Safety Study of Pyridostigmine in Heart Failure
Condition: Heart Failure
MeSH terms: Heart Failure
Intervention: Pyridostigmine Bromide
Intervention description: 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.
Intervention MeSH terms: Bromides; Pyridostigmine Bromide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 33.0
Sex: All
Minimum age: 21 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: heart failure; autonomic function; sympathovagal balance; cholinesterase inhibitors; pharmacology

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.
    

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.