Legemiddelbruk og hoftebrudd

(1)

Legemiddelbruk og hoftebrudd

Oppsummering av ph.d.

GerIT 05.04.16

LIS Marit Stordal Bakken Haraldsplass Diakonale Sykehus

(2)

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 11^th 2015

(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

(5)

Psychotropic drugs

Antidepressants Anxiolytics Hypnotics Antipsychotics

Despair1894 The scream1893 Sleepless night1920 Self portrait in hell 1903

Edvard Munch

(6)

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 %

(7)

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?

(8)

Hip fractures

(9)

Hip fractures

• Highly prevalent - critical events - substantial costs

• Combination osteoporosis + fall

Psychotropics

(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)

(12)

Intermediate care nursing home unit

Haukeland University Hospital Haraldsplass Deaconess Hospital

Municipality of Bergen

Intermediate care nursing home unit

(14)

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

(15)

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

(16)

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

(17)

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)

(18)

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

(19)

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

(20)

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

(21)

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

(22)

Psychotropic drugs

Antidepressants Anxiolytics Hypnotics

Despair1894 The scream1893 Sleepless night1920

Edvard Munch

(24)

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)

(25)

Research database

2005-2010

The Central

Population Registry

All ~ 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 Registry

All ~ 40 000 hip fractures

(26)

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

(27)

Exposed and unexposed person time

(28)

Methods - assumptions

• Purchased drugs = consumed drugs

• Exposed person time = number of days

corresponding to number of defined daily doses (DDD) prescribed

(29)

Paper II

(30)

(31)

Antidepressants

Therapeutic subgroups (ATC)

• Tricyclic antidepressants, TCAs

• Selective serotonergic reuptake inhibitors, SSRIs

• Others

(32)

Results

Therapeutic 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 drug

SIR >1 increased risk of hip fractures during AD exposure

(33)

Antidepressants

Therapeutic subgroups (ATC)

• Tricyclic antidepressants, TCAs

• Selective serotonergic reuptake inhibitors, SSRIs

• Others

Serotonergic effects

• High/intermediate

• Low/no

(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

(35)

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

(36)

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)

(37)

Results

Attributable risk

^{in %}

~ 300 fractures yearly

~ 2000 fractures 2005-2010

Any N06A

Any TCAs

Any SSRIs

Any Others

Any Low/no 5-HT

Any

High/int.

5-HT

All 4.7 0.3 3.6 1.0 0.1 4.6

(38)

Paper III

(39)

(40)

(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

(42)

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

(43)

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)

(44)

Results

Attributable risk

^{in %}

Any

anxiolytic drug

Any

hypnotic drug

Any

SAB, LAB or z-hypnotic drug

Any

z-hypnotic drug

Z-hypnotics day

Z-hypnotics 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

(45)

Strengths and limitations

• Nationwide study

• Prospective design

• 6-year follow-up

Time-varying exposure

• No clinical information

Confounding Comorbidities

• Polypharmacy

• Misclassification

(46)

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

(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

(49)

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)

(50)

Implications for research

• Clinical outcomes

• Serotonergic effects on bone tissue

• Association z-hypnotics and night-time fractures

(51)

Thank you for your attention

(52)

Study participants vs real-life patients

(53)

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)

(54)

Number of patients studied prior to approval

2300 1300

(55)

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

(56)

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