Legemiddelbruk og hoftebrudd

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 11 th 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 % Antipsychotics 5 % 3 % > Increases with age Higher numbers in nursing homes Community-dwelling 60+, proportion of the population using (The Norwegian Prescription database, NorPD) 6

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 13

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 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 ward INHU 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 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 All ~ 906 000 persons born < 1945 The National Hip Fracture Registry All ~ 40 000 hip fractures Research database 2005-2010 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 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 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 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) 36

Results Attributable risk in % 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 ~ 300 fractures yearly ~ 2000 fractures 2005-2010 37

Paper III 38

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Results SIR (95% CI) Anxiolytics & z-hypnotics Any SAB LAB Z-hypnotics anxiolytic (short acting bzd) (long acting bzd) 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 SAB LAB Z-hypnotics anxiolytic (short acting bzd) (long acting bzd) 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 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) ¹ Time 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 day 1.5 2.3 3.2 1.9 1.7 3.3 Z-hypnotics night 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 Haney 2010, Bondesson 2013, Dalleur 2014 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 51

Study participants vs real-life patients GerIT 05.04.16 MSB 52

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 55

GerIT 05.04.16 MSB 56