lis marit stordal bakken haraldsplass diakonale sykehus · haraldsplass diakonale sykehus. u n i v...

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