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

1. Introduction

Population aging and the increasing prevalence of multimorbidity have led to a growing reliance on polypharmacotherapy, which substantially raises the risk of adverse drug reactions and clinically significant drug–drug interactions. Among the key yet still underappreciated challenges in clinical practice is the phenomenon known as the prescribing cascade. This occurs when an adverse drug reaction is misinterpreted as a manifestation of a new disease, prompting the initiation of an additional medication. Such an approach may trigger a vicious cycle of subsequent pharmacological interventions, markedly amplifying the risk of further complications [1,2]. This problem is particularly pronounced in geriatric patients, in whom altered pharmacokinetics and pharmacodynamics, reduced organ reserve, and the coexistence of multiple chronic conditions significantly increase the risk of adverse drug events, their accumulation, and drug–drug interactions [2,3]. Of particular concern are cascades involving cardiovascular, analgesic, and anti-inflammatory agents, which may contribute to renal impairment and even the development of chronic kidney disease and renal failure. The consequences of prescribing cascades therefore extend beyond reduced quality of life and increased risk of hospitalization, encompassing serious organ complications that place an additional burden on healthcare systems. Despite the availability of tools supporting the evaluation of pharmacotherapy appropriateness, such as the Beers Criteria and STOPP/START criteria, prescribing cascades remain insufficiently recognized and often overlooked in clinical practice. The aim of this paper is to review the current evidence regarding the mechanisms and clinical consequences—particularly with respect to renal function deterioration—as well as strategies to prevent prescribing cascades in the geriatric population.

2. Risk Factors for Prescribing Cascades

Identification of risk factors for the occurrence of prescribing cascades is a key element in limiting the prevalence of this phenomenon. It reduces negative health consequences for the patient and enables verification and improvement of treatment standards, particularly in patients with multimorbidity. Preventing and eliminating prescribing cascades is therefore an important step toward improving the quality of care and clinical outcomes [4]. Risk factors for adverse prescribing cascades can be grouped into categories related to the medical status of the patient and those that are “non-medical,” associated with the current ease of access to medications and other medical products. In the first category, we include advanced age, multimorbidity, polypharmacy, and overprescribing, often linked to multispecialist treatment provided by several physicians without mutual verification of ongoing pharmacotherapy. Within this group, particular attention should be paid to the risk of renal injury-both acute kidney injury (AKI) and chronic kidney disease (CKD). Many drugs prescribed concurrently as part of cascades (e.g., nonsteroidal anti-inflammatory drugs, ACE inhibitors, diuretics, and nephrotoxic antibiotics) may exert cumulative renal burden, resulting in progressive renal impairment, especially in geriatric patients. [5,6,7,8]. The second group of risk factors includes obtaining prescriptions online without direct physician consultation, easy availability of over-the-counter drugs (OTC), and, consequently, the possibility of self-medication and unnecessary supplementation (pathosupplementation). Additional contributing factors are the widespread promotion of medications and supplements in pharmacies, mass media advertising (television, internet), and pharmacy-based sales promotions. Table 1 summarizes the risk factors for the occurrence of prescribing cascades [5,6,9].

Prescribing cascades may occur in any patient experiencing health deterioration, but age-related physiological changes naturally predispose to worsening health status. Age is a parameter defining the biological and physiological aspects of aging and is associated with the natural predisposition to age-related diseases and their treatment. In this group, renal impairment is particularly prevalent, increasing susceptibility to adverse drug reactions from medications eliminated renally. Consequently, older adults are more likely to develop acute kidney injury as a result of prescribing cascades, and long-term exposure may even induce chronic kidney disease. Accurate data on the physiology and pathology of aging may help reduce unnecessary polypharmacy. However, clinical trials often exclude or insufficiently represent older adults with multimorbidity, resulting in a lack of evidence-based (EBM) guidelines for combination drug therapy in this population. This leads to suboptimal pharmacotherapeutic choices—frequently involving the use of “older” drugs with a high risk of adverse events, particularly nephrotoxic complications. The lack of data derived from clinical research also contributes to insufficient use of modern therapies in geriatric patients, often justified by concerns about poor tolerability due to age. On the other hand, unexpected cascades may occur when new medications are introduced without a thorough analysis of age-related pathophysiological changes. In summary, the underrepresentation of older adults with multimorbidity in clinical trials results in a lack of precise evidence-based pharmacotherapeutic guidelines for this population, fostering the occurrence of prescribing cascades and increasing the risk of renal insufficiency [5,6,7,10]. Verification of risk factors facilitates the recognition of prescribing cascades, yet practical tools to help physicians reliably identify cascades, assess them appropriately, and manage them effectively are still lacking. Polypharmacy, although considered a risk factor for prescribing cascades, is undoubtedly an essential element of good prescribing practice in aging populations. At the same time, the lack of systematic evaluation of renal function during therapy selection further exacerbates the risk of cascades leading to acute kidney injury or progression of chronic kidney disease. The classification of cascades as appropriate or inappropriate (intended/unintended) may evolve over time depending on the clinical status of the patient. [7,8,12]. Therapeutic regimens, typically designed with a disease- and organ-specific focus, often overlook an interdisciplinary assessment of renal function. Failure to account for this aspect promotes therapeutic decisions that result in additive adverse drug effects and, consequently, increase the risk of prescribing cascades. Thus, a key question arises: Why does the risk of prescribing cascades increase in clinical practice? Table 2 presents cause-and-effect relationships of prescribing cascades, including their association with renal injury progression. [5,6,7,8,9,11,12,15].

3. Examples of Prescribing Cascades and Their Clinical Significance

Prescribing cascades are a common but often underrecognized phenomenon in clinical practice, particularly among older adults. They occur when an adverse drug reaction is misinterpreted as a new medical condition, leading to the initiation of an additional drug rather than recognition of the underlying cause. In the long term, this process not only increases the risk of inappropriate polypharmacy but also heightens the likelihood of drug-related morbidity, hospitalizations, and healthcare costs [1,7,12]. The tables below summarize clinically important prescribing cascades described in recent consensus statements and systematic reviews. Table 3 and Table 4 presents cascades that are particularly relevant in older adults, identified through the ThinkCascades tool and the international list of potentially inappropriate prescribing cascades (PIPC) [1,7,12].

The clinical significance of these cascades is multifaceted. First, they frequently contribute directly to deterioration in patients’ functional status. For example, calcium channel blocker–induced peripheral edema treated with diuretics may result in dehydration and falls. Similarly, benzodiazepine-related cognitive impairment treated with cholinesterase inhibitors only adds to the pharmacological burden without addressing the underlying cause. Second, an important yet often underestimated aspect of prescribing cascades is their impact on renal function. The use of diuretics in response to adverse effects of other medications (e.g., edema caused by calcium channel blockers or NSAIDs) may lead to dehydration, electrolyte disturbances, and accelerated decline in glomerular filtration. Consequently, the risk of nephrotoxicity from additional medications, accumulation of drug metabolites, and further progression of kidney disease increases. In older adults, whose renal reserve is already limited, such cascades can significantly increase the risk of acute kidney injury (AKI) or accelerate the development of chronic kidney disease (CKD). Third, prescribing cascades often contribute to therapeutic inertia, as clinicians may attribute drug-related symptoms (such as dizziness, hypotension, or worsening renal function tests) to aging or disease progression rather than to adverse drug effects [7,12]. Recent systematic reviews emphasize that prescribing cascades are not random events but rather reproducible and predictable patterns observed across healthcare systems [1]. Recognition of these patterns is therefore critical for implementing preventive strategies such as medication review and deprescribing. In particular, the PIPC list developed by the international expert panel provides clinicians with a practical tool for identifying high-risk cascades, while the ThinkCascades tool offers a structured approach to evaluating drug–symptom associations in daily practice [7,12]. Ultimately, the presence of prescribing cascades highlights the importance of regular medication review, interdisciplinary collaboration, and patient education. Raising awareness of well-documented cascades such as those listed above may help clinicians distinguish adverse drug reactions from disease progression—including declining renal function and thereby reduce inappropriate polypharmacy and its associated risks.

Figure 1. Examples of prescribing cascades affecting kidney function. DPP-4, Dipeptidyl peptidase 4; NSAID, Nonsteroidal anti-inflammatory drug. Created in BioRender. Miedziaszczyk, M. (2025) https://BioRender.com/welwul.

Figure 1. Examples of prescribing cascades affecting kidney function. DPP-4, Dipeptidyl peptidase 4; NSAID, Nonsteroidal anti-inflammatory drug. Created in BioRender. Miedziaszczyk, M. (2025) https://BioRender.com/welwul.

4. Consequences of Prescribing Cascades

A prescribing cascade can lead to serious health, social, and economic consequences. Although this phenomenon may appear to result from concern for the patient, it often worsens their clinical condition, leads to inappropriate treatment (so-called "therapeutic vicious circles") and polypharmacotherapy, which turns into polypragmasy. As a result, patients may experience intensified symptoms such as dizziness, drug-induced headaches, falls, delirium, cognitive impairment, balance disorders, orthostatic hypotension, or painsomnia. Importantly, some of these symptoms—such as delirium, balance disturbances, or hypotension—are often mistakenly attributed to the “natural” aging process or progression of the underlying disease, which further delays appropriate intervention. These are only some of the potential consequences of prescribing cascades, which negatively affect patients’ quality of life, leading to reduced mobility and independence and, quite often, the need for hospitalization [12]. Findings from observational studies and systematic reviews, as well as daily clinical practice, clearly indicate that prescribing cascades are a significant risk factor for hospitalization, especially in older adults, where the reason for hospital admission is not the primary disease but rather adverse drug reactions introduced in response to symptoms caused by previous pharmacotherapy. Examples include falls due to hypnotics or dehydration caused by diuretics prescribed in response to edema induced by NSAIDs or certain antidepressants. In the long term, prescribing cascades also contribute to rising healthcare costs, both direct (such as hospitalizations, diagnostics, and additional specialist consultations) and indirect (loss of independence, the need for continuous care). According to Farrell B and McCarthy LM, deprescribing and early identification of prescribing cascades can significantly reduce systemic expenditures as well as ease the burden on medical staff [7,14].

5. Identification and Prevention of Prescribing Cascades

Currently, there is a lack of practical tools to help physicians and pharmacists reliably detect, correctly assess, and manage prescribing cascades. Ponte et al. developed an 8-point (4 questions) scale to assess the prescribing cascade. Prescribing cascade is assumed to occur if the score is 4 or higher, reflecting the severity of the prescribing cascade. Table 5 presents a tool for assessing the occurrence of drug cascade prescription [15].

Dreischulte et al. proposed a tool that assesses whether the prescribing cascade is appropriate or inappropriate [6]. The tool is based on the following 6 questions. Although prescribing cascades are most often perceived as problematic, they may be appropriate and therapeutically beneficial in certain clinical situations. McCarthy et al. point out two important issues to consider when deciding on a prescribing cascade. First, consider whether the intentional initiation of a prescribing cascade aligns with the patient's treatment goals (patient well-being and improved quality of life). Second, consider whether the risks and benefits of the prescribing cascade have been discussed with the patient and whether the patient has been informed of the long-term effects [16]. Table 6 presents the Prescription Cascade Benefit Assessment Tool.

Analyzing everything that has been described, with particular emphasis on the risk factors for the occurrence of prescribing cascades, as well as clinical practices that increase the risk of their occurrence, we made an attempt to formulate general principles which, when implemented in clinical practice, may help prevent prescribing cascades. Table 7 presents the key points of clinical practice, which we can refer to as a list of good clinical practices [3].

6. Conclusions

Prescribing cascades constitute a clinically significant yet underrecognized problem in geriatric pharmacotherapy. Their occurrence not only promotes inappropriate polypharmacy but also contributes to deterioration in patients’ functional status, an increased risk of hospitalization, and higher healthcare costs. Particularly alarming are cascades involving cardiovascular, analgesic, and neurological agents, which may accelerate the decline of renal function and predispose to acute kidney injury or chronic kidney disease. The findings of this review highlight the urgent need to raise awareness among healthcare professionals about the mechanisms and consequences of prescribing cascades. Regular medication reviews, systematic monitoring of renal function, and the use of validated assessment tools—such as the Beers Criteria, STOPP/START, and PIPC—are essential steps toward minimizing the risk of inappropriate prescribing and preventing renal complications. Interdisciplinary collaboration and patient education further strengthen preventive strategies. Ultimately, addressing prescribing cascades is not only a matter of improving medication safety but also a prerequisite for enhancing the quality of life and clinical outcomes in older adults.