BQ-123: Role of Endothelin in Microvascular Dysfunction Following PCI for NSTEMI

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00586820
• Collaborator: (none)
• Enrollment: 23
• Location: 1
• Arms: 2
• Duration (Months): 80
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Myocardial Reperfusion Injury	Drug: BQ-123; Drug: Placebo	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Role of Endothelin in Microvascular Dysfunction Following Percutaneous Coronary Intervention for Non-ST Elevation Myocardial Infarction
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BQ-123 BQ-123 will be infused at 300 nmol/min for 20 minutes prior to percutaneous coronary intervention (PCI).	Drug: BQ-123; 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).
Placebo Comparator: Placebo Subjects randomized to the placebo arm will receive a placebo infusion (saline) for 20 minutes prior to PCI.	Drug: Placebo; Subjects randomized to the placebo arm will receive a placebo infusion (saline) for 20 minutes prior to PCI.

Outcome Measures

Primary Outcome Measures

1. Average Peak Velocity (APV) Immediately Following Percutaneous Coronary Intervention (PCI) [immediately following PCI procedure]

   Coronary microvascular blood flow will be assessed following successful PCI by measuring APV in the culprit vessel using Doppler echocardiography.

Secondary Outcome Measures

1. Percent Change in Creatinine Kinase Isoenzyme Muscle/Brain Type (CK-MB) From Immediately Pre-PCI to 8 and 16 Hours Post-PCI [immediately pre-PCI, 8 hours post-PCI, 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age ≥ 18 years

• Clinical diagnosis of unstable angina or non ST-elevation myocardial infarction, and requiring clinically indicated PCI for the management of non ST elevation acute coronary syndrome.

Exclusion Criteria:

• Systemic hypotension (systolic <90 mmHg)

• Heart failure or known ejection fraction < 30%

• Left main disease

• Culprit lesion is in a saphenous vein graft

• 100% occlusion of the culprit vessel or culprit is an ostial right coronary stenosis

• Currently enrolled in other active cardiovascular investigational studies

• Severe endocrine, hepatic, or renal disorders

• Pregnancy or lactation

• Federal Medical Center inmates

• Inability or unwillingness to provide informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic

Investigators

• Principal Investigator: Abhiram Prasad, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Amir Lerman, Professor of Medicine, College of Medicine, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00586820
• Other Study ID Numbers: 859-05
• First Posted: Jan 7, 2008
• Last Update Posted: Jul 4, 2014
• Last Verified: Jun 1, 2014

• Keywords provided by Amir Lerman, Professor of Medicine, College of Medicine, Mayo Clinic: Coronary Atherosclerosis; Microvascular Dysfunction; Non-ST Elevation Myocardial Infarction
• Additional relevant MeSH terms: Reperfusion Injury; Non-ST Elevated Myocardial Infarction; Myocardial Reperfusion Injury; cyclo(Trp-Asp-Pro-Val-Leu)

Study Results

Participant Flow

Arm/Group Title	BQ-123	Placebo
Arm/Group Description	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).	Subjects randomized to the placebo arm will receive a placebo infusion (saline) for 20 minutes prior to PCI.
Period Title: Overall Study
STARTED	12	11
COMPLETED	11	11
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	BQ-123	Placebo	Total
Arm/Group Description	BQ-123 will be infused at 300 nmol/min for 20 minutes prior to percutaneous coronary intervention (PCI).	Subjects randomized to the placebo arm will receive a placebo infusion (saline) for 20 minutes prior to PCI.	Total of all reporting groups
Overall Participants	11	11	22
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.5 (11.2)	64 (12.5)	64.27 (11.6)
Sex: Female, Male (Count of Participants)
Female	4 36.4%	2 18.2%	6 27.3%
Male	7 63.6%	9 81.8%	16 72.7%
Region of Enrollment (participants) [Number]
United States	11 100%	11 100%	22 100%

Outcome Measures

1. Primary Outcome

Title	Average Peak Velocity (APV) Immediately Following Percutaneous Coronary Intervention (PCI)
Description	Coronary microvascular blood flow will be assessed following successful PCI by measuring APV in the culprit vessel using Doppler echocardiography.
Time Frame	immediately following PCI procedure

Outcome Measure Data

Analysis Population Description

One subject on the BQ-123 arm was excluded from the analysis due to unsuccessful PCI.

Arm/Group Title	BQ-123	Placebo
Arm/Group Description	BQ-123 will be infused at 300 nmol/min for 20 minutes prior to percutaneous coronary intervention (PCI).	Subjects randomized to the placebo arm will receive a placebo infusion (saline) for 20 minutes prior to PCI.
Measure Participants	11	11
Median (Inter-Quartile Range) [cm/s]	30	19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BQ-123, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.029
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Percent Change in Creatinine Kinase Isoenzyme Muscle/Brain Type (CK-MB) From Immediately Pre-PCI to 8 and 16 Hours Post-PCI
Description	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.
Time Frame	immediately pre-PCI, 8 hours post-PCI, 16 hours post-PCI

Outcome Measure Data

Analysis Population Description

One subject on the BQ-123 arm was excluded from the analysis due to unsuccessful PCI.

Arm/Group Title	BQ-123	Placebo
Arm/Group Description	BQ-123 will be infused at 300 nmol/min for 20 minutes prior to percutaneous coronary intervention (PCI).	Subjects randomized to the placebo arm will receive a placebo infusion (saline) for 20 minutes prior to PCI.
Measure Participants	11	11
% Change immediate pre-PCI, 8 hr post-PCI	-17	26
% Change immediate pre-PCI, 16 hr post-PCI	-17	107

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BQ-123, Placebo
	Comments	Change between the groups from immediate pre-PCI and 8 hours post PCI.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BQ-123, Placebo
	Comments	Change between the groups from immediate pre-PCI and 16 hours post-PCI.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Arm/Group Title	BQ-123		Placebo
Arm/Group Description	BQ-123 will be infused at 300 nmol/min for 20 minutes prior to percutaneous coronary intervention (PCI).		Subjects randomized to the placebo arm will receive a placebo infusion for 20 minutes prior to PCI.
All Cause Mortality
	BQ-123		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	BQ-123		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	BQ-123		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/11 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.