- Email: [email protected]
Factors associated with the use of potentially inappropriate medications by older adults with cancer
JGO-00430; No. of pages: 5; 4C: Journal of Geriatric Oncology xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Journal of Geriatric Oncology
Factors associated with the use of potentially inappropriate medications by older adults with cancer Cristiane Moreira Reis a,b, Andrezza Gouvêa dos Santos b, Paula de Jesus Souza b, Adriano Max Moreira Reis b,⁎ a b
Hospital das Clínicas, Universidade Federal de Minas Gerais, Av. Professor Alfredo Balena, 110, Belo Horizonte, Minas Gerais, Brazil Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627 Pampulha Belo Horizonte, Minas Gerais, Brazil
a r t i c l e
i n f o
Article history: Received 18 January 2017 Received in revised form 24 March 2017 Accepted 24 May 2017 Available online xxxx Keywords: Aged Drug therapy Inappropriate prescribing Potentially inappropriate medication list Neoplasm Oncology
a b s t r a c t Objectives: To determine the frequency and the factors associated with the use of potentially inappropriate medications (PIMs) by older adults with cancer at an onco-haematology ambulatory clinic of a teaching hospital in Brazil. Material and Methods: Patients aged 60 years or older (n = 160) subjected to parenteral antineoplastic chemotherapy from May to December 2015 and treated with one or more medications in the ambulatory clinic were interviewed. Data on medications, comorbidities, oncological diagnosis, and functional status were recorded. Functionality was determined using the Vulnerable Elders Survey (VES-13). PIMs were determined using the 2015 Beers Criteria. Logistic regression was used to determine the factors associated with the use of PIMs. Results: A total of 78 (48.1%) older adults used at least one PIM. The PIMs to be avoided by older adults were proton pump inhibitors (33.3%), antiemetics (10.5%), long-acting benzodiazepines (10.5%), and antidepressants (7.6%). Multivariate analysis indicated that PIMs were associated with the use of five or more medications (odds ratio, 3.14; 95% confidence interval, 1.4–6.6), after adjusting for the number of medications, number of comorbidities, depression, and arthritis/arthrosis. Conclusion: The frequency of use of PIMs by older adults at the investigated ambulatory clinic was high. Polypharmacy was positively associated with the use of PIMs. © 2017 Elsevier Ltd. All rights reserved.
1. Introduction A new era in cancer care is underway in many countries owing to demographic transitions. The continued growth in the proportion of ageing population in these countries has resulted in a large number of older adults with cancer. As a consequence of the increase in ageing population and life expectancy, the number of older patients who require cancer management is increasing [1–3]. Older adults have an increased prevalence of comorbidities that can affect cancer prognosis and treatment tolerance [3]. Comorbidities contribute to the use of multiple medications, which can lead to increased adverse drug events [4–8]. Age-associated changes in pharmacokinetics and pharmacodynamics have a significant impact on the clinical pharmacology of antineoplastic agents and also of drugs used to treat comorbidities [1,2,5]. Drug therapy, comorbidities, and the physiologic status of older adults may influence the selection of and tolerance to cancer treatment. Moreover, the biology of certain cancers and their responsiveness to therapy change with the patient's age [3]. In treating older adults with cancer, age-related issues should form the basis for the development ⁎ Corresponding author. E-mail address: [email protected] (A.M.M. Reis).
of guidelines that address special considerations in oncology for older patients [2,3]. Medications can be defined as potentially inappropriate for older people when the risks of adverse events outweigh the clinical benefits, particularly when safer alternatives exist [9,10]. Inappropriate prescribing to older patients has become an important public health issue [4–6,9,10]. The use of polypharmacy and potentially inappropriate medications (PIMs) are relevant pharmacotherapy problems, particularly in older adults, including patients with cancer [3–8]. In older adults, these problems are associated with adverse medication events, falls, fractures, disorientation, cognitive impairment, worsening of the quality of life, hospitalization, and mortality [1,3–8]. The prevalence of the use of PIMs in older adults with cancer ranges from 21% to 51% [3,5,10–15], and the explicit criteria used previously were the 2003 and 2012 Beers Criteria, 2008 Screening Tool for Older Person's Prescription (STOPP), and Healthcare Effectiveness Data and Information Set and Drugs to Avoid in the Elderly (HEDIS-DAE) [5,10, 12–14,16]. The Beers Criteria were updated by the American Geriatric Society in 2015 [9]; however, studies involving the use of PIMs in older adults with cancer using this version have not been published to date. In addition, we have not been able to identify any investigations on the prevalence of use of PIMs in older patients with cancer in Brazil. The purpose of this study was to investigate the frequency of
http://dx.doi.org/10.1016/j.jgo.2017.05.003 1879-4068/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article as: Reis CM, et al, Factors associated with the use of potentially inappropriate medications by older adults with cancer, J Geriatr Oncol (2017), http://dx.doi.org/10.1016/j.jgo.2017.05.003
2
C.M. Reis et al. / Journal of Geriatric Oncology xxx (2017) xxx–xxx
use of PIMs in older adults in an onco-haematology ambulatory clinic and the factors associated with their use. 2. Methods 2.1. Study Design and Patients This cross-sectional study evaluated older adults in an oncohaematology ambulatory clinic of a teaching hospital in southeastern Brazil. The convenience sample consisted of 160 patients, who were enrolled from May to December 2015. The patients were identified from the institution's computerized scheduling system for parenteral chemotherapy. The patients were interviewed before chemotherapy. To be included in the study, patients were required to have met the following criteria: age ≥ 60 years, a diagnosis of neoplasia, treatment with medications classified as L01 (antineoplastic agents) or L02 (endocrine therapy) according to the Anatomical Therapeutic Chemical code classification system [17], and use of one or more medications prescribed to supportive care or diseases other than cancer. 2.2. Data Collection Socio-demographic variables and prescribed and non-prescribed medications were recorded during the patient interview. Older adults were asked to report all medications in use in the last 30 days. The antineoplastic medication and medication used for supportive therapy were recorded in the chemotherapy prescription. The medical record included clinical variables related to cancer and co-morbidities. Information about medications used to treat co-morbidities was also noted in the medical record. 2.3. Variables The dependent variable was the use of PIMs by older adults. The 2015 American Geriatric Society Beers Criteria for PIM Use in Older Adults were used to identify PIMs. This included medications to avoid for many or most older adults outside of palliative care and hospice service [9]. Independent variables were divided into socio-demographic, clinical, pharmacotherapy, and functionality data. Socio-demographic data included sex and age (≥ 70 years and b 70 years). Clinical data included the type of neoplasia and self-reported comorbidities. Pharmacotherapy data included polypharmacy (five or more medications used daily, concomitantly, and according to medical prescription), and overthe-counter medication. In addition, the type of cancer was identified for characterization of the sample. With regard to functionality data, the Vulnerable Elders Survey (VES-13) was used to evaluate the risk of functional decline in 12 months (scores 0–2 versus 3–10), in which higher scores indicated higher vulnerability [11,18]. The VES-13 used in this study was validated in Brazil in a sample of patients with cancer, and showed adequate psychometric properties [18]. 2.4. Data Analysis The data collected were entered into a database created using EpiData 3.1 software. Descriptive analysis was performed by determining the frequencies and percentages of the categorical variables, and measures of central tendency (mean and median) and dispersion (standard deviation and interquartile range [IQR]) were determined for quantitative variables. The association between PIMs and independent variables was analysed using the chi-squared test or Fisher's exact test. The confidence interval used was 95%, and the significance level was 0.05. The independent variables with p-values ≤ 0.25 in the univariate analysis were included in the logistic regression model. The variables with p-values ≤ 0.05 remained in the final model. The likelihood ratio test was used to compare the models. The adequacy of the
final models was evaluated using the Hosmer-Lemeshow test. The magnitude of the association between dependent and independent variables was estimated using the odds ratio (OR) with the interval of 95% of confidence (IC95%) in both univariate and multivariate analysis. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) software version 21.0. 2.5. Ethical Approval The Research Ethics Committee of the University approved the research and the older adults who agreed to participate in the research signed a free and informed consent form. 3. Results The 160 older adults included in the study had a median age of 67.5 years, with an IQR of 10, and 57.5% of the study sample comprised women. The most prevalent comorbidities were hypertension (33.9%), diabetes (13.1%), arthritis/arthrosis (10.6%), and depression (10.2%). The median number of self-reported comorbidities was two. The most prevalent cancer types diagnosed were breast (28.1%), colorectal (22.5%), and lung (7.5%) (Table 1). The median number of medications used daily was three, with a 25th percentile of one and 75th percentile of four, and the maximum number of medications used was eight. The prevalence of polypharmacy was 26.2%. The median number of medications used by the patients, including antineoplastics, was nine, with a 25th percentile of seven and a 75th percentile of 11. Twenty-two older adults (13.8%) reported over the counter medication. The number of older adults who used at least one PIM was 78 (48.1%), and the maximum number of PIMs used was four. Among the 78 older adults, 50 (64.9%) used one PIM, 21 (27.3%) used two PIMS, five (6.5%) used three PIMS, and one (1.3%) used four PIMS. The PIMs most commonly used by the Table 1 Clinical characteristics of the 160 older adults in the study. Characteristic
Value
Score from the VES-13 [median (interquartile range)] Type of cancer Solid tumours Breast Colorectal Lung Stomach Prostate Oesophagus Others Haematologic neoplasias Myelomas Lymphomas Leukaemias Number of comorbidities [median (interquartile range)] Hypertension Diabetes Arthritis/arthrosis Depression Thyroid diseases Others Pharmacotherapy Number of medications per patient [median (interquartile range)] Patients using over-the-counter medications Patients using polypharmacy Patients using potentially inappropriate medications for older adults Number of potentially inappropriate medications for older adults per patient n (%) 1 2 3 4
1.5 (0–5)
n (%) n (%) n (%) n (%) n (%) n (%) n (%)
45 (28.1) 36 (22.5) 12 (7.5) 11 (6.9) 10 (6.3) 7 (4.4) 35 (21.9)
n (%) n (%) n (%)
2 (1.2) 1 (0.6) 1 (0.6) 2 (1–3) 109 (33.9) 42 (13.1) 34 (10.6) 33 (10.2) 19 (5.9) 85 (26.3)
n (%) n (%) n (%) n (%) n (%) n (%)
3 (3) n (%) n (%) n (%)
22 (13.8) 42 (26.2) 78 (48.1)
50 (64.9) 21 (27.3) 5 (6.5) 1 (1.3)
Please cite this article as: Reis CM, et al, Factors associated with the use of potentially inappropriate medications by older adults with cancer, J Geriatr Oncol (2017), http://dx.doi.org/10.1016/j.jgo.2017.05.003
C.M. Reis et al. / Journal of Geriatric Oncology xxx (2017) xxx–xxx
study group belonged to the following therapeutic classes: proton pump inhibitors (33.3%), antiemetics (10.5%), long-acting benzodiazepines (10.5%), and antidepressants (7.6%). Table 2 shows the therapeutic classes and the PIMs used by older adults. The older adults who used PIMs showed the following characteristics compared with those who did not use these medications: used five or more medications daily, VES-13 equal to or greater than three, presence of two or more comorbidities, arthritis/arthrosis, diabetes, depression, and over the counter medication (Table 3). After adjusting for the number of medications, number of comorbidities, depression, and arthritis/arthrosis, only polypharmacy (use of five or more medications of daily use) was independently associated with PIMs in the multivariate logistic regression (Table 3). 4. Discussion The use of PIMs by older adults in the onco-haematology ambulatory clinic investigated was high, and independently associated with polypharmacy. This study is the first to determine the prevalence of PIMs using the 2015 Beers Criteria in older patients on parenteral chemotherapy. High frequency of use of PIMs by older adults with cancer has also been reported in studies developed in the United States using the 2003 and 2012 Beers criteria [11,13]. The association between the use of PIMs and polypharmacy was also consistent with the findings of previous studies involving geriatric patients receiving ambulatory treatment for cancer [7,10,13]. Polypharmacy and the use of PIMs are serious problems in the pharmacotherapy of older adults, because they hinder adherence to treatment and increase the complexity of therapeutic regimens and health care costs. They also increase the risk of adverse drug events, falls, fractures, and disorientation. In the care of older patients with cancer, the management of cancer symptoms is complicated by the patient's complaints, which may be attributed to the cancer or its treatment, but may in fact involve adverse reactions to other medications or the use of PIMs [6,4,14–16]. The prevalence of polypharmacy in older adults found in our study was lower than that found in other studies of older adults with cancer (higher than 50%) [4,7,10]. This can be attributed to the sample characteristics, which included a median of age of 67.5 years and the presence of two comorbidities, whereas other studies have reported higher values. In developed countries, individuals aged 65 years or older are considered older adults, whereas in Brazil, individuals older than
Table 2 Potentially inappropriate medications used by 160 older adults in an oncology ambulatory clinic, according to the 2015 Beers Criteria. Therapeutic class/medication
n
%
Proton pump inhibitor: omeprazole Antiemetic: metoclopramide Long-acting benzodiazepines: diazepam, clonazepam Antidepressants: amitriptyline, paroxetine, nortriptyline First-generation antihistamine: dexchlorpheniramine Antispasmodics: atropine Long-term sulfonylurea: glibenclamide Anti-inflammatories nonselective of cyclooxygenase: diclofenac, ibuprofen Central alpha blockers: clonidine, methyldopa First- and second-generation antipsychotics: risperidone, trifluoperazine Peripheral alpha 1-blocker: doxazoxin Immediate-release nifedipine Digoxin Skeletal muscle relaxant: orphenadrine Amiodarone Anti-infective: nitrofurantoin Barbiturate: phenobarbital Orally administered mineral oil (liquid paraffin) Total
35 11 11 08 07 06 06 04
33.3 10.5 10.5 7.6 6.6 5.7 5.7 3.8
03 03
2.8 2.8
02 02 02 01 01 01 01 01 105
1.9 1.9 1.9 1.0 1.0 1.0 1.0 1.0 100.0
3
60 years are defined as older adults. Another explanation is that the non-communicable disease burden of older adults is higher in developed countries, and susceptibility to non-communicable diseases increases with age [19]. Moreover, in the present study, only prescribed medications used daily, excluding parenteral antineoplastics, were included as polypharmacy. We excluded parenteral antineoplastics because in some studies of polypharmacy were considered only drugs used for long term [20]. Other studies have included over-the-counter drugs and herbal medicines (including alternative and complementary treatments) in their definitions of polypharmacy. An Australian study reported that the frequency of use of PIMs among individuals with cancer aged between 75 and 79 years was 26.5%, and investigated the correlation with fragility [7]. In our study older adults at greater risk of functional decline and consequently with greater chance of vulnerability and fragility were identified using the VES-13. Despite the more frequent use of PIMs among older adults with VES ≥ 3, this variable was not significantly associated with PIMs in the univariate analysis. Fragility decreases physiological function and impairs homeostatic mechanisms [3,7]. Medications included in the Beers list as sedative and anticholinergic agents are associated with incident frailty. Frail older adults show increased risk of adverse drug events, including falls, hospitalization, and mortality. In addition, fragility may influence decisions on the treatment of older adults with cancer [3,7,21]. The use of proton pump inhibitors is frequent in patients with gastrointestinal cancer [16], one of the tumour types that was predominant in our study sample, which may explain the finding that omeprazole was the most commonly used PIM by older adults. Another contributing factor to this high prevalence is the practice by some physicians of prolonging omeprazole therapy even after symptoms improve. Despite the effectiveness of the prolonged therapy for the management of gastro-oesophageal reflux, the prolonged use of proton pump inhibitors may contribute to adverse events in patients with cancer [16], including increased risk of hypokalaemia, hypomagnesaemia, osteoporosis, fractures, and infections [22]. Several studies and five systematic and meta-analysis reviews demonstrated an association between the use of proton pump inhibitors for long periods and infection with Clostridium difficile, as well as bone loss and fractures [9]. In Japanese studies, the use of omeprazole was associated with hypomagnesaemia, bone fractures, and deficient absorption of calcium, vitamin B12, and iron [22,23]. Prior to the development of 5-serotonin, metoclopramide was used as first-line therapy for prevention of nausea and vomiting induced by chemotherapy. However, the current guidelines suggest the use of metoclopramide only for treatment of breakthrough emesis [24,25]. The adverse effects of metoclopramide include neurological effects such as extrapyramidal symptoms and tardive dyskinesia. The 2015 Beers Criteria classify metoclopramide as a PIM because of the occurrence of these drug adverse reactions. The 2016-2 version of the NCCN Guidelines for Antiemesis advises caution in the use of metoclopramide in older adults at risk of falling because of the risk of extrapyramidal symptoms, and warns about the need to monitor the duration of treatment, QT interval prolongation, and dystonic effects. It also highlights that adverse events increase as the dose increases [26]. Metoclopramide was used in the investigated ambulatory clinic because neurokinin antagonists and the new serotonin receptor antagonists were not included in the hospital formulary as therapeutic alternatives in the treatment of emesis induced by antineoplastics. The combined prescription of metoclopramide, ondansetron, and dexamethasone for patients receiving antiemetic treatment is common in the investigated institution. In a study that analysed the relationship between the use of PIMs and chemotherapy toxicity, the authors questioned the classification of metoclopramide, atropine, pro-chlorpheniramine, diphenoxylate, and lorazepam as PIMs because these medications are used to reduce symptoms induced by antineoplastic therapy [1]. The classification of
Please cite this article as: Reis CM, et al, Factors associated with the use of potentially inappropriate medications by older adults with cancer, J Geriatr Oncol (2017), http://dx.doi.org/10.1016/j.jgo.2017.05.003
4
C.M. Reis et al. / Journal of Geriatric Oncology xxx (2017) xxx–xxx
Table 3 Univariate and multivariate analysis of the factors associated with the use of potentially inappropriate medications in a sample of older adults included in the study, Belo Horizonte, MG, Brazil, 2015 (n = 160). Description
Potentially inappropriate medication used
Univariate analysis
Variable
Yes n (%)
No n (%)
Odds ratio (IC 95%)
p-value
47 (51.1) 35 (51.5)
1.0 (0.54–1.90) 1
0.962
34 (55.7) 48 (48.5)
0.7 (0.39–1.41) 1
0.373
13 (31.0) 69 (58.5)
3.1 (1.48–6.64) 1
0.002
26 (48.1) 56 (52.8)
1.2 (0.62–2.32) 1
0.575
45 (47.4) 37 (56.9)
1.5 (0.77–2.77) 1
0.235
14 (41.2) 68 (54)
1.6 (0.77–3.61) 1
0.185
19 (45.2) 63 (53.4)
1.3 (0.68–2.81) 1
0.364
13 (39.4) 69 (53.4)
1.8 (0.83–3.99) 1
0.126
10 (52.6) 72 (51.1)
0.9 (0.36–2.45) 1
0.898
58 (53.2) 24 (47.1)
0.7 (0.40–1.52) 1
0.468
10 (45.5) 72 (52.2)
0.34 1
0.558
Gender Female 45 (48.9) Male 33 (48.5) Age in years ≥70 27 (44.3) b70 51 (51.5) Number of medications ≥5 29 (69) b5 49 (41.5) Score from the Vulnerable Elders Survey (VES-13) ≥3 28 (51.9) b3 50 (47.2) Number of comorbidities ≥2 50 (52.6) b2 28 (43.1) Arthritis/arthrosis Yes 20 (58.8) No 58 (46) Diabetes Yes 23 (54.8) No 55 (46.6) Depression Yes 20 (60.6) No 58 (45.7) Thyroid diseases Yes 9 (47.4) No 69 (48.9) Hypertension Yes 51 (46.8) No 27 (52.9) Over-the-counter medications Yes 12 (54.5) No 66 (47.8)
a drug as a PIM does not indicate that its prescription will be banned; however, it is a warning sign for the need to seek effective and safer alternatives in older adults. Therefore, we decided to classify metoclopramide and atropine as PIMs in this study to evaluate their frequency of use, and to highlight the importance of monitoring their use by older adults in cases in which a safer alternative is not available at the institution. The NCCN Guidelines for Older Adult Oncology version 1.2016 contains a list of medications commonly used for supportive care that are of concern in older patients, and this list includes metoclopramide, H1 antihistamines, histamine H2-receptor antagonists, phenothiazine, antipsychotics, and serotonin reuptake inhibitor antidepressants. The guidelines present treatment alternatives and recommendations to be adopted when a medication from the list should be prescribed to older adults [3]. Several medications listed in the NCCN Guidelines are also present in the 2015 Beers Criteria [9]. Diazepam and clonazepam are long half-life benzodiazepines classified as PIMs. Benzodiazepines are included in international therapeutic guidelines for management of anxiety and insomnia; however, the duration of treatment should be short and not exceed three months. The high prevalence and chronic use of benzodiazepines by older adults, together with the increase in the incidence of dementia in developed countries, are important public health concerns, and have been emphasized by the publication of a case-control study that demonstrated a higher risk of Alzheimer's disease among chronic users of benzodiazepine [27].The high frequency of benzodiazepine in our study is in line with previous investigation that found these class of drug as the PIM most prevalent. In oncological patients, lorazepam, a short half-life benzodiazepine, is used parenterally as an adjuvant in the management of nausea [1]. However, the risks are lower because the treatment period is short. Notwithstanding the short half-life, an association has been found between
Multivariate analysis Odds ratio (IC 95%)
p-value
3.1 (1.48–6.64)
0.003
the use of benzodiazepines and increased risk of falls in older adults [28]. Depression is the most common psychiatric disorder in geriatric and oncological patients. In older patients with cancer, depression compromises the quality of life and increases morbidity and mortality [3,29]. In the selection of antidepressants for older adults, it is important to evaluate anticholinergic load and the ability of the medication to induce falls, fractures, and other adverse events, which may compromise the functionality of these patients. In oncological patients, antidepressants are also used for the treatment of chemotherapy-induced neuropathy. The use of low doses of tricyclic antidepressants in older oncological patients has been recommended to achieve the desired benefits without bringing risks to these patients [3,16]. A medication considered a PIM may be appropriate for an older adult in cases in which a clinical evaluation is performed to assess specific risk factors in this population [3,16]. A comprehensive geriatric evaluation should consider the use of concomitant medications, as well as the functionality and predictors of fragility in older adults, to optimize the care of older adults with cancer [3,6,30]. The contributions of clinical pharmacists to the care of older patients with cancer receiving ambulatory treatment using polypharmacy and PIM, as well as the importance of a comprehensive assessment of pharmacotherapy, have been described [13,14,15]. The assessment of pharmacotherapy should include aspects of geriatric and oncological pharmacotherapy, prescribed medications, over the counter medication, herbal medicines and other alternative and complementary treatments, PIM, taking into account pharmacokinetic and pharmacodynamic changes that result from ageing. This strategy is important to evaluate the treatment of older adults with cancer, increase the effectiveness and safety of pharmacotherapy, and reduce the impact of PIMs on the functionality, autonomy, and quality of life of patients.
Please cite this article as: Reis CM, et al, Factors associated with the use of potentially inappropriate medications by older adults with cancer, J Geriatr Oncol (2017), http://dx.doi.org/10.1016/j.jgo.2017.05.003
C.M. Reis et al. / Journal of Geriatric Oncology xxx (2017) xxx–xxx
This study has some limitations. First, it evaluated a single institution with a small convenience sample, which prevents generalizations. Second, the cross-sectional nature of data collection limited the evaluation of causality between PIMs and the explanatory variables related to functional status, pharmacotherapy, and clinical conditions. Third, a recall bias is possible because older adults may not remember all medications they are taking. To mitigate this bias, we compared their self-reported medications list with their medical record. We did not ask about palliative care, which is another limitation, because the Beers Criteria include all ambulatory settings, with the exception of hospice and palliative care. However, considering the profile of nonantineoplasic drugs used by the patients in the study, the number of patients receiving palliative care could be small. Studies using the Beers Criteria to consider inappropriate medication use in older adults due to drug-disease or drug-syndrome interactions that may exacerbate the disease should be developed, to better assess the prevalence of PIMs in patients with cancer. A strength of this study was that the use of 2015 Beers was validated in ambulatory setting. In conclusion, our findings show that the frequency of use of PIMs by older adults in parenteral antineoplastic therapy at the investigated ambulatory clinic is high. Polypharmacy showed a positive association with the use of PIMs. The use of medications that should be prescribed with caution in older adults is also high. Disclosures and Conflict of Interest Statements The authors declare that they have no conflicts of interest Author Contributions Study concept: CM Reis, AM Reis. Study design: CM Reis, AM Reis. Data acquisition: CM Reis, P de Jesus Souza, A Gouvêa dos Santos. Quality control of data and algorithms: CM Reis, AM Reis. Data analysis and interpretation: CM Reis, AM Reis, P de Jesus Souza; A Gouvêa dos Santos. Statistical analysis: CM Reis, AM Reis. Manuscript preparation: CM Reis, AM Reis. Manuscript editing: CM Reis, AM Reis. Manuscript review: CM Reis, P de Jesus Souza; A Gouvêa dos Santos, AM Reis. Acknowledgements The authors are grateful to the Pró-Reitoria de Pesquisa, Universidade Federal de Minas Gerais for funding this research through the Qualitative Improvement Program of Scientific Production, and to the Fundação de Amparo à Pesquisa do Estado de Minas GeraisFAPEMIG for providing a scientific initiation scholarship. References [1] Maggiore RJ, Dale W, Gross CP, Feng T, Tew WP, Mohile SG, et al. Polypharmacy and potentially inappropriate medication use in older adults with cancer undergoing chemotherapy: effect on chemotherapy-related toxicity and hospitalization during treatment. J Am Geriatr Soc 2014;62:1505–12. http://dx.doi.org/10.1111/jgs.12942. [2] He X, Clarke SJ, Andrew J. Clinical pharmacology of chemotherapy agents in older people with cancer. Curr Gerontol Geriatr Res 2011;628670. http://dx.doi.org/10. 1155/2011/628670. [3] National Comprehensive Cancer Network. NCCN guidelines version1.2016: older adult oncology. Available at: http://www.nccn.org/professionals/physician_gls/ f_guidelines_nojava.asp#age; 2016. (Accessed 15 August 2016). [4] Turner JP, Shakib S, Singhal N, Hogan-Doran J, Prowse R, Johns S, et al. Prevalence and factors associated with polypharmacy in older people with cancer. Support Care Cancer 2014;22:1727–34. http://dx.doi.org/10.1007/s00520-014-2171-x. [5] Sharma M, Loh KP, Nightingale G, Mohile SG, Holmes HM. Polypharmacy and potentially inappropriate medication use in geriatric oncology. J Geriatr Oncol 2016;7:346–53. http://dx.doi.org/10.1016/j.jgo.2016.07.010.
5
[6] Lichtman SM. Polypharmacy: geriatric oncology evaluation should become mainstream. J Clin Oncol 2015;33:1422–3. http://dx.doi.org/10.1200/JCO.2014.60.3548. [7] Saarelainen LK, Turner JP, Shakib S, Singhal N, Hogan-Doran J, Prowse R. Potential inappropriate medication use in older people with cancer: prevalence and correlates. J Geriatr Oncol 2014;5:439–46. http://dx.doi.org/10.1016/j.jgo.2014.07.001. [8] Lees J, Chan A. Polypharmacy in elderly patients with cancer: clinical implications and management. Lancet Oncol 2011;12:1249–57. http://dx.doi.org/10.1016/ S1470-2045(11)70040-7. [9] American Geriatrics Society. Beers Criteria Update Expert Panel. American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2015;63:2227–46. http://dx.doi.org/10.1111/jgs. 13702. [10] O'Mahony D, O'Sullivan D, Byrne S, O'Connor MN, Ryan C, Gallagher P. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing 2015;44:213–8. http://dx.doi.org/10.1093/ageing/afu145. [11] Prithviraj GK, Koroukian S, Margevicius S, Berger NA, Bagai R, Owusu C. Patient characteristics associated with polypharmacy and inappropriate prescribing of medications among older adults with cancer. J Geriatr Oncol 2012;3:228–37. http://dx.doi.org/10.1016/j.jgo.2012.02.005. [12] Flood KL, Carroll MB, Le CV, Brown CJ. Polypharmacy in hospitalized older adult cancer patients: experience from a prospective, observational study of an oncology-acute care for elders unit. Am J Geriatr Pharmacother 2009;7:151–8. http://dx.doi.org/10.1016/j.amjopharm.2009.05.002. [13] Nightingale G, Hajjar E, Swartz K, Andrel-Sendecki J, Chapman A. Evaluation of a pharmacist-led medication assessment used to identify prevalence of and associations with polypharmacy and potentially inappropriate medication use among ambulatory senior adults with cancer. J Clin Oncol 2015;33:1453–9. http://dx.doi. org/10.1200/JCO.2014.58.7550. [14] Park JW, Roh JL, Lee SW, Kim SB, Choi SH, Nam SY, et al. Effect of polypharmacy and potentially inappropriate medications on treatment and posttreatment courses in elderly patients with head and neck cancer. J Cancer Res Clin Oncol 2016;142: 1031–40. http://dx.doi.org/10.1007/s00432-015-2108-x. [15] Turner JP, Jamsen KM, Shakib S, Singhal N, Prowse R, Bell JS. Polypharmacy cutpoints in older people with cancer: how many medications are too many? Support Care Cancer 2016;24:1831–40. http://dx.doi.org/10.1007/s00520-015-2970-8. [16] Whitman AM, DeGregory KA, Morris AL, Ramsdale EE. A comprehensive look at polypharmacy and medication screening tools for the older cancer patient. Oncologist 2016;21:723–30. http://dx.doi.org/10.1634/theoncologist.2015-0492. [17] WHO. Collaborating Centre for Drug Statistics Methodology Norwegian Institute of Public Health ATC/DDD Index. Available at: http://www.whocc.no/atc_ddd_index/. (Accessed 24 February 2016). [18] Augschoell J, Kemmler G, Hamaker ME, Stauder R. PPT and VES-13 in elderly patients with cancer: evaluation in multidimensional geriatric assessment and prediction of survival. J Geriatr Oncol 2014;5:415–21. http://dx.doi.org/10.1016/ j.jgo.2014.08.005. [19] United Nation. World population ageing. Available at: http://www.un.org/en/ development/desa/population/publications/pdf/ageing/WorldPopulationAgeing2013. pdf (Accessed 27 February) 2016. [20] Veehof L, Stewart R, Haaijer-Ruskamp F, Jong BM. The development of polypharmacy. A longitudinal study. Fam Pract 2000;17:261–7. [21] Kenis C, Bron D, Liberty Y, Decoster L, Van Puyvelde K, Scalliet P, et al. Relevance of a systematic geriatric screening and assessment in older patients with cancer: results of a prospective multicentric study. Ann Oncol 2013;24:1306–12. http://dx.doi.org/ 10.1093/annonc/mds619. [22] Abramowitz J, Thakkar P, Isa A, Truong A, Park C, Rosenfeld RM. Adverse event reporting for proton pump inhibitor therapy: an overview of systematic reviews. Otolaryngol Head Neck Surg 2016;155:547–54. http://dx.doi.org/10.1177/ 0194599816648298. [23] Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fratures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep 2010;12:448–57. http://dx.doi.org/10.1007/s11894-0100141-0. [24] Gyawali B, Poudyal BS, Iddawela M. Cheaper options in the prevention of chemotherapy-induced nausea and vomiting. J Global Oncol 2016;2:145–53. http://dx.doi.org/10.1200/JGO.2015.002477. [25] Feyer P, Jordan K. Update and new trends in antiemetic therapy: the continuing need for novel therapies. Ann Oncol 2011;22:30–8. http://dx.doi.org/10.1093/ annonc/mdq600. [26] National comprehensive cancer network clinical practice guidelines in oncology: antiemesis version 2. NCCN org. Availabe at: https://www.nccn.org/professionals/ physician_gls/f_guidelines.asp#supportive; 2016. (Accessed 15 August 2016). [27] Gage SB, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, et al. Benzodiazepine use and risk of Alzheimer's disease: case-control study. BMJ 2014;349:g5205. http://dx.doi.org/10.1136/bmj.g5205. [28] Gregg JA, Tyson RL, Cook D. Benzodiazepines and geriatrics: what clinical practice strategies can be used to reduce the inappropriate prescribing? Rehabil Nurs 2016;41:270–5. http://dx.doi.org/10.1002/rnj.288. [29] Duc S, Rainfray M, Soubeyran P, Fonck M, Blanc JF, Ceccaldi J, et al. Predictive factors of depressive symptoms of elderly patients with cancer receiving first-line chemotherapy. Psychooncology 2017;26:15–21. http://dx.doi.org/10.1002/pon.4090. [30] Lichtman SM, Hurria A, Jacobsen PB. Geriatric oncology: an overview. J Clin Oncol 2014;32:2521–2. http://dx.doi.org/10.1200/JCO.2014.57.4822.
Please cite this article as: Reis CM, et al, Factors associated with the use of potentially inappropriate medications by older adults with cancer, J Geriatr Oncol (2017), http://dx.doi.org/10.1016/j.jgo.2017.05.003
Contents lists available at ScienceDirect
Journal of Geriatric Oncology
Factors associated with the use of potentially inappropriate medications by older adults with cancer Cristiane Moreira Reis a,b, Andrezza Gouvêa dos Santos b, Paula de Jesus Souza b, Adriano Max Moreira Reis b,⁎ a b
Hospital das Clínicas, Universidade Federal de Minas Gerais, Av. Professor Alfredo Balena, 110, Belo Horizonte, Minas Gerais, Brazil Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627 Pampulha Belo Horizonte, Minas Gerais, Brazil
a r t i c l e
i n f o
Article history: Received 18 January 2017 Received in revised form 24 March 2017 Accepted 24 May 2017 Available online xxxx Keywords: Aged Drug therapy Inappropriate prescribing Potentially inappropriate medication list Neoplasm Oncology
a b s t r a c t Objectives: To determine the frequency and the factors associated with the use of potentially inappropriate medications (PIMs) by older adults with cancer at an onco-haematology ambulatory clinic of a teaching hospital in Brazil. Material and Methods: Patients aged 60 years or older (n = 160) subjected to parenteral antineoplastic chemotherapy from May to December 2015 and treated with one or more medications in the ambulatory clinic were interviewed. Data on medications, comorbidities, oncological diagnosis, and functional status were recorded. Functionality was determined using the Vulnerable Elders Survey (VES-13). PIMs were determined using the 2015 Beers Criteria. Logistic regression was used to determine the factors associated with the use of PIMs. Results: A total of 78 (48.1%) older adults used at least one PIM. The PIMs to be avoided by older adults were proton pump inhibitors (33.3%), antiemetics (10.5%), long-acting benzodiazepines (10.5%), and antidepressants (7.6%). Multivariate analysis indicated that PIMs were associated with the use of five or more medications (odds ratio, 3.14; 95% confidence interval, 1.4–6.6), after adjusting for the number of medications, number of comorbidities, depression, and arthritis/arthrosis. Conclusion: The frequency of use of PIMs by older adults at the investigated ambulatory clinic was high. Polypharmacy was positively associated with the use of PIMs. © 2017 Elsevier Ltd. All rights reserved.
1. Introduction A new era in cancer care is underway in many countries owing to demographic transitions. The continued growth in the proportion of ageing population in these countries has resulted in a large number of older adults with cancer. As a consequence of the increase in ageing population and life expectancy, the number of older patients who require cancer management is increasing [1–3]. Older adults have an increased prevalence of comorbidities that can affect cancer prognosis and treatment tolerance [3]. Comorbidities contribute to the use of multiple medications, which can lead to increased adverse drug events [4–8]. Age-associated changes in pharmacokinetics and pharmacodynamics have a significant impact on the clinical pharmacology of antineoplastic agents and also of drugs used to treat comorbidities [1,2,5]. Drug therapy, comorbidities, and the physiologic status of older adults may influence the selection of and tolerance to cancer treatment. Moreover, the biology of certain cancers and their responsiveness to therapy change with the patient's age [3]. In treating older adults with cancer, age-related issues should form the basis for the development ⁎ Corresponding author. E-mail address: [email protected] (A.M.M. Reis).
of guidelines that address special considerations in oncology for older patients [2,3]. Medications can be defined as potentially inappropriate for older people when the risks of adverse events outweigh the clinical benefits, particularly when safer alternatives exist [9,10]. Inappropriate prescribing to older patients has become an important public health issue [4–6,9,10]. The use of polypharmacy and potentially inappropriate medications (PIMs) are relevant pharmacotherapy problems, particularly in older adults, including patients with cancer [3–8]. In older adults, these problems are associated with adverse medication events, falls, fractures, disorientation, cognitive impairment, worsening of the quality of life, hospitalization, and mortality [1,3–8]. The prevalence of the use of PIMs in older adults with cancer ranges from 21% to 51% [3,5,10–15], and the explicit criteria used previously were the 2003 and 2012 Beers Criteria, 2008 Screening Tool for Older Person's Prescription (STOPP), and Healthcare Effectiveness Data and Information Set and Drugs to Avoid in the Elderly (HEDIS-DAE) [5,10, 12–14,16]. The Beers Criteria were updated by the American Geriatric Society in 2015 [9]; however, studies involving the use of PIMs in older adults with cancer using this version have not been published to date. In addition, we have not been able to identify any investigations on the prevalence of use of PIMs in older patients with cancer in Brazil. The purpose of this study was to investigate the frequency of
http://dx.doi.org/10.1016/j.jgo.2017.05.003 1879-4068/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article as: Reis CM, et al, Factors associated with the use of potentially inappropriate medications by older adults with cancer, J Geriatr Oncol (2017), http://dx.doi.org/10.1016/j.jgo.2017.05.003
2
C.M. Reis et al. / Journal of Geriatric Oncology xxx (2017) xxx–xxx
use of PIMs in older adults in an onco-haematology ambulatory clinic and the factors associated with their use. 2. Methods 2.1. Study Design and Patients This cross-sectional study evaluated older adults in an oncohaematology ambulatory clinic of a teaching hospital in southeastern Brazil. The convenience sample consisted of 160 patients, who were enrolled from May to December 2015. The patients were identified from the institution's computerized scheduling system for parenteral chemotherapy. The patients were interviewed before chemotherapy. To be included in the study, patients were required to have met the following criteria: age ≥ 60 years, a diagnosis of neoplasia, treatment with medications classified as L01 (antineoplastic agents) or L02 (endocrine therapy) according to the Anatomical Therapeutic Chemical code classification system [17], and use of one or more medications prescribed to supportive care or diseases other than cancer. 2.2. Data Collection Socio-demographic variables and prescribed and non-prescribed medications were recorded during the patient interview. Older adults were asked to report all medications in use in the last 30 days. The antineoplastic medication and medication used for supportive therapy were recorded in the chemotherapy prescription. The medical record included clinical variables related to cancer and co-morbidities. Information about medications used to treat co-morbidities was also noted in the medical record. 2.3. Variables The dependent variable was the use of PIMs by older adults. The 2015 American Geriatric Society Beers Criteria for PIM Use in Older Adults were used to identify PIMs. This included medications to avoid for many or most older adults outside of palliative care and hospice service [9]. Independent variables were divided into socio-demographic, clinical, pharmacotherapy, and functionality data. Socio-demographic data included sex and age (≥ 70 years and b 70 years). Clinical data included the type of neoplasia and self-reported comorbidities. Pharmacotherapy data included polypharmacy (five or more medications used daily, concomitantly, and according to medical prescription), and overthe-counter medication. In addition, the type of cancer was identified for characterization of the sample. With regard to functionality data, the Vulnerable Elders Survey (VES-13) was used to evaluate the risk of functional decline in 12 months (scores 0–2 versus 3–10), in which higher scores indicated higher vulnerability [11,18]. The VES-13 used in this study was validated in Brazil in a sample of patients with cancer, and showed adequate psychometric properties [18]. 2.4. Data Analysis The data collected were entered into a database created using EpiData 3.1 software. Descriptive analysis was performed by determining the frequencies and percentages of the categorical variables, and measures of central tendency (mean and median) and dispersion (standard deviation and interquartile range [IQR]) were determined for quantitative variables. The association between PIMs and independent variables was analysed using the chi-squared test or Fisher's exact test. The confidence interval used was 95%, and the significance level was 0.05. The independent variables with p-values ≤ 0.25 in the univariate analysis were included in the logistic regression model. The variables with p-values ≤ 0.05 remained in the final model. The likelihood ratio test was used to compare the models. The adequacy of the
final models was evaluated using the Hosmer-Lemeshow test. The magnitude of the association between dependent and independent variables was estimated using the odds ratio (OR) with the interval of 95% of confidence (IC95%) in both univariate and multivariate analysis. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) software version 21.0. 2.5. Ethical Approval The Research Ethics Committee of the University approved the research and the older adults who agreed to participate in the research signed a free and informed consent form. 3. Results The 160 older adults included in the study had a median age of 67.5 years, with an IQR of 10, and 57.5% of the study sample comprised women. The most prevalent comorbidities were hypertension (33.9%), diabetes (13.1%), arthritis/arthrosis (10.6%), and depression (10.2%). The median number of self-reported comorbidities was two. The most prevalent cancer types diagnosed were breast (28.1%), colorectal (22.5%), and lung (7.5%) (Table 1). The median number of medications used daily was three, with a 25th percentile of one and 75th percentile of four, and the maximum number of medications used was eight. The prevalence of polypharmacy was 26.2%. The median number of medications used by the patients, including antineoplastics, was nine, with a 25th percentile of seven and a 75th percentile of 11. Twenty-two older adults (13.8%) reported over the counter medication. The number of older adults who used at least one PIM was 78 (48.1%), and the maximum number of PIMs used was four. Among the 78 older adults, 50 (64.9%) used one PIM, 21 (27.3%) used two PIMS, five (6.5%) used three PIMS, and one (1.3%) used four PIMS. The PIMs most commonly used by the Table 1 Clinical characteristics of the 160 older adults in the study. Characteristic
Value
Score from the VES-13 [median (interquartile range)] Type of cancer Solid tumours Breast Colorectal Lung Stomach Prostate Oesophagus Others Haematologic neoplasias Myelomas Lymphomas Leukaemias Number of comorbidities [median (interquartile range)] Hypertension Diabetes Arthritis/arthrosis Depression Thyroid diseases Others Pharmacotherapy Number of medications per patient [median (interquartile range)] Patients using over-the-counter medications Patients using polypharmacy Patients using potentially inappropriate medications for older adults Number of potentially inappropriate medications for older adults per patient n (%) 1 2 3 4
1.5 (0–5)
n (%) n (%) n (%) n (%) n (%) n (%) n (%)
45 (28.1) 36 (22.5) 12 (7.5) 11 (6.9) 10 (6.3) 7 (4.4) 35 (21.9)
n (%) n (%) n (%)
2 (1.2) 1 (0.6) 1 (0.6) 2 (1–3) 109 (33.9) 42 (13.1) 34 (10.6) 33 (10.2) 19 (5.9) 85 (26.3)
n (%) n (%) n (%) n (%) n (%) n (%)
3 (3) n (%) n (%) n (%)
22 (13.8) 42 (26.2) 78 (48.1)
50 (64.9) 21 (27.3) 5 (6.5) 1 (1.3)
Please cite this article as: Reis CM, et al, Factors associated with the use of potentially inappropriate medications by older adults with cancer, J Geriatr Oncol (2017), http://dx.doi.org/10.1016/j.jgo.2017.05.003
C.M. Reis et al. / Journal of Geriatric Oncology xxx (2017) xxx–xxx
study group belonged to the following therapeutic classes: proton pump inhibitors (33.3%), antiemetics (10.5%), long-acting benzodiazepines (10.5%), and antidepressants (7.6%). Table 2 shows the therapeutic classes and the PIMs used by older adults. The older adults who used PIMs showed the following characteristics compared with those who did not use these medications: used five or more medications daily, VES-13 equal to or greater than three, presence of two or more comorbidities, arthritis/arthrosis, diabetes, depression, and over the counter medication (Table 3). After adjusting for the number of medications, number of comorbidities, depression, and arthritis/arthrosis, only polypharmacy (use of five or more medications of daily use) was independently associated with PIMs in the multivariate logistic regression (Table 3). 4. Discussion The use of PIMs by older adults in the onco-haematology ambulatory clinic investigated was high, and independently associated with polypharmacy. This study is the first to determine the prevalence of PIMs using the 2015 Beers Criteria in older patients on parenteral chemotherapy. High frequency of use of PIMs by older adults with cancer has also been reported in studies developed in the United States using the 2003 and 2012 Beers criteria [11,13]. The association between the use of PIMs and polypharmacy was also consistent with the findings of previous studies involving geriatric patients receiving ambulatory treatment for cancer [7,10,13]. Polypharmacy and the use of PIMs are serious problems in the pharmacotherapy of older adults, because they hinder adherence to treatment and increase the complexity of therapeutic regimens and health care costs. They also increase the risk of adverse drug events, falls, fractures, and disorientation. In the care of older patients with cancer, the management of cancer symptoms is complicated by the patient's complaints, which may be attributed to the cancer or its treatment, but may in fact involve adverse reactions to other medications or the use of PIMs [6,4,14–16]. The prevalence of polypharmacy in older adults found in our study was lower than that found in other studies of older adults with cancer (higher than 50%) [4,7,10]. This can be attributed to the sample characteristics, which included a median of age of 67.5 years and the presence of two comorbidities, whereas other studies have reported higher values. In developed countries, individuals aged 65 years or older are considered older adults, whereas in Brazil, individuals older than
Table 2 Potentially inappropriate medications used by 160 older adults in an oncology ambulatory clinic, according to the 2015 Beers Criteria. Therapeutic class/medication
n
%
Proton pump inhibitor: omeprazole Antiemetic: metoclopramide Long-acting benzodiazepines: diazepam, clonazepam Antidepressants: amitriptyline, paroxetine, nortriptyline First-generation antihistamine: dexchlorpheniramine Antispasmodics: atropine Long-term sulfonylurea: glibenclamide Anti-inflammatories nonselective of cyclooxygenase: diclofenac, ibuprofen Central alpha blockers: clonidine, methyldopa First- and second-generation antipsychotics: risperidone, trifluoperazine Peripheral alpha 1-blocker: doxazoxin Immediate-release nifedipine Digoxin Skeletal muscle relaxant: orphenadrine Amiodarone Anti-infective: nitrofurantoin Barbiturate: phenobarbital Orally administered mineral oil (liquid paraffin) Total
35 11 11 08 07 06 06 04
33.3 10.5 10.5 7.6 6.6 5.7 5.7 3.8
03 03
2.8 2.8
02 02 02 01 01 01 01 01 105
1.9 1.9 1.9 1.0 1.0 1.0 1.0 1.0 100.0
3
60 years are defined as older adults. Another explanation is that the non-communicable disease burden of older adults is higher in developed countries, and susceptibility to non-communicable diseases increases with age [19]. Moreover, in the present study, only prescribed medications used daily, excluding parenteral antineoplastics, were included as polypharmacy. We excluded parenteral antineoplastics because in some studies of polypharmacy were considered only drugs used for long term [20]. Other studies have included over-the-counter drugs and herbal medicines (including alternative and complementary treatments) in their definitions of polypharmacy. An Australian study reported that the frequency of use of PIMs among individuals with cancer aged between 75 and 79 years was 26.5%, and investigated the correlation with fragility [7]. In our study older adults at greater risk of functional decline and consequently with greater chance of vulnerability and fragility were identified using the VES-13. Despite the more frequent use of PIMs among older adults with VES ≥ 3, this variable was not significantly associated with PIMs in the univariate analysis. Fragility decreases physiological function and impairs homeostatic mechanisms [3,7]. Medications included in the Beers list as sedative and anticholinergic agents are associated with incident frailty. Frail older adults show increased risk of adverse drug events, including falls, hospitalization, and mortality. In addition, fragility may influence decisions on the treatment of older adults with cancer [3,7,21]. The use of proton pump inhibitors is frequent in patients with gastrointestinal cancer [16], one of the tumour types that was predominant in our study sample, which may explain the finding that omeprazole was the most commonly used PIM by older adults. Another contributing factor to this high prevalence is the practice by some physicians of prolonging omeprazole therapy even after symptoms improve. Despite the effectiveness of the prolonged therapy for the management of gastro-oesophageal reflux, the prolonged use of proton pump inhibitors may contribute to adverse events in patients with cancer [16], including increased risk of hypokalaemia, hypomagnesaemia, osteoporosis, fractures, and infections [22]. Several studies and five systematic and meta-analysis reviews demonstrated an association between the use of proton pump inhibitors for long periods and infection with Clostridium difficile, as well as bone loss and fractures [9]. In Japanese studies, the use of omeprazole was associated with hypomagnesaemia, bone fractures, and deficient absorption of calcium, vitamin B12, and iron [22,23]. Prior to the development of 5-serotonin, metoclopramide was used as first-line therapy for prevention of nausea and vomiting induced by chemotherapy. However, the current guidelines suggest the use of metoclopramide only for treatment of breakthrough emesis [24,25]. The adverse effects of metoclopramide include neurological effects such as extrapyramidal symptoms and tardive dyskinesia. The 2015 Beers Criteria classify metoclopramide as a PIM because of the occurrence of these drug adverse reactions. The 2016-2 version of the NCCN Guidelines for Antiemesis advises caution in the use of metoclopramide in older adults at risk of falling because of the risk of extrapyramidal symptoms, and warns about the need to monitor the duration of treatment, QT interval prolongation, and dystonic effects. It also highlights that adverse events increase as the dose increases [26]. Metoclopramide was used in the investigated ambulatory clinic because neurokinin antagonists and the new serotonin receptor antagonists were not included in the hospital formulary as therapeutic alternatives in the treatment of emesis induced by antineoplastics. The combined prescription of metoclopramide, ondansetron, and dexamethasone for patients receiving antiemetic treatment is common in the investigated institution. In a study that analysed the relationship between the use of PIMs and chemotherapy toxicity, the authors questioned the classification of metoclopramide, atropine, pro-chlorpheniramine, diphenoxylate, and lorazepam as PIMs because these medications are used to reduce symptoms induced by antineoplastic therapy [1]. The classification of
Please cite this article as: Reis CM, et al, Factors associated with the use of potentially inappropriate medications by older adults with cancer, J Geriatr Oncol (2017), http://dx.doi.org/10.1016/j.jgo.2017.05.003
4
C.M. Reis et al. / Journal of Geriatric Oncology xxx (2017) xxx–xxx
Table 3 Univariate and multivariate analysis of the factors associated with the use of potentially inappropriate medications in a sample of older adults included in the study, Belo Horizonte, MG, Brazil, 2015 (n = 160). Description
Potentially inappropriate medication used
Univariate analysis
Variable
Yes n (%)
No n (%)
Odds ratio (IC 95%)
p-value
47 (51.1) 35 (51.5)
1.0 (0.54–1.90) 1
0.962
34 (55.7) 48 (48.5)
0.7 (0.39–1.41) 1
0.373
13 (31.0) 69 (58.5)
3.1 (1.48–6.64) 1
0.002
26 (48.1) 56 (52.8)
1.2 (0.62–2.32) 1
0.575
45 (47.4) 37 (56.9)
1.5 (0.77–2.77) 1
0.235
14 (41.2) 68 (54)
1.6 (0.77–3.61) 1
0.185
19 (45.2) 63 (53.4)
1.3 (0.68–2.81) 1
0.364
13 (39.4) 69 (53.4)
1.8 (0.83–3.99) 1
0.126
10 (52.6) 72 (51.1)
0.9 (0.36–2.45) 1
0.898
58 (53.2) 24 (47.1)
0.7 (0.40–1.52) 1
0.468
10 (45.5) 72 (52.2)
0.34 1
0.558
Gender Female 45 (48.9) Male 33 (48.5) Age in years ≥70 27 (44.3) b70 51 (51.5) Number of medications ≥5 29 (69) b5 49 (41.5) Score from the Vulnerable Elders Survey (VES-13) ≥3 28 (51.9) b3 50 (47.2) Number of comorbidities ≥2 50 (52.6) b2 28 (43.1) Arthritis/arthrosis Yes 20 (58.8) No 58 (46) Diabetes Yes 23 (54.8) No 55 (46.6) Depression Yes 20 (60.6) No 58 (45.7) Thyroid diseases Yes 9 (47.4) No 69 (48.9) Hypertension Yes 51 (46.8) No 27 (52.9) Over-the-counter medications Yes 12 (54.5) No 66 (47.8)
a drug as a PIM does not indicate that its prescription will be banned; however, it is a warning sign for the need to seek effective and safer alternatives in older adults. Therefore, we decided to classify metoclopramide and atropine as PIMs in this study to evaluate their frequency of use, and to highlight the importance of monitoring their use by older adults in cases in which a safer alternative is not available at the institution. The NCCN Guidelines for Older Adult Oncology version 1.2016 contains a list of medications commonly used for supportive care that are of concern in older patients, and this list includes metoclopramide, H1 antihistamines, histamine H2-receptor antagonists, phenothiazine, antipsychotics, and serotonin reuptake inhibitor antidepressants. The guidelines present treatment alternatives and recommendations to be adopted when a medication from the list should be prescribed to older adults [3]. Several medications listed in the NCCN Guidelines are also present in the 2015 Beers Criteria [9]. Diazepam and clonazepam are long half-life benzodiazepines classified as PIMs. Benzodiazepines are included in international therapeutic guidelines for management of anxiety and insomnia; however, the duration of treatment should be short and not exceed three months. The high prevalence and chronic use of benzodiazepines by older adults, together with the increase in the incidence of dementia in developed countries, are important public health concerns, and have been emphasized by the publication of a case-control study that demonstrated a higher risk of Alzheimer's disease among chronic users of benzodiazepine [27].The high frequency of benzodiazepine in our study is in line with previous investigation that found these class of drug as the PIM most prevalent. In oncological patients, lorazepam, a short half-life benzodiazepine, is used parenterally as an adjuvant in the management of nausea [1]. However, the risks are lower because the treatment period is short. Notwithstanding the short half-life, an association has been found between
Multivariate analysis Odds ratio (IC 95%)
p-value
3.1 (1.48–6.64)
0.003
the use of benzodiazepines and increased risk of falls in older adults [28]. Depression is the most common psychiatric disorder in geriatric and oncological patients. In older patients with cancer, depression compromises the quality of life and increases morbidity and mortality [3,29]. In the selection of antidepressants for older adults, it is important to evaluate anticholinergic load and the ability of the medication to induce falls, fractures, and other adverse events, which may compromise the functionality of these patients. In oncological patients, antidepressants are also used for the treatment of chemotherapy-induced neuropathy. The use of low doses of tricyclic antidepressants in older oncological patients has been recommended to achieve the desired benefits without bringing risks to these patients [3,16]. A medication considered a PIM may be appropriate for an older adult in cases in which a clinical evaluation is performed to assess specific risk factors in this population [3,16]. A comprehensive geriatric evaluation should consider the use of concomitant medications, as well as the functionality and predictors of fragility in older adults, to optimize the care of older adults with cancer [3,6,30]. The contributions of clinical pharmacists to the care of older patients with cancer receiving ambulatory treatment using polypharmacy and PIM, as well as the importance of a comprehensive assessment of pharmacotherapy, have been described [13,14,15]. The assessment of pharmacotherapy should include aspects of geriatric and oncological pharmacotherapy, prescribed medications, over the counter medication, herbal medicines and other alternative and complementary treatments, PIM, taking into account pharmacokinetic and pharmacodynamic changes that result from ageing. This strategy is important to evaluate the treatment of older adults with cancer, increase the effectiveness and safety of pharmacotherapy, and reduce the impact of PIMs on the functionality, autonomy, and quality of life of patients.
Please cite this article as: Reis CM, et al, Factors associated with the use of potentially inappropriate medications by older adults with cancer, J Geriatr Oncol (2017), http://dx.doi.org/10.1016/j.jgo.2017.05.003
C.M. Reis et al. / Journal of Geriatric Oncology xxx (2017) xxx–xxx
This study has some limitations. First, it evaluated a single institution with a small convenience sample, which prevents generalizations. Second, the cross-sectional nature of data collection limited the evaluation of causality between PIMs and the explanatory variables related to functional status, pharmacotherapy, and clinical conditions. Third, a recall bias is possible because older adults may not remember all medications they are taking. To mitigate this bias, we compared their self-reported medications list with their medical record. We did not ask about palliative care, which is another limitation, because the Beers Criteria include all ambulatory settings, with the exception of hospice and palliative care. However, considering the profile of nonantineoplasic drugs used by the patients in the study, the number of patients receiving palliative care could be small. Studies using the Beers Criteria to consider inappropriate medication use in older adults due to drug-disease or drug-syndrome interactions that may exacerbate the disease should be developed, to better assess the prevalence of PIMs in patients with cancer. A strength of this study was that the use of 2015 Beers was validated in ambulatory setting. In conclusion, our findings show that the frequency of use of PIMs by older adults in parenteral antineoplastic therapy at the investigated ambulatory clinic is high. Polypharmacy showed a positive association with the use of PIMs. The use of medications that should be prescribed with caution in older adults is also high. Disclosures and Conflict of Interest Statements The authors declare that they have no conflicts of interest Author Contributions Study concept: CM Reis, AM Reis. Study design: CM Reis, AM Reis. Data acquisition: CM Reis, P de Jesus Souza, A Gouvêa dos Santos. Quality control of data and algorithms: CM Reis, AM Reis. Data analysis and interpretation: CM Reis, AM Reis, P de Jesus Souza; A Gouvêa dos Santos. Statistical analysis: CM Reis, AM Reis. Manuscript preparation: CM Reis, AM Reis. Manuscript editing: CM Reis, AM Reis. Manuscript review: CM Reis, P de Jesus Souza; A Gouvêa dos Santos, AM Reis. Acknowledgements The authors are grateful to the Pró-Reitoria de Pesquisa, Universidade Federal de Minas Gerais for funding this research through the Qualitative Improvement Program of Scientific Production, and to the Fundação de Amparo à Pesquisa do Estado de Minas GeraisFAPEMIG for providing a scientific initiation scholarship. References [1] Maggiore RJ, Dale W, Gross CP, Feng T, Tew WP, Mohile SG, et al. Polypharmacy and potentially inappropriate medication use in older adults with cancer undergoing chemotherapy: effect on chemotherapy-related toxicity and hospitalization during treatment. J Am Geriatr Soc 2014;62:1505–12. http://dx.doi.org/10.1111/jgs.12942. [2] He X, Clarke SJ, Andrew J. Clinical pharmacology of chemotherapy agents in older people with cancer. Curr Gerontol Geriatr Res 2011;628670. http://dx.doi.org/10. 1155/2011/628670. [3] National Comprehensive Cancer Network. NCCN guidelines version1.2016: older adult oncology. Available at: http://www.nccn.org/professionals/physician_gls/ f_guidelines_nojava.asp#age; 2016. (Accessed 15 August 2016). [4] Turner JP, Shakib S, Singhal N, Hogan-Doran J, Prowse R, Johns S, et al. Prevalence and factors associated with polypharmacy in older people with cancer. Support Care Cancer 2014;22:1727–34. http://dx.doi.org/10.1007/s00520-014-2171-x. [5] Sharma M, Loh KP, Nightingale G, Mohile SG, Holmes HM. Polypharmacy and potentially inappropriate medication use in geriatric oncology. J Geriatr Oncol 2016;7:346–53. http://dx.doi.org/10.1016/j.jgo.2016.07.010.
5
[6] Lichtman SM. Polypharmacy: geriatric oncology evaluation should become mainstream. J Clin Oncol 2015;33:1422–3. http://dx.doi.org/10.1200/JCO.2014.60.3548. [7] Saarelainen LK, Turner JP, Shakib S, Singhal N, Hogan-Doran J, Prowse R. Potential inappropriate medication use in older people with cancer: prevalence and correlates. J Geriatr Oncol 2014;5:439–46. http://dx.doi.org/10.1016/j.jgo.2014.07.001. [8] Lees J, Chan A. Polypharmacy in elderly patients with cancer: clinical implications and management. Lancet Oncol 2011;12:1249–57. http://dx.doi.org/10.1016/ S1470-2045(11)70040-7. [9] American Geriatrics Society. Beers Criteria Update Expert Panel. American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2015;63:2227–46. http://dx.doi.org/10.1111/jgs. 13702. [10] O'Mahony D, O'Sullivan D, Byrne S, O'Connor MN, Ryan C, Gallagher P. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing 2015;44:213–8. http://dx.doi.org/10.1093/ageing/afu145. [11] Prithviraj GK, Koroukian S, Margevicius S, Berger NA, Bagai R, Owusu C. Patient characteristics associated with polypharmacy and inappropriate prescribing of medications among older adults with cancer. J Geriatr Oncol 2012;3:228–37. http://dx.doi.org/10.1016/j.jgo.2012.02.005. [12] Flood KL, Carroll MB, Le CV, Brown CJ. Polypharmacy in hospitalized older adult cancer patients: experience from a prospective, observational study of an oncology-acute care for elders unit. Am J Geriatr Pharmacother 2009;7:151–8. http://dx.doi.org/10.1016/j.amjopharm.2009.05.002. [13] Nightingale G, Hajjar E, Swartz K, Andrel-Sendecki J, Chapman A. Evaluation of a pharmacist-led medication assessment used to identify prevalence of and associations with polypharmacy and potentially inappropriate medication use among ambulatory senior adults with cancer. J Clin Oncol 2015;33:1453–9. http://dx.doi. org/10.1200/JCO.2014.58.7550. [14] Park JW, Roh JL, Lee SW, Kim SB, Choi SH, Nam SY, et al. Effect of polypharmacy and potentially inappropriate medications on treatment and posttreatment courses in elderly patients with head and neck cancer. J Cancer Res Clin Oncol 2016;142: 1031–40. http://dx.doi.org/10.1007/s00432-015-2108-x. [15] Turner JP, Jamsen KM, Shakib S, Singhal N, Prowse R, Bell JS. Polypharmacy cutpoints in older people with cancer: how many medications are too many? Support Care Cancer 2016;24:1831–40. http://dx.doi.org/10.1007/s00520-015-2970-8. [16] Whitman AM, DeGregory KA, Morris AL, Ramsdale EE. A comprehensive look at polypharmacy and medication screening tools for the older cancer patient. Oncologist 2016;21:723–30. http://dx.doi.org/10.1634/theoncologist.2015-0492. [17] WHO. Collaborating Centre for Drug Statistics Methodology Norwegian Institute of Public Health ATC/DDD Index. Available at: http://www.whocc.no/atc_ddd_index/. (Accessed 24 February 2016). [18] Augschoell J, Kemmler G, Hamaker ME, Stauder R. PPT and VES-13 in elderly patients with cancer: evaluation in multidimensional geriatric assessment and prediction of survival. J Geriatr Oncol 2014;5:415–21. http://dx.doi.org/10.1016/ j.jgo.2014.08.005. [19] United Nation. World population ageing. Available at: http://www.un.org/en/ development/desa/population/publications/pdf/ageing/WorldPopulationAgeing2013. pdf (Accessed 27 February) 2016. [20] Veehof L, Stewart R, Haaijer-Ruskamp F, Jong BM. The development of polypharmacy. A longitudinal study. Fam Pract 2000;17:261–7. [21] Kenis C, Bron D, Liberty Y, Decoster L, Van Puyvelde K, Scalliet P, et al. Relevance of a systematic geriatric screening and assessment in older patients with cancer: results of a prospective multicentric study. Ann Oncol 2013;24:1306–12. http://dx.doi.org/ 10.1093/annonc/mds619. [22] Abramowitz J, Thakkar P, Isa A, Truong A, Park C, Rosenfeld RM. Adverse event reporting for proton pump inhibitor therapy: an overview of systematic reviews. Otolaryngol Head Neck Surg 2016;155:547–54. http://dx.doi.org/10.1177/ 0194599816648298. [23] Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fratures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep 2010;12:448–57. http://dx.doi.org/10.1007/s11894-0100141-0. [24] Gyawali B, Poudyal BS, Iddawela M. Cheaper options in the prevention of chemotherapy-induced nausea and vomiting. J Global Oncol 2016;2:145–53. http://dx.doi.org/10.1200/JGO.2015.002477. [25] Feyer P, Jordan K. Update and new trends in antiemetic therapy: the continuing need for novel therapies. Ann Oncol 2011;22:30–8. http://dx.doi.org/10.1093/ annonc/mdq600. [26] National comprehensive cancer network clinical practice guidelines in oncology: antiemesis version 2. NCCN org. Availabe at: https://www.nccn.org/professionals/ physician_gls/f_guidelines.asp#supportive; 2016. (Accessed 15 August 2016). [27] Gage SB, Moride Y, Ducruet T, Kurth T, Verdoux H, Tournier M, et al. Benzodiazepine use and risk of Alzheimer's disease: case-control study. BMJ 2014;349:g5205. http://dx.doi.org/10.1136/bmj.g5205. [28] Gregg JA, Tyson RL, Cook D. Benzodiazepines and geriatrics: what clinical practice strategies can be used to reduce the inappropriate prescribing? Rehabil Nurs 2016;41:270–5. http://dx.doi.org/10.1002/rnj.288. [29] Duc S, Rainfray M, Soubeyran P, Fonck M, Blanc JF, Ceccaldi J, et al. Predictive factors of depressive symptoms of elderly patients with cancer receiving first-line chemotherapy. Psychooncology 2017;26:15–21. http://dx.doi.org/10.1002/pon.4090. [30] Lichtman SM, Hurria A, Jacobsen PB. Geriatric oncology: an overview. J Clin Oncol 2014;32:2521–2. http://dx.doi.org/10.1200/JCO.2014.57.4822.
Please cite this article as: Reis CM, et al, Factors associated with the use of potentially inappropriate medications by older adults with cancer, J Geriatr Oncol (2017), http://dx.doi.org/10.1016/j.jgo.2017.05.003