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Adherence to antihypertensive drug treatment in Brazil: A systematic review and meta-analysis
Authors
Juliana Chaves Coelho: Escola de Enfermagem da Universidade de São Paulo, e-mail: juccoelho@usp.br ,Orcid: https://orcid.org/0000-0001-8781-7627
Mayra Cristina da Luz Pádua Guimarães: Escola de Enfermagem da Universidade de São Paulo , e-mail : mayraguimaraes@usp.br, orcid: https://orcid.org/ 0000-0001-6874-0206
Ana Katly Martins Gualberto Vaz: Escola de Enfermagem da Universidade de São Paulo ,e-mail: anagualberto@usp.br, orcid: https://orcid.org/ 0000-0002-0705-8681
Karina Cardoso Meira: Escola de Saúde da Universidade Federal do Rio Grande do Norte,e-mail:ninameira@gmail.com,Orcid:https://orcid.org/0000-0002-1722-5703
Juliano dos Santos: Hospital do Câncer III do Instituto Nacional de Câncer, e-mail:jlnsantos@yahoo.com.br, Orcid:https://orcid.org/0000-0001-9961-3576
Renata Jae Won Lee: Escola de Enfermagem da Universidade de São Paulo, e-mail: renatajaewonlee@usp.br, Orcid: https://orcid.org/0 0000-0002-5589-6292
Luciano Ferreira Drager: Faculdade de Medicina da Universidade de São Paulo, e-mail: luciano.drager@incor.usp.br ,Orcid: Orcid: https://orcid.org/0000-0002-2081-6846
Angela Maria Geraldo Pierin: Escola de Enfermagem da Universidade de São Paulo, e-mail: pierin@usp.br, Orcid: https://orcid.org/0000-0002-3274-7729

ABSTRACT
Objective: To evaluate the adherence to antihypertensive treatment prevalence in the Brazilian population based on peer-reviewed studies which used instruments exclusively designed and/or adapted for this purpose. Methods: A systematic review with meta-analysis based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The search was carried out in the BDENF, SciELO, Cuiden, PsycINFOe, CINAHL, Embase, LILACS, and MEDLINE databases, as well as the AgeLine, Google Scholar and ScienceDirect academic search engines. The protocol was registered with PROSPERO (CRD42021292689). Random effects models were used for a meta-analysis of the prevalence obtained from individual studies. Results: A total of 104 studies were included in the meta-analysis on antihypertensive treatment in the Brazilian population, totaling 38,299 patients. The most used instrument was the four-item Morisky-Green Test (49.5%). The adherence prevalence estimated by the meta-analysis was 44.4% (95%CI: 39.12%-49.94%, I2=91.17, p<0.001), showing high heterogeneity. Conclusion: The adherence to antihypertensive treatment prevalence found in national studies was unsatisfactory, demonstrating that this problem continues to be a major challenge.
Keywords: Hypertension; Medication Adherence; Evaluation of Research Programs and Instruments; Prevalence; Meta-analysis.

INTRODUCTION
Lack of adherence to antihypertensive medication treatment is one of the main causes of inadequate blood pressure control. Systemic Arterial Hypertension (SAH) affects around 1.28 billion adults between 30 and 79 years old worldwide and around 31.0% of the adult population in Brazil , being the main modifiable risk factor for cardiovascular diseases.
Pharmacological treatment for SAH has proven efficacy and effectiveness, however there is a low prevalence of Blood Pressure (BP) control in middle and low-income countries3.
It was estimated in 2019 that only 10.3% (95%CI 9.6-11.0%) of hypertensive patients in these countries had blood pressure control.
Adherence to pharmacological treatment is among the protective factors associated with blood pressure control1-3. According to the World Health Organization (WHO), a patient adheres to antihypertensive pharmacological treatment when he or she uses 80% or more of the prescribed medications1-2.
Adherence is a complex phenomenon influenced by factors associated with the disease, treatment, the patient and the healthcare system , and can be measured directly through an analysis of drug metabolites or biological markers in urine/blood, or indirectly through interviews, self-report instruments, diaries or pill counting4-5.
In this sense, a systematic review brought together studies that used different strategies to assess adherence to antihypertensive treatment, and estimated the worldwide non-adherence prevalence with a wide variation, from 3.3% to 86.1% . The differences in the non-adherence percentage evidenced in this study can be explained by the different methods and instruments used to measure adherence, sociodemographic characteristics, different clinical conditions and the health system of the populations under study5.
There are few population-based studies in Brazil which estimate the adherence to pharmacological treatment prevalence in hypertensive patients, which is necessary information to optimize treatment and achieve blood pressure control goals. Thus, the present study aimed to evaluate the adherence to antihypertensive treatment prevalence in the Brazilian population, based on peer-reviewed studies which used instruments exclusively designed and/or adapted for this purpose.

METHODS
Study design
This is a systematic review with meta-analysis based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . The guiding question consisted of: what is the adherence to antihypertensive pharmacological treatment prevalence in the Brazilian population, based on peer-reviewed Brazilian studies that used instruments exclusively designed and/or adapted for this purpose? The protocol for this meta-analysis was registered in PROSPERO, with identification CRD42021292689.

Literature sources and search strategies
The search in the databases included articles published until November 22, 2021. The following electronic data sources were used to select the articles: Nursing Databases (BDENF), Online Electronic Scientific Library (SciELO), Cuiden, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Excerpta Medica dataBASE (Embase), Latin American and Caribbean Literature in Health Sciences (LILACS), Medical Literature Analysis and Retrieval System (MEDLINE), as well as academic search engines (AgeLine, Google Scholar and ScienceDirect). Descriptors were identified in the Medical Subject Headings (MeSH), Health Sciences Descriptors (Decs) and Embase Subject Headings (Emtree). Controlled descriptors specific to each database were used as a search strategy.

Outcomes
Primary outcome: national estimate of the adherence to antihypertensive medication treatment prevalence, assessed using instruments for this purpose.
Secondary outcomes: national estimate of the adherence to antihypertensive drug treatment prevalence according to decade of publication, geographic region of the study, and the instruments used.

Eligibility criteria
Quantitative studies submitted to peer review, developed in Brazil, in Portuguese, English and Spanish, carried out with adults
(age ≥ 18 years old), without restrictions on year of publication or sample size, which addressed the adherence to antihypertensive drug treatment prevalence using instruments exclusively designed and/or adapted for this purpose, and validated for use in the Brazilian population were selected.
Studies with pregnant women, those which did not evaluate pharmacological adherence or did not consider the prevalence of pharmacological adherence exclusively for arterial hypertension and studies that used the same database were excluded. In addition, review, theoretical, methodological and qualitative articles, as well as publications considered gray literature (theses, dissertations, conference annals, technical standards, commercial literature, websites, among others) were excluded.

Study selection and data extraction
Duplicate articles were identified and excluded in the first selection stage. Next, titles and abstracts were read to evaluate the eligibility criteria and determine the reason for exclusion in the second stage. When the information contained in the title and abstract was not sufficient to make a decision, the articles were kept for reading in full. The last stage consisted of reading the articles in full that did not contain exclusionary information in titles and abstracts.
The steps were performed by two independent reviewers (AK and RJ), and in case of divergence, the analysis was carried out by a third examiner (MC). Data collection took place using a Microsoft Excel® spreadsheet covering the following variables: authors, title, year of publication, journal, place of study, type of study, methods of evaluating pharmacological adherence (direct and/or indirect and their respective measuring instruments). It is noteworthy that the proportion of adherence measured by indirect methods was considered in the present study. Only the prevalence of initial adherence to the study was considered in relation to clinical trials; and in relation to studies which used the four-item Morisky-Green Test in conjunction with other indirect method(s) or instrument(s) of self-report, only the prevalence of the Morisky-Green Test was considered for the meta-analysis, as it is the most used method in studies assessing adherence to treatment.

Assessment of the quality of studies
The studies were individually evaluated for methodological quality considering internal and external validity, response rate and generalization of study results using the 10-item Rating Scale developed by Hoy et al. (2012) for cross-sectional studies, adapted by Bigna et al. (2017) . A corresponding score was used for each item, with 1 (one) point for “Yes” and 0 (zero) for “No”. At the end, the points were added up and evaluated within a score from zero to 10, which was categorized as follows: 8-10 = low risk of bias, 5-7 = medium risk of bias, and 0-4 = high risk of bias. Articles that had a high risk of bias were excluded from the meta-analysis, however all studies were included in the qualitative synthesis.

Data analysis
The characteristics of the studies were described by absolute and relative frequencies. The estimated adherence to treatment rate for arterial hypertension was expressed as prevalence. The prevalence of grouped adherence was calculated using a generalized linear mixed effects model with a restricted maximum likelihood estimator, a method which has shown better fit when the outcome is the proportion. The models are accompanied by residual heterogeneity statistics, divided by unmodeled variability (I²), and subgroup analysis for decade of publication, geographic region in which the study was conducted and the instrument used to assess adherence to antihypertensive drug treatment. The confidence level adopted was 95% and all analyzes were performed in the R 4.1.1 statistical software program using the ‘meta’ and “metafor” package, version 5.0-0.

RESULTS
The database search retrieved 2,735 articles, but 972 duplicates were removed, resulting in 1,761 articles for evaluation. After analyzing titles and abstracts, 1,526 studies were excluded, totaling 235 for full-text evaluation. After evaluating the full texts, 129 were discarded as they did not meet the eligibility criteria for this study, as detailed in Figure 1. Thus,
106 studies which were part of the qualitative synthesis were selected for the final sample (Figure 1).
It is noteworthy that a high percentage of these studies were found between 2011 and 2021 (89.6%), published in national journals (87.7%) and concentrated in journals in the areas of Nursing, Public Health and Cardiology (70. 0%) (Table 1). Regarding the Brazilian region in which the study was conducted, there was an absence of studies carried out exclusively in the North Region, while 38.5% occurred in the Southeast, 33.7% in the Northeast, 21.2% in the South and 4.8% in the Center-West regions (Table 1).
After analyzing the risk of bias, it was found that 1.9% (n=2) of the studies presented a high risk of bias, 51.9% moderate risk (n=55) and 46.2% low risk (n= 49) (Table 1). Therefore, 104 studies were included in the meta-analysis, as they presented a moderate or low risk of bias.
A total of 38,299 patients were obtained among the studies selected for the meta-analysis, whose median sample size of the studies was 145 (Interquartile range=100-299), with a minimum value of 14 patients and a maximum of 1,029. Among the 104 studies, 79.8% were cross-sectional, 5.8% were cohort studies and 12.5% were clinical trials (Table 1).
After meta-analysis of the 104 included studies, an adherence to antihypertensive pharmacological treatment prevalence was estimated at 44.4% (95%CI: 39.1-49.9). The heterogeneity between the estimated prevalence rates was high and statistically significant (I2 = 97.90%; p<0.001) (Figure 2).
The subgroup analysis showed no statistically significant difference in the adherence prevalence between the period in which the studies were carried out (2001-2010 vs. 2011-2021, p=0.704), respectively, presenting the following prevalence rates of 42% (95%CI: 28.76-56.69) and 44.7% (95%CI: 39.01-50.60) (Table 1).
The adherence prevalence assessment according to geographic region identified a lower adherence prevalence in studies carried out in the Central-West and in multicenter studies (conducted in more than one location in Brazil). There was no significant difference in the proportion of adherence to treatment between the South, Southeast, North and Northeast regions. However, there was a difference between the prevalence evidenced in the multicenter study compared to studies carried out in the South, Southeast and Northeast Regions. Nevertheless, this finding must be analyzed with caution, as only two studies were multicenter (Table 1).
The instruments used in the studies selected in this meta-analysis were the: four-item Morisky-Green Test, Morisky eight-item Medication Adherence Scale (MMAS-8), Treatment Adherence Measure (TAM), Brief Medication Questionnaire (BMQ), Medication Adherence Questionnaire – Qualiaids (MAQ-Q), SAH Treatment Adherence Questionnaire (SAHTAQ), Martín-Bayarre-Grade (MBG), Haynes-Sackette Test and Primary Care Assessment Tool (PCAT), Assessment instrument of non-adherence to arterial hypertension treatment developed by Borges, and the Medeiros test.
A higher medication adherence prevalence was observed in the study which used the Primary Care Assessment Tool (89.1%), followed by those that used the SAH Treatment Adherence Questionnaire - SAHTAQ (88.3%) and the Treatment Adherence Measure - TAM (74.1%). Lower prevalence was found in studies which used the Martín-Bayarre-Grade (MBG) (30.5%), the four-item Morisky-Green Test (36.9%) and the eight-item Morisky Medication Adherence Scale (MMAS-8) (36.8%) (Figure 3).

DISCUSSION
The adherence to antihypertensive drug treatment prevalence measured by indirect methods in Brazilian studies was 44.4%. There was no difference in the adherence prevalence between the periods studied and the geographic region in which the study was conducted. It is noteworthy that there were no studies exclusively conducted in the Northern Region of the country, a location with the greatest socioeconomic vulnerability in the country.
The adherence prevalence identified after the meta-analysis was higher than the prevalence of other studies carried out in low- and middle-income countries, whose percentages were around 35.0% , . However, these studies assessed adherence with Morisky’s eight-item Medication Adherence Scale, which also showed a prevalence of approximately 35% in the
present study. Developed countries, such as the United States and Canadá , show a better scenario, but still not desirable, with adherence prevalence of around 68% and 67% evaluated by the Morisky instruments with eight and four items, respectively.
A greater percentage of the articles included were published in nursing journals which, in the context of hypertensive patients, play a fundamental role in improving adherence to treatment; this is important given that the main proposals currently studied, such as self-measurement of blood pressure, adequacy of dosage schemes and use of Mobile health, require direct nursing action with the patient, justifying the large quantity of research published in journals in the area11,12.
Despite the efforts observed in recent years, the results of the present study did not indicate a significant improvement in the adherence prevalence when comparing the period from 2001 to 2010 with the historical period from 2011 to 2021. From the 2000s onwards, Noncommunicable Disease (NCD) prevention gained focus, mainly in developing countries. As a result, several national programs and policies were created, such as: the Plan for Reorganization of Care for Arterial Hypertension and Diabetes mellitus (Plano de Reorganização da Atenção à Hipertensão Arterial e ao Diabetes mellitus - HIPERDIA) ; the Brazilian Popular Pharmacy Program (Programa Farmácia Popular do Brasil - FPB) ; and the Basic Care Booklet and Guidelines and recommendations for comprehensive NCD care (Caderno de Atenção Básica e as Diretrizes e recomendações ao cuidado integral de DCNT) , with these being directed to Primary Healthcare in order to improve the treatment and prevention of these diseases. These initiatives have brought important advances in the management of chronic diseases, however weaknesses are observed, as what occurred in the South of the country based on the HIPERDIA evaluation, in which professionals were observed reporting a much lower number of duties than that established in the protocol, lack of tracking of patients and not prescribing non-pharmacological measures .
Pharmacological treatment has a direct relationship with patient adherence in Brazil, and the public health system is based on the universalization of free access to healthcare for the entire population, with decentralization at all levels from prevention to high complexity, shared by federal, state and municipal governments . Antihypertensive medications are available in the Unified Health System (Sistema Único de Saúde – SUS), with free distribution and a list of medications that include diuretics, beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers through the Farmácia Popular do Brasil Program; this program is fundamental for guaranteeing patients’ medication treatment, and data indicate a decrease in medication accessed/obtained by patients with high blood pressure in Basic Health Units between 2011 and 2017 due to the increase in obtaining medication through Farmácia Popular .
There was also a reduction in the number of hospitalizations and deaths related to systemic arterial hypertension and diabetes mellitus as a result of the program , with disparities in the effectiveness and efficacy of these measures according to the level of socioeconomic development and access to health services in the Federative Units of Brazil. On the other hand, polypharmacy stands out in this context, as the program does not include the use of fixed drug combinations which consist of combining antihypertensive drugs, bringing direct benefits in adherence to treatment , and consequently better cardiovascular protection . Low adherence to medication treatment is a worrying result, as adherence to 80% or more of prescribed medications reduces the risk of target organ damage22.
The high heterogeneity between studies stands out as a limitation of this study, which reflected in the wide variation in the adherence prevalence observed in the studies included in the review, with values between 4.46% and 97.66%. Furthermore, results similar to those observed in other reviews on the topic were found6,23, which highlight that the high heterogeneity is related to the complexity of establishing an ideal method for measurement, being reflected by many self-report instruments developed for this purpose. In this sense, 10 different instruments were used in the present study, with the most used being the four-item Morisky-Green Test, followed by the eight-item Morisky Medication Adherence Scale (MMAS-8). The internal consistency between the instruments varied between 0.61 (Morisky-Green test - 4 items) and 0.89 (Martín-Bayarre-Grade questionnaire). The Brief Medication Questionaire obtained the best results in all domains regarding sensitivity and specificity, ranging from 80.00% to 100.00%.
More recent data indicate greater use of the MMAS-8 worldwide24, however it is necessary to discuss the applicability of some instruments, as they may require a license fee for use, as is the case with the Morisky instruments. A systematic review evaluated publications around the world, identifying 17 instruments to measure adherence to antihypertensive treatment, of which five were validated in different countries, namely the: Hill-Bone compliance to high blood pressure therapy scale (HB); Morisky–Green––Levine test (MGL); 8-item Self-Reported Medication Adherence Measure (MMAS-8); Medication Adherence Self-Efficacy Scale (MASES); and Treatment Adherence Questionnaire for Patients with Hypertension (TAQPH) .
Figure 1
Table 1
Figure 2
Table 2
Figure 3
Despite the limitations presented, this study is the first in Brazil to summarize the adherence to medication treatment prevalence for arterial hypertension in peer-reviewed Brazilian studies, carrying out a broad assessment of the literature with studies that presented a medium or low degree of bias. The findings showed low adherence to treatment in Brazil, which is far below (44.4%) the value recommended by the WHO (≥80%), with no increase in this percentage in the most recent decade (2011 to 2021), and no differences between regions with lower socioeconomic vulnerability and those with greater vulnerability. Furthermore, there were only
two multicenter studies and no studies were carried out in the North Region. These results indicate the need to carry out a national multicenter study in all Federative Units of Brazil using standardized measurement instruments validated for use in the country to facilitate comparing studies, and to identify factors associated with non-adherence to treatment, so that public health actions are planned and evaluated with a view to increasing the adherence to treatment prevalence.

CONCLUSION
The adherence prevalence found herein showed great variability, highlighting the difficulty in measuring this phenomenon. The four-item Morisky-Green Scale was the most used self-report instrument to assess adherence to antihypertensive treatment in Brazil. In the aggregate result, the overall adherence prevalence in Brazil was unsatisfactory (less than half of patients are suspected of having good adherence to treatment), demonstrating that this challenge continues to be a problem that requires actions at the public health level, which include strategies to minimize polypharmacy and optimize access to treatment for hypertensive patients.

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