Back to resultsThe Development of Tolerance to α1-Adrenoceptor Blockade With Chronic Carvedilol Treatment
Primary Purpose
Heart Failure
Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
phenylephrine
Sponsored by
About this trial
This is an interventional treatment trial for Heart Failure
Eligibility Criteria
Inclusion Criteria:
- Age of 18 to 85 years
- Symptomatic heart failure, NYHA class I to III
- Left ventricular ejection fraction < 0.40
- Give written informed consent
Exclusion Criteria:
- active myocarditis
- congenital heart disease
- uncorrected, hemodynamically significant stenotic valvular disease
- hypertrophic cardiomyopathy
- Asthma or other obstructive airway diseases requiring bronchodilators
- Heart rate < 60 beats/min, supine systolic blood pressure < 85 mm Hg, supine diastolic blood pressure > 90 mm Hg
- Uncontrolled Hypertension (Systolic BP >140 mmHg, Diastolic BP > 90 mmHg).
- Sick sinus syndrome, Mobitz type 2 second degree AV block or third degree AV block unless controlled with an artificial implantable pacemaker
- NYHA functional class IV symptoms
- Treatment with an excluded medication (see Excluded Medications below)
- Myocardial infarction or coronary artery intervention (CABG or angioplasty) within three months
- Unstable angina pectoris
- Presence of any progressive systemic disease that would be expected to impact the patient's outcome over the time course of the study
- Uncorrected endocrine disorders including primary aldosteronism, pheochromocytoma, hyperthyroidism, hypothyroidism, brittle type 1 diabetes mellitus
- Evidence of significant renal disease (serum creatinine > 2.5 mg/dl), or hepatic disease (transaminase level > three fold higher than laboratory normal)
- Symptomatic peripheral vascular disease
- Inability or unwillingness to cooperate with study or give written informed consent
Sites / Locations
- University of Utah
Arms of the Study
Arm 1
Arm Type
Other
Arm Label
A
Arm Description
All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.
Outcomes
Primary Outcome Measures
The primary objective of this study is to determine if tolerance to α1-AR blockade develops with the chronic administration of carvedilol in heart failure patients.
Secondary Outcome Measures
All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00585091
Brief Title
The Development of Tolerance to α1-Adrenoceptor Blockade With Chronic Carvedilol Treatment
Official Title
The Development of Tolerance to α1-Adrenoceptor Blockade With Chronic Carvedilol Treatment
Study Type
Interventional
2. Study Status
Record Verification Date
June 2012
Overall Recruitment Status
Completed
Study Start Date
October 2003 (undefined)
Primary Completion Date
August 2007 (Actual)
Study Completion Date
August 2008 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Utah
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
There is now strong evidence from clinical trials that carvedilol therapy in heart failure is superior to therapy with metoprolol. Not only does carvedilol have superior effects on lipid profiles, insulin sensitivity, renal blood flow, and reversal of pathologic remodeling but also its use is associated with fewer deaths compared to metoprolol. These facts make it important to carefully define how metoprolol and carvedilol are pharmacologically different. One potential difference is α1-AR antagonism. If we demonstrate that these α1-AR effects are preserved with chronic therapy, then α1-AR blockade may have an important role in carvedilol favorably altering the natural history of heart failure. On the other hand, if we demonstrate that tolerance to the α1-AR blockade effect of carvedilol decreases with time, then it would be unlikely that this pharmacologic property contributes to the efficacy of carvedilol. In such a case other pharmacologic properties, such as antioxidant activity, would appear to be important. These results will help guide future studies into CHF and AR blockade.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
15 (Actual)
8. Arms, Groups, and Interventions
Arm Title
A
Arm Type
Other
Arm Description
All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.
Intervention Type
Drug
Intervention Name(s)
phenylephrine
Intervention Description
All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.
Primary Outcome Measure Information:
Title
The primary objective of this study is to determine if tolerance to α1-AR blockade develops with the chronic administration of carvedilol in heart failure patients.
Time Frame
Oct 2003-Aug 2008
Secondary Outcome Measure Information:
Title
All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.
Time Frame
Oct 2003-Aug 2008
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age of 18 to 85 years
Symptomatic heart failure, NYHA class I to III
Left ventricular ejection fraction < 0.40
Give written informed consent
Exclusion Criteria:
active myocarditis
congenital heart disease
uncorrected, hemodynamically significant stenotic valvular disease
hypertrophic cardiomyopathy
Asthma or other obstructive airway diseases requiring bronchodilators
Heart rate < 60 beats/min, supine systolic blood pressure < 85 mm Hg, supine diastolic blood pressure > 90 mm Hg
Uncontrolled Hypertension (Systolic BP >140 mmHg, Diastolic BP > 90 mmHg).
Sick sinus syndrome, Mobitz type 2 second degree AV block or third degree AV block unless controlled with an artificial implantable pacemaker
NYHA functional class IV symptoms
Treatment with an excluded medication (see Excluded Medications below)
Myocardial infarction or coronary artery intervention (CABG or angioplasty) within three months
Unstable angina pectoris
Presence of any progressive systemic disease that would be expected to impact the patient's outcome over the time course of the study
Uncorrected endocrine disorders including primary aldosteronism, pheochromocytoma, hyperthyroidism, hypothyroidism, brittle type 1 diabetes mellitus
Evidence of significant renal disease (serum creatinine > 2.5 mg/dl), or hepatic disease (transaminase level > three fold higher than laboratory normal)
Symptomatic peripheral vascular disease
Inability or unwillingness to cooperate with study or give written informed consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark Munger, PharmD
Organizational Affiliation
Professor, Pharmacotherapy
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
18657662
Citation
Van Tassell BW, Rondina MT, Huggins F, Gilbert EM, Munger MA. Carvedilol increases blood pressure response to phenylephrine infusion in heart failure subjects with systolic dysfunction: evidence of improved vascular alpha1-adrenoreceptor signal transduction. Am Heart J. 2008 Aug;156(2):315-21. doi: 10.1016/j.ahj.2008.04.004. Epub 2008 Jun 20.
Results Reference
result
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The Development of Tolerance to α1-Adrenoceptor Blockade With Chronic Carvedilol Treatment
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