Introduction

The improvement of a person’s health and wellbeing is one of pharmacotherapy’s primary objectives, and drugs are the most common healthcare intervention [1]. In normal care, a patient’s outcome may be compromised in relation to medication, and this is known as a drug-related problem (DRPs). DRP is defined by Pharmaceutical Care Network Europe (PCNE) as, “an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes” [2]. This definition is almost the same as the definition of the seminal paper, “Opportunities and Responsibilities in Pharmaceutical Care” [3]. Pharmaceutical care is delivered by pharmacists to rationalize the medications used by patient, a cornerstone activity in pharmaceutical care is services to address DRPs [4]. The centeredness associated with DRPs services dictate that services should be delivered with rapport and to engage patients in the decision making, goal setting, and monitoring for therapies [5]. Pharmaceutical care need has been conceptualized at the end of the last century, which has been reflected on the wide adoption of expanded role of the pharmacists [3,6].

On average, hypertensive and diabetic patients could suffer from 5–6 different DRPs in outpatient clinics in Jordan [7,8]. Many DRPs can be encountered, including: inappropriate drugs, unnecessary drugs affecting older patients, no indication for the drug, the drug dose being too high, and untreated indication in general practice [9,10].

With limited resources, pharmacoeconomic analysis is needed to estimate the financial implications of the healthcare interventions, whilst preserving the best outcomes. In addition, identification, valuation, and estimating the monetary effect associated with DRPs is important to shed light on the outcomes associated with DRPs, facilitate DRPs reduction services and emphasize the role of pharmacists [11]. More outcomes that can be associated with unaddressed DRPs are drug-related mortality and associated costs [12]. In other cases, potential DRPs may be present, whilst not currently causing problematic outcomes, However, these DRPs could affect a patient in the future if left unaddressed.

A number of studies that has been carried in Jordan assessing the cost of DRPs and these studies were focused on hospitalized patients and other focused groups of patients, i.e. asthma [13,14]. In Jordan, a number of challenges have been identified within the pharmacy sector, including the high incidence of DRPs in a community setting, low provision of services to address DRPs by community pharmacists, low consultation time from physicians and low dispensing time of pharmacies [15–17]. Based on these observations, it is important to have convincing evidence of the value that pharmacists provide to address DRPs. Thus, the aim of the present study was to analyze the amount of costs avoided by clinical pharmacists’ interventions to address drug-related problems.

Methods

The present study was a cross-sectional, prospective study that reviewed patients’ medicines for the presence of DRPs. Interventions proposed and cost avoided were the focus of the present study.

Results

The number of patients included in the study was 2747 patients. The most common types of interventions were linked to the following DRPs categories including miscellaneous (e,g., a need for additional or more frequent monitoring) (13935 interventions), inappropriate knowledge (6972interventions), and efficacy (3395intervention). A low number of interventions were proposed to address untreated condition (3 interventions). Table 1 Summarizes the relationship of a number of demographic variables with DRPs, that the present study focused on. Those aged less than 40 years old were more likely to have no DRPs, whereas age more than 40 years old was associated with DRPs (p<0.001). More females (approximately 60%) were recruited than males (40%). Approximately 80% of the study sample were married. Secondary education and further was associated with no DRPs, on the other hand, primary education and less were associated with DRPs. Most of the sample size were unemployed, despite this, the overwhelming majority of them (about 96%) were covered with health insurance.

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Table 1. Demographic characteristics of the study sample by DRPs present.

https://doi.org/10.1371/journal.pone.0302287.t001

It seems that the clinical pharmacists intervened extensively. The interventions were linked to the category of DRPs. For example, diagnostic-related interventions were utilized in 95.07% of the 13935-linked DRP, miscellaneous. Common DRPs identified included miscellaneous (n = 13935), inappropriate knowledge (n = 6972) and Inappropriate adherence (n = 4447). Common interventions utilized included patient related which was commonly (87.43%) utilized for the DRP unnecessary drug therapy, knowledge which was commonly (99.13%) linked to the DRP inappropriate knowledge and adherence which was commonly (87.81%) linked to the DRP inappropriate adherence. Full details are shown in Table 2.

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Table 2. Different types of interventions proposed for different categories for DRPs.

https://doi.org/10.1371/journal.pone.0302287.t002

Regarding the cost avoided from identified DRPs. The highest costs avoided and would be incurred if DRPs are not identified and addressed were related to the DRP category inappropriate knowledge which was JOD 431,385.5. Other categories of DRPs associated with high costs included inappropriate adherence (JOD 321,011.1) and miscellaneous DRPs JOD 292,189.1). The total cost avoided through the study period was JOD 292,189.1. In relation to the “cost saved” from the pharmacist intervention for the whole study period, efficacy-related DRPs were associated with highest cost saved (JOD 12,192.987), followed by unnecessary drug therapy (JOD 4,119.226), then safety-related DRPs (JOD 937.991). The total cost for saved for the whole study period by the clinical pharmacist intervention that included the sum of the three aforementioned costs saved was estimated to be JOD 17,250.204Full details regarding the costs avoided from identified DRPs are illustrated in Table 3.

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Table 3. Costs avoided and saved from identified DRPs.

https://doi.org/10.1371/journal.pone.0302287.t003

The results of the one-way sensitivity analysis are represented in Fig 1. The high level of number of DRPs for inappropriate knowledge was responsible for most of the highest avoidable costs associated with DRPs (JOD 1,634,412.62). Table 4 summarizes the independent predictors associated with having a DRP (including the odds ratios). The final predictors included increased age (>25 years old), number of medications prescribed (odds ratio = 1.105), prescribed gastrointestinal drugs (BNF category; odds ratio = 3.485), prescribed drugs for infection (BNF category; odds ratio = 3.326), and prescribed musculoskeletal drugs (BNF category; odds ratio = 1.368).

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Fig 1. One-way sensitivity analysis for the estimated costs avoided from pharmacist intervention to address DRPs represented via tornado diagram.

https://doi.org/10.1371/journal.pone.0302287.g001

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Table 4. Independent predictors associated with DRPs.

https://doi.org/10.1371/journal.pone.0302287.t004

Discussion

DRPs in Jordan are more likely to occur in an outpatient setting as opposed to a hospital setting due to the high rates of DRPs in the outpatient setting [15] and the limited provision of intervention to address DRPs by community pharmacists [16]. This emphasizes the necessity of research output informing the value and importance of pharmacist input to enhance the management of outpatient medications. Given the limited amount of healthcare resources available, justification based on pharmacoeconomic evidence is crucial. The present study attempted to identify and categorize the interventions to address DRPs and value the costs avoided by the interventions to address DRPs in a sample of patients attending outpatient clinics. Pharmacists intervened actively. The most common type of DRPs identified was miscellaneous category (n = 13935) and patient-related intervention was commonly (87.43%) utilized for the DRP unnecessary drug therapy. The estimated avoided costs for the attendees of study outpatient clinics per month would be JOD 1,418,720. Increased age, increased number of medications and prescribed gastrointestinal, infectious or musculoskeletal drug are predictors of DRPs.

The results highlight the benefits of pharmacist services to address DRPs in outpatient settings. Such benefits strengthen the societal need for services to address DRPs, a serious avoidable economic problem.

It seems that certain demographics were associated with DRPs, e.g., age, educational level, and occupation. Increased age, i.e., elderly, was associated with DRPs, as well as having secondary education and higher was associated with low DRPs. The results highlight those elders are more likely to have polypharmacy and age-related changes in pharmacokinetics and pharmacodynamics that increase the odds for DRPs. Geriatrics utilize many of the healthcare resources and the majority of elderly patients suffer from DRPs.[2] It is recommended to pay attention to this group of patients when designing DRPs services, particularly those with multimorbidity and polypharmacy. Whereas secondary and tertiary education was found less associated with DRPs and this is related to that this group expected to have higher health literacy compared with participants with primary education or illiterate. Indeed, it has been reported that education below high school was associated with hospitalization implicated by DRPs [26].

It seems that many interventions were proposed, that indicate that high number of DRPs present within the outpatient setting. The control of the use of medication particularly in administration moves to patients in an outpatient setting. Despite this, the high level of DRPs is not related to patient management of medications but is most probably a care issue from the healthcare professionals. Most problems identified are related to need for monitoring (part of miscellaneous DRPs) and inappropriate adherence and knowledge. The increased number of medications and complexity of healthcare make medication management by practitioners difficult. Thus, increased enhanced clinical pharmacy services is important in outpatient clinics, which to date is not provided, and as evident in the present study can help reduce the number of DRPs, particularly serious DRPs, with reduced cost to the healthcare system. Within the outpatient setting many interventions were provided by pharmacists [27–29], which provides evidence based on the importance of increased pharmacist input to address DRPs within this setting, particularly in developing countries. Medication therapy management services provided to patients in community pharmacies in the United States are considered a model that provides pharmaceutical care in routine service. This model has been scrutinized and optimized through cumulative experience with medication therapy management services [30,31].

Common DRPs identified by the clinical pharmacist review included need for monitoring (part of miscellaneous DRPs) and inappropriate adherence and knowledge. Such DRPs are considered a priority in outpatient settings and pharmacists and other healthcare professionals should remain vigilant to these DRPs. Published research has found many DRPs occur in different settings [32–34]. These include adverse drug events and medication errors,[35] as well as they, have a prevalence of 18% in outpatient settings [36]. Interventions provided by clinical pharmacists further document the need for further service to address DRPs in the outpatient setting routinely. This can be achieved via a collaborative approach with other healthcare professionals to address issues such as changing drugs, stopping drugs, starting new drugs… etc. Also, of benefit in this regard would be adopting the patient-centered approach in which the pharmacist can work directly with the patient to counsel, educate and increase the knowledge of the patient regarding his disease and medications and trying to consider the patient preferences within the therapeutic plan [37,38].

The DRPs and associated costs to the healthcare system are important in the resource-scarce healthcare system. Such data supported the case of the need for clinical pharmacy services in the outpatient setting. The cost per one month was JOD 1,418,720 which is not insignificant and highlights that many of the costs of care for patients can be related to untreated and unidentified DRPs. The development of clinical pharmacy services in the outpatient setting is highly needed. An estimation of the cost of drug-related morbidity and mortality in 2000 using the decision-making model was $177.4 billion, mostly due to hospital admission (70%) [12]. It is not known how much is spent on medications in the outpatient setting and in nursing facilities it was estimated that when there is a spent of $1 on medications an additional $1.33 are spent on DRPs from different healthcare resources [39]. Excess costs associated with DRPs are not identified easily through a literature review, it seems that an adverse drug event associated with an avoidable cost of $4685 as it is estimated to lead to increasing in-hospital stay [40]. These costs provide an indication of the effects of the DRPs, however, these figures are not ready for use in the Jordanian health system and are not considered recent statistics.

Independent predictors associated with DRPs on the multivariate analysis provided an insight into the group of patients that DRP-reduction services should focus on. Such targeting is an important initial step in the development of interventions to address DRPs. Increased age increased the odds of DRPs due to the fact that this group of patients is more likely to have polypharmacy. In addition, polypharmacy on its own is associated with DRPs. Polypharmacy was an important risk factor for DRPs in the multidisciplinary triangulation process [41]. A number of drug groups including gastrointestinal, infection, and musculoskeletal drugs were associated with DRPs on multivariate analysis. Possible reasons for the appearance of these medications as predictors can be related to the comorbidities they represent, the risk associated with these medications (considered high alert medications), and the self-use of these medications by the patients without consultation with a physician. Indeed, gastrointestinal medications were associated with important DRPs through a predictive model [42]. Pharmacists and other healthcare professionals should keep an eye on these predictors in order to develop a successful medication management service to address DRPs.

Despite that currently no centralized patient records present in Jordan, the technological integration in healthcare has received momentum, particularly with the implementation of centralized or interconnected healthcare administration system (Hakeem) which was launched in 2009, with enthusiastic hopes to be an e-health system of national health records [43]. Also, the electronic library of medicine (ELM) was another governmental initiative in Jordan that provide free access to many evidence-based resources and references, including medical books, scientific journals and other resources, that aim to incorporate evidence-based direct patient care, safeguarding best possible patient outcomes [44]. In the regulatory aspect, since 2012 it has been required for drug pricing to conduct an economic analysis and it is expected that pharmacoeconomic evidence to inform formulary addition [45]. The health care system in Jordan has witnessed unavoidable challenges, including the arrival of Syrian refugees, albeit some organization of medical care was provided by United Nations High Commissioner for Refugees (UNHCR), the capacity of the present healthcare system and the society was unable to meet their health needs and, as such, they were considered a burden on the healthcare sector [46].

The current study gave research proof of the pharmcoeconomic impact of clinical pharmacy services, which can stimulate the discussion on the significance of putting DRPs-reduction services in implementation. A reasonable sample size, a prospective, multicenter study, and the fact that few similar studies carried out in Jordan highlight the proof the present study is providing. The present study is limited, despite the data collection was done by trained pharmacists and accompanied by an implementation procedure, there is a chance of inter-rater variation, however it can indicate a component of effectiveness. It is worth mentioning that it was not possible to estimate the probability of harm and cost avoided in cases of no intervention provided, this might limit the generalizability of the study. Future research proposed could expand the availability of clinical pharmacy medication reviews to other settings such as community pharmacies and primary care clinics and redesign how the reviews are conducted, such as telemedicine and virtual clinics. Also, there is a need to determine whether patients and physician accept the pharmacists’ intervention and services and what targeting mechanism to be employed. Given that the legislative framework to facilitate medication review implementation in community pharmacy is under development, the results of the current study suggest to clinical practice that medication review provided to patients at risk of DRPs is conceivable and that such a service can be quickly implemented. The current study suggests to the scientific community that a variety of cost-avoiding measures and DRP-addressing interventions can aid in promoting the provision of services to address DRPs.

Conclusion

Clinical pharmacists were heavily involved in resolving DPRs. The most prevalent DRP intervention, was the need for additional diagnostic testing to address the miscellaneous-related DRP. The highest expenditures avoided and spent if DRPs were not detected and addressed were related to the DRP category in appropriate knowledge. The anticipated avoided cost for study outpatient clinic attendance was JOD 1,418,720 per month. DRPs’ high frequency and cost make a compelling justification for additional pharmacist services input by pharmacists in order to improve patient care. More efforts can be put forward to implement services to address DRPs from pharmacists, taking in consideration the full range of settings and innovative techniques, as well as making sure that a viable business model is formed that is accepted by other healthcare professionals and patients themselves.