Risk factors associated with drug therapy among elderly people with Alzheimer’s disease: a cross-sectional study

ABSTRACT BACKGROUND: Improving knowledge and establishing strategies and policies for better patient safety are worldwide priorities. OBJECTIVE: To evaluate drug safety among elderly people with Alzheimer’s disease (AD). DESIGN AND SETTING: Cross-sectional study among elderly people within the National AD Assistance Protocol (PCDTDA/MS) who were living in the municipality of Araraquara, Brazil, in 2017. METHODS: Through interviews conducted with relatives/caregivers of elderly people with diagnoses of AD, the following variables were evaluated: comorbidities, drug therapy used, use of potentially inappropriate medications for the elderly (PIMs), presence of potentially inappropriate interactions (PIIs) and medication regimen complexity index. Factors associated with AD severity were also evaluated. Multivariate and simple logistic regressions were applied. RESULTS: 143 elderly people enrolled in PCDTDA/MS were analyzed. The majority were women (67.1%); assisted only through the public healthcare system (75.5%); polymedicated (57.4%); using at least one PIM (63.6%); presenting at least one PII (63.6%); and under drug therapy of low to medium complexity (92.2%). No semi-annual monitoring of the effectiveness of PCDTDA/MS drugs was identified. The proportion using AD drug therapy at daily doses differing from those recommended by the World Health Organization was 75.6%. However, these doses were not associated with drug risk. CONCLUSION: The data from this study raise the hypothesis that use of polypharmacy might show a correlation with severity of AD. The drug safety risk may be associated with comorbidities of the metabolic syndrome, anxiety and off-label use of PIMs, such as risperidone and quetiapine, and benzodiazepines (i.e. clonazepam and flunitrazepam).


OBJECTIVE
The objectives of the present study were to characterize elderly people with a diagnosis of AD; identify comorbidities, drug therapy complexity, use of PIMs and presence of PIIs; and raise hypotheses regarding possible drug risk factors. Through this, we aimed to contribute to national and international patient safety goals.

Study design and ethics
A cross-sectional study was conducted in Araraquara, Brazil, over the course of the year 2017.
The study design was based on the guidelines for Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). 18 The protocol for this study was approved by the Research Ethics

Setting and participants
The study was conducted at the Araraquara Reference Center for Elderly Patients (CRIA) and at the Regional Health Directorate III (DRS-III) for services of specialized nature.
Elderly individuals with a diagnosis of AD are referred by the healthcare services to the CRIA. CRIA provides medium-complexity services and specializes in geriatric care, using protocols for treating forgetfulness, dementia, stroke sequelae and mild depression.
In DRS-III, drug therapy for AD is dispensed. In 2017, 260 elderly people were registered at the DRS-III of Araraquara within the Clinical Protocol and Therapeutic Guidelines for Alzheimer's Disease of the Ministry of Health (PCDTDA/MS), 19 including both new and old cases.
These guidelines are documents based on scientific evidence that establish criteria for diagnosing the health problem and make recommendations for treatments and dosages and for monitoring the therapeutic results.
The elderly people who were registered within the PCDTDA/ MS had been diagnosed with AD (ICD-10: G30) in accordance with the criteria of the National Institute on Aging and the Alzheimer's Disease and Related Disorders Association, which have been endorsed by the Brazilian Academy of Neurology. 20 AD is diagnosed through the following procedures: evaluation of the clinical history; cognitive screening through the clinical parameters of the Mini-Mental State Examination (MMSE) 21 and the Clinical Dementia Rating (CDR); 22 laboratory tests (vitamin B12, folic acid, electrolytes, blood glucose, urea, creatinine, alanine aminotransferase, aspartate aminotransferase and thyroid-stimulating hormone); and magnetic resonance imaging or computed tomography scans. 19 In addition, the drug therapy that has been approved for treating AD, i.e. donepezil, galantamine and rivastigmine (acetylcholinesterase inhibitors) and memantine, is available free of charge to elderly patients who are included in the PCDTDA/MS. AD drug therapy dispensing is performed through the public healthcare system in order to ensure access and integrality of the treatment at the outpatient level.
Thus, elderly individuals who had been registered within the PCDTDA/MS were included in this study. Elderly individuals who were living in long-term institutions were excluded for ethical reasons, given the advanced stage of their disease and the absence of a relative or caregiver to participate in the interview.

Data
This study was conducted through interviews with relatives or caregivers of elderly patients who were seen at CRIA and at the time of dispensing of AD drug therapy in DRS-III. The data obtained through the interview were confirmed using secondary sources, i.e. from medical records available at the healthcare service, prescriptions and clinical laboratory tests on the elderly subjects.

Comorbidities
Comorbidities were identified through the relatives' or caregivers' reports or through self-reports; and from secondary data sources (medical records).

Severity of Alzheimer's disease
The severity of Alzheimer's disease was assessed through insertion of memantine either in association with anticholinesterases or as monotherapy. The insertion of memantine was evaluated to ensure that this was not associated with anticholinesterase intolerance, but rather with the severity of AD, in accordance with the MMSE and CDR scores that had been pre-established within the PCDTDA/MS. 19

Metabolic syndrome
Metabolic syndrome (MetS) consists of a set of factors that increase the risk of coronary heart disease. 23 The guidelines developed through the National Cholesterol Education Program for detection of MetS recommend measurement of abdominal circumference, blood glucose levels, cholesterol levels (LDL and HDL) and blood pressure. 23 However, since it was not possible to make these measurements in this study, the following criteria were used to define MetS: BMI of 30 kg/m 2 or greater) and use of antihypertensives antidiabetics and antidyslipidemics, as recommended in the literature.
Thus, presence of MetS was ascertained in terms of the presence of at least three of the factors described above.

Medication regimen complexity index (MCRI)
The complexity of drug therapy results from the multiplicity of prescribed regimen factors.  24 The more complex the dosage schedule and the process of drug use are, the higher the score assigned will be.
The minimum score is 1.5 points, which represents a single tablet or capsule taken once a day. There is no limit to the number of drugs to be analyzed.
The MRCI is the gold standard for assessing the complexity of drug therapy. 25 However, it has some limitations, considering that observation of which scores correspond to higher scores shows that there is no maximum score or stratification of these scores. This was the reason why we made our own stratification for this study.

Potentially inappropriate medications
Prescription guides have been developed to identify any use of drugs that is considered inappropriate for elderly individuals.
These are termed potentially inappropriate medications (PIMs), i.e. drugs for which the tradeoff between risk and benefit does not justify their use.
In our study, PIM assessments were made through the following prescription guides: updated Beers criteria, 26,27 STOPP/START version 2, 28 French consensus panel 29 and Canadian national consensus panel, 30 and Strand criteria. 31 These guides report on the drugs that are considered to be PIMs, depending on the clinical condition of the elderly individual, dose, length of time prescribed and PIM-comorbidity interactions.

Drug risk variables
In order to evaluate drug safety among patients with AD, we defined the following variables as drug risk variables: PIM use and PII, evaluated through the updated Beers criteria, 26,27 STOPP/ START version 2, 28 French consensus panel 29 , Canadian national consensus panel 30 and Strand criteria; 31 the complexity of drug therapy according to the medication regimen complexity index (MRCI); 24 comorbidities identified through self-reports and with confirmation from medical records; and presence of polypharmacy, which was defined as use of five or more drugs for a period greater than or equal to 90 days.

Sample size
Given that a total of 260 elderly people had been registered within the PCDTDA/MS, the sample size for a confidence level of 90% (α = 0.05) was 133 elderly people.

Statistical analysis
The variables of interest were described in terms of their absolute and relative frequencies.
Two statistical analyses were conducted: multivariate and simple logistic regressions.
To analyze the severity of AD in relation to the presence of drug risk variables (presence of polypharmacy, high-complexity MRCI, PIM use and occurrence of PII), multivariate logistic regression was used.
From another perspective, to evaluate the influence of each variable of this study on the severity of AD and/or in the presence of one or more variables that had been defined as drug risk variables, simple logistic regression was used. The aim of this analysis was to evaluate whether there were any variables that influenced the severity of AD. For this, AD severity and the drug risk variables were considered to be the dependent variables and the others were independent variables.
Female gender, schooling ≤ 4 years and presence of high-complexity MRCI were defined as independent variables in the simple logistic regression. Individual comorbidities were analyzed, as were comorbidities grouped in accordance with the

International Statistical Classification of Diseases and Related
Health Problems (ICD-10).
The statistical software used was BioEstat (version 5.3).

RESULTS
Out of the 260 elderly people who were enrolled in the PCDTDA/ MS, 16 were excluded because they were living in long-term institutions. Thus, 244 elderly individuals were eligible for inclusion in this study. Fourteen did not agree to participate and there were another 87 losses, due to the following: AD drug therapy was not received through the public healthcare system (n = 49); AD drug therapy was dispensing to relatives or caregivers who did not know the clinical history of the elderly individual (n = 31); or AD drug therapy was dispensed through a means of transportation that had been hired just to obtain it (n = 7) (Figure 1). The age of the elderly individuals within the PCDTDA/MS ranged from 64 to 97 years. Their median age was 81 years (Q1 = 76; Q3 = 87) and they had had their diagnosis of AD for a median period of four years (Q1 = 02; Q3 = 7.5). Most of these elderly people were women (67.1%); did not have any family history of AD (60.1%); were assisted only through the public healthcare system (75.5%); and had had less than four years of schooling (83.2%). Twenty of these elderly people were illiterate and only six of them had had higher education.
In addition, most of them were polymedicated (57.4%); were making use of at least one PIM (63.6%) and had one PII (63.6%). The mean number of drugs in use was five drugs/elderly person [standard deviation, SD: 2.69] and the drug therapy of 92.2% of these elderly individuals was classified as presenting low or medium complexity.
Furthermore, although diabetes mellitus, arterial hypertension and dyslipidemia were among the most prevalent comorbidities, most of these elderly people did not have metabolic syndrome. However, it was also noted that most of them had one or more of the prodromal symptoms of AD: anxiety, insomnia and depression. These symptoms are frequently treated with drugs that are considered to be PIMs ( Table 1).
Among the drugs used, which were available through PCDTDA/ MS, galantamine (46.1%) and donepezil (33.61%) were the ones most prescribed. Most of the elderly individuals were receiving monotherapy (88%), at daily doses above the defined daily dose that are recommended by the WHO (60.2%) ( Table 2).
It was noted that no record of MMSE and CDR screening tests has yet been identified, thus making it impossible to evaluate the effectiveness of anticholinesterase treatment. Therefore, no semiannual reevaluation of the effectiveness of these tests that had been predicted through the PCDTDA/MS was done.     Furthermore, from analysis on all comorbidities according to their ICD-10 classifications, the classes of mental and behavioral disorders (P-value: 0.0109) and circulatory system diseases (P-value: 0.0010) were also found to be associated with the presence of drug risk variables.

DISCUSSION
Most of the elderly people with AD, in the present study, showed drug risks due to polypharmacy and because they had comorbidities of anxiety, high cholesterol, hypertension, diabetes and metabolic syndrome.
It was observed that the drug therapy for these elderly individuals with AD was of low or medium complexity. We did not find any studies in the literature that identified or discussed the MRCI among elderly people with AD. However, a recent study showed that cognitive impairment was associated with lower MRCI scores than those of other chronic diseases. 32 The complexity of drug therapy varies according to the morbidity that elderly patients present. 32 There are correlations not only with the number of drugs in use, but also with other factors such as dosage form and dosage schedule. 24 On the other hand, although the drug therapy was assessed as presenting low to medium complexity, most of the elderly patients were using five or more drugs. Moreover, simple logistic regression showed that polypharmacy was the only drug risk factor associated with AD severity. Although we are not aware of any studies that have identified an association between polypharmacy and AD severity, there have been some recent studies showing that polypharmacy is a risk factor for dementia. 33,34 Other studies have also correlated polypharmacy with prescription of PIMs 1 and occurrence of PIIs. 3 Presence of these factors is associated with increased mortality among elderly people. 35,36 In the present study, the most commonly used PIM drug classes with PIMs and PIIs were antipsychotics and BZDs. Both of these classes are commonly prescribed for management of behavioral and psychological symptoms of dementia (BPSD). 37,38 Even though antipsychotics are frequently prescribed for treating BPSD, this is an off-label use of this drug class, according to the Food and Drug Administration, since these are standard drugs for treating schizophrenia. 39 Opinions regarding the risk/benefit relationship of this use are divergent. While some studies have shown that antipsychotics are efficacious for improvement of BPSD, 40 others have shown that their use is associated with a more pronounced cognitive and functional decline and a lack of improvement of BPSD. 41 The BZD class has mainly been prescribed for management of insomnia and anxiety. In contrast, because sleep disorders are usually related to brain changes arising from AD itself, it is not  (Figure 2).
Only 9.1% and 1.4% of the elderly patients declared that they were alcohol users and smokers, respectively. However, 24 elderly people were former alcohol users and 49 former smokers.
After multivariate logistic regression, the severity of AD was found not to be a risk factor for the presence of the following drug risk variables: PIM use (P-value: 0.6838), occurrence of PII (P-value: 0.6838), use of polypharmacy (P-value: 0.0781) and occurrence of high-complexity MRCI (P-value: 0.8419).
However, from another perspective, simple logistic regression to assess whether the other variables identified in this study were risk factors for AD severity (such as sociodemographic characteristics or comorbidities, among others) showed that polypharmacy was the only possible risk factor for severity (P-value: 0.0206).
In addition, although comorbidities were not associated with AD severity, it was found that dyslipidemia (P-value: 0.0110), diabetes (P-value: 0.0352), hypertension (P-value: 0.041) and   n = number of elderly; SD = standard deviation; ATC = Anatomical Therapeutic Chemical. *An elderly person can make use of more than one BZD simultaneously; **CNS (central nervous system)-active drugs: antipsychotics, benzodiazepines, nonbenzodiazepines, tricyclic antidepressants, selective serotonin reuptake inhibitors and opioids.
clear whether the drugs actually used are effective, since the use of these drugs in the context of comorbid neurological disease is also considered to be off-label. 42,43 With regard to chronic use of BZD as a risk factor for AD, a recent meta-analysis showed that its use was a risk factor. 44 From another perspective, a systematic review identified studies in which negative effects from BZD on the cognition of elderly people who already had the diagnosis of AD were reported. 45 However, we did not find any association between use of BZD and cognitive impairment or progression of AD. This may be explained by the chronic use of BZD before and after the diagnosis of AD was made, the absence of the clinical parameters of MMSE and CDR and the small sample size.
In addition, it was observed that MetS and its risk factors (cholesterol, hypertension and diabetes) and anxiety (a comorbidity that is considered to be a prodromal symptom of AD) were associated with drug risk.
MetS was previously shown to be a risk factor for AD. 46,47 Its presence allowed the trajectory of the prodromal stage of AD to become significantly extended to the symptomatic stage. 46 BPSD have been found to be present both before the diagnosis and during the course of the disease. 37 Anxiety was an aggravating factor for drug safety among the elderly individuals with AD in the present study and was usually treated with BZD. MetS risk factors were treated with immediate-release nifedipine, propranolol and glibenclamide, and all of these were considered to be PIMs. Nevertheless, these PIMs have been standardized as essential by the WHO and by RENAME-Brazil. However, their respective safer therapeutic equivalents for the elderly, i.e. captopril, losartan and metformin, have also been standardized.
Another important finding from the present study was the absence of determinations of clinical MMSE and CDR parameters among the patients. These findings show that no monitoring of the effectiveness of this drug therapy was being done and, consequently, that there was non-compliance with the guidelines recommended in the PCDTDA/MS. 48 Therefore, the "minor" complexity of the drug therapy for these elderly individuals with AD did not mean that there were no safety issues or drug-related problems (DRPs) to be identified, prevented, monitored and resolved.
In this context, medication therapy management based on the underlying disease, taking into account the comorbidities and therapeutic experience of the patient and family/caregiver, may be form of pharmaceutical care that would be of interest for promoting drug safety, compliance with drug therapy 49 and resolution of DRPs. 50,51 Thus, important data about the drug safety of patients with Alzheimer's disease were identified through the present study.
Our findings suggest that patients with AD should be regarded in an overall manner: not only managing the number of drugs in use or the complexity of drug therapy, but also taking into account the patient's needs and comorbidities, along with the experience and expectations of the caregiver/familiar regarding the treatment, and the outcomes when drug risk variables are present.

Limitations of this study
The main limitation of this study was that the severity of AD was Moreover, the cross-sectional design of this study did not allow us to identify causal associations.

CONCLUSION
Even though the drug therapy of our elderly patients with AD was of low complexity, the majority of these drugs presented safety risks in relation to the comorbidities of anxiety, cholesterol, hypertension, diabetes and metabolic syndrome. Although we did not identify any evidence in the literature that would correlate polypharmacy with AD severity, our data suggest that this is a possible drug safety risk. Off-label use of PIMs, such as risperidone, quetiapine and benzodiazepines like clonazepam and flunitrazepam, also present a drug safety risk for elderly people with AD.