title: Heart rate-lowering efficacy and respiratory safety of ivabradine in patients with obstructive airway disease: a randomized, double-blind, placebo-controlled, crossover study.
abstract: BACKGROUND
  There is substantial evidence that heart rate (HR) is a powerful predictor of mortality in both normal individuals and in patients with cardiovascular disease. The use of β-adrenoceptor antagonists (β-blockers) has confirmed the importance of lowering elevated HR in a patient's prognosis. However, these agents can have undesirable adverse effects (AEs) and due to the risk of bronchoconstriction are contraindicated in patients with obstructive airway disease. A selective bradycardic agent, without such undesirable effects, could be of therapeutic interest. Ivabradine, a new I(f) inhibitor that acts specifically on the sino-atrial node, is a pure HR-lowering agent.
  
  
  OBJECTIVE
  The objective of this study was to assess HR-lowering efficacy and respiratory safety of ivabradine in patients with asthma and chronic obstructive pulmonary disease (COPD).
  
  
  METHODS
  This was a randomized, single-center, double-blind, placebo-controlled, crossover trial. Enrolment began in May 2009, and the last patient completed the study in January 2011. The study was conducted in an ambulatory setting. A total of 40 patients completed the study (20 asthmatic patients and 20 COPD patients). Inclusion criteria were: documented diagnosis of asthma or COPD according to international guidelines, age 18-75 years, and mean HR on Holter ECG recording of ≥60 beats/min. Exclusion criteria included disease exacerbation in a previous month or inability to understand instructions on the study procedures. All patients received ivabradine 7.5 mg twice daily for 5 days and placebo twice daily for 5 days in a crossover manner, in one of the two arms of the study, with at least 2 days of washout between treatments. The main outcome measures included the difference in HR between ivabradine and placebo treatment and change in HR in comparison with baseline. Other evaluated outcomes were differences in the peak expiratory flow rate (PEFR), the daily symptom score, rescue medication consumption, and AEs.
  
  
  RESULTS
  Ivabradine produced significantly lower mean HR than placebo in both groups of patients: asthma 67.4 ± 8.38 versus 82.85 ± 11.19 beats/min (p < 0.001) and COPD 69.75 ± 8.9 versus 81.05 ± 9.75 beats/min (p < 0.001). Similar results were observed for the minimal HR as well as for the maximal noted HR. In comparision with baseline, ivabradine significantly reduced HR in both groups of studied patients (all p < 0.05), whereas placebo did not have such an effect. No significant difference, in either the asthma or the COPD group, was found between ivabradine and placebo in morning and evening peak expiratory flow rate, peak expiratory flow diurnal variability, daily symptom scores, and rescue medication usage (all p > 0.05). Both treatments were well tolerated. The incidence of AEs was low and generally similar in both periods of treatment, except for visual symptoms during treatment with ivabradine, which was reported by 5% of the patients.
  
  
  CONCLUSIONS
  Our study demonstrated that selective HR reduction with ivabradine is effective in patients with asthma and COPD, with no alteration in respiratory function or symptoms over the duration of the study. Ivabradine offers an interesting alternative, as an HR-lowering agent, in patients with respiratory disease and contraindications to β-blockers.
  
  
  BACKGROUND
  Registered at www.clinicaltrials.gov (NCT01365286).
authors.affiliation: Department of Pneumology and Allergy, Medical University of Lodz, Poland. sebastian.majewski@umed.lodz.pl
authors.forename: Sebastian
authors.initials: S
authors.lastname: Majewski
authors.forename: Sebastian
authors.initials: S
authors.lastname: Slomka
authors.forename: Ewa
authors.initials: E
authors.lastname: Zielinska-Wyderkiewicz
authors.forename: Maciej
authors.initials: M
authors.lastname: Ciebiada
authors.forename: Pawel
authors.initials: P
authors.lastname: Gorski
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000188:drug therapy*; D001552:Benzazepines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D000077550:Ivabradine; D008297:Male; D008875:Middle Aged; D010366:Peak Expiratory Flow Rate / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D001552:Benzazepines; D000077550:Ivabradine