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Hospital Pharmacy Service, Hospital General de Granollers, Av. Francesc Ribas S/n, 08400, Granollers, Barcelona, SpainHospital Pharmacy Service, Fundación Privada Hospital d'Olot i Comarcal de la Garrotxa, Avinguda Dels Països Catalans, 86, 17800, Olot, Girona, Spain
This study presents information about the characteristics of the Chagas disease population in a non-endemic country.
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It contributes information about developing a Chagas disease pharmacist intervention program.
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It provides data about pharmaceutical intervention and its outcomes enriching the currently limited information in the literature.
Abstract
Background
Spain has the second highest number of Chagas disease-infected patients among non-endemic countries. However, there is limited knowledge about pharmacist involvement in managing patients with Chagas disease.
Method
A retrospective observational study was performed in two periods (before and after intervention) to describe the characteristics of patients with Chagas disease. Pharmacist intervention, based on two pharmacist-visit programs and development of information for patients, was applied to patients under pharmacological treatment in a non-endemic country. Depending on the initial results in 2010–2011, specific pharmacist attention program for patients with Chagas disease was implemented in 2012. The results of 2010–2011 (before intervention) and 2013 (after intervention) were compared.
Results
A high number of adverse drug reactions were reported in both periods, 50.0% (2010–2011) vs. 90.9% (2013). With regard to treatment completion, in 2010–2011, 60% achieved the treatment completion criteria (>95% days of treatment) vs. 68.2% in 2013 (p = 0.580). There was, however, a significant increase in the detection of ADRs in the second period (50.0% vs. 90.9%; p = 0.003) and an increase in the severity (75% [6/8] of uncompleted treatments were due to ADRs vs. 100% [7/7] in the first and second period, respectively).
Conclusions
This study was useful to provide more information about patients with Chagas disease, provide pharmacist intervention/information material to patients, and detect a point of improvement in hospital follow-up care. Although it was not possible to demonstrate it with a statistically significant result, we believe that pharmacist intervention that includes in-depth patient information about possible ADRs and their management could increase adherence and treatment completion rates. In addition, pharmacist intervention helped to better detect and control ADRs that could lead to generating better health outcomes in Chagas disease. Although our patients' health literacy was not evaluated, it would be a potential avenue for future research.
]. Considered by the World Health Organization (WHO) as one of the 17 neglected tropical diseases, an estimated 7 million people are infected worldwide [
]. Typically endemic in all South and Central American countries and Mexico, nowadays it is increasingly becoming a global health problem. Migration of T. cruzi-infected patients from endemic countries implies that the estimated number of patients outside Latin-America is now over 400,000. The non-endemic regions affected the most are North America, Europe, and the Western Pacific Region [
]. This can probably be explained by the fact that chronically infected patients remain asymptomatic for a long time, health professionals in non-endemic areas are unaware of Chagas disease, and the migrant population encounters barriers with regard to healthcare access [
There is no general regulation by the European Commission, and therefore, there is no guarantee of controlling Chagas disease transmission in European countries. In Spain, some regions have developed regional screening strategies to control Chagas transmission, the most important “imported” disease to emerge in Spain in recent decades [
]. However, the high prevalence of this imported disease in a non-endemic area implies the need for specialized pharmaceutical interventions for these patients. Specific pharmaceutical intervention requires specific training to support patients with Chagas disease during their treatment and follow-up visits to thereby improve patient outcomes.
Phases and clinical evolution/Pathogenesis
Chagas disease can be divided into two phases:
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Acute: it lasts 4–8 weeks and is usually asymptomatic or characterized by non-specific symptoms [
Chronic: it begins 2–3 months after the initial infection. About 60–70% of patients will never have clinical manifestations, known as the indeterminate form of Chagas disease. The other 30–40% will progress to a determinate form of Chagas disease that is further classified into four major types: cardiac (20–30%), digestive (10–15%), cardiodigestive (10–15%), and central nervous system (5%) [
Since they were developed in the late 1960s and 1970s, benznidazole and nifurtimox are the only two currently available and effective drugs to treat T. cruzi infection [
In Spain, both are classified as “drugs in special situations,” and they may only be dispensed to patients through hospital pharmacy services. This situation is due to the restriction applied jointly by the Spanish Agency of Medicines and Medical Devices and the WHO to guarantee supplies for patients with proven infection after an approximate 1-year period of global shortage between 2011 and 2012 [
Adverse drug reaction (ADR) information varies widely in literature reports. Benznidazole is usually better tolerated and therefore is chosen as the first-line drug by most experts; however, nifurtimox is the alternative treatment when benznidazole is not well tolerated [
The aim of the treatment is to eradicate the parasite and stop the disease progression. However, treatment is not recommended in all patients; the current treatment recommendations depend on age, phase, and clinical form of the illness [
In Spain, pharmacists have to follow a 4-year specialization program before being allowed to work as a specialized hospital pharmacist in a hospital. Spanish health care coverage contemplates some special drugs to be dispensed by hospital pharmacist or under its supervision to patients for free. Some of the criteria to select these drugs are low drug availability, drugs that need a narrow follow-up of outcomes, adherence, and toxicity or even economic criteria due to high cost of some treatments dispensed without charge to the patient, e.g., HIV, hepatitis C, immunosuppressor treatments.
As mentioned above, the treatment of Chagas disease lasts 60 days, is characterized by frequent ADRs and difficulties in drug availability (hospital pharmacy), and follows a twice-daily regimen with several pill combinations, which can interfere with correct medication intake and management.
Complex regimens, lack of information about benefits, ADRs and how to manage them, not considering patient lifestyles, and poor therapeutic relationships with medication providers create potential barriers to adherence that must be taken into account to achieve a successful treatment outcome [
It has been well-documented in other diseases that a direct interaction between pharmacists and patients, as well as pharmacist-coordinated hospital follow-up visits, improves therapeutic adherence, patient quality of life [
]. In fact, low health literacy skills are considered a major obstacle in effective professional-patient communication; poor understanding of health information becomes the basis for medical errors and problems with adherence [
]. In those countries, beforehand educational information and knowledge of general health professionals about Chagas are often insufficient; the professional expertise grows as the need for giving treatment and patient support appears. Territorial dispersion of affected population leads to a low number of patients distributed into different hospitals, even in countries with the highest prevalence of this imported disease such as The USA and Spain, and this makes it difficult for political health organizations to recognize the need and develop further and specific training for the sanitary professionals and institutions involved in the attention of these patients.
The objective of this study was to describe the characteristics of our Chagas disease patient population, share the material developed to support the pharmaceutical attention, describe the effects of pharmacist intervention in patients on pharmacological treatment, and the initial results in a non-endemic country.
Methods
Location
This study was carried out at a regional hospital with 295 acute care beds that provides health-related care to 399,900 inhabitants. It is situated in the region of Catalonia, on the northeast coast of Spain, where in 2010 the regional health administration implemented a special program to screen and prevent vertical transmission. According to the Statistical Institute of Catalonia (IDESCAT), in 2014, there were 4564 inhabitants from Latin American countries living within the healthcare district of this hospital [
This study was conducted in two main periods, as shown in Fig. 1. All the data were collected retrospectively. Informed written consent was not required because the study did not compromise the standard practice of care, although oral consent was asked and recorded in medical history. The standard practice was changed in 2013 on the basis of the results obtained from the analysis of patients treated in 2010–2011 and with the aim of improving patient care.
Figure 1Review and development of the pharmaceutical intervention process.
All patients were treated with benznidazole (Abarax ®) in an outpatient regimen and with the WHO standard dosage of 5 mg/kg body weight per day, administered orally as two daily doses for 60 days.
After the global shortage occurred between 2011 and 2012, we had a large number of patients waiting to be treated as soon as the shortage was resolved. We decided to collect data on the patients treated in the past to find out their patient characteristics, disease phase, and treatment-related behavior: adherence, frequency of adverse effects, adherence to follow up-visits, and information about cure rates.
Evaluation of these data revealed multiple opportunities for improvement in the Chagas pharmacist intervention. Thus, after analyzing the results of this first period, we designed an intervention plan with the aim of obtaining improved results. This intervention plan was based on two main points:
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Information sheet: An information sheet was drafted with the aim of giving useful and accessible written information to patients. (Annex 1, supplementary information-published online only)
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Two-visit hospital pharmacist regimen: Visit 1 (day 1): Structured pharmacist-patient hospital interview on day 1 for delivering oral information, written information, and medication for 1 month. Visit 2 (day 30): Pharmacist-patient hospital interview to review the oral information given on day 1, ask about compliance and ADRs, and provide medication for 1 month.
At both visits, oral and written information, instructions about drug intake, prohibition of alcohol intake and pregnancy, and preventative measures for sun exposure during the treatment period were clearly explained.
The main ADRs, their management, and contact information in case of impossible home management or any questions with regard to treatment were also explained.
The intervention plan was set up as soon as the medication shortage was resolved (late 2012). To simplify the analysis and guarantee the correct implementation of the intervention plan, the comparative group includes only patients treated in 2013 (post-intervention group).
Electronic medical records were reviewed in both groups, recording the following data: demographics, disease phase, adherence, and side effects. Patients with medical records on paper were excluded. The fact that in both groups, data was obtained through the review of medical records guarantees that differences in the detection of ADRs or other data recorded are not due to any principal investigator bias.
Benznidazole adherence monitoring
Adherence was evaluated by self-report, pill dispensation, and electronic medical record review. The treatment was considered to be complete when 95% of the treatment days were achieved, i.e., 57/60 days of treatment were completed. Those patients who accomplished 95% of the treatment days despite having temporary suspension due to ADRs were considered as completed treatments.
Adverse drug reactions
ADRs were collected by reviewing clinical histories. They were classified as dermatological, neurological, gastrointestinal, and others, which included bone marrow disorders, fever, myalgia, arthralgia, etc.
Theory/Calculation
Continuous variables were reported as mean value with standard deviation, while frequency was reported as a percentage for categorical variables. Mann–Whitney U-test was performed to detect differences in continuous variables between groups because there was no basis for the assumption of normal distribution. Chi-squared test was performed to evaluate differences between categorical data, and the Fisher's exact test was used when the former was not applicable. All statistical tests were two-tailed, and only differences with a p value less than 0.05 were considered to be statistically significant. The statistical analysis was performed with the SPSS statistical software (version 20.0).
Results
Demographic information
During the pre-intervention period (2010–2011), 22 patients (20 adults and 2 children) were prescribed benznidazole following WHO criteria (adult: 5 mg/kg body weight, administered twice daily for 60 days; children 10 mg/kg body weight, administered twice daily for 60 days).
The average age was 37.2 ± 8.7 years in the adult group, of which 2/20 (10.0%) were over 50 years old; 70% (14/20) were female.
In 2010–2011, all patients were treated in the chronic phase of the illness; at the beginning of treatment, 8/20 (40.0%) patients had chronic cardiac Chagas disease, 5/20 (25.0%) had chronic digestive Chagas disease, and 1/20 (5.0%) had chronic cardiodigestive Chagas disease. The remaining 6/20 (30.0%) patients had an indeterminate form of chronic Chagas disease; 3 of them referred having neurological symptoms but were not classified by physicians as having neurological involvement.
In 2013 (post-intervention period), a total of 23 patients were analyzed (22 adults and 1 child). The average age of adults was 39.9 ± 8.4 years, and 5/22 (22.7%) were over 50 years old; 77.3% (17/22) were female.
All the patients treated in this second period (2013) were in a chronic phase of Chagas disease. The number of patients with an indeterminate form was 13/22 (59.1%); the remaining 9/22 (49.9%) had organ involvement, distributed as 3/22 (13.6%) chronic cardiac, 5/22 (22.7%) chronic digestive, and 1/22 (4.5%) chronic cardiodigestive. There were two patients (one in the cardiac involvement group and another in the digestive involvement group) who also had neurological symptoms but were not classified by physicians as having Chagas neurological involvement.
Adverse drug reactions
A high number of ADRs were reported in both periods. In 2010–2011, ADRs were reported in 10/20 (50.0%) patients, and those most commonly detected were 8/10 (80.0%) dermatological, 3/10 (30.0%) gastrointestinal, 2/10 (20.0%) neurological, and 4/10 (40.0%) other type of involvement. As can be inferred from the data, several patients, i.e., 5/10 (50.0%), had multiple system involvement.
In the post-intervention period (2013), ADRs were detected in organ systems in 20/22 patients. Reported ADRs were 14/20 (70.0%) dermatological, 7/20 (35.0%) gastrointestinal including two cases of toxic hepatitis, 6/20 (30.0%) neurological, and 7/20 (35.0%) other type of involvement including one case of miscarriage. Moreover, 9/20 (45.0%) patients suffered from multiple system ADRs. Our results were consistent with those in the literature, shown in Table 1, although superior compared to recent randomized trials [
In the first period, as shown in Fig. 2, only 12/20 (60.0%) achieved the treatment completion criteria (>95% days of treatment). In 75% (6/8) of the uncompleted treatments, the cause was ADRs; the rest, 25% (2/8), were due to loss of monitoring and were counted as uncompleted treatment in the results analysis.
Figure 2Distribution of complete treatment in 2010–2011 and 2013.
In the 2013 period, 15/22 (68.2%) patients achieved the treatment completion criteria (>95% days of treatment). All the uncompleted treatments, 100% (7/7), were due to ADRs (0 patients were missing from follow-up during the treatment period).
Pediatric group
All the pediatric patients included in our study were newborns from mothers with chronic Chagas disease monitored through the special regional program for the screening and prevention of vertical transmission.
At our hospital, three pediatric patients were proposed to receive treatment with benznidazole: two boys in 2010–2011 and one girl in 2013, with an average age of 48 and 205 days of life, respectively. From the first period, one patient was lost to follow-up and the other was not treated because serological and PCR tests were negative in the third month of follow-up.
The patient from the second period was treated following the WHO benznidazole dosage regime and duration recommendations; 10 months post-treatment, all the diagnostic tests were negative.
Discussion
By analyzing the first period of this study, we were able to realize that we needed to improve our pharmaceutical intervention performance.
Although our patients' health literacy was not evaluated, we decided to design a structured pharmacist interview to impart concise and relevant information, aiming to use common words, examples, and visual aids to achieve good understanding. We attempted to inform patients about the indication of the medication, expected benefits, duration of therapy, and potential adverse effects, in addition to information identifying the drug name, instructions for use, and warnings.
Treatment with benznidazole usually involves managing pills to obtain the correct dose and a clear explanation of the management technique, and an explanatory pill chart is necessary to guarantee the correct dose administration.
We decided that these patients would benefit if our information sheet contained the main written information, supported with charts. We also considered it necessary to have on the same sheet a dosage calendar where patients could note the doses taken, with a separate space to write down any problems related to dose administration such as missing a dose and ADRs. This tool helped patients to facilitate their own treatment and served as a guide to explain their problems at the next doctor/pharmacist visit. Written information can be used to reinforce specific instructions or warnings. It can also provide a means for introducing supplemental information that may be difficult to convey during a brief counseling session [
]. Our written materials included details concerning medication intake instructions, expected duration of therapy, adverse effects, what to do in the event of adverse effects, and what to do if a dose is missed.
The fact that Chagas disease may have no clinical manifestations limits disease detection because patients do not attend health centers. This explains why our study has a greater percentage of cardiac and digestive forms of Chagas and a lower number of indeterminate forms than data from the literature. Our situation in a non-endemic country and the silent characteristics of this disease led us to detect more number of cardiac and digestive forms of the disease (more forms in which illnesses had developed) because symptoms are the reason why patients consult health centers.
Focusing on our study, there was a statistically increasing trend highlighting the differences in the percentage of diagnoses of the indeterminate and cardiac forms between 2010 and 2011 and 2013 (30.0% vs. 59.0%; p = 0.059 and 40.0% vs. 13.6%; p = 0.052, respectively). Awareness surrounding the disease at our health center probably increased from 2010–2011 to 2013. This situation most likely led to an earlier diagnosis of the disease during the second period as patients from endemic areas who contacted the healthcare center received Chagas disease screening [
Although the treatment selected was benznidazole, which is considered to be better tolerated than nifurtimox, there was a high number of ADRs in our patients. In the post-intervention group, there was a statistically significantly higher number of ADRs reported (50.0% vs. 90.9%; p = 0.003); they were considered to be more severe because there were two cases of toxic hepatitis and one miscarriage in the post-intervention group. This was probably because patients in the second period had more information about ADRs and more contact with the healthcare system as they had to come twice to the hospital pharmacy to get the medication, leading to greater detection of ADRs. It should be underlined that in both groups, ADR reports were collected through medical history revision, so there was no investigator bias.
The ADRs reported during treatment were also consistent with those reported in the literature, although there was a greater number of dermatological ADRs reported in both our groups compared to that in the literature: 80.0% in the pre-intervention group and 74.0% in the post-intervention group vs. 29.0–50.0% reported in the literature [
The pharmaceutical intervention program, which included follow-up and in-depth information about possible ADRs during treatment and their management, may increase adherence and treatment completed rates, thereby helping control and generate health outcomes in Chagas disease.
Nevertheless, despite an extensive explanation about why it is important not to get pregnant during treatment, we encountered a miscarriage. Incorporating a pregnancy test into systematic laboratory analyses should be considered.
Furthermore, it was not possible to analyze our pediatric population because of the small number of participants.
Limitations
This was a non-randomized study.
The small number of patients included in our study limits the power to detect statistically significant differences in the adherence between patients in the two groups.
Population groups are different when considering organ affectation distribution; this could be because of improvement in clinical expertise and the early detection programs implemented in our hospital that led to the detection of patients in earlier stages of illness.
A health literacy analysis of our patients could have helped us to adapt our support material to patients' needs; further studies should include questionnaires to measure the health literacy level of patients with Chagas disease.
It would be necessary to have serological patient data for at least 10 years after treatment [
] to associate pharmaceutical intervention and cure rates.
Conclusion
This study was useful to provide more information about patients with Chagas disease and to detect a point of improvement in hospital follow-up care. Moreover, it demonstrates how pharmacist intervention, which includes in-depth patient information about possible ADRs during treatment and their management, could increase adherence and treatment completion rates, although the difference was not statistically significant in this study. Moreover, pharmacist intervention also helped to better detect and control ADRs that could lead to better health outcomes in Chagas disease. Furthermore, our patients' health literacy was not evaluated, and it would be a potential avenue for future research.
Although it is very difficult because of high patient mobility, low curation rates, and long time to detect curation, it would be interesting to prolong the following up of the patients to obtain curation rates and more interesting results of this intervention.
Ethics
Oral informed consent was obtained and recorded in medical history. Written consent was considered not necessary as clinical practice was not changed. All data used was anonymized.
Authorship statement
All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript.
Conflicts of interest
Authors declare no conflict of interest.
Funding
No funding was received.
Provenance and peer review
Not commissioned; externally peer reviewed.
Appendix A. Supplementary data
The following is the supplementary data related to this article:
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