well as the studies reported by Makkar et al. and Chakravarty et al., a medium smooth reconstruction kernel has been used for image analysis.6, 9 In other studies, e.g in the study by Pache et al., a sharp reconstruction
EP
kernel has been proposed for image analysis. 5 Whether the use of different reconstruction kernels would influence the diagnosis of leaflet thickening remains unknown, however,
AC C
owing to the non-calcified nature of this phenomenon, an influence of reconstruction kernel on diagnosing leaflet thickening would probably be minimal. More importantly, a standardized approach for assessment of leaflet thickening/thrombosis is crucial for structured reporting. In this context, Jilaihawi et al. recently proposed a systematic CT methodology for assessment of leaflet thrombosis/reduced leaflet motion. 18 Some limitations need to be acknowledged. We included a relatively small patient population in this study. Furthermore, we included consecutive all-comer patients referred for follow-up CT after TAVI. Indication for CT imaging included routine follow-up imaging as well as symptom-triggered acquisitions which may have led to selection bias. Also, of all patients treated by TAVI in our institution, a significant number were lost to CT-follow-up. 12
ACCEPTED MANUSCRIPT In conclusion, leaflet thickening following implantation of transcatherter heart valves deemed as leaflet thrombosis is relatively frequent. It is substantially more frequent in individuals who are not on oral anticoagulation. However, in patients with relevant increase in prosthetic gradients, symptomatic presentations are possible with improvement on oral
AC C
EP
TE D
M AN U
SC
RI PT
anticoagulation.
13
ACCEPTED MANUSCRIPT References
AC C
EP
TE D
M AN U
SC
RI PT
1. Kapadia SR, Goel SS, Svensson L, Roselli E, Savage RM, Wallace L, Sola S, Schoenhagen P, Shishehbor MH, Christofferson R, Halley C, Rodriguez LL, Stewart W, Kalahasti V, Tuzcu EM. Characterization and outcome of patients with severe symptomatic aortic stenosis referred for percutaneous aortic valve replacement. J Thorac Cardiovasc Surg 2009;137(6):1430-5. 2. Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Bärwolf C, Levang OW, Tornos P, Vanoverschelde JL, Vermeer F, Boersma E, Ravaud P, Vahanian A. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003;24(13):1231-43. 3. Holmes DR, Mack MJ, Kaul S, Agnihotri A, Alexander KP, Bailey SR, Calhoon JH, Carabello BA, Desai MY, Edwards FH, Francis GS, Gardner TJ, Kappetein AP, Linderbaum JA, Mukherjee C, Mukherjee D, Otto CM, Ruiz CE, Sacco RL, Smith D, Thomas JD. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol 2012;59(13):1200-54. 4. Achenbach S, Delgado V, Hausleiter J, Schoenhagen P, Min JK, Leipsic JA. SCCT expert consensus document on computed tomography imaging before transcatheter aortic valve implantation (TAVI)/transcatheter aortic valve replacement (TAVR). J Cardiovasc Comput Tomogr 2012;6(6):366-80. 5. Pache G, Schoechlin S, Blanke P, Dorfs S, Jander N, Arepalli CD, Gick M, Buettner HJ, Leipsic J, Langer M, Neumann FJ, Ruile P. Early hypo-attenuated leaflet thickening in balloon-expandable transcatheter aortic heart valves. Eur Heart J 2015. 6. Makkar RR, Fontana G, Jilaihawi H, Chakravarty T, Kofoed KF, de Backer O, Asch FM, Ruiz CE, Olsen NT, Trento A, Friedman J, Berman D, Cheng W, Kashif M, Jelnin V, Kliger CA, Guo H, Pichard AD, Weissman NJ, Kapadia S, Manasse E, Bhatt DL, Leon MB, Sondergaard L. Possible Subclinical Leaflet Thrombosis in Bioprosthetic Aortic Valves. N Engl J Med 2015;373(21):2015-24. 7. Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, Krucoff MW, Mack M, Mehran R, Miller C, Morel MA, Petersen J, Popma JJ, Takkenberg JJ, Vahanian A, van Es GA, Vranckx P, Webb JG, Windecker S, Serruys PW. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium. Eur Heart J 2011;32(2):205-17. 8. Leetmaa T, Hansson NC, Leipsic J, Jensen K, Poulsen SH, Andersen HR, Jensen JM, Webb J, Blanke P, Tang M, Norgaard BL. Early aortic transcatheter heart valve thrombosis: diagnostic value of contrast-enhanced multidetector computed tomography. Circ Cardiovasc Interv 2015;8(4). 9. Chakravarty T, Sondergaard L, Friedman J, De Backer O, Berman D, Kofoed KF, Jilaihawi H, Shiota T, Abramowitz Y, Jorgensen TH, Rami T, Israr S, Fontana G, de Knegt M, Fuchs A, Lyden P, Trento A, Bhatt DL, Leon MB, Makkar RR, Resolve, Investigators S. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet 2017;389(10087):2383-2392. 10. Hansson NC, Grove EL, Andersen HR, Leipsic J, Mathiassen ON, Jensen JM, Jensen KT, Blanke P, Leetmaa T, Tang M, Krusell LR, Klaaborg KE, Christiansen EH, Terp K, Terkelsen CJ, Poulsen SH, Webb J, Botker HE, Norgaard BL. Transcatheter Aortic Valve Thrombosis: Incidence, Predisposing Factors, and Clinical Implications. J Am Coll Cardiol 2016;68(19):2059-2069. 14
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
11. Holmes DR, Jr., Mack MJ, Kaul S, Agnihotri A, Alexander KP, Bailey SR, Calhoon JH, Carabello BA, Desai MY, Edwards FH, Francis GS, Gardner TJ, Kappetein AP, Linderbaum JA, Mukherjee C, Mukherjee D, Otto CM, Ruiz CE, Sacco RL, Smith D, Thomas JD, Harrington RA, Bhatt DL, Ferrari VA, Fisher JD, Garcia MJ, Gardner TJ, Gentile F, Gilson MF, Hernandez AF, Jacobs AK, Kaul S, Linderbaum JA, Moliterno DJ, Weitz HH, American Heart A, American Society of E, European Association for Cardio-Thoracic S, Heart Failure Society of A, Mended H, Society of Cardiovascular A, Society of Cardiovascular Computed T, Society for Cardiovascular Magnetic R. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement: developed in collabration with the American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Thorac Cardiovasc Surg 2012;144(3):e29-84. 12. Joint Task Force on the Management of Valvular Heart Disease of the European Society of C, European Association for Cardio-Thoracic S, Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33(19):2451-96. 13. Blanke P, Schoepf UJ, Leipsic JA. CT in transcatheter aortic valve replacement. Radiology 2013;269(3):650-69. 14. Cordoba-Soriano JG, Puri R, Amat-Santos I, Ribeiro HB, Abdul-Jawad Altisent O, del Trigo M, Paradis JM, Dumont E, Urena M, Rodes-Cabau J. Valve thrombosis following transcatheter aortic valve implantation: a systematic review. Rev Esp Cardiol (Engl Ed) 2015;68(3):198-204. 15. Hochholzer W, Trenk D, Fromm MF, Valina CM, Stratz C, Bestehorn HP, Buttner HJ, Neumann FJ. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol 2010;55(22):2427-34. 16. Huck V, Schneider MF, Gorzelanny C, Schneider SW. The various states of von Willebrand factor and their function in physiology and pathophysiology. Thromb Haemost 2014;111(4):598-609. 17. Mylotte D, Andalib A, Theriault-Lauzier P, Dorfmeister M, Girgis M, Alharbi W, Chetrit M, Galatas C, Mamane S, Sebag I, Buithieu J, Bilodeau L, de Varennes B, Lachapelle K, Lange R, Martucci G, Virmani R, Piazza N. Transcatheter heart valve failure: a systematic review. Eur Heart J 2015;36(21):1306-27. 18. Jilaihawi H, Asch FM, Manasse E, Ruiz CE, Jelnin V, Kashif M, Kawamori H, Maeno Y, Kazuno Y, Takahashi N, Olson R, Alkhatib J, Berman D, Friedman J, Gellada N, Chakravarty T, Makkar RR. Systematic CT Methodology for the Evaluation of Subclinical Leaflet Thrombosis. JACC Cardiovasc Imaging 2017;10(4):461-470.
15
ACCEPTED MANUSCRIPT
0.7±0.2²
0.6±0.3 cm²
0.5
66±23 mmHg 39±14 mmHg 6% 30% 2%
64±29 mmHg 42±19 mmHg 7% 40% 13%
0.7 0.6 0.89 0.48 0.07
15% 2% 14%
13% 7% 20%
0.85 0.33 0.58
14% 2% 2% 75% 21% 19% 64%
7% 7% 20% 73% 46% 20% 40%
0.48 0.33 0.01 0.87 0.06 0.93 0.1
48%
20% 5±4 months 11% Phenprocoumon or NOAC Sapien XT (n=1) Sapien 3 (n=14) Portico (n=2) Symetis Acurate neo (n=1) 5% (1/18)
0.06 0.5 0.002
TE D
M AN U
RI PT
Patients with leaflet thrombosis (n=18) 81±4 67% 53%±10
EP
Age Male sex Ejection fraction (mean ±SD) Aortic Valve Area (mean±SD) Pre-procedural Echocardiographic Gradient Max Mean Previous MI Previous PCI Peripheral Arterial Disease COPD Carotid Stenosis >50% Chronic renal Insufficiency Previous Pacemaker Previous ICD Previous Stroke Hypertension Diabetes mellitus Dyslipidemia Pulmonary Hypertension Atrial fibrillation Time to CT imaging Peri-interventional medication Implanted Prosthesis
Patients without leaflet thrombosis (n=60) 81±4 42% 53%±10
SC
Table 1: Baseline clinical characteristics:
AC C
5±8 months 50% phenprocoumon or NOAC Sapien XT (n=3) Sapien 3 (n=50) Portico (n=3) Symetis Acurate neo (n=4) 15% (9/60)
Post-Procedural Angiographic Aortic Regurgitation ≥2
16
P 0.99 0.5 0.98
0.26
RI PT
ACCEPTED MANUSCRIPT
TE D
M AN U
SC
Figure 1: Multiplanar reconstruction of the aortic valve prosthesis (Sapien 3) in a patient with leaflet thickening affecting both right coronary and left coronary cusps (a). Reference lines were aligned orthogonally on the affected leaflet (a, b) to avoid overestimation of the maximal leaflet thickening (c).
AC C
Figure 3:
EP
Figure 2: Multiplanar reconstruction simulating a short-axis view of the aortic valve prostheses in 3 patients with leaflet thickening. Cusp affection is assigned according to former native cusp. (a) right coronary cusp, (b) right and left coronary cusp, (c) right, left and acoronary cusp affection.
17
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Figure 3: 73 year old patient with ischemic cardiomyopathy, status post TAVI 12/2014. CT was performed on follow-up 8 months following intervention. (a) Multiplanar reconstruction simulating echocardiographic parasternal long axis view showing leaflet thickening of the aortic valve prosthesis (Sapien 3). (B) Patient received oral anticoagulation and the CT was performed 1 month later showing resolution of the leaflet thickening.
18