Clinical trial NCT01415921: Safety Study of Pyridostigmine in Heart Failure
Official title: Augmentation of Parasympathetic Signaling With Pyridostigmine in Heart Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure
Keywords: heart failure
autonomic function
sympathovagal balance
cholinesterase inhibitors
pharmacology
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
Collaborators: name: Nathan Kline Institute for Psychiatric Research
name: Oklahoma State University
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2011-08-12
Enrollment: 33
Sex: ALL
Minimum age (years): 21
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Baseline Heart Rate Recovery
timeFrame: Baseline
measure: Post Exercise Heart Rate Recovery
timeFrame: 12 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
Study officials:
affiliation: NYU Langone Health
name: Stuart D Katz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Androne AS, Hryniewicz K, Goldsmith R, Arwady A, Katz SD. Acetylcholinesterase inhibition with pyridostigmine improves heart rate recovery after maximal exercise in patients with chronic heart failure. Heart. 2003 Aug;89(8):854-8. doi: 10.1136/heart.89.8.854.