Abstract
Background: Muscarinic receptor antagonists are the standard of care for patients with overactive bladder (OAB). However, they can increase heart rate, and this can be disadvantageous in patients with coronary heart disease (CHD) or congestive heart failure (CHF). Comedications frequently used in the treatment of cardiovascular disease can further increase the risk for elevation of heart rate.
Objective: As such high-risk patients have not been well represented in most randomized trials of muscarinic receptor antagonists, we investigated whether the muscarinic receptor antagonist solifenacin alters heart rate or has other cardiovascular adverse effects during routine use in OAB patients. The study evaluated these effects both in the overall group and in pre-defined risk groups. The overall tolerability and safety of solifenacin were also explored.
Methods: This open-label, post-marketing surveillance study was specifically designed to evaluate the cardiovascular safety of solifenacin 5–10 mg once daily during a 12-week treatment course without specific inclusion or exclusion criteria but with systematic documentation of heart rate-relevant co-morbidities and comedications. The study was conducted in 4450 patients with OAB under the care of office-based urologists. The primary outcome measurement was heart rate. Secondary outcome measures were blood pressure and overall adverse events, which were systematically recorded before, during (after 1 week) and at study end; in many cases, an ECG was also conducted.
Results: CHD, previous myocardial infarction or CHF were reported by 11.9%, 1.6% and 7.0% of patients, respectively, and >60% were receiving at least one comedication. An ECG was conducted prior to solifenacin treatment in 915 patients and revealed abnormalities in 17.3%. At study end, 72.4% and 19.1% of patients were taking solifenacin 5 mg and 10 mg, respectively. No clinically relevant alterations in mean heart rate (75.2 ± 8.2 beats/min pre-treatment vs 74.5 ± 7.6 beats/min at study end) or mean blood pressure (137/82 mmHg pretreatment vs 134/81 mmHg at study end) were observed. In the subgroup of patients who underwent ECG both before and during treatment, no increase in the prevalence of pathological findings was noted. Adverse effects were rare (affecting 4.8% of patients), and treatment discontinuations due to adverse effects occurred in only 1.4% of patients. Among various possible cofactors, only age >80 years and the presence of comedications significantly affected adverse event incidence.
Conclusion: In real-life conditions, i.e. with inclusion of large numbers of patients with cardiovascular co-morbidities and taking comedications, therapeuti-cally effective doses of solifenacin did not increase heart rate or blood pressure.
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Acknowledgements
This study was supported by Astellas Pharma GmbH and conducted as part of the post-marketing surveillance of solifenacin, as recommended by the German regulatory authorities. The institution of Professor Martin Michel and Dr Jean de la Rosette has received funds from the sponsor for development of the study design, the statistical analysis plan and data analysis. The study design was developed by one of the authors (Professor Martin Michel) together with the medical department of the sponsor. The study was executed by the sponsor. Data collection was by the sponsor. Data analysis was conducted by Medidata, a contract research organization, based upon a statistical analysis plan developed by the authors. The manuscript was written by the authors, and reviewed and approved by the sponsor.
Professor Martin Michel has received research grants, consultancy and speaker honoraria from Astellas, Boehringer, Elbion, Bayer, Eli Lilly and Pfizer. Monika Vogel is an employee of the sponsor. Professor Ulrich Wetterauer has received a speaker honorarium from the sponsor. Professor Jean de la Rosette has no conflicts of interest that are directly relevant to the content of this study.
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Michel, M.C., Wetterauer, U., Vogel, M. et al. Cardiovascular Safety and Overall Tolerability of Solifenacin in Routine Clinical Use. Drug-Safety 31, 505–514 (2008). https://doi.org/10.2165/00002018-200831060-00005
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DOI: https://doi.org/10.2165/00002018-200831060-00005