Safety Study of Pyridostigmine in Heart Failure

Phase 2

Completed

Brief Summary: 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: 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.

Recruitment & Eligibility

Inclusion Criteria

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.

Arm && Interventions

Group	Intervention	Description
Pyridostigmine Bromide	Pyridostigmine Bromide	Forced titration protocol 15-60 mg every 8 hours as tolerated
Placebo	Pyridostigmine Bromide	Matching placebo forced titration 15-60 mg as tolerated

Primary Outcome Measures

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

Secondary Outcome Measures