Safety Study of Pyridostigmine in Heart Failure (APP-HF)

NYU Langone Health

Status and phase

Completed

Phase 2

Conditions

Heart Failure

Treatments

Drug: Pyridostigmine Bromide

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01415921

1R01HL103988 (U.S. NIH Grant/Contract)

10-02167 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

33 patients

Sex

All

Ages

21 to 75 years old

Volunteers

No Healthy Volunteers

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.