Medication Review With Follow-up for End-stage Renal Disease: Drug-Related Problems and Negative Outcomes Associated With Medication. A Systematic Review

1. Introduction

Chronic kidney disease (CKD) has been recognized as a worldwide public health problem [1,2,3] that requires early detection and treatment to delay progression. When the disease progresses to a stage where kidney failure occurs, patients require renal replacement therapies, either by dialysis or by transplantation [1,2,4,5,6].

Regional differences in the prevalence of CKD have been documented around the world [7]. The global estimated prevalence of CKD is 13.4% (11.7%–15.1%), and the number of patients with end-stage renal disease (ESRD) needing renal replacement therapy is estimated to be between 4.902 and 7.083 million [1].

Chronic kidney disease is defined as abnormalities of kidney structure or function, present for more than 3 months, with health implications. It has five stages according to the glomerular filtration rate (GFR). The end stage of chronic renal insufficiency is characterized by severe irreversible kidney damage (as measured by the level of proteinuria and the reduction of the GFR to less than 15 ml/min/1.73 m2). These patients generally require hemodialysis (HD), peritoneal dialysis (PD), or kidney transplantation (KT) [5].

Chronic kidney failure and ESRD are medically complex, require multiple medications to treat their various comorbidities [8], and generate high costs for the healthcare system. Patients with these conditions are at risk of drug-related problems [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31] (DRPs) that may lead to increased morbidity, mortality, and costs [32].

A DRP is defined as an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes [33,34].

A negative outcome associated with medication (NOM) is a result affecting the health of the patient that is or may be associated with the use of medications [34,35]. They can affect ESRD patients [36,37,38].

A medication review with follow-up (MRF) is a service in which the pharmacist evaluates the patient’s pharmacotherapy and intervenes in collaboration with the general practitioner and the patient themselves to ensure that the therapeutic goals are being achieved [39]. It is a structured evaluation of patient medications to optimize medication use and improve health outcomes, detect DRPs, and recommend interventions [40].

There are systematic reviews that focus on DRPs in stages 1–5 of CKD, but do not focus on ESRD and MRF [2,41,42]. There is a lack of studies on NOMs in ESRD identified by MRF [30,38].

For all the reasons mentioned above, it seems essential to carry out a review of DRPs and NOMs identified by MRF in patients with ESRD.

Therefore, the objective of this article was to identify, evaluate, and summarize the findings of all relevant individual studies on DRPs and NOMs identified by MRF for patients with ESRD, making the available evidence more accessible to decision-makers.

2. Materials and Methods

2.1. Design and Procedure

A cross-sectional descriptive study and critical analysis of systematically retrieved works.

By reviewing the scientific literature, a systematic critical analysis of the relevant articles and grey literature was performed.

This systematic review was conducted based on “The PRISMA 2020 statement: an updated guideline for reporting systematic reviews”[43]. It is registered in the international prospective register of systematic reviews [PROSPERO: CRD42022324729] [44].

2.2. Source of Data Collection

All data were obtained by direct online consultation of the scientific literature in the following databases: MEDLINE (via PubMed), Web of Science, SCOPUS, Cochrane Library: The Cochrane Central Register and Control Trials (CENTRAL) and Literatura Latinoamericana y del Caribe (LILACS), Medicina en Español (MEDES), and the SciELO bibliographic database (collection of scientific journals).

Journals, reference lists of the studies included, and previous scoping reviews related to DPRs and NOMs were searched to find additional studies. Other grey literature search engines, such as TESEO or DART for doctoral theses, were also used. The systematic review was supplemented by a comprehensive search of Internet resources to identify grey literature on the subject, including websites specific to the research area, such as the Spanish Society of Nephrology, the Spanish Society of Hospital Pharmacy, the Spanish Society of Clinical and Community Pharmacy, and the Pharmaceutical Care Foundation (Spain).

2.3. Information Search

The thesaurus developed by the U.S. National Library of Medicine was referred to for the recovery of articles. No subject qualifiers (subheadings) were used, nor were tag applications necessary.

The search strategy was planned around three domains:

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Population: adults with ESRD aged 18 years or older.

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Intervention: medication review.

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Outcome: DRPs and NOMs.

For this, the search syntax was generated using the Boolean intersection of three equations: Equations (1)–(3).

Equation (1): “end-stage renal disease”

“kidney failure, chronic”[MeSH Terms] OR “kidney failure chronic”[Title/Abstract] OR “ESRD”[Title/Abstract] OR “end stage renal failure”[Title/Abstract] OR “end stage renal disease”[Title/Abstract] OR “chronic kidney failure”[Title/Abstract] OR “end-stage kidney disease”[Title/Abstract]

Equation (2): “medication review”

“medication review”[MeSH Terms] OR “medication review”[Title/Abstract] OR “medication reviews”[Title/Abstract] OR “review medication”[Title/Abstract] OR “reviews medication”[Title/Abstract]

Equation (3): “drug related problems and negative outcomes associated with medication”

“drug related problems”[Title/Abstract] OR “drug therapy problems”[Title/Abstract] OR “medicines related problems”[Title/Abstract] OR “medication therapy problems”[Title/Abstract] OR OR (“negative outcomes associated with medication”[Title/Abstract] OR “medication-related”[All Fields] AND “negative outcomes”[Title/Abstract]) OR “outcomes associated with medication”[Title/Abstract]

The following filters (limits) were used: “Humans”, “Adults (more than 18 years)”. These filters were subsequently adapted for the databases mentioned above.

The final search equation was developed to be used in the MEDLINE database, via PubMed. Subsequently, this strategy was adapted to the characteristics of each of the other databases consulted and was completed by examining the bibliographic references of the selected articles to reduce the number of articles unrecovered by the review.

The search was carried out from the first available database, according to the characteristics of each database, until 30 May 2023 (the time of the latest update).

Additionally, a search using a supplementary strategy was conducted to reduce the possibility of publication bias by searching the reference lists of relevant guidelines. Furthermore, experts in the domain were contacted by email to avoid missing relevant grey literature (materials and research produced by organizations outside the traditional commercial or academic publishing and distribution channels).

2.4. Study Selection

The final selection of papers was made according to the following inclusion criteria: observational studies, original articles published in peer-reviewed journals, and pertinent works with available complete text, which had to be written in English, Portuguese, or Spanish (Figure 1).

The following were the exclusion criteria:

1)

Articles written in a language other than English, Portuguese, or Spanish.

2)

Articles without an abstract.

3)

Articles that do not mention any MRF in patients with ESRD.

4)

Articles that do not mention DRPs or NOMs in patients with ESRD.

5)

Articles mentioning patients under 18 years of age.

6)

Articles without a methods section, review articles, or case reports.

A selection of references was performed first on the basis of title and abstract and then after full-text review. Articles were selected based on the availability of the complete text. Any articles that did not meet the inclusion criteria were excluded.

2.5. Data extraction

Two authors (A.P.C. and A.J.M.) assessed the suitability of the studies independently. For the selection process to be considered valid, it was established that the concordance between the two authors’ assessments (Kappa index) had to be higher than 0.60 (good or very good strength of concordance). Whenever this condition was met, any discrepancies were resolved by consulting the third author (M.A.C.H.), and subsequently by consensus among all the authors.

Double-entry tables were used to check the extracted data; this made it possible to detect errors and correct them by re-consulting the original documents.

2.6. Study Variables

Articles were collected according to study variables to systematize and facilitate comprehension of the results. The following data were considered:

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Author, year and country: first author of the article selected, year of publication of the article, and location where the study took place.

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Study design and duration: procedures, methods, and techniques through which the article was accepted for review. Duration of the study.

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Population studied: adults with ESRD (age, ethnicity, sex).

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Study aim: objective or aim of the study.

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DRPs: Total, type, and frequency of DRPs.

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NOMs: Total, type, and frequency of NOMs.

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Pharmacist interventions: Total and relevant findings of pharmacist interventions related to DRPs and NOMs.

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Types of medication most commonly associated with DRPs/NOMs.

2.7. Methodological Quality Assessment

The quality of the selected articles was assessed using the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) [45] checklist as a support. This contains 22 essential items that should be included in the reporting of observational studies.

A score of 1 or 0 was recorded for each item according to whether or not the article met that criterion. In the event that evaluation of a particular item was not necessary, no score was assigned for that item and it was recorded as not applicable (NA). When an item was composed of several points, these were evaluated independently, giving each the same weight, and the final result for that item was the average of these separate scores, so that in no case could the score exceed 1 point per item.

3. Results

With the search criteria described, 59 references were retrieved: 35 in the Web of Science (59.3%), 14 in Scopus (23.7%), and 10 in MEDLINE (19.9%). No references were retrieved from the Cochrane Library Literatura Latinoamericana y del Caribe (LILACS), Medicina en Español (MEDES), or the SciELO bibliographic database (collection of scientific journals).

Nine additional studies were identified from other sources (manual search and contribution by experts) [30,37,46,47,48,49,50,51,52].

After elimination of duplicates, application of the inclusion and exclusion criteria, consultation of the bibliographies of the selected articles, and consultation with experts (Figure 1), 16 documents with full text available were selected and retrieved [20,30,37,46,47,48,49,50,51,52,53,54,55,56,57,58]. One of them was a doctoral thesis [37] and was related to another selected study [30]. The characteristics of the studies are summarized in Table 1.

The concordance between the evaluators on the relevance of the articles was 100%.

3.1. Study Characteristics and Quality

The 16 studies identified were carried out in the U.S.A. (n = 6), Spain (n = 2), Singapore (n = 2), Indonesia (n = 2), and Saudi Arabia, Taiwan, New Zealand, and India, with 1 study each. Most of the articles reviewed were written in English, except 2 that were written in Spanish [30,37].

Of the papers reviewed, 12 were observational studies [46,47,48,49,50,51,52,53,55,56,57,58] (10 cross-sectional and 2 cohort [49,57]). In addition, 2 were clinical trials [20,54] (1 of which was controlled randomly selected [20]) and 2 had a quasi-experimental design [30,37]. The follow-up time ranged from 1 to 18 months.

The studies were carried out in various health care settings: hospitals [30,37,46,48,49,56], HD units [20,50,51,52,53,55,57,58] and KT units [47,54].

Articles included patients receiving kidney replacement therapy: from available data, 841 patients were treated with HD [20,30,37,46,48,49,50,51,52,53,55,56,57,58], 253 with KT [30,37,47,54] and 6 with PD [46].

The patients included in the studies were aged 49 to 66 years on average; 3 studies did not mention the age of the patients [47,48,50].

There were 12 studies that included both male and female patients; 2 did not mention the patients’ sex [47,50].

The studies included patients of a range of ethnicities, at various frequencies. However, 10 of the studies reviewed did not mention ethnicity [30,37,47,48,49,50,51,52,53,54].

3.2. Medication Review with Follow-up Method

With regard to the MRF method used, 14 studies followed a specific clinical methodology for MRF and 2 studies [30,37] followed the Dáder Method developed by the Pharmaceutical Care Research Group at the University of Granada [34].

3.3. Drug-Related Problems

From the data available, a total of 10250 DRPs were identified and classified in 15 of the studies [20,30,46,47,48,49,50,51,52,53,54,55,56,57,58]. The DRPs were of the following kinds: wrongly administered drug [30,56], inappropriate dose (underdose or overdose), dosage schedule, and/or duration [20,46,47,48,49,50,51,52,54,55,56,57], duplication [30,46,51,56], non-adherence [30,55,56,58], drug interactions [30,46,48,51,53,56,58], ADRs [20,30,46,47,48,49,52,54,56,57,58], health problem not adequately treated [20,47,48,51,54,55,56,58], and others [46,47,48,49,50,51,52,54,56,58].

With regard to the DRP classification system, 7 studies [20,46,47,51,54,55,58] used Strand et al. [59], 1 study [57] used Medi-Span (Wolters Kluwer), 1 study [30] used the Granada Third Consensus [34], and 2 studies [49,52] used the Pharmaceutical Care Network Europe classification system [33]. However, 4 studies did not mention the DRP classification system used [48,50,53,56].

Ten studies [20,30,46,47,51,52,54,55,57,58] mentioned the medication classes most commonly involved (cardiovascular medications, immunosuppressants, anemia and mineral bone disease medications).

Two of the papers reviewed [52,55] mentioned factors for multiple DRPs: ethnicity [55], length of time on dialysis [55], age [55], comorbidities [52], and number of medications prescribed [52].

3.4. Negative Outcomes Associated with Medication

Only 1 study related to cinacalcet (mineral bone disease medication) identified 9 NOMs [37,38] in 34 ESRD patients, according to the Granada Third Consensus [34], as follows:

The patient suffers a health problem associated with a non-quantitative safety problem of the medication (n = 5), the patient suffers a health problem associated with quantitative ineffectiveness of the medication (n = 2), the patient suffers a health problem associated with a quantitative safety problem of the medication (n = 1), and the patient suffers a health problem as a consequence of not receiving the medicine that they need (n = 1) or an untreated health problem.

3.5. Pharmacist’s Interventions

Eleven studies [30,37,47,49,50,51,52,53,54,56,58] mentioned pharmacist interventions related to resolved DRPs or NOMs highly accepted by the patient or the physician. From the available data, a total of 3153 interventions were made.

3.6. Quality

The scores achieved in the quality assessment of the selected articles using the STROBE questionnaire ranged between 11 and 22 (Table 2).

Five of the journals involved, in which 8 of the articles reviewed were published [20,46,47,50,53,54,57,58], are listed in the Journal Citation Report (JCR). Three, containing 3 of the articles reviewed [30,49,51], are listed in the Emerging Source Citation Index (ESCI) of the JCR. However, four journals, containing 4 of the articles reviewed [48,52,55,56], are not listed in the JCR or the ESCI. One of the studies is a doctoral thesis [37].

4. Discussion

This systematic review provides relevant findings on DRPs and NOMs in ESRD. From the information analyzed, it can be seen that DRPs are a real health issue affecting people with CKD in its different stages, especially those undergoing renal replacement therapy, as their polymedication and multi-pathology characteristics [2,37,42] increase as CKD evolves, leading to NOMs (manifest or potential).

Although NOMs are important in clinical practice, few studies have been published [37], opening up a field of research in this area that can support clinical practice, including patient-centered models.

The main DRPs identified in ESRD were wrongly administered drugs [30,56], inappropriate dose (underdose or overdose), dosage schedule, and/or duration [20,46,47,48,49,50,51,52,54,55,56,57], duplication [30,46,51,56], nonadherence [30,55,56,58], drug-drug interactions [30,46,48,51,53,56,58], probably due to ADRs [20,30,46,47,48,49,52,54,56,57,58], health problems insufficiently treated [20,47,48,51,54,55,56,58], and others [46,47,48,49,50,51,52,54,56,58].

In terms of NOMs in ESRD [37,38], the following stand out: untreated health problems, quantitative and non-quantitative ineffectiveness, and quantitative and non-quantitative safety.

Immunosuppressants, medications for mineral bone disorder, and antianemic preparations are associated with DRPs. Pharmacists made interventions to resolve or prevent these.

This review has certain possible limitations. The design of the cross-sectional and cohort studies reviewed [49,57] provides an evidence level and a recommendation grade of IIb and III, according to the U.S. Agency for Health Research and Quality. However, the topic of study must be considered as DRPs and NOMs, and consequently it must be assumed that it is probably not possible to aspire to a high design and recommendation grade [8,42].

Although systematic reviews must be based on observational studies and designs that guarantee stronger scientific evidence, in this analysis all the studies that focused on the subject topic were included.

The real limitations of this review are those of each study: for example, the number of medications per patient, study duration, and acceptance rate for pharmacist interventions in Alshamrani et al. [51], and the small sample size and lack of control group in the case of Mirkov [55]. In addition, the retrospective analysis of observational data and descriptive statistics by Daifi et al [58]. potentially involves residual confounding bias, and Chen’s study [56] also has several limitations (a single-site study with a small sample size).

The methodological quality of the studies available in this systematic review and the heterogeneity of the studies evaluated limit the possibility of meta-analysis.

In addition to providing an opportunity to describe the NOMs and DRPs most frequently found in this population, this systematic review may raise awareness among healthcare professionals to help them identify such problems in clinical practice. Negative outcomes associated with medication, as well as their causes or DRPs, can be detected and resolved through physician-pharmacist collaboration, with the aid of MRF.

In addition, this review encourages further study of the clinical, human, and economic impact of NOMs on ESRD in clinical practice, the collaboration of nephrologists and pharmacists, and the methodological quality of research.

5. Conclusion

In conclusion, DRPs and NOMs affect ESRD patients, mainly those receiving renal replacement therapy. More evidence is needed, especially for NOMs.