Purpose of Review
In this narrative review, we focus on aspects of the complicated relationship between frailty and medications that we feel would be of particular interest to researchers and health care practitioners.
Frailty and polypharmacy (≥5 medications) are inter-related with evidence of a bidirectional potentially casual relationship. Medication review and withdrawal of potentially inappropriate medications is frequently advised for the management of frailty. Changes in the pharmacokinetics and pharmacodynamics of drugs with frailty are felt to parallel those seen with aging though possibly more pronounced. While both frailty and polypharmacy are associated with adverse outcomes, recent research suggests that relative measures of associated risk may be blunted among older adults with frailty compared to non-frail older adults.
Research on drug therapy in later life should include a consideration of frailty and how changes in frailty status may affect the balance between benefit and risk with pharmacotherapy.
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Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
• Bergman H, Ferrucci L, Guralnik J, Hogan DB, Hummel S, Karunananthan S, et al. Frailty: an emerging research and clinical paradigm – issues and controversies. J Gerontol A Biol Sci Med Sci. 2007;62(7):731–7 Classic article on the currently accepted conceptual framework for frailty.
Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet. 2013;381:752–62.
Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci. 2004;59(3):255–63.
•• Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146–56 Classic article on the origins and clinical relevance of the physical phenotype approach to identifying frailty.
• Campitelli MA, Bronskill SE, Hogan DB, Diong C, Amuah JE, Gill S, et al. The prevalence and health consequences of frailty in a population-based older home care cohort: a comparison of different measures. BMC Geriatr. 2016;16:133 Demonstrated the predictive accuracy and clinical relevance of a frailty index (FI) derived from items on a population-based, standardized clinical assessment.
• Kojima G, Iliffe S, Morris RW, Taniguchi Y, Kendrick D, Skelton DA, et al. Frailty predicts trajectories of quality of life over time among British community-dwelling older people. Qual Life Res. 2016;25(7):1743–50 One of a few articles to explore the association between frailty and quality of life as a relevant outcome.
• Rolfson DB, Majumdar SR, Tsuyuki RT, Tahir A, Rockwood K. Validity and reliability of the Edmonton Frail Scale. Age Ageing. 2006;35(5):526–9 Classic article on the development and clinical relevance of a commonly used multidimensional frailty measure.
Hogan DB, Maxwell CJ, Afilalo J, Arora RC, Bagshaw S, Basran J, et al. A scoping review of frailty and acute care in middle-aged and older individuals with recommendations for future research. Can Geriatr J. 2017;20(1):22–37.
• Xue QL, Tian J, Walston JD, Chaves PHM, Newman AB, Bandeen-Roche K. Discrepancy in frailty identification: move beyond predictive validity. J Gerontol A Biol Sci Med Sci 2019. doi: https://doi.org/10.1093/gerona/glz052. [Epub ahead of print]. Exploration of discrepant findings and potential implications when using different frailty measures.
•• Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci. 2007;62:722–77 Classic article on the origins and clinical relevance of the health deficit accumulation approach (i.e., frailty index [FI}) to identifying and understanding frailty.
Collard RM, Boter H, Schoevers R, Oude Voshaar RC. Prevalence of frailty in community-dwelling older persons: a systematic review. J Am Geriatr Soc. 2012;60:1487–92.
• Ofori-Asenso R, Chin KL, Mazidi M, Zomer E, Ilomaki J, Zullo AR, et al. Global incidence of frailty and prefrailty among community-dwelling older adults: a systematic review and meta-analysis. JAMA Netw Open. 2019;2(8):e198398 Recent robust systematic review with meta-analysis focused on frailty incidence.
• Morin L, Johnell K, Laroche ML, Fastbom J, Wastesson JW. The epidemiology of polypharmacy in older adults: register-based prospective cohort study. Clin Epidemiol. 2018;10:289–98 Estimated the prevalence and incidence of polypharmacy and hyperpolypharmacy using population based registry data.
Canadian Institute for Health Information: Drug Use Among Seniors in Canada, 2016. Ottawa, ON: CIHI; 2018 Available at: https://wwwcihica/sites/default/files/document/drug-use-among-seniors-2016-en-webpdf Accessed December 9, 2019.
Rawle MJ, Richards M, Davis D, Kuh D. The prevalence and determinants of polypharmacy at age 69: a British birth cohort study. BMC Geriatr. 2018;18(1):118.
• Wastesson JW, Cedazo Minguez A, Fastbom J, Maioli S, Johnell K. The composition of polypharmacy: a register-based study of Swedes aged 75 years and older. PLoS One. 2018;13(3):e0194892 Recent exploration of the key medication classes making the largest contributions to the prevalence of polypharmacy in older adults.
Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014;13(1):57–65.
Wastesson JW, Morin L, Tan ECK, Johnell K. An update on the clinical consequences of polypharmacy in older adults: a narrative review. Expert Opin Drug Saf. 2018;17(12):1185–96.
Almodóvar AS, Nahata MC. Associations between chronic disease polypharmacy, and medication-related problems among Medicare beneficiaries. J Manag Care Spec Pharm. 2019;25(5):573–7.
• Gutiérrez-Valencia M, Izquierdo M, Cesari M, Casas-Herrero Á, Inzitari M, Martínez-Velilla N. The relationship between frailty and polypharmacy in older people: a systematic review. Br J Clin Pharmacol. 2018;84(7):1432–44 A comprehensive overview of findings illustrating the bidirectional association between frailty and polypharmacy.
•• Palmer K, Villani ER, Vetrano DL, Cherubini A, Cruz-Jentoft J, Curtin D, et al. Association of polypharmacy and hyperpolypharmacy with frailty states: a systematic review and meta-analysis. Eur Geriatr Med. 2019;10:9–36 Largest and most recent systematic review and meta-analysis on the relationship between polypharmacy / hyperpolypharmacy and frailty.
• Gnjidic D, Hilmer SN, Blyth FM, Naganathan V, Cumming RG, Handelsman DJ, et al. High risk prescribing and incidence of frailty among older community-dwelling men. Clin Pharmacol Ther. 2012;91:521–8 One of the initial studies to examine medications and incident frailty.
Veronese N, Stubbs B, Noale M, Solmi M, Pilotto A, Vaona A, et al. Polypharmacy is associated with higher frailty risk in older people: an 8-year longitudinal cohort study. J Am Med Dir Assoc. 2017;18(7):624–8.
Saum KU, Schöttker B, Meid AD, Holleczek B, Haefeli WE, Hauer K, et al. Is polypharmacy associated with frailty in older people? Results from the ESTHER cohort study. J Am Geriatr Soc. 2017;65(2):e27–32.
• Herr M, Robine JM, Pinot J, Arvieu JJ, Ankri J. Polypharmacy and frailty: prevalence, relationship, and impact on mortality in a French sample of 2350 old people. Pharmacoepidemiol Drug Saf. 2015;24(6):637–46 One of the initial studies to examine the impact of both frailty and polypharmacy on health outcomes in older adults.
Bonaga B, Sánchez-Jurado PM, Martínez-Reig M, Ariza G, Rodriguez-Manas L, Gnjidic D, et al. Frailty, polypharmacy, and health outcomes in older adults: the frailty and dependence in Albacete study. J Am Med Dir Assoc. 2018;19(1):46–52.
Shmuel S, Lund JL, Alvarez C, Hsu CD, Palta P, Kucharska-Newton A, et al. Polypharmacy and incident frailty in a longitudinal community-based cohort study. J Am Geriatr Soc. 2019;67(12):2482–9.
• Herr M, Sirven N, Grondin H, Pichetti S, Sermet C. Frailty, polypharmacy, and potentially inappropriate medications in old people: findings in a representative sample of the French population. Eur J Clin Pharmacol. 2017;73(9):1165–72 One of the earlier studies to examine the relevance of the quality of medication prescribing to frailty.
• Maclagan LC, Maxwell CJ, Gandhi S, Guan J, Bell CM, Hogan DB, et al. Frailty and potentially inappropriate medication use at nursing home transition. J Am Geriatr Soc. 2017;65(10):2205–12 Demonstrated the relevance of frailty to potentially inappropriate medication use during the transition to nursing home care.
American Geriatrics Society. Beers criteria update expert panel: American Geriatrics Society 2015 updated beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2015. 2015;63(11):2227–46.
Martinot P, Landré B, Zins M, Goldberg M, Ankri J, Herr M. Association between potentially inappropriate medications and frailty in the early old age: a longitudinal study in the GAZEL cohort. J Am Med Dir Assoc. 2018;19(11):967–73.
• Muhlack DC, Hoppe LK, Saum KU, Haefeli WE, Brenner H, Schöttker B. Investigation of a possible association of potentially inappropriate medication for older adults and frailty in a prospective cohort study from Germany. Age Ageing 2019 https://doi.org/10.1093/ageing/afz127. [Epub ahead of print] Methodologically robust prospective investigation of the association between potentially inappropriate medication (PIM) use and frailty illustrating the importance of PIM type.
Cil G, Park J, Bergen AW. Self-reported prescription drug use for pain and for sleep and incident frailty. J Am Geriatr Soc. 2019;67(12):2474–81.
Lim R, Kalisch Ellett LM, Widagdo IS, Pratt NL, Roughead EE. Analysis of anticholinergic and sedative medicine effects on physical function, cognitive function, appetite and frailty: a cross-sectional study in Australia. BMJ Open. 2019;9(9):e029221.
Shi S, Klotz U. Age-related changes in pharmacokinetics. Curr Drug Metab. 2011;12(7):601–10.
Trifirò G, Spina E. Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems. Curr Drug Metab. 2011;12(7):611–20.
• Hilmer SN, Wu H, Zhang M. Biology of frailty: implications for clinical pharmacology and drug therapy in frail older people. Mech Ageing Dev. 2019;181:22–8 Recent narrative review of key physiological consequences of frailty on the pharmacokinetics and pharmacodynamics of drugs.
Falsarella GR, Gasparotto LP, Barcelos CC, Coimbra IB, Moretto MC, Pascoa MA, et al. Body composition as a frailty marker for the elderly community. Clin Interv Aging. 2015;10:1661–6.
• Ballew SH, Chen Y, Daya NR, Godino JG, Windham BG, McAdams-DeMarco M, et al. Frailty, kidney function, and polypharmacy: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis. 2017;69(2):228–36 Demonstrated the association between frailty and kidney function measures and variation across measures.
Johnston C, Hilmer SN, McLachlan AJ, Matthews ST, Carroll PR, Kirkpatrick CM. The impact of frailty on pharmacokinetics in older people: using gentamicin population pharmacokinetic modeling to investigate changes in renal drug clearance by glomerular filtration. Eur J Clin Pharmacol. 2014;70(5):549–55.
Gill SS. All, some or none? Statin prescribing for frail older adults. CMAJ. 2019;191(2):E30–1.
Lindley RI. Drug trials for older people. J Gerontol A Biol Sci Med Sci. 2012;67A(2):152–7.
Bennett A, Gnjidic D, Gillett M, Carroll P, Matthews S, Johnell K, et al. Prevalence and impact of fall-risk-increasing drugs, polypharmacy, and drug-drug interactions in robust versus frail hospitalised falls patients: a prospective cohort study. Drugs Aging. 2014;31(3):225–32.
• Pugh JA, Wang CP, Espinoza SE, Noel PH, Bollinger M, Amuan M, et al. Influence of frailty-related diagnoses, high-risk prescribing in elderly adults, and primary care use on readmissions in fewer than 30 days for veterans aged 65 and older. J Am Geriatr Soc. 2014;62(2):291–8 One of the initial studies to explore the role of frailty as an effect modifier of drug-related adverse outcomes.
Warwick J, Falaschetti E, Rockwood K, Mitnitski A, Thijs L, Beckett N, et al. No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: an investigation of the impact of frailty upon treatment effect in the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over. BMC Med. 2015;13:78.
• Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, Chertow GM, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA. 2016;315(24):2673–82 Findings revealed no meaningful effect modification for treatment benefits for frail older adults.
Stock KJ, Hogan DB, Lapane K, Amuah JE, Tyas SL, Bronskill SE, et al. Antipsychotic use and hospitalization among older assisted living residents: does risk vary by frailty status? Am J Ger Psych. 2017;25(7):779–90.
Jamsen KM, Bell JS, Hilmer SN, Kirkpatrick CMJ, Ilomäki J, Le Couteur D, et al. Effects of changes in number of medications and drug burden index exposure on transitions between frailty states and death: the Concord health and ageing in men project cohort study. J Am Geriatr Soc. 2016;64(1):89–95.
• Porter B, Arthur A, Savva GM. How do potentially inappropriate medications and polypharmacy affect mortality in frail and non-frail cognitively impaired older adults? A cohort study. BMJ Open. 2019;9(5):e026171 Illustrated the potential for blunted relative risk measures among older cognitively impaired persons with greater frailty.
•• Maxwell CJ, Campitelli MA, Hogan DB, Diong C, Austin PC, Amuah JE, et al. Relevance of frailty to mortality associated with the use of antipsychotics among community-residing older adults with impaired cognition. Pharmacoepidemiol Drug Saf. 2018;27(3):289–98 This study clearly showed a more pronounced effect on mortality with antipsychotic use in robust participants compared to frail ones.
De Groot MH, van Campen JPCM, Kosse NM, de Vries OJ, Beijnen JH, Lamoth CJC. The association of medication-use and frailty-related factors with gait performance in older patients. PLoS One. 2016;11(2):e0149888.
De Groot MH, van Campen JPCM, Moek MA, Tulner LR, Beijnen JH, Lamoth CJC. The effects of fall-risk-increasing drugs on postural control: a literature review. Drugs Aging. 2013;30(11):901–20.
Holmes HM, Hayley DC, Alexander GC, Sachs GA. Reconsidering medication appropriateness for patients late in life. Arch Intern Med. 2006;166(6):605–9.
Ekerstad N, Bylin K, Karlson BW. Early rehospitalizations of frail elderly patients – the role of medications: a clinical, prospective, observational study. Drug Healthc Patient Saf. 2017;9:77–88.
Campitelli MA, Maxwell CJ, Giannakeas V, Bell CM, Daneman N, Jeffs L, et al. The variation of statin use among nursing home residents and physicians: a cross-sectional analysis. J Am Geriatr Soc. 2017;65(9):2044–51.
• Campitelli MA, Maxwell CJ, Maclagan LC, Ko DT, Bell CM, Jeffs L, et al. One-year survival and admission to hospital for cardiovascular events among older residents of long-term care facilities who were prescribed intensive-and moderate-dose statins. CMAJ. 2019;191(2):E32–9 Methodologically robust investigation of statin dose on cardiovascular events illustrating similar outcomes among frail older residents of nursing homes receiving intensive- vs moderate-dose statins.
Alcusky M, McManus DD, Hume AL, Fisher M, Tjia J, Lapane KL. Changes in anticoagulant utilization among United States nursing home residents with atrial fibrillation from 2011 to 2016. J Am Heart Assoc. 2019;8(9):e012023.
Oqab Z, Pournazari P, Sheldon RS. What is the impact of frailty on prescription of anticoagulation in elderly patients with atrial fibrillation? A systematic review and meta-analysis. J Atr Fibrillation. 2018;10(6):1870.
• Wilkinson C, Todd O, Clegg A, Gale CP, Hall M. Management of atrial fibrillation for older people with frailty: a systematic review and meta-analysis. Age Ageing. 2019;48(2):196–203 Recent systematic review of the association between validated frailty measures, atrial fibrillation and clinical outcomes with meta-analysis of the association between frailty and oral anticoagulants.
Yamamoto T, Yamashita K, Miyamae K, Koyama Y, Izumimoto M, Kamimura Y, et al. The influence of frailty under direct oral anticoagulant use in patients with atrial fibrillation. Heart Asia. 2019;11(2):e011212.
Brook R, Aswapanyawongse O, Tacey M, Kitipornchai T, Ho P, Lim HY. Real-world direct oral anticoagulants experience in atrial fibrillation: falls risk and low dose anticoagulation are predictive of both bleeding and stroke risk. Intern Med J. 2019. https://doi.org/10.1111/imj.14640 [Epub ahead of print].
Kojima G. Frailty as a predictor of future falls among community-dwelling older people: a systematic review and meta-analysis. J Am Med Dir Assoc. 2015;16(12):1027–33.
Vetrano DL, Palmer KM, Galluzzo L, Giampaoli S, Marengoni A, Bernabei R, et al. Hypertension and frailty: a systematic review and meta-analysis. BMJ Open. 2018;8(12):e024406.
• Todd OM, Wilkinson C, Hale M, Wong NL, Hall M, Sheppard JP, et al. Is the association between blood pressure and mortality in older adults different with frailty? A systematic review and meta-analysis. Age Ageing. 2019;48(5):627–35 Findings suggest the benefits of aggressive therapy may not be as evident in frail older patients.
Anonymous. Frailty, polypharmacy and deprescribing. Drug Ther Bull. 2016;54:69–72.
Hilmer SN, Gnjidic D. Prescribing for frail older people. Aust Prescr. 2017;40(5):174–8.
• Dent E, Lien C, Lim WS, Wong WC, Wong CH, Ng TP, et al. The Asia-Pacific clinical practice guidelines for the management of frailty. J Am Med Dir Assoc. 2017;18(7):564–75 Expert panel review with recommendations to review and act on potentially inappropriate medication use among older adults with frailty.
Abbasi M, Rolfson D, Khera AS, Dabravolskaj J, Dent E, Xia L. Identification and management of frailty in the primary care setting. CMAJ. 2018;190(38):E1134–40.
Dent E, Martin FC, Bergman H, Woo J, Romero-Ortuno R, Walston JD. Management of frailty: opportunities, challenges, and future directions. Lancet. 2019;394:1376–86.
Jiwa M: Optimising mediation in frail older people. Accessed November 25, 2019 at: https://www.prescriber.co.uk/article/optimising-medication-in-frail-older-people/
Tjia J, Lapane K. Guideline-based prescribing in frail elderly patients. JAMA Intern Med. 2017;177(2):262–3.
• Potter K, Flicker L, Page A, Etherton-Beer C. Deprescribing in frail older people: a randomised controlled trial. PLOS One. 2016;11(3):e0149984 Illustrated the potential of reducing the number of medications among frail older residents of care facilities with no major adverse effects on other clinical outcomes.
Thillainadesan J, Gnjidic D, Green S, Hilmer SN. Impact of deprescribing interventions in older hospitalised patients on prescribing and clinical outcomes: a systematic review of randomised trials. Drugs Aging. 2018;35(4):303–19.
Pruskowski JA, Springer S, Thorpe CT, Klein-Fedyshin M, Handler SM. Does deprescribing improve quality of life? A systematic review of the literature. Drugs Aging. 2019;36:1097–110.
Rochon PA, Holmes HM. Drug therapy and frailty: chicken or the egg? J Am Geriatr Soc. 2019;67:2441–3.
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Hogan, D.B., Maxwell, C.J. Frailty and Unintended Risks of Medications. Curr Epidemiol Rep (2020). https://doi.org/10.1007/s40471-020-00226-5
- Older adults
- Adverse drug reactions
- Health outcomes