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

NCT00585091 | Completed DMC

• 2 other identifiers: 00011909IRB# 00011909
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (1)

• 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.

  Oct 2003-Aug 2008

Secondary Outcomes (1)

• All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.

  Oct 2003-Aug 2008

Study Arms (1)

A

OTHER

All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.

Drug: phenylephrine

Interventions

phenylephrine DRUG

All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.

A

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age of 18 to 85 years
• Symptomatic heart failure, NYHA class I to III
• Left ventricular ejection fraction \< 0.40
• Give written informed consent

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Utah: lead

Study Sites (1)

University of Utah

Salt Lake City, Utah, 84112, United States

Location

Related Publications (1)

• 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.

  PMID: 18657662 RESULT

MeSH Terms

Conditions

Heart Failure

Interventions

Phenylephrine

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines

Study Officials

• Mark Munger, PharmD

  Professor, Pharmacotherapy

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: December 26, 2007
• First Posted: January 3, 2008
• Study Start: October 1, 2003
• Primary Completion: August 1, 2007
• Study Completion: August 1, 2008
• Last Updated: June 13, 2012

Record last verified: 2012-06

Locations

US (1)