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

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.

Study Overview

• Status: Completed
• Conditions: Inflammation; Thrombosis; Aortic Stenosis
• Intervention / Treatment: Drug: Clopidogrel; Drug: Ticagrelor

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 Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • UH Cleveland Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard care/clopidogrel; 300mg load followed by 75mg daily.	Drug: Clopidogrel; Standard ADP receptor blockade
Experimental: Ticagrelor; 180mg load followed by 90mg twice daily for 30 days.	Drug: Ticagrelor; High potency ADP receptor blockade

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet Reactivity	Platelet reactivity will be measured and reported as platelet reactivity units (PRU) using the VerifyNow system.	Day 0,1,7,&30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory Monocyte Proportion	The percentage of inflammatory (CD14+CD16+) monocytes as a proportion of total monocytes will be measured using flow cytometry on whole blood.	Day 0,1,7&30
Change in D-Dimer Levels as Measured by Blood Test		Day 0,1,7,&30
Change in sCD14 as Measured by Blood Test.		Day 0,1,7,&30
Change in IL-6 as Measured by Blood Test.		Day 0,1,7,&30
Change in IL-8 as Measured by Blood Test		Day0,1,7,&30
Change in Mono-CD62P as Measured by Blood Test		Day 0,1,7,&30
Change in Mono-2b3a as Measured by Blood Test		Day 0,1,7,&30

Collaborators and Investigators

• Sponsor: University Hospitals Cleveland Medical Center

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): January 1, 2019
• Study Completion (Actual): January 1, 2019

Study Registration Dates

• First Submitted: May 26, 2015
• First Submitted That Met QC Criteria: June 26, 2015
• First Posted (Estimate): July 1, 2015

Study Record Updates

• Last Update Posted (Actual): July 20, 2022
• Last Update Submitted That Met QC Criteria: June 24, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Inflammation; Aortic Valve Stenosis; Thrombosis; Constriction, Pathologic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor; Clopidogrel
• Other Study ID Numbers: UH IRB # 06-14-33