Polypharmacy and specific medication profiles as predictors of treatment and health outcomes in dementia Dr Christoph Mueller, NIHR Academic Clinical Lecturer Dr Gayan Perera, Epidemiologist

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Dementia

Dementia

Dementia

Dementia Guthrie et al., 2012, BMJ; Barnett et al., 2012, Lancet

Polypharmacy

Psychotropics & Polypharmacy

Overview Mortality Polypharmacy Hospitalisation & A&E attendance Cognitive decline Polypharmacy Psychiatric Medications Acetylcholinesterase inhibitors (AChEIs) Antidepressants Antipsychotics (by indication) Anticholinergics

SLAM Biomedical Research Centre (BRC) Case Register King’s College London (KCL) United Kingdom London South London South London and Maudsley (SLAM)

BRC Case Register

Clinical Record Interactive Search Methods - Linkages Clinical Record Interactive Search HES Moor

Health of the Nation Outcome Scale (HoNOS65+) Clinician rated problems: 0  - No problem 1  - Minor problem (sub threshold) 2  - Mild problem but definitely present 3  - Moderate problem 4  - Severe problem Mental health problem scales: Behavioral disturbance (aggressive behavior) Non-accidental self-injury (self harm) Problem-drinking or drug use (Cognitive problems) Hallucinations and/or delusions Depressive symptoms Problems related to physical illness/disability No problem (Score 0-1) Problem present (Score 2-4) Functional problem scales: Social or supportive relationships Activities of daily living Living conditions Work and leisure activities – quality of daytime environment

MMSE Perera et al., PLOS ONE, 2014

Dementia on the BRC case register 17.224 patients diagnosed between 2006 - 2016 12% severe / 44% moderate / 44% mild 58% AD / 29% VaD Antidementia medication Anticholinergic medication Median number of medications 4-6 medications ≥ 7 medications ≥ 10 medications 33% 43% 4.0 24% 16% 9%

1. Polypharmacy – A&E attendance   Cumulative incidence (%) Age & gender, MMSE adjusted HR (95% CI) Fully adjusted HR (95% CI) 0-3 medications 57.1% 1 [reference] 4-6 medications 64.6% 1.27 (1.16-1.39) 1.21 (1.11-1.33) > 7 medications 67.5% 1.54 (1.39-1.71) 1.40 (1.26-1.56) Risk increase per additional medication 1.06 (1.05-1.07) 1.05 (1.04-1.06) > 4 medications: > 21% ⬆️ risk

1. Polypharmacy - Hospitalisation   Cumulative incidence (%) Age & gender, MMSE adjusted HR (95% CI) Fully adjusted HR (95% CI) 0-3 medications 63.0% 1 [reference] 4-6 medications 69.2% 1.21 (1.11-1.32) 1.14 (1.04-1.24) > 7 medications 75.9% 1.63 (1.48-1.79) 1.35 (1.22-1.50) Risk increase per additional medication 1.06 (1.04-1.07) 1.04 (1.02-1.05) > 4 medications: > 14% ⬆️ risk

1. Polypharmacy - Mortality   Cumulative incidence (%) Age & gender adjusted HR (95% CI) Fully adjusted HR (95% CI) 0-3 medications 21.2% 1 [reference] 4-6 medications 28.2% 1.37 (1.20-1.57) 1.32 (1.14-1.53) > 7 medications 31.1% 1.61 (1.38-1.87) 1.44 (1.22-1.70) Risk increase per additional medication 1.06 (1.05-1.08) 1.05 (1.03-1.07) > 4 medications: > 32% ⬆️ risk

2. Acetylcholinesterase inhibitors - Mortality AChEI prescribed 23% ⬇️ risk Mueller et al., Age & Ageing, 2017

3. Antidepressants - Mortality   Antidepressant receipt prior (and post) dementia diagnosis Antidepressant receipt post dementia diagnosis only Multivariate Cox regression models Hazard ratio (95% CI) Unadjusted 1.15 (1.04-1.29) 1.26 (1.08-1.46)  Fully adjusted (for demographics, cognitive scores, and all HoNOS65+ subscales, and vascular co-morbidity) 1.20 (1.06-1.35) 1.25 (1.06-1.48) Adjusted using propensity score as co-variate 1.22 (1.08-1.37) 1.22 (1.04-1.45) Antidepressant prescribed: > 22% ⬆️ risk Mueller et al., JAMDA, 2017

3. Antidepressants - Mortality   Patients with depressed mood± (n=483) Patients with depressed mood and agitation/psychosis± (n=170) Patients with agitation/psychosis, but not depressed mood± (n=653) Patients without neuropsychiatric symptoms± (n=3,975) Antidepressant receipt prior (and post) dementia diagnosis 1.56 (1.12-2.17) 0.97 (0.54-1.74) 1.27 (0.95-1.69) 1.20 (1.03-1.39) Antidepressant receipt post dementia diagnosis 1.11 (0.68-1.83) 1.91 (0.89-4.11) 1.31 (0.94-1.83) 1.22 (0.97-1.53) Mueller et al., JAMDA, 2017

4. Antipsychotics - Mortality

Treatment x factor interaction 4. Antipsychotics Factor present Factor not present Treatment x factor interaction % with event in Risperidone % with event in Placebo % with events in Placebo Stroke risk: Delusions 3.1% 2.0% 6.6% 1.2% 0.043 Depression 3.6% 5.6% 5.1% 1.3% 0.025 Mortality risk: No death in Risperidone group 9.3% 4.4% 2.6% <0.001 NSAIDs 5.2% 1.4% 3.4% 3.8% 0.021

4. Antipsychotics - Mortality Agitation & Psychosis (Ag+/Ps+) n=320 No Agitation, but Psychosis (Ag-/Ps+) n=401 Agitation, no Psychosis (Ag+/Ps-) n=742 No agitation, No psychosis (Ag-/Ps-) n=3,855

4. Antipsychotics - Mortality Agitation & Psychosis (Ag+/Ps+) HR: 1.15 (0.85-1.56) No Agitation, but Psychosis (Ag-/Ps+) HR: 1.02 (0.81-1.27) Agitation, no Psychosis (Ag+/Ps-) HR: 1.26 (1.01-1.57) No agitation, No psychosis (Ag-/Ps-) HR: 0.99 (0.84-1.15)

4. Antipsychotics - Mortality Agitation & Psychosis (Ag+/Ps+) HR: 1.15 (0.85-1.56) No Agitation, but Psychosis (Ag-/Ps+) HR: 1.02 (0.81-1.27) Agitation, no Psychosis (Ag+/Ps-) HR: 1.26 (1.01-1.57) No agitation, No psychosis (Ag-/Ps-) HR: 0.99 (0.84-1.15) All dementia patients with psychosis (+/-Ag; n=721) HR: 1.14 (0.94-1.39) All dementia patients with depressed mood (+/-Ag, Ps; n=701) HR: 1.06 (0.81-1.37)

5. Anticholinergic medications (AChEI users) Lu & Tune, 2003 Am J Geriatr Psychiatry

5. Anticholinergic medications (AChEI users)

5. Anticholinergic medications (AChEI users)

Conclusions

Thank you Acknowledgements: Dr Richard Hayes Professor Robert Stewart BRC Nucleus Team