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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 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 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 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) 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 The National Hip Fracture Registry All ~ 906 000 persons born < 1945 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 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) 36 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 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