89urn:lsid:arphahub.com:pub:CCBBD2E1-BDAF-5702-AE4B-0E4910A4C7D6PharmaciaPHAR0428-02962603-557XBulgarian Pharmaceutical Scientific Society10.3897/pharmacia.73.e201120201120Research ArticleClinical pharmacologyPharmaceuticsPharmacological reviewsPharmacologyDetection of DRPs in geriatric patients with rare diseases: a systematic review and retrospective analysisParvanovaAleksinaaleksina.parvanova@gmail.comhttps://orcid.org/0000-0002-5304-992X1MilushewaPetyap.milusheva@pharmfac.mu-sofia.bghttps://orcid.org/0000-0002-6606-50481TachkovKonstantinhttps://orcid.org/0000-0002-3961-75561VandevaSilviahttps://orcid.org/0000-0003-3447-3028234ElenkovaAtanaskahttps://orcid.org/0000-0001-9821-4952234Department of Organization and Еconomics of Pharmacy, Faculty of Pharmacy, Medical University of Sofia, Sofia, BulgariaDepartment of Organization and Еconomics of Pharmacy, Faculty of Pharmacy, Medical University of SofiaSofiaBulgariahttps://ror.org/01n9zy652Department of Endocrinology, Faculty of Medicine, Medical University of Sofia, Sofia, BulgariaDepartment of Endocrinology, Faculty of Medicine, Medical University of SofiaSofiaBulgariahttps://ror.org/01n9zy652USHATE “Acad. Ivan Penchev”, Sofia, BulgariaUSHATE ''Acad. Ivan Penchev''SofiaBulgariaExpert Center for Rare Endocrine Diseases, Sofia, BulgariaExpert Center for Rare Endocrine DiseasesSofiaBulgaria
20262409202673e2011201F310FD2-FADC-5FA1-B8B5-4C2BF1AE817A2805202622082026Aleksina Parvanova, Petya Milushewa, Konstantin Tachkov, Silvia Vandeva, Atanaska ElenkovaThis is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Introduction: The development of medicine and the introduction of new therapeutic options are leading to increasing scientific attention to rare diseases (RDs) affecting older adults. This requires the application of a systematic approach to drug therapy, with a focus on the identification and management of drug-related problems (DRPs).
Objectives: To systematically review the evidence on DRPs in older adults with rare diseases and to evaluate DRPs in a real-world cohort of older patients with acromegaly.
Methods: A three-step approach was applied: (1) a systematic review of the literature on DRPs in geriatric patients with RDs; (2) a retrospective study of patients with acromegaly hospitalized at the Expert Center of Rare Endocrine Diseases, University Hospital for Active Treatment in Endocrinology (USHATE) “Acad. Ivan Penchev,” Sofia, Bulgaria, in 2021, with application of the STOPP/START criteria for the assessment of DRPs; and (3) an exploratory analysis of the odds of experiencing a DRP according to the presence of polypharmacy and multimorbidity.
Results: A total of six studies met the inclusion criteria in the systematic review. The most common DRPs were associated with therapeutic failure and adverse drug reactions (ADRs), which were inherently serious because they led to hospitalization or death. Based on the retrospective study, a total of 16 DRPs were identified among 42 geriatric patients with acromegaly. Ten potentially inappropriate medications and four cases of prescribing omissions were identified, and a review of the Summary of Product Characteristics revealed two additional DRPs. The variables polypharmacy (OR = 1.3043, p = 0.7701) and multimorbidity (OR = 3.9804, p = 0.3720) were not statistically significant factors for the development of DRPs in the study group.
Conclusion: The study identified clinically relevant DRPs and demonstrated the potential value of tools such as the STOPP/START criteria in evaluating therapy in geriatric patients. The results highlight that, despite the severity of DRPs, some of them can be identified and prevented through comprehensive pharmacotherapeutic analysis. This emphasizes the need for more in-depth research on risk factors and long-term follow-up by a clinical pharmacist to optimize pharmacotherapy.
Rare diseases (RDs) are life-threatening, chronic, and debilitating conditions with a very low prevalence and incidence, and according to European legislation, they affect fewer than 1 in 2,000 people (Regulation (EC) No 141/2000 2000). Many of them are genetically determined and manifest in early childhood, having a negative impact on both the duration and quality of life of patients (Nguengang Wakap et al. 2020). However, there are certain RDs, such as chronic myeloid leukemia and cystic fibrosis, for which a significant increase in average life expectancy (by more than 10 years) has been observed in recent decades (Bower et al. 2016). This breakthrough is mainly due to improved medical care, as well as the development and implementation of new therapeutic alternatives (Mazzucato et al. 2026). However, the aforementioned processes create a growing gap in the continuum of care for geriatric patients, which draws attention to the need for further research to address not only lifespan but also their health-related quality of life.
Acromegaly is a rare, chronic endocrine disease caused by supraphysiological secretion of growth hormone (GH) by a GH-producing pituitary tumor and, in isolated cases, by somatotroph hyperplasia resulting from ectopic growth hormone-releasing hormone (GHRH) secretion by a neuroendocrine tumor (Katznelson et al. 2014). Due to advances in diagnostic techniques, treatment, and long-term disease management, acromegaly is also among the diseases in which the number of patients reaching older age is increasing (Pavlikyanova et al. 2024). Despite improvements in medication access and reimbursement practices (Rusenova et al. 2022), several studies conducted in Bulgaria have indicated the clinical, economic, and quality-of-life burden of acromegaly, as well as challenges related to treatment adherence and long-term disease management (Kamusheva et al. 2020, 2021, 2023; Rusenova et al. 2022; Rusenova et al. 2022). Achieving biochemical control is crucial for the patient’s quality of life (Rusenova et al. 2022), while managing the high prevalence of comorbid conditions is also considered important for disease control and reducing health-related costs (Kamusheva et al. 2021).
Drug-related problems (DRPs) are defined as events or circumstances that are related to the effectiveness or safety of therapy and that may have a negative impact on therapeutic outcomes. According to the Pharmaceutical Care Network Europe (PCNE) Classification of DRPs (version 9.1), DRPs encompass a broad range of issues, such as adverse drug reactions (ADRs), suboptimal therapeutic response, overdose, inappropriate prescribing, dosing problems, and medication-related safety concerns (Pharmaceutical Care Network Europe Association 2020). Older adults with RDs might be vulnerable to DRPs because of delayed diagnosis, limited evidence from clinical trials, multimorbidity, polypharmacy, and the need for lifelong therapy. The accumulation of age-related changes, such as reduced physiological reserve and altered homeostasis, combined with complications from RDs, requires a timely and adequate response, as any delay in adjusting a patient’s therapy can lead to rapid deterioration of the clinical condition. Therefore, timely detection and resolution of DRPs are essential to optimize therapy and prevent complications. Clinical pharmacists play an important role in this process through structured medication review and individualized pharmacotherapeutic assessment (Ahmad et al. 2014; Sabbà et al. 2019). This role is also relevant in patients with acromegaly, whose long-term treatment and multiple comorbidities require monitoring as an essential component of improving therapeutic outcomes and preventing DRPs (Parvanova et al. 2020).
Although several validated tools, such as the STOPP/START criteria, Beers Criteria, STOPPFrail, and others, are specifically designed and available for identifying potentially inappropriate prescribing in geriatric patients, their applicability to patients with RDs remains largely unexplored (de Oliveira Alves et al. 2014; O’Mahony 2015; Lavan et al. 2017). Given the limited evidence in the field, the present study combines a systematic review of the literature with a real-world analysis of older patients with acromegaly. The review provides an overview of the available evidence on DRPs across RDs, whereas the clinical cohort offers disease-specific insight into the characteristics of DRPs in clinical practice. Acromegaly represents an appropriate model for studying DRPs in older adults with RDs because increasing life expectancy, lifelong pharmacotherapy, multiple comorbidities, and complex treatment regimens place these patients at particularly high risk of medication-related problems (Jallad and Bronstein 2019; Giustina et al. 2020). Moreover, in Bulgaria, patients with acromegaly are monitored at the designated national Expert Center for Rare Endocrine Diseases (National Center of Public Health and Analyses 2026), located in Sofia, the capital of Bulgaria. This centralized organization of care facilitates long-term follow-up, multidisciplinary management, and comprehensive documentation of pharmacotherapy, making this population particularly suitable for studying DRPs in routine clinical practice (Kamusheva et al. 2020).
Therefore, the aims of this study were (1) to systematically review the literature on DRPs among geriatric patients with RDs and (2) to characterize DRPs in a cohort of older patients with acromegaly to compare real-world findings with the available evidence in the field.
Materials and methodsSystematic review
A systematic review (SR) was conducted to identify and analyze the type, nature, and severity of DRPs reported among older patients with RDs. The review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Moher et al. 2009). A search was conducted in the PubMed and Google Scholar databases covering the period from February 2015 to February 2025. The search strategy combined Medical Subject Headings (MeSH) and free-text terms as follows: ((“Medication Review”[Mesh]) OR (((((drug-related problem) OR (medication errors)) OR (medication related problems)) OR (drug issues)) OR (drug-related problems))) AND ((“Rare Diseases”[Mesh]) OR (((rare disorder) OR (rare condition)) OR (rare syndrome))). The eligibility criteria were defined. Studies were included if they (1) were published in English or Bulgarian; (2) included patients aged ≥65 years diagnosed with a rare disease, condition, or disorder; and (3) reported at least one DRP. Studies were excluded if they were duplicate records, were published in languages other than Bulgarian or English, or if the full text was unavailable.
The Rayyan systematic review platform was used for study selection (Ouzzani et al. 2016). After duplicate removal, titles and abstracts were screened independently by two researchers. Potentially eligible studies underwent a full-text assessment according to the predefined criteria, and any disagreements between reviewers were resolved through discussion with a third reviewer. The study selection process was documented using a PRISMA flow diagram.
For each included study, the following data were extracted: first author, year of publication, study design and origin, number of participants, patient age, type of RD, reported DRP, causes of DRPs, interventions, clinical outcomes, and quality assessment. DRPs were identified and classified according to the PCNE classification for DRPs, version 9.1, taking into consideration the primary problem domain (treatment effectiveness, safety, or other) (Pharmaceutical Care Network Europe Association 2020). DRPs related to treatment safety were defined as any adverse event experienced by the patient, while DRPs related to treatment effectiveness were defined as those hindering the target therapeutic response. Reported causes of DRPs were also listed according to the corresponding PCNE cause domains when sufficient information was available. The clinical severity of the reported DRPs was analyzed separately from the PCNE classification, based on the reported clinical consequences (hospitalization, permanent disability, life-threatening events, and death) (Tharanon et al. 2022).
Observational retrospective study
An observational retrospective study was conducted among patients aged ≥65 years with acromegaly who were hospitalized at the University Hospital for Active Treatment in Endocrinology (USHATE) “Acad. Ivan Penchev.” In Bulgaria, this is the only national Expert Center for Rare Endocrine Diseases that serves as the main referral center for patients with acromegaly in the country, enabling standardized long-term follow-up and systematic collection of clinical data. The inclusion criteria were age ≥65 years, a diagnosis of acromegaly, and signed informed consent for participation. Patients with incomplete medical documentation or a lack of data on prescribed drug therapy were excluded. For the assessment of potentially inappropriate prescribing (PIP) and potential prescribing omissions (PPOs), the validated comprehensive STOPP/START tool, version 2, developed specifically for patients aged ≥65 years, was applied (O’Mahony 2015; Buda et al. 2020). The identification of DRPs was carried out independently by a clinical pharmacist and a physician, and a consensus was reached in cases of discrepancies. The STOPP (Screening Tool of Older Persons’ Prescriptions) criteria identify potentially inappropriate medications (PIMs) with a high risk of adverse effects or duplication of therapy. The START (Screening Tool to Alert to Right Treatment) criteria identify PPOs involving medications with proven benefit (statins for diabetes mellitus or anticoagulants for atrial fibrillation). The prescribed medicinal products were analyzed both upon admission to the hospital and upon discharge, using a descriptive approach with a quantitative summary of the observed cases. In addition to the STOPP/START analysis, an independent evaluation of the prescribed therapies was carried out by comparison with the Summary of Product Characteristics (SmPC). This strategy allowed for the identification of DRPs outside the scope of the STOPP/START criteria. The main outcome measures were the type and number of DRPs.
The study was approved by the hospital Ethics Committee, and informed consent was provided by each included patient.
Analysis of the odds of <abbrev xlink:title="Drug-related problem type">DRP</abbrev> occurrence
Polypharmacy (defined as the use of five or more medications) and multimorbidity (defined as the presence of two or more diseases) were examined as potential factors associated with the occurrence of DRPs (Skou et al. 2022; Varghese et al. 2024). Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated from 2 × 2 contingency tables. The Haldane–Anscombe correction was applied when a zero cell was present. A p-value < 0.05 was considered statistically significant. Due to the limited sample size, the analyses were considered exploratory. Statistical analyses were performed using MedCalc, version 16.4.1.
Quality of the included studies
All studies were assessed for risk of bias using the Joanna Briggs Institute (JBI) critical appraisal tools appropriate to each study design: the Textual Evidence/Opinion checklist for expert-opinion articles, the Case Series checklist for retrospective case series and survey-based studies, and the Case Report checklist for single-patient reports. Full appraisal results are reported in Suppl. material 1.
ResultsSystematic review of DRPs among patients with rare diseases
A total of 188 publications were identified in the primary PubMed database. After applying the inclusion and exclusion criteria, the final analysis included a total of six studies (Fig. 1).
Table 1 summarizes the data on the types of DRPs affecting the safety (n = 4) or effectiveness (n = 3) of therapy. Of the included studies, two were conducted in Italy, two in the United States, and the remaining two in Greece and China. Four of the publications were case reports or case series. Critical appraisal indicated overall acceptable methodological quality across the included studies; however, reporting of participant demographics and statistical methodology was frequently unclear, particularly among the retrospective and survey-based studies (Suppl. material 1). Due to heterogeneity in reporting, the total number of geriatric patients and the distribution by sex remain unknown. According to the Orphanet classification, the majority of diagnoses belonged to oncological diseases (neoplasms) (n = 3), infectious diseases (n = 1), diseases of the immune system (n = 1), diseases of the nervous system (n = 1), and diseases of the renal system (n = 1) (some of the patients had more than one rare disease). The medicines bortezomib, lenalidomide, dabrafenib, trametinib, rituximab, and colchicine are orphan medicines, and the remaining medicinal products were prescribed for comorbidities.
DRPs identified in the course of the systematic review.
Toxicity: bortezomib, lenalidomide; neuropathy: thalidomide, bortezomib; carfilzomib—caution in adults
Included
(Saunders et al. 2019), USA
Retrospective study (case series)
n = 9 (<65); n = 1 (>65)
77 years
Erdheim-Chester disease
DS
Toxicity and ADR: congestive heart failure after dabrafenib + trametinib
Included
(Cheng et al. 2024), China
Clinical case
1
65 years
Chronic inflammatory demyelinating polyneuropathy (CIDP) with pulmonary nocardiosis
DE
Glucocorticoid therapy in combination with mycophenolate mofetil (MMF); the patient died despite the prescribed antibiotic therapy
Included
(Fenoglio et al. 2021), Italy
Retrospective study (case series)
n = 2 (<65); n = 1 (>65)
66 years
Goodpasture’s syndrome (patient already diagnosed with adenocarcinoma)
DE
Despite initiating therapy with apheresis and immunomodulators with rituximab, as well as corticosteroids, anti-GBM antibody levels rose again after 1 week
Included
(Cortes et al. 2016), USA
Retrospective study of data from 2 current, open-label, international surveys
n = 818; n >65 = N/A
>65
Philadelphia chromosome-positive leukemia
DS
Age over 65 years and a history of diabetes are factors associated with the occurrence of vascular/cardiac events when taking tyrosine kinase inhibitors
Included
(Talerico et al. 2020), Italy
Clinical case
1
65 years
Familial Mediterranean fever
DS and DE
Mesothelioma of the peritoneum due to lack of therapy in a patient with colchicine intolerance
Included
ADR: Adverse drug reaction; DS: Drug safety; DE: Drug effectiveness; MA: Mean age; N/R: Not reported; SR: Systematic review; DRP type: Drug-related problem type; 1Full critical appraisal is available in Suppl. material 1. 2Gavriatopoulou et al. and Cortes et al. report no age data for their study populations but were retained because the study population is inherently restricted to an elderly-predominant cohort based on disease epidemiology.
According to the PCNE classification, the included studies reported safety-related DRPs (ADRs, n = 4) and treatment effectiveness-related DRPs (n = 3), with one study reporting both types. Most of the reported DRPs resulted in serious clinical outcomes, including hospitalization, disability, or severe adverse events (Cortes et al. 2016; Gavriatopoulou et al. 2018; Talerico et al. 2020). None of the studies reported the use of a standardized method for DRP identification or classification.
Safety-related DRPs were often a result of improper dosage of the medicinal product. Dose reduction or treatment modification was described as a key intervention in frail patients with plasma cell dyscrasias to minimize the risk of ADRs such as neutropenia, anemia, infections, and thrombocytopenia (Gavriatopoulou et al. 2018). In Erdheim-Chester disease, drug-induced congestive heart failure required discontinuation of trametinib (MEK inhibitor) and a reduction in the dose of dabrafenib (BRAF kinase inhibitor), as a result of which partial remission was achieved (Saunders et al. 2019). Older age and a history of diabetes were indicated as factors associated with the occurrence of cardiovascular events in patients with Philadelphia chromosome-positive chronic myeloid leukemia receiving tyrosine kinase inhibitors. Coronary artery disease, acute myocardial infarction, and congestive heart failure were among the most common serious adverse events that occurred in patients prescribed bosutinib or imatinib. DRPs in both clinical trials were most often managed with concomitant therapy, dose reduction, and, less commonly, discontinuation of therapy (Cortes et al. 2016).
Effectiveness-related DRPs were often linked to the complex clinical condition of the patients. In a patient with chronic inflammatory demyelinating polyneuropathy, DRPs associated with non-adherence to therapy (patient-related drug problem) were registered, as well as late diagnosis of the infection (pulmonary nocardiosis secondary to immunosuppressive therapy), non-compliance with monthly visits, and non-compliance with preventive therapy with sulfamethoxazole/trimethoprim. The patient’s refusal to receive intravenous immunoglobulin further complicated the condition, and the patient subsequently died despite the prescribed antibiotic therapy (Cheng et al. 2024).
In the clinical case of a patient with Goodpasture syndrome, no restoration of renal function was achieved despite the prescribed therapy, and emphasis was placed on the importance of performing a biopsy, as well as on the specific knowledge of medical professionals about the biology of oncological diseases and the corresponding therapy (Fenoglio et al. 2021).
In a 65-year-old patient with familial Mediterranean fever hospitalized due to progressive abdominal enlargement, both DE- and DS-related problems were identified (Talerico et al. 2020). Initially, the patient proved to be a colchicine non-responder, and subsequently, due to issues with canakinumab availability in the region, anakinra was administered, which further worsened the patient’s condition. The authors suggested that, in cases of colchicine intolerance, interleukin (IL)-1 inhibition should be initiated to alleviate the abdominal inflammation.
The reviewed studies indicate that DRPs in older adults with rare diseases are frequently associated with severe clinical consequences and often require treatment modification, dose adjustment, or discontinuation of therapy. Fatal outcomes were reported in patients with CIDP and in some patients with chronic myeloid leukemia despite the prescribed treatment (Cortes et al. 2016; Cheng et al. 2024).
Analysis of DRPs among patients with acromegaly in Bulgaria
Of the 180 hospitalized patients with acromegaly, 42 (23.3%) met the inclusion criterion of geriatric age (≥65 years) and were included in the retrospective analysis (Table 2). The majority of patients were women (n = 30, 71%), and the average age at diagnosis was 52 years (SD = 11.46). Somatostatin analog monotherapy was the most frequently prescribed therapy for acromegaly (n = 30). Polypharmacy and multimorbidity affected 83% and 95% of the study population, respectively (Table 3). A total of 14 DRPs were identified using the STOPP/START tool in 14 of the patients (33%) (Tables 2, 3).
Demographic characteristics of patients with acromegaly (≥65 years at hospital admission).
Number of DRPs identified using STOPP/START criteria
14
Number of DRPs based on the SmPC
2
Polypharmacy
35 (83%)
Multimorbidity
40 (95%)
*Some patients have more than one DRP. DRP: Drug-related problem; SmPC: Summary of Product Characteristics.
A total of 10 PIMs were identified, mainly affecting the endocrine, cardiovascular, and central nervous systems: use of extended-acting sulfonylureas (n = 5); prescription of centrally acting antihypertensive agents (n = 1); long-term use of benzodiazepines (n = 2); concomitant use of two or more drugs with antimuscarinic/anticholinergic effects (n = 1); and duplicate therapy with nootropics (vinpocetine/piracetam) (n = 1). The analysis of the START criteria revealed four cases of PPOs affecting key aspects of the therapy of comorbidities: lack of proton pump inhibitors (PPIs) in patients with severe gastropathy (n = 2) and deficiencies in the prescription of beta-blockers for coronary heart disease (CHD) and alpha-blockers for symptomatic prostatic hyperplasia (n = 2). By comparison with the SmPC, two additional DRPs were identified related to the prescription of medicinal products in cases of contraindications or outside the approved indications in elderly patients. Torasemide was prescribed to a patient with gout, which is stated as a contraindication in the SmPC due to a lack of clinical data. Another DRP was the concomitant use of empagliflozin with diuretics and ACE inhibitors due to the increased risk of hypovolemia. These cases do not fall within the scope of the standard STOPP/START criteria but highlight the clinical relevance of individualized structured medication reviews.
Two independent variables (polypharmacy and multimorbidity) were analyzed to assess their potential association with the occurrence of DRPs (Table 4). Polypharmacy was present in 12 of 14 patients with DRPs and in 23 of the 28 patients without DRPs. The estimated odds ratio (OR = 1.3043; 95% CI: 0.22–7.75; p = 0.77) suggests that patients with polypharmacy have 1.3-fold higher odds of a DRP. However, this association was not statistically significant (p > 0.05). The high prevalence of polypharmacy in both groups (83% overall) might explain the lack of a differentiating effect. Multimorbidity was present in all 14 patients with DRPs, while three patients in the group without DRPs did not have multimorbidity.
Distribution of patients according to multimorbidity and number of prescribed drugs.
Factor
DRP (+) n = 14
DRP (-) n = 28
Odds ratio (95% CI)
p-value
Polypharmacy
12
23
1.3043 (0.2195–7.7517)
0.7701
Without polypharmacy
2
5
Multimorbidity
14
25
3.9804 (0.1918–82.5938)
0.3720
No multimorbidity
0
3
Although the estimated OR for multimorbidity (OR = 3.98) suggests a potentially stronger association with DRPs than polypharmacy, the association was not statistically significant (95% CI: 0.1918–82.5938; p = 0.37). The extremely wide confidence interval and high p-value are direct outcomes of the limited sample size and data distribution, which do not allow statistical conclusions to be drawn about the influence of multimorbidity on the occurrence of DRPs in the studied patients with acromegaly. Therefore, these analyses should be considered exploratory and hypothesis-generating.
Discussion
The systematic review demonstrated a lack of evidence regarding DRPs in geriatric patients with rare diseases. None of the included studies applied a standardized approach for DRP identification and classification according to the PCNE classification, and no validated DRP tools were reported. The reported DRPs were highly disease-specific and related to complex treatment regimens, making their identification using the STOPP/START criteria difficult. These findings highlight the need for disease-specific pharmacotherapeutic recommendations and structured medication review in patients with rare diseases. The findings of the present systematic review indicate that DRPs in patients with RDs represent a substantial clinical challenge, frequently associated with serious outcomes—hospitalization, disease exacerbation, the need for surgical intervention, and, in some cases, mortality. The literature indicates that DRPs arise not only from suboptimal pharmacotherapy but also from delayed diagnosis, delayed recognition of disease progression, and insufficient documentation of clinical symptoms. Collectively, these findings illustrate the complexity of managing RDs and highlight the need for a systematic and multidisciplinary approach to patient care. Despite these findings, the current review did not reveal sufficient evidence regarding the long-term consequences of DRPs or the availability of effective interventions to prevent or resolve them. Additionally, the limited number of patients enrolled in the studies and the absence of a sufficient number of studies focused exclusively on adult patients with RDs also represent limitations.
The second part of the study extends the findings of the SR by demonstrating how structured pharmacotherapeutic assessment can be applied in clinical practice. Using the validated STOPP/START criteria, PIMs and PPOs were identified in 33% of older patients with acromegaly. These findings support the value of structured medication review for detecting potentially preventable DRPs, even in a rare endocrine disease characterized by a high burden of comorbidities. While the systematic review outlines the severe and potentially fatal consequences of unrecognized or inadequately managed DRPs, the retrospective cohort study suggests that some of these problems may be proactively identified and potentially prevented through targeted medication review. Poor adherence is a well-recognized contributor to DRPs in patients with acromegaly, and the lack of disease-specific guidelines further complicates the optimization of therapy (Kamusheva et al. 2021, 2023).
Comparison with international data suggests that the prevalence of potentially inappropriate prescribing observed in the present study was lower than that reported for other chronic diseases. According to systematic reviews, the prevalence of PIMs according to the STOPP criteria ranged between 67.8% and 87.7%, and that of PPOs according to the START criteria ranged between 39.5% and 99.7% (Delgado Silveira et al. 2009). A study in Romania reported 25.8% PIMs and 41.7% PPOs (Buda et al. 2020). The relatively lower prevalence observed in the present study may reflect the specific characteristics of patients with acromegaly and their regular follow-up in a tertiary center with proven expertise in acromegaly management. The identified PIMs should always be interpreted within their clinical context. Sulfonylureas, centrally acting antihypertensive agents, and long-term use of benzodiazepines may compromise cognitive awareness and cause orthostatic hypotension in older adults (Buda et al. 2020). However, these medications may remain clinically appropriate in selected patients when the expected benefits outweigh the potential risks and close clinical monitoring is ensured. Similarly, combinations such as torasemide in patients with gout or empagliflozin combined with a diuretic and an ACE inhibitor should be justified in the presence of multiple comorbidities.
Within the context of Bulgarian clinical practice, the STOPP/START criteria have previously been applied primarily in geriatric populations, particularly among patients with cardiovascular diseases, where a PIM prevalence of approximately 15% has been reported (Krustev et al. 2022). Although focused on a different patient group, the present study supports the clinical validity of the STOPP/START criteria and suggests their applicability within the Bulgarian healthcare system. Notably, based on current knowledge, no prior studies have investigated DRPs in patients with acromegaly using this methodological approach. Therefore, the present study can be considered an initial contribution to this area of research. However, certain systemic barriers remain. In patients with acromegaly, limitations related to reimbursement policies and restricted access to alternative therapies may impede treatment optimization. For example, patients with adequate metabolic control treated with metformin and sulfonylureas might be unable to transition to newer therapeutic options due to restrictive reimbursement criteria.
The relatively small sample size should be interpreted in the context of both the rarity of the disease and the organization of patient care in Bulgaria. Acromegaly is a rare endocrine disorder, and consequently, the number of eligible geriatric patients is inherently limited. Furthermore, the present study included all patients aged ≥65 years who were followed during the study period at the national Expert Center for Rare Endocrine Diseases, which serves as the national referral center for patients with pituitary disorders in Bulgaria. Therefore, the study cohort represents the entire eligible population managed at this specialized center rather than a selected sample. In addition, previously published nationwide data (Kamusheva et al. 2020) have shown that the majority of Bulgarian patients with acromegaly are younger than 60 years of age, while patients aged ≥65 years constitute only a small proportion of the overall acromegaly population. Consequently, the limited sample size reflects the epidemiology of the disease and the age distribution of the Bulgarian acromegaly population rather than limitations in patient recruitment.
Although polypharmacy and multimorbidity are recognized as risk factors for DRPs, the exploratory OR analyses performed in the current study did not demonstrate statistically significant associations between polypharmacy or multimorbidity and the occurrence of DRPs. These findings should be interpreted with caution due to the limited sample size, which reduced the statistical power of the analysis, as reflected by the wide confidence intervals around the estimated odds ratios.
Strengths and limitations of the study
A key strength of this study lies in the use of validated pharmacotherapeutic assessment tools, combined with a focus on geriatric patients with a rare disease. In addition, the integration of a systematic review with original real-world clinical data provides a more comprehensive perspective on DRPs and their relevance in the context of rare diseases.
Several limitations should also be acknowledged. The small number of studies and patients identified in the systematic review, along with the retrospective design of the original analysis, restrict the robustness of the findings. Furthermore, incomplete data regarding the use of all medications, including over-the-counter products and dietary supplements, may have led to an underestimation of DRPs. These factors limit both the identification of statistically significant predictors and the generalizability of the results. Most of the studies did not focus solely on the geriatric population, which does not allow for a definitive description of DRPs specific to older adults.
Future research guidelines
Larger, prospective studies focused on adults and geriatric patients with rare diseases are needed to allow for a more in-depth analysis of the role of polypharmacy, multimorbidity, and other potential risk factors for DRPs. Furthermore, the integration of structured pharmacotherapeutic assessment tools into routine clinical practice, alongside the development of disease-specific recommendations for patients with rare diseases, may contribute to reducing both the incidence and severity of DRPs over the long term.
Conclusion
In conclusion, although the available evidence is limited, DRPs appear to represent a clinically relevant issue in geriatric patients with RDs. The systematic review highlights important gaps in the reporting and characterization of DRPs and demonstrates the limited evidence available regarding their occurrence and management in older adults with rare diseases. The application of the STOPP/START criteria in patients with acromegaly suggests that structured pharmacotherapeutic assessment may help identify potentially inappropriate medications and prescribing omissions, even in complex and understudied populations. Taken together, these findings underline the need for greater attention to medication safety in RDs. Further large-scale, prospective studies are needed to better characterize DRPs, evaluate their clinical significance, and determine the role of structured medication review in optimizing pharmacotherapy and care in patients with rare diseases.
Acknowledgments
The authors would like to thank Maria Kamusheva for her contribution to this article.
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The authors have declared that no competing interests exist.
Ethical statements
The authors declared that no clinical trials were used in the present study.
The authors declared that no experiments on humans or human tissues were performed for the present study.
Informed consent from the humans, donors or donors’ representatives: Ethics Committee of USHATE “Acad. Ivan Penchev, Sofia
The authors declared that no experiments on animals were performed for the present study.
The authors declared that no commercially available immortalised human and animal cell lines were used in the present study.
Artificial Intelligence (AI) use
The authors accept full responsibility for the content of the manuscript, including the disclosure of any use of AI.
No AI tools were used in the preparation of this manuscript.
Funding
No funding was reported.
Author contributions
Petya Milusheva and Aleksina Parvanova conducted the literature search and data analysis. Data for the Bulgarian patients with acromegaly was collected by Silvia Vandeva and Atanaska Elenkova. The initial draft of the manuscript was written by Aleksina Parvanova and Konstantin Tashkov. All authors have carefully revealed and given their approval to the final version of the manuscript.
Author ORCIDs
A. Parvanova https://orcid.org/0000-0002-5304-992X
P. Milushewa https://orcid.org/0000-0002-6606-5048
K. Tachkov https://orcid.org/0000-0002-3961-7556
S. Vandeva https://orcid.org/0000-0003-3447-3028
A. Elenkova https://orcid.org/0000-0001-9821-4952
Data availability
All of the data that support the findings of this study are available in the main text or Supplementary Information.
Critical appraisal of included studies using the JBI critical appraisal tools for textual evidence and opinion, case series, case reports, and cohort studies
docx
https://binary.pensoft.net/file/1789278This dataset is made available under the Open Database License (http://opendatacommons.org/licenses/odbl/1.0). The Open Database License (ODbL) is a license agreement intended to allow users to freely share, modify, and use this Dataset while maintaining this same freedom for others, provided that the original source and author(s) are credited. Alexina Parvanova, Petya Milushewa, Konstantin Tachkov, Silvia Vandeva, Atanaska Elenkova