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Update On OAB

Update On OAB. Joon Chul Kim The Catholic University of Korea. Overactive Bladder Syndrome : ICS Definition. Urgency, with or without urge incontinence, usually with frequency and nocturia Absence of pathologic or metabolic conditions that might explain these symptoms

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Update On OAB

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  1. Update On OAB Joon Chul Kim The Catholic University of Korea

  2. Overactive Bladder Syndrome: ICS Definition • Urgency, with or without urge incontinence, usually with frequency and nocturia • Absence of pathologic or metabolic conditions that might explain these symptoms • Urgency - Sudden, compelling desire to pass urine that is difficult to defer Abrams P et al. Urology. 2003;61:37-49.

  3. Intensity of desire to void Intervoid Interval First Sensation Volume Voided Desire to Void (Urge to Void) and Normal Micturition Process Void Urge Intensity Bladder Volume(—) 300 – 500 cc 100 cc Time • Urge: A physiological desire to void • Gradual onset • Increases as a function of bladder volume • Can usually be deferred with appropriate strategies Chapple CR et al. BJU Int. 2004; 94:738-744.

  4. Reduction in Volume VoidedDue to Urgency Presumed NormalVoid Volume Reduction of Intervoid Interval Urgency: Micturition Process in OAB Urgency Desire to Void Bladder Volume (—) Intensity Void(voluntary and/orinvoluntary) Time Chapple CR et al. BJU Int. 2004; 94:738-744.

  5. Urgency Drives the Other Symptoms of OAB Urgency 1 Incontinence Nocturia Increased Frequency and Reduced Intervoid Interval 2 2 1 Reduced Volume Voided per Micturition • Proven direct effect • Effect correlated with urgency but inconsistent due to multifactorial etiology of the symptom Chapple CR et al. BJU Int. 2004; 94:738-744.

  6. Prevalence of OAB by Gender in Korea The Overall Prevalence of OAB in Korea was 12.2% (10.0% Men and 14.3% Women) 25 Men Women 20 *For population 40+ years of age, OAB = 14.9% (male 11.2%; female 18.4%) Estimation of people with OAB in Korea: 5,951,437 15 Prevalence,* % 10 5 0 Korea

  7. Prevalence of OAB by Gender in Korea Total Men Women 30 25 20 15 Prevalence of OAB, % 10 5 0 >=70 18-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 Age Group, years

  8. OAB Initiating Treatment • If there is no significant abnormality of physical exam, urine analysis and PVR, treatment for OAB can be initiated without further workup • In some cases where abnormalities are found, treatment can be initiated, but abnormality must be worked up (e.g. hematuria) • UDS in select patients

  9. Antimuscarinics 2008 in Korea • Oxybutynin IR BID-TID • Oxybutynin ER QD • Tolterodine IR/ER BID / QD • Trospium BID / QD* • Solifenacin QD

  10. What’s The Difference?? • Efficacy • No great differences • Dose dependent • Tolerability • Safety • Clinical Effectiveness – different for different patients depending on expectations

  11. Differences Among Anticholinergics • Metabolism • Hepatic • Renal • Pharmacokinetics • Delivery system • Bioavailability • Receptor selectivity • Chemical structure • Permeability • Dose titration • 50-60% of patients will choose higher dose Produce a number of clinically measurable and theoretical differences

  12. Why is Efficacy So Hard to Measure in the OAB Population • Different patients have different: • Primary bother symptoms • Expectations from treatment • Different studies have different populations

  13. Efficacy of Antimuscarinic Agents vs Placebo *Median % change for baseline **Mean % change from baseline.

  14. Side Effects: Dry Mouth Incidence Drug Placebo Oxybutynin ER 10mg 28.1-29.7% n.a. Tolterodine ER 4mg 23% 8% Oxybutynin TDS 9.6% 8.3% Solifenicin 5 mg 14% 4.9% Solifenicin 10 mg 21.3% 4.9% Darifenicin 7.5 mg 18.8% 13.2% Darifenicin 15 mg 31.3% 13.2% Ratio 2.9 1.2 2.9 4.3 1.4 2.4

  15. Side Effects: Constipation Incidence DrugPlacebo Oxybutynin ER 10mg 6.4-7.0% n.a. Tolterodine ER 4mg 6% 4% Oxybutynin TDS <2% <2% Solifenicin 5mg 7.2% 1.9% Solifenicin 10 mg 7.8% 1.9% Darifenicin 7.5mg 14.8% 6.7% Darifenicin 15mg 21.3% 6.7% Ratio 1.5 ~1 3.8 4.1 2.2 3.2

  16. Urgency: Defining Symptom of OAB • How is it measured? • Yes/no • Degree • VAS, IUSS, UPS • Warning time • OAB voids • Recent studies have shown positive effects on antimuscarinics on urgency • Darifenicin and solifenicin using yes/no scales • Tolterodine and trospium using fixed scales • Darifenicin using a VAS

  17. -3.91 n=348 † -2.73 n=336 Solifenacin Placebo Reduction in Urgency Episodes/24 hrs Episodes Mean baseline: 6.15 6.03 End of study mean: 2.24 3.30 4 63.6% 3 Mean change from baseline to endpoint 45.3% 2 1 0 P<0.0001 †Flexible dosing with solifenacin 5 or 10mg. Patients were allowed to dose increase at wk 4 and increase/decrease at wk 8 Serels S et al.Urology 2006; 68 (suppl 5a): 73 MP-04.11

  18. 2.4% 6.8% 18.7% 18.6% 22.0% 56.0% 61.6% 67.8% 63.6% 50.2% 19.5% 13.3% 12.0% 5.9% Improvement in IUSS Score: Baseline to End of Study Lower IUSS score indicates reduced urgency IUSS score 100 3 = Severe 90 2 = Moderate 80 1 = Mild 70 0 = None 60 Percent 50 40 30 20 10 0.3% 0.3% 0 Baseline End of Study Baseline End of Study Solifenacin Placebo Serels S et al.Urology 2006; 68 (suppl 5a):73 MP-04.11

  19. 7.2% 9.0% 46.7% 56.0% 46.1% 35.0% Improvement in Urgency Perception Score: Baseline to End of Study 1 = Usually not able to hold urine 2 = Usually able to hold urine until I reach the toilet if I go immediately 3 = Usually able to finish what I am doing before going to the bathroom 100 15.2% 15.1% 90 80 70 60 68.4% 73.2% Percent 50 40 30 20 10 16.4% 11.7% 0 Baseline End of Study Baseline End of Study Solifenacin Placebo Higher UPS score indicates reduced urgency Serels S et al.Urology 2006; 68 (suppl 5a):73 MP-04.11

  20. Tolterodine LA Nighttime Dosing Reduced 24-Hour Frequency Study 037 Placebo (n=421) Tolterodine LA (n=429) Normal† OAB‡ Total* 0 -10 9.4 11.5 14.7 12.3 -20 18.1 18.6 Median Reduction inMicturitions, % -30 -40 P=.0068 -50 P=.1571 P=.0012 -60 P=.0225 Micturition episodes defined as: *Urgency score of 1–5 on urgency scale †Urgency score of 1–2 on urgency scale ‡Urgency score of 3–5 on urgency scale Rackley et al. Urology. 2006;67:731-736.

  21. Individual AgentsAdvantages and Drawbacks

  22. Oxybutynin - ER • Advantages • Widest range of dose titration • Only compound approved for “high dose” administration • Drawbacks • Effects on cognitive function

  23. Tolterodine • Advantages • Long safety record • Number 1 prescribed drug • New CNS data favorable • Data on male OAB • Drawbacks: • Lack of titration • Mild increase in QT interval at super therapeutic doses

  24. Advantages No hepatic metabolism Less drug-drug interactions Less crossing of blood-brain barrier ? Clinical correlation at this time Higher urine concentration ? Clinical meaning Trospium • Drawbacks • BID dosing • No dose titration • Slight increase • in heart rate

  25. Solifenicin • Advantages • Dose titration • Relatively low dry mouth incidence • Drawbacks • Mild increase in QT interval at super therapeutic doses

  26. Antimuscarinics Summary • Efficacy among antimuscarinic agents is similar • There are several different advantages (some theoretical) which may influence drug choice in a particular patient • Expect in cases of high dose antimuscarinics, decisions are more likely to revolve around tolerability and safety (or perceived safety)

  27. Male LUTS Can Be Associated With the Bladder, the Prostate, or Both Bladder Condition: OAB Prostate Condition: BPH Urgency, with or without urgency incontinence, usually with frequency and nocturia Term used and reserved for the typical histological pattern that defines the disease Pharmacologic Therapy for OAB: Antimuscarinics Pharmacologic Therapy for BPH: alpha-Blockers 5-ARIs BPH = benign prostatic hyperplasia; OAB = overactive bladder; 5-ARI = 5-alpha-reductase inhibitor. Abrams P et al. Urology. 2003;61:37-49.

  28. Timing of combination treatment • Primary vs. Add-on : Many patients with BPH and OAB have benefit from alpha blocker only : Initially treated with an alpha blocker : Anticholinergics is added in patients who report partial response to the alpha blocker but still have persistent OAB symptoms

  29. In Men With OAB, Treatment With Tolterodine Was Not Associated With Increased Incidence of AUR Subanalyses of Male Patients With OAB in Tolterodine ER Studies Roehrborn CG et al. BJU Int. 2006;97:1003-1006. Abrams P et al. J Urol. 2006;175:999-1004. Elinoff V et al. Intl J Clin Pract. 2006;60:745-751. *Tolterodine ER 4 mg/d. †Open-label study.

  30. TIMES Study: Urinary Retention Summary Kaplan SA et al. JAMA. 2006;296:2319-2328.

  31. Concerns about the risk of AUR • Several recent clinical trials have refuted • But, given the exclusion criteria should be considered • Exclusion criteria for PVR in clinical trials - greater than 30-40% of maximum capacity - or 50-200ml

  32. Concerns about the risk of AUR • Post-void residual volume should be measured to exclude baseline urinary retention • The safety in patients with baseline urinary retention is not known

  33. Recommendation Low PVR: <40% of functional capacity Jaffe WI, Te AE, Current Urology Reports 2005

  34. Summary: OAB in Men • Available data suggests that antimuscarinics are safe in men with OAB + BOO, but PVR should be considered • Optimal way to use + alpha blockers needs to be sorted out • It should be evaluated which patient benefit from adding of antimuscarinics initially in real life practice

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