Cardiac safety of tiotropium in patients with COPD: a combined analysis of Holter-ECG data from four randomised clinical trials

Int J Clin Pract. 2015 Jan;69(1):72-80. doi: 10.1111/ijcp.12596. Epub 2014 Dec 11.

Abstract

Background: Tiotropium is generally well tolerated; however, there has been debate whether antimuscarinics, particularly tiotropium administered via Respimat(®) Soft Mist(™) Inhaler, may induce cardiac arrhythmias in a vulnerable subpopulation with cardiovascular comorbidity. The aim of this study was to provide evidence of the cardiac safety of tiotropium maintenance therapy.

Methods: Combined analysis of Holter electrocardiogram (ECG) data from clinical trials of tiotropium in chronic obstructive pulmonary disease (COPD). Trials in the Boehringer Ingelheim clinical trials database conducted between 2003 and 2012, involving tiotropium HandiHaler(®) 18 μg and/or tiotropium Respimat(®) (1.25-, 2.5-, 5.0- and 10-μg doses) were reviewed. All trials involving Holter-ECG monitoring during this period were included in the analysis. Men and women aged ≥ 40 years with a smoking history of ≥ 10 pack-years, and a clinical diagnosis of COPD were included. Holter ECGs were evaluated for heart rate (HR), supraventricular premature beats (SVPBs), ventricular premature beats (VPBs) and pauses. Quantitative and categorical end-points were derived for each of the Holter monitoring days.

Results: Four trials (n = 727) were included in the analysis. Respimat(®) (1.25-10 μg) or HandiHaler(®) (18 μg) was not associated with changes in HR, SVPBs, VPBs and pauses compared with placebo or the pretreatment baseline period. In terms of cardiac arrhythmia end-points, there was no evidence for an exposure-effect relationship.

Conclusions: In this analysis, tiotropium maintenance therapy administered using Respimat(®) (1.25-10 μg) or HandiHaler(®) (18 μg) once daily for periods of up to 48 weeks was well tolerated with no increased risk of cardiac arrhythmia in patients with COPD.

Trial registration: ClinicalTrials.gov NCT00168831 NCT00168844 NCT00239460 NCT01222533.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Electrocardiography / statistics & numerical data
  • Female
  • Heart / drug effects*
  • Humans
  • Male
  • Middle Aged
  • Muscarinic Antagonists / adverse effects
  • Patient Safety*
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Randomized Controlled Trials as Topic*
  • Tiotropium Bromide / adverse effects*
  • Tiotropium Bromide / pharmacology
  • Tiotropium Bromide / therapeutic use

Substances

  • Muscarinic Antagonists
  • Tiotropium Bromide

Associated data

  • ClinicalTrials.gov/NCT00168831
  • ClinicalTrials.gov/NCT00168844
  • ClinicalTrials.gov/NCT00239460
  • ClinicalTrials.gov/NCT01222533