final slide deck for dr iglesia
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TRANSCRIPT
Faculty Disclosure
Dr. Iglesia has no relevant conflicts to disclose.
Objectives
• Develop effective treatment plans for women with overactive bladder.
• Describe how to communicate realistic goals of overactive bladder treatment with patients.
• Review how to minimize medication side effects in treatment plans for women with overactive bladder.
• Describe the efficacy and safety of new and emerging therapies for women with overactive bladder.
Urinary Incontinence (UI):Prevalence
• 13 million Americans• Gender– Female: 10%-55%– Male: 2%-5%
• Prevalence and severity increase with age
• Seen in over 50% of nursing home patients
Changing the Face of UI
Stereotype Reality
For illustrative purposes only. Not indicative of population distribution.
Prevalence of Any UIBy Age and Severity
Minassian VA, et al. Obstet Gynecol. 2008;111(2 Pt 1):324-331.
Minassian VA, et al. Obstet Gynecol. 2008;111(2 Pt 1):324-331.
Prevalence of Urge UIBy Age and Severity
Patient Case: Background (1)
• Mrs. D is a 48-year-old, perimenopausal, White female.
• Approximately one month ago, she began experiencing urgency, frequency, and occasional urge urinary incontinence (UI).
• In the past 6 months she has gained nearly 25 lbs, which she attributes to perimenopause. She now has a BMI of 28.5.
Patient Case: Background (2)
• She has noticed a significant decline in sexual desire and satisfaction since the onset of her bladder problems.
• She feels anxious and is nervous that she will embarrass herself in public.
• She takes HCTZ and propranolol for hypertension, and SSRI for mild depression.
Defining Overactive Bladder
• Urinary urgency, with or without urge incontinence, usually with urinary frequency and nocturia, in the absence of pathologic or metabolic factors that would explain these symptoms
The International Continence Society defines OAB as:
National Association for Continence (2008) www.nafc.org
Therefore, ask about URGENCY
Major Types of Urinary Incontinence
Stress
Urge Overflow Transient Functional
OAB in the United StatesIncontinent Versus Continent: NOBLE
Stewart WF, et al. World J Urol. 2003;20(6):327-336.
37%Incontinent
63%Continent
12.2 million (6.1% of the population)
21.2 million (10.5% of the adult population)
OAB
33.3million(>16% of pop.)
Functional Incontinence: Causes(AKA Transient or Reversible Incontinence)
• Patient-related• Environmental-related• Disease-related• Medication-related
• Delirium• Infection• Atrophy• Pharmacologic• Psychologic• Endocrinologic• Restricted mobility• Stool impaction
“DIAPPERS”Mnemonic
Physical• Limitations or
cessation of physical activities
Qualityof Life
Sexual• Avoidance of sexual
contact and intimacy
Occupational• Absence from work• Decreased
productivity
Social• Reduction in social
interaction• Limit and plan travel
around toilet accessibilityDomestic• Require specialized
underwear, bedding• Special precautions with
clothing
Psychological• Guilt/depression• Loss of self-esteem• Fear of:
– Being a burden– Lack of bladder
control– Urine odor
Tubaro A. Urology. 2004;64(6 suppl 1):2-6.
Impact on Quality of Life:The Silent Sufferers
Lower Urinary Tract Function
• Bladder and urethral functions– Storage– Micturition
• These functions are controlled by the central nervous system (CNS) through reflexes that coordinate the activity of:– Bladder (smooth muscle)– Urethra (smooth and striated muscles)– Pelvic floor muscles
Lower Urinary Tract Innervation
+M3
Pelvic Nerve(Parasympathetic) ACh
+N
Pudendal Nerve(Somatic) ACh
-3
+1 Hypogastric Nerve
(Sympathetic) NE
Acetylcholine (ACh)
SYM
ON
Spinal Relay Neuron
Hypogastric Nerve
Pudendal Nerve
Pelvic Nerve
+ 1
+ M2,3
Inhibition
Storage ReflexMicturition Reflex
Bladder
Rhabdosphincter
Periaqueductal Gray
PAR
Pontine Micturition
Center
- ß3
+N+N
NeuroUrology
Spinal Reflex
Initial Assessment
• Medical history
• Screening questions
• Urinalysis
• Physical examination
Evaluation and Management
• Urinalysis
• Simple pelvic examination
Patient Case: Continued
• Based on her assessment, you learned she suffers from constipation and has tried to increase her water intake to address that issue.
• With further questioning, she also reports that she has been getting up to urinate at least 4 times a night. – Is it nocturia or nocturnal polyuria?
Screening: Intake/Output Diary
Nocturia vs Nocturnal Polyuria
• Assessed with simple 24-hour urine collection
• Common causes: Sleep apnea, CHF, diabetes mellitus
• Sleep apnea– Most under-recognized cause of nocturnal
polyuria– Treatment with CPAP significantly reduces
nocturic frequency
Fitzgerald MP, et al. Am J Obstet Gynecol. 2006;194(5):1399-1403.
Drugs That Cause OAB-Like Symptoms
Ouslander JG. New Engl J Med. 2004;350(8):786-799.
• Alpha-adrenergic receptor agonists• Tricyclic antidepressants• Psychotropics (sedatives, hypnotics)• Cholinesterase inhibitors• Narcotic analgesics, opioids • Calcium channel blockers• Diuretics• Methylxanthines • NSAIDS
Patient Case: Management
• Change HTN medication• Eliminate caffeine• Decrease fluid consumption• Manage constipation• Lose weight
Behavioral Interventions• Behavioral Training Techniques– Pelvic floor muscle (PFM) training
• Physical therapy (PT)• Kegel exercises
– Bladder training: • Biofeedback• Timed voiding
• Behavioral Modification– Lifestyle modifications: Eliminating bladder irritants from
diet, managing fluid intake, weight control, monitoring bowel regularity, smoking cessation, and patient education
Wyman J, et al. Int J Clin Pract. 2009;63(8):1177-1191.
Pelvic Muscle Rehabilitation
Pelvic PT and Exercise Adherence Study
• Less than ¼ of women continued exercises.
• No difference in rate of subsequent SUI surgery in women who had intensive pelvic PT vs those who did not.
• Marked benefit of initial therapy not maintained 15 years later.
Bo K, et al. Obstet Gynecol. 2005;105(5 Pt 1):999-1005.
Pelvic Floor Muscle (PFM) Training(Kegel Exercises)
• Rationale: strong and fast PFM contraction increases urethral pressure and prevents leakage during sudden increase in abdominal pressure
• Recommendation:– 3 sets of 8-12 slow-velocity maximum voluntary
contractions, sustained for 6-8 seconds, performed 3-4 times a week for at least 15-20 weeks
• Effectiveness: depends upon type of exercise, frequency, intensity, and duration of training
Weighted Vaginal Cones
Pessary for Incontinence: Useful for Stress, Not Urge
Pessary in position
Behavioral Modification
• Elimination of bladder irritants from diet– Eliminate stimulants, such as caffeine and over-the-
counter prescription medication with caffeine. – Evidence suggests aspartame and other artificial
sweeteners may contribute to OAB symptoms.
• Smoking cessation– Smoking may cause chronic coughing, which in turn
may increase the intra-abdominal pressure and cause UI.
– Smoking cessation education should be offered, stressing the relationship between smoking and UI.
Wyman J, et al. Int J Clin Pract. 2009;63(8):1177-1191.
Behavioral Modification (cont)• Management of fluid intake
– When is too much, too much?– When is too little, not enough?
• Management of bowel regularity– Avoid constipation– Increase dietary fiber– Engage in regular exercise– Establish regular defecation plan
• Weight control– First-line option for treatment of UI for obese clients– Goal should be set to decrease BMI to <30 kg/m2
Wyman J, et al. Int J Clin Pract. 2009;63(8):1177-1191.
Patient Case
• Mrs. D eliminates caffeine from her diet; reduces her HTN medication; and tries do Kegel exercises regularly.
• She is still experiencing some leaking and continued, though less frequent, night urgencies.
• You suggest trying a pharmacologic agent.
Drugs for OABHave I got the pill for you?
Heading CE. Curr Opin CPNS Inves Drugs. 2000;3:321-325. Napier C, et al. Proc ICS. 2002:445. Abstract.
*Animal models.
1.33.6
12 12.3
59.2
0
10
20
30
40
50
60
Trospium Tolterodine Solifenacin Oxybutynin Darifenacin
Inhi
bitio
n Co
nsta
nt R
atio
(Ki)
for
Mus
carin
ic R
ecep
tor S
ubty
pes* M3 selective
Primarily M3 selectiveNonselective
(M3/M2)
Receptor Selectivity
Muscarinic Receptor Distribution and Potential Adverse Events
With Antagonist Use
• M2 reverses sympathetically mediated smooth muscle relaxation• M3 causes detrusor contraction
Potential AEsTissue Distribution
EyeM3
Decreased lacrimation Decreased accommodation
Salivary glandsM3
Xerostomia (dry mouth)
HeartM2-M3
Cardiovascular
BrainM1-M5
Decreased cognitive functionShort-term memory lossAltered sleep cycle
IntestineM3
Constipation
Urinary retention BladderM2-M3
Abrams P, et al. Br J Pharmacol. 2006;148(5):565-578.
M-3 Selective Antagonists
• Solifenacin
• Darifenacin
STAR Trial: N=1200
• 12-week, European, prospective, randomized, double-blind, double-dummy, 2-arm, parallel-group trial
• Dose titration regimen of solifenacin (5 mg or 10 mg qd) or a single dose of tolterodine LA 4 mg qd
• Primary objective: Non-inferiority study
• Primary endpoint: Micturition frequency
• Secondary endpoints: Incontinence episodes, urge incontinence episodes, urgency, volume voided, and tolerability
Chapple CR, et al. Eur Urol. 2005;48(3):464-470.
EndpointSolifenacin
(pooled 5 mg/10 mg)
Tolterodine(4 mg qd) P value
PRIMARY (non-inferiority) [PPS]*
Micturition frequency/24 h –2.45 –2.24 .004
SECONDARY (FAS)†
Urgency episodes/24 h –2.85 –2.42 .035
Incontinence episodes/24 h –1.60 –1.11 .006
Nocturia episodes –0.71 –0.63 .730
Urge incontinence episodes/24 h –1.42 –0.83 <.01
Mean volume voided (mL/void) 38.00 31.00 .01
Patients dry (%) 59.00 49.00 .006
Pads/24 h –1.72 –1.19 .0023
Perception of bladder condition –1.51 –1.33 .0061
STAR Trial Reported Endpoints
*Per protocol set. †Full analysis set.
(n=525) (n=524)
(n=578) (n=599)
Chapple CR, et al. Eur Urol, 2005:48(3):464-470.
Darifenacin
• Bladder selectivity (marginal) in animal studies: Not more than tolterodine or oxybutynin in guinea pigs
• Multicenter, placebo-controlled RCT (n=561)
• Reduction in incontinent episodes:– 67.7% Darifenacin 7.5 mg (P = .010)
– 72.8% Darifenacin 15 mg (P = .017)
– 55.9% Placebo
– No reductions in nocturia
Haab F, et al. Eur Urol. 2004;45(4):420-429.
Darifenacin and Warning Time?
Difference in Medians at Week 2 = 4.3 minutes (P = .003)
n=32 n=35
Cardozo L, et al. J Urol. 2005;173:1214-1218.
• Quaternary amine• Used in Europe for 20 years: Many studies• Efficacy not different from standard agents• Poor bioavailability• RCT in US (phase 3, N=523):*– 20 mg bid– Urge UI: 59% drug vs 44% placebo– Nocturnal frequency decreased by week 4– Side effects: Dry mouth 21.8%
Non-Selective Muscarinic Antagonists:
Trospium
*Zinner N, et al. J Urol. 2004;171(6 Pt 1):2311-2315.
Reasons for Nonadherence
Adapted from: BCG analysis, Harris interactive 10,000 Patient Survey, 2002.
Tailor Therapy to Each Patient to Improve Adherence
• Does it fit into their schedule? Do they need reminders to take?
• Cost: Have you reviewed formularies, copayments, availability of generics?
• Do they understand how long it might take to work? Is it working for them?
• Can you reduce potentiality of side effects?
Side Effects
• Dry mouth (higher than M2 agents)
• Constipation (higher than M2 agents)
• Blurred vision
• Exacerbation of gastroesophageal reflux
• Cardiac changes
• Urinary retention
CNS Considerations in the Treatment of Overactive Bladder:
Passive Diffusion Across the BBB
Lipophilicity Diffusion
Charge/polarity, hydrogen bonding Diffusion
Molecular “bulkiness” Diffusion
Pardridge WM. J Neurochem. 1998;70:1781-1792. Habgood MD, et al. Cell Mol Neurobiol. 2000;20:231-253.
Vasculature CNSBBB
-+ --+
---++
+
+-
+
BBB: blood-brain barrier
Effect of Darifenacin and Oxybutynin ER on Memory in Older Subjects
• 3-week, randomized, double-blind, double-dummy, parallel-group, placebo-controlled, multicenter study
• 150 healthy volunteers ‑ age range 60–83 (12.7% ≥75 years)‑ 62% female
• 2-week screening to assess eligibility• Active treatments administered according to US
prescribing information• Computerized battery of cognitive function tests
assessed effect of each drug at end of weeks 1, 2, & 3
Kay GG, et al. Eur Urol. 2006;50:317-326.
Primary Endpoint: Delayed Memory Recall in
The Name-Face Association Test
*P < .05 vs placebo; †P < .05 vs darifenacin (ANCOVA, adjusted for baseline score, age, and sex)Patient (n) numbers reflect baseline values
Score for accuracy(least square mean)
* *† †
Kay GG, et al. Eur Urol. 2006;50:317-326.Reprinted with permission from Elsevier
Week
Mea
n Sc
ore
for d
elay
ed re
call
Nam
e-Fa
ce A
ssoc
iatio
n Te
st
Placebo (n=50)Oxybutynin ER (n=49)Darifenacin (n=46)
Self-Rated Memory Assessment (MAC-S)
MAC-S score(least square mean)
Patient (n) numbers reflect baseline values
Placebo (n=50)Oxybutynin ER (n=49)Darifenacin (n=46)
Kay GG, et al. Eur Urol. 2006;50:317-326. Novartis Pharmaceuticals. Data on File
Alternative Therapies/Treatments
• Botulinum
• InterStim Therapy
• Tension-Free Vaginal Tape- only for mixed UI
InterStim Therapy
Tension-Free Vaginal Tape
Treatment for OAB:Never Surgery
• Mixed UI may be managed with mid-urethral slings, but efficacy is lower than pure SUI
Conclusions
• UI is common.
• Most women go untreated.
• Highly efficacious therapies exist.
• Encourage women to be proactive about treating quality-of-life conditions.