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

Sponsor:	University of Utah
Information provided by:	University of Utah
ClinicalTrials.gov Identifier:	NCT00585091

Purpose

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:	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:

MedlinePlus related topics: Heart Failure

Drug Information available for: Phenylephrine Phenylephrine hydrochloride Carvedilol Oxymetazoline Oxymetazoline hydrochloride

U.S. FDA Resources

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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

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 ]

Estimated Enrollment:	15
Study Start Date:	October 2003
Estimated Study Completion Date:	August 2008
Estimated Primary Completion Date:	August 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
A 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.

Eligibility

Ages Eligible for Study:	18 Years to 85 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00585091

Locations

United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84112

Sponsors and Collaborators

University of Utah

Investigators

Principal Investigator:

Mark Munger, PharmD

Professor, Pharmacotherapy

More Information

No publications provided

Responsible Party:	University of Utah, Univerisity of Utah
ClinicalTrials.gov Identifier:	NCT00585091 History of Changes
Other Study ID Numbers:	00011909, IRB# 00011909
Study First Received:	December 26, 2007
Last Updated:	January 2, 2008
Health Authority:	United States: Institutional Review Board

Additional relevant MeSH terms:

Heart Failure
Heart Diseases
Cardiovascular Diseases
Phenylephrine
Oxymetazoline
Carvedilol
Adrenergic alpha-1 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Cardiotonic Agents

Cardiovascular Agents
Therapeutic Uses
Mydriatics
Autonomic Agents
Peripheral Nervous System Agents
Sympathomimetics
Vasoconstrictor Agents
Nasal Decongestants
Respiratory System Agents
Protective Agents
Adrenergic beta-Antagonists
Adrenergic Antagonists
Antihypertensive Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists

ClinicalTrials.gov processed this record on February 09, 2012