Safety Study of Pyridostigmine in Heart Failure

Study Overview
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Brief Summary
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Heart failure, a common heart disease affecting nearly 6 million Americans, is associated with high rates of hospitalization and death. Abnormalities in the autonomic nervous system are thought to play an important role in the progression of heart failure. This proposal aims to determine whether novel application of pyridostigmine, a drug currently approved by the FDA only for the treatment of neuromuscular disease, can improve autonomic nervous system function in heart failure patients.

Detailed Description
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Autonomic dysregulation of the cardiovascular system, characterized by heightened sympathetic activity and withdrawal of parasympathetic activity promotes progression of heart failure. Pharmacological blockade of sympathetic overactivity is associated with reduced mortality risk, but there are few data on pharmacologic augmentation of parasympathetic withdrawal. Acetylcholinesterase inhibitors augment parasympathetic neurotransmission by blocking the enzymatic breakdown of acetylcholine at cholinergic receptor sites. Pyridostigmine is a short-acting, reversible acetylcholinesterase inhibitor approved by the FDA for the treatment of myasthenia gravis. Investigators propose a Phase II prospective randomized, double-blind trial to compare 12 weeks of treatment with ascending doses of pyridostigmine (15, 30, and 60 mg every 8 hours) vs. matching placebo in 60 patients with symptomatic chronic heart failure associated with left ventricular systolic dysfunction.

Official Title
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Augmentation of Parasympathetic Signaling With Pyridostigmine in Heart Failure

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Pyridostigmine Bromide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 21-75 years Symptomatic NYHA Class II-III heart failure >6 months Left ventricular ejection fraction <35% Previous implantation of implantable cardiovertor defibrillator or pacemaker Guideline-recommended heart failure treatment for > 3 months Able and willing to provide written informed consent Exclusion Criteria: Contraindications to cholinergic stimulation Heart failure primarily attributable to genetic, valvular, infiltrative diseases Persistent atrial fibrillation Sick sinus syndrome Pacemaker dependency during exercise Severe chronotropic incompetence with peak exercise heart rate < 100 min-1 Severe exercise intolerance (unable to complete first stage of Bruce Protocol) Coronary or cerebral atherothrombotic events within the past year Hospitalization of emergency room visit for heart failure within last 3 months ICD shock in last 6 months Diabetes mellitus with peripheral neuropathy Autonomic or peripheral neuropathy of any cause Systolic blood pressure <90 or >160 mmHg Resting heart rate <60 or >100 min-1 Serum sodium < 132 mmol/L Serum creatinine >2.5 mg/dl Liver function tests >3 times upper limit of normal Severe anemia (Hemoglobin <10 gm/dl) FEV1.0 < 60% of predicted or FEV1.0/FVC ratio <70% PR interval >240 msec or second or third degree heart block on electrocardiogram Exercise limited primarily by angina or non-cardiac co-morbid condition Pregnant or breast-feeding women Current treatment with medications known to interact with pyridostigmine Known intolerance of oral preparations containing bromides Any condition (e.g., psychiatric illness or active substance abuse) or situation that, in the investigator's opinion, may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject's ability to adhere with study procedures.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 75 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pyridostigmine Bromide<br>Forced titration protocol 15-60 mg every 8 hours as tolerated | Drug: Pyridostigmine Bromide<br>* 15, 30, and 60 mg tabs, 1 tab every 8 hours for 10 weeks. Forced titration protocol increases dose at 2 week intervals from 15 to 30 to 60 mg as tolerated. Continue maximally tolerated dose for 4 weeks and then downtitrate at weekly intervals (60 to 30 to 15) and then discontinue.<br>* Other names: Mestinon;|
| Placebo Comparator: Placebo<br>Matching placebo forced titration 15-60 mg as tolerated | Drug: Pyridostigmine Bromide<br>* 15, 30, and 60 mg tabs, 1 tab every 8 hours for 10 weeks. Forced titration protocol increases dose at 2 week intervals from 15 to 30 to 60 mg as tolerated. Continue maximally tolerated dose for 4 weeks and then downtitrate at weekly intervals (60 to 30 to 15) and then discontinue.<br>* Other names: Mestinon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline Heart Rate Recovery | Change in peak HR at end of exercise to 1 minute post-exercise (beats per minute) | Baseline | 
| Post Exercise Heart Rate Recovery | Change in heart rate from peak exercise to 1 minute post-exercise (beats per minute) | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure, autonomic function, sympathovagal balance, cholinesterase inhibitors, pharmacology