Validation of the Differential Cardiovascular Effects of the Antimuscarinic Agents Darifenacin and Tolterodine in a Randomized, Placebo-Controlled, 3-Way Crossover Study
ABSTRACT
INTRODUCTION:Previous studies have demonstrated that antimuscarinics used for the treatment of overactive bladder (OAB), such as tolterodine and darifenacin, exert differential effects on heart rate (HR) and HR variability (HRV). OAB is a chronic symptomatic condition of high prevalence in older patients with cardiovascular (CV) comorbidities. Physicians prescribing these medications should take into consideration their specific effects on the parasympathetic control of the heart.
OBJECTIVE: The primary objective was to detect if there was a difference between tolterodine and darifenacin in change from baseline in mean HR over 24 hours during once-daily administration of these compounds in healthy participants. The protocol was designed to confirm results from a previous study.
METHODS:This was a 3-way crossover, placebo-controlled, double-blind study in healthy participants of similar age to OAB patients (≥ 50 years). Participants were randomized to one of 6 possible treatment sequences and consecutively received once-daily tolterodine 4 mg, darifenacin 15 mg, and matched placebo for at least 7 days in separate treatment periods. Electrocardiogram monitoring (Holter) for 24 hours was used to assess changes in mean HR and HRV between treatment arms
RESULTS: Tolterodine but not darifenacin significantly increased mean HR over 24 hours compared with darifenacin (2.24 beats per minute [bpm], P = .0004) and placebo (1.84 bpm, P = .0037). In contrast, darifenacin did not significantly alter HR compared with placebo (–0.40, P = .5219). Overall, HRV over 24 hours decreased with tolterodine but not with darifenacin or placebo.
CONCLUSION: Tolterodine increased HR and reduced HRV compared with darifenacin and placebo in healthy participants aged ≥ 50 years. Because increased HR and decreased HRV are associated with increased CV risk and patients with OAB often have CV comorbidities, careful selection of antimuscarinic treatment for OAB patients may be warranted.
KEYWORDS: Antimuscarinic; Cardiovascular effects; M3 selectivity
CORRESPONDENCE: Brian Olshansky, MD, Professor of Medicine, University of Iowa Hospitals, 4426a JCP, 200 Hawkins Drive, Iowa City, Iowa 52242, USA ().
CITATION: Urotoday Int J. 2009 Aug;2(4). doi:10.3834/uij.1944-5784.2009.08.07