Cardiovascular safety and overall tolerability of solifenacin in routine clinical use: a 12-week, open-label, post-marketing surveillance study.
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 pre-treatment 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.


CONCLUSIONS
In real-life conditions, i.e. with inclusion of large numbers of patients with cardiovascular co-morbidities and taking comedications, therapeutically effective doses of solifenacin did not increase heart rate or blood pressure.
Michel
Martin C
MC
Department of Pharmacology and Pharmacotherapy and Department of Urology, Academic Medical Center, University of Amsterdam, the Netherlands. m.c.michel@amc.uva.nl
Wetterauer
Ulrich
U
Vogel
Monika
M
de la Rosette
Jean J M C H
JJ
D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure / Q000187:drug effects; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000453:epidemiology; D005260:Female; D005858:Germany; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D011358:Product Surveillance, Postmarketing; D011812:Quinuclidines / Q000008:administration & dosage / Q000009:adverse effects*; D000069464:Solifenacin Succinate; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000009:adverse effects*
D018727:Muscarinic Antagonists; D011812:Quinuclidines; D044005:Tetrahydroisoquinolines; D000069464:Solifenacin Succinate