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Legemiddelbruk og hoftebrudd
Oppsummering av ph.d.
GerIT 05.04.16
LIS Marit Stordal Bakken
Haraldsplass Diakonale Sykehus
U N I V E R S I T Y O F B E R G E N
Potentially inappropriate drug use and
hip fractures among older peoplePharmacoepidemiological studies
Marit Stordal Bakken
September 11th 2015
Contents
• Background
• Research aims
• Study I (paper I)
• Study II (papers II and III)
• Implications
3
Drug use among older people
• Norwegian nursing home patients: 10
• Acutely hospitalized Irish 85 year-olds: 7 (regular only)
• Swedish general population
70-79: 4.8 - 5.0
80-89: 5.7 - 6.1
90 +: 6.1 - 6.6
4Soraas 2014, Dalleur 2014, Hovstadius 2010
Psychotropic drugs
Antidepressants Anxiolytics Hypnotics Antipsychotics
Despair 1894 The scream 1893 Sleepless night 1920 Self portrait in hell 1903
Edvard Munch
5
Psychotropic drug use
♀ > ♂Increases with age
Higher numbers in nursing homes
Drug group Women 60+ Men 60+
Antidepressants 14 % 7 %
Anxiolytics 17 % 9 %
Hypnotics & sedatives 29 % 16 %
Antipsychotics 5 % 3 %
6Community-dwelling 60+, proportion of the population using (The Norwegian Prescription database, NorPD)
Inappropriate drug use
• Risks outweigh benefits
• Major impact on health outcomes
• Number of drugs and psychotropic drug useassociated with adverse drug events
• Drug use and prescribing quality among acutelyhospitalized older people in Norway?
7Petrovic 2012, Fastbom 2015, Pirmohamed 2004, Wu 2010, Bradley 2012
Hip fractures
8
Hip fractures
• Highly prevalent - critical events - substantial costs
• Combination osteoporosis + fall
Psychotropics
9Coupland 2011, Haney 2010, Cumming 1997
Contents
• Background
• Research aims
• Study I (paper I)
• Study II (papers II and III)
• Implications
10
Overall research aims
• To examine aspects of prescribing quality among older people acutely admitted to hospital
(study I, paper I)
• To explore associations between exposure to psychotropic drugs and the risk of hip fracture
(study II, papers II and III)
11
Contents
• Background
• Research aims
• Study I (paper I)
• Study II (papers II and III)
• Implications
12
Intermediate care nursing home unit
Haukeland University Hospital
Haraldsplass Deaconess Hospital
Municipality of Bergen
Intermediate care nursing
home unit
13
Intermediate care nursing home unit
• Inclusion criteria>70 years, community-dwellingAcutely admitted to hospital Transfer within 72 hours Discharge (home) within 3 weeks realisticInformed consent required
• Exclusion criteriaSurgery, intensive care, delirium, severe dementia
• Multidisciplinary geriatric approach
14
Research aims
• To identify inappropriate prescribing among older people (≥70) on acute hospital admission and on discharge from an intermediate-care nursing home unit (INHU) and hospital wards (HWs)
• To compare changes in inappropriate prescribing within and between these groups during stay
15
Methods
• Study period August 2007 - June 2008
• Data collectionDemographics: age, gender, length of stayMedications (admission and discharge): regular + on demand
• Outcome measuresDrug usePotentially inappropriate medicines (PIMs)
NORGEP: 21 drugs + 15 combinations to avoidDrug-drug interactions (DDIs)
interaksjoner.no: 4 point severity scale
16
Study population
400 hospital
200 interm. 157
200 hospital 133
Drop-outs-complete medication lists unavailable (6)-not retrospectively identifiable in hospital datasystems (10)-not meeting inclusion criteria or randomized ≥ 1 (80)-consent withdrawn (14)
17
Results I
• Demographics
N=290 (INHU=157, HW=133)
Mean age 85 years, 71% women
• Drug use
Mean 6.0 – 9.3 drugs
Increased: analgesics, laxatives, hypnotics, cough medications
Reductions: none
HW – hospital wardINHU – intermediate care nursing home unit
18
Results II
• Potentially inappropriate medicines (PIMs)
23/34 (eligible) NORGEP items
At least one PIM: admission 24% – discharge 35%
Most frequent PIM: ≥3 psychotropic drugs
PIMs increased: ≥3 psychotropic drugs, NSAIDs combinations
PIMs reduced: none
• INHU patients less likely to have diazepam initiated
HW – hospital wardINHU – intermediate care nursing home unit
19
Results III
• Drug-drug interactions (DDIs)
At least one DDI: admission 53% – discharge 68%
Severe DDIs (“should be avoided”) scarce on admission, remained unchanged in both settings
No significant group differences
Trend: DDIs ”precautions necessary” increased more in HWs
HW – hospital wardINHU – intermediate care nursing home unit
20
Summary of results study I
• Drug use extensive and PIMs and DDIs frequent on admission - increased regardless of setting
Several psychotropic drugs Unadvisable drug combinations including NSAIDs Severe DDIs were scarce
• No reductions in number of drugs, PIMs or DDIs were identified in either setting
• Minor differences in prescribing quality identified
21
Contents
• Background
• Research aims
• Study I (paper I)
• Study II (papers II and III)
• Implications
22
Psychotropic drugs
Antidepressants Anxiolytics Hypnotics
Despair 1894 The scream 1893 Sleepless night 1920
Edvard Munch
23
Aims
• To examine associations between antidpressant (paperII) and anxiolytic or hypnotic (paper III) drug exposureand the risk of hip fracture among older (60+) Norwegians 2005-2010
• To examine associations between exposure to hypnotic drugs and the time of hip fracture (paper III)
• Provided associations found, to estimate attributable risk: effect on number of hip fractures per year (papers II and III)
24
Research database
2005-2010
The Central
Population RegistryAll ~ 906 000 persons born < 1945
The Norwegian Prescription Database All ~ 2.8 million prescriptions for antidepressants
All ~ 7.5 million prescriptions for anxiolytics and hypnotics
The National
Hip Fracture RegistryAll ~ 40 000 hip fractures
25
Methods
Standardized incidence ratio (SIR)Birth year, sex, time of year of fracture
Hip fracture incidence during drug exposure
vs
Hip fracture incidence during non-exposure
SIR >1 indicates increased risk of hip fracture during exposure
26Engeland 2007
Exposed and unexposed person time
2005 201027
Methods - assumptions
• Purchased drugs = consumed drugs
• Exposed person time = number of dayscorresponding to number of defined daily doses (DDD) prescribed
28Engeland 2007
Paper II
29
Antidepressants
Therapeutic subgroups (ATC)• Tricyclic antidepressants, TCAs • Selective serotonergic reuptake inhibitors, SSRIs• Others
31
ResultsTherapeutic subgroups SIR(95% CI)
Any AD TCAs SSRIs Others
Men 1.9 (1.8-2.0) 1.4 (1.1-1.8) 2.1 (1.9-2.2) 1.6 (1.4-1.8)
Women 1.7 (1.6-1.7) 1.4 (1.3-1.6) 1.7 (1.7-1.8) 1.6 (1.5-1.7)
All 1.7 (1.7-1.8) 1.4 (1.3-1.5) 1.8 (1.7-1.8) 1.6 (1.5-1.7)
AD = antidepressant drugSIR >1 increased risk of hip fractures during AD exposure
32
Antidepressants
Therapeutic subgroups (ATC)• Tricyclic antidepressants, TCAs • Selective serotonergic reuptake inhibitors, SSRIs• Others
Serotonergic effects• High/intermediate • Low/no
33
ResultsSerotonergic effects SIR(95% CI)
Any AD Low/no High/intermediate
Men 1.9 (1.8-2.0) 1.3 (0.8-1.9) 1.9 (1.8-2.1)
Women 1.7 (1.6-1.7) 1.2 (1.0-1.5) 1.7 (1.6-1.8)
All 1.7 (1.7-1.8) 1.2 (1.1-1.5) 1.7 (1.7-1.8)
Low/no
TCAs: nortryptiline, doxepin, trimipramine.
Others: moclobemide, bupropion, reboxetine.
High/intermediate
All SSRIs. TCAs: clomipramine, amitryptiline.
Others: mianserin, mirtazapine, venlafaxine, duloxetine. 34
ResultsSerotonergic effects SIR(95% CI)
Any AD Low/no High/intermediate
Men 1.9 (1.8-2.0) 1.3 (0.8-1.9) 1.9 (1.8-2.1)
Women 1.7 (1.6-1.7) 1.2 (1.0-1.5) 1.7 (1.6-1.8)
All 1.7 (1.7-1.8) 1.2 (1.1-1.5) 1.7 (1.7-1.8)
Low/no
TCAs: nortryptiline, doxepin, trimipramine.
Others: moclobemide, bupropion, reboxetine.
High/intermediate
All SSRIs. TCAs: clomipramine, amitryptiline.
Others: mianserin, mirtazapine, venlafaxine, duloxetine. 35
ResultsAge and gender SIR (95% CI)
All 1935-1944 1925-1934 1915-1924 <1915
Men 1.9 (1.8-2.0) 2.9 (2.6-3.4) 2.2 (2.0-2.4) 1.4 (1.2-1.6) 1.0 (0.5-1.7)
Women 1.7 (1.6-1.7) 2.5 (2.3-2.7) 1.9 (1.8-2.0) 1.4 (1.3-1.5) 1.2 (1.0-1.4)
All 1.7 (1.7-1.8) 2.6 (2.4-2.8) 1.9 (1.8-2.0) 1.4 (1.3-1.5) 1.2 (1.0-1.4)
36
ResultsAttributable risk in %
~ 300 fractures yearly
~ 2000 fractures 2005-2010
Any N06A
Any TCAs
AnySSRIs
AnyOthers
AnyLow/no5-HT
AnyHigh/int. 5-HT
All 4.7 0.3 3.6 1.0 0.1 4.6
37
Paper III
38
39
40
Results SIR (95% CI)
Anxiolytics & z-hypnotics
Any
anxiolytic
SAB
(short acting bzd)
LAB
(long acting bzd)
Z-hypnotics
Men 1.6 (1.4-1.7) 1.7 (1.5-2.0) 1.2 (1.2-1.3) 1.3 (1.2-1.4)
Women 1.4 (1.4-1.5) 1.4 (1.3-1.5) 1.2 (1.2-1.3) 1.1 (1.1-1.2)
All 1.4 (1.4-1.5) 1.5 (1.4-1.6) 1.3 (1.2-1.5) 1.2 (1.1-1.2)*
Anxiolytics: diazepam, oxazepam, alprazolam and hydroxyzine
SABs: oxazepam, alprazolam and midazolam
LABs: diazepam, nitrazepam and flunitrazepam
Z-hypnotics: zopiclone, zolpidem
41
Results SIR (95% CI)
Anxiolytics & z-hypnotics
Any
anxiolytic
SAB
(short acting bzd)
LAB
(long acting bzd)
Z-hypnotics
Men 1.6 (1.4-1.7) 1.7 (1.5-2.0) 1.2 (1.2-1.3) 1.3 (1.2-1.4)
Women 1.4 (1.4-1.5) 1.4 (1.3-1.5) 1.2 (1.2-1.3) 1.1 (1.1-1.2)
All 1.4 (1.4-1.5) 1.5 (1.4-1.6) 1.3 (1.2-1.5) 1.2 (1.1-1.2)*
* Day/night
Anxiolytics: diazepam, oxazepam, alprazolam and hydroxyzine
SABs: oxazepam, alprazolam and midazolam
LABs: diazepam, nitrazepam and flunitrazepam
Z-hypnotics: zopiclone, zolpidem
42
Results SIR (95% CI)
Fractures day (08:00-19:59) and night (20:00-07:59)
Z-hypnotics day¹
Z-hypnotics night¹
Exposed person days n SIR n SIR
14 574 1.2 (1.1–1.4) 277 1.4 (1.2–1.5)
DDD 1835 1.1 (1.1–1.2) 884 1.3 (1.2–1.4)
¹Time of fracture known in 51% of cases (hip fractures occurring during exposure to hypnotic drugs)
Hypnotics:
benzodiazepine derivates (nitrazepam, flunitrazepam, midazolam),benzodiazepine-related drugs or
z-hypnotics (zopiclone, zolpidem) and melatonin receptor agonists (melatonin)
43
ResultsAttributable risk in %
Anyanxiolyticdrug
Anyhypnoticdrug
AnySAB, LAB or z-hypnoticdrug
Anyz-hypnoticdrug
Z-hypnoticsday
Z-hypnoticsnight
1.5 2.3 3.2 1.9 1.7 3.3
Anxiolytics: diazepam, oxazepam, alprazolam and hydroxyzine
Hypnotics: nitrazepam , flunitrazepam, midazolam, zopiclone, zolpidem and melatonin
SABs: oxazepam, alprazolam and midazolam
LABs: diazepam, nitrazepam and flunitrazepam
Z-hypnotics: zopiclone, zolpidem
44
Strengths and limitations
• Nationwide study
• Prospective design
• 6-year follow-up
Time-varying exposure
• No clinical information
Confounding
Comorbidities
• Polypharmacy
• Misclassification
45
Summary of results – study II
• Increased risk of hip fracture among persons using
Antidepressants - SSRIs/similar properties Anxiolytics - SABs > LABs Hypnotics - excess risk at night
• High number of fractures attributable to psychotropic drug use
46
Contents
• Background
• Research aims
• Study I (paper I)
• Study II (papers II and III)
• Implications
47
Implications for clinical practice
• Main findings
Inappropriate prescribing common - psychotropics
Clinically relevant associations psychotropics - hip fracture
• Improved drug treatment for older people needed
Look for inappropriate prescribing
Multidisciplinary medication reviews
• Recommended psychotropic drugs (SSRIs, SABs and z-hypnotics) not safer than traditional alternatives with regard to hip fractures
Non-pharmacological treatment options
Be aware of fall risk and possible effects on bone tissue
Follow-up 48Haney 2010, Bondesson 2013, Dalleur 2014
Appropriate drug therapy
• Evidence-based knowledge
Drug use widespread
Inappropriate prescribing (IP) widespread
Increased risk of severe adverse events, readmissions and mortality
Check-lists and medication reviews reduce IP
• Evidence scarce
Clinical outcomes of interventions
Reductions in falls and readmissions
Multifaceted interventions promising (e.g. CGA)
49Moriarty F et al Eur J Clin Pharmacol 2015, Gallagher P et al Int J Clin Pharmacol 2008,
Beijer H et al Pharm World Sci 2002, Ebbesen J Arch Intern Med 2001 , Petrovic M et al Drugs Ageing 2012, Saltvedt I et al JAGS 2002
Implications for research
• Clinical outcomes
• Serotonergic effects on bone tissue
• Association z-hypnotics and night-time fractures
50
Thank you for your attention
The sun EM 1910-1351
Study participants vs real-life patients
52GerIT 05.04.16 MSB
Approval of drugs
• Pre-marketing studies
Recommendations (drugs intended for chronic use)
≥ 1000 patients in total
≥ 100 of these ≥ 12 months (80% of drugs 2000-2010)
53Dujinhoven R et al PLoS Med 2013
Number of patients studied prior to approval
2300 1300
54Dujinhoven R et al PLoS Med 2013
Approval of drugs
• Safety and long-term efficacy – knowledge lacking
Insufficient number of patients studied before marketing
50% of drugs, severe adverse effects identified after approval
10% restricted use
3% of drugs withdrawn
Pharmacovigilance – reporting matters!
• Generalizability – limited
Older adults frequent users, vulnerable AND under-represented
55Dujinhoven R et al PLoS Med 2013, Schroll J et al PLoS One 2012
56GerIT 05.04.16 MSB