Intravenous Allopurinol to Improve Heart Function in Individuals With Dilated Cardiomyopathy

Sponsor

University of Pennsylvania (Other)

Overall Status

Withdrawn

CT.gov ID

NCT00281255

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

Enrollment

Location

Arms

120

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will determine whether an acute infusion of intravenous allopurinol improves the inotropic response to dobutamine in patients with idiopathic dilated cardiomyopathy (DCM) as measured by cardiac magnetic resonance imaging (CMR).

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Diseases Cardiomyopathy, Dilated Heart Diseases Heart Failure, Congestive	Drug: Allopurinol Drug: Dobutamine	Phase 1/Phase 2

Detailed Description

BACKGROUND:

DCM is a poorly understood cause of systolic heart failure and is the most common indication for heart transplantation in the United States. Despite advances in medical and device therapy, the 5-year mortality of patients with DCM remains near 50%.

Oxidative stress, an imbalance between the formation and degradation of free radicals within the myocardium, contributes to metabolic derangements in patients with DCM. The enzyme xanthine oxidase (XO), a potent source of oxidative stress, is expressed in the failing heart, and it uncouples cardiac energy consumption from cardiac contraction in the setting of chronic heart failure. These effects can be reversed by inhibiting XO with the XO inhibitor allopurinol, resulting in a marked increase in cardiac efficiency. These findings provide a rationale for using allopurinol to enhance cardiac function in DCM. However, there is little data on the effects of allopurinol therapy on cardiac function. Therefore, the primary aim of this study is to determine whether an acute infusion of intravenous allopurinol improves the inotropic response to beta-adrenergic stimulation in patients with idiopathic DCM.

Decreased beta-adrenergic responsiveness is a characteristic feature of DCM that is attributable in part to decreased expression of the beta 1-receptor in chronic heart failure, as well as dysregulation of down-stream signaling pathways. Improvement in beta-adrenergic responsiveness is a useful surrogate marker for long-term improvement in cardiac structure, function, and decreased cardiac events. Traditionally, invasive hemodynamic monitoring using pressure and pressure/volume catheters has been the method of choice to quantify the inotropic response in heart failure. However, newly developed magnetic resonance imaging (MRI) techniques now allow precise assessment of the inotropic response non-invasively. Studies have shown that tagged CMR is a reproducible, noninvasive method to quantify the inotropic response to the beta 1 agonist dobutamine in individuals with structurally normal hearts. Specifically, radial strain (E1) and circumferential strain (E2) are measured at increasing doses of dobutamine using tagged CMR. Changes in these strain parameters, now referred to as delta E1 and delta E2, are precise measurements of the beta-inotropic response.

DESIGN NARRATIVE:

An estimated 20 patients with DCM will be randomized in a 1:1 ratio fashion to receive allopurinol or placebo. The primary aim of this investigation is to determine whether an acute infusion of intravenous allopurinol improves the inotropic response to dobutamine in patients with idiopathic DCM as measured by CMR. Specifically, the study will test the hypothesis that a single dose of intravenous allopurinol, compared to placebo, enhances delta E1 and delta E2. Secondary aims of this study are as follows: 1) to determine whether the response to allopurinol is associated with baseline XO activity and levels of natriuretic peptides (investigators predict that augmentation in delta E1 and delta E2 will correlate positively with baseline plasma uric acid and plasma B-type natriuretic peptide [BNP]); and 2) to demonstrate that tagged dobutamine CMR is a useful non-invasive technique to assess pharmacologic responses in patients with heart failure.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Basic Science

Official Title:

Allopurinol and Cardiac Function Pilot Study in Idiopathic Dilated Cardiomyopathy

Study Start Date :

Jun 1, 2003

Actual Primary Completion Date :

Jun 1, 2013

Actual Study Completion Date :

Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: allopurinol	Drug: Allopurinol Drug: Dobutamine
Placebo Comparator: placebo	Drug: Dobutamine

Arm

Intervention/Treatment

Experimental: allopurinol

Drug: Allopurinol

Drug: Dobutamine

Placebo Comparator: placebo

Drug: Dobutamine

Outcome Measures

Primary Outcome Measures

radial and circumferential strain after infusion of allopurinol as measured by cardiac MRI (measured at Day 1) []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of idiopathic cardiomyopathy (defined by an ejection fraction less than or equal to 35% that has been assessed by any method within 6 months prior to study entry AND no evidence of coronary artery disease, as determined by coronary angiography or stress perfusion imaging within 2 years prior to study entry)
New York Heart Association (NYHA) Class I - II heart failure
Stable heart failure medication for at least 1 month prior to study entry
Able to lie flat for 45 minutes

Exclusion Criteria:

History of poorly controlled hypertension and concentric left ventricular hypertrophy on echocardiography suggesting hypertensive cardiomyopathy
History of biopsy-proven myocarditis
Peripartum cardiomyopathy
Allopurinol therapy within the 6 months prior to study entry
Allopurinol allergy
Contraindication to allopurinol because of concomitant therapy with one of the following: azathioprine, cyclophosphamide, dicumarol, uricosuric agents (e.g., probenecid), ampicillin, amoxicillin, chlorpropamide, or cyclosporine
Acute gout
Estimated creatinine clearance less than 20 ml/min
Total bilirubin greater than 2 times upper limit of normal
Serum aspartate AST or alanine ALT greater than 3 times the upper limit of normal
White blood cell count less than 2,000
Platelet count less than 80,000
Hemoglobin less than 8 mg/dl
Use of intravenous inotropes
History of untreated symptomatic ventricular tachycardia
History of sustained ventricular tachycardia induced by dobutamine
Contraindication to MRI because of one of the following:

Starr-Edwards pre-6000 series prosthetic valves or prosthetic valves for which model can not be determined
Implanted pacemaker
Implanted cardioverter-defibrillator intracranial aneurysm clips
Other implanted medical devices that are known to be MRI incompatible (e.g., cochlear implants and spinal stimulators)
History of foundry-work that could create ocular metallic fragments