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

Study Overview
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Brief Summary
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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.

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

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: phenylephrine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: A<br>All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment. | Drug: phenylephrine<br>* All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All patients undergo repeated phenylephrine infusions during standard up-titration and maintenance of carvedilol treatment. |  | Oct 2003-Aug 2008 |