Comparison of cardiovascular events among treatments for overactive bladder: a Danish nationwide cohort study
The purpose of this study is to explore the cardiovascular safety of antimuscarinic drugs to treat overactive bladder (OAB) in Denmark.
This was a cohort study using data recorded in Danish registries from patients newly exposed to darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium in 2004–2012. We estimated crude and standardized incidence rates (IRs) for acute myocardial infarction (AMI); stroke; cardiovascular mortality; major adverse cardiac events (MACE, a combined endpoint of the previous three outcomes); and all-cause death for the individual and combined drugs. We also estimated crude, standardized, and propensity score-stratified incidence rate ratios (IRRs) comparing individual antimuscarinic drugs to tolterodine as the reference.
Among 72,917 new users of OAB drugs (mean age, 66 years; 60% women), the standardized IR (95% confidence interval) per 1000 person-years for current use of any OAB drug was 2.7 (2.5–2.9) for AMI, 1.3 (1.2–1.5) for stroke, 7.8 (7.5–8.1) for MACE, 4.8 (4.5–5.0) for cardiovascular mortality, and 15.2 (14.8–15.6) for all-cause mortality. Propensity score-stratified IRRs for current use (reference, tolterodine) were close to the null for all drugs and endpoints.
We did not identify differences in the risk of cardiovascular events or mortality among users of individual antimuscarinic OAB drugs.
KeywordsDenmark Pharmacoepidemiology Urinary bladder, overactive Cardiovascular diseases Muscarinic antagonists
We would like to thank Adele Monroe and Whitney Krueger from RTI Health Solutions for their help preparing the manuscript, Morten Olesen from the University of Southern Denmark with assistance during data analysis, and Stefan de Vogel and Kwame Appenteng from Astellas for their input during the study.
All authors fulfilled the ICMJE authorship criteria. Additionally, the authors were involved as follows: substantial contribution to the design of the study: AVM, JH, AP, NSK, WJA, CVL, SPG and AA; acquisition and analysis of the data: JH, AP, NSK; interpretation of the data: all authors; drafting or revising critically for important intellectual content: all authors; final approval: all authors; agreement to be accountable for all parts of the work: all authors.
Compliance with ethical standards
Retrospective registry studies do not require ethics committee notification or approval, since they do not fall under the Danish definition of health science research.
Conflict of interest
The study was funded by Astellas Pharma Global Development, Inc., of which Willem Jan Atsma, Billy Franks, and Milbhor D’Silva are employees. Andrea Margulis, Alejandro Arana, and Susana Perez-Gutthann are full-time employees of RTI International, an independent non-profit research organization that does work for government agencies and pharmaceutical companies. Cristina Varas-Lorenzo was a full-time employee of RTI International at the time of the conduct of the study. Jesper Hallas, Nina Sahlertz. Kristiansen, and Anton Pottegård have worked on a project commissioned by Astellas, with funding paid to their employer. The contract granted the research team independent publication rights.
- 3.Irwin DE, Milsom I, Hunskaar S et al (2006) Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 50:1306–1314; discussion:1314–1305. https://doi.org/10.1016/j.eururo.2006.09.019
- 15.Sturmer T, Rothman KJ, Avorn J, Glynn RJ (2010) Treatment effects in the presence of unmeasured confounding: dealing with observations in the tails of the propensity score distribution—a simulation study. Am J Epidemiol 172:843–854. https://doi.org/10.1093/aje/kwq198 CrossRefPubMedPubMedCentralGoogle Scholar
- 16.ENCePP. EU PAS registration for study post-authorization safety program—validation of the Danish data resources for the study of cardiovascular and neoplasm events in users of treatments for overactive bladder. London: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance 26 July 2016. http://www.encepp.eu/encepp/viewResource.htm?id=14406. Accessed 18 October 2016
- 18.Asche CV, Kim J, Kulkarni AS, Chakravarti P, Andersson KE (2012) Presence of central nervous system, cardiovascular and overall co-morbidity burden in patients with overactive bladder disorder in a real-world setting. BJU Int 109:572–580. https://doi.org/10.1111/j.1464-410X.2011.10436.x CrossRefPubMedGoogle Scholar
- 19.Sundbøll J, Adelborg K, Munch T, Frøslev T, Sørensen HT, Bøtker HE, Schmidt M (2016) Positive predictive value of cardiovascular diagnoses in the Danish National Patient Registry: a validation study. BMJ Open 6:e012832. https://doi.org/10.1136/bmjopen-2016-012832 CrossRefPubMedPubMedCentralGoogle Scholar