Evidence-Based Deprescribing: Reversing the Tide of Potentially Inappropriate Polypharmacy

From the Department of Internal Medicine and Clinical Epidemiology, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland, Australia (Dr. Scott), School of Medicine, The University of Queensland, Herston Road, Brisbane, Australia (Dr. Scott), Centre of Research Excellence in Quality & Safety in Integrated Primary-Secondary Care, The University of Queensland, Herston Road, Brisbane, Australia (Ms. Anderson), and Charming Institute, Camp Hill, Brisbane, Queensland, Australia (Dr. Freeman).

Abstract

• Objective: To review the adverse drug events (ADEs) risk of polypharmacy; the process of deprescribing and evidence of efficacy in reducing inappropriate polypharmacy; the enablers and barriers to deprescribing; and patient and system of care level strategies that can be employed to enhance deprescribing.
• Methods: Literature review.
• Results: Inappropriate polypharmacy, especially in older people, imposes a significant burden of ADEs, ill health, disability, hospitalization and even death. The single most important predictor of inappropriate prescribing and risk of ADEs in older patients is the number of prescribed medicines. Deprescribing is the process of systematically reviewing, identifying, and discontinuing potentially inappropriate medicines (PIMs), aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies, and deprescribing protocols have been developed and validated for clinical use. Barriers and enablers to deprescribing by individual prescribers center on 4 themes: (1) raising awareness of the prevalence and characteristics of PIMs; (2) overcoming clinical inertia whereby discontinuing medicines is seen as being a low value proposition compared to maintaining the status quo; (3) increasing skills and competence (self-efficacy) in deprescribing; and (4) countering external and logistical factors that impede the process.
• Conclusion: In optimizing the scale and effects of deprescribing in clinical practice, strategies that promote depresribing will need to be applied at both the level of individual patient–prescriber encounters and systems of care.

In developed countries in the modern era, about 30% of patients aged 65 years or older are prescribed 5 or more medicines [1]. Over the past decade, the prevalence of polypharmacy (use of > 5 prescription drugs) in the adult population of the United States has doubled from 8.2% in 1999–2000 to 15% in 2011–2012 [2]. While many patients may benefit from such polypharmacy [3] (defined here as 5 or more regularly prescribed medicines), it comes with increased risk of adverse drug events (ADEs) in older people [4] due to physiological changes of aging that alter pharmacokinetic and pharmacodynamic responses to medicines [5]. Approximately 1 in 5 medicines commonly used in older people may be inappropriate [6], rising to a third among those living in residential aged care facilities [7]. Among nursing home residents with advanced dementia, more than half receive at least 1 medicine with questionable benefit [8]. Approximately 50% of hospitalized nursing home or ambulatory care patients receive 1 or more unnecessary medicines [9]. Observational studies have documented ADEs in at least 15% of older patients, contributing to ill health [10], disability [11], hospitalization [12] and readmissions [13], increased length of stay, and, in some cases, death [14]. This high level of iatrogenic harm from potentially inappropriate medicines (PIMs) mandates a response from clinicians responsible for managing medicines.

In this narrative review, we aim to detail the ADE risk of polypharmacy, the process of deprescribing and evidence of its efficacy in reducing potentially inappropriate polypharmacy, the enablers and barriers to deprescribing, and patient and system of care level strategies that can be employed in enhancing deprescribing.

Polypharmacy As a Risk Factor for Medicine-Related Harm

The number of medicines a patient is taking is the single most important predictor of medicine-related harm [15]. One report estimated the risk of ADEs as a contributory cause of patients presenting acutely to hospital emergency departments to be 13% for 2 drugs, 38% for 4 drugs, and 82% for 7 drugs or more [16]. The more medicines an individual takes, the greater their risk of experiencing an adverse drug reaction, a drug-drug interaction, a drug-disease interaction, cascade prescribing (where more medicines are added to counteract side effects of existing medicines), nonadherence, and drug errors (wrong drug, wrong dose, missed doses, erroneous dosing frequency) [17–20]. Once the number of regular medicines rises above 5 (commonly regarded as the threshold for defining polypharmacy), observational data suggest that additional medicines independently increase the risk of frailty, falling, and hospital admission [21].

The benefits of many medicines in frail older people remain unquantified. As many as 50% of clinical trials have a specific upper age limit and approximately 80% of clinical trials exclude people with comorbidities [22,23]. Single-disease treatment guidelines based on such trials are often extrapolated to older people with multimorbidity despite an absence of evidence for benefit [24] and with little consideration of the potential burdens and harms of polypharmacy resulting from treating multiple diseases in the one patient [25]. By contrast, the risks from many medicines in older people are well known. Older people are at high risk of ADEs and toxicity due to reduced renal and liver function and age-related changes in physiological reserve, body composition, and cellular metabolism [26]. While the adverse effects of polypharmacy or of comorbidities targeted for treatment are difficult to separate, the burden of medicine-induced decline in function and quality of life is becoming better defined and appreciated [27].

Defining Evidence-Based Deprescribing

While many definitions have been proposed [28], we define evidence-based deprescribing as follows: the active process of systematically reviewing medicines being used by individual patients and, using best available evidence, identifying and discontinuing those associated with unfavorable risk–benefit trade-offs within the context of illness severity, advanced age, multi-morbidity, physical and emotional capacity, life expectancy, care goals, and personal preferences [29]. An enlarging body of research has demonstrated the feasibility, safety and patient benefit of deprescribing, as discussed further below. It employs evidence-based frameworks that assist the prescriber [30] and are patient-centered [31].

Importantly, deprescribing should be seen as part of the good prescribing continuum, which spans medicine initiation, titrating, changing, or adding medicines, and switching or ceasing medicines. Deprescribing is not about denying effective treatment to eligible patients. It is a positive, patient-centered intervention, with inherent uncertainties, and requires shared decision-making, informed patient consent and close monitoring of effects [32]. Deprescribing involves diagnosing a problem (use of a PIM), making a therapeutic decision (withdrawing it with close follow-up) and altering the natural history of the problem (reducing incidence of medicine-related adverse events).

Our definition of evidence-based deprescribing is a form of direct deprescribing applied at the level of the individual patient-prescriber/pharmacist encounter. Direct deprescribing uses explicit, systematic processes (such as using an algorithm or structured deprescribing framework or guide) applied by individual prescribers (or pharmacists) to the medicine regimens of individual patients (ie, at the patient level), and which targets either specific classes of medicines or all medicines that are potentially inappropriate. This is in contrast to indirect deprescribing, which uses more generic, programmatic strategies aimed at prescribers as a whole (ie, at the population or system level) and which seek to improve quality use of medicines in general, including both underuse and overuse of medicines. Indirect deprescribing entails a broader aim of medicines optimization in which deprescribing is a possible outcome but not necessarily the sole focus. Such strategies include pharmacist or physician medicine reviews, education programs for clinicians and/or patients, academic detailing, audit and feedback, geriatric assessment, multidisciplinary teams, prescribing restrictions, and government policies, all of which aim to reduce the overall burden of PIMs among broad groups of patients. While intuitively the 2 approaches in combination should exert synergistic effects superior to those of either by itself, this has not been studied.

Evidence For Deprescribing

Indirect Deprescribing

Overall, the research into indirect interventions has been highly heterogenous in terms of interventions and measures of medicine use. Research has often been of low to moderate quality, focused more on changes to prescribing patterns and less on clinical outcomes, been of short duration, and produced mixed results [33]. In a 2013 systematic review of 36 studies involving different interventions involving frail older patients in various settings, 22 of 26 quantitative studies reported statistically significant reductions in the proportions of medicines deemed unnecessary (defined using various criteria), ranging from 3 to 20 percentage points [34]. A more recent review of 20 trials of pharmacist-led reviews in both inpatient and outpatient settings reported a small reduction in the mean number of prescribed medicines (–0.48, 95% confidence interval [CI] –0.89 to –0.07) but no effects on mortality or readmissions, although unplanned hospitalizations were reduced in patients with heart failure [35]. A 2012 review of 10 controlled and 20 randomized studies revealed statistically significant reductions in the number of medicines in most of the controlled studies, although mixed results in the randomized studies [36]. Another 2012 review of 10 studies of different designs concluded that interventions were beneficial in reducing potentially inappropriate prescribing and medicine-related problems [37]. A 2013 review of 15 studies of academic detailing of family physicians showed a modest decline in the number of medications of certain classes such as benzodiazepines and nonsteroidal anti-inflammatory drugs [38]. Another 2013 review restricted to 8 randomized trials of various interventions involving nursing home patients suggested medicine-related problems were more frequently identified and resolved, together with improvement in medicine appropriateness [39]. In 2 randomized trials conducted in aged care facilities and centered on educational interventions, one aimed at prescribers [40] and the other at nursing staff [41],the number of potentially harmful medicines and days in hospital was significantly reduced [40,41], combined with slower declines in health-related quality of life [40]. In a randomized trial, patient education provided through community pharmacists led to a 77% reduction in benzodiazepine use among chronic users at 6 months with no withdrawal seizures or other ill effects [42].

Direct Deprescribing Targeting Specific Classes of Medicines

The evidence base for direct patient-level deprescribing is more rigorous as it pertains to specific classes of medicines. A 2008 systematic review of 31 trials (15 randomized, 16 observational) that withdrew a single class of medicine in older people demonstrated that, with appropriate patient selection and education coupled with careful withdrawal and close monitoring, antihypertensive agents, psychotropic medicines, and benzodiazepines could be discontinued without harm in 20% to 100% of patients, although psychotropics showed a high post-trial rate of recommencement [43]. Another review of 9 randomized trials demonstrated the safety of withdrawing antipsychotic agents that had been used continuously for behavioural and psychological symptoms in more than 80% of subjects with dementia [44]. In an observational study, cessation of inappropriate antihypertensives was associated with fewer cardiovascular events and deaths over a 5-year follow-up period [45]. A recent randomized trial of statin withdrawal in patients with advanced illness and of whom half had a prognosis of less than 12 months demonstrated improved quality of life and no increased risk of cardiovascular events over the following 60 days [46].