Looking beyond age to understand adverse reaction risk in older patients

Research / 13 May 2024

When it comes to pharmacovigilance in older patients, age alone is insufficient as a measure of adverse reaction risk. Here is what we should consider instead.

According to the World Health OrganiZation, healthy ageing is the “process of developing and maintaining the functional ability that enables wellbeing in older age”.  Whilst disease prevention is the ideal, older age often comes with the accumulation of multiple long-term conditions and associated polypharmacy which increases the risk of experiencing adverse drug reactions (ADRs) and drug interactions. For decades, it has been known that older patients may experience ADRs that differ in frequency, severity, and type from those experienced by younger adults. Ageing can bring exaggerated responses to some medicines and a decreased effect on others due to pharmacodynamic modifications. Through biological ageing, body composition changes (the ratio between adipose tissue and total body weight increases), while hepatic blood flow and kidney function decrease, thus altering the pharmacokinetics of medicinal products. In addition, geriatric conditions like delirium, falls, fainting, urinary incontinence, and muscle loss can increase the risk of ADRs, and ADRs can aggravate existing geriatric conditions.

Consequently, regulators have acknowledged the need to separately evaluate the safety profile of medicinal products in older adults.  Some examples include regulatory guidelines requiring marketing authorisation applications to present data by age groups (for example, 65-74, 75-84, and older than 85 years of age); periodic safety update reports (documents on how the knowledge of the safety and benefit of a medicinal product changes with time) discussing the risks of medicinal products relating to older adults, and performing signal detection by age group. However, regulators have acknowledged that stratification by age is a sub-optimal approach to identifying older patients at risk of experiencing ADRs. Ageing affects people differently, causing varied changes in their bodies, minds, and social circumstances. Therefore, basing the associated harms from medicines entirely on chronological age is overly simplistic. A more helpful stratification method may be through the concept of frailty.

Significantly correlated with ageing, frailty broadens our approach as it captures the decline that comes with ageing that is influenced by genetic, environmental, and epigenetic factors. The Food and Drug Administration and the European Medicines Agency recognise its importance, defining frailty as a state of increased vulnerability resulting from ageing, and often a disease-associated decline in reserve and function across multiple physiological systems such that the ability to cope with acute stressors is reduced, leading to increased risk of adverse health outcomes. Frailty is directly linked with an increased risk of experiencing ADRs, in that frail patients are twice as likely to experience an ADR compared to non-frail patients. Frailty and polypharmacy are both correlated with harm from medicines that require healthcare intervention.

Furthermore, frailty is multifactorial, varies within and between individuals, is dynamic and bi-directional, and there are multiple ways to measure it. This makes it hard to integrate frailty into pharmacovigilance practice.



So, what challenges must we overcome to see frailty used in the field of pharmacovigilance? Firstly, we must decide on which frailty measure(s) to use. Frailty can be measured using a range of methods which require varying degrees of clinical judgement and time. An example is the Fried phenotype model, which focuses on pre-defined criteria (unintentional weight loss, self-reported exhaustion, low muscle strength, slower gait speed and low energy expenditure relative to age-defined normative values), where the presence of three or more indicates frailty. Another is the cumulative deficits approach, where the number of deficits relating to symptoms, disease, and physiological function are added to generate a Frailty Index (FI). Secondly, we must address the lack of routinely available frailty status of older patients in individual case safety reports.

However, we see progress being made in both areas. For example, in the evaluation of the PARAGON-HF clinical trial, an FI was constructed to determine the impact of frailty on the risks and benefits of sacubitril/valsartan. With regards to frailty status, NHS England has contracted General Practice to identify and record moderate to severe frailty status for those over 65.

While we work to overcome these challenges, multimorbidity combined with age, rather than age alone, may be used to stratify older patients at increased risk of harm from medicines. Multimorbidity likely contributes to the risk in some older adults better than age alone, but it does not fully capture the complexity or vulnerability that leads to increased adverse reaction risk like frailty does.

Pharmacovigilance practices have considered age as a risk factor for increased risk of ADRs for many years.  However, using age alone oversimplifies this relationship between age and medicinal harm. Frailty as a measure better captures the factors that lead to medicinal harm in older adults, but further work is needed to include it in individual case safety reports so that this parameter, alongside age, can be used to identify patients’ categories at an increased of experiencing ADRs. With better measures, we may more reliably monitor medicines safety in this patient group.

Acknowledgements: The authors would like to thank Finbarr Martin, Emeritus Professor of Medical Gerontology, Population Health Sciences, King's College London, for his contributions to the article.

Disclaimer: Giovanni Furlan is an employee of Pfizer. The content of this article reflects the personal view of the author and does not reflect Pfizer’s position or of any institution to which the author is affiliated, as well as the views of Uppsala Monitoring Centre.

Read more:

“Studies in Support of Special Populations: Geriatrics; E7”, ICH, 1993. Current Step version 4, 24 June 1993.

“Reflection paper in physical frailty: instruments for baseline characterization of older populations in clinical trials”, EMA, 2018.

S Cullinan, et al, “Use of a frailty index to identify potentially inappropriate prescribing and adverse drug reaction risks in older patients”, Age and Ageing, 2016.

JM Stevenson, et al, “A multi-centre cohort study on healthcare use due to medication-related harm: the role of frailty and polypharmacy”, Age and Ageing 2022.

JM Stevenson, JG Davies, FC Martin, “Medication-related harm: a geriatric syndrome”, Age and Ageing, 2019.

JH Butt, et al, “Sacubitril/Valsartan and Frailty in Patients With Heart Failure and Preserved Ejection Fraction”, Journal of the American College of Cardiology, 2022.

M Denkinger, et al, “Inclusion of functional measures and frailty in the development and evaluation of medicines for older adults”, Lancet Healthy Longevity, 2023.

G Furlan, et al, “Drug Safety in Geriatric Patients: Current Status and Proposed Way Forward”, Drug Safety, 2020.

Giovanni Furlan
Worldwide Safety Site Lead, Safety Risk Lead, Pfizer

Jennifer M Stevenson @JenMStevenson
Lead Pharmacist Older Adults, Guy’s and St. Thomas’ NHS Foundation Trust/Honorary Senior Lecturer, Institute of Pharmaceutical Science, King’s College London

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