FEMALE UROLOGY

Increased warning time with darifenacin: a new concept in the management of urinary urgency
Cardozo L, Dixon A
Urogynaecology Department, King’s College Hospital, London, United Kingdom
J Urol. 2005; 173: 1214-8

• Purpose: We assessed the effect of darifenacin, an M3 selective receptor antagonist, on the warning time associated with urinary urgency.
• Materials and Methods: In this multicenter, double-blind study subjects with urinary urgency for 6 months or greater and episodes of urgency 4 times or greater daily were randomized to darifenacin controlled release tablets (30 mg once daily) or placebo. Warning time was defined as the time from the first sensation of urgency to voluntary micturition or incontinence. Data were collected using electronic event recorders during 6-hour clinic visits or 3 urge-void cycles, if shorter, at baseline and at treatment end.
• Results: A total of 72 subjects entered the study and 67 were included in the primary efficacy analysis (darifenacin in 32 and placebo in 35). Darifenacin treatment resulted in a significant increase in mean warning time with a median increase of 4.3 minutes compared with placebo (p = 0.003). Overall 47% of darifenacin treated subjects compared with 20% receiving placebo achieved a 30% increase or greater in mean warning time (OR 5.6, p = 0.009). Median and minimum warning times were also significantly increased following darifenacin treatment vs. placebo (p = 0.004 and 0.017, respectively). The median difference in minimum warning time was 1.9 minutes in favor of darifenacin vs. placebo.
• Conclusions: To our knowledge this is the first study to evaluate change in warning time, which is potentially important to individuals with symptoms associated with overactive bladder. Darifenacin increases mean, median and minimum warning time compared with placebo, allowing subjects more time to reach a toilet and potentially avoiding the embarrassing experience of incontinence.
  
  
• Editorial Comment
  The authors analyze the efficacy of darifenacin, a selective M3 receptor antagonist, with regard to the parameter of micturitional warning time. Warning time was defined as the point from first sensation of urinary urgency to the patient voluntarily voiding or experiencing episode of urinary urge incontinence. The authors found that darifenacin affected a significant increase in warning time over those patients treated with placebo.
  This is an excellent paper from one of the world’s top urogynecologists. The analysis of warning time may produce a new benchmark of efficacy for OAB medications. This parameter, as it finds its way in use in more and more studies, will evolve. Currently, it is judged as the time between first sensation of urgency to the point of voluntary micturition or incontinence. Since voluntary micturition is a volitional act and urinary incontinence is not, this may be an area of further refinement. In reviewing the study groups, the differences in median baseline warning times between the darifenacin and placebo groups does present a potential “possible imbalance” as suggested by the authors.
  In addition, darifenacin is a M3 selective receptor antagonist. The potential changes in M2 receptor density as opposed to M3 in the denervated bladder has been discussed previously in the literature (1). Consequently, some have postulated that M3 specific antagonists may be at a potential therapeutic disadvantage secondary to the M2 up regulation in the diseased bladder (2).

References
1. Hegde SS, Choppin A, Bonhaus D, Briaud S, Loeb M, Moy TM, Loury D, Eglen RM: Functional role of M2 and M3 muscarinic receptors in the urinary bladder of rats in vitro and in vivo. Br J Pharmacol. 1997; 120: 1409-18.
2. Gillberg PG, Sundquist S, Nilvebrant L: Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists. Eur J Pharmacol. 1998; 349: 285-92.

Dr. Steven P. Petrou
Associate Professor of Urology
Mayo Clinic College of Medicine
Jacksonville, Florida, USA