Prescribing Cascade as a Therapeutic Error: A Danger for Geriatric Patients with Multimorbidity

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1- Table 1: Please add another column referring to number of references regarding each risk factor.

2- Table 3 is ok and well understood. But Table 4 is not well understood. Please reconsider

3- Table 7: The author used medical terms like oligopharmacotherapy, and contexual pharmacotherapy. They need further explanation in text form

4- The authors should make a link between deprescription, personalized medicine and therapeutic cascades errors

 

Author Response

1 - Done. The approximate number of supporting references for each risk factor reflects the relative strength and consistency of evidence available in the current literature, as summarized in Table 1.

2- A short explanatory sentence has been added to the text preceding Table 4, indicating that it provides a non-exhaustive overview of additional, less frequently discussed prescribing cascades, organized by physiological systems, and is intended to illustrate the breadth and complexity of prescribing cascades rather than to offer specific management recommendations. This clarification was introduced to distinguish Table 4 conceptually from Table 3 and to improve its interpretability for the reader.

What's more: "Drug A -> the sequence “Drug A → Clinical Effect” has been visually emphasized using bold formatting to clearly highlight the causal relationship underlying each prescribing cascade and to facilitate easier interpretation by the reader.

3 - To address this point, we have added a short explanatory paragraph to the manuscript immediately preceding Table 7, in which the terms oligopharmacotherapy and contextual pharmacotherapy are briefly defined and explained. This addition was intended to clarify the meaning of these concepts for the reader and to improve the overall comprehensibility of Table 7.

4 - In response, we have added a new paragraph at the end of Section 5 that explicitly links deprescribing with personalized medicine and frames prescribing cascades as therapeutic errors arising from non-contextual, guideline-driven prescribing. This addition emphasizes the role of deprescribing as a core component of patient-centered, personalized pharmacotherapy and clarifies its importance in preventing and reversing therapeutic cascades.

Reviewer 2 Report

Comments and Suggestions for Authors

I agreed with enthusiasm to provide a review for the review entitled „Prescribing csacade as a therapeutic error: A danger for geriatric patients with multimorbidity”. I confirm that the topic is highly relevant and important, especially in the elderly population. However, I identified major problems with the manuscript. In the abstract, the authors indicate that they would like to focus on nephrotoxicity, but neither in the title, nor in manuscript text this aspect is in the focus. This makes the study aim unclear. It is also not clear from the text that what this review adds to existing knowledge. I also lack that prescribing cascade (PC) are not put in context. Some of them can be desirable, as it is mentioned in Table 6. No text elaborate on this aspect. No definitions are provided for the different type of PCs, for overprescribing, for pathosupplementation, oligopharmacotherapy, contextual pharmacotherapy, etc….which precludes clear understanding and evaluation. What is the difference between polipharmacy and chronic use of multiple medications? What are overlapping ADE? There are many repetitions and false statement througout the text, I list below some of them. What is the role of risk assessment tools? What is the interpretation of different scores? What actions should be taken? Prevention and identification of PCs is two separate thing, should be discussed and interpreted separetely. Below I list some specific critics, but this is not the full list.

 

line 55: drug-drug interactions are not the effect but rather one of the causes of ADEs

What is the definition of adverse prescrbing cascade?

How do you group adverse prescribing cascades? Is this your own definition or is it from previous literature?

Table 1: please provide for each line a reference which proved the existence of the particular risk factor. The title of the second column is not clear. Please group the risk factors and provide logical order. First comes the multimorbidity, than polipharmacy. Why misinterpretation of symptom is a separate category? This is true for many lines in the table.

What is the difference between polipharmacy and chronic use of multiple medications. What are overlapping ADE? There are also other overlapping categories: self medication and pathospupplementation

Why you state the lack of MUR foster the development of prescribing cascades?

line 91-95: unclear text

line 98? what you mean by accurate data

line 103: why you state that older drugs have higher risk of ADE. This is nit true

 

Table 2: Add references and add examples for each row. The first category (uncritical and context free…) overlaps with „Fragmemtation of multimorbodity. Why you state that uniform class affect does not exist? This is not true. Why you list here uncritical use of electronic tools for assessing interactions?

 

line 129-135: this information is the third repetition

 

Table 3: Add the sources, provide logic ordering (e.g. cognitive imparments one after the other, etc)

Table 4: What is the rational for this table? It contains overlap with the previous table. Why not merging with Table 3. The title is very vague and columnd heading are not clear, difficult to identify causes and effects.

The first column should be a row

Table 5: no interpretation provided

Table 6: should be inserted much earlier, when PC are categorised

Table 7: vague and some categories overlaps

Comments on the Quality of English Language

Many strange words 

Author Response

We thank the Reviewer for the thorough and detailed evaluation of our manuscript and for recognizing the clinical relevance of the topic. We appreciate the opportunity to clarify several conceptual and structural aspects of the paper. Below, we address the comments thematically to improve clarity and avoid repetition.

Scope, Aim, and Novelty of the Manuscript

Primary aim of this manuscript is to highlight prescribing cascades as a clinically relevant therapeutic error in geriatric patients with multimorbidity, with renal function deterioration used as a clinically important example of organ-specific harm, rather than as the sole or dominant focus of the manuscript.

The reference to nephrotoxicity in the abstract reflects this illustrative role. Our intention was not to provide a comprehensive nephrology-focused analysis, but to emphasize that renal injury represents one of the most frequent and clinically consequential outcomes of prescribing cascades in older adults. This has now been clarified in the introduction to better align the stated aim with the manuscript content.

The novelty of the manuscript lies in its integrated clinical perspective, combining risk factors, real-world prescribing cascades, their consequences, and prevention strategies, with a particular emphasis on geriatric multimorbidity and everyday clinical decision-making.

Definitions and Conceptual Clarifications

In response to the Reviewer’s comments, we have added explicit definitional clarification to the Introduction. In particular, we now define a prescribing cascade as a process in which an adverse drug reaction is misinterpreted as a new medical condition, leading to the initiation of an additional medication rather than modification or discontinuation of the causative drug.

We also clarify that prescribing cascades may be unintentional and inappropriate, but in selected clinical circumstances they may be intentional and appropriate, provided that the benefit–risk balance is favorable and aligned with patient-centered therapeutic goals. This conceptual distinction underpins the rationale of Table 6 and is now explicitly stated in the text.

Terms such as polypharmacy, chronic use of multiple medications, pathosupplementation, oligopharmacotherapy, and contextual pharmacotherapy are used in their established clinical meanings. Polypharmacy is treated primarily as a quantitative concept (concurrent use of multiple drugs), whereas chronic use of multiple medications refers to long-term exposure with cumulative adverse effects. Overlapping adverse drug events are understood as additive or synergistic adverse effects arising from multiple agents with similar toxicity profiles.

 

Risk Factors and Assessment Tools

The risk factors presented in Table 1 reflect a clinical synthesis of well-recognized contributors to prescribing cascades, rather than a formal causal hierarchy. The table was not intended to function as an evidence-graded risk assessment tool, but as a practical aid for clinicians. For this reason, not every row is accompanied by a single, isolated primary reference; instead, the table summarizes patterns consistently described across multiple reviews and consensus publications, which are cited in the table caption and reference list.

Medication Use Review and structured medication assessment are discussed as preventive strategies because the absence of systematic medication review is widely recognized as a contributor to inappropriate prescribing and failure to recognize adverse drug reactions. This reflects clinical practice realities rather than a claim of exclusive causality.

Tables 2–7: Rationale, Structure, and Interpretation

All tables included in the manuscript represent original, author-developed narrative syntheses, based on published literature and clinical experience, rather than reproductions or adaptations of existing tables.

Table 2 was designed to illustrate cause–effect mechanisms leading to prescribing cascades, not to provide an exhaustive or mutually exclusive taxonomy. Some conceptual overlap is therefore unavoidable and reflects real-world clinical complexity.

Tables 3 and 4 intentionally separate well-established, clinically important cascades from a broader, system-based overview to illustrate the breadth of the phenomenon. They serve complementary, not repetitive (dup;icate), purposes.

Tables 5 and 6 are presented as clinical reasoning support tools, not validated scoring systems, and are discussed accordingly in the text.

Table 7 summarizes principles of good clinical practice and is intentionally pragmatic, acknowledging that some domains may overlap in everyday clinical care.

We deliberately avoided merging or restructuring tables in a way that would impose artificial hierarchies or suggest formal validation beyond the scope of a narrative review.

Identification vs. Prevention of Prescribing Cascades

Identification and prevention are discussed as related but conceptually distinct processes. Identification focuses on recognizing existing cascades, whereas prevention emphasizes clinical strategies to avoid their development. These topics are therefore addressed in separate but sequential sections to preserve conceptual clarity and clinical logic.

Repetition, Language, and Editorial Issues

We acknowledge that certain core concepts necessarily recur throughout the manuscript to reinforce key clinical messages. Minor editorial repetitions and language issues will be addressed during final language polishing; however, these do not affect the scientific content or conclusions of the review.

Final Remarks

We believe that the revisions and clarifications introduced in response to the Reviewer’s comments strengthen the manuscript without altering its intended scope, structure, or clinically oriented focus. We respectfully submit that the current format is appropriate for a conceptual, practice-oriented review aimed at improving awareness and recognition of prescribing cascades in geriatric care.

Reviewer 3 Report

Comments and Suggestions for Authors

See attached File 

Comments for author File: Comments.pdf

Comments on the Quality of English Language

could be improved 

Author Response

Improved. See attached File.

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

Overall this is an important topic in geriatric practice.  However, there are themes to make this paper stronger and help to further contribute to the science. 

1) Noted this is a REVIEW. How was this review conducted with key search terms. 

2) Appreciate how this was broken down into sections with MANY tables but added comments on how to support statements and maybe refine the tables. 

3) Appreciated the renal focus but would be more specific within the article on this aspect both into terms of clinical impact (references) as well as priority areas. 

4) Due to the language differences there are terms used not as common here in US based practice. 

Again- overall helpful article but hopefully these suggestions as well as the ones on the manuscript will help refine the approach and strengthen it. 

 

Comments for author File: Comments.pdf

Comments on the Quality of English Language

Made comments within the article. 

Author Response

1- 
We thank the Reviewer for this comment. This manuscript is a narrative review intended to synthesize and contextualize existing evidence on prescribing cascades in geriatric patients, rather than a systematic review. We have clarified the review methodology in the manuscript by briefly describing the literature search strategy, including the databases consulted and the key search terms used, in order to improve transparency while remaining consistent with the narrative review design.

2- 
DONE

3- 
Renal impairment was intentionally highlighted as a clinically relevant example of organ-specific harm associated with prescribing cascades in older adults.

4- 
The manuscript is primarily addressed to an international audience of clinicians and healthcare professionals. Some terms reflect European or international clinical terminology that may be less commonly used in US-based practice.

 

See attached File.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The article has been improved

Author Response

We would like to thank the Reviewer for the positive evaluation of our manuscript and for the constructive comments. We appreciate the recognition that the manuscript may contribute to increasing awareness of the prescribing cascade.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have adequately addressed all the reviewers’ comments and implemented the requested revisions. The manuscript has substantially improved and is now in good shape and suitable for publication.

Comments on the Quality of English Language

could be improved 

Author Response

We would like to thank the Reviewer for the positive evaluation of our manuscript and for the constructive comments. We appreciate the recognition that the manuscript may contribute to increasing awareness of the prescribing cascade.