Given the difficulties involved in applying the results of clinical studies to older people, physicians should carefully consider their sources of evidence and recommendations to find the right balance between avoiding the ‘risk/treatment paradox’ (high‐risk older patients denied safe medications capable of materially improving survival or quality of life) and avoiding inappropriate use of medications for which risks are likely to outweigh benefits (Scott 2010). It must also be noted that the intervention studies included in this review focused on reducing inappropriate prescribing of prescription medications and over‐the‐counter (OTC) medication use was often not assessed, nor was it specifically examined as part of this review. OTC medication use is common among older patients receiving prescription medications with the potential for drug interactions to occur (Agbabiaka 2017). This should not be overlooked by healthcare professionals when reviewing older patients’ medication use.

Based on the findings of our updated review, we are still uncertain about which elements of the intervention processes constitute success in improving appropriate polypharmacy, and a number of questions remain unanswered. For example, is it sufficient to provide the intervention during a single episode of care, or should patients be exposed to the intervention on a daily/weekly or monthly basis? What is the optimal duration of an intervention, and should interventions ideally be multi‐faceted or uni‐faceted? It is clear that control of processes to support fidelity and control of the chosen interventions is critical. Staff training is important to ensure consistency; the receptiveness of prescribers, patients and staff in various settings will have an impact on the uptake and effectiveness of interventions in older people.

Uncertainty about which elements of the intervention are critical to successful outcomes needs to be addressed. On the basis of the studies included in this review, this poses challenges, as details of intervention development and delivery were lacking. Methods of specifying and reporting complex interventions, as well as their implementation strategies, are necessary to strengthen the evidence base required for interventions to be more effective, implementable and replicable across different settings (Michie 2011; Proctor 2013). Future intervention studies targeting appropriate polypharmacy could benefit from guidance provided by the framework of the Medical Research Council (MRC) on the design of complex interventions (MRC 2008). This framework recognises the importance of the initial stage of intervention development, in which evidence and theory are used to inform the selection of relevant components before the intervention is piloted, and the feasibility of delivering it in practice is assessed. These initial stages precede formal evaluations seeking to establish the effectiveness of the intervention. Despite the potential availability of the MRC guidelines before the start of the new studies highlighted in this update, only one included study (Clyne 2015) and two ongoing studies (Anrys 2016; Sinnott 2017) referred to using the MRC guidelines when developing and evaluating their interventions.

Adequate documentation of intervention development and intervention content as well as the training and background of providers that may be critical to intervention effectiveness is essential for facilitating replication of successful interventions in practice. However, no studies included in this review referred to using available intervention tools reporting, such as TIDieR (Template for Intervention Description and Replication) checklist (Hoffmann 2014).

The framework of the MRC 2008 also outlines the potential application of qualitative methodologies, such as semi‐structured interviews, to involve users and to gain insights into the processes of change that underlie the intervention. For example, establishing the reasons why not all interventions are accepted may be enlightening and may support research into the development of more successful interventions. There appears to be a ceiling effect (approximately 75%), whereby inappropriate prescribing continues despite the evidence base of interventions (Furniss 2000; Zermansky 2006). Qualitative interviews of prescribers may uncover reasons as to why they did not accept interventions (e.g. timing or appropriateness of provision of the intervention, the expertise of providers). Additionally, poor prescribing practice must be explored and understood with the goal of learning how to improve it and how to enhance patient safety by reducing the need for intervention. The importance of these investigations extends beyond the research context alone. Given the high financial expenditure that has been attributed to potentially inappropriate prescribing (PIP) in older people (Bradley 2012; Cahir 2010), it is likely that policy makers will continue to be interested in the costs of these types of interventions.

In the previous version of this review (Patterson 2014), we recommended that future studies should utilise clearer definitions of appropriate polypharmacy because the term ‘polypharmacy’ can be both negative and positive, and this duality of meaning makes objective research difficult (Bushardt 2008). Reports by the King’s Fund in the UK (King’s Fund 2013) and Scottish Guidance on polypharmacy (Scottish Government Model of Care 2018), discussed the need to reconsider current definitions of polypharmacy on account of the increasing numbers of medications being prescribed to patients and recommended that polypharmacy should be defined as appropriate (i.e. medicine use has been optimised and medicines prescribed according to best evidence) or problematic (i.e. medicines have been prescribed inappropriately or intended benefits have not been realised). Although the potential benefit of having a simple means of identifying patients at particular risk for inappropriate prescribing and adverse effects was acknowledged, the authors of the King’s Fund report noted that existing thresholds used to define polypharmacy, such as four or five or more medicines, may be too low. A pragmatic approach was proposed to identify patients warranting medication review, which focused on particular patient groups (e.g. patients receiving ≥ 10 regular medicines, patients receiving four to nine medicines with other risk factors).

For the purpose of this update, the definition of polypharmacy was not changed from that used in the original review. Although a threshold of four or more medicines may now be considered to be low in the context of older people with multimorbidity, it is important to recognise that the number of medicines used to define polypharmacy is arbitrary. Furthermore, conceptualising polypharmacy solely on the basis of the number of medicines prescribed is often unhelpful as this approach fails to recognise that the appropriate number of medicines varies according to individual patients’ clinical needs and, moreover, may overlook the omission of potentially beneficial medications, which can equally have a negative impact on clinical outcomes (Cadogan 2016). Hence, for the purpose of the current update, our focus was on interventions targeting the appropriateness of the medications prescribed for older people. However, future updates of this review may reconsider the criteria used to define polypharmacy were validated tools to assess potentially inappropriate prescribing in older people, such as Beers criteria, are not specifically designed to measure appropriate polypharmacy, it is important that future interventions should include assessments of potentially inappropriate omissions/under‐prescribing with the goal of improving appropriate polypharmacy.

The judgement as to whether many (appropriate polypharmacy) or too many (inappropriate polypharmacy) medications are used is difficult. The complexity of the clinical situation, patient attributes and wishes and the individuality of prescribing for older complex patients will remain a challenge in this regard. Development of a new, universal, easily applied, valid and reliable outcome measure of appropriate polypharmacy in primary care is currently underway (Burt 2016). Ideally, this measure should be globally applicable across various healthcare and cultural settings.

It is important that sufficient detail about the context in which complex interventions are conducted, such as those included in this review, is reported and understood, so the transferability of complex interventions can be assessed (Wells 2012). For example, heterogeneity among older people in relation to differing levels of frailty (Spinewine 2007a) means that translational research and retesting of successful interventions may be necessary in dissemination to new populations, as a population of quite healthy 70‐year‐old people may respond differently to an intervention compared with a group of very frail 92‐year‐old individuals.

It is worth noting that only one of the included studies followed participants for longer than 12 months (Frankenthal 2014). The lack of evidence of effectiveness of pharmaceutical care interventions may be due in part to inadequate length of follow‐up. Future studies should be longer in duration to address this issue and to evaluate the longer‐term sustainability of pharmaceutical care interventions in improving the appropriate use of polypharmacy for older people.

Perhaps most critically, the selection of clinical and humanistic outcomes appropriate for older people (e.g. hospital admissions, adverse drug events (ADEs)) will be important to consider in future studies. Strategies for improving the evidence base for older patient care have been reviewed by Scott 2010. Indeed, a key challenge for interventions aimed at improving appropriate polypharmacy for older people is the selection and reporting of consistent outcomes (i.e. patient‐related or medication‐related outcomes). The Core Outcome Measures for Effectiveness Trials (COMET) initiative was launched to develop and apply core outcome sets (COS), which have been proposed as one method of addressing this problem (Williamson 2017). A COS is an agreed and standardised set of outcomes or outcome domains which should be measured and reported, as a minimum, in all trials in a specific clinical area. Alongside the Core Outcome Set‐STAndards for Reporting (COS‐STAR) guidelines (Kirkham 2016), the development of COSs in a specific health area should facilitate more robust synthesis of evidence in the future. A COS for use in interventions to improve the appropriate use of polypharmacy for older people in primary care is now available (Rankin 2018). The adoption of this COS will streamline the outcomes routinely measured in trials investigating appropriate polypharmacy in older people in primary care. This will ultimately facilitate the comparison and synthesis of outcome data across studies, thereby helping to determine which interventions work and inform both clinical decision making and health policy.