The phenomenon of prescribing cascades, where additional medications are prescribed to manage adverse drug effects, is a growing concern, particularly in poly-medicated older population (Kalisch et al., 2011; Rochon and Gurwitz, 2017). One such cascade involves the concurrent prescription of amlodipine, a calcium channel blocker for hypertension and angina, and frusemide, a loop diuretic for fluid retention and edema (Savage et al., 2020; Woodford, 2020; Shahid et al., 2024). While this combination is common, concerns about its safety have been raised, particularly regarding increased fall risk due to its effects on blood pressure regulation and orthostatic hypotension (Savage et al., 2020; Ndai et al., 2024).

Amlodipine is linked to dose-dependent peripheral edema, a common adverse effect that often prompts the addition of frusemide (Shahid et al., 2024). However, studies suggest that diuretics may not effectively mitigate calcium channel blockers-induced edema, leading to unnecessary medication use and exposing patients to additional adverse drug reactions, such as dehydration, electrolyte imbalance, and hypotension (van Hamersvelt et al., 1996).

Therefore, amlodipine and frusemide combination (AFC) serves as a key example of a prescribing cascade that may inadvertently increase the risk of falls, particularly among older patients. Fall risk is multifactorial, influenced by factors such as advanced age, polypharmacy, chronic comorbidities, and medications that affect hemodynamic stability (Liu et al., 1995; Gale et al., 2016; Juraschek et al., 2017; Rashedi et al., 2019; Amano et al., 2024). Falls among older populations represent a major public health concern, as they are a leading cause of morbidity, disability, and mortality (Liu et al., 1995; Milos et al., 2014). Orthostatic hypotension-inducing drugs (OHDs) and fall-risk increasing drugs (FRIDs) are frequently implicated in fall-related hospitalizations (Milos et al., 2014; Al-Qurain et al., 2020). Given that both amlodipine and frusemide have hypotensive effects, their concurrent use requires careful assessment of fall risk, particularly in patients with additional predisposing factors.

Despite concerns regarding the safety of AFC prescriptions, limited research has explored the prevalence of this combination and its association with known fall risk factors. Understanding these associations is crucial for optimizing prescribing practices and minimizing unnecessary medication exposure, especially among poly-medicated older patients (Alqurain et al., 2024a). This study aims to determine the prevalence of AFC prescriptions in an outpatient cardiology clinic, identify the prevalence of key fall risk factors, including polypharmacy, comorbidities, and medication-related risks, among AFC users, and evaluate the association between AFC prescriptions and the presence of fall risk factors. By addressing these objectives, this study provides essential data that may inform safer prescribing practices and enhance fall prevention strategies for patients receiving AFC prescriptions.

This study included 3,681 patients, with a prevalence of AFC prescription of 18%. Female patients were more frequent prescribed AFC compared to male patients (54% vs. 46%, p = 0.02) (Table 1). Patients prescribed AFC were older (70 vs. 64 years, p < 0.001), had a higher body weight (79 kg vs. 77 kg, p = 0.01), a lower average CrCl value (87 mL/min vs. 92 mL/min, p = 0.009) and a higher median CCI score (7 vs. 5, p < 0.001) compared to those not prescribed AFC. Interestingly, patients prescribed AFC were also more frequently prescribed OHDs and FRIDs compared to those not prescribed AFC (2.8 vs. 1.3, p < 0.001 and 0.7 vs. 0.5, p < 0.001 respectively) (Table 1). As shown in Table 1, patients prescribed AFC had a significantly higher prevalence of diabetes mellitus (65% vs. 44%, p < 0.001), anemia (55% vs. 32%, p < 0.001), musculoskeletal pain (65% vs. 57%, p = 0.001) and osteoporosis (51% vs. 38%, p < 0.001) compared to those not prescribed AFC. Table 1 shows that patients with AFC prescription had higher prevalence of hypertension (91% vs. 64%, p < 0.001), ischemic heart diseases (100% vs. 61%, p < 0.001) and arrhythmia (8% vs. 1%, p < 0.001) compared to those not prescribed AFC.

Another analysis was conducted to determine the pattern of AFC occurrence across different age groups. Figure 1 illustrates a progressive increase in AFC occurrence with advancing age. Further analysis was conducted to assess the different characteristics between older vs. middle-aged patients. The analysis revealed that older patients were more likely to be female individuals (56% vs. 45%, p < 0.001), had a higher CCI score (7 vs. 4, p < 0.001) and had a lower CrCl value (73 vs. 108, p < 0.001) (Table 2). In addition, older patients presented with a higher prevalence of diabetes mellitus (52% vs. 43%, p < 0.001), anaemia (40% vs. 33%, p < 0.001), osteoporosis (44% vs. 37%, p < 0.001), hypertension (70% vs. 67%, p = 0.03), ischemic heart diseases (70% vs. 76%, p = 0.002), and arrhythmia (3% vs. 1%, p < 0.001) (Table 2). Interestingly, Table 2 shows that older patients were prescribed AFC more often compared to middle-aged patients (24% vs. 12%, p < 0.001).

After adjusting for confounding covariates including age, body weight, sex, CCI, CrCl, OHDs and FRIDs, logistic regression analysis demonstrated that AFC prescription was positively associated with increasing body weight (OR = 1.02, 95% CI 1.01–1.024), higher CCI score (OR = 1.5, 95% CI 1.4–1.6), and greater OHDs prescription (OR = 2.5, 95% 2.3–2.7), while it was negatively associated with increasing FRIDs prescription (OR = 0.8, 95% CI 0.7–0.9) (Table 3).

This study highlights significant associations between the prescription of AFC and factors contributing to an increased risk of falls. The findings demonstrate that AFC prescriptions were prevalent among older adults and were strongly associated with higher CCI score, the use of OHDs prescriptions, and the presence of anaemia. Considering these associations, healthcare providers must carefully evaluate the appropriateness of AFC use in older patients, ensuring that the therapeutic benefits outweigh the potential risks while minimizing adverse drug reactions.

A key finding from this study is that 18% of the included cohort were prescribed AFC, a notably higher proportion compared to previously reported values. A study from the United States reported that 5%–12% of the cohort were exposed to and continued using AFC, whereas another study reported that about 3.5% of older patients with hypertension were prescribed AFC during their first year of therapy (Vouri et al., 2018; Ndai et al., 2024). The high prevalence reported in the current study highlights the importance of early detection of this combination to mitigate the risk of falls associated with orthostatic hypotension.

Another key finding is the significant association between increasing CCI scores and AFC occurrence. A higher CCI score reflects a greater burden of chronic illness, which inherently increases the risk of falls (Charlson et al., 1987; Milos et al., 2014; Rashedi et al., 2019). Additionally, due to the retrospective design of the current study, the CCI index was used as an alternative measure of frailty (Al-Qurain et al., 2021). Frail older patients exhibit a higher rate of falls, including recurrent falls compared to non-frail (Wong et al., 2015; Cheng and Chang, 2017). Recent studies have further demonstrated that frailty is associated with an increased risk of orthostatic hypotension and falls in older patients (Kocyigit et al., 2019; Shaw et al., 2019).

Another significant observation is the association between the prescription of OHDs and the occurrence of AFC. This finding is particularly relevant given that a recent study highlighted that OHDs prescriptions, including antihypertensives, increase the likelihood of polypharmacy by 20% among older patients (Alqurain et al., 2024a). Polypharmacy is a well-established risk factor for falls due to the increased potential for drug-drug interactions and adverse drug reactions (Alqurain et al., 2024a). Considering this association, routine medication reviews should prioritize minimizing unnecessary OHDs use, while maintaining optimal cardiovascular management (Scott et al., 2015; Zhou et al., 2017). Collaboration between pharmacists and healthcare providers is essential to evaluate whether alternative treatment strategies can be employed to reduce fall risk while achieving therapeutic goals.

Another important finding from the current study is the inverse association observed between FRIDs prescriptions and AFC use (OR = 0.8, 95% CI 0.7–0.9). This may reflect clinician-driven deprescribing behaviours, as prescribers intentionally avoid or reduce FRIDs use in patients already exposed to falls risk increasing drugs. This explanation is supported by previous study finding as prescribers often reduce or deprescribe medications potentiating risk of falls among vulnerable patients presented with polypharmacy and frailty (Reeve et al., 2014). Similarly, a clinical review reported that similar interventions are linked to reduced fall risk via medication review and deprescribing strategies (Van Poelgeest et al., 2021).

Furthermore, the study identified a high prevalence of diabetes mellitus, anaemia, and osteoporosis among AFC users, conditions that collectively increase the risk of falls. Diabetes mellitus contributes to fall risk through peripheral neuropathy and hypoglycaemia-related dizziness, while anaemia exacerbates fatigue and muscle weakness due to impaired oxygen delivery. (Stauder and Thein, 2014; Zhou et al., 2017; Rashedi et al., 2019; Amano et al., 2024). Osteoporosis further increases susceptibility to severe injuries following a fall, increasing morbidity and mortality risk (Avdic et al., 2004; Wang et al., 2021). The combination of AFC prescriptions and these comorbid conditions emphasizes the need for targeted fall prevention strategies, including regular screening for anaemia, careful monitoring of glucose levels, and interventions aimed at enhancing bone health in high-risk individuals.

Older patients are at an increased risk of lower extremity edema and prescribing amlodipine may further exacerbate this risk, potentially leading to the concurrent use of frusemide (Vouri et al., 2018; Ndai et al., 2024). Notably, this study identified a higher prevalence of AFC prescription among older patients. Advanced age is also associated with the presence of multiple morbidities, which often necessitate the use of multiple drugs, leading to polypharmacy (Al-Qurain et al., 2020). Therefore, healthcare providers should consider conducting comprehensive medication reviews to assess the risk of adverse drug reactions associated with AFC prescription among older patients, ensuring the effective management of hypertension while minimizing adverse drug reactions and drug-drug interactions (Al-Qurain et al., 2021).

Another finding from the current study is that age, gender, and body weight were significantly higher in the AFC group. This finding aligns with previously published studies where these characteristics were linked to increased risk of falls and falls related injuries among older population (Wei and Hester, 2014; Waters et al., 2019; Minhee et al., 2023). However, the regression model did not identify significant association between these characteristics and AFC prescribing. Instead, these variables were included in the multivariable regression model to control for their confounding effect. The associations observed between AFC prescribing and high CCI scores and OHD use suggest an independent link, supporting the need for caution in AFC prescribing irrespective of baseline demographic differences.

In the current study, patients with CHF, CKD, and ESRD were excluded from the definition of AFC to reduce misclassification because the retrospective design precludes confirmation of prescribing intent. Therefore, we cannot definitively confirm whether frusemide was added to manage amlodipine-induced oedema. To address this, a sensitivity analysis excluding patients with liver cirrhosis, a potential alternative indication for diuretics, was conducted and the results were consistent with the early findings. However, prospective studies are needed to accurately establish causality and sequence of prescribing decisions.

This study has several notable strengths. The current study is the first of its kind to report on the prevalence of AFC prescriptions and evaluate factors contributing to increased fall risk among patients attending a cardiology clinic in the Eastern Region of Saudi Arabia. Specifically, amlodipine and frusemide are common medications prescribed for older populations and their use can be defined as prescriber cascade in some cases which is an important medication related problem especially in the geriatric medicine. Additionally, the study benefits from a large sample size, providing robust statistical power to detect associations between AFC prescription and the identified risk factors. The comprehensive analysis, incorporating binary linear regression, allows for a more thorough assessment of the factors contributing to increased fall risk associated with AFC prescription. Furthermore, the study explores differences in AFC prescription patterns between middle-aged and older patients, which could help develop strategies for detecting the phenomenon and mitigating fall risk in different patient groups.

However, several limitations should be acknowledged. As retrospective cross-sectional study, it was difficult to accurately identify the phenomenon of prescribing cascade owing to the inability to determine the exact initiation date of the prescribed medications. To address this, the study investigated the concurrent prescription of amlodipine and frusemide as an indicator for the occurrence of this phenomenon (Vouri et al., 2018; Savage et al., 2020). Another limitation is the lack of information regarding the duration of AFC prescription. Due to the retrospective design and the nature of electronic health records used in this study, we were unable to determine whether the prescriptions were chronic or short-term. As such, the AFC exposure was assessed only as a binary variable, and the impact of duration on fall risk could not be evaluated. In addition, the cross-sectional design limited the ability to assess the appropriateness of medications and to interpret adverse drug reactions more broadly. Another limitation is the absence of body mass index data due to incomplete height documentation in the medical records, which precluded the assessment of obesity status. While body weight was included in the analysis, it may not fully capture obesity-related risk. Frailty was not directly measured in this study due to the retrospective nature of data collection. While CCI was used as a proxy indicator of frailty-related burden (Charlson et al., 1987), we recognize that it is primarily a mortality risk tool and not a validated frailty assessment instrument, but was used to estimate frailty status based on the patients’ current disease states. Future prospective studies should incorporate structured frailty tools for more accurate risk stratification. The Lack of follow-up data further limited the understanding of longer-term treatment outcomes, including efficacy, adverse drug reactions, and readmission rates. Lastly, due to its cross-sectional in nature, this study did not allow for an examination of the trajectory of AFC prescription over time or their associations with changes in hypertension and fall incidence trajectories.

Based on our results, interventions should be implemented to increase healthcare providers’ awareness of the potential fall risk associated with AFC prescriptions. Such interventions could include educational programs, clinical guidelines, or decision-support tools to equip healthcare professionals with the necessary knowledge to identify and prevent unnecessary prescribing cascades in these patients.

The phenomenon of prescribing cascade has gained attention within geriatric medicine as a significant contributor to the global challenge of polypharmacy (Brath et al., 2018). Therefore, early detection and assessment of AFC prescription are a crucial component of comprehensive care for these patients (Scott et al., 2015). It is recommended that patients at risk of falls associated with AFC prescription be closely monitored to ensure appropriate management of blood pressure and prevention of adverse drug reactions.

AFC prescriptions remain an ongoing concern, with 18% of the cohort being prescribed this combination. Older age, diabetes mellitus and anemia were more common among patients prescribed AFC. AFC prescriptions were associated with OHDs prescriptions and increasing CCI score. This study highlights the importance of comprehensive patient assessment to minimize fall risk and related complications among patients prescribed AFC.