Background
A hip fracture is associated with considerable socio-economic costs [
1] and constitutes a high-risk situation for an elderly patient, as the mortality for patients older than 65 years is 12–35% within the first year after the fracture [
2] and remains elevated for several years [
3]. Several medications have been identified as fall-risk-increasing drugs (FRIDs) [
4‐
8]. The association between an increased risk of falling and the use of psychotropic medications, such as antidepressants, antipsychotics and benzodiazepines, seems well established, as indicated by odds ratios ranging from 1.3 to 2 in a recent metanalysis [
8]. The association between falls and the use of cardiovascular medications, including antihypertensives and antiarrhythmics, does not seem quite as consistent [
6]. However, in clinical practice, cardiovascular medications are often regarded as FRIDs, [
9,
10] as their adverse effects can directly or indirectly cause dizziness, hypotension and orthostatic hypotension. Several reports have shown that more than 90% of elderly people experiencing a fall or a hip fracture are taking FRIDs [
10,
11]. Thus, FRIDs can be regarded as a modifiable risk factor. Furthermore, a recent study showed that 85% of elderly patients with a hip fracture were prescribed potentially inappropriate medications (PIMs), which may be unnecessary or entail a high risk of adverse effects [
12]. The Screening Tool of Older Persons’ Prescriptions (STOPP) [
13] may guide the performance of a medication review, both by pointing out situations in which certain medications are potentially inappropriate and by identifying certain FRIDs as PIMs.
Given the high prevalence of FRIDs and PIMs among elderly patients, it may be hypothesized that medication reviews and interventions to reduce FRIDs and PIMs in this group would effectively reduce the risk of falling. However, two recent randomized studies investigating the effect of FRID-withdrawal among more than 600 elderly people experiencing a fall [
9], and the effect of medication reviews [
14] among 199 elderly patients with hip fractures [
14] did not find an effect of these interventions on the rate of falls during a 12-month follow-up period. Possible explanations include competing risk factors for falling, such as comorbidities, and impaired cognition, balance, or vision. In addition, extrinsic factors influencing the subject [
15,
16] may play a role in many falls.
Even though the prevalence of FRID users among patients with a hip fracture is high, it is not known how often FRIDs actually contribute to the fall. This knowledge is essential to understanding how much the incidence of hip fracture could potentially be reduced by stopping the use of these medications. Thus, the aims of our study were to estimate the prevalence of medication-related falls leading to a hip fracture in a population of elderly patients admitted to a joint orthopaedic and geriatric ward and to assess the role of FRIDs and PIMs.
Methods
Study design and population
This study was a retrospective cross-sectional study. Two hundred consecutive patients with hip fracture, aged 65 years or older, admitted to a Danish University Hospital during a period of 24 weeks in 2017 were identified by a search in the hospital’s database using the ICD-10 codes for fracture of the femur (DS72-DS729).
Evaluation and definition of medication-related falls, FRIDs and PIMs
A consultant in Clinical Pharmacology (CUA) reviewed all patient records, focusing on 1) the description of the fall episode, including fall-related symptoms and the conclusions regarding the causes of the fall, made by the attending geriatrician during admission; 2) comorbidities, demographic data and medication list at the time of admission; 3) blood pressure, respiratory frequency, peripheral saturation, body temperature and heart rate at the time of and during admission; 4) laboratory data including c-reactive protein, leucocyte count, electrolytes, haemoglobin, liver and renal parameters, and blood glucose; 5) the results of other diagnostic evaluations performed during admission; and 6) medication withdrawals or changes during admission.
FRIDs were defined in accordance with previous work on fall-risk-related medications [
6‐
8,
13,
17,
18]: 1) psychotropic medications (antidepressants, antipsychotics, antiepileptic medications, medications for Parkinson’s disease, medications for dementia, first-generation antihistamines, benzodiazepines or benzodiazepine-like medications (zopiclone and zolpidem) and opioids); 2) cardiovascular medications (calcium antagonists, angiotensin converting enzyme (ACE)-inhibitors, angiotensin-II receptor (AT-II) antagonists, beta-adrenoceptor antagonists, alpha-adrenoceptor antagonists, diuretics, nitrous vasodilators, and anti-arrhythmic medications); and 3) urinary antispasmodics. PIMs were identified by review of the patients’ medication lists according to the STOPP version 2, [
13] available from the Danish Geriatric Society. Furthermore, the indications, contra-indications and interactions for each prescribed medication, as listed in the Summary of Product Characteristics found on the homepage of the Danish Medicines Agency, were also considered for each patient. All data mentioned above was entered in case report forms during the initial review.
The clinical pharmacologist excluded a suspected medication-related fall if a patient had not experienced a fall, was not using any medications or FRIDs, or if a non-medication-related fall cause was described in the patient record. Otherwise, the clinical pharmacologist and a consultant in Geriatrics (POL, HU, or NA) discussed the case in order to obtain a consensus about whether one or more medications were likely contributors to the fall. Medications were generally considered likely contributors to the fall if their effects, adverse effects or interactions could have caused or aggravated symptoms or clinical findings related to the fall episode, for example, orthostatic hypotension. If we concluded that medications were likely contributors to the fall, we defined the patient as having had a suspected medication-related fall. If the fall was more likely explained by the consequences of acute or chronic disease, tripping or extrinsic factors, we did not consider medications likely contributors. Patients who were not attended by an on-site geriatrician during admission were evaluated retrospectively following the same procedure as that used for the rest of the patients.
Data handling and statistical analysis
Study data were collected and managed using REDCap (Vanderbilt, USA) electronic data capture tools hosted at Aalborg University. REDCap is a secure, web-based application designed to support data capture for research studies [
19]. Data were exported for statistical analysis or graphics in STATA (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC). The distribution of variables was evaluated according to histograms and Q-norm plots, and data that had a normal distribution were summarized as means ± standard deviations (SDs). Variables that were not normally distributed were summarized by medians [25th percentile, 75th percentile], and differences between two groups were tested by the Wilcoxon rank-sum test. Differences in the prevalence of diseases between patients with and without a suspected medication-related fall were analysed by two-sample z-test. Differences in age, clinical data and the number of medications and FRIDs among multiple groups were analysed by regression with a bootstrap analysis. The differences between proportions of patients with PIMs among multiple groups were compared by pairwise two-sample z-tests. Power calculation to estimate study size was not performed due to lack of data to support this. Analyses were performed without imputation of missing data. The number of patients with missing data are indicated for each variable in footnotes of tables. Percentages of patients with a given condition (e.g. sodium < 132 mmol/l) were calculated by dividing the number of confirmed cases with the total number of patients in the population (200).
Discussion
We found that the prevalence of suspected medication-related falls leading to hip a fracture among elderly patients was 41%. Furthermore, we identified at least one of the medications found to contribute to the fall as potentially inappropriate in 90% of patients with a suspected medication-related fall.
The clinical data point to an influence of factors other than medication, e.g., extrinsic sources or chronic or acute illness, in the incident leading to a hip fracture in more than half of the patients. However, the estimated 41% prevalence of suspected medication-related falls suggests that medications are a major risk factor. We have not identified other studies estimating the prevalence of medication-related falls in hip fracture patients, and we were expecting a higher occurrence of suspected medication-related falls due to the frequent use of FRIDs in hip fracture patients [
10,
11]. Medications can be considered modifiable risk factors, and we identified an overlap between medications found to contribute to the fall episode and medications identified as PIMs in the majority of the patients with a suspected medication-related fall. Interestingly, the number of medications suspected to be involved in the fall episode was often higher than the number identified as PIMs. Hence, a medication review may reduce the risk of medication-related falls but cannot eliminate it in all at-risk patients, suggesting that the prevalence of potentially
avoidable medication-related fall-induced hip fractures might be markedly lower than 41%. This suggests that trials exploring the effect of medication reviews either requires a very large number of participants with falls or should be targeted at high risk groups. Our data may guide studies on the latter. In line with this, it has yet to be proven that withdrawal of medications reduces the risk of falls [
9,
14,
20]. The randomized study by Boye et al. [
9] showed that withdrawal of FRIDs did not alter the fall rate or number of FRIDs after 12 months, and they proposed a lack of compliance with the withdrawal or prescription of new medications as possible explanations [
9]. Accordingly, the number of FRIDs may actually increase after a hip fracture, [
21] indicating that medication reviews among elderly patients should be a primary prophylactic modality. To select patients in whom to perform a medication review, our data points towards patients prescribed a higher number of medications and FRIDs, as these were the only obvious risk factors that detected those individuals with a suspected medication-related fall. The finding of a higher prevalence of ischaemic heart disease and previous fractures may be explained by an association of these conditions with a higher usage of medications.
We found that the most common FRIDs associated with suspected medication-related falls were psychotropic medications, particularly selective serotonin reuptake inhibitors and benzodiazepines or benzodiazepine-like medications, followed by antihypertensives and diuretics. This can be explained by the known adverse effects of these drugs [
6,
8] and their widespread use. Thus, it is important to focus on these medications when performing medication reviews in order to reduce the risk of medication related falls. Nevertheless, thiazides may also have a beneficial effect on bone strength by increasing renal calcium reabsorption [
22]. The use of medications with an established bone-demineralizing effect, such as oral corticosteroids, aromatase inhibitors and enzyme-inducing anti-epileptics, was infrequent in our population, suggesting a limited contribution to falls by these medications among hip fracture patients. However, we could not evaluate the lifetime use of medications, and the long-term effect of prior use of such medications cannot be excluded in our study.
This study has several limitations. For one thing, the population is relatively small. The retrospective design implies that we had to rely on data obtained routinely and the possibility of focused examinations and interviews was precluded. The evaluation of clinical data and falls was not blinded to the list of medications, and the evaluations of the role of medications may have varied depending on the observer. On the other hand, the retrospective design [
23] allowed us to study an unselected population of consecutive elderly patients with hip fractures, with access to clinical data, laboratory data and a detailed description of the fall episode. The validity of the description of the fall episode in the patient record is strengthened by the fact that this is a designated clinical task for the on-site consultant in geriatrics. Furthermore, the joint expertise of the clinical pharmacologist and the geriatrician in the evaluation of the individual patient records strengthens the evaluations and conclusions in our report. The female preponderance, age, high frequency of comorbidities, widespread use of medications, FRIDs, and PIMs in our patients correspond well to those from other studies of Danish and international cohorts of patients with hip fractures [
11,
12,
24‐
26]. Thus, our population may be a representative sample of elderly patients with hip fracture. Altogether, we consider our result to be a qualified estimate of the prevalence of medication-related falls in elderly hip fracture patients.
Conclusions
The prevalence of suspected medication-related falls was 41% in elderly patients admitted with a hip fracture. It seems likely that a medication review followed by withdrawal of inappropriate medications could have reduced, though not eliminated, the risk of falling in 74 (37%) of the total population. Still, intervention studies are warranted and the present data may support planning of such studies.
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