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

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

Condition Intervention
Heart Failure
Drug: phenylephrine

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Development of Tolerance to α1-Adrenoceptor Blockade With Chronic Carvedilol Treatment

Resource links provided by NLM:

Further study details as provided by University of Utah:

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. [ Time Frame: Oct 2003-Aug 2008 ]

Secondary Outcome Measures:
  • All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment. [ Time Frame: Oct 2003-Aug 2008 ]

Enrollment: 15
Study Start Date: October 2003
Study Completion Date: August 2008
Primary Completion Date: August 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.
Drug: phenylephrine
All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.


Ages Eligible for Study:   18 Years to 85 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
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Please refer to this study by its identifier: NCT00585091

United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
University of Utah
Principal Investigator: Mark Munger, PharmD Professor, Pharmacotherapy
  More Information

Responsible Party: edward gilbert, Professor of Medicine, University of Utah Identifier: NCT00585091     History of Changes
Other Study ID Numbers: 00011909
IRB# 00011909
Study First Received: December 26, 2007
Last Updated: June 12, 2012

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antihypertensive Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists
Cardiotonic Agents
Autonomic Agents
Peripheral Nervous System Agents
Vasoconstrictor Agents
Nasal Decongestants
Respiratory System Agents
Adrenergic alpha-1 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Protective Agents processed this record on April 28, 2017