Prevalence of Drug-Related Problems and Complementary and Alternative Medicine Use in Malaysia: A Systematic Review and Meta-Analysis of 37,249 Older Adults

Drug-related problems (DRPs) in the elderly include polypharmacy, potentially inappropriate medications, nonadherence, and drug-related falls. In this systematic review and meta-analysis, the prevalence of DRPs and complementary and alternative medicine (CAM) use among the Malaysian elderly was estimated. PubMed, Scopus, Web of Science, and Google Scholar databases were searched to identify studies published since their inception up to 24 August 2020. A random-effects model was used to generate the pooled prevalence of DRPs along with its corresponding 95% confidence interval (CI). The heterogeneity of the results was estimated using the I2 statistics, and Cochran’s Q test and sensitivity analyses were performed to confirm the robustness of the results. We identified 526 studies, 23 of which were included in the meta-analysis. (n = 29,342). The pooled prevalence of DRPs among Malaysian elderly was as follows: (1) polypharmacy: 49.5% [95% CI: 20.5–78.6], (2) potentially inappropriate medications: 28.9% [95% CI: 25.4–32.3], (3) nonadherence to medications: 60.6% [95% CI: 50.2–70.9], and (4) medication-related falls 39.3% [95% CI: 0.0–80.8]. Approximately one in two Malaysian elderly used CAM. The prevalence of polypharmacy and potentially inappropriate medications among the Malaysian elderly population was high, calling for measures and evidence-based guidelines to ensure the safe medication use.


Introduction
Pharmacological treatment not only improves the health status of the elderly, but also brings about harmful outcomes [1]. Drug-related problems (DRPs) in the elderly include (i) polypharmacy, (ii) inappropriate drug use, (iii) nonadherence, (iv) inappropriate use of complementary and alternative medicine (CAM), and (v) drug-related falls. Polypharmacy, defined as the regular use of five or more prescription drugs, is common among the elderly with multiple chronic medical conditions [2]. Inappropriate drug use, on the other hand, is the term used to collectively describe the use of potentially inappropriate medications (PIMs), potentially inappropriate prescribing (PIP) and potential prescribing omissions (PPOs) [3]. Such problems can be detected using the Beers or the START/STOPP criteria when they take place in the elderly [4]. Both PIMs and PPOs have been reported to cause adverse drug events as well as prolonged hospitalization [5]. Additionally, concurrent use of certain medications could increase the risk of falls by up to 2.8 times in the elderly [6].
To deal with complicated health conditions, medication adherence also remains a significant challenge in the elderly [7,8]. Nonadherence to treatment has been resulting in treatment failure and hospitalization over the years [9]. Apart from that, older individuals generally tend to consume many over-the-counter (OTC) products and CAM [10]. Ginkgo biloba, St John's-wort, danshen, licorice, ma-huang, and garlic are among of the widely used products that are likely to interact with prescription drugs, such as warfarin, protease inhibitors and anticancer drugs. Due to the expanded life expectancy, the elderly population in Malaysia has grown substantially. The rampant use of these products coupled with insufficient knowledge of drug-drug interactions may lead to life-threatening adverse events.
The prevalence of polypharmacy reported in Malaysia widely varied from 45.9% to 80.6% [11][12][13], while almost one-third of the elderly in the country are using PIMs [13,14]. Nonadherence to treatment was also reported in more than half of Malaysian elderly [15]. Nearly 60% of the elderly also regularly consume supplements [13], while approximately one-fifth of them use CAM [16].
To date, there is a lack of evidence on DRPs and CAM use among the elderly population in Malaysia. Moreover, the outcomes of the individual study are inconclusive. In this systematic review and meta-analysis, we estimated the pooled prevalence of DRPs among the Malaysian elderly population.

Literature Search
A total of 526 records were obtained from the electronic databases. However, 180 records including duplicate studies (n = 173), review articles (n = 4), case report (n = 1), and commentary (n = 2) were removed. Subsequently, the abstracts of the remaining 346 records were screened. Of 27 studies retained for the systematic review, 23 of which were included in the meta-analysis ( Figure 1).

Meta-Analysis
Polypharmacy occurred in 49.5% [95% CI: 20.5-78.6] of the Malaysian elderly ( Figure 2). Interestingly, the elderly who sought care from the healthcare facilities had a higher prevalence of polypharmacy [ Figure S1).

Study Quality Assessment and Publication Bias
The result of the quality assessment of the included studies is presented in Table S1. In summary, 11 (40.7%) studies were of a high quality, 12 (44.5%) were of a moderate quality, and 4 (14.8%) were of a low-quality (high-risk of bias). Based on the funnel plot and Egger's test, we did not find any significant publication bias ( Figure 3).

Sensitivity Analyses
The possible range of the pooled prevalence of polypharmacy relative to the main results ranged from −22.8% to +1.8% (Table 3 and Figure S2). The pooled prevalence of studies reporting PIMs ranged from 1.7% lower to 4.5% higher relative to the main results. The sensitivity analyses suggested that the prevalence of polypharmacy and PIMs presented in the studies was not only robust but also reliable (Table 3 and Figure S2). Three outlier studies on polypharmacy [11,30,37] and one on PIMs [36] were identified from the Galbraith plot ( Figure S3).

Sensitivity Analyses
The possible range of the pooled prevalence of polypharmacy relative to the main results ranged from −22.8% to +1.8% (Table 3 and Figure S2). The pooled prevalence of studies reporting PIMs ranged from 1.7% lower to 4.5% higher relative to the main results.

Discussion
To our knowledge, this is the first systematic review and meta-analysis which synthesized the pooled prevalence of multiple outcomes related to DRPs and CAM use in a Malaysian elderly population. This meta-analysis involved a large number of patients from mostly high-and moderate-quality studies with no publication bias. However, there was a high level of heterogeneity in the studies included in this meta-analysis. Nevertheless, our findings served as an informative overview of DRPs and CAM use among the elderly population in Malaysia.
According to the studies included in this review, the possible range of prevalence of polypharmacy in the Malaysian elder population was between 20.3% [33] and 100% [37]. Such a great variation is attributable to the different definitions of polypharmacy. Polypharmacy is very common among older adults with multiple diseases [38]. Our study indicates that nearly half of the older adults in Malaysia experienced polypharmacy. Similar findings were also reported in Singapore (58.6%) [39], India (45.0%) [40], Australia (43.3%) [41], and in some European countries (49.7%) [42], indicating that there is a room for improvement in the elderly care.
Based on our meta-analysis, individuals who sought care from health facilities had a higher prevalence of polypharmacy, and this was likely due to their medical conditions and/or treatment regimens [28,33]. Polypharmacy was associated with an increased risk of adverse outcomes [9] in older adults. The concept of "appropriate polypharmacy" should be advocated when there is a need to achieve multiple therapeutic goals [43]. Additionally, a collaborative intervention between healthcare professionals from multiple disciplines [44] should be further explored, researched and fostered for a better integrated care in the elderly population.
The prevalence of PIMs could range from 18.7% to 36.1% according to the existing studies [12,36]. The findings suggest that almost one-third of the elderly in Malaysia is affected by PIMs (28.9%), similar to the conditions in Brazil (34.5%) [45], Chile (32.0%) [46], Nigeria (25.5%) [47], Finland (34.9%) [48], Australia (35.3%) [49], and the United Kingdom (37.1%) [50]. Therefore, interventions such as medication review, evidence-based therapeutic guidelines and computerized clinical decision support may be useful in not only reducing PIMs [51] but also PPO [52]. However, the impact of these interventions in reducing medication-related problems, hospitalization and improving quality of life in the elderly population remains unclear [52].
It is also worth mentioning that studies on medication adherence in Malaysia were mainly conducted among the general adult population [53][54][55]. Our meta-analysis indicated that more than half of the elderly in Malaysia were not adherent to their medications. In comparison, the nonadherence rates from studies conducted in the European countries and the United States ranged widely between 6.7% and 69.6% [56,57]. Although various behavioral and educational interventions have been investigated to improve medication adherence among the elderly, their effectiveness remains inconclusive [58]. Additionally, the effectiveness of technology-based interventions such as automated reminders on mobile phones in improving medication adherence among older adults has yet to be explored [59].
Falls among the elderly commonly lead to hip and head injuries which can sometimes be fatal [60]. Generally, the Western elderly population reported a comparatively higher [61] fall rate (35.5%) as compared with their Asian counterparts (14.7-34.0%) [62]. Based on our findings, the Malaysian elderly reported a slightly higher fall rate (39.3%) than that reported for the entire Asia. Both polypharmacy and the use of certain drugs are associated with increased risk of fall [62,63]; consistent with one of the local studies by Zia et al. [6]. Therefore, education on home safety, exercise interventions, and replacing fall-risk increasing drugs with alternatives may be suggested to reduce the rate effectively [64]. The effectiveness of these interventions should be further evaluated in the local elderly population.
The use of CAM among elderly seeking care from health facilities was higher than that reported among the community-dwelling older adults (72.5% vs. 43.0%). Increased use of CAM was significantly associated with polypharmacy [13], consistent with the findings among the elderly population in the United States [65]. Meanwhile, a systematic review of 22 studies in the United States and European countries consisting of 18,399 participants reported that the prevalence of the elderly population taking supplements along with prescription medicines was high (5.3−88.3%). To worsen the situation, only one-third of them disclosed their practice to their healthcare providers [66,67]. While drug-drug or drug-herb interactions remain a concern, effective communication and comprehensive history taking are important to ensure patient safety besides optimizing treatment outcome [67].
Meanwhile, several studies reported the safety and potential benefits of CAM use. In Italy, the use of CAM was prevalent among cancer patients, in which one out of every two people used CAM. Higher educational level was significantly associated with CAM use, but not older patients [68]. Remarkably, the use of CAM such as resveratrol and ascorbic acid in treating cancer and chronic diseases such as cardiovascular complications had become increasingly popular [69,70]. The safety of CAM was demonstrated as most of the CAM users (96.5%) did not experience any side effects caused by the CAM. Given the paucity of local studies on the safety and efficacy of CAM use among the elderly population, this research area should be further explored in the near future.
Based on our findings, drug-related problems were prevalent among the local elderly population. Prompt action should be taken to improve the appropriateness of medication use among the elderly population which can be enhanced through pharmaceutical and educational interventions [71]. Collaboration of a multidisciplinary team could improve medication adherence and appropriateness. Within this context, implementation of geriatric medication therapy adherence via clinical pharmacists' involvement in geriatric clinics may be beneficial in reducing DRP and optimizing treatment outcomes [72].
Our review had several limitations. To date, there is no standardized tool used to detect inappropriate medication and adherence among the elderly population. A standardized tool would be ideal for easing comparison in future reviews. A significant heterogeneity among the studies in the meta-analysis existed. Although the source of heterogeneity was not identified via the subgroup analyses or Galbraith plot examination, some outlier studies were detected. Nevertheless, based on the sensitivity analyses, the findings of this meta-analysis are deemed as both robust and reliable.
More studies are required to assess the effectiveness of incorporating different interventions, including introducing the medication adherence clinics to improve medication appropriateness and patients' health outcomes. The prevalence, potential risk and benefits of concurrent dietary supplement use with prescription medications warrant further research.

Materials and Methods
For this systematic review and meta-analysis, DRPs referred to the presence of any one of following events: polypharmacy, PIMs, PIP, nonadherence, PPOs, and drug-related falls. The findings were reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The study was registered with PROS-PERO (registration no. CRD42021223174) and the Malaysia National Medical Research Registry (NMRR-20-131-52835).

Search Strategies and Eligibility Criteria
Articles published in peer-reviewed journals before 24 August 2020 were searched using the following electronic databases: PubMed, Scopus, Web of Science, and Google Scholar with no language restriction placed. The search strategy is presented in Table S2. Cross-sectional, cohort or case-control studies assessing DRPs in Malaysians above 60 years of age were retained for further review. Letters to the editor, commentaries, case reports, case series, news reports, editorials, study protocols, clinical guidelines, monographs, and review articles were excluded from the study. Potential articles identified from the bibliographies of the included studies were also hand-searched. EndNote X8 software was used to remove the duplicates.

Identification and Selection of Studies
Three authors (C-T.C., J-Y.A. and M.A.I.) independently screened the titles and abstracts of the articles. Any discrepancies regarding the eligibility of a study were resolved by consensus among three of them.

Data Extraction and Risk of Bias Assessment
Two authors (C.-T.C. and J.-Y.A.) performed the data extraction independently. The following information was extracted into a Microsoft Excel spreadsheet from the eligible studies: first author's last name, year of publication, study design, the total number of participants, gender distribution, age, study tools used, outcome measures of DRPs, and the prevalence of DRPs.
A random-effects model was used to generate the pooled prevalence and its corresponding 95% confidence intervals (CIs) for DRPs among the elderly. Two authors (C.-T.C. and J.-Y.A.) independently assessed the quality of the included studies using the Joanna Briggs Institute critical appraisal checklist for studies reporting prevalence data [73]. The following nine criteria were used to assess the risk of bias of each selected study: sampling frame, sampling method, sample size, study subjects and setting description, coverage bias, validity of measurement tools, data collection procedures, statistical analysis, and response rate. The quality of each study reviewed was reported as "yes", "no", "unclear", or "not applicable". The studies which met ≥70% criteria were considered as having a low risk of bias (high-quality study), 50-60% as moderate risk of bias (moderate-quality study), and <50% as high risk of bias (low-quality study) [74]. Publication bias was assessed using a funnel plot, while the asymmetry of funnel plots was evaluated using the Egger's test.
We assessed the heterogeneity of the results by using the I 2 statistics (I 2 > 75% representing substantial heterogeneity). The significance of the heterogeneity test was assessed using the Cochran's Q test, in which a p-value of <0.05 implied significant heterogeneity. Subgroup analyses were also performed to determine the prevalence of DRPs in different settings and types (polypharmacy, PIMs and the use of CAM). We also conducted sensitivity analyses for any analysis consisting of more than five studies to examine the sources of heterogeneity as well as to confirm the robustness. The sensitivity analysis was performed by (i) excluding small studies (n < 100), (ii) excluding low-and moderate-quality studies and (iii) including only cross-sectional studies. Furthermore, the Galbraith plot was used to identify the source of heterogeneity. All analyses were performed by using metaprop codes in meta (version 4.15-1) and metafor (version 2.4-0) packages of R (version 3.6.3) in RStudio (version 1.3.1093).

Conclusions
The prevalence of polypharmacy and PIMs among the Malaysian elderly population was high. Specific measures and evidence-based guidelines to ensure safe medication use among the elderly population are warranted. Based on a small number of studies, it is suggestive that medication-related falls, medication nonadherence and CAM use among the elderly population was common among the elderly population, however, more studies are required in this respect to confirm the findings.  Table S1: Quality assessment of the included studies, Table S2

Data Availability Statement:
The data presented in this study are available in the main text and supplementary materials.

Conflicts of Interest:
The authors declare no conflict of interest.