A Comparison of 2 Therapies for Urgency Urinary Incontinence
A Comparison of 2 Therapies for Urgency Urinary Incontinence
Visco AG, Brubaker L, Richter HE, et al
N Engl J Med. 2012;367:1803-1813
Urgency urinary incontinence (UUI), which is often associated with overactive bladder (OAB), is a common and bothersome condition. The primary medical therapy for UUI is anticholinergic medications. Last year, onabotulinumtoxinA was approved for the treatment of neurogenic detrusor overactivity. Phase 3 studies evaluating its efficacy to treat UUI secondary to OAB have been completed, and a decision from the US Food and Drug Administration (FDA) regarding this indication is pending. The study reviewed here, the Anticholinergic versus Botulinum toxin Comparison (ABC) trial, compared outcomes in women with UUI who were treated with the 2 modalities.
A total of 472 women were screened to enter this 6-month trial, which was both double-blinded and placebo-controlled. Patients were assigned 1:1 to an oral anticholinergic plus placebo injection of saline or an intradetrusor injection of 100 U of onabotulinumtoxinA plus oral placebo. The initial anticholinergic used was solifenacin at 5 mg. If adequate improvement was not noted based on the Patient Global Symptom Control Instrument, then solifenacin was increased to 10 mg at 2 months. If there was still inadequate improvement, a switch to trospium XR 60 mg occurred at 4 months. A similar ability to uptitrate and switch medications occurred in the placebo arm for patients who received onabotulinumtoxinA injection. The primary outcome measure was reduction in UUI episodes. Quality-of-life data were obtained as well as adverse events and need to perform clean intermittent catheterization (CIC).
A total of 249 women were randomly assigned, 247 were treated, and 241 had complete data available at study end. Baseline UUI episodes/day were similar between the 2 groups -- 5.2 in the anticholinergic group and 4.8 in the onabotulinumtoxinA group. With regard to the primary outcome measure (ie, decrease in UUI episodes), a similar reduction was noted between the 2 groups (reduction of 3.4 episodes/day for the anticholinergic group and 3.3 episodes/day for the onabotulinumtoxinA group) during the 6-month period. Complete resolution of UUI was greater for the onabotulinumtoxinA group (27% vs 13%, P = .003). In regard to adverse events, anticholinergics had a higher rate of dry mouth (46% vs 31%, P = .001), and onabotulinumtoxinA had a higher need for CIC (5% vs 0%, P = .01) and rate of urinary tract infections (33% vs 13%, P < .001).
What does this mean for clinical practice? Several important points are worth emphasizing. First, it is important to remember that onabotulinumtoxinA does not presently have an FDA indication for UUI. Although some insurance carriers may reimburse for this, it is still an off-label indication at this time. It is thought that the FDA may come to a decision on the phase 3 onabotulinumtoxinA trials in early 2013. Those phase 3 trials that evaluated onabotulinumtoxinA for the treatment of UUI did so in patients who were anticholinergic failures. In this study, 41% of patients were naive to prior anticholinergic use. In addition, it is unclear whether patients in the ABC trial who were on anticholinergics (and were washed out prior to study entry) were actually having an inadequate response. If onabotulinumtoxinA will ultimately be approved by the FDA for UUI in patients who have failed on anticholinergics, are we comparing apples to oranges because almost half of this patient population had not previously tried an anticholinergic? One could also make the argument that the anticholinergic arm may have done better in this trial than what we might normally see due to the fact that medications were provided gratis. That may positively affect long-term adherence with drugs, which is known to be quite poor in medical claims studies. Lastly, there are thoughts that patients do better when a medication is changed on a "switch study." Certainly, patients had the opportunity to both increase the dose and change medications on the anticholinergic arm; it is unclear how much of the improvement might have been affected by this switch. Therefore, what does this mean for clinical practice? This study has shown that both treatments improve symptoms of UUI and that there are possible adverse events for both. It is unlikely that the treatment paradigm will change. As per the American Urological Association's guideline for the treatment of OAB, first-line therapy will continue to be behavioral/pelvic floor therapy and anticholinergics (and likely beta-agonists as well in a future revision). Options for initial treatment failures include onabotulinumtoxinA, sacral nerve stimulation, and posterior tibial nerve stimulation.
I hope that this study will lead to further investigations on other issues and questions that could be answered for this patient population. What is the true overall cost of the 2 arms? In order to answer this question, many variables need to be taken into account in addition to the cost of the medications, including the duration of effect of onabotulinumtoxinA, cost of diapers/pads, cost of catheters, social cost of UUI, and other symptoms of OAB. Can we predict which patients may or may not respond to oral therapy? Can we predict which patients injected with onabotulinumtoxinA are at greater risk for CIC? If CIC is required, does this negatively affect the quality-of-life improvements noted with decreased UUI? Clearly, more is to be learned until we are optimally able to treat this patient population.
Abstract
Anticholinergic Therapy vs. OnabotulinumtoxinA for Urgency Urinary Incontinence
Visco AG, Brubaker L, Richter HE, et al
N Engl J Med. 2012;367:1803-1813
Study Summary
Urgency urinary incontinence (UUI), which is often associated with overactive bladder (OAB), is a common and bothersome condition. The primary medical therapy for UUI is anticholinergic medications. Last year, onabotulinumtoxinA was approved for the treatment of neurogenic detrusor overactivity. Phase 3 studies evaluating its efficacy to treat UUI secondary to OAB have been completed, and a decision from the US Food and Drug Administration (FDA) regarding this indication is pending. The study reviewed here, the Anticholinergic versus Botulinum toxin Comparison (ABC) trial, compared outcomes in women with UUI who were treated with the 2 modalities.
A total of 472 women were screened to enter this 6-month trial, which was both double-blinded and placebo-controlled. Patients were assigned 1:1 to an oral anticholinergic plus placebo injection of saline or an intradetrusor injection of 100 U of onabotulinumtoxinA plus oral placebo. The initial anticholinergic used was solifenacin at 5 mg. If adequate improvement was not noted based on the Patient Global Symptom Control Instrument, then solifenacin was increased to 10 mg at 2 months. If there was still inadequate improvement, a switch to trospium XR 60 mg occurred at 4 months. A similar ability to uptitrate and switch medications occurred in the placebo arm for patients who received onabotulinumtoxinA injection. The primary outcome measure was reduction in UUI episodes. Quality-of-life data were obtained as well as adverse events and need to perform clean intermittent catheterization (CIC).
A total of 249 women were randomly assigned, 247 were treated, and 241 had complete data available at study end. Baseline UUI episodes/day were similar between the 2 groups -- 5.2 in the anticholinergic group and 4.8 in the onabotulinumtoxinA group. With regard to the primary outcome measure (ie, decrease in UUI episodes), a similar reduction was noted between the 2 groups (reduction of 3.4 episodes/day for the anticholinergic group and 3.3 episodes/day for the onabotulinumtoxinA group) during the 6-month period. Complete resolution of UUI was greater for the onabotulinumtoxinA group (27% vs 13%, P = .003). In regard to adverse events, anticholinergics had a higher rate of dry mouth (46% vs 31%, P = .001), and onabotulinumtoxinA had a higher need for CIC (5% vs 0%, P = .01) and rate of urinary tract infections (33% vs 13%, P < .001).
Viewpoint
What does this mean for clinical practice? Several important points are worth emphasizing. First, it is important to remember that onabotulinumtoxinA does not presently have an FDA indication for UUI. Although some insurance carriers may reimburse for this, it is still an off-label indication at this time. It is thought that the FDA may come to a decision on the phase 3 onabotulinumtoxinA trials in early 2013. Those phase 3 trials that evaluated onabotulinumtoxinA for the treatment of UUI did so in patients who were anticholinergic failures. In this study, 41% of patients were naive to prior anticholinergic use. In addition, it is unclear whether patients in the ABC trial who were on anticholinergics (and were washed out prior to study entry) were actually having an inadequate response. If onabotulinumtoxinA will ultimately be approved by the FDA for UUI in patients who have failed on anticholinergics, are we comparing apples to oranges because almost half of this patient population had not previously tried an anticholinergic? One could also make the argument that the anticholinergic arm may have done better in this trial than what we might normally see due to the fact that medications were provided gratis. That may positively affect long-term adherence with drugs, which is known to be quite poor in medical claims studies. Lastly, there are thoughts that patients do better when a medication is changed on a "switch study." Certainly, patients had the opportunity to both increase the dose and change medications on the anticholinergic arm; it is unclear how much of the improvement might have been affected by this switch. Therefore, what does this mean for clinical practice? This study has shown that both treatments improve symptoms of UUI and that there are possible adverse events for both. It is unlikely that the treatment paradigm will change. As per the American Urological Association's guideline for the treatment of OAB, first-line therapy will continue to be behavioral/pelvic floor therapy and anticholinergics (and likely beta-agonists as well in a future revision). Options for initial treatment failures include onabotulinumtoxinA, sacral nerve stimulation, and posterior tibial nerve stimulation.
I hope that this study will lead to further investigations on other issues and questions that could be answered for this patient population. What is the true overall cost of the 2 arms? In order to answer this question, many variables need to be taken into account in addition to the cost of the medications, including the duration of effect of onabotulinumtoxinA, cost of diapers/pads, cost of catheters, social cost of UUI, and other symptoms of OAB. Can we predict which patients may or may not respond to oral therapy? Can we predict which patients injected with onabotulinumtoxinA are at greater risk for CIC? If CIC is required, does this negatively affect the quality-of-life improvements noted with decreased UUI? Clearly, more is to be learned until we are optimally able to treat this patient population.
Abstract
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