1. Leaflet Thrombosis Following Transcatheter Aortic Valve Replacement: Insights from the MAUDE Database
Ankur Kalra, Abdul Moiz Hafiz, Ronnie Ramadan, Marie-France Poulin,
Ali Andalib, Colin T. Phillips, Deepak L. Bhatt, Michael J. Reardon,
Neal S. Kleiman, Jeffrey J. Popma

3. Disclosures
Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute (including for serving as DMC Chair for the PORTICO trial funded by St. Jude, now Abbott), Mayo Clinic, Mount Sinai School of Medicine, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott); Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, PLx Pharma, Takeda.
Dr. Reardon reports a personal fees from Medtronic, Inc.
Dr. Popma discloses the following relationships - Institutional Grants: Medtronic, Inc., Boston Scientific, Abbott Vascular; Medical Advisory Board: Boston Scientific, Abbott Vascular; Consultant: Direct Flow Medical.
None of the other authors report any conflicts of interest or have any disclosures to make.

4. Background
Leaflet thrombosis is a recently recognized and important mechanism of transcatheter heart valve failure.1-3
It is not known whether leaflet thrombosis after transcatheter aortic valve replacement (TAVR) has serious clinical consequences.2
The Manufacturer and User Facility Device Experience (MAUDE) database houses adverse events involving medical devices submitted to the FDA by mandatory and voluntary reporters.4,5
MAUDE provides the opportunity to identify device-related events that may be underrecognized, or previously regarded as infrequent.
1Chakravarty T, Søndergaard L, Friedman J, et al.; RESOLVE; SAVORY Investigators. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet. 2017;389:
2Holmes DR, Mack MJ. Uncertainty and possible subclinical valve leaflet thrombosis. N Engl J Med. 2015;373:
3Makkar RR, Fontana G, Jilaihawi H, et al. Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med. 2015;373:
4https:// Accessed April 30, 2017.
5http:// Accessed April 30, 2017.

5. Methods: Data Collection
Between January October 2015, the MAUDE database was searched with identifier code, “NPT,” designated by the FDA to identify TAVR-related adverse events.
Selected entries were searched further containing the following terms:
Leaflet
Central aortic regurgitation (AR)
Aortic stenosis
The following data were recorded:
Presentation of leaflet thrombosis (aortic stenosis or regurgitation or mixed valve lesion)
Mode of diagnosis (echocardiography, computed tomography, surgical explantation, or autopsy)
Timing of onset after TAVR
January October 2015
“NPT”
leaflet
central AR
aortic stenosis

6. Methods: Exclusion Criteria
All reports under the “NPT” code category that did not have the term “leaflet” were excluded
Other exclusion criteria were cases of structural valve dysfunction (SVD):
Due to procedure-related factors
Valve embolization
Malpositioning
Not classified into leaflet restriction or malcoaptation
Termed “other/unknown”
“NPT” entries in MAUDE database (n=5,691)
EXCLUDED
No term “leaflet” in entries
Procedure-related complications
Other/unknown SVD

7. Methods: Data Collection
Diagnosis of leaflet thrombosis:
Presence of acute- or subacute-onset of heart failure, or
Stroke/TIA symptoms with
either
Direct visualization of leaflet thrombosis on echocardiogram, or
Increase in mean gradient > 10 mmHg with no thrombus visible, or
Regression of elevated mean gradient after oral anticoagulation therapy or
Presence of reduced leaflet motion or hypoattenuated leaflet thickening on computed tomography angiogram
Evidence of device thrombosis at autopsy or via examination of tissue during reoperation

8. Methods: Data Collection
Timing of presentation after TAVR6:
Acute (0-3 days)
Subacute (3 days to 3 months)
Late (3 months to 1 year)
Very late (> 1 year)
Outcomes:
Stroke or TIA
Cardiogenic shock (vasopressor or mechanical circulatory support)
Death from any cause
Adverse event entries were also stratified by valve type:
Balloon-expandable valve
Self-expanding valve
6Dangas GD, Weitz JI, Giustino G, Makkar R, Mehran R. Prosthetic heart valve thrombosis. J Am Coll Cardiol. 2016;68:

9. Methods: Statistical Analysis
Descriptive statistical methods were used to describe medians for continuous variables, and frequency for categorical variables.
Data analysis was performed using STATA 14.0 (StataCorp, TX).

10. Results
There were 5,691 TAVR-related adverse events reported in MAUDE database.
Of these, 546 adverse events were segregated based on pre-specified search terms.
The final analysis included 156 adverse events of structural valve dysfunction:
Leaflet restriction (n=129)
Leaflet malcoaptation (n=27)
Structural valve dysfunction due to leaflet thrombosis occurred in 30 cases:
Edwards-Sapien = 20
CoreValve® = 10
“NPT” entries in MAUDE database (n=5,691)
Structural valve dysfunction
(n=546)
EXCLUDED
Procedure-related complications
(n=295)
Structural valve dysfunction
(n=251)
Other/unknown SVD
(n=95)
Leaflet restriction
(n=129)
Leaflet malcoaptation
(n=27)
Total leaflet thrombosis (n=30)
Leaflet thrombosis
(n=29)
Leaflet thrombosis
(n=1)

11. Results 60% (18/30) cases occurred in the first year following TAVR15 12 9 6 3
Number of cases
0-6
7-12
13-18
19-24
25-30
31-36
37-42
43-48
49-54
55-60
Time (months)
Number of cases of leaflet thrombosis post TAVR 15 12 9 6 3
Number of cases
Time
Leaflet thrombosis post TAVR
60% (18/30) cases occurred in the first year following TAVR
40% (12/30) cases occurred during months
Structural valve dysfunction presented as either:
Aortic stenosis 53.3% (16/30)
Regurgitation 23.3% (7/30)
Both 13.3% (4/30)
The remainder of 3/30 patients had stroke/TIA
Timing of occurrence after TAVR:
Aortic stenosis 15.5±12.2 months
Regurgitation 10.1±10.9 months 15 12 9 6 3
Number of cases
Aortic stenosis post TAVR
Time 15 12 9 6 3
Time
Aortic regurgitation post TAVR
Number of cases
Acute: 0 - 3d
Subacute: 3d - 3mo
Late: 3mo - 1yr
Very late: > 1yr

12. Results Antiplatelet or anticoagulant therapy 26.7% (8/30)
Interventions to address leaflet thrombosis:
Antiplatelet or anticoagulant therapy 26.7% (8/30)
Valve-in-valve TAVR 10.0% (3/30)
Surgery 46.7% (14/30)
Diuretics (n=1); thrombus aspiration (n=1); balloon aortic valvuloplasty (n=2); no intervention (n=2)
Outcome following leaflet thrombosis:
Stroke/TIA 10.0% (3/30)
Cardiogenic shock 6.7% (2/30)
Death 30.0% (9/30)

13. Limitations Ascertainment bias
Lack of independent verification of each report
Time lapse and interim management decisions between adverse event occurrence and final interventions not available
Plausible that a different diagnosis other than leaflet thrombosis was considered in patients that had surgery (e.g. infective endocarditis)
Incomplete capture of all events due to lack of standard definitions during the study period, leading to missed diagnoses, and underreporting by manufacturers
Search terms did not include “stroke/TIA,” due to uncertainty with regard to appropriate adjudication of stroke/TIA events in the TAVR population

14. Conclusions
Leaflet thrombosis is a serious adverse event following TAVR.
Most cases occurred in the first year following TAVR, presented as aortic stenosis or regurgitation, and required surgery in 46.7% of cases.
Clinically manifest leaflet thrombosis was associated with serious clinical manifestations including:
Stroke
Cardiogenic shock
Death
While these data do not provide the frequency of these events, and undoubtedly the clinical events often led to the recognition of leaflet thrombosis, they are useful in that they establish definitive evidence of its occurrence.
Early diagnosis of leaflet thrombosis may be crucial for planning appropriate management and optimizing clinical outcome for patients.

15. Published in
Hafiz, A.M., Kalra, A., Ramadan, R., Poulin, M-F., Andalib, A., Phillips, C.T., Bhatt, D.L., Reardon, M.J., Kleiman, N.S., Popma, J.J.
Clinical or Symptomatic Leaflet Thrombosis Following Transcatheter Aortic Valve Replacement: Insights from the U.S. FDA MAUDE Database. Structural Heart. 2017;1(5-6): doi: /
Available online at