The Development of Tolerance to α1-Adrenoceptor Blockade With Chronic Carvedilol Treatment

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
edward gilbert, University of Utah
ClinicalTrials.gov Identifier:
NCT00585091
First received: December 26, 2007
Last updated: June 12, 2012
Last verified: June 2012

December 26, 2007
June 12, 2012
October 2003
August 2007   (final data collection date for primary outcome measure)
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 ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT00585091 on ClinicalTrials.gov Archive Site
All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment. [ Time Frame: Oct 2003-Aug 2008 ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
The Development of Tolerance to α1-Adrenoceptor Blockade With Chronic Carvedilol Treatment
The Development of Tolerance to α1-Adrenoceptor Blockade With Chronic Carvedilol Treatment

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.

Not Provided
Interventional
Not Provided
Allocation: Non-Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Heart Failure
Drug: phenylephrine
All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.
A
All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.
Intervention: Drug: phenylephrine
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. Epub 2008 Jun 20.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
15
August 2008
August 2007   (final data collection date for primary outcome measure)

Inclusion Criteria:

  1. Age of 18 to 85 years
  2. Symptomatic heart failure, NYHA class I to III
  3. Left ventricular ejection fraction < 0.40
  4. Give written informed consent

Exclusion Criteria:

  1. active myocarditis
  2. congenital heart disease
  3. uncorrected, hemodynamically significant stenotic valvular disease
  4. hypertrophic cardiomyopathy
  5. Asthma or other obstructive airway diseases requiring bronchodilators
  6. Heart rate < 60 beats/min, supine systolic blood pressure < 85 mm Hg, supine diastolic blood pressure > 90 mm Hg
  7. Uncontrolled Hypertension (Systolic BP >140 mmHg, Diastolic BP > 90 mmHg).
  8. Sick sinus syndrome, Mobitz type 2 second degree AV block or third degree AV block unless controlled with an artificial implantable pacemaker
  9. NYHA functional class IV symptoms
  10. Treatment with an excluded medication (see Excluded Medications below)
  11. Myocardial infarction or coronary artery intervention (CABG or angioplasty) within three months
  12. Unstable angina pectoris
  13. Presence of any progressive systemic disease that would be expected to impact the patient's outcome over the time course of the study
  14. Uncorrected endocrine disorders including primary aldosteronism, pheochromocytoma, hyperthyroidism, hypothyroidism, brittle type 1 diabetes mellitus
  15. Evidence of significant renal disease (serum creatinine > 2.5 mg/dl), or hepatic disease (transaminase level > three fold higher than laboratory normal)
  16. Symptomatic peripheral vascular disease
  17. Inability or unwillingness to cooperate with study or give written informed consent
Both
18 Years to 85 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00585091
00011909, IRB# 00011909
Yes
edward gilbert, University of Utah
University of Utah
Not Provided
Principal Investigator: Mark Munger, PharmD Professor, Pharmacotherapy
University of Utah
June 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP