drug treatment choice in older adults with urinary incontinence catherine e. dubeau, md professor of...
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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
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