Heart Failure
Conditions
Keywords
heart failure, autonomic function, sympathovagal balance, cholinesterase inhibitors, pharmacology
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.
Interventions
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.
Sponsors
Nathan Kline Institute for Psychiatric Research
Oklahoma State University
National Heart, Lung, and Blood Institute (NHLBI)
NYU Langone Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) |
Countries
United States
Participant flow
Recruitment details
Admissions logs and other existing electronic hospital information systems
Participants by arm
| Arm | Count |
|---|---|
| Pyridostigmine Bromide Forced titration protocol 15-60 mg every 8 hours as tolerated
Pyridostigmine Bromide: 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. | 16 |
| Placebo Matching placebo forced titration 15-60 mg as tolerated
Pyridostigmine Bromide: 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. | 17 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Other | 2 | 0 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Pyridostigmine Bromide | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 15 Participants | 29 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 6 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 8 Participants | 9 Participants | 17 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United States | 16 participants | 17 participants | 33 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 14 Participants | 15 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 16 | 10 / 17 |
| serious Total, serious adverse events | 2 / 16 | 3 / 17 |
Outcome results
Primary
Baseline Heart Rate Recovery
Change in peak HR at end of exercise to 1 minute post-exercise (beats per minute)
Time frame: Baseline
Population: Heart rate recovery is also measured as beats/min (peak HR at end of exercise - HR 1 min post exercise = HRR).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pyridostigmine Bromide | Baseline Heart Rate Recovery | 32.5 beats per minute | Standard Deviation 12.8 |
| Placebo | Baseline Heart Rate Recovery | 30.4 beats per minute | Standard Deviation 14.8 |
Primary
Post Exercise Heart Rate Recovery
Change in heart rate from peak exercise to 1 minute post-exercise (beats per minute)
Time frame: 12 weeks
Population: Heart rate recovery is also measured as beats/min (peak HR at end of exercise - HR 1 min post exercise = HRR).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pyridostigmine Bromide | Post Exercise Heart Rate Recovery | 38.5 beats per minute | Standard Deviation 12.2 |
| Placebo | Post Exercise Heart Rate Recovery | 34.9 beats per minute | Standard Deviation 16.1 |