Predicting and detecting adverse drug reactions in old age: challenges and opportunities

Abstract

Increased, often inappropriate, drug exposure, pharmacokinetic and pharmacodynamic changes, reduced homeostatic reserve and frailty increase the risk of adverse drug reactions (ADRs) in the older population, thereby imposing a significant public health burden. Predicting and diagnosing ADRs in old age presents significant challenges for the clinician, even when specific risk scoring systems are available. The picture is further compounded by the potential adverse impact of several drugs on more ‘global’ health indicators, for example, physical function and independence, and the fragmentation of care (e.g., increased number of treating doctors and care transitions) experienced by older patients during their clinical journey. The current knowledge of drug safety in old age is also curtailed by the lack of efficacy and safety data from pre-marketing studies. Moreover, little consideration is given to individual patients' experiences and reporting of specific ADRs, particularly in the presence of cognitive impairment. Pending additional data on these issues, the close review and monitoring of individual patients' drug prescribing, clinical status and biochemical parameters remain essential to predict and detect ADRs in old age. Recently developed strategies, for example, medication reconciliation and trigger tool methodology, have the potential for ADRs risk mitigation in this population. However, more information is required on their efficacy and applicability in different healthcare settings.

Keywords::

• adverse drug reactions
• drug safety
• monitoring
• older patients
• outcomes

1. Epidemiology of adverse drug reactions in older patients

Older patients are generally prescribed more drugs than younger people [1]. Changes in pharmacokinetics and pharmacodynamics, poor homeostatic reserve and increased frailty significantly increase the risk of adverse drug reactions (ADRs) in old age [1-4]. There is good evidence that ADRs are a common cause of morbidity and mortality in older patients, thereby imposing a significant public health burden [5]. A UK study showed that ADRs accounted for 6.5% of hospital admissions. Patients admitted with ADRs were significantly older than patients without ADRs (median 76 years, interquartile range (IQR) 65 – 83 vs 66 years, IQR 46 – 79, p < 0.0001). In-hospital death, as a direct result of an ADR, occurred in 2.3%. The drugs most commonly associated with ADRs-related admissions included aspirin, diuretics, warfarin and non-steroidal anti-inflammatory drugs. The most common ADR was gastrointestinal bleeding [6]. A recent US study has shown that ADRs account for about 100,000 hospitalizations per year in patients > 65 years. Patients ≥ 80 years were involved in 48.1% of hospitalizations. Warfarin, insulins, oral antiplatelet agents and oral hypoglycemic agents were implicated in 67.0% of hospitalizations [7].

2. Predicting and detecting adverse drug reactions

Predicting and detecting ADRs in this group present significant challenges for several reasons. First, the frequent, and often inappropriate, polypharmacy increases the chances that two or more drugs taken by a patient lead to the same ADR, for example, both digoxin and opiates can cause nausea and poor appetite. Second, the onset of new symptoms and/or signs might prompt the diagnosis of a new medical problem, potentially requiring additional pharmacological treatment, rather than the recognition of an ADR secondary to a drug currently prescribed, that is, ‘the prescribing cascade’ [8]. This is further compounded by the fact that several medical conditions might have different, often non-specific, clinical presentations in old age. Third, the lack of pre-marketing efficacy and safety data in older patients, with frequent off-label prescribing of several drugs within important therapeutic classes, for example, antidepressants, antipsychotics and anticonvulsants, means that the risk, type and severity of ADRs might differ from those reported in younger patients.

The traditional concept, diagnosis and clinical impact of ADRs might also differ in old age [9]. For example, antimuscarinic drugs are known to increase the risk of specific ADRs, secondary to their antagonistic effects toward peripheral muscarinic receptors, for example, dry mouth, urinary retention and constipation [10]. There is increasing evidence that antimuscarinic drugs might also increase the risk of functional decline and mortality [10,11]. Defining and quantifying the onset and progression of functional decline might be challenging for the purposes of ADRs classification [12]. However, physical functioning is fundamental to the independent living and quality of life in old age, and strongly predicts clinical outcomes [12]. Another potential issue with the standardization of ADRs reporting is the lack of data on individual patients' views on specific ADRs. In pharmacoepidemiological studies, different ADRs are generally given similar weight, and little effort is made to rank their severity and significance using patient-centered scales. Moreover, predicting and detecting ADRs is particularly challenging in patients with cognitive impairment, which affects up to 10% of people > 80 years. The presence of cognitive impairment might reduce a clinician's ability to identify ADRs because of the often poorly reliable patient's history and symptoms description [13].

Several scoring systems have been recently developed to predict the risk of ADRs in the older population with specific drugs or drug classes, for example, antimuscarinic drugs [10]. Although this might enhance risk stratification when considering treatment options, the available scoring systems are far from perfect. Important pharmacological characteristics such as dose, plasma concentration, binding affinity to specific receptors, ability to cross the blood–brain barrier and markers of drug clearance are not accounted for [10,14]. These parameters are particularly important when designing risk prediction tools in a patient group characterized by high inter-individual biological variability. Moreover, different drugs taken by the same patient are often assumed, without any evidence, to exert ‘additive’ effects on the risk of ADRs. The possibility of more complex pharmacokinetic and pharmacodynamic drug–drug interactions is largely ignored. Recently developed simulators integrating human physiological, genetic and epidemiological information with in vitro or clinical data, for example, Simcyp, might better predict the pharmacokinetics and pharmacodynamics of drugs in the older population. These systems, currently used in drug development, could be tested in the clinical setting in a not too distant future [15].

3. Potential strategies to mitigate the impact of adverse drug reactions

With the constant introduction of new drugs and therapeutic classes, largely untested in older patients in the pre-marketing phase, predicting and detecting ADRs in old age will remain a challenging task in the years to come. Computerized decision support systems have been developed to prevent drug–drug interactions by using automated alerts within electronic prescribing platforms. There is good evidence that such systems reduce inappropriate prescribing, particularly in primary care, potentially reducing ADRs [16,17]. This approach, however, needs refinement as patient-specific information is often lacking and data on current medications rely on different sources, for example, patient, carer and doctor, particularly in the acute setting. Moreover, several drug–drug interactions are unlikely to be clinically significant, with potential for over-reporting [18,19]. At least two recently developed strategies, that is, medication reconciliation and trigger tools methodology, might help to mitigate the impact of ADRs in this group by enhancing the monitoring of drug therapy in the context of acute changes in clinical status and organ function.

3.1 Medication reconciliation

The delivery of healthcare to older patients has faced significant changes over the last 20 – 30 years. The development of post-acute and step-down facilities (e.g., intermediate care and rehabilitation wards) and the introduction of new legislations (e.g., the European Working Time Directive) have contributed to the ‘fragmentation’ of care. As a result, patients are managed by an increasing number of doctors and experience different care transitions. These factors increase the risk that the information on medication use, for example, initiation, discontinuation and dose changes, is either lost or misinterpreted during the patient's clinical journey. The problem is further compounded by the availability of different sources of medication information, for example, patient, carer, family member, pharmacist and general practitioner.

Medication reconciliation is part of the medication history taking process and aims to ensure that medications are not added, omitted or changed inadvertently during care transitions. It requires a coordinated effort of several professional groups, for example, physicians, pharmacists and nurses, and can be conducted using medical records either on paper or electronically [20]. There is some evidence that medication reconciliation facilitates drug therapy monitoring and reduces discrepancies between medications that have potential to cause ADRs in older hospitalized patients [21,22]. Medication reconciliation strategies might differ, depending on staff training and availability, management support and quality of Information Technology (IT) services. More research is needed to test the hypothesis that medication reconciliation reduces the risk of ADRs in different settings and patient groups, for example, patients with dementia in long-term care facilities.

3.2 Trigger tools methodology

This approach, originally developed in North America, consists of using a number of selected clinical (e.g., lethargy, falls, development of skin rash), biochemical (e.g., increase in serum creatinine concentration, increase in International Normalized Ratio) and pharmacological (e.g., increase in serum digoxin concentrations, use of opiate antagonists) ‘sentinel tools’, and their combinations, to increase the detection of ADRs. Such tools can be tailored to specific healthcare settings, medical conditions and drugs [23]. Easy access to this information, for example, electronic medical records linked with electronic prescribing platforms and laboratory reports, is a key element of success, although paper chart reviews are also feasible [24]. Theoretically, electronic access to such tools might allow ‘real-time’ patient assessment, with the potential for close monitoring of drug therapy and ADRs prevention as well as detection. The trigger tools methodology has been tested in older patients in several settings, for example, ambulatory care and hospital. Notably, a limited number of tools might account for the vast majority of ADRs detected, suggesting opportunities for refinement and simplification [25].

4. Conclusions

The high medication exposure, disease burden and frailty associated with old age make rational drug prescribing and regular medication review essential components of an effective and comprehensive management plan in this patient group. Pharmacoepidemiology and drug safety are constantly evolving with the availability of new drugs and post-marketing data and, together with further developments in pharmacokinetics and pharmacogenetics, are likely to make ‘personalized medicine’ an achievable goal in older patients. Pending further advances in these fields, this editorial has discussed some of the challenges faced by clinicians in preventing and detecting ADRs in old age. Strategies are being developed in different settings to reduce the health and financial burden of ADRs in this patient group. However, the existing approaches, for example, medication reconciliation and trigger tools methodology, are still in their infancy. More research is urgently needed to test their feasibility and to demonstrate measurable, and clinically relevant, patient benefits.

5. Expert opinion

Advances in the capacity to predict and detect ADRs in old age are unlikely to lead to significant changes in clinical practice within the next 5 years. The main barrier remains the lack of pre-marketing drug efficacy and safety data, particularly in patients > 80 years, the fastest growing subgroup. The picture is further compounded by the often inappropriate drug prescribing and poor medication review, and by the potential adverse impact of several drugs and drug classes on ‘non-conventional’ and poorly measurable ADRs, for example, functional decline and loss of independence.

Several strategies to minimize the impact of ADRs in older patients, for example, medication reconciliation and trigger tools methodology, are being developed. Despite some promising results, these tools need further validation and refinement. More evidence is needed to demonstrate their efficacy on preventing ADRs and reducing the associated health and financial burden. The large-scale adoption of these methodologies will require the combined effort of several professional and patient groups, support from senior management and health policy makers and resource availability. In the current environment, it is unlikely that financial support is shifted from other sources to allow the development and implementation of ADRs mitigating strategies without a clear cost–benefit evaluation. It is hoped that such analyses will be conducted soon.

In the meantime, the regular monitoring of individual patients’ medications, clinical status and specific biochemical parameters of drug clearance (e.g., renal and liver function) remain essential to minimize the impact of ADRs in old age.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.