Electrocardiographic Findings Among Asymptomatic Adults With Haemophilia

Abstract Background: People with haemophilia (PwH) are living longer. Therefore, they can develop atherosclerotic cardiovascular disease (ASCVD). Electrocardiogram (ECG) alterations may be a sign of initial ASCVD before the occurrence of symptoms. Objective: To describe the prevalence of resting ECG alterations among PwH adults asymptomatic for ASCVD. Methods: PwH aged ≥ 30 years without previous ASCVD events were considered for the analysis. Resting ECG traces were analysed according to international reference values and the Brazilian Longitudinal Adult Health Study (ELSA-Brasil) results for asymptomatic Brazilian men. Based on the established normal values and using the QT index, we further described the altered ECGs as minor or major changes, according to the Minnesota Code. Differences between prevalences were evaluated by Pearson's χ2 test. Differences between medians were evaluated by the Mann-Whitney U test. A p-value < 0.05 was accepted as statistically significant. Results: A total of 64 PwH were included in the study. Median age was 44 years (interquartile range 35-52). Most patients had haemophilia A (81%) and 47% were severe. The prevalence of obesity, systemic arterial hypertension (SAH), diabetes mellitus (DM), and dyslipidaemia were 16%, 56%, 14%, and 72%, respectively. All the PwH had sinus rhythm, except for one, who had an implanted pacemaker due to idiopathic third-degree atrioventricular block. Altered ECGs were found in 25% and 30% of PwH, according to established criteria and ELSA-Brasil criteria, respectively. Major changes were found in eight (13%) PwH according to the Minnesota Code, including two ECGs with ischaemia-like wall inactivity. Conclusions: The prevalence of altered ECG varied from 25% to 30% among asymptomatic PwH.

Efficacy/effectiveness and safety of emicizumab prophylaxis of people with hemophilia A: a systematic review and meta-analysis.

BACKGROUND: Emicizumab is a monoclonal antibody approved for prophylaxis against bleeds for people with hemophilia A (PwHA). A systematic review was conducted evaluating the efficacy/effectiveness and the safety of emicizumab as prophylaxis for PwHA compared to prophylaxis with factor VIII (FVIII) or bypassing agents (BPA), respectively in patients without and with inhibitors. RESEARCH DESIGN AND METHODS: Database-directed search strategies were performed in Aug/26/2022 and updated in Mar/16/2023. Studies evaluating the prophylaxis with emicizumab versus prophylaxis with FVIII or BPA in PwHA without or with inhibitors, respectively, were selected by two independent reviewers. Data were extracted by two independent reviewers. Annualized bleeding rates for total treated bleeding events (ABR-all) were evaluated by meta-analysis. The quality of studies and certainty of evidence were assessed. RESULTS: A total of 11 studies were included. The standard mean differences for ABR-all were -0.6 (95%CI -1.0 to -0.2, p-value = 0.0002), among PwHA without inhibitors, and -1.7 (95%CI -2.4 to -0.9, p-value <0.00001), among PwHA with inhibitors. However, there was moderate heterogeneity in both meta-analyses. The most frequent adverse event was injection site reaction. CONCLUSIONS: Emicizumab prophylaxis was superior in reducing the ABR-all when compared with prophylaxis with FVIII or BPA.

Emicizumab prophylaxis for people with hemophilia A: Waste estimation and the Brazilian perspective.

Costs of hemophilia A treatment are increasing. Waste of clotting products should be avoided. To estimate the first-year waste of emicizumab prophylaxis for people with hemophilia A and inhibitors (PwHAi) who failed immune tolerance induction (ITI), in Brazil. We evaluated the manufacturer and the Brazilian Ministry of Health (MoH) protocol-recommended regimens in a budget impact model. The loading dose consisted of 3.0 mg/kg/Q1W for 4 weeks, for both recommendations. The manufacturer maintenance regimens comprised 1.5 mg/kg/Q1W, 3.0 mg/kg/Q2W, and 6.0 mg/kg/Q4W. The MoH protocol maintenance regimen encompassed a hybrid Q1W/Q2W administration, depending on the body weight. The Q4W regimen was not recommended by the MoH protocol. Analyses were performed to estimate waste given its expense based on the World Health Organization body weight range (percentiles [P] 15, 50, and 85). The first-year emicizumab waste was estimated individually and for the disclosed PwHAi who failed ITI (n = 114). The highest emicizumab waste was estimated for the lowest body weights and the Q1W regimen. The Q4W regimen resulted in the lowest emicizumab waste, followed by the MoH protocol regimen. The total reconstituted costs estimated for the PwHAi who failed ITI according to the hybrid MoH protocol ranged from US$32,858,777 (P15) to US$47,186,858 (P85), with emicizumab waste ranging from 7.9 % (US$2,594,515) to 3.7 % (US$1,738,750), respectively. Lost resources due to current protocols for emicizumab prophylaxis for PwHAi who failed ITI in Brazil are considerable. Waste was more pronounced due to lower body weight and shorter administration intervals.

Cardiovascular Risk Scores among Asymptomatic Adults with Haemophilia. / Escores de Risco Cardiovascular entre Adultos Assintomáticos com Hemofilia.

BACKGROUND: The mortality rate of Brazilian people with haemophilia (PwH) is decreasing, but the relative incidence of deaths associated with cardiovascular disease (CVD) is increasing. OBJECTIVES: We aimed to describe the CVD risk score of PwH according to Pooled Cohort Equations Risk (PCER) Calculator tool and its treatment recommendations. We also compared the PCER estimates with the respective Framingham Risk Score (FRS). METHODS: This cross-sectional study included male PwH ≥ 40 years treated at the Comprehensive Haemophilia Treatment Centre of Pernambuco (Recife/Brazil). PwH with a previous CVD event or a low-density lipid cholesterol ≥ 5.0 mmol/L were excluded. Interviews, medical file reviews, and blood tests were performed. The PCER tool was used to estimate the CVD risk and compare it with the respective FRS. A p-value < 0.05 was accepted as statistically significant. RESULTS: Thirty PwH were included. Median age was 51.5 [interquartile range-IQR; 46.0-59.5] years. The prevalence of obesity, systemic arterial hypertension, diabetes mellitus, hypertriglyceridaemia, hypercholesterolaemia, and hypoHDLaemia were 20%, 67%, 24%, 14%, 47%, and 23%, respectively. The median PCER score was 6.9% [IQR; 3.1-13.2], with 50% having a high risk (PCER ≥ 7.5%). Statin use was suggested for 54% of PwH. Blood pressure was poorly controlled in 47% of PwH. The agreement between PCER and FRS was 80% (κ = 0.60; p = 0.001). CONCLUSIONS: Half of the male people with haemophilia aged 40 years or older had a 10-year high risk of developing CVD with strong recommendations to improve control of dyslipidaemia and blood pressure.

FUNDAMENTO: A taxa de mortalidade de pessoas com hemofilia (PCH) no Brasil está diminuindo, mas a incidência relativa de mortes associadas a doenças cardiovasculares (DCV) tem aumentado. OBJETIVOS: Nosso objetivo foi descrever o escore de risco de DCV de PCHs de acordo com a ferramenta Pooled Cohort Equations Risk (PCER) Calculator e suas recomendações de tratamento. Além disso, foram comparadas as estimativas da PCER com o respectivo escore de risco de Framingham (FRS). MÉTODOS: Este estudo transversal incluiu PCHs do sexo masculino, com idade igual ou superior a 40 anos, tratados no Centro de Tratamento Integral de Hemofilia de Pernambuco (Recife/Brasil). PCHs com um evento cardiovascular prévio ou colesterol lipídico de baixa densidade ≥ 5,0 mmol/L foram excluídas. Entrevistas, revisões de prontuários médicos e exames de sangue foram realizados. A ferramenta PCER foi utilizada para estimar o risco de DCV e compará-lo com o respectivo FRS. Um valor de p < 0,05 foi aceito como estatisticamente significativo. RESULTADOS: Trinta PCHs foram incluídas. A idade mediana foi de 51,5 [intervalo interquartil-IIQ; 46,0-59,5] anos. A prevalência de obesidade, hipertensão arterial sistêmica, diabetes mellitus, hipertrigliceridemia, hipercolesterolemia e hipoHDLemia foi de 20%, 67%, 24%, 14%, 47% e 23%, respectivamente. O escore mediano da PCER foi de 6,9% [IIQ; 3,1-13,2], com 50% de alto risco (PCER ≥ 7,5%). O uso de estatina foi sugerido para 54% das PCHs. A pressão arterial estava mal controlada em 47% das PCHs. A concordância entre PCER e FRS foi de 80% (κ = 0,60; p = 0,001). CONCLUSÕES: Metade dos homens com hemofilia, com 40 anos de idade ou mais, teve um alto risco de desenvolver DCV em 10 anos, com fortes recomendações para melhorar o controle da dislipidemia e da pressão arterial.

ICU Admission, Invasive Mechanical Ventilation, and Mortality among Children and Adolescents Hospitalized for COVID-19 in a Private Healthcare System.

Aim: The COVID-19 pandemic devastated healthcare around the world. Data about the COVID-19 outcomes among young people are still scarce. We aim to identify factors associated with the composite outcome among children and adolescents hospitalized due to COVID-19. Methods: We performed a search in the database of a large Brazilian private healthcare system. Insured people aged 21 years or younger who were hospitalized due to COVID-19 from Feb/28th/2020 to Nov/1st/2021 were included. The primary endpoint was the composite outcome consisting of ICU admission, need for invasive mechanical ventilation, or death. Results: We evaluated 199 patients who had an index hospitalization due to COVID-19. The median monthly rate of index hospitalization was 2.7 (interquartile range [IQR], 1.6-3.9) per 100,000 clients aged 21 years or less. The median age of the patients was 4.5 years (IQR, 1.4-14.1). At the index hospitalization, the composite outcome rate was 26.6%. The composite outcome was associated with all the previous coexisting morbidities evaluated. The median follow-up was 249.0 days (IQR, 152.0-438.5). There were 27 readmissions (16 patients) within 30 days after the discharge. Conclusions: In conclusion, hospitalized children and adolescents had a composite outcome rate of 26.6% at the index hospitalization. Having previous chronic morbidity was associated with the composite.

Economic Evaluation of Immune Tolerance Induction in Children With Severe Hemophilia A and High-Responding Inhibitors: A Cost-Effectiveness Analysis of Prophylaxis With Emicizumab.

OBJECTIVE: This study aimed to measure the cost-effectiveness of prophylaxis with emicizumab in PsHAhri on ITI in Brazil. METHODS: A cost-effectiveness modeling analysis was used to estimate the costs per PsHAhri on ITI and the number of prevented bleedings from undertaking one intervention (prophylaxis with BpA) over another (prophylaxis with emicizumab), based on the Brazilian Ministry of Health perspective. Costs of ITI with recombinant FVIII, prophylaxis with BpA or emicizumab, and treated bleeding episodes with BpA costs were evaluated for PsHAhri who had ITI success or failure. This study was conducted with the perspective of the Brazilian Ministry of Health (payer). RESULTS: During ITI, prophylaxis with BpA cost US $924 666/PsHAhri/ITI, whereas prophylaxis with emicizumab cost US $488 785/PsHAhri/ITI. During ITI, there was an average of 9.32 bleeding episodes/PsHAhri/ITI when BpA were used as prophylaxis and 0.67 bleeding/PsHAhri/ITI when emicizumab was used. By univariate deterministic sensitivity analysis, emicizumab remained dominant whichever variable was modified. CONCLUSION: In this study, prophylaxis with emicizumab during ITI is a dominant option compared with prophylaxis with BpA during ITI.

Escores de Risco Cardiovascular entre Adultos Assintomáticos com Hemofilia / Cardiovascular Risk Scores among Asymptomatic Adults with Haemophilia

Resumo Fundamento A taxa de mortalidade de pessoas com hemofilia (PCH) no Brasil está diminuindo, mas a incidência relativa de mortes associadas a doenças cardiovasculares (DCV) tem aumentado. Objetivos Nosso objetivo foi descrever o escore de risco de DCV de PCHs de acordo com a ferramenta Pooled Cohort Equations Risk (PCER) Calculator e suas recomendações de tratamento. Além disso, foram comparadas as estimativas da PCER com o respectivo escore de risco de Framingham (FRS). Métodos Este estudo transversal incluiu PCHs do sexo masculino, com idade igual ou superior a 40 anos, tratados no Centro de Tratamento Integral de Hemofilia de Pernambuco (Recife/Brasil). PCHs com um evento cardiovascular prévio ou colesterol lipídico de baixa densidade ≥ 5,0 mmol/L foram excluídas. Entrevistas, revisões de prontuários médicos e exames de sangue foram realizados. A ferramenta PCER foi utilizada para estimar o risco de DCV e compará-lo com o respectivo FRS. Um valor de p < 0,05 foi aceito como estatisticamente significativo. Resultados Trinta PCHs foram incluídas. A idade mediana foi de 51,5 [intervalo interquartil-IIQ; 46,0-59,5] anos. A prevalência de obesidade, hipertensão arterial sistêmica, diabetes mellitus, hipertrigliceridemia, hipercolesterolemia e hipoHDLemia foi de 20%, 67%, 24%, 14%, 47% e 23%, respectivamente. O escore mediano da PCER foi de 6,9% [IIQ; 3,1-13,2], com 50% de alto risco (PCER ≥ 7,5%). O uso de estatina foi sugerido para 54% das PCHs. A pressão arterial estava mal controlada em 47% das PCHs. A concordância entre PCER e FRS foi de 80% (κ = 0,60; p = 0,001). Conclusões Metade dos homens com hemofilia, com 40 anos de idade ou mais, teve um alto risco de desenvolver DCV em 10 anos, com fortes recomendações para melhorar o controle da dislipidemia e da pressão arterial.

Abstract Background The mortality rate of Brazilian people with haemophilia (PwH) is decreasing, but the relative incidence of deaths associated with cardiovascular disease (CVD) is increasing. Objectives We aimed to describe the CVD risk score of PwH according to Pooled Cohort Equations Risk (PCER) Calculator tool and its treatment recommendations. We also compared the PCER estimates with the respective Framingham Risk Score (FRS). Methods This cross-sectional study included male PwH ≥ 40 years treated at the Comprehensive Haemophilia Treatment Centre of Pernambuco (Recife/Brazil). PwH with a previous CVD event or a low-density lipid cholesterol ≥ 5.0 mmol/L were excluded. Interviews, medical file reviews, and blood tests were performed. The PCER tool was used to estimate the CVD risk and compare it with the respective FRS. A p-value < 0.05 was accepted as statistically significant. Results Thirty PwH were included. Median age was 51.5 [interquartile range-IQR; 46.0-59.5] years. The prevalence of obesity, systemic arterial hypertension, diabetes mellitus, hypertriglyceridaemia, hypercholesterolaemia, and hypoHDLaemia were 20%, 67%, 24%, 14%, 47%, and 23%, respectively. The median PCER score was 6.9% [IQR; 3.1-13.2], with 50% having a high risk (PCER ≥ 7.5%). Statin use was suggested for 54% of PwH. Blood pressure was poorly controlled in 47% of PwH. The agreement between PCER and FRS was 80% (κ = 0.60; p = 0.001). Conclusions Half of the male people with haemophilia aged 40 years or older had a 10-year high risk of developing CVD with strong recommendations to improve control of dyslipidaemia and blood pressure.

Time between inhibitor detection and start of immune tolerance induction: Association with outcome in the BrazIT study.

BACKGROUND: Immune tolerance induction (ITI) is the treatment of choice for eradication of anti-factor VIII (FVIII) neutralizing alloantibodies (inhibitors) in people with inherited hemophilia A and high-responding inhibitor (PwHA-HRi). The association between ITI outcome and time elapsed between inhibitor detection and start of ITI (∆tinhi-ITI ) is debatable. OBJECTIVE: The aim of this study was to evaluate this association among a large cohort of severe PwHA-HRi. METHODS: Severe (factor VIII activity level <1%) PwHA-HRi on ITI (n = 142) were enrolled in 15 hemophilia treatment centers. PwHA-HRi were treated according to the Brazilian ITI Protocol. ITI outcomes were defined as success (i.e., recovered responsiveness to exogenous FVIII) and failure (i.e., no responsiveness to exogenous FVIII and requirement of bypassing agents to control bleeding). RESULTS: Median ages at inhibitor detection and at ITI start were 3.2 years (interquartile range [IQR], 1.6-8.1) and 6.9 years [IQR, 2.6-20.1), respectively. PwHA-HRi were stratified according to ∆tinhi-ITI quartiles: first (0.0-0.6 year), second (>0.6-1.7 year), third (>1.7-9.2 years), and fourth quartile (>9.2-24.5 years). The overall success rate was 65.5% (93/142), with no difference among first, second, third, and fourth quartiles (62.9%, 69.4%, 58.3%, and 71.4%, respectively) even after adjusting the analyses for potential confounders. CONCLUSION: In conclusion, delayed ITI start is not associated with failure of ITI in PwHA-HRi. Therefore, ITI should be offered for these patients, regardless of the time elapsed between the detection of inhibitor and the ITI start.

Predictors of the outcome of immune tolerance induction in patients with haemophilia A and inhibitors: The Brazilian Immune Tolerance (BrazIT) Study protocol.

The development of inhibitors is the main complication of haemophilia A (HA) treatment. Immune tolerance induction (ITI) is the treatment of choice for inhibitor eradication. We describe the methodology of the Brazilian Immune Tolerance Induction (BrazIT) Study, aimed to identify clinical, genetic, and immune biomarkers associated with response to ITI and inhibitor recurrence. This cohort study includes people with HA (PwHA) and inhibitors (a) who require bypassing agents to treat and/or prevent bleeding, and (b) who are at any stage of ITI treatment. Patients are included in each haemophilia treatment centre (HTC). Factor VIII (FVIII) and inhibitor assessments are performed at local laboratories of each HTC. The ITI regimen followed the national protocol of the Brazilian Ministry of Health. All PwHA starts with low-dose ITI (50 IU/kg three times weekly); high-dose regimen (100 IU/kg daily) is used if there is lack of response to the low-dose ITI. Outcomes are classified as total or partial success, and failure. Standardized case report forms with clinical, laboratory, and treatment data are collected from medical files and interviews. Blood samples are collected for genetic and immune biomarkers at the time of inclusion in the study and at the end of ITI. The study is ongoing and, currently, 202/250 (80.8%) PwHA from 15 HTCs have been included. BrazIT Study is the largest cohort of PwHA and inhibitor under treatment with the same ITI regimen reported to date. This study is likely to contribute with novel predictors of ITI response.

Third-degree atrioventricular block and pacemaker implantation in a man with severe hemophilia A: A case report.

Hemophilia A (HA) is a rare bleeding disorder characterized by reduced factor VIII (FVIII) activity and consequently spontaneous bleeding. Since the introduction of prophylaxis with safer FVIII concentrates, people with HA are ageing. Interestingly, they are developing cardiovascular diseases as their non-hemophilia counterparts. We describe a 48-year-old patient with severe HA who presented a third-degree atrioventricular block. A DDDR pacemaker was implanted under supervision of the Hematology Clinics. There were no adverse events during the procedure. The procedure was safe, and it should be performed under the supervision of a hemophilia expert.

Cardiovascular risk factors among adult patients with haemophilia.

Since the introduction of episodic and prophylactic treatments with safer factor concentrates, the life expectancy of people with haemophilia (PwH) has improved considerably. Ageing-related diseases such as cardiovascular disease (CVD) have also become more prevalent in PwH. This cross-sectional study aimed to evaluate CVD risk factors and estimate 10-year risk for CVD events among PwH. Male patients ≥ 30 years were interviewed and examined. Blood tests were performed at the local laboratory. Eighty-two patients were included, of whom 83% had haemophilia A and half had severe disease. Median age at study entry was 43.0 years (interquartile range [IQR], 36.0-51.3). Prevalence of obesity, systemic arterial hypertension (SAH) and diabetes mellitus were 16%, 60% and 16%, respectively. Hypertriglyceridaemia, hypercholesterolaemia and low HDL blood levels were present in 18%, 41% and 30% of patients, respectively. Metabolic syndrome was found in 37%. The Framingham Risk Score showed that 39% of PwH had a high risk of developing cardiovascular events in the following 10 years. We conclude that, in this cohort, PwH have a higher prevalence of SAH when compared with Brazilian men without haemophilia and about two-fifths have a high risk of developing a CVD event in the following 10 years.

Construção e validação de instrumento de consulta de enfermagem para pessoas com hemofilia / Construcción y validación de un instrumento de consulta de enfermería para personas con hemofilia / Construction and validation of a nursing consultation tool for people with hemophilia

RESUMO Objetivo: construir e validar um instrumento de consulta de enfermagem para pessoas com hemofilia. Método: estudo metodológico realizado de fevereiro de 2017 a fevereiro de 2018, em um serviço referência de hematologia do Nordeste do Brasil. Utilizou-se a técnica Delphi para validação, por três grupos de enfermeiras juízas (n=29): Especialistas em hemofilia (n=nove) de nove hemocentros do país; Residência em Hematologia (n=oito); Enfermeiras do Serviço (n=12). A concordância entre as juízas foi verificada por escala Likert e teste exato de Fisher. Resultados: 89,6% não apresentaram dificuldade para compreender o instrumento. Quanto ao grau de relevância, as características 'credibilidade' e 'cientificidade' apresentaram maiores percentuais de extremamente relevante (90%). O teste exato de Fisher foi significativo no grau de satisfação de 'clareza das afirmações' (p<0,05). Conclusão: o instrumento foi considerado válido, proporcionando autonomia, apoio técnico e respaldo ético ao enfermeiro, contribuindo na melhoria da qualidade da assistência.

RESUMEN Objetivo: construir y validar un instrumento de consulta de enfermería para personas con hemofilia. Método: estudio metodológico realizado de febrero de 2017 a febrero de 2018, en un servicio de referencia de hematología del Nordeste de Brasil. Para la validación se utilizó la técnica Delphi, por parte de tres grupos de enfermeras jueces (n=29): Especialistas en hemofilia (n=nueve) de nove hemocentros del país; Residencia en Hematología (n=ocho); Enfermeras del Servicio (n=12). La concordancia entre las jueces se verificó mediante la escala Likert y la prueba exacto de Fisher. Resultados: 89,6% não apresentaram dificuldade para compreender o instrumento. Quanto ao grau de relevância, as características 'credibilidade' e 'cientificidade' apresentaram maiores percentuais de extremamente relevante (90%). O teste exato de Fisher foi significativo no grau de satisfação de 'clareza das afirmações' (p<0,05). Conclusión: o instrumento foi considerado válido, proporcionando autonomia, apoio técnico e respaldo ético ao enfermeiro, contribuindo na melhoria da qualidade da assistência.

ABSTRACT Objective: to construct and validate a nursing consultation instrument for people with hemophilia. Method: methodological study conducted from February 2017 to February 2018, in a hematology reference service in Northeast Brazil. The Delphi technique was used for validation, by three groups of nurse judges (n=29): hemophilia specialists (n=nine) from nine blood centers in the country; Hematology Residency (n=eight); Service Nurses (n=12). Inter-rater agreement was checked by Likert scale and Fisher's exact test. Results: 89.6% had no difficulty in understanding the instrument. As for the degree of relevance, the characteristics 'credibility' and 'scientificity' showed higher percentages of extremely relevant (90%). Fisher's exact test was significant in the degree of satisfaction of 'clarity of statements' (p<0.05). Conclusion: the instrument was considered valid, providing autonomy, technical support, and ethical support to the nurse, contributing to the improvement of the quality of care.