The Development of Tolerance to α1-Adrenoceptor Blockade With Chronic Carvedilol Treatment
This study has been completed.
Sponsor:
University of Utah
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
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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: | Allocation: Non-Randomized Endpoint Classification: Pharmacodynamics Study 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
Oxymetazoline
Oxymetazoline hydrochloride
Carvedilol
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 ]
| 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 |
|---|---|
|
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 More Information
Publications:
| Responsible Party: | edward gilbert, Professor of Medicine, University of Utah |
| ClinicalTrials.gov Identifier: | NCT00585091 History of Changes |
| Other Study ID Numbers: | 00011909, IRB# 00011909 |
| Study First Received: | December 26, 2007 |
| Last Updated: | June 12, 2012 |
| 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 June 18, 2013