Frailty and Unintended Risks of Medications
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.
KeywordsFrailty Medications Older adults Adverse drug reactions Health outcomes
Dr. Maxwell and Dr. Hogan report grants from Canadian Institutes of Health Research (CIHR), and grants from the Canadian Frailty Network during the conduct of the study.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights
All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki Declaration and its amendments, institutional/national research committee standards, and international/ national/ institutional guidelines).
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.• 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. PubMedPubMedCentralCrossRefGoogle Scholar
- 4.•• 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. PubMedCrossRefPubMedCentralGoogle Scholar
- 5.• 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.Google Scholar
- 6.• 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. PubMedPubMedCentralCrossRefGoogle Scholar
- 9.• 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.
- 10.•• 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. PubMedCrossRefPubMedCentralGoogle Scholar
- 12.• 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. PubMedPubMedCentralCrossRefGoogle Scholar
- 13.• 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. PubMedPubMedCentralCrossRefGoogle Scholar
- 14.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.
- 16.• 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. PubMedPubMedCentralCrossRefGoogle Scholar
- 20.• 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. PubMedPubMedCentralCrossRefGoogle Scholar
- 21.•• 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. CrossRefGoogle Scholar
- 22.• 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. PubMedCrossRefPubMedCentralGoogle Scholar
- 25.• 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. PubMedCrossRefPubMedCentralGoogle Scholar
- 28.• 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. PubMedCrossRefPubMedCentralGoogle Scholar
- 29.• 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. PubMedCrossRefPubMedCentralGoogle Scholar
- 30.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.Google Scholar
- 32.• 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. PubMedPubMedCentralCrossRefGoogle Scholar
- 37.• 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. PubMedCrossRefGoogle Scholar
- 39.• 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. PubMedCrossRefGoogle Scholar
- 40.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.PubMedCrossRefPubMedCentralGoogle Scholar
- 43.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.PubMedCrossRefPubMedCentralGoogle Scholar
- 44.• 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. PubMedCrossRefPubMedCentralGoogle Scholar
- 45.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.PubMedPubMedCentralCrossRefGoogle Scholar
- 46.• 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. PubMedPubMedCentralCrossRefGoogle Scholar
- 48.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.PubMedCrossRefPubMedCentralGoogle Scholar
- 49.• 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. PubMedPubMedCentralCrossRefGoogle Scholar
- 50.•• 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. PubMedCrossRefPubMedCentralGoogle Scholar
- 56.• 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. PubMedPubMedCentralCrossRefGoogle Scholar
- 59.• 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. PubMedCrossRefPubMedCentralGoogle Scholar
- 61.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].
- 64.• 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. CrossRefGoogle Scholar
- 67.• 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. PubMedCrossRefPubMedCentralGoogle Scholar
- 70.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/
- 72.• 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. PubMedPubMedCentralCrossRefGoogle Scholar