Although uncommon, increases in heart rate may be associated with inhaled anticholinergics. Tiotropium, an inhaled anticholinergic, provides 24-hour efficacy with once-daily dosing. While peak plasma levels occur within 5 minutes, steady state occurs following several weeks of treatment. We sought to examine electrocardiographic findings of tiotropium in COPD patients following acute and chronic dosing.
A 12-week, randomized, double-blind, placebo-controlled, parallel-group study was performed in COPD patients. ECGs (pre-dose and 5 minutes post-dose) and 24-hour Holter monitoring were performed at baseline and following 8 and 12 weeks of tiotropium 18 mcg once daily or placebo delivered via the HandiHaler®. Efficacy measures (spirometry, prn albuterol use, global COPD ratings, EQ5D) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies.
196 patients were randomized: mean age 65 years; 58% male; mean FEV1 1.022 L. Mean changes in heart rate (HR) from baseline (beats/min) were similar between groups (table
Mean changes in heart rate (HR) from baseline (beats/min)HR (beats/min)TiotropiumPlacebo8 wks12 wks8 wks12 wksECG pre-dose0.87-0.351.061.55ECG post-dose-1.73-2.09-0.110.6524-hour Holter0.260.20.730.55
Mean changes in heart rate (HR) from baseline (beats/min)below). There were no differences in percent of patients developing abnormalities in rhythms or conduction. Frequency of premature beats, and mean and maximal changes in PR, QRS, QT, QTcB and QTcF were similar between groups. No patients developed new onset QT or QTc >500 msec; there were no differences in percent of patients developing new QT prolongation <30 msec, 30-60 msec or >60 msec. Cardiac adverse events were observed in 1 tiotropium and 4 placebo patients. At 12 weeks, improvements with tiotropium over placebo in morning pre and post-dose FEV1 were 184 and 265 mL respectively (p<0.001); prn use of albuterol was reduced by 25% (p<0.05). Global ratings of COPD by physicians and patients, and EQ5D visual analogue scale were improved with tiotropium (p<0.05).
Tiotropium was not associated with electrocardiographic evidence of changes in heart rate, rhythm, QT intervals and conduction. Tiotropium provided spirometric and symptomatic benefits to patients with COPD.
Tiotropium 18 mcg daily has a favorable therapeutic profile in patients with COPD.
S. Kesten, Boehringer-Ingelheim