Abstract
Background
To reduce prescribing cascades occurring in clinical practice, healthcare providers require information on the prescribing cascades they can recognize and prevent.
Objective
This systematic review aims to provide an overview of prescribing cascades, including dose-dependency information and recommendations that healthcare providers can use to prevent or reverse them.
Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed. Relevant literature was identified through searches in OVID MEDLINE, OVID Embase, OVID CINAHL, and Cochrane. Additionally, Web of Science and Scopus were consulted to analyze reference lists and citations. Publications in English were included if they analyzed the occurrence of prescribing cascades. Prescribing cascades were included if at least one study demonstrated a significant association and were excluded when the adverse drug reaction could not be confirmed in the Summary of Product Characteristics. Two reviewers independently extracted and grouped similar prescribing cascades. Descriptive summaries were provided regarding dose-dependency analyses and recommendations to prevent or reverse these prescribing cascades.
Results
A total of 95 publications were included, resulting in 115 prescribing cascades with confirmed adverse drug reactions for which at least one significant association was found. For 52 of these prescribing cascades, information regarding dose dependency or recommendations to prevent or reverse prescribing cascades was found. Dose dependency was analyzed and confirmed for 12 prescribing cascades. For example, antipsychotics that may cause extrapyramidal syndrome followed by anti-parkinson drugs. Recommendations focused on dosage lowering, discontinuing medication, and medication switching. Explicit recommendations regarding alternative options were given for three prescribing cascades. One example was switching to ondansetron or granisetron when extrapyramidal syndrome is experienced using metoclopramide.
Conclusions
In total, 115 prescribing cascades were identified and an overview of 52 of them was generated for which recommendations to prevent or reverse them were provided. Nonetheless, information regarding alternative options for managing prescribing cascades was scarce.
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Avoid common mistakes on your manuscript.
We identified 115 distinct potential prescribing cascades for which at least one study demonstrated a significant positive association. |
For 52 prescribing cascades, recommendations for preventing and reversing prescribing cascades were provided or could be derived from a dose-dependency analysis. |
Dosage lowering was often recommended without confirmation of a dose-dependent relationship and switching or discontinuation of medication was often recommended without specifying an alternative option. |
1 Introduction
A prescribing cascade occurs when medication causes an adverse drug reaction (ADR), which is subsequently addressed by prescribing additional medications [1, 2]. This is often due to a misinterpretation of the ADR as a new medical condition or symptom [1, 2]. Prescribing cascades may lead to unnecessary medication therapies, decreased quality of life, and increased healthcare costs [3,4,5]. They can occur in any patient using one or more medications but are more likely in patients taking multiple medications [3].
Prescribing cascades can be prevented by timely recognition of the ADR or reversed by either lowering the dose, discontinuing the medication causing the ADR, or switching to (pharmacotherapeutic) alternatives [3]. To facilitate this, healthcare providers (HCPs) need to have information about prescribing cascades related to recognizable ADRs that can occur in practice. In addition, HCPs need information on how to reverse ADRs and thereby the prescribing cascade.
Many prescribing cascades have been described in the literature and several reviews have been published [3, 6,7,8]. One of the reviews was limited by including only prescribing cascades that were identified through a prescription sequence symmetry analysis [7], whereas another review identified prescribing cascades occurring with pain medication [6]. A review published in 2022 aimed to identify all published prescribing cascades in community-dwelling adults, including hypothesis-free studies employing data-mining techniques and studies with negative associations or inverse causality [8]. This review identified 78 publications, resulting in an overview of 25 commonly identified prescribing cascades. However, by including hypothesis-free studies and studies with negative associations or inverse causality, the evidence of the related ADRs can be limited. This reduces the evidence of an overview for assisting HCPs in preventing prescribing cascades. In addition, information on how to prevent or reverse specific prescribing cascades has not been summarized.
Our aim is to conduct a systematic review and provide an overview of prescribing cascades including dose-dependency information and recommendations that HCPs can use to prevent or reverse prescribing cascades. Therefore, our focus is on prescribing cascades related to confirmed ADRs (i.e., prescribing cascades showing a significant positive association in at least one study and confirmed ADRs in the Summary of Product Characteristics (SmPC) of the involved medication) occurring in clinical practice that are recognizable for HCPs.
2 Methods
In this systematic review, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement has been followed (Table 1 of the Electronic Supplementary Material [ESM]) [9] and the protocol was published in Prospero (CRD42021253004) [10].
2.1 Search Strategy and Data Sources
Based on a previous scoping review [3], an initial literature search was developed (OA, SPV, FKC, AM,) and performed in PubMed to identify relevant publications. The initial search revealed that many (older) publications did not use the term ‘prescribing cascade’. Therefore, the indexed keywords and text terms were extracted from the publications identified in the initial search. This was done using PubReMiner [11] and OVID Embase [12] to create an extensive search strategy to identify as many publications as possible that described prescribing cascades. No restriction was made regarding the study design. This extensive search strategy included: (1) publications that mention the term ‘prescribing cascade’; (2) publications that mention terms referring to ADRs or side effects and use a sequence symmetry analysis to quantify the occurrence of a prescribing cascade; and (3) reports or case-control studies of an ADR or side effect treated with medication. This extensive search strategy was checked for the inclusion of relevant publications from the initial search, reviewed by two information specialists and adjusted accordingly. The final search strategy can be found in Table 2 of the ESM, and was performed in OVID MEDLINE, OVID Embase, OVID CINAHL, The Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials from inception until 2 September, 2021.
We conducted backward citation [13], checking on all publications describing a prescribing cascade, including (systematic) reviews, case reports, and case series. An additional forward citation [13] analysis was performed in Web of Science (core collection) and Scopus in January 2022 for these publications. This approach was adopted to maximize the identification of prescribing cascades.
2.2 Inclusion and Exclusion of Publications
Publications in English and reporting a statistical analysis (e.g., prescription sequence symmetry analysis, regression) to identify or confirm prescribing cascades in adults (aged ≥ 18 years) were included. Case reports and case series as well as (systematic) reviews were excluded at this point. Furthermore, we excluded publications with hypothesis-free or discovery-driven analyses. For example, pharmacovigilance studies using data-mining techniques to detect unconfirmed potential ADRs.
First, titles and abstracts were reviewed for eligibility by reviewers individually, divided over five reviewers (AM, OA, MY, FKC, and JH). Second, full texts were independently screened by two reviewers (OA, AM) according to the inclusion and exclusion criteria. Any disagreements between the reviewers were resolved by consensus, if needed with the support of a senior reviewer (FKC).
2.3 Inclusion and Exclusion of Prescribing Cascades
A prescribing cascade was defined as the description of a first medication (index medication), an ADR that could be confirmed in the SmPC [14] of the index medication, and the initiation of a second medication that could ‘treat’ the ADR (marker medication), for which an association between index and marker medication was confirmed in at least one study. Prescribing cascades used as positive controls were included.
A prescribing cascade was excluded if the treatment with the marker medication was intentional. Intentional treatment was either as stated in the publication itself or derived from guidelines (e.g., prescribing a laxative to prevent ADRs when prescribing opioids) [15]. Prescribing cascades were also excluded if a medical device or a medical product (e.g., urinary incontinence products) [16] was used to treat the ADR. In addition, prescribing cascades were excluded if the index medication was described at an unspecific level. For example, the highest level of the World Health Organization Anatomical Therapeutic Chemical (ATC) classification for medication (e.g., Cardiovascular system; ATC code C) [17]. Finally, prescribing cascades were excluded if the medication could not be found in the European Medicines Agency [18] or US Food and Drug Administration [19] websites between July and November 2022, indicating the medication was no longer available.
2.4 Data Extraction
A data extraction form in MS Excel 2016 (Microsoft Corporation, Redmond, WA, USA) was used. The senior reviewers (FKC, JH, PD, PvdB, LM) checked the data extracted from 45 publications to refine the data extraction form. Extracted data included information about study characteristics, the identified prescribing cascade, the patient population, and the method of statistical analysis (Table 3 of the ESM). Results of the main statistical analysis regarding the prescribing cascade were extracted as showing: (1) a positive significant association; (2) a non-significant association; or (3) an inverse significant association. Additionally, analyses on dose dependency regarding the occurrence of prescribing cascades along with the corresponding results were extracted. Finally, information and recommendations on how to prevent or reverse the prescribing cascades as provided by the authors were extracted and classified as a dose reduction, a medication switch, or a discontinuation of the index medication (including the recommended alternatives). Data were extracted by one of three reviewers and checked by one of the other reviewers (OA, AM, or RV). Disagreements between the reviewers were resolved by consensus, if needed with the support of a senior reviewer (FKC). An extra check was performed by FKC to confirm that all recommendations were extracted.
2.5 Data Synthesis
To provide a concise overview that HCPs can use to prevent or reverse prescribing cascades, similar prescribing cascades were grouped at the medication and ADR levels. To group prescribing cascades that were described both at the chemical substance level (e.g., lisinopril) and at the related pharmacological or chemical subgroup level (e.g., angiotensin-converting enzyme inhibitor), the index and marker medication were grouped using the World Health Organization Anatomical Therapeutic Chemical classification system [17]. However, when the ADR could not be confirmed for at least half of the chemical substances within a pharmacological or chemical subgroup, the prescribing cascades were presented for the individual substances. In addition, similar ADRs (e.g., dribbling of urine and urinary incontinence) were grouped using the Medical Dictionary for Regulatory Activities classification system [20]. In this way, reports of distinct prescribing cascades were created (for further details, see Table 4 of the ESM).
3 Results
A total of 6834 publications were screened on titles and abstracts, 375 of which required full-text eligibility assessment, resulting in 95 publications that met the eligibility criteria and were included (see Fig. 1). Reasons for excluding 280 full text publications can be found in Table 5 of the ESM.
PRISMA (Preferred Reporting Items for Systematic Reviews) flow diagram. Summary of evidence search and selection
Of the included publications, 80 concerned cohort studies and 15 were case-control studies. The prescription sequence symmetry analysis was used as the main analysis in 45 publications, and most studies were conducted in the primary care setting (Table 1) [16, 21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114].
3.1 Prescribing Cascades
In the 95 publications, 571 reports of non-distinct prescribing cascades were identified that were grouped into 214 distinct prescribing cascades. Of these, 29 were excluded for various reasons, most commonly because the ADR was not found in the SmPC (n = 10) [see Table 6 of the ESM for all exclusion reasons). For the remaining 185 prescribing cascades, 70 showed no significant positive association (Table 7 of the ESM), whereas at least one significant positive association was found for 115 prescribing cascades (Tables 8 and 9 of the ESM). For 52 (45.2%) of these 115 prescribing cascades, information was available on either dose dependency of the occurrence of prescribing cascades or a recommendation to prevent or reverse the prescribing cascades (Table 2).
3.2 Dose Dependency and Recommended Actions
An analysis on the dose dependency was presented for 12 distinct prescribing cascades in 14 publications. For all prescribing cascades, the dose dependency was confirmed, although for one prescribing cascade conflicting results were found (i.e., inhaled glucocorticosteroids causing oral candidiasis treated with anti-infective agents). Other dose dependencies were found with metoclopramide/antipsychotics causing extrapyramidal syndrome, thiazides causing gout, amiodarone causing both hypo- and hyperthyroidism, calcium channel blockers causing peripheral edema, acitretin causing candidiasis, glucocorticoids causing hyperglycemia, non-steroidal anti-inflammatory drugs/diflunisal causing hypertension, and pregabalin/gabapentin causing peripheral edema (Table 2). Differences were found between studies regarding cut-offs used for defining a high dose. For example, Avorn et al. [54] used > 150 mg of chlorpromazine-equivalent per day as a high dose for antipsychotics whereas Schillevoort et al. [55] used > 375 mg of chlorpromazine-equivalent.
For 22 prescribing cascades, recommendations were made to switch the index medication but only for three it was mentioned to which medication (Table 2). Avorn et al. [21] recommended the switch to ondansetron or granisetron when extrapyramidal syndrome is experienced using metoclopramide. Vegter et al. [26, 28] recommended the switch to an angiotensin-receptor-blocker when a cough is experienced using angiotensin-converting enzyme inhibitors. Kirwan et al. [72] recommended the switch to betaxolol when an obstructive airways disorder is experienced when using antiglaucoma preparations, whereas Avorn et al. [71] recommended to switch to any other antiglaucoma preparation.
4 Discussion
This systematic review resulted in 115 distinct prescribing cascades, involving an ADR that was confirmed for the index medication in the SmPC, for which a significant positive association was found between the index and marker medication in at least one study. For 52 of these confirmed prescribing cascades, recommendations on how to prevent or reverse it were provided or could be derived from a dose-dependency analysis. Dose dependency was tested and shown for 12 prescribing cascades. Dosage lowering was often recommended without confirmation of a dose-dependent association. Switching to another medication and discontinuation of medication were often recommended without specifying an alternative.
4.1 Comparison with Previous Publications
Several reviews on prescribing cascades have been published but none provided information on how to prevent or reverse them. The most recently published systematic review (2022) of Doherty et al. aimed to identify prescribing cascades in community-dwelling adults [8]. In their review, they identified 76 publications, whereas our review included 95 publications. Our review was not limited to community-dwelling adults like Doherty et al. or to a specific medication group as done by Nunnari et al. [6], resulting in the inclusion of 33 additional publications compared to both. Of note, Doherty et al. identified nine publications and Nunnari et al. identified 11 publications that were excluded from our review, as they concerned hypothesis-free studies, case reports, or ADRs that could not be confirmed in the SmPC of the index medication. A direct comparison of identified prescribing cascades is complicated by differences in the level at which the prescribing cascades are presented in the reviews. Nonetheless, our review included three prescribing cascades not identified by Doherty et al. [8]. This concerned calcium channel blockers causing depression treated with antidepressants, glucocorticosteroids causing hyperglycemia treated with diabetes drugs, and diabetes drugs causing depression treated with antidepressants. Based on the opinion of experts, McCarthy et al. recently provided an overview of nine clinically important prescribing cascades [115]. All of these were also included in our review.
4.2 Implications for Policy, Practice, and Research
An overview of clinically relevant prescribing cascades can serve as a tool for HCPs to raise awareness on prescribing cascades [115]. The overview presented can be the starting point for specific interventions or policies on preventing and reversing prescribing cascades. The 52 confirmed prescribing cascades with information about dose dependency and recommendations can aid HCPs in recognizing and addressing potentially preventable prescribing cascades. Confirmation that the ADR can be caused by the index medication is relevant for HCPs because it is often difficult to recognize whether a new symptom might be an ADR, particularly in patients using multiple medications [5].
Additionally, knowing whether the ADR and the related prescribing cascade have been confirmed for multiple substances within a pharmacological subgroup can help HCPs determine whether switching a medication within a subgroup is a viable strategy for reversing a prescribing cascade. For 12 confirmed prescribing cascades, evidence was found that they were dose dependent. This implies that dosage lowering may reverse these prescribing cascades.
For prescribing cascades with consistent positive associations in the studies and concrete recommendations, development of electronic decision support tools could help manage these prescribing cascades (e.g., angiotensin-converting enzyme inhibitors induced cough, metoclopramide induced extrapyramidal syndrome, calcium channel blocker induced peripheral edema). For others, it may be helpful to create alerts so that the prescriber can reconsider the benefit-risk balance of the index medication. In some cases, particularly among the very old and frail patients, discontinuation may be an option.
More research is needed to assess whether using low dosages in patients at a high risk of developing an ADR, such as older people or women [75, 86, 116], can prevent prescribing cascades and is also sufficient to reverse existing ADRs. Furthermore, recommendations to switch a medication without specific advice are not helpful for HCPs. Knowledge synthesis is needed to create an overview of prescribing cascades with specific details on alternative options.
4.3 Strengths
This systematic review has several strengths. The extensive literature search strategy without limitations on medication groups, patient population, setting, study design, or method of analysis increased the chance of finding prescribing cascades relevant for HCPs. Publications on this topic do not necessarily use the term ‘prescribing cascade’ or relevant indexed terms. Therefore, forward and backwards citation searches were conducted for included studies, systematic reviews, and case reports/series, which led to the inclusion of additional publications. Recommendations for conducting systematic reviews were followed and in all steps at least two researchers were involved. Furthermore, SmPCs providing information as certified by marketing authorities were used to confirm ADRs, and existing classification systems were used to group medications and ADRs.
4.4 Limitations
Prescribing cascades were included that showed a significant association in at least one study. This indicates that the prescribing cascade occurred in clinical practice but it does not imply that an ADR actually occurred in all cases nor that the marker medication was prescribed for that reason. Some studies included small sample sizes or used suboptimal data or designs, which can result in missing some relevant prescribing cascades. To address this limitation, we included all identified prescribing cascades in the supplementary material. Finally, some prescribing cascades were assessed in many studies, whereas others were assessed in one study or may not have been studied at all. It should be noted that the occurrence of prescribing cascades can be country, culture, or care setting dependent. Treatment guidelines and available and approved medication can differ per country. Whether people visit their doctor with specific complaints may also differ depending on the culture or setting. For these reasons, not all of the confirmed prescribing cascades presented in our review may be relevant for all HCPs. Furthermore, some of the prescribing cascades for which no significant association has been shown might still be relevant in specific settings. Our overview of confirmed prescribing cascades should therefore be seen as a first step to support HCPs.
5 Conclusions
From 185 distinct prescribing cascades identified in 95 publications, 115 showed a significant positive association between the index and marker medication in at least one study. Of these, an overview of 52 prescribing cascades was created, for which information on dose dependency or recommendations on how to prevent or reverse the prescribing cascade was provided. This review illustrates that specific recommendations on how to reverse and prevent prescribing cascades is often lacking.
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Acknowledgements
We thank Mustafa Yasar for his help in the preparation of this review and Hanneke Wessemius for her extra validation.
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The Royal Dutch Association of Pharmacists (KNMP) has supported the study with a non-conditional grant (Grant number PR20_0103). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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The authors declare that none of them have received honoraria, reimbursement, or fees from any pharmaceutical companies related to this study.
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Study concept and design: FKC, PD, PvdB, JH. Study selection and data extraction: FKC, PD, AM, OA, RV, LM, SPV. Data, analysis: FKC, PD, PvdB, JH, AM, OA, RV. Interpretation of data: FKC, PD, PvdB, JH, AM, OA, RV. Preparation of manuscript: AM, OA. Critically reviewing the manuscript: all authors.
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Adrien, O., Mohammad, A.K., Hugtenburg, J.G. et al. Prescribing Cascades with Recommendations to Prevent or Reverse Them: A Systematic Review. Drugs Aging 40, 1085–1100 (2023). https://doi.org/10.1007/s40266-023-01072-y
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DOI: https://doi.org/10.1007/s40266-023-01072-y