Urinary antispasmodic use and the risks of ventricular arrhythmia and sudden death in older patients

The introduction of new medications to treat overactive bladder has resulted in a significant increase in the number of individuals with this condition who use medications for symptoms. Formal epidemiological studies of the safety of these medications in typical patient populations are lacking, particularly studies of serious events. We sought to determine whether the use of urinary antispasmodics increases the risk of ventricular arrhythmias or sudden death.

Retrospective cohort study.

Retrospective analysis of data of participants in community, hospital or nursing home setting.

Fourteen thousand six hundred thirty-eight subjects with a diagnosis of urinary incontinence made between January 1, 1991, and June 30, 1995; all were aged 65 and older and enrolled in Medicare and Medicaid or the Pharmacy Assistance for the Aged and Disabled programs of New Jersey.

Filled prescriptions for oxybutynin (Ditropan), flavoxate (Urispas), hyoscyamine (Cystospas), and hyoscyamine sulfate (Cystospas-M) were used to define days of exposure to these drugs. We also identified all use of nonsedating antihistamines and cytochrome P450 3A4 inhibitors, and their concurrent use, to serve as a positive control exposure. Two outcomes were then defined: a new diagnosis of ventricular arrhythmia combined with initiation of an antiarrhythmic medication and sudden death. Other covariates, including clinical, demographic, medication use, and healthcare utilization variables, were also assessed. Adjusted risk ratios of ventricular arrhythmia and sudden death were derived from multivariable Cox proportional hazards models.

There was no significant association between periods of use of urinary antispasmodics and the development of ventricular arrhythmias (adjusted risk ratio (RR) = 1.23, 95 confidence interval (CI) = 0.87-1.75) or sudden death (adjusted RR = 0.70, 95% CI = 0.28-1.74). A significantly increased risk of ventricular arrhythmia was observed for the positive control regimen, concurrent use of nonsedating antihistamines and cytochrome P450 3A4 inhibitors (adjusted RR = 5.47; 95% CI = 1.34-22.26), but not for use of either drug group alone. Concurrent use of nonsedating antihistamines and cytochrome P450 3A4 inhibitors was also associated with a significant increase in the risk of sudden death (adjusted RR = 21.50, 95% CI = 5.23-88.37). Other variables significantly associated with ventricular arrhythmia included ischemic heart disease and congestive heart failure, whereas nursing home use before the index date was associated with a decreased likelihood of receiving a diagnosis of and treatment for ventricular arrhythmia. Other variables significantly associated with sudden death included male gender, black race, and congestive heart failure.

Antimuscarinic urinary antispasmodics available before 1996 were not associated with an increased risk of ventricular arrhythmias and sudden death. Additional study will be required to confirm these results, exclude the possibility of unmeasured confounders contributing to any lack of an observed relationship, and extend these findings to newer agents such as tolterodine.