Brief Title
Inflammation and Thrombosis in Patients With Severe Aortic Stenosis After Transcatheter Aortic Valve Replacement (TAVR)
Official Title
Inflammation and Thrombosis in Patients With Severe Aortic Stenosis After Transcatheter Aortic Valve Replacement (TAVR)
Brief Summary
The central hypothesis of this study is that TAVR leads to platelet deposition and
inflammatory cell activation that can be attenuated by the potent anti-platelet and/or
pleiotropic effects of ticagrelor.
This single center, prospective randomized trial addresses the following specific aims:
1. To determine whether high-potency ADP receptor blockade reduces measures of platelet
activation in patients after TAVR.
2. To determine whether high-potency ADP receptor blockade mitigates the pro-thrombotic
inflammatory response observed after TAVR.
Detailed Description
BACKGROUND
Transcatheter Aortic Valve Replacement (TAVR) has emerged as an important alternative to
surgical aortic valve replacement. While this technology represents an important advance over
medical therapy or surgical AVR in poor operative candidates, the absolute mortality rates
remain high, even in the great majority in whom an optimal hemodynamic result is achieved. In
the randomized literature, the majority of these patients die within two years and two thirds
of these deaths are due to cardiovascular (CV) events.
The mechanisms responsible for this limited survival are unclear from the clinical trials
completed to date. While persistent valve disease undoubtedly plays a role in a subset of
patients, particularly in patients with significant aortic regurgitation, the majority of
events are due to non-valve related co-morbidities.
The hypothesis of this study is that TAVR results in at least three simultaneous CV insults:
1) the abrupt release of severely elevated left ventricular pressure into a non-compliant
systemic vasculature leads to generalized endothelial cell activation, 2) the exposure of the
pro-thrombotic and neo-antigenic contents of a degenerated aortic valve (known to
histologically resemble atherosclerosis), and 3) the exposure of the replacement valve
(bovine valve, stainless steel frame, polyester wrap). The investigators propose that these
proximate events lead to platelet activation. Given the important link between thrombosis and
inflammation governed by platelet-derived mediators and leukocyte-platelet interactions, they
further hypothesize that monocyte activation is mediated, at least in part, by
platelet-monocyte interactions, which has been shown to induce the expansion of inflammatory
monocytes. Given the pro-thrombotic nature of inflammatory monocytes, they suspect a positive
feedback loop may exist via the interplay of these thrombotic -inflammatory mechanisms, which
may be abrogated via high potency ADP-receptor blockade.
TRIAL DESIGN Primary Objective of the Study This trial is designed to determine whether
high-potency ADP-receptor blockade with ticagrelor, compared to standard care with
clopidogrel, affects platelet responsiveness and the pattern of prothrombotic monocyte
activation seen early after TAVR.
Primary and Secondary Outcomes The primary endpoint will be platelet responsiveness: platelet
function will be measured one day after TAVR using the VerifyNow P2Y12 assay, and expressed
in platelet reactivity units. The key secondary outcome measure will be the percentage of
inflammatory monocytes, measured one day after TAVR. Inflammatory monocytes will be
determined by flow cytometry, and expressed as a percentage of total monocytes.
Study Phase
Early Phase 1
Study Type
Interventional
Primary Outcome
Platelet reactivity
Secondary Outcome
Inflammatory monocyte proportion
Condition
Aortic Stenosis
Intervention
Clopidogrel
Study Arms / Comparison Groups
Standard care/clopidogrel
Description: 300mg load followed by 75mg daily.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
60
Start Date
June 2015
Completion Date
January 2019
Primary Completion Date
January 2019
Eligibility Criteria
Inclusion Criteria:
1. Valvular heart disease and a clinical indication for TAVR
2. Age of 18 years or older
3. Capable of informed consent
4. Planned transfemoral TAVR
Exclusion Criteria:
1. Prior history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage
2. Established bleeding diathesis or thrombocytopenia (<150k/dl)
3. End-stage renal disease
4. Severe hepatic impairment or liver cirrhosis
5. Pregnancy
6. Current infection
7. History of autoimmune disease
8. Established allergy to contrast agents, thienopyridines, aspirin, or ticagrelor
9. History of solid organ transplantation
10. Atrial Fibrillation, DVT, PE or other indication for long term anti-coagulation
11. Plan for direct aortic access or trans-apical TAVR
12. Enrollment in another clinical trial
13. Recent (< 12 months) or active excessive bleeding
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
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Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT02486367
Organization ID
UH IRB # 06-14-33
Responsible Party
Principal Investigator
Study Sponsor
University Hospitals Cleveland Medical Center
Study Sponsor
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Verification Date
July 2019