Aortic StenosisPhase 4NCT02486367
Inflammation and Thrombosis in Patients With Severe Aortic Stenosis After Transcatheter Aortic Valve Replacement (TAVR)
A Phase 4 study testing Clopidogrel and Ticagrelor in people with Aortic Stenosis and Inflammation, run by University Hospitals Cleveland Medical Center at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Aortic Stenosis, Inflammation, Thrombosis
- What is being tested?
- Clopidogrel and Ticagrelor
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2015to Jan 2019
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Valvular heart disease and a clinical indication for TAVR
- Age of 18 years or older
- Capable of informed consent
- Planned transfemoral TAVR
Who cannot join
- Prior history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage
- Established bleeding diathesis or thrombocytopenia (<150k/dl)
- End-stage renal disease
- Severe hepatic impairment or liver cirrhosis
- Pregnancy
- Current infection
Show all 13Show fewer
- History of autoimmune disease
- Established allergy to contrast agents, thienopyridines, aspirin, or ticagrelor
- History of solid organ transplantation
- Atrial Fibrillation, DVT, PE or other indication for long term anti-coagulation
- Plan for direct aortic access or trans-apical TAVR
- Enrollment in another clinical trial
- Recent (< 12 months) or active excessive bleeding
Trial locations and contacts
1 site in 1 country.
About this study
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:
- To determine whether high-potency ADP receptor blockade reduces measures of platelet activation in patients after TAVR.
- To determine whether high-potency ADP receptor blockade mitigates the pro-thrombotic inflammatory response observed after TAVR.
Read the 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
- Being tested
- Clopidogrel, Ticagrelor
- Medical subject headings
- Aortic Valve Stenosis, Inflammation, Thrombosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ClopidogrelDrug
Standard ADP receptor blockade
TicagrelorDrug
High potency ADP receptor blockade
| Study group | Role | What they receive |
|---|---|---|
| Standard care/clopidogrel | Active comparator | 300mg load followed by 75mg daily. Receives: Drug: Clopidogrel |
| Ticagrelor | Experimental | 180mg load followed by 90mg twice daily for 30 days. Receives: Drug: Ticagrelor |
What is being measured
The primary outcome is the main question the study is designed to answer.
Platelet Reactivity
Platelet reactivity will be measured and reported as platelet reactivity units (PRU) using the VerifyNow system.
Measured: Day 0,1,7,&30
Secondary outcomes (7)
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.
Measured: Day 0,1,7&30
Change in D-Dimer Levels as Measured by Blood Test
Measured: Day 0,1,7,&30
Change in sCD14 as Measured by Blood Test.
Measured: Day 0,1,7,&30
Change in IL-6 as Measured by Blood Test.
Measured: Day 0,1,7,&30
Change in IL-8 as Measured by Blood Test
Measured: Day0,1,7,&30
Change in Mono-CD62P as Measured by Blood Test
Measured: Day 0,1,7,&30
Change in Mono-2b3a as Measured by Blood Test
Measured: Day 0,1,7,&30
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jul 2015 (estimated)
- Study startJun 2015
- Primary completionJan 2019
- Study completionJan 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Aortic StenosisStudies of the same condition, open and under way.
- More trials run by University Hospitals Cleveland Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospitals Cleveland Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, David A. Zidar, University Hospitals Cleveland Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02486367
- Sponsor's protocol ID
- UH IRB # 06-14-33
- Status last verified
- Jun 2022
- First submitted
- 26 May 2015
- Last updated
- 20 Jul 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 20 Jul 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Inflammation and Thrombosis in Patients With Severe Aortic Stenosis After Transcatheter Aortic Valve Replacement (TAVR)
- ClinicalTrials.gov ID
- NCT02486367
- Acronym / sponsor ID
- UH IRB # 06-14-33
- Conditions
- Aortic Stenosis, Inflammation, Thrombosis
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- University Hospitals Cleveland Medical CenterUniversity, hospital or other
- Study start
- Jun 2015
- Primary completion
- Jan 2019 (actual)
- Study completion
- Jan 2019 (actual)
- First posted
- 1 Jul 2015 (estimated)
- Results
- Posted 20 Jul 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- To determine whether high-potency ADP receptor blockade reduces measures of platelet activation in patients after TAVR.
- 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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Standard care/clopidogrel | Active comparator | Drug: Clopidogrel300mg load followed by 75mg daily. |
| Ticagrelor | Experimental | Drug: Ticagrelor180mg load followed by 90mg twice daily for 30 days. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Valvular heart disease and a clinical indication for TAVR
- Age of 18 years or older
- Capable of informed consent
- Planned transfemoral TAVR
Key exclusion criteria (13 listed)
- Prior history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage
- Established bleeding diathesis or thrombocytopenia (<150k/dl)
- End-stage renal disease
- Severe hepatic impairment or liver cirrhosis
- Pregnancy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ClopidogrelStandard ADP receptor blockade | Drug | Standard care/clopidogrel |
| TicagrelorHigh potency ADP receptor blockade | Drug | Ticagrelor |
Primary outcome
Platelet Reactivity
Time frame: Day 0,1,7,&30
Platelet reactivity will be measured and reported as platelet reactivity units (PRU) using the VerifyNow system.
7 secondary outcomes
Inflammatory Monocyte Proportion
Time frame: Day 0,1,7&30
Change in D-Dimer Levels as Measured by Blood Test
Time frame: Day 0,1,7,&30
Change in sCD14 as Measured by Blood Test.
Time frame: Day 0,1,7,&30
Change in IL-6 as Measured by Blood Test.
Time frame: Day 0,1,7,&30
Change in IL-8 as Measured by Blood Test
Time frame: Day0,1,7,&30
Change in Mono-CD62P as Measured by Blood Test
Time frame: Day 0,1,7,&30
Change in Mono-2b3a as Measured by Blood Test
Time frame: Day 0,1,7,&30
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Jul 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Clopidogrel and Ticagrelor in people with Aortic Stenosis and Inflammation, run by University Hospitals Cleveland Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Jul 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Platelet Reactivity (time frame: Day 0,1,7,&30). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Jul 2022.