It is estimated that around five to 10.0% of hospital admissions occur due to clinical conditions resulting from pharmacotherapy. Clinical pharmacist's activity can enhance drug therapy's effectiveness and safety through pharmacotherapy interventions (PIs), thus minimizing drug-related problems (DRPs) and optimizing the allocation of financial resources associated with health care. This study aimed to estimate the DRPs prevalence, evaluate PI which were performed by clinical pharmacists in the Neurology Unit of a Brazilian tertiary teaching hospital and to identify factors associated with the occurrence of PI-related DRP. A single-arm trial included adults admitted in the referred Unit from 2012 July to 2015 June. Patients were evaluated during their hospitalization period and PIs were performed based on trigger DRPs that were detected in medication reconciliation (admission or discharge) or during inpatient follow-up. Student's t-test, Chi-square test, Pearson and Multiple logistic regression models to analise the association among age, number of drugs, hospitalization period, and number of diagnoses with occurrence of DRPs. Analyses level of significance was 5%. In total 409 inpatients were followed up [51.1% male, mean age of 49.1 (SD 16.5)]. Patients received, on average, 11.9 (SD 5.8) drugs, ranging from two to 38 drugs per patient, and 54.3% of the sample presented at least one DRP whose most frequent description was "untreated condition". From all 516 performed PIs that resulted from DRPs, 82.8% were accepted and the majority referred to "drug introduction" (27.5%). Multiple logistic regression showed that age, length of hospital stay, number of drugs used, diagnosis of epilepsy, multiple sclerosis and myasthenia gravis would be clinical variables associated with DRP (p < 0,05). Monitoring the use of drugs allowed the clinical pharmacist to detect DRPs and to suggest interventions that promote rational pharmacotherapy.
Keywords: Research Article; Medicine and health sciences; Pharmacology; Routes of administration; Drug interactions; Drug-food interactions; Pharmaceutics; Drug therapy; People and places; Population groupings; Professions; Medical personnel; Pharmacists; Drug screening; Drug administration; Neurological drug therapy; Adverse reactions
Inappropriate use of medication constitutes a major public health issue that negatively affects treatment response and increases costs regarding the management of drug-related problems (DRPs). DRP refers to drug treatment events which may interfere its results, being a frequent cause of morbidities, hospitalizations and mortality. They can be associated to aspects, such as indication need, treatment effectiveness, safety, which includes detection and prevention of adverse drug reactions, and drug therapy adherence [[
Moreover, around 5.0 to 10.0% of hospital admissions are estimated to occur due to DRPs, from which up to 60.0% are preventable [[
Considering the hospital setting, clinical pharmacist's performance should occur during the whole hospitalization period, from admission to discharge. At these specific two moments, it is recommended to perform the medication reconciliation, a practice whose purpose is to review and evaluate if current medical prescriptions are coherent with the previous prescriptions, and also with medical history. Hence, it is possible to detect divergencies that may impact on clinical evolution of patients and impair their health [[
Among the potential patients for CPSs, it is noteworthy that individuals who are diagnosed with neurological diseases are more susceptible to the occurrence of DRPs, once medications indicated to manage most common conditions have complex dosage regimens, potential for interaction with other drugs and/or are associated with the occurrence of important adverse reactions [[
From this backgroung, this study aimed to estimate the DRPs prevalence, evaluate PIs which were performed by clinical pharmacists in the Neurology Unit of a quaternary teaching hospital, and to identify factors associated with the occurrence of PI-related DRP.
We carried out a single-arm trial at the adult Neurology Unit of the General Hospital of Medical School of Ribeirão Preto, University of São Paulo, Brazil (HCFMRP-USP). HCFMRP-USP is a tertiary teaching hospital focused on teaching, researching, and assisting Brazilian Public Health System patients. Inpatients medical prescriptions, as well as their clinical and laboratorial information were accessed through the hospital's eletronic information system. Regarding Neurology Unit, there are 26 beds for the hospitalization of adults with previously diagnosed neurological disease or for diagnostic investigation.
The inclusion criteria embraced individuals of both sexes, aged 18 years or more, who were admitted in the adult Neurology Unit of HCFMRP-USP between 2012 July 1st and 2015 June 30th. We did not include patients who were hospitalized exclusively to undergo polysomnography examination, as well as individuals whose hospitalization lasted less than 24 hours and those who did not agree with the Informed Consent Form. All patients included signed the Informed Consent. Sample size calculation was performed through a prevalence formula [[
The CPS that was performed from Monday to Friday by one researcher pharmacist takes place in three steps: reconciliation on admission, follow-up based on daily pharmacotherapy review and e hospital discharge reconciliation. Patient follow-up and information collection through structured CPS forms began at hospital admission (Fig 1). The main objective of the professional's activity at this moment was to record patient's clinical history mainly related to the use of drugs at home. If it was detected any inconsistency between collected information and hospital medical prescription, the pharmacist did intervene through a PI to the physician in order to solve the discrepancy or DRP. Admission medication reconciliation occurred through direct contact with the patient and/or caregiver and also by means of analysing other prescriptions brought by the patients, regarding their home treatment routine.
From the admission medication reconciliation until hospital discharge, the collection and examination of clinical data from each patient was performed on a daily basis, as well as the pharmacotherapy follow-up. Information about the clinical condition was recorded as suggested by the SOAP method (Subjective-Objective-Assessment-Plan) [[
Pharmacotherapy follow-up activities focused on issues related to patient's need, as well as to treatment effectiveness and safety. Therefore, a careful analysis of medical prescription was undertaken with respect to indication, dose, effectiveness, adverse drug reactions, drug-drug and drug-food interactions, interactions between drug and enteral nutrition, among others.
After subjective and objective collection data and daily prescription analysis, the pharmacist proceeded to the case evaluation and to the establishment of an intervention plan. These steps were registered into the clinical evolution form, according to the SOAP method.
Medication reconciliation at discharge was performed by reviewing both patient's medical history and medical prescriptions evolution, and then counseling was provided to the patient and/or his caregiver. If any inconsistency was detected between the previous medical prescriptions and the discharge prescription, the pharmacist then formulated a PI addressed to the physician in order to solve the DRP. During patient and/or caregiver advice, following medication reconciliation, the pharmacist delivered information on access, storage, and use of drugs. This occurred verbally, and also written through tools such as tables and pictograms, in order to assure interlocutors understanding. Thus, at hospital discharge, the pharmacist could perform two types of interventions: intervention to the physician as a result of a DRP detected and intervention with patient/caregiver related to education about the correct use of drugs at home. Intervention related to education was executed even if there was not a DRP. Data from these practices were recorded in specific forms for discharge medication reconciliation.
All PIs carried out during pharmaceutical follow-up, admission reconciliation and discharge medication reconciliation were conducted verbally and registered into the electronic patient record. Categorization of performed PI that result from a DRP was made according to the trigger DRP classification (Table 1), which was adapted from Cipolle, Strand and Morley (2004) [[
Table 1: Types of DRPs and PIs performed by clinical pharmacist from the CPS in the Neurology Unit of HCFMRP-USP.
DRP classification DRP description or cause Feasible PI based on detected DRP Need for indication Untreated condition Drug introduction Unnecessary treatment Drug withdrawal (unnecessary or duplicated) Effectiveness Ineffective or potentially ineffective drug Dose increase Drug substitution Introduction of a new drug Administration schedule change Administration route change (same drug) Drug interaction Withdrawal of a drug due to decreased effect of another. Increase in dose of drug whose effect is reduced Dose decrease of drug that reduces the effect of the other Administration schedule change Drug substitution Introduction of a new drug Drug-food interaction Drug or food administration schedule change Subtherapheutic dosage1 Dose increase Extension of treatment period Increase of i.v.5 drug infusion rate Drug-enteral feeding tube interaction Drug substitution Pharmaceutical formulation change (same drug and administration route) Administration route change (same drug) Physical-chemical incompatibility2 Administration schedule change Dose/concentration decrease Diluent substitution Administration route change Safety ADR3/Potential ADR/Contraindication Drug substitution Drug withdrawal Dose decrease Administration schedule change Administration route change Drug introduction for ADR management / prevention Overdosage4 Daily dosage decrease Reduction of treatment period Decrease of i.v.5 drug infusion rate Drug interaction Withdrawal of the drug which is causing ADR Dose decrease of the drug which is causing ADR Withdrawal of drug that increases serum level of another Dose decrease of the drug that increases serum level of another Dose decrease of one of the drugs due to synergistic effect Dose decrease of both drugs due to synergistic effect Drug substitution Physical-chemical incompatibility2 Administration schedule change Dose / concentration decrease Diluent substitution Administration route change Other Laboratory monitoring not performed6 Laboratory test order Cost/Access7 Drug substitution Administration route change (same drug) Change of marketed formulation (same drug and pharmaceutical formulation) Complex pharmacotherapy regimen8 Administration schedule change Change of marketed formulation (same drug and pharmaceutical formulation) Other Education / discharge advice Other
- 9 DRP: drug-related problem; PI: pharmacotherapy interventions; CPS: clinical pharmaceutical service.
1
- 3
2 Drugs or drug and diluent which are prescribed for i.v. administration but their concomitant use through i.v. route is contraindicated. Precipitate or insoluble complexes formation may occur, resulting for example in ineffectiveness and / or adverse events to the patient - 4
3 ADR: adverse drug reaction - 5
4 Dose is higher than the upper established limit for the respective indication or condition. It occurs, for instance, in cases where renal damage is present but the recommended dose adjustment has not been performed - 2
5 i.v.: intravenous route - 6
6 Pharmacist suggests to the physician the request of laboratory tests to monitor pharmacotherapy effectiveness/safety - 7
7 Pharmacist suggests the change of either the drug, the administration route, or the pharmaceutical formulation, aiming to minimize the costs after hospital discharge for both the health system and patient - 8
8 This results in an intervention in order to provide the patient a more rational and convenient treatment scheme. An example would be the suggestion to adjust the administration schedule so that some drugs can be taken at the same time—as long as there are no drug interactions that contraindicate it.
It is importante to highlight that one single DRP may result in different PIs that will be performed at the same time. A safety DRP, for example, may result in both drug withdrawal and introduction of a new drug to manage the respective adverse reactions signs and symptoms.
The pharmacist recorded each PI and the description of its trigger DRP in specific form, and also at what moment the DRP was detected–by admission, during the hospitalization or by discharge. PI described as "Education/Discharge advice" refers to the aforementioned counseling which was provided to patient and/or caregiver after discharge medication reconciliation.
In order to identify factors associated with the occurrence of DRPs, the following variables were considered: sex, age, hospitalization period, etiological diagnosis related to neurological disorder, number of diagnosed conditions, and number of prescribed drugs. Additionally, drugs related to PI were classified according to the following systems: Anatomical Therapeutic Chemical (ATC), and Defined Daily Dose (DDD) [[
Then, unpaired Student's t-test was performed to compare the categories' means with respect to hospitalization period and age, Chi-square test (χ2) was used to identify the association between patient's sex and the occurrence of DRP, and finally, we calculated Poisson model to compare number of diagnoses and number of prescribed drugs during hospitalization. Multiple logistic regression model was employed to verify the adjusted association among: most common etiological diagnoses that led to hospitalization at neurology ward, age, number of prescribed drugs, length of hospital stay (days), and number of diagnoses with occurrence of DRPs through the adjusted Odds Ratio. Analyses level of significance (α) was set at 5% and were delevoped through Statistical Package for Social Sciences Program (SPSS Inc., version 17.1.0).
This study was approved by the Research Ethics Committee of HCFMRP-USP, approval number 1888333.
A total of 409 adults admitted to the Neurology Unit of HCFMRP-USP were followed up, with a mean age of 49.1 years (SD 16.5). Regarding gender, men composed 51.1% of the sample. Among all patients, 222 (54.3%) presented at least one DRP during the hospitalization period; adding up to 516 DRPs, a mean of 2.3 (SD 2.1) per patient, and a minimum and maximum value of one and 14, respectively.
Most of identified DRP was classified as "need for indication" and described as untreated condition (26.9%). Fig 2 depicts all causes of detected DRPs, as well as the number of times each was observed by the clinical pharmacist. The 516 DRPs resulted in the same number of PIs which were suggested to physicians, from which 427 (82.8%) were accepted. Regarding the moment in which the intervention that resulted from a problem was performed, 460 (89.2%) occurred during hospitalization follow-up, while 25 (4.8%) were performed by the hospital admission's medication reconciliation, and 31 (6.0%) during the discharge medication reconciliation. "Drug introduction", most frequent PI from DRP trigger, accounted for 27.5% of these interventions, followed by "drug withdrawal" (16.9%), and "administration schedule change" (15.7%) (Fig 3). In addition to the 516 PIs described previously, there were 148 hospital discharge orientation for patients and/or caregivers. Thus, in total, the clinical pharmacist performed 664 interventions.
Drugs associated with DRP that resulted in PIs were categorized into 43 different pharmacotherapeutic classifications, the main are described in Table 2. It is noteworthy that vitamin B12 was the most frequent drug regarding PI "drug introduction" (68.4%). Considering "drug withdrawal" category, antithrombotic agents were the most prevalent (13.6%), followed by psychoanaleptics (12.5%) and drugs for functional gastrointestinal dysfunctions (12.5%). Among antithrombotics, the main observed drug was enoxaparin (66.6%), while amitriptyline and fluoxetine composed the majority of psychoanaleptics (54.5%) and bromopride was the most frequent considering the management of gastrointestinal dysfunctions (90.9%). Levothyroxine was the main drug related to the need of change on the administration schedule (13.6%).
Table 2: Main pharmacotherapeutic classes related to performed PIs resulting from DRPs.
ATC classification Total PI (%*) Vitamins 47 (9.1) Antithrombotic agents 39 (7.6) Antiepileptics 30 (5.8) Psychoanaleptics 29 (5.6) Drugs for gastrointestinal dysfunctions 27 (5.2) Antiinfectives for systemic use 27 (5.2) Mineral supplements 23 (4.5) Drugs for acid related disorders 22 (4.3) Drugs used in diabetes 22 (4.3) Agents acting on the renin-angiotensin system 21 (4.1) Lipid modifying agents 19 (3.7) Drugs for constipation 16 (3.1) Thyroid therapy 15 (2.9) Antiinflammatory and antirheumatic products 15 (2.9) Anti-parkinson drugs 15 (2.9) Psycholeptics 15 (2.9) Antianemic preparations 10 (1.9) Calcium channel blockers 10 (1.9)
- 11 ATC: anatomical therapeutic chemical; DRPs: drug-related problems; PIs: pharmacotherapy interventions.
- 10 *Total sample size = 516.
Patients who presented any DRP had a higher mean age (mean: 53.0; SD: 16.2) in comparison with those who did not (mean: 44.5; SD: 15.7) [mean difference = -8.52; p < 0.001 (95% CI: -11.63, -5.40)]. However, there was no evidence of association between patient gender and the occurrence of DRP (χ2 = 3.73; p = 0.600). The mean period of hospitalization was 15.8 days (SD 15.0), ranging from one to 144. Those who presented DRP remained hospitalized, on average, 10.1 days longer (95% CI: 7.37, 12.88; p < 0.001) than individuals who have not present DRP.
According with ATC [[
About the etiological diagnoses related to neurological conditions that led to hospitalization, the most common diseases are described in Table 3.
Table 3: Most common etiological diagnoses of the neurological disorders that led to hospitalization at neurology ward.
Admitting diagnoses n (%) Epilepsy 44 (10.8) Vitamin B12 deficiency 33 (8.1) Central nervous system infections 32 (7.8) Parkinson disease 18 (4.4) Multiple sclerosis 16 (3.9) Myasthenia gravis 16 (3.9) Stroke 13 (3.2) Drug-induced Parkinsonism/Other ADR 11 (2.7) Motor neuron disease 10 (2.4)
12 The number of patients diagnosed and the frequencies of the diseases that led to at least 10 hospitalazations. ADR: adverse drug reactions.
Patients received, on average, 11.9 (SD 5.8) drugs, ranging from two to 38 drugs per patient. Those who presented any DRP showed a higher mean for this variable [14.0 (DP 6.1), ranging from 3 to 38 drugs per patient] when compared to the patients without DRP [9.3 (SD 4.3), ranging from 2 to 23 drugs per patient] (χ
Multiple logistic regression model (R
Table 4: Multiple logistic regression model for DRP occurrence related to: most common etiological diagnoses of the neurological disorders, length of stay, number of diagnoses, total drugs in use, and age of patients followed at the Neurology Unit of HCFMRP-USP.
Independent variable β-coefficient Standard error Adjusted OR (95% CI) p value Stroke -0.596 0.910 0.551 (0.093; 3.283) 0.513 Vitamin B12 deficiency 0.044 0.502 1.045 (0.39; 2.798) 0.930 Motor neuron disease -0.112 0.806 0.894 (0.184; 4.338) 0.889 Parkinson disease -0.354 0.622 0.702 (0.207; 2.377) 0.570 Multiple sclerosis 2.194 0.860 8.967 (1.661; 48.409) 0.011 Epilepsy 0.773 0.389 2.167 (1.012; 4.642) 0.047 Central nervous system infections -0.025 0.483 0.975 (0.378; 2.515) 0.958 Myasthenia gravis 1.192 0.590 3.294 (1.037; 10.459) 0.043 Drug-induced Parkinsonism/ Other ADR 1.336 0.691 3.805 (0.982; 14.74) 0.053 Age (years) 0.018 0.007 1.018 (1.003; 1.033) 0.016 Number of diagnoses 0.123 0.090 1.13 (0.947; 1.349) 0.175 Total number of drugs used 0.144 0.028 1.155 (1.094; 1.22) 0.001 Length of hospital stay (days) 0.085 0.015 1.089 (1.058; 1.12) 0.001 Intercept -7.336 2.181 0.001
13 ADR: adverse drug reaction; DRP: drug-related problem; OR: odds ratio; CI: confidence interval.
DRP related to indication need were the most common, particularly those classified as "untreated condition" (26.9%). Untreated health problems potentially aggravate patient's clinical condition, which may extend the length of hospitalization, consequently increasing the costs to the health system [[
Antithrombotics were the second class of PI-related drugs (7.6%). In Neurology units, the hospitalization of patients with neurological conditions that are associated with motor alterations and reduced mobility is common. The indication of antithrombotics for preventing venous thromboembolism in bedridden patients who have other risk factors, such as elderly age, smoking and obesity should always be considered. Nevertheless, this class prescription should be made rationally, due to the risk of adverse reactions such as thrombocytopenia and hemorrhage [[
Bromopride whose use should be avoided in subjects with Parkinson's disease due to its antidopaminergic effect on the central nervous system [[
"Drug substitution" was another common PI that frequently involves venous thromboembolism prophylaxis therapy. Enoxaparin is generally indicated in HCFMRP-USP, due to its simpler and safer dosage schedule in relation to unfractionated heparin, other available option in the hospital. However, if a significant alteration in renal function is observed, fractional heparin (enoxaparin) should be shifted to unfractionated heparin [[
Levothyroxine accounted for 13.6% of all "administration schedule change" PI, which, in turn, was the third most prevalent PI (15.7%). Administrating levothyroxine with food reduces drug absorption and may lead to drug ineffectiveness and hypothyroidism decompensation [[
Despite this study setting, most prevalent diseases referred to disorders of the circulatory and endocrine systems. These results reflect epidemiological data regarding general adult population in most countries which show a high prevalence of diseases, such as hypertension and diabetes mellitus [[
Multiple logistic regression showed that age, number of drugs used, length of hospital stay, diagnosis of epilepsy, multiple sclerosis and myasthenia gravis were factors associated to DRP (Table 4). Patient's age is an important variable and should be considered when planning the pharmacotherapy, once the aging process results in both pharmacokinetic and pharmacodynamic changes on drugs' metabolism, which interferes with the drugs effectiveness. It is also important to highlight that polytherapy increases the risk of DRP [[
Polypharmacy is a worldwide reality when it comes to drug use reports. The mean number of drugs used by the patients (11.9; SD 5.8) was higher than those found in other two studies undertaken in hospitals whose average numbers of drugs per patient were 6.3 and 7.9, respectively [[
The percentage of acceptance of PIs performed to the physicians was 82.8%, while published data vary between 70.0% and 100.0% [[
Most of PIs were performed during the follow-up of inpatients (89.2%). Spalla and Castilho have described that either the omission or the absence of prescribing medications which are being used by the patient at home, prior to hospitalization, may represent from 42.0 to 60.0% of all errors occurred during hospital admission and discharge [[
It is noteworthy that the clinical pharmacist performed his clinical activities for six hours a day during this study, from Mondays to Fridays. The aforementioned CPS routine contributed to the fact that most PIs were performed during the hospital follow-up, since the absence of the pharmacist did not allow his effective participation in a considerable number of both medication reconciliations and discharge advices. This situation contributes to possible underestimated number about reconciliation-related DRPs in comparison to other studies. Another limitation of this study was the impossibility to evaluate the impact of both PIs and CPS on patients health and quality of life after hospital discharge. In addition, the influence of admitting diagnosis severity on the occurrence of DRP was not assessed in this study. Finally, it was not possible to perform a randomized controlled study which would allow comparing the outcomes with a control group (without CPS) due to the hospital routine regarding the activities of the clinical pharmacist. Despite the cited limitations, the design of this study represents the real-life context and shows evidence the relevance and acceptability of CPS in the hospital routine.
DRPs were quite prevalent in patients admitted to the Neurology Unit of HCFMRP-USP, especially among elderly patients and in the presence of politherapy. However, monitoring the patients clinical evolution and the use of drugs allowed the clinical pharmacist to detect DRPs and to suggest interventions that contributed to the optimization of pharmacotherapy and was well accepted by physicians.
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DIAGRAM: Fig 1: Summarizing algorithm for the care process offered by the pharmacist during the hospitalization of patients in the Neurology Unit of HCFMRP-USP. * Moments in which pharmacotherapy interventions (PIs) may be performed.
DIAGRAM: Fig 2: Causes of detected DRPs at the Neurology Unit of HCFMRP-USP during the study period. DRPs: drug-related problems. ADRs: adverse drug reactions.
DIAGRAM: Fig 3: PIs that resulted from DRPs performed at the Neurology Unit of HCFMRP-USP during the study period. DRPs: drug-related problems. PIs: pharmacotherapy interventions.
By João Paulo Vilela Rodrigues, Writing – original draft; Fabiana Angelo Marques, Writing – original draft; Ana Maria Rosa Freato Gonçalves, Writing – original draft; Marília Silveira de Almeida Campos, Writing – original draft; Tiago Marques dos Reis, Writing – original draft; Manuela Roque Siani Morelo, Writing – review & editing; Andrea Fontoura, Writing – original draft; Beatriz Maria Pereira Girolineto, Data curation; Helen Palmira Miranda de Camargo Souza, Writing – original draft; Maurílio de Souza Cazarim, Data curation; Lauro César da Silva Maduro, Data curation and Leonardo Régis Leira Pereira, Writing – review & editing