Fourth International Consultation On Incontinence (ICI) - Drug Treatment Committee Highlights

Main Category: Urology / Nephrology
Also Included In: Pharmacy / Pharmacist
Article Date: 24 Jul 2008 - 3:00 PDT

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Karl-Erik Andersson, MD, PhD, and Christopher Chapple, MD, Committee Chairs

PARIS, FRANCE (UroToday.com) - Dr. Andersson began this presentation with a brief overview of the updated 2002 ICS definitions regarding lower urinary tract function and OAB and proposed theories for the pathophysiology of OAB. He described the paradigm shift that has taken place over the last several years with respect to the recognition of the important, even dominant role of the urothelium and afferent activity in the generation of OAB.

With respect to anticholingergic therapy, Dr. Andersson reviewed the structure of the urothelium/suburothelium and the interplay with afferent C-fibers and Adelta fibers. He showed a study demonstrating that oxybutynin dramatically decreases afferent activity. Anticholingergics are active during the filling phase and may block receptor activation from acetylcholine that has "leaked" from the urothelium because of stretching or from damaged cholinergic nerves. This inhibition of afferent activity occurs at much lower concentrations of drug than is required for inhibition of voiding activity, yielding a "therapeutic window" for OAB pharmacotherapy. This is a possible explanation for why the newer studies of anticholinergic use in male "BPH" patients generally do not show an increased risk of urinary retention or elevated post-void residuals with anticholinergic therapy. Including information from the last consultation, the committee identified 73 trials for inclusion in a meta-analysis. All five commercially marketed anticholinergic treatments attained Level 1 evidence and Grade A recommendation for treatment (tolterodine, fesoterodine, darifenacin, solifenacin and trospium). Oxybutynin was included in the drugs with mixed effects and also achieved Level 1/Grade A status.

Several other notable drugs commonly used for UI were also mentioned. Imipramine has non-selective antimuscarinic activity, alpha-adrenergic activity, and effects on renal water absorption. The committee noted serious issues with the cardiac toxicity profile and recommended imipramine be used with caution (Level 3 Grade C). Duloxetine, like imipramine, does not have an FDA indication for incontinence but is useful for pharmacological treatment of UI (Level 2 Grade B).

Vasopressin/DDAVP was given a Grade B recommendation for treatment of nocturia and Grade C for treatment of OAB. Treatment of OAB with alpha 1 antagonists has Level 1 evidence but received only a Grade D recommendation due to lack of proven efficacy. There is Level 2 evidence with a Grade B recommendation for Beta 3 agonists and lower levels of evidence for Beta 2 agonists. Treatment of LUTS with phosphodiesterase type 5 inhibitors is an area of tremendous clinical interest recently and there are several new RCT's in this arena. The committee gave a Grade B recommendation with Level 1 evidence.

Next, Dr. Andersson addressed intravesical therapies for neurogenic DO, most of which have level 2 evidence. Botulinum toxin A was given a grade A recommendation. Capsaicin, Resiniferatoxin and Botulinum toxin B were all given Grade C recommendations. For use in non-neurogenic patients (idiopathic DO), Botulinum toxin A has Level 2 evidence with a Grade B recommendation by the committee. Estrogen for OAB has Level 2 evidence with a Grade C recommendation.

Addressing pharmacotherapy for stress incontinence, Dr. Andersson noted the only standout drug is duloxetine with Level 1 evidence and a Grade A recommendation; the drug does not have an indication for SUI in the U.S., and the committee is concerned with the efficacy to adverse events ratio. Imipramine has Level 3 evidence and a Grade D, while estrogen also received a Grade D recommendation.

The committee pointed out that optimal dosing and pharmacokinetic interactions need further study. Dr. Andersson noted that the afferent system and higher centers will likely be areas of future investigation. One questioner asked what endpoints the committee chose to look at in evaluating drug treatments, as the primary endpoints differ greatly across studies. Dr. Chapple stated that the committee was aware of the challenges presented by this, and the committee attempted to gauge "overall efficacy" when evaluating the literature. There was also a question about using DDAVP in elderly patients who are more susceptible to the side effect of hyponatremia. The panel generally agreed that it is used in clinical practice but with caution.

Moderated by Christopher Chapple, MD, and Willie Davila, MD, at the Fourth International Consultation on Incontinence (ICI) - July 5 - 8, 2008. Palais des Congres, Paris, France.

Written by William Jaffe, MD, a Contributing Editor with UroToday.

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