Download Potentially inappropriate drug use and hip

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 people
Pharmacoepidemiological 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
Soraas 2014, Dalleur 2014, Hovstadius 2010
4
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
Drug group
Women 60+ Men 60+
Antidepressants
14 %
7%
Anxiolytics
17 %
9%
Hypnotics & sedatives
29 %
16 %
5%
3%
Antipsychotics
♀>♂
Increases with age
Higher numbers in nursing homes
6
Community-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 use
associated with adverse drug events
• Drug use and prescribing quality among acutely
hospitalized older people in Norway?
Petrovic 2012, Fastbom 2015, Pirmohamed 2004, Wu 2010, Bradley 2012
7
Hip fractures
8
Hip fractures
• Highly prevalent - critical events - substantial costs
• Combination osteoporosis + fall
Psychotropics
Coupland 2011, Haney 2010, Cumming 1997
9
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
Intermediate care nursing
home unit
Municipality of Bergen
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Intermediate care nursing home unit
• Inclusion criteria
>70 years, community-dwelling
Acutely admitted to hospital
Transfer within 72 hours
Discharge (home) within 3 weeks realistic
Informed consent required
• Exclusion criteria
Surgery, 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 collection
Demographics: age, gender, length of stay
Medications (admission and discharge): regular + on demand
• Outcome measures
Drug use
Potentially inappropriate medicines (PIMs)
NORGEP: 21 drugs + 15 combinations to avoid
Drug-drug interactions (DDIs)
interaksjoner.no: 4 point severity scale
16
Study population
200 interm.
157
200 hospital
133
400 hospital
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)
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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 ward
INHU – intermediate care nursing home unit
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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 ward
INHU – 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 ward
INHU – 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 (paper
II) and anxiolytic or hypnotic (paper III) drug exposure
and 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
The Norwegian Prescription Database
All ~ 2.8 million prescriptions for antidepressants
All ~ 7.5 million prescriptions for anxiolytics and hypnotics
The Central
Population Registry
The National
Hip Fracture Registry
All ~ 906 000 persons born < 1945
All ~ 40 000 hip fractures
Research
database
2005-2010
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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
Engeland 2007
26
Exposed and unexposed person time
2005
2010
27
Methods - assumptions
• Purchased drugs = consumed drugs
• Exposed person time = number of days
corresponding to number of defined daily doses
(DDD) prescribed
Engeland 2007
28
Paper II
29
Antidepressants
Therapeutic subgroups (ATC)
• Tricyclic antidepressants, TCAs
• Selective serotonergic reuptake inhibitors, SSRIs
• Others
31
Results
Therapeutic subgroups SIR(95% CI)
Any AD
TCAs
SSRIs
Others
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
1.4 (1.3-1.5)
1.8 (1.7-1.8)
1.6 (1.5-1.7)
Men
1.7 (1.7-1.8)
AD = antidepressant drug
SIR >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
Results
Serotonergic 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
Results
Serotonergic 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
Results
Age 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)
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Results
Attributable risk in %
All
Any
N06A
Any
TCAs
Any
SSRIs
Any
Others
Any
Low/no
5-HT
Any
High/int.
5-HT
4.7
0.3
3.6
1.0
0.1
4.6
~ 300 fractures yearly
~ 2000 fractures 2005-2010
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)*
Anxiolytics: diazepam, oxazepam, alprazolam and hydroxyzine
SABs: oxazepam, alprazolam and midazolam
LABs: diazepam, nitrazepam and flunitrazepam
Z-hypnotics: zopiclone, zolpidem
* Day/night
42
Results SIR (95% CI)
Fractures day (08:00-19:59) and night (20:00-07:59)
Z-hypnotics
day¹
Exposed person days
Z-hypnotics
night¹
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
Results
Attributable risk in %
Any
anxiolytic
drug
Any
hypnotic
drug
Any
SAB, LAB or
z-hypnotic
drug
Any
z-hypnotic
drug
Z-hypnotics Z-hypnotics
day
night
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
Haney 2010, Bondesson 2013, Dalleur 2014
Follow-up
48
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)
Moriarty F et al Eur J Clin Pharmacol 2015, Gallagher P et al Int J Clin Pharmacol 2008,
49
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 1910-13
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Study participants vs real-life patients
GerIT 05.04.16 MSB
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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)
Dujinhoven R et al PLoS Med 2013
53
Number of patients studied prior to approval
2300
1300
Dujinhoven R et al PLoS Med 2013
54
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
Dujinhoven R et al PLoS Med 2013, Schroll J et al PLoS One 2012
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GerIT 05.04.16 MSB
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