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Percutaneous coronary intervention (PCI) for acute coronary syndromes frequently fails to restore myocardial perfusion despite establishing epicardial vessel patency. Endothelin-1 (ET-1) is a potent vasoconstrictor and its expression is increased in atherosclerotic coronary arteries. Our hypothesis is that increased activity of the endogenous endothelin system contributes to microvascular dysfunction, and adjunctive therapy with an endothelin receptor antagonist will result in improved microvascular blood flow.
Aims: The aims of the study are to assess in patients with non ST-elevation myocardial infarction, whether: 1) PCI causes an increase in coronary blood ET-1 level; 2) an endothelin receptor antagonist acutely improves coronary microvascular blood flow following PCI.
Non-ST segment elevation myocardial infarction (NSTEMI) is one type of heart attack. It is defined as the development of heart muscle necrosis results from an acute interruption of blood supply to a part of the heart which is demonstrated by an elevation of cardiac markers Creatinine Kinase Isoenzyme Muscle/Brain Type (CK-MB) in the blood and the absence of ST-segment elevation in ECG (electrocardiography). ST-segment is a portion of ECG, its elevation indicates full thickness damage of heart muscle. Absence of ST-segment elevation in NSTEMI indicates partial thickness damage of heart muscle occurs. Therefore, NSTEMI is less severe type of heart attack compared to STEMI (ST-segment elevation myocardial infarction) in which full thickness damage of heart muscle occurs.
Our hypothesis is that the endogenous endothelin system contributes to microvascular dysfunction and impaired myocardial reperfusion following successful PCI for non ST-elevation MI, and that endothelin receptor antagonism will improve microvascular flow. The study will provide new insight into the humoral regulation of the microcirculation in patients presenting with acute coronary syndromes.
General methods: This section describes our approach to investigating the specific aims. The study is a prospective, double blind, placebo-controlled trial to assess the efficacy of a selective endothelin type A receptor antagonist (BQ-123), as adjunctive therapy for PCI for non ST elevation MI. The control group will receive placebo rather than another vasodilator in order to specifically elucidate the role of the endogenous endothelin system.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| BQ-123 | Experimental | BQ-123 will be infused at 300 nmol/min for 20 minutes prior to percutaneous coronary intervention (PCI). |
|
| Placebo | Placebo Comparator | Subjects randomized to the placebo arm will receive a placebo infusion (saline) for 20 minutes prior to PCI. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| BQ-123 | Drug | BQ-123 is a cyclic peptide consisting of five amino acids. BQ-123 will be infused at 300 nmol/min for 20 minutes prior to percutaneous coronary intervention (PCI). |
|
| Measure | Description | Time Frame |
|---|---|---|
| Average Peak Velocity (APV) Immediately Following Percutaneous Coronary Intervention (PCI) | Coronary microvascular blood flow will be assessed following successful PCI by measuring APV in the culprit vessel using Doppler echocardiography. | immediately following PCI procedure |
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change in Creatinine Kinase Isoenzyme Muscle/Brain Type (CK-MB) From Immediately Pre-PCI to 8 and 16 Hours Post-PCI | CK-MB is a cardiac marker that can demonstrate the development of heart muscle necrosis resulting from an acute interruption of blood supply to a part of the heart. CK-MB is measured by a blood test. | immediately pre-PCI, 8 hours post-PCI, 16 hours post-PCI |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Abhiram Prasad, M.D. | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic | Rochester | Minnesota | 55905 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27547429 | Derived | Guddeti RR, Prasad A, Matsuzawa Y, Aoki T, Rihal C, Holmes D, Best P, Lennon RJ, Lerman LO, Lerman A. Role of endothelin in microvascular dysfunction following percutaneous coronary intervention for non-ST elevation acute coronary syndromes: a single-centre randomised controlled trial. Open Heart. 2016 Aug 4;3(2):e000428. doi: 10.1136/openhrt-2016-000428. eCollection 2016. |
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| ID | Title | Description |
|---|---|---|
| FG000 | BQ-123 | The selective endothelin type A receptor antagonist (BQ-123) will be infused at 300 nmol/min for 20 minutes prior to percutaneous coronary intervention (PCI). |
| FG001 | Placebo | Subjects randomized to the placebo arm will receive a placebo infusion (saline) for 20 minutes prior to PCI. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
12 subjects were enrolled on the BQ-123 arm, but 1 subject was excluded due to unsuccessful PCI.
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| ID | Title | Description |
|---|---|---|
| BG000 | BQ-123 | BQ-123 will be infused at 300 nmol/min for 20 minutes prior to percutaneous coronary intervention (PCI). |
| BG001 | Placebo | Subjects randomized to the placebo arm will receive a placebo infusion (saline) for 20 minutes prior to PCI. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Average Peak Velocity (APV) Immediately Following Percutaneous Coronary Intervention (PCI) | Coronary microvascular blood flow will be assessed following successful PCI by measuring APV in the culprit vessel using Doppler echocardiography. | One subject on the BQ-123 arm was excluded from the analysis due to unsuccessful PCI. | Posted | Median | Inter-Quartile Range | cm/s | immediately following PCI procedure |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | BQ-123 | BQ-123 will be infused at 300 nmol/min for 20 minutes prior to percutaneous coronary intervention (PCI). |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Amir Lerman | Mayo Clinic | 507-255-6670 | lerman.amir@mayo.edu |
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| ID | Term |
|---|---|
| D015428 | Myocardial Reperfusion Injury |
| D003324 | Coronary Artery Disease |
| D000072658 | Non-ST Elevated Myocardial Infarction |
| ID | Term |
|---|---|
| D009202 | Cardiomyopathies |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D017202 | Myocardial Ischemia |
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| ID | Term |
|---|---|
| C072247 | cyclo(Trp-Asp-Pro-Val-Leu) |
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| Placebo | Drug | Subjects randomized to the placebo arm will receive a placebo infusion (saline) for 20 minutes prior to PCI. |
|
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
|
| Secondary | Percent Change in Creatinine Kinase Isoenzyme Muscle/Brain Type (CK-MB) From Immediately Pre-PCI to 8 and 16 Hours Post-PCI | CK-MB is a cardiac marker that can demonstrate the development of heart muscle necrosis resulting from an acute interruption of blood supply to a part of the heart. CK-MB is measured by a blood test. | One subject on the BQ-123 arm was excluded from the analysis due to unsuccessful PCI. | Posted | Median | Inter-Quartile Range | percent change | immediately pre-PCI, 8 hours post-PCI, 16 hours post-PCI |
|
|
|
|
| 0 |
| 12 |
| 0 |
| 12 |
| EG001 | Placebo | Subjects randomized to the placebo arm will receive a placebo infusion for 20 minutes prior to PCI. | 0 | 11 | 0 | 11 |
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| D014652 |
| Vascular Diseases |
| D015427 | Reperfusion Injury |
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D003327 | Coronary Disease |
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D009203 | Myocardial Infarction |
| D007238 | Infarction |
| D007511 | Ischemia |
| D009336 | Necrosis |
| 0.007 |
| No |
| Superiority or Other |