Download Drug Treatment Choice in Older Adults with Urinary Incontinence

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
Disclosures
Pfizer
Astellas
Novartis
Drug Choice for UI in Older Adults
Factors in Management - Ease of Use
Efficacy
Tolerability
Pathophysiology
Drug Choice for UI in Older Adults
Factors in Management - Ease of Use
Efficacy
Tolerability
Aging
Comorbidity
Pathophysiology
Pathophysiology
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
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..?
Water soluble
agents
Tight junction
Lipophilic
agents
Plasma
proteins
Cationization
Drugs
Efflux pumps
Transport
proteins
Metabolism
Neuwelt EA. Neurosurgery 2004; 54:131-142
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
Impact of Drugs on Continence and LUTS in Older Persons
Nocturia
Nifedipine
“Glitazones”
NSAIDs/COX2
Gabapentin
Pregabalin
Constipation
Calcium blockers
Anticholinergics
Narcotics
Mobility
Antipsychotics
Mentation
Sedative hypnotics
Benzos
Anticholinergics
Stress UI
ACE inhibitors
LUT function
Decrease contractility
Anticholinergics
Calcium blockers
 Sphincter tone
Alpha agonist
 Sphincter tone
Alpha blocker
Diuretics
Common Drugs for Common Conditions
Nocturia
Nifedipine
“Glitazones”
NSAIDs/COX2
Gabapentin
Pregabalin
Constipation
Calcium
blockers
Anticholinergics
Narcotics
Mobility
Antipsychotics
Mentation
Sedative hypnotics
Benzos
Anticholinergics
Stress UI
ACE inhibitors
LUT function
Decrease contractility
Anticholinergics
Calcium blockers
 Sphincter tone
Alpha agonists
 Sphincter tone
Alpha blockers
Diuretics
Use of Medications Affecting Continence in Women (median age 80) Attending a
Geriatric
Continence
Clinic
GCC Patient Use of Medications that Could
Affect Voiding
Symptoms
and their Treatment (n= 66)
Effect on continence, LUTS, and antimuscarinic drug treatment
Medication
%
NSAIDs
Ca+ Blocker
Steroids
Glitazone
Narcotics
Tricyclic
antidepressant
Atypical
antipsychotic
Antispasmodic
Loop diuretic
Hypnotic
Estrogen
Benzodiazepene
Calcium
Other
antidepressants*
ACE Inhibitor
20
35
3
45
8
Pedal
edema
X
X
X
X
DU
Urine
Output
Cognition
X
Bowels
Cough
Incr
UI
Drug –
drug
interact
X
X
X
X
X
5
X
X
X
3
3
9
2
5
5
20
X
X
X
X
X
X
X
X
X
6.1
29
X
X
X
X
X
X
X
X
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 emptying
Nocturia,  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 emptying
Nocturia,  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
Placebo 2.7 mg
Median %
Change
UI
QoL
Placebo 5.4 mg
0
-20
-40
-34.8%
Perception
-44.8%
-60
-66.7%
-80
†
-75.9%
†
Placebo
OAB Drug A
“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
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”)
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
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
What do older persons want from treatment?
Variance in Limitation in Daily
Life from OAB
• Bother - 42%
Urgency and Nocturia
• UI - 17%
• Urgency/Frequency - 12%
• Nocturia - 11%
Treatment, months
Michel MC et al, Neurourol Urodynam 2007
ADE Risk in Older Patients
Functional capacity
Minimum function
• Not due to chronological age
• Important factors vary by
individual
needed (eg, GFR >20)
– Pharmacokinetic changes
– Pharmacodynamic changes
– Physiologic
• Age-related changes in organ
systems
• Comorbidity and associated
medications
• Decreased functional reserve:
“homeostenosis”
Age/Disease 
Gurwitz and Avorn, Ann Int Med 1991
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
Takes only 2 more pts
to see harm
– NNH = 1/.18 = 5.6
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)
3 week RCT Comparing Darifenacin, Oxybutynin ER and Placebo
Delayed Name-Face Association Test (lower score = worse)
7
6
5
*†
*†
Darifenacin (n=46)
Oxybutynin ER (n=49)
Placebo (n=50)
4
0
Baseline
Week 1
Week 2
Week 3
Kay G et al, Eur Urol 2006
Was the Study Design Biased?
High starting dose
7.5 mg
10 mg
7.5 mg
15 mg
Different titration schedule
15 mg
20 mg
Very high end dose
7
Are other
commonlyused drugs
even worse?
6
5
*†
*†
Darifenacin (n=46)
Oxybutynin ER (n=49)
Placebo (n=50)
4
0
Baseline
Week 1
Kay G et al, Eur Urol 2006
Week 2
Week 3
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 selfrated 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
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
Drug Choice for UI in Older Adults
Factors in Management - Ease of Use
Efficacy
Tolerability
Aging
Comorbidity
Pathophysiology
Pathophysiology
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)
No Differences
All decrease UI ~70%,
~25% cure rate
Efficacy
• Dry mouth: oxybutynin worst
• Constipation: darifenacin, solifenacin worst
• Least: Oxytrol patch (but rash in 15%)
Tolerability
Adverse effects
4th International Consultation on Incontinence, 2008
Chapple C et al, Eur Urol 2005
Shamliyan TA et al, Ann Int Med 2008
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;49:700
Malone-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 information
Layton 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
• 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
Montanez M et al, Arch Intern Med. 2004
Sharp DS, Ann Int Med 1998
QTc Prolongation and Mortality Risk
• Degree of QTc prolongation during treatment with QTcprolonging 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
Upper, Middle, and Lower Quartiles of Life Expectancy by Age
Walter, L. C. et al. JAMA 2001;285:2750-2756.
Copyright restrictions may apply.
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
Walter, L. C. et al. JAMA 2001;285:2750-2756.
Copyright restrictions may apply.
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
Male veterans > 65 yo on > 5 prescribed meds
27%
Ness J et al, Am J Geriatr Pharmacother 2006
Placebo
OAB Drug A
“Older patients” not
compared directly with
younger patients
A - low dose
A - high dose
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