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

NCT ID: NCT02486367

Last Updated: 2022-07-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-06-30
• Study Completion Date: 2019-01-31

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.

Conditions

Aortic Stenosis; Inflammation; Thrombosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Standard care/clopidogrel

300mg load followed by 75mg daily.

Group Type: ACTIVE_COMPARATOR

Clopidogrel

Intervention Type: DRUG

Standard ADP receptor blockade

Ticagrelor

180mg load followed by 90mg twice daily for 30 days.

Group Type: EXPERIMENTAL

Ticagrelor

Intervention Type: DRUG

High potency ADP receptor blockade

Interventions

Clopidogrel

Standard ADP receptor blockade

Intervention Type: DRUG

Ticagrelor

High potency ADP receptor blockade

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospitals Cleveland Medical Center

OTHER

Sponsor Role: lead

Responsible Party

David A. Zidar

Assistant Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

UH Cleveland Medical Center

Cleveland, Ohio, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

UH IRB # 06-14-33

Identifier Type: -

Identifier Source: org_study_id