Drug Treatment Choice in Older Adults with Urinary

Incontinence

Catherine E. DuBeau, MDProfessor of Medicine

Director, Geriatric Continence ClinicCo-Director, Urology Resident Geriatric Education

Program

PfizerAstellasNovartis

Disclosures

Tolerability

Pathophysiology

Efficacy

Drug Choice for UI in Older Adults

Factors in Management - Ease of Use

Tolerability

Pathophysiology

Efficacy

Drug Choice for UI in Older Adults

Factors in Management - Ease of Use

Pathophysiology

Aging

Comorbidity

Homogeneity of Youth

Punk rockers, 1978

Heterogeneity of Age

Punk rockers, 2008

Aging effects on UI drug effects

• Pharmacokinetics• Pharmacodynamics• Age-related changes in micturition

– Structure– Function– Receptors– Impact of comorbidity on voiding and

toileting

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 absorptionDistribution• 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..?

Water soluble agents

Lipophilic agents

Plasma proteins

Drugs

Tight junction

Efflux pumpsCationization

Neuwelt EA. Neurosurgery 2004; 54:131-142

Metabolism

Transport proteins

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

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

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

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

MentationSedative hypnoticsBenzosAnticholinergics

MobilityAntipsychotics

Impact of Drugs on Continence and LUTS in Older Persons

NocturiaNifedipine“Glitazones”NSAIDs/COX2GabapentinPregabalin

LUT functionDecrease contractility Anticholinergics Calcium blockers Sphincter tone Alpha agonist Sphincter tone Alpha blockerDiuretics

Stress UIACE inhibitors

ConstipationCalcium blockersAnticholinergicsNarcotics

MentationSedative hypnoticsBenzosAnticholinergics

MobilityAntipsychotics

NocturiaNifedipine“Glitazones”NSAIDs/COX2GabapentinPregabalin

LUT functionDecrease contractility Anticholinergics Calcium blockers Sphincter tone Alpha agonists Sphincter tone Alpha blockersDiuretics

Stress UIACE inhibitorsConstipation

Calcium blockersAnticholinergicsNarcotics

Common Drugs for Common Conditions

GCC Patient Use of Medications that Could Affect Voiding Symptoms and their Treatment (n= 66)

Effect on continence, LUTS, and antimuscarinic drug treatment

Medication % Pedal edema DU

Urine Output Cognition Bowels

Cough

Incr UI

Drug – drug

interact

NSAIDs 20 X

Ca+ Blocker 35 X X X

Steroids 3 X X

Glitazone 45 X

Narcotics 8 X X X X Tricyclic antidepressant 5 X X X

X

Atypical antipsychotic 3 X X X

X

Antispasmodic 3 X X X X

Loop diuretic 9 X

Hypnotic 2 X

Estrogen 5 X

Benzodiazepene 5 X

Calcium 20 X Other antidepressants* 6.1 X

ACE Inhibitor 29 X

Use of Medications Affecting Continence in Women (median age 80) Attending a Geriatric Continence Clinic

DuBeau and Shanti, Am Geriatr Soc Annual Meeting, 2006

The Prescribing Cascade

77 yo woman with urgency; gets nifedipine for HTN

Edema, constipation, impaired bladder emptyingNocturia, urgency, some UI

OAB!

Add antimuscarinic

constipation Add laxative....

The Prescribing Cascade

77 yo woman with urgency; gets nifedipine for HTN

Edema, constipation, impaired bladder emptyingNocturia, urgency, some UI

OAB!

Add antimuscarinic

constipation Add laxative....

Efficacy

“Do urge UI drugs work in older persons?”

Oxytolfesosolidaritros in Patients Aged > 65 yr

Analysis of pooled phase III fixed dose clinical data

Oxytolfesosolidaritros in Patients Aged > 65 yr

Analysis of pooled phase III fixed dose clinical data

-34.8%

-66.7%

-44.8%

-75.9%-80

-60

-40

-20

0

Placebo 2.7 mg Placebo 5.4 mg

††

Median % Change

UI

QoL

Perception

OAB Drug A

Placebo

“Older patients” in trials often much healthier than those in primary care

<65 y

>65 y

OAB Drug A

OAB Drug B

UIE

Decrease UIE A B 65 - 70 y -2.5 -1.0 71 - 75 y -2.5 -1.0 > 75 y -2.5 -2.5 Total mean -2.5 -1.5

<65 y

>65 y

• 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”)

Problems with existing efficacy studies

• Little to no stratification by age group• No stratification by comorbidity• Little stratification by previous

treatmentNo multivariate analyses despite large N’s

If you control for age, you can’t evaluate it

Problems with existing efficacy studies

• 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

Efficacy: Are we looking at the right outcomes?

DuBeau et al, J Am Geriatr Soc 2006DuBeau et al, J Am Geriatr Soc 1998

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

Urgency and Nocturia

Treatment, months

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

Age/Disease

Functional capacity

Minimum function needed (eg, GFR >20)

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

Safety of OAB Drugs in Older Persons

Takes only 2 more pts to see harm

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)

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)

* *† †

Placebo (n=50)

Oxybutynin ER (n=49)

Darifenacin (n=46)

0

4

5

6

7

Baseline Week 1 Week 2 Week 3

Kay G et al, Eur Urol 2006

Delayed Name-Face Association Test (lower score = worse)

3 week RCT Comparing Darifenacin, Oxybutynin ER and Placebo

* *† †

Placebo (n=50)

Oxybutynin ER (n=49)

Darifenacin (n=46)

0

4

5

6

7

Baseline Week 1 Week 2 Week 3

Kay G et al, Eur Urol 2006

7.5 mg

10 mg

7.5 mg

15 mg

15 mg

20 mg

High starting doseDifferent titration schedule

Very high end dose

Was the Study Design Biased?

Are other commonly-used drugs even worse?

• 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

3 week RCT Comparing Darifenacin, Oxybutynin ER and Placebo

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

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

Tolerability

Pathophysiology

Efficacy

Drug Choice for UI in Older Adults

Factors in Management - Ease of Use

Pathophysiology

Aging

Comorbidity

Choosing an Antimuscarinic

EfficacyTolerability

Adverse effects

No Differences

All decrease UI ~70%, ~25%

cure rate

4th International Consultation on Incontinence, 2008

Chapple C et al, Eur Urol 2005

Shamliyan TA et al, Ann Int Med 2008

• Dry mouth: oxybutynin worst

• Constipation: darifenacin, solifenacin worst• Least: Oxytrol patch (but rash in 15%)

• 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)

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

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

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

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;49:700Malone-Lee et al, J Urol 2001;165:1452

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)

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?

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

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

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

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

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 informationLayton et al, Drug Safety 2001; 24:703 Shader and Oesterheld, J Clin Psychopharm 1995; 15:378

Further Confusion• Unknown if pts with Alzheimer’s truly at

higher risk because impaired central cholinergic systems

• Concomitant cholinesterase inhibitors: – One case report of delirium in pt also taking

bladder relaxant– Unknown if bladder relaxant efficacy affected– Do cholinesterase inhibitors cause UI?– Is the blood-brain barrier the most important

factor?Ouslander et al, J Am Med Dir Assoc 2001;2:207-214 Womack and Heilman, Arch Neurol 2003;60:771-773.

Impact of DM on Continence Determinants

• Function: neuropathy, poor vision, amputation

• Cognition: vascular dementia• Comorbidity

– CAD/CHF: nocturia– Constipation– UTIs– Med side effects

• Glitazones, Avandia: edema → nocturia• ACEI: cough→ stress UI

Antimuscarinic Adherence

• Medicare Managed Care enrollees ( n ~14,000) with OAB (ICD-9 codes and at least one antimuscarinic Rx q6 mos) (n = 279, 2%)

• Medication Possession Ratio (MRP)

– # days of Rx dispensed/days between prescription (30 tabs refilled every 30 days = 100% adherence)

• OAB antimuscarinics MRP = 0.42

– Higher with better general health perception

– Lower with comorbidity and greater # prescriptions

– 10% in antimuscarinic MRP associated with 6% total health costs

– Unclear if relationship between MRP with costs specific to antimuscarinic

Balkrishnan et al, J Urol March 2006

Drug-Drug Interactions

• Antimuscarinics add to pre-existing anticholinergic burden

• Bladder antimuscarinic metabolism– Agents metabolized via CY2D6 and 34A

ubiquitous in primary care

• Clinical implications– Drug-drug interactions fact of life for all

prescribing– Electronic tools (Epocrates, etc)– Start low: is your formulation small enough?

QTc Prolongation and Mortality Risk

Montanez M et al, Arch Intern Med. 2004Sharp DS, Ann Int Med 1998

• Review of 7 prospective cohort studies of prolonged QTc and overall and cardiovascular mortality; n = 36,03; 2677 (8.7%) had QTc >440 msec

• 1 study: no association (relative risk, 1.02; 95% CI 0.70-1.49)• 6 studies inconsistent associations overall and across subgroups

(age, sex, and comorbidities)• Only consistent findings were in subgroup with prior CV disease

– Total mortality, RR 1.1 - 3.8 – CV mortality, 1.2 - 8.0– Rudden death, 1.0 - 2.1 for

• Caveat: cannot directly address QTc prolongation related to medication use

• Other interations: impaired lung function, low body weight

• Degree of QTc prolongation during treatment with QTc-prolonging drugs is prognostic for the risk of torsade

• QTc prolonging drugs should probably not be prescribed for patients with a QTc >460 ms

• Medicare database study: no association between antimuscarinics and ventricular arrythmias

• Other considerations: concomitant or interval use of other QTc prolonging agents, eg quinolones

Elming H, Cardiac Electrophysiol Rev 2002

Wang PS, J Am Geriatr Soc 2002

QTc Prolongation and Mortality Risk

Copyright restrictions may apply.

Walter, L. C. et al. JAMA 2001;285:2750-2756.

Upper, Middle, and Lower Quartiles of Life Expectancy by Age

Copyright restrictions may apply.

Walter, L. C. et al. JAMA 2001;285:2750-2756.

Upper, Middle, and Lower Quartiles of Life Expectancy by Age

77 yo man in lower quartile of LE won’t live long enough to experience symptomatic benefit of finasteride over alpha-blocker

Anticholinergic use in 372 community-dwelling elderly in France

14% (51) on anticholinergic at baseline

30 still on anticholinergic agent at one year

Ancelin M et al, BMJ 2006

Ness J et al, Am J Geriatr Pharmacother 2006

27%

Male veterans > 65 yo on > 5 prescribed meds

OAB Drug A

Placebo

A - low dose A - high dose

“Older patients” not compared directly with younger patients

Tolerability and Safety

Lack of adequate safety info in all drug trials• Analysis of RCTs of drug Rx (HTN in elderly, HIV,

antibiotics for sinusitis, thrombolysis, NSAIDs for RA, H Pylori, GI tract decontamination); N = 130,074 pts

• Severity of ADEs and toxicity adequately defined in only 39% and 29% of reports

• Only 46% stated the frequency of specific reasons for discontinuation due to toxicity

• Median space allocated to safety results was same as that devoted to contributor names and affiliation

Ioannidis JP & Lau J. JAMA 2001, 285:437