Pharmacodynamics, Safety, and Tolerability of Pyridostigmine Bromide in Heart Failure

Fig. 1. Schematic of study protocol. The study was designed as a prospective randomized double-blind forced titration clinical trial to compare the effects of 3 ascending doses of pyridostigmine bromide (pyrido; at 15, 30, and 60 mg TID) versus matching placebo on postexercise heart rate recovery, and measures of sympathovagal balance, safety, and tolerability. Visit numbers are shown in small black rectangles. When an eligible subject was identified after completion of screening and single-blind placebo run-in, the randomly assigned study drug was initiated at 15 mg every 8 hours for 2 weeks (visit 4) with subsequent forced titration to 30 mg every 8 hours for 2 weeks (visit 6) and 60 mg every 8 hours for 4 weeks (visit 8) according to prespecified safety and tolerability criteria. Primary and secondary end points were assessed before randomization (visit 2) and after completion of the 4-week maintenance phase at the highest tolerated dose of study drug (Post-treatment (Tx) visit 9). The study drug was then downtitrated at 1-week intervals with safety assessment 1 week after cessation of study drug (visit 12).

Fig. 2. Consolidated Standards of Reporting Trials diagram of subject participation. Fifty subjects were screened for participation, and 33 eligible subjects were randomly assigned. The most common reasons for ineligibility were atrial fibrillation (n = 4), low forced expiratory volume at 1 second/forced vital capacity ratio (n = 4), low blood pressure (n = 2), and inability to complete >3 minutes of exercise (n = 2). Six randomly assigned subjects did not complete poststudy drug assessment of sympathovagal balance (3 in the pyridostigmine bromide group and 3 in the placebo group).

Fig. 3. Estimated mean ± SEM for postexercise heart rate recovery at 1 minute (beats per minute) by treatment group before study drug treatment (pre-treatment, visit 2) and after 4 weeks of the maximally tolerated dose of study drug (post-treatment, visit 9). Postexercise heart rate recovery did not differ between groups before study drug administration and increased significantly from pretreatment baseline after 4 weeks of maximally tolerated dose within the pyridostigmine bromide group (light gray) but did not change from pretreatment baseline after 4 weeks of maximally tolerated dose within the placebo group (black). The estimated mean change from baseline did not differ between randomized treatment groups.

Fig. 4. Red blood cell acetylcholinesterase (RBC AChE) activity by treatment group (pyridostigmine bromide [PYR] shown in red; placebo shown in blue) over time. RBC AChE activity was measured twice (just before and 2 hours after study drug administration) for all study visits with initiation, uptitration, or downtitration of study drug dose. Panel A shows mean ± SEM RBC AChE activity for each study visit in activity units (1 U = activity hydrolyzing 1 µmol/min under the conditions of the assay); panel B shows RBC AChE activity expressed as change from prestudy drug baseline. Pyridostigmine bromide significantly decreased RBC AChE activity compared with placebo (P-value for treatment by visit interaction < 0.02). After 4 weeks of the highest tolerated dose of study drug at visit 9, the RBC AChE activity decreased from pretreatment baseline by 22% in the PYR group and increased by 20% in the placebo group (P < 0.001 for treatment by time interaction).