Drug Treatment Choice in Older Adults with Urinary Incontinence

1. Drug Treatment Choice in Older Adults with Urinary Incontinence Catherine E. DuBeau, MD Professor of Medicine Director, Geriatric Continence Clinic Co-Director, Urology Resident Geriatric Education Program

2. Disclosures Pfizer Astellas Novartis

3. Factors in Management - Ease of Use Tolerability Drug Choice for UI in Older Adults Efficacy Pathophysiology

4. Drug Choice for UI in Older Adults Factors in Management - Ease of Use Efficacy Tolerability Aging Comorbidity Pathophysiology Pathophysiology

5. Homogeneity of Youth Punk rockers, 1978

6. Heterogeneity of Age Punk rockers, 2008

7. Aging effects on UI drug effects • Pharmacokinetics • Pharmacodynamics • Age-related changes in micturition • Structure • Function • Receptors • Impact of comorbidity on voiding and toileting

8. Pharmacokinetics in Older Persons - 1 Absorption • Healthy: No change • Neuro & GI disease: impaired swallowing • Diabetes, anticholinergics: delayed gastric emptying • Frail: decreased subcutaneous fat affecting topical absorption Distribution • Healthy: No change • Inactive, frail: low muscle, higher fat mass • Longer half life of lipophilic agents • Higher serum concentration of water soluable agents • CNS penetration..?

9. Water soluble agents Lipophilic agents Plasma proteins Drugs Cationization Efflux pumps Tight junction Transport proteins Metabolism Neuwelt EA. Neurosurgery 2004; 54:131-142

10. Blood-Brain Barrier in Age & Aging-related Diseases • Data from studies using CSF/serum albumin ratio (C/s) as indication of BBB dysfunction • C/s increases with age • C/s correlates with severity of white matter signal abnormalities (WMSA) on CT in pts with and without dementia • WMSA also associated with vascular risk factors (HTN, DM, hyperlipidemia • WMSA associated with urgency severity Blennow et al, Eur Neurol 1993; Wallin et al, Eur Neurol 2000: Kuchel GA et al, AGS 2008

11. Pharmacokinetics in Older Persons - 2 Metabolism • Healthy • No change in hepatic glycosylation • No definite change in P450 enzymes •  Hepatic mass and blood flow: less first-pass effect and increased serum levels of un-metabolized drug • Comorbid disease • Further decrease in hepatic mass and blood flow • Polypharmacy - medications that induce or inhibit P450 enzymes Clearance • Healthy • Renal: small decrease in GFR • Comorbid disease • Renal: Significant decrease in GFR, under-estimated by serum creatinine • GI: decreased transit time

12. Pharmacodynamics • Age-related changes in detrusor muscarinic receptors • Normal contraction: M3 > M2 effect • With age: Decrease in M3 but not M2 mRNA • Age-related decrease in M receptor number in men (aging vs obstruction effect?) • Decrease in muscarinic-mediated contraction • Extrapolation to clinical data uncertain Mansfield KJ. et al. Brit J Pharmacol 2005,144:1089 Andersson KE. Schroder A. Urologe (Ausg. A) 2004,43:552

13. Impact of Comorbidity: Polypharmacy Polypharmacy is the norm for older patients • Average number of meds = 5 • Among older women reporting medication use in previous week, 57% took > 5 agents • Current disease guidelines promote polypharmacy • Recommended regimen for 74 yo woman with HTN, DM, CHF, arthritis, osteoporosis = 12 meds, taken at 4 different times during the day • Leads to burden and cost disincentives to adding another drug Boyd CM et al. JAMA 2005, 294:716 Kaufman DW et al. JAMA. 2002, 287:337 Ernst ME. Iyer SS, Doucette WR. Value in Health. 2003, 6:51

14. Impact of Drugs on Continence and LUTS in Older Persons Mentation Sedative hypnotics Benzos Anticholinergics Nocturia Nifedipine “Glitazones” NSAIDs/COX2 Gabapentin Pregabalin Stress UI ACE inhibitors Constipation Calcium blockers Anticholinergics Narcotics • LUT function • Decrease contractility • Anticholinergics • Calcium blockers •  Sphincter tone • Alpha agonist • Sphincter tone Alpha blocker Diuretics Mobility Antipsychotics

15. Common Drugs for Common Conditions Mentation Sedative hypnotics Benzos Anticholinergics Nocturia Nifedipine “Glitazones” NSAIDs/COX2 Gabapentin Pregabalin Stress UI ACE inhibitors Constipation Calcium blockers Anticholinergics Narcotics • LUT function • Decrease contractility • Anticholinergics • Calcium blockers •  Sphincter tone • Alpha agonists • Sphincter tone Alpha blockers Diuretics Mobility Antipsychotics

16. Use of Medications Affecting Continence in Women (median age 80) Attending a Geriatric Continence Clinic DuBeau and Shanti, Am Geriatr Soc Annual Meeting, 2006

17. The Prescribing Cascade 77 yo woman with urgency; gets nifedipine for HTN Edema, constipation, impaired bladder emptying Nocturia,  urgency, some UI OAB! Add antimuscarinic  constipation Add laxative....

18. The Prescribing Cascade 77 yo woman with urgency; gets nifedipine for HTN Edema, constipation, impaired bladder emptying Nocturia,  urgency, some UI OAB! Add antimuscarinic  constipation Add laxative....

19. Efficacy “Do urge UI drugs work in older persons?”

20. Oxytolfesosolidaritros in Patients Aged > 65 yr Analysis of pooled phase III fixed dose clinical data

21. Oxytolfesosolidaritros in Patients Aged > 65 yr Analysis of pooled phase III fixed dose clinical data Placebo 2.7 mg Placebo 5.4 mg Median % Change UI QoL Perception † †

22. “Older patients” in trials often much healthier than those in primary care Placebo OAB Drug A <65 y >65 y

23. OAB Drug A OAB Drug B  UIE <65 y >65 y

24. Problems with existing efficacy studies • Inadequate heterogeneity of study population • Lack of racial-ethnic and SES diversity • Include only cognitively and functionally intact • Exclusion of comorbidities known to affect micturition and continence • Limited to patients with high daytime frequency (>8 times daily) • Failure to include older- and oldest-old • Failure to include or assess whether patients have age-related detrusor underactivity (“DHIC”)

25. Problems with existing efficacy studies • Little to no stratification by age group • No stratification by comorbidity • Little stratification by previous treatment No multivariate analyses despite large N’s If you control for age, you can’t evaluate it

26. Efficacy: Are we looking at the right outcomes? • Patient perception: interaction with expectations? • Patient (and family) concerns about adverse drug effects • Marginal trade-off: drug benefit vs polypharmacy and cost • Dissatisfaction with previous inadequate treatment • Previous encounters with ageist providers • Nocturia: never normalized to hours in bed/sleeping • QoL and Bother • Few scales derived using patient-based data from older persons • Floor effects regarding “social” and “role” functions • None validated in oldest old, cognitively +/- functionally impaired • Alternative measures: in nursing home residents, prevalent and especially incident UI have negative impact on social interactions • DuBeau et al, J Am Geriatr Soc 2006 • DuBeau et al, J Am Geriatr Soc 1998

27. Urgency and Nocturia Treatment, months What do older persons want from treatment? • Variance in Limitation in Daily Life from OAB • Bother - 42% • UI - 17% • Urgency/Frequency - 12% • Nocturia - 11% Michel MC et al, Neurourol Urodynam 2007

28. Functional capacity Minimum function needed (eg, GFR >20) Age/Disease  ADE Risk in Older Patients • Not due to chronological age • Important factors vary by individual • Pharmacokinetic changes • Pharmacodynamic changes • Physiologic • Age-related changes in organ systems • Comorbidity and associated medications • Decreased functional reserve: “homeostenosis” Gurwitz and Avorn, Ann Int Med 1991

29. Takes only 2 more pts to see harm Safety of OAB Drugs in Older Persons Consider number needed to harm (NNH) - inverse of attributable risk • Typical antimuscarinic • Decrease in urge UI: drug 70%, placebo 44% • Dry mouth: drug 28%, placebo 10% • NNT = 1/.26 = 3.8 • NNH = 1/.18 = 5.6

30. Cognitive Impairment from Antimuscarinics? • Case reports • RCTs using non-standard cognitive measures • Oxybutynin “worse than Benadryl” (Katz, JAGS 1998) • Quantitative EEG studies: oxybutynin worse than tolterodine, trospium (Todorova, J Clin Pharmacol 2001) • Epidemiological studies • Prescription-event monitoring: more hallucinations with tolterodine than 10 non-antimuscarinic, non-CNS active drugs, RR = 4.85 (95% CI, 2.72-8.66) (Layton, Drug Safety 2001) use of • 372 elderly in France: anticholinergics associated with impairments in multiple domains of a cognitive battery (Ancelin, BMJ 2006)

31. Evidence for Cognitive Impairment from Antimuscarinics • RCTs using standard cognitive batteries • Nursing home residents: oxybutynin ER 5 mg daily did not increase incidence of delirium (measured by CAM) over placebo (Lackner, JAGS 2008) • Older healthy patients: in 3-period crossover trial, variable doses of darifenacin no different than placebo on computerized cognitive battery; however, no intrapatient comparisons, only half of eligible patients randomized (Lipton, J Urol 2005) • Older healthy patients: oxybutynin ER did and darifenacin did not cause more impairment in delayed recall than placebo (Kay, Eur Urology 2006)

32. 3 week RCT Comparing Darifenacin, Oxybutynin ER and Placebo Delayed Name-Face Association Test (lower score = worse) 7 6 5 * * † † Darifenacin (n=46) 4 Oxybutynin ER (n=49) Placebo (n=50) 0 Baseline Week 1 Week 2 Week 3 Kay G et al, Eur Urol 2006

33. High starting dose Different titration schedule Very high end dose Are other commonly-used drugs even worse? Was the Study Design Biased? 7.5 mg 10 mg 7.5 mg 15 mg 15 mg 20 mg 7 6 5 * * † † Darifenacin (n=46) 4 Oxybutynin ER (n=49) Placebo (n=50) 0 Baseline Week 1 Week 2 Week 3 Kay G et al, Eur Urol 2006

34. 3 week RCT Comparing Darifenacin, Oxybutynin ER and Placebo • No differences between darifenacin, oxybutynin ER, and placebo on other tests of delayed recall, immediate recall, visual attention, psychomotor reaction time, information processing speed, or self-rated memory. • In the French community study, anticholinergics were not associated with impairment in delayed recall Kay G et al, Eur Urol 2006; Ancelin, BMJ 2006

35. Drug-Drug Interactions • Agents utilizing CY2D6 and 34A ubiquitous in primary care • Highly protein-bound drugs (eg, trospium) can compete with digoxin, increasing digoxin serum levels • Toxic digoxin level lower in elderly (> 0.8) • Antimuscarinics may add to pre-existing anticholinergic burden • Implications • Accept and acknowledge drug-drug interactions as fact of life • Use of electronic tools/EMR for checks and alerts

36. Drug-Disease Interactions: The Example of Diabetes • Renal impairment: drug clearance • Slowed gastric motility: drug absorption • Constipation:  ADE risk and impact • Cognitive impairment:  ADE risk and impact • Glycosuria: masks antimuscarinic efficacy • DM medications • “Glitazones”: CHF; pedal edema causing nocturia • Metformin: competes for clearance with trospium • ACE inhibitors: cough exacerbates mixed UI • Gabapentin, pregabalin: edema causing nocturia • Tricyclics:  PVR , constipation

37. Drug Choice for UI in Older Adults Factors in Management - Ease of Use Efficacy Tolerability Aging Comorbidity Pathophysiology Pathophysiology

38. Choosing an Antimuscarinic • Cost (variable) • Dose size and escalation (start Detrol LA 2 mg; Ditropan XL widest range) • Once daily vs other dosing (extended release forms best) • Timing with other meds, meals (trospium: empty stomach) • Drug-drug interactions (CYP 2D6 – SSRIs; 3A4 - antifungals, macrolides) • Drug-disease interactions (trospium – renal clearance) • Dry mouth: oxybutynin worst • Constipation: darifenacin, solifenacin worst • Least: Oxytrol patch (but rash in 15%) No Differences All decrease UI ~70%, ~25% cure rate Tolerability Adverse effects Efficacy 4th International Consultation on Incontinence, 2008 Chapple C et al, Eur Urol 2005 Shamliyan TA et al, Ann Int Med 2008

39. Research Agenda for Oxytolfesosolidaritros in Older Patients • Efficacy & tolerability • Assess across a spectrum of comorbidity and impairment • Predictors of response • With and without behavioral interventions • Absolute benefits and risk, NNT and NNH • Patient-based treatment utilities • Outcome measures specific to the spectrum of disease/disability and patient preferences

41. The Example of Dry Mouth • 30% of older people already have it • Most already take at least one drug that causes it • Morbidity: dental caries, problems chewing, poorly fitting dentures, dysphagia, nutritional problems, sleeping difficulty, poor QoL Ship JA et al J Amer Geriatr Soc 2002 Fonda D et al. Frail Elderly, 3rd ICI

42. Age and Physiology • Inter- and intra-individual variability increases • Chronological age poor marker of health status • “Age-associated” vs “age -related” • Both phenomena may be independent of function and symptoms

43. Antimuscarinic Drug Trials in Older Patients • Tolterodine • At 4 weeks, urge UI episodes greater in pts 75 yr (P <0.02) • Reduction in voiding frequency similar in both age groups • No differences in efficacy in pts </> 65 years • No differences in dry mouth by age Malone-Lee et al, JAGS 2001;49:700 Malone-Lee et al, J Urol 2001;165:1452

44. What is the “placebo effect”? “Perceived” placebo effect • Natural history • Maximum expected improvement 42% at 1 yr (6% at 8 wk) • Regression to mean, esp with severe symptoms at entry • MERIT population 3 UI episodes/day, but 45% sx > 5yr • Time effects related to pts • Early improvement leads to hope for good outcome • Unintended parallel interventions • Earlier improvers may be more likely to perform/continue other behavioral modifications (eg, decrease fluids)

45. What is the “placebo effect”? “True” placebo effect • Conditioning • No difference in previous treatment or its efficacy • Impact of informed consent: improvement is “reasonably expected”; listing of potential side effects • Study participation • Amplification of placebo response by increased hope of good outcomes simply by entering a trial • Outcome measure • If overly sensitive, placebo effect increased • Bladder diary valid/reliable, but subjective/QoL measures?

46. Preserved Plasticity • Systems can continue to adapt and change “despite” advanced age • Weight training increases muscle mass and strength in 90 year olds • Persons who stay intellectually engaged have improved quality of life • New evidence that CNS plasticity preserved

47. What Increases ADE Risk? • Not chronological age • The important factors vary by individual • Pharmacokinetic changes • Pharmacodynamic changes • Physiologic: both co-morbidity (and meds to treat it) and decreased reserve • Functional characteristics Gurwitz and Avorn, Ann Int Med 1991

48. The Example of Dry Mouth • 30% of older people already have it • Most already take at least one drug that causes it • Morbidity: dental caries, problems chewing, poorly fitting dentures, dysphagia, nutritional problems, sleeping difficulty, poor QoL Ship JA et al J Amer Geriatr Soc 2002 Fonda D et al. Frail Elderly, 3rd ICI

49. Adverse Drug Effects • Common with all drugs in older persons (prevalence 35-66%) • Changes placing elderly at higher risk for anticholinergic AEs: • Altered cholinergic receptor number and distribution • Age and disease effects on blood-brain barrier (BBB) • Drug metabolism, drug-drug interactions • Pre-existing dry mouth and constipation • Impaired visual accomodation

50. The Confusion around Confusion • Incidence unclear • Ditropan XL: “confusion” rate 2 to <5% in all studies • Detrol LA: “confusion” not listed; hallucinations in UK post-marketing survey, 4.5% rate/1000 pt-yrs (95% CI 2.9 – 6.8) • Case reports: “The addled nonagenarian” • Definition unclear • Is it worsening memory? Delirium? Both? • What are the best measures? Do proxy measures (eg, EEG) correlate clinically? US Ditropan XL prescribing information US Detrol LA prescribing information Layton et al, Drug Safety 2001; 24:703 Shader and Oesterheld, J Clin Psychopharm 1995; 15:378