Inflammation and Thrombosis in Patients With Severe Aortic Stenosis After Transcatheter Aortic Valve Replacement (TAVR)

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

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

, ,

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

, ,

Verification Date

July 2019