Warfarin use is associated with higher aortic bioprosthetic 18F-fluoride PET uptake.

BACKGROUND: Prevalence of bioprosthetic valve degeneration (BVD) is rising as the use of bioprosthetic aortic valves increases. Detecting early signs of BVD remains a challenge, with conventional imaging methods often failing to identify early deterioration stages. 18F-fuoride positron emission tomography (PET-CT) is an emerging technique that offers promising prospects to detect subclinical BVD. This study aimed to compare early PET parameters of fluoride uptake with echocardiographic hemodynamic parameters and compare outcomes according to anticoagulation in patients who received bioprosthetic valves. METHODS: This is a sub-study of the ANTIPRO clinical trial, which involved patients undergoing surgical aortic valve replacement (SAVR) with a porcine bioprosthesis and randomized them into anticoagulated and non-anticoagulated groups. Hemodynamic changes were assessed by transthoracic echocardiography (TTE), while 18F-fluoride PET-CT quantified fluoride uptake and divided the patients in two groups: high-uptake and low-uptake. Mean and maximum gradients by TTE at three years were compared between the two uptake groups. Fluoride uptake was also compared between the anticoagulated and control groups. RESULTS: We found no significant differences in transprosthetic gradients between high-uptake(21.4 ± 8.6 mmHg) and low-uptake(17.3 ± 11.2 mmHg.p = 0.244) PET-defined groups in this specific timeframe. Notably, anticoagulated patients exhibited significantly risk of higher fluoride uptake(OR = 4.34;95%CI:1.04-18.21.p = 0.045). CONCLUSIONS: No association was found between fluoride uptake and hemodynamic evaluation. Anticoagulation was associated with higher fluoride uptake. These findings highlight the emerging role of PET-CT in studying bioprosthetic aortic valves and emphasize the need for extended follow-up to evaluate the impact of anticoagulation on valve degeneration.

Long-term survival in venous thromboembolic disease: rivaroxaban vs. warfarin - propensity score matching study.

BACKGROUND: Venous thromboembolic disease (VTE) is characterized by obstruction of venous blood flow by a thrombus. Survival data, frequency of disease recurrence, and bleeding rate in patients on anticoagulant therapy with warfarin compared to rivaroxaban in the Latin American population are limited in VTE. METHODS: A retrospective cohort study with propensity score matching analysis was conducted in patients with pulmonary embolism and/or deep vein thrombosis anticoagulated with warfarin or rivaroxaban treated. Survival analysis was performed using a Kaplan-Meier curve for each of the intervention groups, and it was compared using a Log Rank test. RESULTS: Of 2193 potentially eligible patients with a suspected diagnosis of VTE, 505 patients entered the analysis; of these, 285 subjects were managed with warfarin and 220 anticoagulated with rivaroxaban. Major bleeding at 12 months occurred in 2.7% (6/220) of patients treated with Rivaroxaban, compared to 10.2% (29/285) in the Warfarin group in the unmatched population (p = 0.001). In the matched population, bleeding at 12 months occurred in 2.9% (6/209) of patients on Rivaroxaban and in 11.0% (23/209) of patients on Warfarin (p = 0.001). The survival rates at 6 months were 97.1% for Rivaroxaban and 97.6% for Warfarin (p = 0.76). At 12 months, the survival rates were 94.7% for Rivaroxaban and 95.7% for Warfarin (p = 0.61). CONCLUSION: In the treatment of VTE, there is no differences on 6 and 12-month survival or a reduction in the occurrence of new thromboembolic events when comparing rivaroxaban to warfarin. However, a lower risk of major bleeding is observed at 12 months with Rivaroxaban.

Case studies of clinical decision-making through prescriptive models based on machine learning.

BACKGROUND: The development of computational methodologies to support clinical decision-making is of vital importance to reduce morbidity and mortality rates. Specifically, prescriptive analytic is a promising area to support decision-making in the monitoring, treatment and prevention of diseases. These aspects remain a challenge for medical professionals and health authorities. MATERIALS AND METHODS: In this study, we propose a methodology for the development of prescriptive models to support decision-making in clinical settings. The prescriptive model requires a predictive model to build the prescriptions. The predictive model is developed using fuzzy cognitive maps and the particle swarm optimization algorithm, while the prescriptive model is developed with an extension of fuzzy cognitive maps that combines them with genetic algorithms. We evaluated the proposed approach in three case studies related to monitoring (warfarin dose estimation), treatment (severe dengue) and prevention (geohelminthiasis) of diseases. RESULTS: The performance of the developed prescriptive models demonstrated the ability to estimate warfarin doses in coagulated patients, prescribe treatment for severe dengue and generate actions aimed at the prevention of geohelminthiasis. Additionally, the predictive models can predict coagulation indices, severe dengue mortality and soil-transmitted helminth infections. CONCLUSIONS: The developed models performed well to prescribe actions aimed to monitor, treat and prevent diseases. This type of strategy allows supporting decision-making in clinical settings. However, validations in health institutions are required for their implementation.

Assessment of the relationship between the level of patient knowledge on warfarin therapy and the quality of oral anticoagulation: A systematic review and meta-analysis.

The present study aimed to investigate the relationship between the level of patient knowledge on warfarin therapy and the quality of oral anticoagulation. This is a systematic review and meta-analysis written on the basis of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Searches at MEDLINE, EMBASE, Scopus and LILACS electronic databases were carried out on February 13, 2023, using the descriptors "Patient Medication Knowledge", "Patient Education as Topic", "Health Education", "Patient Education" and Warfarin. The steps of selection, data extraction and quality analysis of articles were performed independently by two reviewers. The analysis was performed considering patient knowledge as a possible modifier of time in therapeutic range (TTR). The meta-analysis included studies that reported the correlation coefficient (Pearson or Spearman) between patient knowledge and TTR. A subgroup analysis was performed according to questionnaires employed to measure patient knowledge. Twelve studies were selected with an overall sample size of 7634 participants and mean age 58.2 (standard deviation (SD)±12,8) years. Eleven (92.0%) cross-sectional studies. The mean TTR was 57.8% (SD±11,3%) and the average level of knowledge was 60.4%. The meta-analysis indicated that patient level of knowledge on warfarin therapy was moderately associated with TTR (rs = 0.435; 95% confidence interval (CI) = 0.163-0.645; I2 = 96%). Subgroup analysis indicated association between knowledge level and TTR in studies employing the OAK test (rs = 0.617; 95% CI = 0.192-0.847; I2 = 97%) and the AKA (rs = 0.269; 95% CI = 0.002 to 0.501; I2 = 94%). However, the subgroup analysis presented no significant difference between them (p = 0.14). The meta-regression showed a non-significant negative effect of age on the correlation (estimate = -0.028, 95% CI = -0.073 to 0.016, p = 0.207). No publication bias was noted (p = 0.881). To our knowledge, this is the first systematic review and meta-analysis gathering evidence about the relationship between the level of patient knowledge on oral anticoagulation with warfarin and TTR. The implementation of structured and patient-centered educational interventions is essential to effectively increase the level of patient knowledge and, thus, to improve the quality and safety of warfarin therapy. Systematic review registration number: PROSPERO CRD42023398030.

Construction and Validation of a Protocol Targeting Patients on Oral Anticoagulation with Warfarin. / Construção e Validação do Protocolo EmpoderACO Direcionado a Pacientes em Anticoagulação Oral com Varfarina.

BACKGROUND: Warfarin is an oral anticoagulant that is very useful in preventing thromboembolism, though it is considered a drug with a high risk of causing adverse events. Considering the practical challenges in controlling oral anticoagulation, the patients on warfarin could benefit from educational strategies aimed at behavioral changes, active participation in self-care, and adherence to drug therapy. OBJECTIVE: The aim was to construct and validate the EmpoderACO protocol for behavioral changes in warfarin patients. METHODS: The methodological steps were: definition of concepts and domains of self-care, identification of objectives, construction and selection of items, assessment of content validity, and pre-test in the target population. RESULTS: Relevance, adequacy, clarity, and internal reliability of the instrument's items were assessed by a multidisciplinary judges committee (JC) through the E-surv web platform, obtaining an average agreement of ≥0.91. The understanding of the instrument measured by the target population revealed adequate clarity with a coefficient average of 0.96. CONCLUSION: EmpoderACO can aid in qualifying the communication process between medical professionals and patients, as well as in improving adherence to both treatment and clinical outcomes, and can be replicated in healthcare settings.

FUNDAMENTO: A varfarina é um anticoagulante oral útil para prevenção de tromboembolismo, embora seja considerado fármaco de alto risco de causar eventos adversos. Considerando os desafios práticos no controle da anticoagulação oral, os pacientes poderiam se beneficiar de estratégias educacionais que visem mudança de comportamento, participação ativa no autocuidado e adesão à farmacoterapia. OBJETIVO: Construir e validar o protocolo EmpoderACO para mudança de comportamento em pacientes em uso de varfarina. MÉTODOS: As etapas metodológicas foram: definição de conceitos e domínios do autocuidado, identificação dos objetivos, construção e seleção dos itens, avaliação da validade de conteúdo e pré-teste na população alvo. RESULTADOS: Relevância, adequação, clareza e confiabilidade interna dos itens do instrumento foram avaliadas por comitê de juízes multiprofissional pela plataforma web E-surv, obtendo-se média de concordância ≥0,91. A compreensão do instrumento pela população-alvo teve clareza adequada com média de 0,96. CONCLUSÃO: O EmpoderACO poderá contribuir para qualificar o processo de comunicação entre profissionais e pacientes, melhorar a adesão ao tratamento e os resultados clínicos, podendo ser replicado nos serviços de saúde.

Frequency of polymorphisms in the CYP2C9, VKORC1, and CYP4F2 genes related to the metabolism of Warfarin in healthy donors from Cali, Colombia.

Alleles in the VKORC1, CYP2C9, and CYP4F2 genes can influence Warfarin dose requirement. We aimed to determine the frequency of the polymorphisms in these genes in healthy individuals from Cali, Colombia. Observational study where total blood was collected from 107 healthy donors who attended a higher educational institution in Cali, Colombia. Sanger sequencing of exons 2, 3, 5, and 7 of the CYP2C9 gene; the common promoter region of CYP (rs12777823); exon 11 of CPY4F2 and the polymorphism c.-1639G > A in the VKORC1 gene promoter was performed. CYP2C9*2, CYP2C9*3, CYP2C9*8, CYP2C9*9, CYP2C9*11, CYP4F2*3, rs12777823, and VKORC1*2 were detected. The latter had the highest frequency with 80 (74.8%) participants in a heterozygous or homozygous state. The least frequent allele was CYP2C9*11 with only 1 carrier. Combined haplotypes (VKORC1 *1/*2 or *2/*2 and CYP2C9 *1/*2 or *2/*2) were identified in 14 (13.7%) subjects. Both frequencies found in the VKORC1 and CYP2C9 alleles were similar to the ones reported for Latin Americans of European and Native American Ancestry. VKORC1*2 allele, the main genetic contributor to Warfarin dosing requirement, was the variant with the highest frequency (74.8% subjects, with a frequency of the alternative allele (A) of 50%). Our findings provide researchers with a greater insight regarding the frequency of common polymorphisms that affect anticoagulation treatment in the Cali (Colombia) population.

Perfil dos pacientes em uso de anticoagulantes orais diretos atendidos via judicial em um município de médio porte do estado de Minas Gerais / Profile of patients in the use of direct oral anticoagulants assisted judicially in a medium-sized municipality of the state of Minas Gerais

Fundamentos: O sistema de saúde brasileiro é embasado nos princípios estabelecidos na Constituição Federal, que in-cluem igualdade, universalidade, equidade e participação popular, em um modelo de saúde totalmente gratuito. O Brasil vive um grande desafio para ofertar assistência de qualidade para toda população. Muitas vezes, é necessário solicitar à justiça um suporte para conseguir acesso à saúde pública. Entre os processos judiciais envolvendo questões de saúde, a maioria são referentes ao fornecimento de medicamentos. Dentre os medicamentos solicitados, destacam-se os anticoagulantes orais diretos (DOACs), cujos estudos apontam que apresentam melhor segurança e eficácia similar em relação à varfarina, medicamento padronizado no SUS para o tratamento do tromboembolismo venoso e fibrilação atrial. Objetivo: Avaliar o perfil dos pacientes e das solicitações dos DOACs atendidos por via judicial. Métodos: Estudo documental descritivo realizado em Divinópolis/MG a partir de todos os processos julgados com parecer favorável pela justiça referentes à solicitação dos DOACs. A coleta de dados foi realizada em três fontes secundárias: os pro-cessos judiciários, prontuários dos pacientes nas unidades básicas de saúde e no Sistema de Informações em Saúde. Resultados: Foram incluídos no estudo um total de 74 processos referentes à solicitação dos DOACs no município de Divinópolis-MG. Observou-se que 74,3% dos indivíduos eram do sexo feminino, com média de idade de 70 anos. O diagnóstico mais observado foi a fibrilação atrial (36,5%). Cerca de 52,7% dos médicos registraram que houve tenta-tiva terapêutica com varfarina antes da introdução dos DOACs e a comodidade (24,3%) foi a justificativa mais utilizada por optar pelos DOACs seguida por dificuldade em controlar a RNI (20,3%). Outro dado encontrado foi que 25,7% dos pacientes nunca obtiveram na farmácia do SUS o medicamento solicitado por via judicial. Conclusão: Concluímos que a demanda judicial que afoga tanto o sistema judiciário como o sistema de saúde, poderia ser evitada se fossem seguidas as recomendações da Comissão Nacional de Incorporação de Tecnologias no Sistema Único de Saúde para estabelecer a distribuição dos insumos de saúde. Além disso, nos processos judiciais faltam informações importantes para auxiliar o juiz a emitir um parecer, sendo baseadas, na maioria das vezes, em apenas uma opinião médica. (AU)

Fundamentals: The Brazilian health system is based on the principles established in the Federal Constitution, which include equality, universality, equity, and popular participation in a completely free health model. Brazil is under great challenge to offer quality care to the entire population. It is often necessary to ask the court for support to gain access to public health.Among the court proceedings involving health issues, the majority refer to the supply of medicines. Among the drugs requested, direct oral anticoagulants (DOACs) stand out, which indicate that they have better safety and similar efficacy concerning warfarin, a standardized medication in the SUS to treat venous thromboembolism (VTE) and atrial fibrillation (AF). Objective: Assess the profile of patients and requests for direct oral anticoagulants (DOACs) served by the court. Methods: Descriptive documental study carried out in Divinópolis/MG from all cases judged with a favorable opinion by the court regarding the request of DOACs. Data collection was carried out from three secondary sources: court proceedings, medical records of patients in basic health units, and the Health Information System (SIS). Results:A total of 74 lawsuits referring to the DOACs request in the city of Divinópolis-MG were included in the study. It was observed that 74.3% of the individuals were female, with a mean age of 70 years. The most common diagnosis was atrial fibrillation (36.5%). About 52.7% of physicians reported that there was a therapeutic attempt with warfarin before the introduction of DOACs, and convenience (24.3%) was the most used justification for choosing DOACs, followed by difficulty in controlling the INR (20.3%). Another finding was that 25.7% of the patients never obtained the medication requested through the courts at the SUS pharmacy. Conclusion: We concluded that the judicial demand that drowns both the judicial system and the health system could be avoided if the recommendations of the National Commission for the Incorporation of Technologies in the Unified Health System were followed to establish the distribution of health education. In addition, in court proceedings, important information is lacking to assist the judge in issuing an opinion and is most often based on only one medical opinion. (AU)

Pharmacogenetics of clopidogrel and warfarin in the treatment of cardiovascular diseases: an overview of reviews.

Pharmacogenetics (PGx) is the relationship between an individual's genetic variations and the response to pharmacological treatment. We chose to perform an overview of reviews on PGx testing-guided treatment for cardiovascular diseases, based on clinically relevant gene-drug pairs. We conducted a search on Medline, Embase and Cochrane Library, from their inception to 18 June 2020. The most studied gene-drug pairs were clopidogrel and warfarin associated with cytochrome p450 and vitamin K epoxide reductase complex subunit 1 genes (CYP2C19, CYP2C9 and VKORC1), classified as critically low quality. There is a need for more quality primary studies and systematic reviews that assess the risk of bias, with consistent definitions of clinical outcomes to consider the benefits of PGx testing for cardiovascular diseases.

Notas técnicas para judicialização de anticoagulantes orais diretos: uma avaliação do perfil / Technical notes for judicialization of direct oral anticoagulants: a profile assessment

Fundamentos: A judicialização da saúde no Brasil gera aumento anual significativo das demandas por recursos financei-ros. Em 2016, com intuito de promover uma comunicação entre o sistema jurídico e o sistema de saúde, implementaram o sistema e-NatJus (Núcleos de Apoio Técnico do Poder Judiciário). A função do e-NatJus é fornecer apoio técnico aos juízes nas questões relativas à saúde por meio da elaboração de Notas Técnicas (NT). Objetivo: Analisar o perfil e a qualidade das NT de solicitação de anticoagulantes orais diretos (DOACs) disponíveis no portal eletrônico do e-NatJus para consultas por juízes. Métodos: Trata-se de um estudo documental descritivo, em que foram avaliadas as características sociodemo-gráficas, do diagnóstico e tratamento dos pacientes, bem como informações sobre as evidências da eficácia e segurança da tecnologia e conclusão de todas as NT referentes à solicitação de DOACs obtidas na plataforma e-NatJus desde sua im-plantação em 2018 até junho de 2020. Resultados: Foram incluídas no estudo 181 NT: rivaroxabana (67,0%), apixabana (16,0%), dabigatrana (12,0%) e edoxabana (5,0%). A média de idade dos indivíduos foi de 65,7 (±15,1) anos, sendo, (50,3%) do sexo feminino. São Sebastião do Paraíso foi o município que mais solicitou apoio nas NT (5,0%), e o estado com mais solicitações foi Santa Catarina (34,8%). Em relação ao diagnóstico dos pacientes, os mais prevalentes foram fibrilação atrial (FA)(31,5%) e troembolismo venoso (TEV)(16,4%). Aproximadamente 86 NT estavam com conteúdo semelhante no item evidência científica. Observou-se que (57,5%) tiveram a conclusão não favorável para disponibilizar o medicamento solicitado. Dentre as 77 NT que tiveram a conclusão favorável, (57,1%) não avaliaram as recomendações da Comissão Na-cional de Incorporação de Tecnologias (CONITEC). Conclusão: De forma geral, nosso estudo permitiu conhecer o perfil das NT e os principais motivos de solicitações dos DOACs, com intuito de compreender melhor se são realizadas realmente de forma consciente e responsável. A população que solicitou os DOACs via judicial é uma população idosa e não houve grande diferença entre os sexos. Os diagnósticos mais prevalentes nas NT foram FA e TEV corroborando com a indicação desses medicamentos. Pode-se observar que a maioria das NT que concedeu parecer favorável não evidenciou consulta à CONITEC e não apresentou evidência científica que contemplava de forma concreta sua decisão (AU)

Background: The judicialization of health in Brazil generates an annual increase in demands for financial resources. In 2016, to promote communication between the legal system and the health system, the implementation of e-NatJus system (Technical Support Centers of the Judiciary). The role of e-NatJus is to provide technical support to judges on health-related issues through the preparation of Technical Notes (NT). Objective: Analyze the profile and quality of TNs requesting Direct Oral Anticoagulants (DOACs) available on the e-NatJus electronic portal for consultation by judges. Methods: This is a descriptive documentary study, which evaluated the sociodemographic characteristics, diagnosis, and treatment of patients, as well as information on the evidence of the efficacy and safety of technology and the conclusion of all NT related to the request for DOACs obtained in the e-NatJus platform since its implementation in 2018 to June 24, 2020. Results: The study included 181 NT: rivaroxaban (67,0%), apixaban (16,0%), dabigatran (12,0%), and edoxaban (5,0%). The mean age of the individuals was 65.7 (±15.1) years, being (50,3%) female. São Sebastião do Paraíso was the municipality that most requested support in the NT (5,0%), and the state with the most requests was Santa Catarina (34,8%). Regarding the diagnosis, the most prevalent patients were AF (31,5%) and VTE (16,4%). Approximately 86 NT had similar content in the scientific evidence item. It was observed that (57,5%) had an unfavorable conclusion about making the requested drug available. Among the 77 NT that had a favorable conclusion, (57,1%) did not evaluate the rec-ommendations of the National Commission for the Incorporation of Technologies (CONITEC). Conclusion: In general, our study is effective to know the profile of the NT and the main reasons for consulting DOACs, to better understand the form of knowledge and the DOACs. It can be observed that most NTs granted a favorable opinion, did not evidence CONITEC and did not present scientific evidence that contemplated the concrete form of their decision (AU)

Implementation of a text messaging intervention to patients on warfarin therapy in Brazilian primary care units: a quasi-experimental study.

BACKGROUND: Warfarin remains the most affordable oral anticoagulant in many countries. However, it may have serious side effects, and the success of the therapy depends on the patient's understanding of the medication and their adherence to treatment. The use of short messages services (SMS) is a strategy that can be used to educate patients, but there are no studies evaluating this intervention in patients taking warfarin. Therefore, we aimed to develop, implement, and assess the feasibility of an intervention using SMS to primary care patients taking warfarin in a medium-sized Brazilian city. METHODS: A bank of 79 SMS was drafted and validated by an expert panel. During 6 months, three times a week, patients received messages about anticoagulation with warfarin. At baseline and after 3 months, we assessed their knowledge and adherence with validated instruments. At the end of the follow-up, participants answered a satisfaction questionnaire. Subsequently, a scale-up phase was conducted, with another round of the intervention including 82 participants (29 from the first phase and 53 newly recruited). Seven months after the end of the scale-up, we asked the patients for their insights about the long-term effects of this program. All patients signed informed consent. The study was approved by the Research and Ethics committee of the Universidade Federal de Minas Gerais. RESULTS: In the pilot, 33 (89.2%) patients completed the follow-up. Among the participants who answered the satisfaction questionnaire (n = 29), 86.2% considered that the intervention motivated a healthy lifestyle and improved their understanding of warfarin therapy. All patients were willing to continue receiving the messages. Adherence measured by the Measure of Adherence to Treatment (MAT) test was high in the pre-intervention assessment and remained high (96.7% vs. 93.3%; p = 1.0000). The proportion of patients who achieved > 75% correct answers on the Oral Anticoagulation Knowledge (OAK) test increased from 6.5% to 25.6, p = 0.0703. In the scale-up, 23 patients answered the long-term assessment questionnaire. The main long-term knowledge reported was dietary information. Nine patients received the messages but did not remember their content. CONCLUSION: The intervention was well-accepted and had a positive impact on patient's knowledge about oral anticoagulation therapy. The scale-up assessment reinforced the need to constantly monitor digital interventions.

Anticoagulation in Atrial Fibrillation Associated with Mitral Stenosis.

Rheumatic valve disease is present in 0.4 % of the word population, mainly in lowincome countries. Rheumatic mitral stenosis affects more women and between 40 to 75 % of patients may have atrial fibrillation (AF), more frequently in upper-middle income countries. This rhythm disturbance is due to increased atrial pressure, chronic inflammation, fibrosis, and left atrial enlargement. There is also an increase in the prevalence of AF with age in patients with mitral stenosis. The risk of stroke is 4 % per year. Success rates for cardioversion, Cox-Maze procedure, and catheter ablation are low. Therefore, anticoagulation with vitamin K antagonist is mandatory for Evaluated Heart valves, Rheumatic or Artificial (EHRA) classification type 1. However, this anticoagulation is used by less than 80 % of those eligible and less than 30 % have the international normalized ratio in the therapeutic range. The safety and efficacy of using rivaroxaban, a direct factor Xa inhibitor anticoagulant, were demonstrated in the RIVER trial with a sample of 1005 patients with AF and bioprosthetic mitral valve. The indication for valve replacement, that is, if severe mitral stenosis or severe mitral regurgitation, was not specified. A randomized, open-label study (DAVID-MS) is underway to compare the effectiveness and safety of dabigatran and warfarin therapy for stroke prevention in patients with AF and moderate or severe mitral stenosis. Thus, the applicability of the use of direct anticoagulants in patients with AF and mitral stenosis and also in those undergoing mitral bioprostheses surgery will be the subject of further studies. The findings may explain if specific atrial changes of mitral stenosis even after the valve replacement will influence thromboembolic events with direct anticoagulants.

Self-report instruments for assessing adherence to warfarin therapy: a systematic review.

BACKGROUND: The assessment of adherence to warfarin therapy is useful in clinical practice due to its wide variability in dose-response and risks of complications. The aim of this study was to investigate validated instruments used to assess adherence to warfarin therapy. METHODS: Information was collected from the MEDLINE (PubMed), LILACS, EMBASE, and Cochrane Library databases. Search strategies were applied for each database, with no time limit or language restriction. Inclusion criteria consisted of study participants of ≥ 18 years of age, from both sexes, on chronic anticoagulation with warfarin for any indication and the use of validated instruments to assess adherence to warfarin therapy. Exclusion criteria consisted of duplicate articles, narrative or systematic reviews, and meta-analyses, as well as case reports/series and experimental studies involving animals. Two independent reviewers performed the following steps: evaluation of titles/abstracts, selection of studies after full reading, data extraction, and evaluation of potential bias. Discrepancies were resolved by a third reviewer. RESULTS: Overall, 19 articles were selected for this systematic review, including 17 cross-sectional studies, one cohort study, and one quasi-experimental study, published from 2009 to 2019. The validated instruments identified in this review were Morisky Medication Adherence Scale (MMAS), the eight-item Morisky Medication Adherence Scale (MMAS-8), Measurement of Treatment Adherence (MTA), and Brief Medication Questionnaire (BMQ). Only MMAS-8 was tested for reliability, using the internal consistency assessment, with Cronbach's α range 0.56-0.71. CONCLUSIONS: This review highlighted a gap in knowledge regarding the scarcity of validated instruments to assess adherence to warfarin therapy. Limitations were found in instruments that comprised the assessment of the isolated use of medication and the lack of analysis of other relevant therapeutic aspects. Future studies are needed to develop and validate more comprehensive instruments in an attempt to assess adherence to warfarin therapy. PROSPERO: Registration number CRD42019128324.

Examining therapeutic equivalence between branded and generic warfarin in Brazil: The WARFA crossover randomized controlled trial.

OBJECTIVES: To determine whether the generic and branded warfarins used as anticoagulants in Brazil are therapeutic equivalents based on their international normalized ratio (INR) results. METHODS: This crossover randomized controlled trial had four periods. We used the branded Marevan and two generic versions of warfarin sodium tablets, manufactured by União Química and Teuto laboratories, all purchased from retail drugstores. Eligible participants were outpatients from an anticoagulation clinic at a university hospital in São Paulo, Brazil. They had atrial fibrillation or flutter and had been using warfarin for at least 2 months with an INR therapeutic range of 2.0-3.0. Randomization was by numbered, opaque, sealed envelopes. Healthcare personnel and outcome assessors were blinded to treatments, but patients were not. The primary outcome was the variability in the INR (ΔINR) and secondary outcomes included mean INR. We accepted formulations as equivalent if the 95% confidence interval (CI) of the comparison of ΔINR between branded and generic formulations was within the limit of ±0.49. RESULTS: One hundred patients were recruited and randomized to six sequences of treatment (four sequences with n = 17 and two sequences with n = 16). União Química generic warfarin had equivalent variability in the INR to Marevan (ΔINR +0.09 [95% CI -0.29 to +0.46], n = 84). Comparison between Teuto generic warfarin and Marevan was inconclusive (ΔINR +0.29 [95% CI -0.09 to +0.68], n = 84). CONCLUSIONS: Marevan and União Química warfarin had equivalent therapeutic effectiveness and both could be confidently used for anticoagulation. The comparison between Marevan and TW was inconclusive and does not warrant a statement of equivalence. Our methods are especially important for comparing generic and branded drugs that raise concerns and may be subject of future investigations by regulatory agents. TRIAL REGISTRATION: ClinicalTrials.gov NCT02017197.

The effect of reinforcing an educational programme using telephone follow-up on health-related quality of life of individuals using warfarin: A randomised controlled trial.

OBJECTIVES: To evaluate the effect of reinforcing an educational programme through telephone follow-up on health-related quality of life and anxiety and depression symptoms in individuals starting warfarin therapy. BACKGROUND: Educational interventions have improved quality of life in individuals using warfarin. Few studies have examined the addition of telephone follow-up to enhance educational interventions. DESIGN: Randomised controlled trial in outpatient setting. METHODS: Hospitalised adults starting warfarin therapy who agreed to participate received an educational programme about the warfarin treatment. At discharge, they were randomised to receive either five telephone follow-up calls (intervention) or no telephone calls (controls). Both groups were evaluated for health-related quality of life (using Duke Anticoagulation Satisfaction Scale) and symptoms of anxiety and depression (using Hospital Anxiety and Depression Scale) at three and six months post-discharge. Groups were compared at each time by independent-samples t test, and over time by repeated-measures analysis of variance, with time (three and six months), groups (intervention and control) and an interaction between time and group as factors. Level of significance was set at 0.05. The Consolidated Standards of Reporting Trials was used for reporting. RESULTS: Fifty-two individuals (26 per group) completed the study. There were no statistical differences between groups in health-related quality of life, anxiety and depression symptoms, at both times post-discharge. Participants who received follow-up telephone calls reported better positive psychological impact (a subscale of quality of life) than controls. CONCLUSIONS: Reinforcing an educational programme with telephone follow-ups did not have an overall effect on health-related quality of life of individuals using warfarin but promoted positive psychological impact. RELEVANCE TO CLINICAL PRACTICE: The low cost of reinforcing educational programmes with telephone calls and the improvement in positive psychological aspects indicate that this type of intervention is still a promising intervention that could be further investigated and improved.

Budget Impact Analysis of Anticoagulation Clinics in Patients with Atrial Fibrillation under Chronic Therapy with Oral Anticoagulants.

OBJECTIVES: To assess budget impact of the implementation of an anticoagulation clinic (AC) compared to usual care (UC), in patients with non-valvular atrial fibrillation (NVAF). METHOD: A decision tree was designed to analyze the cost and events rates over a 1-year horizon. The patients were distributed according to treatment, 30% Direct Oral Anticoagulant (DOAC) regimens and the rest to warfarin. The thromboembolism and bleeding were derived from observational studies which demonstrated that ACs had important impact in reducing the frequency of these events compared with UC, due to higher adherence with DOACs and proportion of time in therapeutic range (TTR) with warfarin. Costs were derived from the transactional platform of Colombian government, healthcare authority reimbursement and published studies. The values were expressed in American dollars (USD). The exchanged rate used was COP $3.693 per dollar. RESULTS: During 1 year of follow-up, in a cohort of 228 patients there were estimated 48 bleedings, 6 thromboembolisms in AC group versus 84 bleedings, and 12 thromboembolisms events in patients receiving UC. Total costs related to AC were $126 522 compared with $141 514 in UC. The AC had an important reduction in the cost of clinical events versus UC ($52 085 vs $110 749) despite a higher cost of care facilities ($74 436 vs $30 765). A sensibility analysis suggested that in the 83% of estimations, the AC produced savings varied between $27 078 and $135 391. CONCLUSIONS: This study demonstrated that AC compared with UC, produced an important savings in the oral anticoagulation therapy for patients with NVAF.

Clinical characteristics and stratification of the cerebrovascular accident risk among patients with atrial fibrillation in Colombia, 2011-2016.

Background: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia worldwide. This study aimed to determine the sociodemographic and clinical features of AF in a Colombian population.Methods: An observational, retrospective study was conducted using a sample of patients diagnosed with AF. Electronic medical records were reviewed to determine specific sociodemographic, clinical, risk stratification, outcome, and pharmacological variables.Results: A total of 357 patients with a mean age of 69.4 ± 13.3 years were included; 52.4% (n = 187) were women. Most patients (84.0%; n = 300) had an elevated risk of thromboembolism and an indication for anticoagulation, but 72 (24.0%) of these patients did not receive such treatment. Among the patients, 23.2% had HAS-BLED scores ≥3. During the study period, 76 patients (21.3%) had 121 adverse events, of which 75.2% (n = 91) were any bleeding events (major, minor, etc.) and 24.8% (n = 30) were thrombosis events (i.e., stroke). At the end of the follow-up period, the number of prescriptions for direct anticoagulants had increased, and warfarin decreased.Conclusions: AF primarily affects Colombian adults >65 years old. A high burden of comorbidities and a risk of thromboembolism were found in most patients; however, lack of treatment was evident in a large percentage of cases.