Prevalence of polypharmacy and associated adverse health outcomes in adult patients with chronic kidney disease: protocol for a systematic review and meta-analysis

Polypharmacy, the concurrent use of multiple medications by an individual, is a significant and growing public health threat worldwide [1‐3]. In 2017, the World Health Organization (WHO) highlighted polypharmacy as a key action to address unsafe medication practices and medication errors which are often associated with significant patient injury and preventable harm [1]. Globally, the prevalence of polypharmacy continues to increase, with estimates of 10–20% in the general population and 40–60% in the elderly [4‐6]. There is no standard definition of polypharmacy; various definitions and related terms have been used (reviewed in detail by Masnoon et al.) [7]. Variability in the numerical threshold used in characterizing polypharmacy, as well as the reported inconsistencies regarding duration of therapy, healthcare setting, and inclusion of over-the-counter (OTC), and traditional and complementary medicines often creates challenges when defining polypharmacy [7]. Most studies, however, define polypharmacy as the concomitant use of ≥ 5 medications which is supported by evidence on medication-related adverse effects associated with polypharmacy [8].

Aging and multimorbidity are the key driving factors of polypharmacy [2, 3]. It is estimated that about half of individuals over the age of 65 years have at least three coexisting chronic conditions, and about 20% have five or more [ 9]. Given a rising burden of multimorbidity among the elderly, there is a corresponding increase in the amount of medication use in this group, thus increasing the prevalence of polypharmacy [2, 3]. In the USA, more than 4 in 10 older adults take 5 or more prescription medications daily—a marked rise of 300% from 1994 to 2014 [10]. This proportion increases to 7 in 10 older adults if OTC medications and supplements are counted [11] and nearly 20% of older adults take ≥ 10 drugs [10]. Similarly, the Canadian Institute for Health Information (CIHI) have reported that almost two-thirds of individuals aged 65 years and over used ≥ 5 drug classes, while 27% ≥ 10 and 8.6% used ≥ 15 [12]. Table 1 summarizes other driving forces of polypharmacy.

Polypharmacy is associated with a broad range of adverse health outcomes, resulting in significant costs to both the patient and the healthcare system [13‐15], with the risk and severity of harm increasing with an increasing number of medications [16]. Polypharmacy has also been strongly associated with adverse drug events (ADEs), adverse drug reactions (ADRs), drug-drug interactions, and drug-disease interactions [13‐15]. In the USA, ADRs are estimated to claim between 100,000 and 218,000 lives annually and cost the healthcare system up to $137–177 billion [24]. The true incidence of ADRs are estimated to be much higher since underreporting is shown to be as high as 94% [25]. Studies have also shown that the risk of ADEs increases by up to 7–10% for each additional medication taken, and that outpatients using 5 or more medications have an 88% increased chance of experiencing an ADE compared to those taking less medications [26].

Polypharmacy has also been directly associated with mortality. In a systematic review that investigated the association between polypharmacy and mortality, a significant association between polypharmacy and death was observed when polypharmacy was defined as a discrete variable (pooled-adjusted odds ratio [aOR] 1.08 [95% CI 1.04–1.12]) [27]. When polypharmacy was defined categorically, a dose-response relationship was also observed across increasing thresholds of medications use, i.e., 1–4 medications [aOR 1.24]; 5 medications [aOR 1.31] and 6–9 medications [aOR 1.59]. Excessive polypharmacy (i.e., use of ≥ 10 medications) was also significantly associated with death [aOR 1.96] [27]. Other negative consequences associated with polypharmacy are also summarized in Table 1 [13‐23].

An increasingly aging and multimorbid population has contributed to the rising prevalence of chronic kidney disease (CKD) [28, 29]. Individuals with CKD are highly vulnerable to polypharmacy given that CKD risk factors (e.g., diabetes mellitus and hypertension) and other cardiovascular diseases and risk factors are more prevalent in this population [30, 31]. Furthermore, patients with CKD require additional medications to limit the progression of CKD and manage disease-related complications (e.g., anemia, metabolic disorders, hyperlipidemia, mineral, and bone disorders) as kidney function deteriorates [32]. In CKD, all mechanisms of kidney excretion are impaired, including glomerular filtration, tubular secretion, and reabsorption. Since most drugs are largely eliminated through the kidneys, reduced kidney function causes a wide-ranging changes to the pharmacokinetic (drug absorption, distribution, metabolism, and excretion) and pharmacodynamic (drug-receptor interactions) properties of drugs thereby increasing the likelihood of potentially life-threatening toxicities, drug-drug interactions, and ADRs [33, 34]. The substantial burden of medications in individuals with CKD is well-documented, with studies showing that between 70.4–81% of patients with CKD take ≥ 5 medications [35, 36]. In a German study of 5217 patients with CKD, the prevalence of polypharmacy at baseline and follow-up was almost 80%, the median number of different medications per day was 8 (range 0–27), and factors associated with polypharmacy were increasing CKD stage, age, body mass index (BMI), diabetes mellitus, cardiovascular disease, and a history of smoking [35]. Another study found that 35.5% of older individuals with CKD took ≥ 10 medications, vitamins, and supplements [36].

Polypharmacy is also the main reason for potentially inappropriate medications (PIMs) use, with the number of PIMs increasing with the number of prescribed medications [37]. In individuals with CKD, numerous studies have revealed that PIM use as well as renally inappropriate medications use (RIMs) is common [36‐39] and often overlooked [38, 39]. The prevalence of PIMs is estimated to be as much as 62–67% of patients in the inpatient and ambulatory care setting [40]. The recently published CKD-REIN study revealed that a large proportion of medications prescribed to patients with CKD were contraindicated, suggesting a lack of regular and/or thorough assessment of patients’ medication lists as kidney function declined [41].

The number of older persons is expected to have doubled by 2050 (reaching nearly 2.1 billion) [42], and this is likely to further increase the burden of multimorbidity and prevalence of individuals with CKD on polypharmacy [28]. Given the relationship between multimorbidity and CKD, and that such patients are at high risk of polypharmacy, PIMs, and adverse health effects associated with polypharmacy, this study will provide adequate information characterizing the burden of these conditions among patients with CKD. This will likely improve caution when prescribing medications for patients with CKD and reduce the frequency of adverse health effects related to polypharmacy in this population.

The aim of this systematic review will be to assess the prevalence of polypharmacy among adult patients with CKD, and the potential association between polypharmacy and adverse health outcomes within this population.

The present protocol has been registered within the PROSPERO database (registration number CRD42020206514) and is being reported in accordance with the guidance provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement [43] (see checklist in Additional file 1). The planned review will be reported according to the Preferred Reporting Items for Reporting Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement [44], and the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) reporting guideline [45].

To the best of our knowledge, this review is the first to comprehensively assess the prevalence of polypharmacy in patients with CKD as well as reporting the incidence of adverse health outcomes associated with polypharmacy in such patients. As polypharmacy is a major and growing public health issue, our findings will highlight the hazards associated with polypharmacy as well as medication thresholds associated with adverse outcomes. Our study will also draw attention to the prognostic importance of improving medication practices as a key priority area to help minimize the use of inappropriate medications in patients with CKD. A potential limitation of this study could be non-uniform reporting of adverse outcomes and their associations with polypharmacy. This could make it difficult to identify adverse outcomes associated with use of medications in the CKD population. Another limitation could be that identified studies are mostly of low quality which could impact on the final reporting of our outcomes. Despite these, we expect that the results of this study will inform medication education, physician practice guidelines, and various quality improvement initiatives to address polypharmacy. Any amendments we make to this protocol when conducting the review will be outlined in PROSPERO and reported in the final manuscript.