Acessibilidade / Reportar erro

Impact of pharmacist intervention in patients with Alzheimer's disease

Abstract

To assess the therapy relative to indication, effectiveness, safety and adherence in patients with Alzheimer’s disease (AD). An interventional, prospective, non-randomized study was conducted in a single secondary care center in Brazil. The pharmacist-led medication therapy management (MTM) was conducted to detect drug-related problems (DRPs) at baseline and after six months of intervention. The health status outcomes (i.e. cognitive screening tests; levels of glucose; total cholesterol; triglycerides; thyroid stimulating hormone; serum free thyroxine and blood pressure) were measured. 66 patients with AD were included, of whom 55 patients completed the follow-up of six months. 36 patients (36/55) were non-adherent to AD drug therapy. Out of detected 166 DRPs, 116 were solved. Four patients were withdrawn from the AD protocol due to resolution of prodromal symptoms. On the conclusion of the study, the MTM improved and controlled blood pressure, glucose, total cholesterol, triglycerides levels (p<0.05). The pharmacist-led MTM was effective in solving 69.8% of DRPs, improving and controlling the clinical parameters evaluated.

Keywords:
Elderly; Face-to-face; Medication adherence; Medication errors; Medication review

INTRODUCTION

Dementia has become a major public health problem due to the increased prevalence, chronicity, caregiver overload, and high personal and financial costs of health and care, as well as being a major cause of disability (Alzheimer’s Association, 2017Alzheimer’s Association. Alzheimer’s Disease Facts and Figures. Alzheimers Dement. 2017;13,325-373. https://doi.org/10.1016/j.jalz.2017.02.001
https://doi.org/10.1016/j.jalz.2017.02.0...
; World Health Organization, 2012World Health Organization, Dementia: a public health priority. 2012.). The most prevalent type of dementia is Alzheimer's Disease (AD) (Burns, Iliffe, 2009Burns A, Iliffe S. Alzheimer’s disease. BMJ. 2009;338:b158. https://doi.org/10.1136/bmj.b158
https://doi.org/10.1136/bmj.b158...
).

Patients with dementia are more susceptible to Drug Related Problems (DRPs) due to pharmacokinetic and pharmacodynamic changes (Reeve et al., 2017Reeve E, Trenaman SC, Rockwood K, Hilmer SN. Pharmacokinetic and pharmacodynamic alterations in older people with dementia. Expert Opin Drug Metab Toxicol. 2017;13(6):651-668.), cognitive impairment, changes in the blood-brain barrier (Mehta et al., 2015Mehta DC, Short JL, Hilmer SN, Nicolazzo JA. Drug access to the central nervous system in Alzheimer’s disease: Preclinical and clinical insights. Pharm Res. 2015;32(3):819-39. https://doi.org/10.1007/s11095-014-1522-0.
https://doi.org/10.1007/s11095-014-1522-...
), and inadequate adherence to drug therapy (Hayes et al., 2009Hayes TL, Larimer N, Adami A, Kaye JA. Medication adherence in healthy elders: Small cognitive changes make a big difference. J Aging Health. 2009;21(4):567-80. https://doi.org/10.1177/0898264309332836.
https://doi.org/10.1177/0898264309332836...
).

In addition, studies have found that among these patients, approximately 65 - 93% of them had at least one DRPs (Gustafsson et al., 2016Gustafsson M, Sjölander M, Pfister B, Jonsson J, Schneede J, Lövheim H. Drug-related hospital admissions among old people with dementia. Eur J Clin Pharmacol. 2016;72(9):1143-53. https://doi.org/10.1007/s00228-016-2084-3
https://doi.org/10.1007/s00228-016-2084-...
; Wucherer et al., 2017Wucherer D, Thyrian JR, Eichler T, Hertel J, Kilimann I, Richter S, et al. Drug-related problems in community-dwelling primary care patients screened positive for dementia. Int Psychogeriatrics. 2017;29(11):1857-1868. https://doi.org/10.1017/S1041610217001442.
https://doi.org/10.1017/S104161021700144...
), such as use of potentially inappropriate drugs (Forgerini et al., 2020Forgerini M, Herdeiro MT, Galduróz JCF, Mastroianni PC. Risk factors associated with drug therapy in the elderly with Alzheimer's disease. São Paulo Med J. 2020;138(3):216-218.), therapeutic ineffectiveness, use of unnecessary drugs (Gustafsson et al., 2016Gustafsson M, Sjölander M, Pfister B, Jonsson J, Schneede J, Lövheim H. Drug-related hospital admissions among old people with dementia. Eur J Clin Pharmacol. 2016;72(9):1143-53. https://doi.org/10.1007/s00228-016-2084-3
https://doi.org/10.1007/s00228-016-2084-...
), and treatment non-adherence that could range from 17% to 100% (Smith et al., 2017Smith D, Lovell J, Weller C, Kennedy B, Winbolt M, Young C, et al. A systematic review of medication nonadherence in persons with dementia or cognitive impairment. PLoS ONE. 2017;12(2):e0170651. https://doi.org/10.1371/journal.pone.0170651.
https://doi.org/10.1371/journal.pone.017...
; Wucherer et al., 2017Wucherer D, Thyrian JR, Eichler T, Hertel J, Kilimann I, Richter S, et al. Drug-related problems in community-dwelling primary care patients screened positive for dementia. Int Psychogeriatrics. 2017;29(11):1857-1868. https://doi.org/10.1017/S1041610217001442.
https://doi.org/10.1017/S104161021700144...
).

Nonetheless, few studies have evaluated the impact of pharmacist-led interventions on the outcomes of use of medications, since the majority of them focused on withdrawal of dementia drug therapy or antipsychotics medications (Nguyen et al., 2019Nguyen TA, Gilmartin-Thomas J, Tan ECK, Kalisch-Ellett L, Eshetie T, Gillam M, et al. The impact of pharmacist interventions on quality use of medicines, quality of life, and health outcomes in people with dementia and/or cognitive impairment: A systematic review. J Alzheimer’s Dis. 2019;71(1):83-96. https://doi.org/10.3233/JAD-190162
https://doi.org/10.3233/JAD-190162...
). Thus, most of studies did not evaluate the impact of integration of information about patient assessment, drug therapy and clinical parameters considering AD, dementia or cognitive impairment, as well the comorbidities and therapeutic experience.

Hence, our hypothesis was to assess whether pharmacist-led Medication Therapy Management (MTM) in the full assessment contributed to the resolution of DRPs related to indication, effectiveness, safety, and adherence (IESA) in patients with AD.

METHODS

Study Design and Ethical Aspects

A prospective, uncontrolled, non-randomized, and interventional study was conducted by means of a before-after analysis (quasi-experimental study). Although a quasi-experimental study was not a true experimental study, the report was based on TREND Statement Checklist (Des Jarlais, Lyles, Crepaz, 2004Des Jarlais DC, Lyles C, Crepaz N. Improving the Reporting Quality of Nonrandomized Evaluations of Behavioral and Public Health Interventions: The TREND Statement. Am J Public Health. 2004. https://doi.org/10.2105/AJPH.94.3.361
https://doi.org/10.2105/AJPH.94.3.361...
), recommended for intervention and non-randomized studies.

The study was approved by the Research Ethics Committee (2.043.644) and was conducted in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. This study was registered with ClinicalTrials.gov, number NCT02222181.

Setting and Participants

The study was conducted at the “Centro de Referência do Idoso de Araraquara (CRIA)”, Brazil. CRIA is a care unit specialized in geriatric ambulatory care of the Public Health System with the use of protocols for forgetfulness, dementia, mild depression and sequelae of stroke.

The patients eligible for the study were those with diagnosis of AD enrolled in the Clinical Protocol and Therapeutic Guidelines of Alzheimer's disease (PCDTDA) (Costa et al., 2017Costa AF, Chaves MLF, Picon PD, Krug BC, Gonçalves CBT, Amaral KM, et al. Protocolo Clínico e Diretrizes Terapêuticas - Doença de Alzheimer. Portaria conjunta No 13, 28 novembro 2017:147-167.).

According to the PCDTDA guidelines, the diagnosis of AD consists of an evaluation of the patients’ clinical history; cognitive screening in accordance with clinical parameters of the Mini Mental State Examination (MMSE), and Clinical Dementia Rating (CDR); laboratory tests (blood count, electrolytes, blood glucose, urea, creatinine, thyroid-stimulating hormone, alanine aminotransferase, aspartate aminotransferase, vitamin B12, folic acid, serum serology for syphilis, and HIV tests); in addition to magnetic resonance or computed tomography (Costa et al., 2017Costa AF, Chaves MLF, Picon PD, Krug BC, Gonçalves CBT, Amaral KM, et al. Protocolo Clínico e Diretrizes Terapêuticas - Doença de Alzheimer. Portaria conjunta No 13, 28 novembro 2017:147-167.). Furthermore, after diagnosis, the AD is classified as probable, possible (absence of other neurological, psychiatric or systemic disorders which may induce dementia) and defined (postmortem confirmation only) (Costa et al., 2017Costa AF, Chaves MLF, Picon PD, Krug BC, Gonçalves CBT, Amaral KM, et al. Protocolo Clínico e Diretrizes Terapêuticas - Doença de Alzheimer. Portaria conjunta No 13, 28 novembro 2017:147-167.).

Therefore, patients enrolled in the PCDTDA and assisted at CRIA for at least a year were included. Patients who resided in nursing homes were excluded, due to ethical considerations.

For the recruitment of participants, all patients considered eligible were invited to participate in the study, therefore a convenience sample was obtained.

All the caregivers, relatives or patients provided written informed consent and agreed to participate in the follow-up period for at least six months.

The defined follow-up time of six months was established in accordance with the PCDTDA guidelines that provide for semiannual monitoring according to the clinical parameters of cognitive screening to evaluate the effectiveness of anticholinesterase treatment (Costa et al., 2017Costa AF, Chaves MLF, Picon PD, Krug BC, Gonçalves CBT, Amaral KM, et al. Protocolo Clínico e Diretrizes Terapêuticas - Doença de Alzheimer. Portaria conjunta No 13, 28 novembro 2017:147-167.).

Interventions

The MTM is a clinical method that systematizes the process of identifying, solving and preventing DRPs, according to the taxonomy of drug evaluation of IESA (Cipolle et al., 2012Cipolle RJ, Strand LM, Morley PC. Pharmaceutical Care Practice: The Patient Centered Approach to Medication Management. 3rd Edition, McGraw-Hill, Health Professions Division, New York. Pharmacol Pharm. 2012.; Strand, Cipolle, Morley, 1988Strand LM, Cipolle RJ, Morley PC. Documenting the clinical pharmacist’s activities: back to basics. Drug Intell Clin Pharm. 1988;22(1):63-67. https://doi.org/10.1177/106002808802200116
https://doi.org/10.1177/1060028088022001...
).

Interventions were conducted by one pharmacist during three steps: initial patient assessment (identifying medication needs, DRPs and therapeutic experience); care plan (solving DRPs, and negotiating therapeutic goals), and care plan evaluation (clinical outcome assessment, therapeutic monitoring and identifying the new therapeutic experience) (Cipolle et al., 2012Cipolle RJ, Strand LM, Morley PC. Pharmaceutical Care Practice: The Patient Centered Approach to Medication Management. 3rd Edition, McGraw-Hill, Health Professions Division, New York. Pharmacol Pharm. 2012.; Strand et al., 1988Strand LM, Cipolle RJ, Morley PC. Documenting the clinical pharmacist’s activities: back to basics. Drug Intell Clin Pharm. 1988;22(1):63-67. https://doi.org/10.1177/106002808802200116
https://doi.org/10.1177/1060028088022001...
). Decision making was discussed with the pharmacist’s team.

The follow-up and interventions were carried out with the patient and caregiver/relatives for six months, during scheduled appointment at the CRIA and at the patient's home. The first visit and returns lasted about an hour and 30 minutes, respectively. The frequency of returns depended on the medication needs and clinical condition of the patient; with the number of visits ranging from twice a week to fortnightly returns.

The interventions were stratified into pharmaceutical and educational interventions. The pharmacist acted in patient counseling, suggestions for adjusting in drug therapy, ordering laboratory tests, monitoring results, reporting and referral to other health care providers or services. A pill box, medication schedule, written reminders, wake-up calls and medication provided in dose-dispensing units were strategies adopted according to the patient's medication needs to promote adherence (Table I). In addition, interventions were also conducted together with CRIA healthcare professionals when needed.

TABLE I
Variables of interest and sources of measures and measurement

Hypothesis

The hypothesis tested (H1) was that MTM would contribute to solving problems related to indication, effectiveness, safety and adhesion (IESA) in patients with AD.

Outcomes

The primary outcome measures were to evaluate the effectiveness of MTM in solving DRPs and improving physical and biochemical parameters. The secondary outcome measure was to assess the cognitive impairment resulting from chronic use of benzodiazepines (BZD).

The main source of information was interviews (face-to-face) with patients and caregivers; cognitive/mental assessment test; drug prescription; laboratory tests; and patient self-monitoring data. In addition, medical records were used as secondary sources of data.

Sample Size

As this was a convenience sample, as previously reported, the sample size was not calculated.

Blinding

There was no blinding of the researcher who conducted the interventions, or of those who assessed the outcomes. However, there was blinding of the statistics that led to the analyses.

Unit of Analysis and Statistical Methods

The Shapiro-Wilk test was used with the software Statistica 8.0® to analyze the normality, and for interpretation and analysis of the results, the Student’s-t test (software Microsoft Excel 2010©) was used. The Student’s-t test was applied for comparison of the characteristics at baseline and after intervention. The level of significance was 5%.

The non-parametric Mann-Whitney test was used to compare the cognitive impairment of BZD users and non-users, because it was a small, independent and unpaired sample.

RESULTS

In this study, 66 patients were included, however, only 55 patients completed the entire follow-up period (Figure 1).

FIGURE 1
Flowchart of patient selection for the Medication Therapy Management

The majority if the patients were women, aged 62 to 93, who had less than four years of schooling. The most frequent comorbidities were high blood pressure (n=30), dyslipidemia (n=22), depression (n=14), diabetes (n=14), insomnia (n=13), and dysphagia (n=08).

All patients had at least one DRP, with an average of three DRPs per patient. The mean number of interventions per patient was five (standard deviation: ±2.8), and the patients with the most interventions were those with the highest number of DRPs.

In total, 285 interventions were performed: 190 pharmaceutical and 95 educational interventions with patients, caregiver/relatives, and healthcare professionals.

The most frequent pharmaceutical interventions were adjusting dosages (n=61), referring patients to other health services (n=41), home blood pressure and glycemic monitoring (n=17), providing medication in dose-dispensing units (n=16), withdrawing drug therapy (n=10), among others. Half of the pharmaceutical interventions to improve therapeutic effectiveness and adherence were dosage adjustments relative to the medication schedule, mainly concerning administration of anticholinesterase donepezil for the night period. Interventions of an educational nature were related to health problems, appropriate use of the drug therapy and the benefits of adherence (n=40); and healthy nutrition (n=55) (Table II).

TABLE II
Description of interventions conducted with patients with diagnosis of Alzheimer's disease and their caregivers/relatives and health professional and their absolute frequencies, Araraquara

The most prevalent DRPs concerned indication and safety. As regards indication DRPs, the majority were related to the need for additional drugs for dyslipidemia and high blood pressure, identified through laboratory tests and residential blood pressure monitoring. Safety DRPs were associated with adverse drug events (ADE), medication errors and drug therapy in high doses.

Of the DRPs identified, 69.8% were solved. The DRPs were identified by using more than one strategy was used, the most common being face-to-face interviews and interventions, followed by monitoring the effectiveness of drug therapy through laboratory tests that contributed to identifying and monitoring half of the DRPs found (Table III; Table IV).

TABLE III
Description of Drug related problem (DRP), according to nature, the adopted strategy and rate of problem-solving by Medication Therapy Management, Araraquara
TABLE IV
Request for laboratory tests to identify and monitor the Drug Related Problem (DRP) identified and the respective rate of problem-solving indices by the Medication Therapy Management, Araraquara

Thirty-six patients (36/55) were non-adherent to AD drug therapy. At the end of the study, thirty of the non-adherent patients started to comply with AD drug therapy. The main problems of non-adherence identified were negative therapeutic occurrences experienced by the patient and the caregiver, mainly of ADE type; little or no information regarding drugs, the complex therapeutic scheme, and comorbidities.

An important finding of this study was the fact that at baseline time, three patients had Mini Mental State Examination (MMSE) scores that classified them as having normal cognitive function; that is, the scores did not meet the criteria for patient enrollment in the PCDTDA. However, we did not exclude these patients from the study, because we proposed to solve possible DRPs that led to the patient having a possible cognitive impairment and consequently a misdiagnosis of AD.

Among the 55 patients included, 30 had preservation of cognitive function according to the MMSE score. In addition, six patients had improvement in cognitive function: four were discharged from the PCDTDA, because the problems of antidepressant drug therapy were effectively resolved; and in two patients, their cognitive function improved, and changed from advanced to moderate impairment. Whereas, 13 patients had a three-point decline in the MMSE score (Table V; Table VI).

TABLE V
Assessment of cognitive impairment of patients with Alzheimer's disease (n=55) trough cognitive screening tests Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) and impact of chronic benzodiazepine use on these parameters performed by the Medication Therapy Management (before-after), Araraquara
TABLE VI
Assessment biochemical and hemodynamic parameters of patients (n=55) in Alzheimer's disease treatment, mean cognitive screening tests Mini Mental State Examination (MMSE) and staging of disease Clinical Dementia Rating (CDR), performed by the Medication Therapy Management (before-after), Araraquara

When only the preservation of cognitive function of the patients who had some type of adherence problem was considered, preservation of cognitive ability was also observed, according to the MMSE and CDR screening test scores. This was because of the 36 non-adherent patients initially identified, 26 remained in the same range, and six showed evidence of an improvement in the degree of cognitive impairment.

In addition, among the 16 patients taking BZD (16/55), preservation of cognitive function was observed, irrespective of the use of this class of medication (Table V).

DISCUSSION

Pharmacist intervention based on the underlying disease (AD), including evaluation of the therapeutic experience and monitoring of the indication, effectiveness, safety and adherence to the drug therapy, allowed the identification of the DRPs, and a resolution of 69.8% of these.

Machuca and Silva-Castro (2010Machuca-González M, Silva Castro MM. Evaluación de la farmacoterapia a partir de la enfermedad de base. Pharm Care Espana. 2010;12(1):192-194.) recommend that analysis of DRPs should begin with the underlying disease to enable comprehensive evaluation of drug therapy for the purpose of knowing and excluding the potential confounding factors associated with the disease (Machuca González, Silva Castro, 2010Machuca-González M, Silva Castro MM. Evaluación de la farmacoterapia a partir de la enfermedad de base. Pharm Care Espana. 2010;12(1):192-194.).

During the clinical diagnosis of AD, other reversible causes, which may promote cognitive deficits are excluded, such as depression (Potter, Steffens, 2007Potter GG, Steffens DC. Contribution of depression to cognitive impairment and dementia in older adults. Neurologist. 2007;13(3):105-17. https://doi.org/10.1097/01.nrl.0000252947.15389.a9
https://doi.org/10.1097/01.nrl.000025294...
), low vitamin B12 levels (Costa et al., 2017Costa AF, Chaves MLF, Picon PD, Krug BC, Gonçalves CBT, Amaral KM, et al. Protocolo Clínico e Diretrizes Terapêuticas - Doença de Alzheimer. Portaria conjunta No 13, 28 novembro 2017:147-167.), and hypothyroidism (Ceresini et al., 2009Ceresini G, Lauretani F, Maggio M, Ceda GP, Morganti S, Usberti E, et al. Thyroid function abnormalities and cognitive impairment in elderly people: Results of the invecchiare in chianti study. J Am Geriatr Soc. 2009;57(1):89-93. https://doi.org/10.1111/j.1532-5415.2008.02080.x
https://doi.org/10.1111/j.1532-5415.2008...
). However, depression is a comorbidity that can be considered both a confounding factor for the diagnosis of AD, and a prodromal symptom of dementia itself (Muliyala, Varghese, 2010Muliyala KP, Varghese M. The complex relationship between depression and dementia. Ann Indian Acad Neurol. 2010;13(6):69-73. https://doi.org/10.4103/0972-2327.74248
https://doi.org/10.4103/0972-2327.74248...
). This fact may erroneously influence the diagnosis of AD.

With regard to confounding factors, in our study, an integrated view allowed us to identify patients who had problems with therapeutic effectiveness of the antidepressants and when the DRPs were solved, the patients’ mood and cognition improved. Consequently, they were excluded from the PCDTDA, since untreated depression can cause cognitive deficits (Potter, Steffens, 2007Potter GG, Steffens DC. Contribution of depression to cognitive impairment and dementia in older adults. Neurologist. 2007;13(3):105-17. https://doi.org/10.1097/01.nrl.0000252947.15389.a9
https://doi.org/10.1097/01.nrl.000025294...
).

The proposed intervention was observed to make an effective contribution to compliance with the PCDTDA, as there were weaknesses in patient inclusion (Picon et al., 2010Picon PD, Camozzato AL, Lapporte EA, Picon RV, Filho HM, Cerveira MO, et al. Increasing rational use of cholinesterase inhibitors for Alzheimer’s disease in Brazil: Public health strategy combining guideline with peer-review of prescriptions. Int J Technol Assess Health Care. 2010;26(2):205-10. https://doi.org/10.1017/S0266462310000097.
https://doi.org/10.1017/S026646231000009...
) and monitoring of the protocol (Forgerini, Mastroianni, 2020Forgerini M, Mastroianni PC. Monitoring compliance of Clinical Protocol and Therapeutic Guidelines for Alzheimer’s disease. Dement Neuropsychol. 2020;14(1):24-27. https://doi.org/10.1590/1980-57642020dn14-010004
https://doi.org/10.1590/1980-57642020dn1...
).

Furthermore, the care taken of all patients’ health problems and assessment of their comorbidities, such as diabetes mellitus, hypertension and dyslipidemia allowed the control of the physiological and biochemical parameters, which showed evidence in the solution of the adherence problems and effectiveness of the drug therapy.

Improvement in cognitive impairment scores was also observed in six patients after resolution of the DRPs, which could perhaps be associated with control of the clinical parameters of the comorbidities. We raised this hypothesis because studies have identified greater cognitive impairment when clinical parameters such as blood glucose, total cholesterol, triglycerides and systolic blood pressure were uncontrolled (Crane et al., 2013Crane PK, Walker R, Hubbard R, Li G, Nathan DM, Zheng H, et al. Glucose levels and risk of dementia. N Engl J Med. 2013;369(6):540-8. https://doi.org/10.1056/NEJMoa1215740
https://doi.org/10.1056/NEJMoa1215740...
; Matsuzaki et al., 2011Matsuzaki T, Sasaki K, Hata J, Hirakawa Y, Fujimi K, Ninomiya T, et al. Association of Alzheimer disease pathology with abnormal lipid metabolism: The hisayama study. Neurology. 2011;77(11):1068-75. https://doi.org/10.1212/WNL.0b013e31822e145d
https://doi.org/10.1212/WNL.0b013e31822e...
; Nation et al., 2012Nation DA, Delano-Wood L, Bangen KJ, Wierenga CE, Jak AJ, Hansen LA, et al. Antemortem pulse pressure elevation predicts cerebrovascular disease in autopsy-confirmed alzheimer’s disease. J Alzheimer’s Dis. 2012;30(3):595-603. https://doi.org/10.3233/JAD-2012-111697.
https://doi.org/10.3233/JAD-2012-111697...
).

However, Sha et al. for instance, found that blood pressure control did not contribute to changes in cognitive status in the elderly (Sha, Cheng, Yan, 2018Sha T, Cheng W, Yan Y. Prospective associations between pulse pressure and cognitive performance in Chinese middle-aged and older population across a 5-year study period. Alzheimer’s Res Ther. 2018;10(1):29. https://doi.org/10.1186/s13195-018-0355-1.
https://doi.org/10.1186/s13195-018-0355-...
). Moreover, it should be taken into account that in our study, the patients had a progressive and neurodegenerative morbidity in which, even with AD drug therapy, there was continuous progression (Burns, Iliffe, 2009Burns A, Iliffe S. Alzheimer’s disease. BMJ. 2009;338:b158. https://doi.org/10.1136/bmj.b158
https://doi.org/10.1136/bmj.b158...
).

Another frequent comorbidity identified in the study was dysphagia, which is capable of compromising the medication taking process and adherence to it (Kelly, D'Cruz, Wright, 2010Kelly J, D’Cruz G, Wright D. Patients with dysphagia: Experiences of taking medication. J Adv Nurs. 2010;66(1):82-91. https://doi.org/10.1111/j.1365-2648.2009.05145.x
https://doi.org/10.1111/j.1365-2648.2009...
). In this context, quantitative ineffectiveness of the drugs donepezil, memantine and sertraline was observed, because of the need to adapt the pharmaceutical form by maceration and addition of water, to enable the administration of the drug (Benzi, Mastroianni, 2016Benzi JRL, Mastroianni PC. Analysis of extemporaneous oral liquid from commercially available drugs in hospital. Braz J Pharm Sci. 2016;52,517-525. https://doi.org/10.1590/s1984-82502016000300017
https://doi.org/10.1590/s1984-8250201600...
; Mastroianni, Forgerini, 2018Mastroianni PC, Forgerini M. Drug administration adjustments for elderly patients with dysphagia: A case report. Dement Neuropsychol . 2018;12(1):97-100. https://doi.org/10.1590/1980-57642018dn12-010015
https://doi.org/10.1590/1980-57642018dn1...
).

Adaptation of the pharmaceutical form for the elderly is commonly occurs, because frequently, there is no compatible form for individuals needs of the patient. However, little is known about the safety, quality and effectiveness of the drugs after this adaptation, which may lead to increased toxicity, decreased effectiveness and other safety and stability problems, and may expose the patient to adverse drug events (ADE) (Benzi, Mastroianni, 2016Benzi JRL, Mastroianni PC. Analysis of extemporaneous oral liquid from commercially available drugs in hospital. Braz J Pharm Sci. 2016;52,517-525. https://doi.org/10.1590/s1984-82502016000300017
https://doi.org/10.1590/s1984-8250201600...
; Paradiso et al., 2008Paradiso LM, Roughead EE, Gilbert AL, Cosh D, Nation RL, Barnes L, et al. Crushing or altering medications: what’s happening in residential aged-care facilities? Australas J Ageing. 2008;21(3):123-127. https://doi.org/10.1111/j.1741-6612.2002.tb00432.x.
https://doi.org/10.1111/j.1741-6612.2002...
).

From another perspective, in the process of intervention, it is important to understand the patient's behavior and decision about taking medication. Knowledge about the patient's therapeutic experience contributes to improved adherence and clinical results. This is because if patients are satisfied with the results of their drug therapy, if there are no barriers in the communication between the patients and health-care professionals, and if there are no problems with the safety and effectiveness of their treatment to discourage them from taking their drugs, these factors are associated with better adherence (Manary et al., 2013Manary MP, Boulding W, Staelin R, Glickman SW. The Patient Experience and Health Outcomes. N Engl J Med. 2013;368(3):201-3. https://doi.org/10.1056/NEJMp1211775.
https://doi.org/10.1056/NEJMp1211775...
).

Consequently, after the interventions conducted the majority of the patients began to move onto AD drug therapy. Such strategies and interventions can promote the patients’ feelings of autonomy and co-responsibility relative to the medication process, or, particularly, those of the relatives/caregivers, who feel more motivated to adhere to treatment, shown by evidence that simple adjustments or uncomplicated interventions are efficient (Arismendi et al., 2012Arismendi E, Martínez F, Antiñolo AT, Ibáñez MG. Evaluación e impacto de la intervención farmacéutica mediante seguimiento farmacoterapeutico a pacientes con enfermedad de alzheimer. Tese [Doutorado] - Universidad de Granada; 2012.; Mastroianni, Forgerini, 2019Mastroianni PC, Forgerini M. Compliance and Drug Related Problems in probable Alzheimer’s disease elderly. Int Psychogeriatr. 2019;31(11):1677-1678. https://doi.org/10.1017/S104161021800234X
https://doi.org/10.1017/S104161021800234...
; Sabater et al., 2005Sabater D, Fernandez-Llimos F, Parras M, Faus MJ. Types of pharmacist intervention in pharmacotherapy follow-up/Tipos de intervenciones farmacéuticas en seguimiento farmacoterapéutico. Seguim Farmacoter. 2005;3(2):90-97.; Santschi et al., 2014Santschi V, Chiolero A, Colosimo AL, Platt RW, Taffé P, Burnier M, et al. Improving blood pressure control through pharmacist interventions: a meta-analysis of randomized controlled trials. J Am Heart Assoc. 2014;3(2):e000718. https://doi.org/10.1161/JAHA.113.000718
https://doi.org/10.1161/JAHA.113.000718...
).

As regards the exposure to BZD, despite the controversies about the association between BZD use and dementia (Lucchetta et al., 2018Lucchetta RC, da Mata BPM, Mastroianni PC. Association between Development of Dementia and Use of Benzodiazepines: A Systematic Review and Meta-analysis. Pharmacother. 2018;38(10):1010-1020. https://doi.org/10.1002/phar.2170
https://doi.org/10.1002/phar.2170...
) and relative to worsening cognitive impairment in patients who already have the diagnosis (Defrancesco et al., 2015Defrancesco M, Marksteiner J, Wolfgang FW Blasko. Use of benzodiazepines in Alzheimer’s disease: A systematic review of literature. Int J Neuropsychopharmacol. 2015;18(10):pyv055. https://doi.org/10.1093/ijnp/pyv055.
https://doi.org/10.1093/ijnp/pyv055...
), BZDs are often prescribed for the treatment of psychological and behavioral symptoms of dementia (Glass et al., 2005Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto E, Lanctot KL, et al. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ. 2005;331:1169. https://doi.org/10.1136/bmj.38623.768588.47
https://doi.org/10.1136/bmj.38623.768588...
; Høiseth et al., 2013Høiseth G, Kristiansen KM, Kvande K, Tanum L, Lorentzen B, Refsum H. Benzodiazepines in geriatric psychiatry: What doctors report and what patients actually use. Drugs Aging. 2013;30:113-118. https://doi.org/10.1007/s40266-012-0045-9
https://doi.org/10.1007/s40266-012-0045-...
).

Nonetheless, deprescription could be a necessary step (Pottie et al. 2018Pottie K, Thompson W, Davies S, Grenier J, Sadowski C, Welch V, et al. Deprescribing benzodiazepine receptor agonists: Evidence-based clinical practice guideline. Clin Pract Guidel. 2018;64:339-351. PMID: 29760253) due the association of adverse drug events with the use of BZD. Whereas, the deprescription process is complex due to the positive therapeutic experiences of patients and family/caregivers, in addition the easy access to BZD - a standardized medication distributed by the public health system free-of-charge.

In the present study, it was not possible to relate the higher level of impairment to the use of BZD. However, this was not the primary outcome of this study, therefore no follow-up period or the necessary sample size relative to it were considered.

Statistical power was a limitation, since a convenience sample was used in the study and sample size had no statistical significance. However, the sample was complex due to AD being a neurodegenerative and progressive disease, in addition to the ethical issues involved and stigma attached to the entire morbidity. Moreover, to the best of our knowledge, this has been the only study that conducted a follow-up and performed interventions with AD patients, integrating all reported variables (Nguyen et al., 2019Nguyen TA, Gilmartin-Thomas J, Tan ECK, Kalisch-Ellett L, Eshetie T, Gillam M, et al. The impact of pharmacist interventions on quality use of medicines, quality of life, and health outcomes in people with dementia and/or cognitive impairment: A systematic review. J Alzheimer’s Dis. 2019;71(1):83-96. https://doi.org/10.3233/JAD-190162
https://doi.org/10.3233/JAD-190162...
).

Despite the limitations of this study, our data provided support for the guidelines established by OFIL (Organización Farmacéuticos Ibero-Latinoamericanos., 2012Organización Farmacéuticos Ibero-Latinoamericanos. Guía para la implantación de Servicios de Gestión Integral de la farmacoterapia. 2012. Acessed in 17 January, 2020.), whose proposal would be the implementation of business incubators in partnership with universities for: undergraduate and postgraduate training in MTM (education) (Mendonça, Freitas, Oliveira, 2017Mendonça SAM, Freitas EL, Oliveira DR. Competencies for the provision of comprehensive medication management services in an experiential learning project. PLoS One. 2017;12(9):e0185415. doi: 10.1371/journal.pone.0185415
https://doi.org/10.1371/journal.pone.018...
), a model providing services for the dissemination and knowledge about MTM to the community (extension) (Silva et al., 2016Silva DF, Meireles BL, Mendonça SAM, Oliveira DR. A extensão universitária como caminho para a construção do serviço de gerenciamento da terapia medicamentosa na atenção primária à saúde. Rev Bras Farm Hosp Serv Saúde São Paulo. 2016;7(2):15-21.), generating result indicators and establishing research to promote the safe use of medicines (research).

In addition, the larger number of qualified health service professionals and offer of MTM are in line with the Ministry of Health (Brasil, 2013Brasil. Ministério da Saude. Gabinete do Ministro. Portaria n. 529, de 1o de abril de 2013a. Institui o Programa Nacional de Segurança do Paciente (PNSP). D. Of. Bras. Seção 1. 2013; p.43-44.) and World Health Organization (World Health Organization, n.d.World Health Organization, n.d. World Alliance for Patient Health: forward programme 2008-2009. 2009, Education, 1st ed. Genebra.) policies on patient safety, among whose proposed strategies, we highlight the training of health professionals for the third national challenge of safe medication.

SOURCES OF FUNDING AND ACKNOWLEDGMENTS

The Authors thank the following financing agencies: Conselho Nacional para o Desenvolvimento Científico e Tecnológico (CNPq, Funding Numbers 459461/2014-1, and 131206/2017-6), The São Paulo Research Foundation – FAPESP (Funding Numbers 2014/00312-5, and 2018/07501-9), and “Pró- Reitoria de Extensão Universitária da UNESP” (PROEX-UNESP), for their for their financial contributions and thank the Centro de Referência do Idoso de Araraquara (CRIA) and all the professionals who who collaborated with this pharmaceutical care project. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES)—Finance Code 001.

REFERENCES

  • Alzheimer’s Association. Alzheimer’s Disease Facts and Figures. Alzheimers Dement. 2017;13,325-373. https://doi.org/10.1016/j.jalz.2017.02.001
    » https://doi.org/10.1016/j.jalz.2017.02.001
  • Arismendi E, Martínez F, Antiñolo AT, Ibáñez MG. Evaluación e impacto de la intervención farmacéutica mediante seguimiento farmacoterapeutico a pacientes con enfermedad de alzheimer. Tese [Doutorado] - Universidad de Granada; 2012.
  • Benzi JRL, Mastroianni PC. Analysis of extemporaneous oral liquid from commercially available drugs in hospital. Braz J Pharm Sci. 2016;52,517-525. https://doi.org/10.1590/s1984-82502016000300017
    » https://doi.org/10.1590/s1984-82502016000300017
  • Brasil. Ministério da Saude. Gabinete do Ministro. Portaria n. 529, de 1o de abril de 2013a. Institui o Programa Nacional de Segurança do Paciente (PNSP). D. Of. Bras. Seção 1. 2013; p.43-44.
  • Burns A, Iliffe S. Alzheimer’s disease. BMJ. 2009;338:b158. https://doi.org/10.1136/bmj.b158
    » https://doi.org/10.1136/bmj.b158
  • Ceresini G, Lauretani F, Maggio M, Ceda GP, Morganti S, Usberti E, et al. Thyroid function abnormalities and cognitive impairment in elderly people: Results of the invecchiare in chianti study. J Am Geriatr Soc. 2009;57(1):89-93. https://doi.org/10.1111/j.1532-5415.2008.02080.x
    » https://doi.org/10.1111/j.1532-5415.2008.02080.x
  • Cipolle RJ, Strand LM, Morley PC. Pharmaceutical Care Practice: The Patient Centered Approach to Medication Management. 3rd Edition, McGraw-Hill, Health Professions Division, New York. Pharmacol Pharm. 2012.
  • Costa AF, Chaves MLF, Picon PD, Krug BC, Gonçalves CBT, Amaral KM, et al. Protocolo Clínico e Diretrizes Terapêuticas - Doença de Alzheimer. Portaria conjunta No 13, 28 novembro 2017:147-167.
  • Crane PK, Walker R, Hubbard R, Li G, Nathan DM, Zheng H, et al. Glucose levels and risk of dementia. N Engl J Med. 2013;369(6):540-8. https://doi.org/10.1056/NEJMoa1215740
    » https://doi.org/10.1056/NEJMoa1215740
  • Defrancesco M, Marksteiner J, Wolfgang FW Blasko. Use of benzodiazepines in Alzheimer’s disease: A systematic review of literature. Int J Neuropsychopharmacol. 2015;18(10):pyv055. https://doi.org/10.1093/ijnp/pyv055
    » https://doi.org/10.1093/ijnp/pyv055
  • Des Jarlais DC, Lyles C, Crepaz N. Improving the Reporting Quality of Nonrandomized Evaluations of Behavioral and Public Health Interventions: The TREND Statement. Am J Public Health. 2004. https://doi.org/10.2105/AJPH.94.3.361
    » https://doi.org/10.2105/AJPH.94.3.361
  • Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198. https://doi.org/10.1016/0022-3956(75)90026-6
    » https://doi.org/10.1016/0022-3956(75)90026-6
  • Forgerini M, Mastroianni PC. Monitoring compliance of Clinical Protocol and Therapeutic Guidelines for Alzheimer’s disease. Dement Neuropsychol. 2020;14(1):24-27. https://doi.org/10.1590/1980-57642020dn14-010004
    » https://doi.org/10.1590/1980-57642020dn14-010004
  • Forgerini M, Herdeiro MT, Galduróz JCF, Mastroianni PC. Risk factors associated with drug therapy in the elderly with Alzheimer's disease. São Paulo Med J. 2020;138(3):216-218.
  • Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto E, Lanctot KL, et al. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ. 2005;331:1169. https://doi.org/10.1136/bmj.38623.768588.47
    » https://doi.org/10.1136/bmj.38623.768588.47
  • Gustafsson M, Sjölander M, Pfister B, Jonsson J, Schneede J, Lövheim H. Drug-related hospital admissions among old people with dementia. Eur J Clin Pharmacol. 2016;72(9):1143-53. https://doi.org/10.1007/s00228-016-2084-3
    » https://doi.org/10.1007/s00228-016-2084-3
  • Hayes TL, Larimer N, Adami A, Kaye JA. Medication adherence in healthy elders: Small cognitive changes make a big difference. J Aging Health. 2009;21(4):567-80. https://doi.org/10.1177/0898264309332836
    » https://doi.org/10.1177/0898264309332836
  • Høiseth G, Kristiansen KM, Kvande K, Tanum L, Lorentzen B, Refsum H. Benzodiazepines in geriatric psychiatry: What doctors report and what patients actually use. Drugs Aging. 2013;30:113-118. https://doi.org/10.1007/s40266-012-0045-9
    » https://doi.org/10.1007/s40266-012-0045-9
  • Kelly J, D’Cruz G, Wright D. Patients with dysphagia: Experiences of taking medication. J Adv Nurs. 2010;66(1):82-91. https://doi.org/10.1111/j.1365-2648.2009.05145.x
    » https://doi.org/10.1111/j.1365-2648.2009.05145.x
  • Lucchetta RC, da Mata BPM, Mastroianni PC. Association between Development of Dementia and Use of Benzodiazepines: A Systematic Review and Meta-analysis. Pharmacother. 2018;38(10):1010-1020. https://doi.org/10.1002/phar.2170
    » https://doi.org/10.1002/phar.2170
  • Machuca-González M, Silva Castro MM. Evaluación de la farmacoterapia a partir de la enfermedad de base. Pharm Care Espana. 2010;12(1):192-194.
  • Manary MP, Boulding W, Staelin R, Glickman SW. The Patient Experience and Health Outcomes. N Engl J Med. 2013;368(3):201-3. https://doi.org/10.1056/NEJMp1211775
    » https://doi.org/10.1056/NEJMp1211775
  • Mastroianni PC, Forgerini M. Compliance and Drug Related Problems in probable Alzheimer’s disease elderly. Int Psychogeriatr. 2019;31(11):1677-1678. https://doi.org/10.1017/S104161021800234X
    » https://doi.org/10.1017/S104161021800234X
  • Mastroianni PC, Forgerini M. Drug administration adjustments for elderly patients with dysphagia: A case report. Dement Neuropsychol . 2018;12(1):97-100. https://doi.org/10.1590/1980-57642018dn12-010015
    » https://doi.org/10.1590/1980-57642018dn12-010015
  • Matsuzaki T, Sasaki K, Hata J, Hirakawa Y, Fujimi K, Ninomiya T, et al. Association of Alzheimer disease pathology with abnormal lipid metabolism: The hisayama study. Neurology. 2011;77(11):1068-75. https://doi.org/10.1212/WNL.0b013e31822e145d
    » https://doi.org/10.1212/WNL.0b013e31822e145d
  • Mehta DC, Short JL, Hilmer SN, Nicolazzo JA. Drug access to the central nervous system in Alzheimer’s disease: Preclinical and clinical insights. Pharm Res. 2015;32(3):819-39. https://doi.org/10.1007/s11095-014-1522-0
    » https://doi.org/10.1007/s11095-014-1522-0
  • Mendonça SAM, Freitas EL, Oliveira DR. Competencies for the provision of comprehensive medication management services in an experiential learning project. PLoS One. 2017;12(9):e0185415. doi: 10.1371/journal.pone.0185415
    » https://doi.org/10.1371/journal.pone.0185415
  • Morris JC. The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology. 1993;43(11):2412-2412. https://doi.org/10.1212/WNL.43.11.2412-a
    » https://doi.org/10.1212/WNL.43.11.2412-a
  • Muliyala KP, Varghese M. The complex relationship between depression and dementia. Ann Indian Acad Neurol. 2010;13(6):69-73. https://doi.org/10.4103/0972-2327.74248
    » https://doi.org/10.4103/0972-2327.74248
  • Nation DA, Delano-Wood L, Bangen KJ, Wierenga CE, Jak AJ, Hansen LA, et al. Antemortem pulse pressure elevation predicts cerebrovascular disease in autopsy-confirmed alzheimer’s disease. J Alzheimer’s Dis. 2012;30(3):595-603. https://doi.org/10.3233/JAD-2012-111697
    » https://doi.org/10.3233/JAD-2012-111697
  • Nguyen TA, Gilmartin-Thomas J, Tan ECK, Kalisch-Ellett L, Eshetie T, Gillam M, et al. The impact of pharmacist interventions on quality use of medicines, quality of life, and health outcomes in people with dementia and/or cognitive impairment: A systematic review. J Alzheimer’s Dis. 2019;71(1):83-96. https://doi.org/10.3233/JAD-190162
    » https://doi.org/10.3233/JAD-190162
  • Obreli-Neto PR, Guidoni CM, Oliveira Baldoni A, Pilger D, Cruciol-Souza JM, Gaeti-Franco, et al. Effect of a 36-month pharmaceutical care program on pharmacotherapy adherence in elderly diabetic and hypertensive patients. Int J Clin Pharm. 2011;33(4):642-9. https://doi.org/10.1007/s11096-011-9518-x
    » https://doi.org/10.1007/s11096-011-9518-x
  • Organización Farmacéuticos Ibero-Latinoamericanos. Guía para la implantación de Servicios de Gestión Integral de la farmacoterapia. 2012. Acessed in 17 January, 2020.
  • Paradiso LM, Roughead EE, Gilbert AL, Cosh D, Nation RL, Barnes L, et al. Crushing or altering medications: what’s happening in residential aged-care facilities? Australas J Ageing. 2008;21(3):123-127. https://doi.org/10.1111/j.1741-6612.2002.tb00432.x
    » https://doi.org/10.1111/j.1741-6612.2002.tb00432.x
  • Picon PD, Camozzato AL, Lapporte EA, Picon RV, Filho HM, Cerveira MO, et al. Increasing rational use of cholinesterase inhibitors for Alzheimer’s disease in Brazil: Public health strategy combining guideline with peer-review of prescriptions. Int J Technol Assess Health Care. 2010;26(2):205-10. https://doi.org/10.1017/S0266462310000097
    » https://doi.org/10.1017/S0266462310000097
  • Potter GG, Steffens DC. Contribution of depression to cognitive impairment and dementia in older adults. Neurologist. 2007;13(3):105-17. https://doi.org/10.1097/01.nrl.0000252947.15389.a9
    » https://doi.org/10.1097/01.nrl.0000252947.15389.a9
  • Pottie K, Thompson W, Davies S, Grenier J, Sadowski C, Welch V, et al. Deprescribing benzodiazepine receptor agonists: Evidence-based clinical practice guideline. Clin Pract Guidel. 2018;64:339-351. PMID: 29760253
  • Ramalho-de Oliveira D, Shoemaker SJ, Ekstrand M, Alves MR. Preventing and resolving drug therapy problems by understanding patients’ medication experiences. J Am Pharm Assoc. 2012;52(1):71-80. https://doi.org/10.1331/JAPhA.2012.10239
    » https://doi.org/10.1331/JAPhA.2012.10239
  • Reeve E, Trenaman SC, Rockwood K, Hilmer SN. Pharmacokinetic and pharmacodynamic alterations in older people with dementia. Expert Opin Drug Metab Toxicol. 2017;13(6):651-668.
  • Sabater D, Fernandez-Llimos F, Parras M, Faus MJ. Types of pharmacist intervention in pharmacotherapy follow-up/Tipos de intervenciones farmacéuticas en seguimiento farmacoterapéutico. Seguim Farmacoter. 2005;3(2):90-97.
  • Santschi V, Chiolero A, Colosimo AL, Platt RW, Taffé P, Burnier M, et al. Improving blood pressure control through pharmacist interventions: a meta-analysis of randomized controlled trials. J Am Heart Assoc. 2014;3(2):e000718. https://doi.org/10.1161/JAHA.113.000718
    » https://doi.org/10.1161/JAHA.113.000718
  • Sha T, Cheng W, Yan Y. Prospective associations between pulse pressure and cognitive performance in Chinese middle-aged and older population across a 5-year study period. Alzheimer’s Res Ther. 2018;10(1):29. https://doi.org/10.1186/s13195-018-0355-1
    » https://doi.org/10.1186/s13195-018-0355-1
  • Silva DF, Meireles BL, Mendonça SAM, Oliveira DR. A extensão universitária como caminho para a construção do serviço de gerenciamento da terapia medicamentosa na atenção primária à saúde. Rev Bras Farm Hosp Serv Saúde São Paulo. 2016;7(2):15-21.
  • Smith D, Lovell J, Weller C, Kennedy B, Winbolt M, Young C, et al. A systematic review of medication nonadherence in persons with dementia or cognitive impairment. PLoS ONE. 2017;12(2):e0170651. https://doi.org/10.1371/journal.pone.0170651
    » https://doi.org/10.1371/journal.pone.0170651
  • Strand LM, Cipolle RJ, Morley PC. Documenting the clinical pharmacist’s activities: back to basics. Drug Intell Clin Pharm. 1988;22(1):63-67. https://doi.org/10.1177/106002808802200116
    » https://doi.org/10.1177/106002808802200116
  • World Health Organization, Dementia: a public health priority. 2012.
  • World Health Organization, n.d. World Alliance for Patient Health: forward programme 2008-2009. 2009, Education, 1st ed. Genebra.
  • Wucherer D, Thyrian JR, Eichler T, Hertel J, Kilimann I, Richter S, et al. Drug-related problems in community-dwelling primary care patients screened positive for dementia. Int Psychogeriatrics. 2017;29(11):1857-1868. https://doi.org/10.1017/S1041610217001442
    » https://doi.org/10.1017/S1041610217001442

Publication Dates

  • Publication in this collection
    08 Aug 2022
  • Date of issue
    2022

History

  • Received
    27 Oct 2019
  • Accepted
    16 Mar 2020
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br