M Seibert1, V Mühlbauer2,3, J Holbrook1, S Voigt-Radloff4,5, S Brefka2,3, D Dallmeier2,3,6, M Denkinger2,3, C Schönfeldt-Lecuona3,7, S Klöppel8, C A F von Arnim9,10. 1. Department of Neurology, University Clinic Ulm, Ulm, Germany. 2. Agaplesion Bethesda Clinic, Institute for Geriatric Research, Ulm University, Ulm, Germany. 3. Geriatric Center Ulm/Alb-Donau, Ulm, Germany. 4. Center for Geriatric Medicine and Gerontology, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany. 5. Institute for Evidence in Medicine (for Cochrane Germany Foundation), Medical Center and Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany. 6. Department of Epidemiology, Boston University School of Public Health, Boston, USA. 7. Department of Psychiatry and Psychotherapy III, University Clinic Ulm, Ulm, Germany. 8. University Hospital of Old Age Psychiatry, University of Bern, Bern, Switzerland. 9. Geriatric Center Ulm/Alb-Donau, Ulm, Germany. christine.arnim@med.uni-goettingen.de. 10. Division of Geriatrics, University Medical Centre, Georg August University, Robert-Koch-Str. 40, 37075, Göttingen, Germany. christine.arnim@med.uni-goettingen.de.
Abstract
BACKGROUND: Many patients with Alzheimer's disease (AD) are physically frail or have substantial functional impairments. There is growing evidence that such patients are at higher risk for medication-induced adverse events. Furthermore, frailty seems to be more predictive of poor clinical outcomes than chronological age alone. To our knowledge, no systematic review of clinical trials examining drug therapy of AD or behavioural and psychological symptoms of dementia (BPSD) has specifically focused on the topic of physical frailty. Our objective was to evaluate the efficacy and safety of pharmacotherapy in AD patients with frailty or significant functional impairments. METHODS: We performed a systematic literature search in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) for randomized controlled trials (RCTs) of drug therapy of AD and BPSD in patients with significant functional impairments according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Cochrane research criteria. Significant functionally impaired patient populations were identified using the recommendations of the Medication and Quality of Life in frail older persons (MedQoL) Research Group. Screening, selection of studies, data extraction and risk of bias assessment were performed independently by two reviewers. Outcomes including functional status, cognitive function, changes in BPSD symptoms, clinical global impression and quality of life were analysed. For assessing harm, we assessed adverse events, drop-outs as a proxy for treatment tolerability and death. Results were analysed according to Cochrane standards and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Of 45,045 search results, 38,447 abstracts and 187 full texts were screened, and finally, 10 RCTs were included in the systematic review. Selected articles evaluated pharmacotherapy with acetylcholinesterase-inhibitors (AChEI), anticonvulsants, antidepressants and antipsychotics. Studies of AChEIs suggested that patients with significant functional impairments had slight but significant improvements in cognition and that AChEIs were generally well tolerated. Studies of antidepressants did not show significant improvements in depressive symptoms. Antipsychotics and anticonvulsants showed small effects on some BPSD items but also higher rates of adverse events. However, due to the very small number of identified trials, the quality of evidence for all outcomes was low to very low. Overall, the small number of eligible studies demonstrates that significantly functional impaired older patients have not been adequately taken into consideration in most clinical trials investigating drug therapy of AD and BPSD. CONCLUSION: Due to lack of evidence, it is not possible to give specific recommendations for drug therapy of AD and BSPD in frail older patients or older patients with significant functional impairments. Therefore, clinical trials focussing on frail older adults are urgently required. A standardized approach to physical frailty in future clinical studies is highly desirable.
BACKGROUND: Many patients with Alzheimer's disease (AD) are physically frail or have substantial functional impairments. There is growing evidence that such patients are at higher risk for medication-induced adverse events. Furthermore, frailty seems to be more predictive of poor clinical outcomes than chronological age alone. To our knowledge, no systematic review of clinical trials examining drug therapy of AD or behavioural and psychological symptoms of dementia (BPSD) has specifically focused on the topic of physical frailty. Our objective was to evaluate the efficacy and safety of pharmacotherapy in ADpatients with frailty or significant functional impairments. METHODS: We performed a systematic literature search in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) for randomized controlled trials (RCTs) of drug therapy of AD and BPSD in patients with significant functional impairments according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Cochrane research criteria. Significant functionally impaired patient populations were identified using the recommendations of the Medication and Quality of Life in frail older persons (MedQoL) Research Group. Screening, selection of studies, data extraction and risk of bias assessment were performed independently by two reviewers. Outcomes including functional status, cognitive function, changes in BPSD symptoms, clinical global impression and quality of life were analysed. For assessing harm, we assessed adverse events, drop-outs as a proxy for treatment tolerability and death. Results were analysed according to Cochrane standards and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Of 45,045 search results, 38,447 abstracts and 187 full texts were screened, and finally, 10 RCTs were included in the systematic review. Selected articles evaluated pharmacotherapy with acetylcholinesterase-inhibitors (AChEI), anticonvulsants, antidepressants and antipsychotics. Studies of AChEIs suggested that patients with significant functional impairments had slight but significant improvements in cognition and that AChEIs were generally well tolerated. Studies of antidepressants did not show significant improvements in depressive symptoms. Antipsychotics and anticonvulsants showed small effects on some BPSD items but also higher rates of adverse events. However, due to the very small number of identified trials, the quality of evidence for all outcomes was low to very low. Overall, the small number of eligible studies demonstrates that significantly functional impaired older patients have not been adequately taken into consideration in most clinical trials investigating drug therapy of AD and BPSD. CONCLUSION: Due to lack of evidence, it is not possible to give specific recommendations for drug therapy of AD and BSPD in frail older patients or older patients with significant functional impairments. Therefore, clinical trials focussing on frail older adults are urgently required. A standardized approach to physical frailty in future clinical studies is highly desirable.
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