Coronary Artery DiseaseNCT00855374
PAR Regulation of Platelet Function in Diabetic Patients
An observational study of Coronary Artery Disease and Acute Coronary Syndrome, run by Vanderbilt University at 1 site in United States.
Trial summary
Thrombin is the most potent activator of platelets, and platelet activation is a hallmark of thrombosis. Coronary artery disease (CAD) is the major cause of mortality and morbidity in the United States and other industrialized countries, and thrombotic sequelae are the key cause of death in diabetes. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Coronary Artery Disease, Acute Coronary Syndrome, Diabetes
- How many people
- 195 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2008to Jun 2013
- Phase
- Observational
- Are there results?
- None posted in the registry
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
- Healthy volunteers accepted
- Adult, Older adult
Study population: Diabetic patients in the Vanderbilt General Clinical Research Center
Who may be able to join
- Age: over 18, Sex: male and female.
- Patients who undergo clinically indicated coronary angiography and/or PCI. Patients in Group 1 (elective PCI) include those presented with stable angina (ACC definition for stable angina).
- Coronary angiography reveals severe stenosis (>70%) that requires PCI.
- Patients in Group 2 (elective PCI in subjects with diabetes) include those who present with stable angina, or with findings on non-invasive testing (exercise or pharmacologic stimulation with imaging by nuclear perfusion imaging or stress echocardiography) in whom coronary angiography reveals severe stenosis (>70%) that requires PCI.
- Patients in Group 2 (ACS) include those presented with unstable angina or non-ST elevation myocardial infarction (as defined by the ACC).
- Coronary angiography reveals severe stenosis (>70%) that requires PCI.
Who cannot join
- Significant left main coronary artery disease.
- Severely impaired left ventricular systolic function (EF<35%).
- Prior treatment with enoxaparin, Bivalirudin (or other thrombin inhibitors), Warfarin, or thrombolytic agents <48 hours. Prior history of myocardial infarction (<6 weeks).
- Prior history of stroke (<6 weeks).
- Prior history of coronary intervention (<6 weeks).
- History of HIV/AIDS.
Show all 13Show fewer
- The patients will be identified in the following manner:
- All subjects will be picked from a pool of patients diagnosed with stable angina and diabetes from the Vanderbilt Page-Campbell Heart Institute at Vanderbilt University Medical Center and undergo a complete history and physical examination. Patients with acute coronary syndrome will be referred from the acute cardiology patient service at Vanderbilt University Medical Center.
- Subjects with hematologic, renal (creatinine > 2.0 mg/dl), hepatic, inflammatory, and neoplastic disorders, and those who sustained a recent (< 1 month) myocardial infarction, ACS, or stroke will be excluded.
- Patients who used nonsteroidal anti-inflammatory drugs, corticosteroids, or hormone replacement therapy will also be excluded.
- Pregnancy will be excluded in women of child bearing potential by measurement of urine ß-HCG (it is standard of care to determine if a woman is pregnant prior to elective PCI and will be screened as part of their PHI).
- For healthy volunteers, pregnancy will be excluded per verbal report.
- Data will be collected regarding patient demographics including height and weight, abdominal circumference, blood pressure, comorbid medical conditions, triglycerides, HDL, fasting glucose and medication use (including prescription of antithrombotic agents, ACE inhibitors, angiotensin receptor blockers, beta blockers, calcium channel antagonists and HMG-CoA inhibitors).
Trial locations and contacts
1 site in 1 country.
United States1 site
Vanderbilt University Medical Center
Nashville, Tennessee, 37232
About this study
Thrombin is the most potent activator of platelets, and platelet activation is a hallmark of thrombosis. Coronary artery disease (CAD) is the major cause of mortality and morbidity in the United States and other industrialized countries, and thrombotic sequelae are the key cause of death in diabetes. The accumulation of thrombin at sites of vascular injury provides one of the major mechanisms of recruiting platelets into a hemostatic plug. Thrombin works by activation of the G protein-coupled protease activated receptors PAR1 and PAR4 on human platelets to initiate signaling cascades leading to increases in [Ca]i, secretion of autocrine activators, trafficking of adhesion molecules to the plasma membrane, and shape change, which all promote platelet aggregation. The thrombin receptors work in a progressive manner, with PAR1 activated at low thrombin concentrations, and PAR4 recruited at higher thrombin concentrations. As direct thrombin inhibitors become widely used in clinical practice, it is important to assess their effects on vascular function. Our hypothesis is that PAR1 and PAR4 do not signal through the same G protein pathways, and that PAR4 is not a strong platelet agonist. To investigate this hypothesis, the investigators will study the G protein pathways downstream of PAR4, and assess ex-vivo platelet responsiveness to thrombin, PAR1, and PAR4 agonist peptides, both in normal human subjects, and along the stages of pathology, from patients with stable angina as well as unstable angina who are undergoing angioplasty. Similarly, the investigators will examine platelet function in patients with metabolic syndrome as well as diabetes, along the continuum from insulin resistance to full-blown disease. These studies will provide deeper insight into the G protein pathways used by PARs. They will elucidate the contribution of PAR receptors to normal platelet function as well as the abnormal platelet activation in thrombotic states. The long term goal is to understand the implications for PAR receptors as therapeutic targets for anti-platelet therapies that may carry less bleeding risk.
Read the detailed description
Given the known roles of proteases and PARs in coagulation, inflammation, pain, healing and protection, the need for development of a PAR antagonist as a therapeutic agent for treatment of thrombosis, atherosclerosis and inflammation is well-recognized. Thus, blocking PAR action by inhibiting the PAR-G protein interface is an alternative target for blocking downstream consequences of thrombin-mediated cellular activation. Since there are two PARs on human platelets, PAR1 and PAR4, it is critical to define the roles of both receptors in several likely clinical settings where PAR antagonists would be used. In this proposal both the G protein pathways underlying PAR signaling mechanisms as well as their roles in pathologies characterized by activated platelets will be studied in detail. We propose in our grant to investigate the specific roles of individual PARs in mediating the events leading to the multi-stage process of platelet activation and clot formation. The long term goals of these studies are to determine novel PAR-specific anti-platelet therapies. The 2002 estimates of the DHHS suggest that 6.3% of the population of the United States (18.2 Million people) have diabetes, with estimated annual costs of $132 Billion (Centers for Disease Control and Prevention). The complications of coronary artery and of cerebrovascular disease account for up to 65% of deaths in patients with diabetes. The prevalence, complexity and complications of cardiovascular disease are increased in patients with diabetes. This appears related to the frequent association of diabetes and of insulin resistance with traditional risk factors for atherosclerosis. Recent studies by Haffner and other investigators have established the concept of diabetes as a coronary risk equivalent; this is reflected in the guidelines for therapeutic targets set by the ADA, AHA and ACC.
The clinical importance of platelet activation is reflected by the benefits of aspirin and clopidogrel and GPIIbIIIa inhibitors in diabetics. Epidemiologic data demonstrates that the metabolic syndrome is associated with an increased incidence of atherosclerotic events. Type 2 diabetes shares many features in common with the metabolic syndrome, and may represent a precursor condition, Stern described this in the "common soil hypothesis". Hsueh and Law have more recently proposed that the progression of insulin resistance to type 2 diabetes parallels the progression of endothelial dysfunction to atherosclerosis.
These studies were designed to study PAR signaling and G protein activation states in patients with platelet activation in the setting of the continuum of the metabolic syndrome and diabetes mellitus. The degree of platelet activation as determined by assays of platelet reactivity and by the expression of markers of platelet activation will be correlated with the changes in PAR signaling. These studies will provide a comprehensive assessment of platelet activation in the setting of the metabolic syndrome, and will compare the extent of activation in this setting with that in a group of contemporaneously studied patients with diabetes mellitus. Finally, the influence of the direct thrombin inhibitor, bivalirudin on platelet activation and signaling will be assessed.
- Medical subject headings
- Coronary Artery Disease, Acute Coronary Syndrome, Diabetes Mellitus, Metabolic Syndrome
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Mar 2009 (estimated)
- Study startJun 2008
- Primary completionJun 2013
- Study completionJun 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Coronary Artery DiseaseStudies of the same condition, open and under way.
- 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
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 195 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Heidi Hamm, Vanderbilt University
- Investigators
- Heidi E Hamm, Ph.D., Principal investigator, Vanderbilt University Medical Center, Pharmacology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00855374
- Sponsor's protocol ID
- 070474
- Status last verified
- Apr 2017
- First submitted
- 2 Mar 2009
- Last updated
- 11 Apr 2017
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 11 Apr 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- PAR Regulation of Platelet Function in Diabetic Patients
- ClinicalTrials.gov ID
- NCT00855374
- Acronym / sponsor ID
- 070474
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 195 participants (actual)
- Lead sponsor
- Vanderbilt UniversityUniversity, hospital or other
- Study start
- Jun 2008
- Primary completion
- Jun 2013 (actual)
- Study completion
- Jun 2013 (actual)
- First posted
- 4 Mar 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Thrombin is the most potent activator of platelets, and platelet activation is a hallmark of thrombosis. Coronary artery disease (CAD) is the major cause of mortality and morbidity in the United States and other industrialized countries, and thrombotic sequelae are the key cause of death in diabetes. The accumulation of thrombin at sites of vascular injury provides one of the major mechanisms of recruiting platelets into a hemostatic plug. Thrombin works by activation of the G protein-coupled protease activated receptors PAR1 and PAR4 on human platelets to initiate signaling cascades leading to increases in [Ca]i, secretion of autocrine activators, trafficking of adhesion molecules to the plasma membrane, and shape change, which all promote platelet aggregation. The thrombin receptors work in a progressive manner, with PAR1 activated at low thrombin concentrations, and PAR4 recruited at higher thrombin concentrations. As direct thrombin inhibitors become widely used in clinical practice, it is important to assess their effects on vascular function. Our hypothesis is that PAR1 and PAR4 do not signal through the same G protein pathways, and that PAR4 is not a strong platelet agonist. To investigate this hypothesis, the investigators will study the G protein pathways downstream of PAR4, and assess ex-vivo platelet responsiveness to thrombin, PAR1, and PAR4 agonist peptides, both in normal human subjects, and along the stages of pathology, from patients with stable angina as well as unstable angina who are undergoing angioplasty. Similarly, the investigators will examine platelet function in patients with metabolic syndrome as well as diabetes, along the continuum from insulin resistance to full-blown disease. These studies will provide deeper insight into the G protein pathways used by PARs. They will elucidate the contribution of PAR receptors to normal platelet function as well as the abnormal platelet activation in thrombotic states. The long term goal is to understand the implications for PAR receptors as therapeutic targets for anti-platelet therapies that may carry less bleeding risk.
Detailed description
Given the known roles of proteases and PARs in coagulation, inflammation, pain, healing and protection, the need for development of a PAR antagonist as a therapeutic agent for treatment of thrombosis, atherosclerosis and inflammation is well-recognized. Thus, blocking PAR action by inhibiting the PAR-G protein interface is an alternative target for blocking downstream consequences of thrombin-mediated cellular activation. Since there are two PARs on human platelets, PAR1 and PAR4, it is critical to define the roles of both receptors in several likely clinical settings where PAR antagonists would be used. In this proposal both the G protein pathways underlying PAR signaling mechanisms as well as their roles in pathologies characterized by activated platelets will be studied in detail. We propose in our grant to investigate the specific roles of individual PARs in mediating the events leading to the multi-stage process of platelet activation and clot formation. The long term goals of these studies are to determine novel PAR-specific anti-platelet therapies. The 2002 estimates of the DHHS suggest that 6.3% of the population of the United States (18.2 Million people) have diabetes, with estimated annual costs of $132 Billion (Centers for Disease Control and Prevention). The complications of coronary artery and of cerebrovascular disease account for up to 65% of deaths in patients with diabetes. The prevalence, complexity and complications of cardiovascular disease are increased in patients with diabetes. This appears related to the frequent association of diabetes and of insulin resistance with traditional risk factors for atherosclerosis. Recent studies by Haffner and other investigators have established the concept of diabetes as a coronary risk equivalent; this is reflected in the guidelines for therapeutic targets set by the ADA, AHA and ACC.
The clinical importance of platelet activation is reflected by the benefits of aspirin and clopidogrel and GPIIbIIIa inhibitors in diabetics. Epidemiologic data demonstrates that the metabolic syndrome is associated with an increased incidence of atherosclerotic events. Type 2 diabetes shares many features in common with the metabolic syndrome, and may represent a precursor condition, Stern described this in the "common soil hypothesis". Hsueh and Law have more recently proposed that the progression of insulin resistance to type 2 diabetes parallels the progression of endothelial dysfunction to atherosclerosis.
These studies were designed to study PAR signaling and G protein activation states in patients with platelet activation in the setting of the continuum of the metabolic syndrome and diabetes mellitus. The degree of platelet activation as determined by assays of platelet reactivity and by the expression of markers of platelet activation will be correlated with the changes in PAR signaling. These studies will provide a comprehensive assessment of platelet activation in the setting of the metabolic syndrome, and will compare the extent of activation in this setting with that in a group of contemporaneously studied patients with diabetes mellitus. Finally, the influence of the direct thrombin inhibitor, bivalirudin on platelet activation and signaling will be assessed.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- Diabetic patients in the Vanderbilt General Clinical Research Center
Key inclusion criteria (6 listed)
- Age: over 18, Sex: male and female.
- Patients who undergo clinically indicated coronary angiography and/or PCI. Patients in Group 1 (elective PCI) include those presented with stable angina (ACC definition for stable angina).
- Coronary angiography reveals severe stenosis (>70%) that requires PCI.
- Patients in Group 2 (elective PCI in subjects with diabetes) include those who present with stable angina, or with findings on non-invasive testing (exercise or pharmacologic stimulation with imaging by nuclear perfusion imaging or stress echocardiography) in whom coronary angiography reveals severe stenosis (>70%) that requires PCI.
- Patients in Group 2 (ACS) include those presented with unstable angina or non-ST elevation myocardial infarction (as defined by the ACC).
Key exclusion criteria (13 listed)
- Significant left main coronary artery disease.
- Severely impaired left ventricular systolic function (EF<35%).
- Prior treatment with enoxaparin, Bivalirudin (or other thrombin inhibitors), Warfarin, or thrombolytic agents <48 hours. Prior history of myocardial infarction (<6 weeks).
- Prior history of stroke (<6 weeks).
- Prior history of coronary intervention (<6 weeks).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Apr 2017.
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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.
Heidi E Hamm, Ph.D. principal investigator
Vanderbilt University Medical Center, Pharmacology
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Coronary Artery Disease and Acute Coronary Syndrome, run by Vanderbilt University 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 6 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 11 Apr 2017. 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.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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.
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 11 Apr 2017.