Comparison of Intravenous Adenosine Infusion With Regadenoson Bolus for Inducing Maximal Coronary Hyperemia

• Sponsor: St. Louis University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01161121
• Collaborator: University of Florida (Other), Astellas Pharma US, Inc. (Industry)
• Enrollment: 46
• Locations: 2
• Arm: 1
• Duration (Months): 33
• Patients Per Site: 23
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if regadenoson is as safe and effective as adenosine when used in the cardiac catheterization lab during measurement of coronary flow reserve and fractional flow reserve. The study hypothesis is the assessment of Fractional Flow Reserve (FFR) in the catheterization lab can be performed with equivalent accuracy when hyperemia is induced with IV Regadenoson compared with IV Adenosine without compromising patient safety.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease	Drug: adenosine; Drug: regadenoson	Phase 1

Detailed Description

Patients with clinical indications to be assessed by fractional flow reserve (FFR) will be included. Following diagnostic angiography in the catheterization lab, the patient will have a guide catheter placed in the artery to be assessed followed by placing a pressure guidewire down the coronary vessel and past the lesion of interest. FFR will be measured in the traditional manner, with intravenous adenosine infusing at 140 mcg/kg/min until maximal steady state hyperemia is reached. At this point, the FFR will be recorded as Pd (distal pressure from the pressure wire in the coronary artery) divided by Pa (proximal pressure from the guide catheter). The adenosine infusion will then be stopped and the patient's hemodynamics allowed to return to baseline. Once baseline state is again achieved, an intravenous bolus of regadenson (0.4 mg) will be given and FFR will be remeasured as the lowest steady state Pd/Pa. Patients will be enrolled at two sites, The University of Florida

• where FFR will be measured alone, and Saint Louis University, where coronary flow will be measured simultaneously to evaluate the effect of regadenoson on coronary flow velocity as compared to adenosine. The primary endpoint of the study will be to compare the FFR achieved with adeonsine to that obtained with regadenoson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Utilization of Lexiscan (Regadenoson)in the Cardiac Catheterization Lab to Achieve Maximal Hyperemia for Coronary Physiologic Assessment With Fractional Flow Reserve
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Apr 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Adenosine then Regadenoson Adenosine infusion will be compared to Regadenoson for efficacy and safety/side effects. Arterial blood pressure, coronary pressure, heart rate, oxygen saturation and coronary flow, FFR, and coronary flow velocity will be assessed. Safety will be assessed by monitoring for any side effects such as chest pain, headache, flushing, nausea, or arrhythmias. Adenosine infusion will be administered at 140 mcg/kg for 2 minutes and once mean coronary flow velocity returns to within 15% of pre-dose value, Regadenoson IV bolus 0.4 mg/5 ml will be administered followed by a 5 cc normal saline flush.

Drug: adenosine; Measuring FFR and Coronary Flow Reserve after administration of IV adenosine 140 mcg/kg/min for 2 minutes.; Other Names: Adenoscan(adenosine) ; Drug: regadenoson; Measuring FFR and Coronary Flow Reserve after administration of IV regadenoson 0.4 mg over 10 seconds.; Other Names: Lexiscan

Outcome Measures

Primary Outcome Measures

1. Difference in FFR Between IV Adenosine and IV Regadenoson [At maximal, steady-state hyperemia]

   FFR (as calculated by the ratio of lowest Pd/Pa at maximal hyperemia) was compared between hyperemia achieved with adenosine and with regadenoson

Secondary Outcome Measures

1. Heart Rate Changes With Drug [During drug infusion and until restoration of baseline hemodynamics]

   Maximal heart rate documented following the administration of each agent

2. Side Effects of Medication Administration [During drug infusion and until restoration of baseline hemodynamics]

   Chest pain, chest discomfort, burning, flushing, headache, nausea, or shortness of breath

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• male or female patients greater than 18 years old (If female, pt. must be post-menopausal, surgically sterile, or be non-pregnant as determined by a negative urine or serum beta human chorionic gonadotropin (B-HCG) pregnancy test within 24 hours prior to enrollment.

• Provided written consent approved by Institutional Review Board and provided Health Insurance Portability and Accountability Act (HIPAA) authorization

• Have at least one coronary stenosis (greater or equal to 40% but less than 70& narrowing by visual inspection) and technically accessible coronary artery into which the pressure wire may be introduced.

Exclusion Criteria:

• ST elevation myocardial infarction

• Cardiogenic shock

• Pregnancy

• Total vessel occlusion

• Extremely tortuous coronary arteries

• Second and third degree heart block without pacemaker

• Severe chronic obstructive pulmonary disease and active bronchospasm

• Less than age 18 years

• Have received theophylline, aminophylline, pentoxifylline or dipyridamole within 12 hours of FFR measurement.

• Has severe 3 vessel disease defined by >80% luminal narrowing by visual inspection

• Known hypersensitivity to adenosine or regadenoson

• Recent uncontrolled ventricular arrhythmia

• History of greater than Type I atrioventricular block, symptomatic resting bradycardia, sick sinus syndrome (without permanent pacemaker)

• History of heart transplantation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Jacksonville	Florida	United States	32209
2	St. Louis University	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• St. Louis University
• University of Florida
• Astellas Pharma US, Inc.

Investigators

• Principal Investigator: Michael J Lim, MD, St. Louis University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Iskandrian AE, Bateman TM, Belardinelli L, Blackburn B, Cerqueira MD, Hendel RC, Lieu H, Mahmarian JJ, Olmsted A, Underwood SR, Vitola J, Wang W; ADVANCE MPI Investigators. Adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging: results of the ADVANCE phase 3 multicenter international trial. J Nucl Cardiol. 2007 Sep-Oct;14(5):645-58.
• Lim MJ, Kern MJ. Coronary pathophysiology in the cardiac catheterization laboratory. Curr Probl Cardiol. 2006 Aug;31(8):493-550. Review.
• Pijls NH, Van Gelder B, Van der Voort P, Peels K, Bracke FA, Bonnier HJ, el Gamal MI. Fractional flow reserve. A useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow. Circulation. 1995 Dec 1;92(11):3183-93.
• Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, Klauss V, Manoharan G, Engstrøm T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009 Jan 15;360(3):213-24. doi: 10.1056/NEJMoa0807611.

• Responsible Party: Michael J. Lim, Director, Division of Cardiology, St. Louis University
• ClinicalTrials.gov Identifier: NCT01161121
• Other Study ID Numbers: Rega-9I06
• First Posted: Jul 13, 2010
• Last Update Posted: Jun 23, 2017
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Michael J. Lim, Director, Division of Cardiology, St. Louis University: Fractional flow reserve; adenosine; regadenoson
• Additional relevant MeSH terms: Coronary Artery Disease; Hyperemia; Adenosine; Regadenoson

Study Results

Participant Flow

Recruitment Details	Patients provided written consent for participation in the study prior to cardiac catheterization. Diagnostic coronary angiography was performed utilizing standard techniques. Patients in whom the operator believed needed physiologic coronary assessment with Fractional Flow Reserve (FFR) were then eligible for participation in the study.

Arm/Group Title	Adenosine Then Regadenoson
Arm/Group Description	Adenosine infusion will be compared to Regadenoson for efficacy and safety/side effects. Arterial blood pressure, coronary pressure, heart rate, oxygen saturation and coronary flow, FFR, and coronary flow velocity will be assessed. Safety will be assessed by monitoring for any side effects such as chest pain, headache, flushing, nausea, or arrhythmias. All patients to receive Adenosine infusion followed by Regadenoson IV bolus upon return of coronary flow velocity to 15% of pre-dose value. Adenosine : Injection of IV Adenosine for 2 minutes at rate of 140mcg/kg to dilate coronary arteries and provoke maximal hyperemia. Regadenoson : Administration of IV regadenoson bolus 0.4 mg/5 mls over 10 seconds followed by a 5 cc NS saline flush
Period Title: Overall Study
STARTED	46
COMPLETED	46
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Adenosine, Regadenoson
Arm/Group Description	Each patient underwent standard intravenous adenosine infusion (140mcg/kg/min) with invasive pressure recordings for 2 min, or until maximal hyperemia occurred. Five minutes after return to baseline hemodynamics, a single intravenous bolus of 0.4 mg regadenoson was administered, and pressures were recorded for 5 min. FFR values were compared by linear regression and Bland-Altman analysis.
Overall Participants	46
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	39 84.8%
>=65 years	7 15.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59 (10)
Sex: Female, Male (Count of Participants)
Female	10 21.7%
Male	36 78.3%
Region of Enrollment (participants) [Number]
United States	46 100%

Outcome Measures

1. Primary Outcome

Title	Difference in FFR Between IV Adenosine and IV Regadenoson
Description	FFR (as calculated by the ratio of lowest Pd/Pa at maximal hyperemia) was compared between hyperemia achieved with adenosine and with regadenoson
Time Frame	At maximal, steady-state hyperemia

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Adenosine	Regadenoson
Arm/Group Description	Adenosine infusion will be compared to Regadenoson for safety/side effects. Arterial blood pressure, coronary pressure, heart rate, oxygen saturation and coronary flow, FFR, and coronary flow velocity will be assessed. Safety will be assessed by monitoring for any side effects such as chest pain, headache, flushing, nausea, or arrhythmias. Adenosine : Injection of IV Adenosine for 2 minutes at rate of 140mcg/kg to dilate coronary arteries and provoke maximal hyperemia	Once the mean coronary flow velocity returns to within 15% pre-dose value following IV infusion of Adenosine, Regadenoson IV injection will be given at 0.4 mg 5/ml- 0.08mg/ml over 10 seconds followed by a 5 cc IV saline flush. regadenoson : Measuring FFR and Coronary Flow Reserve after administration of IV regadenoson 0.4 mg over 10 seconds.
Measure Participants	46	46
Mean (Standard Deviation) [ratio (Pd/Pa)]	0.84 (0.11)	0.84 (0.10)

2. Secondary Outcome

Title	Heart Rate Changes With Drug
Description	Maximal heart rate documented following the administration of each agent
Time Frame	During drug infusion and until restoration of baseline hemodynamics

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Adenosine	Regadenosine
Arm/Group Description	With infusion of 140 mcg/kg/min	With bolus infusion of 0.4 mg
Measure Participants	46	46
Baseline Heart Rate	70.8 (11.5)	72.4 (12.0)
Maximal Heart Rate	81.7 (13.4)	90.4 (13.0)

3. Secondary Outcome

Title	Side Effects of Medication Administration
Description	Chest pain, chest discomfort, burning, flushing, headache, nausea, or shortness of breath
Time Frame	During drug infusion and until restoration of baseline hemodynamics

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Adenosine	Regadenoson
Arm/Group Description	Adenosine infusion will be compared to Regadenoson for safety/side effects. Arterial blood pressure, coronary pressure, heart rate, oxygen saturation and coronary flow, FFR, and coronary flow velocity will be assessed. Safety will be assessed by monitoring for any side effects such as chest pain, headache, flushing, nausea, or arrhythmias. Adenosine : Injection of IV Adenosine for 2 minutes at rate of 140mcg/kg to dilate coronary arteries and provoke maximal hyperemia	Once the mean coronary flow velocity returns to within 15% pre-dose value following IV infusion of Adenosine, Regadenoson IV injection will be given at 0.4 mg 5/ml- 0.08mg/ml over 10 seconds followed by a 5 cc IV saline flush. regadenoson : Measuring FFR and Coronary Flow Reserve after administration of IV regadenoson 0.4 mg over 10 seconds.
Measure Participants	46	46
Dyspnea	14 30.4%	13 NaN
Chest Pain	16 34.8%	13 NaN
Any Symptom	27 58.7%	28 NaN

Adverse Events

Arm/Group Title	Adenosine		Regadenoson
Arm/Group Description	Adenosine infusion will be compared to Regadenoson for safety/side effects. Arterial blood pressure, coronary pressure, heart rate, oxygen saturation and coronary flow, FFR, and coronary flow velocity will be assessed. Safety will be assessed by monitoring for any side effects such as chest pain, headache, flushing, nausea, or arrhythmias. Adenosine : Injection of IV Adenosine for 2 minutes at rate of 140mcg/kg to dilate coronary arteries and provoke maximal hyperemia adenosine : Measuring FFR and Coronary Flow Reserve after administration of IV adenosine 140 mcg/kg/min for 2 minutes. regadenoson : Measuring FFR and Coronary Flow Reserve after administration of IV regadenoson 0.4 mg over 10 seconds.		Once the mean coronary flow velocity returns to within 15% pre-dose value then Regadenoson IV injection will be given at 0.4 mg 5/ml- 0.08mg/ml. Then, a 5 cc saline flush will be administered. regadenoson : Measuring FFR and Coronary Flow Reserve after administration of IV regadenoson 0.4 mg over 10 seconds.
All Cause Mortality
	Adenosine		Regadenoson
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Adenosine		Regadenoson
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/46 (0%)		0/46 (0%)
Other (Not Including Serious) Adverse Events
	Adenosine		Regadenoson
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/46 (58.7%)		28/46 (60.9%)
Cardiac disorders
Cardiac General -Chest Pain	16/46 (34.8%)	16	13/46 (28.3%)	13
Gastrointestinal disorders
Nausea	2/46 (4.3%)	2	5/46 (10.9%)	5
Respiratory, thoracic and mediastinal disorders
Shortness of Breath	14/46 (30.4%)	14	13/46 (28.3%)	13
Skin and subcutaneous tissue disorders
Flushing	6/46 (13%)	6	9/46 (19.6%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.