Primary results from post hoc analysis of the apollo-b brazilian subpopulation, a phase 3 study of patisiran in patients with transthyretin amyloidosis with cardiomyopathy

BACKGROUND: Transthyretin amyloidosis (ATTR) is a progressive, fatal disease caused by toxic misfolded transthyretin (TTR) amyloid deposits. Patisiran, an RNA interference therapeutic, inhibits synthesis of wild-type and variant TTR and is approved for the treatment of hereditary ATTR with polyneuropathy. OBJECTIVE: Describe efficacy and safety of patisiran in patients from Brazil with ATTR cardiomyopathy (ATTR-CM) via a post hoc subgroup analysis of the global APOLLO-B study (NCT03997383). METHODS: Patients 18­85 years of age with ATTR-CM and heart failure were randomized 1:1 to patisiran 0.3 mg/kg or placebo every 3 weeks for 12 months. Primary endpoint was change from baseline (CFB) in functional capacity (6-minute walk test) at Month 12 for patisiran vs placebo. Secondary endpoints included CFB to Month 12 in health status and quality of life (Kansas City Cardiomyopathy QuestionnaireOverall Summary [KCCQ-OS]). Exploratory endpoints included CFB in cardiac biomarkers and Perugini grade by Tc-99m scintigraphy, the latter assessed in a subset of patients in an imaging study within APOLLO-B. RESULTS: Of 360 patients in APOLLO-B, 42 were from Brazil (patisiran, n=20; placebo, n=22): median (range) age at screening, 73 (51, 85) years; male, 81%; wild-type ATTR, 54.8%. No patients were receiving tafamidis at baseline. Patisiran showed benefit vs placebo in 6-minute walk test (median [95% CI] CFB [meters]: −2.02 [−58.5, 42.9] vs −30.1 [−72.2, 3.5]; HodgesLehmann estimate of median difference [95% CI]: 31.4 [−16.6, 79.4]; Figure 1A) and in KCCQ-OS (least squares mean [SEM] CFB: 9.4 [3.8] vs 2.6 [3.7]; least squares mean difference [SEM]: 6.8 [5.3]; Figure 1B). Death was reported in 0 patisiran patients vs 3 (13.6%) placebo. The ratio of adjusted geometric mean fold-change (patisiran:placebo [95% CI]) was 0.77 (0.57, 1.03) for NT-proBNP and 0.87 (0.68, 1.12) for troponin I. In the imaging subset (n=35), 11/18 (61.1%) patisiran patients improved Perugini grade vs 0/10 placebo at Month 12 (Figure 2). Few patisiran patients experienced serious (8 [40%]) or severe (4 [20%]) adverse events; none were drug related. CONCLUSION: In Brazilian patients with ATTR-CM, potential benefit was observed with patisiran on functional capacity, health status and quality of life, cardiac biomarkers, and Perugini grade, consistent with data from the global APOLLO-B population. The results are descriptive; the study was not powered to detect treatment effects specific to this subgroup.

Análise Comparativa do ECG com o Holter na avaliação da Frequência Cardíaca na Insuficiência Cardíaca com Fração de Ejeção Reduzida e Ritmo Sinusal / Comparative Analysis of ECG and Holter Monitoring in the Assessment of Heart Rate in Heart Failure with Reduced Ejection Fraction and Sinus Rhythm

Resumo Fundamento A frequência cardíaca (FC) na insuficiência cardíaca com fração de ejeção reduzida (ICFEr) e ritmo sinusal apresenta valor prognóstico. Entretanto, o método de mensuração é debatido na literatura. Objetivos Comparar em pacientes com ICFEr e ritmo sinusal a FC no Holter com três eletrocardiogramas de repouso: ECG1, ECG2 e ECG3. Metodologia Estudo transversal com 135 pacientes portadores de insuficiência cardíaca com fração de ejeção ≤ 40% e ritmo sinusal. A FC foi avaliada por ECG e Holter. Análises incluíram o coeficiente de correlação intraclasse (CCI), regressão robusta, raiz do erro quadrático médio, Bland-Altman e a área sobre a curva ROC. Adotou-se nível de significância de 0,05 e o ajuste de Bonferroni-Holm para minimizar erros tipo I. Resultados As medianas [intervalo interquartil] de idade e fração de ejeção foram de 65 anos [16] e 30% [11], respectivamente. O CCI dos 3 ECG foi de 0,922 (intervalo de confiança de 95%: 0,892; 0,942). Os coeficientes de regressão robusta para ECG1 e ECG3 foram 0,20 (intervalo de confiança de 95%: 0,12; 0,29) e 0,21 (intervalo de confiança de 95%: 0,06; 0,36). O R2 robusto foi de 0,711 (intervalo de confiança de 95%: 0,628; 0,76). Na análise de concordância de Bland-Altman, os limites de concordância foram de −17,0 (intervalo de confiança de 95%: −19,0; −15,0) e 32,0 (intervalo de confiança de 95%: 30,0; 34,0). A área sob a curva ROC foi de 0,896 (intervalo de confiança de 95%: 0,865; 0,923). Conclusão A FC do ECG mostrou alta concordância com a FC do Holter, validando seu uso clínico em pacientes com ICFEr e ritmo sinusal. Contudo, a concordância foi subótima em um terço dos pacientes com FC inferior a 70 bpm pelo ECG, devendo ser considerada a realização de Holter neste contexto.

Abstract Background Heart rate (HR) has shown prognostic value in patients with heart failure with reduced ejection fraction (HFrEF) and sinus rhythm. However, the method of measurement is debated in the literature. Objectives To compare HR on Holter with 3 resting electrocardiograms (ECG1, ECG2, and ECG3) in patients with HFrEF and sinus rhythm. Methods This was a cross-sectional study with 135 patients with heart failure with ejection fraction ≤ 40% and sinus rhythm. HR was assessed by ECG and Holter. Analyses included intraclass correlation coefficient (ICC), robust regression, root mean squared error, Bland-Altman, and area under the receiver operating characteristic (ROC) curve. A significance level of 0.05 and Bonferroni-Holm adjustment were adopted to minimize type I errors. Results The median [interquartile range] age and ejection fraction were 65 years [16] and 30% [11], respectively. The ICC of the 3 ECGs was 0.922 (95% confidence interval: 0.892; 0.942). The robust regression coefficients for ECG1 and ECG3 were 0.20 (95% confidence interval: 0.12; 0.29) and 0.21 (95% confidence interval: 0.06; 0.36). The robust R2 was 0.711 (95% confidence interval: 0.628; 0.76). In the Bland-Altman agreement analysis, the limits of agreement were −17.0 (95% confidence interval: −19.0; −15.0) and 32.0 (95% confidence interval: 30.0; 34.0). The area under the ROC curve was 0.896 (95% confidence interval: 0.865; 0.923). Conclusion The HR on ECG showed high agreement with the HR on Holter, validating its clinical use in patients with HFrEF and sinus rhythm. However, agreement was suboptimal in one third of patients with HR below 70 bpm on ECG; thus, 24-hour Holter monitoring should be considered in this context.

Clinical and genetic profiles of patients with hereditary and wild-type transthyretin amyloidosis: the transthyretin cardiac amyloidosis registry in the state of São Paulo, Brazil (REACT-SP)

BACKGROUND: Transthyretin amyloidosis (ATTR) is a multisystem disease caused by the deposition of fibrillar protein in organs and tissues. ATTR genotypes and phenotypes are highly heterogeneous. We present data on physical signs and symptoms, cardiac and neurological assessments and genetic profile of patients enrolled in the Transthyretin Cardiac Amyloidosis Registry of the State of São Paulo, Brazil. RESULTS: Six hundred-forty-four patients were enrolled, 505 with the variant form (ATTRv) and 139 with wild-type (ATTRwt). Eleven different mutations were detected, the most common being Val50Met (47.5%) and V142Ile (39.2%). Overall, more than half of the patients presented cardiac involvement, and the difference in this proportion between the ATTRv and ATTRwt groups was significant (43.9 vs. 89.9%; p < 0.001). The prevalence of the neurological phenotype also differed between ATTRv and ATTRwt (56.8 vs. 31.7%; p < 0.001). The mixed phenotype was found in 25.6% of the population, without a significant difference between ATTRv and ATTRwt groups. A group of patients remained asymptomatic (10.4%), with a lower proportion of asymptomatic ATTRwt patients. CONCLUSIONS: This study details the clinical and genetic spectrum of patients with ATTR in São Paulo, Brazil. This preliminary analysis highlights the considerable phenotypic heterogeneity of neurological and cardiac manifestations in patients with variant and wild-type ATTR.

Clinical and genetic profiles of patients with hereditary and wild-type transthyretin amyloidosis: the Transthyretin Cardiac Amyloidosis Registry in the state of São Paulo, Brazil (REACT-SP).

BACKGROUND: Transthyretin amyloidosis (ATTR) is a multisystem disease caused by the deposition of fibrillar protein in organs and tissues. ATTR genotypes and phenotypes are highly heterogeneous. We present data on physical signs and symptoms, cardiac and neurological assessments and genetic profile of patients enrolled in the Transthyretin Cardiac Amyloidosis Registry of the State of São Paulo, Brazil. RESULTS: Six hundred-forty-four patients were enrolled, 505 with the variant form (ATTRv) and 139 with wild-type (ATTRwt). Eleven different mutations were detected, the most common being Val50Met (47.5%) and V142Ile (39.2%). Overall, more than half of the patients presented cardiac involvement, and the difference in this proportion between the ATTRv and ATTRwt groups was significant (43.9 vs. 89.9%; p < 0.001). The prevalence of the neurological phenotype also differed between ATTRv and ATTRwt (56.8 vs. 31.7%; p < 0.001). The mixed phenotype was found in 25.6% of the population, without a significant difference between ATTRv and ATTRwt groups. A group of patients remained asymptomatic (10.4%), with a lower proportion of asymptomatic ATTRwt patients. CONCLUSIONS: This study details the clinical and genetic spectrum of patients with ATTR in São Paulo, Brazil. This preliminary analysis highlights the considerable phenotypic heterogeneity of neurological and cardiac manifestations in patients with variant and wild-type ATTR.

Perfis clínicos e genéticos de pacientes com amiloidose transtiretina hereditária e do tipo selvagem: o registro de amiloidose cardíaca transtiretina no Estado de São Paulo, Brasil (REACT-SP) / Clinical and genetic profiles of patients with hereditary and wild-type transthyretin amyloidosis: the transthyretin cardiac amyloidosis registry in the State of São Paulo, Brazil (REACT-SP)

INTRODUÇÃO: A amiloidose transtiretina (ATTR) é uma doença multissistêmica causada pela deposição de proteína fibrilar em órgãos e tecidos. Os genótipos e fenótipos da ATTR são altamente heterogêneos. MÉTODOS: Apresentamos dados sobre sinais e sintomas físicos, avaliações cardíacas e neurológicas, e genética em pacientes incluídos no Registro de Amiloidose Cardíaca Transtiretina no Estado de São Paulo (REACT-SP), Brasil. RESULTADOS: Foram incluídos 644 pacientes, sendo 505 com a forma variante (ATTRv) e 139 com a forma selvagem (ATTRwt). Dezesseis mutações diferentes foram detectadas, sendo as mais comuns Val50Met (48,3%) e V142Ile (40,8%). No geral, mais da metade dos pacientes apresentou envolvimento cardíaco, e a diferença nessa proporção entre os grupos ATTRv e ATTRwt foi significativa (43,9 vs. 89,9%; p<0,001). O fenótipo neurológico também diferiu entre ATTRv e ATTRwt (56,8 vs. 31,7%; p<0,001). O fenótipo misto foi encontrado em 25,6% da população, sem diferença significativa entre as formas de amiloidose. Um grupo de pacientes permaneceu assintomático (10,4%), com uma proporção menor de pacientes assintomáticos no grupo ATTRwt. CONCLUSÕES: Este estudo detalha o espectro clínico e genético de pacientes com ATTR em São Paulo, Brasil. Esta análise preliminar destaca a considerável heterogeneidade fenotípica das manifestações neurológicas e cardíacas em pacientes com ATTR variante e ATTR do tipo selvagem.

Cardiovascular Complications in Patients with Heart Failure and COVID-19: CARDIO COVID 19-20 Registry.

Since early 2020, different studies have shown an increased prevalence of COVID-19 and poorer prognosis in older adults with cardiovascular comorbidities. This study aimed to assess the impact of heart failure (HF) on cardiovascular complications, intensive care unit (ICU) admissions, and in-hospital mortality in patients hospitalized with COVID-19. The CARDIO COVID 19-20 registry includes 3260 hospitalized patients with a COVID-19 serological diagnosis between May 2020 and June 2021 from Latin American countries. A history of HF was identified in 182 patients (5.6%). In patients with and without previous HF, the incidence of supraventricular arrhythmia was 16.5% vs. 6.3%, respectively (p = 0.001), and that of acute coronary syndrome was 7.1% vs. 2.7%, respectively (p = 0.001). Patients with a history of HF had higher rates of ICU admission (61.5% vs. 53.1%, respectively; p = 0.031) and in-hospital mortality (41.8% vs. 24.5%, respectively; p = 0.001) than patients without HF. Cardiovascular mortality at discharge (42.1% vs. 18.5%, respectively; p < 0.001) and at 30 days post-discharge (66.7% vs. 18.0%, respectively) was higher for patients with a history of HF than for patients without HF. In patients hospitalized with COVID-19, previous history of HF was associated with a more severe cardiovascular profile, with increased risk of cardiovascular complications, and poor in-hospital and 30-day outcomes.

Multifaceted Strategy Based on Automated Text Messaging After a Recent Heart Failure Admission: The MESSAGE-HF Randomized Clinical Trial.

Importance: Readmissions after an index heart failure (HF) hospitalization are a major contemporary health care problem. Objective: To evaluate the feasibility and efficacy of an intensive telemonitoring strategy in the vulnerable period after an HF hospitalization. Design, Setting, and Participants: This randomized clinical trial was conducted in 30 HF clinics in Brazil. Patients with left ventricular ejection fraction less than 40% and access to mobile phones were enrolled up to 30 days after an HF admission. Data were collected from July 2019 to July 2022. Intervention: Participants were randomly assigned to a telemonitoring strategy or standard care. The telemonitoring group received 4 daily short message service text messages to optimize self-care, active engagement, and early intervention. Red flags based on feedback messages triggered automatic diuretic adjustment and/or a telephone call from the health care team. Main Outcomes and Measures: The primary end point was change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to 180 days. A hierarchical win-ratio analysis incorporating blindly adjudicated clinical events (cardiovascular deaths and HF hospitalization) and variation in NT-proBNP was also performed. Results: Of 699 included patients, 460 (65.8%) were male, and the mean (SD) age was 61.2 (14.5) years. A total of 352 patients were randomly assigned to the telemonitoring strategy and 347 to standard care. Satisfaction with the telemonitoring strategy was excellent (net promoting score at 180 days, 78.5). HF self-care increased significantly in the telemonitoring group compared with the standard care group (score difference at 30 days, -2.21; 95% CI, -3.67 to -0.74; P = .001; score difference at 180 days, -2.08; 95% CI, -3.59 to -0.57; P = .004). Variation of NT-proBNP was similar in the telemonitoring group compared with the standard care group (telemonitoring: baseline, 2593 pg/mL; 95% CI, 2314-2923; 180 days, 1313 pg/mL; 95% CI, 1117-1543; standard care: baseline, 2396 pg/mL; 95% CI, 2122-2721; 180 days, 1319 pg/mL; 95% CI, 1114-1564; ratio of change, 0.92; 95% CI, 0.77-1.11; P = .39). Hierarchical analysis of the composite outcome demonstrated a similar number of wins in both groups (telemonitoring, 49 883 of 122 144 comparisons [40.8%]; standard care, 48 034 of 122 144 comparisons [39.3%]; win ratio, 1.04; 95% CI, 0.86-1.26). Conclusions and Relevance: An intensive telemonitoring strategy applied in the vulnerable period after an HF admission was feasible, well-accepted, and increased scores of HF self-care but did not translate to reductions in NT-proBNP levels nor improvement in a composite hierarchical clinical outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT04062461.

Multifaceted strategy based on automated text messaging after a recent heart failure admission: the MESSAGE-HF Randomized Clinical Trial

IMPORTANCE: Readmissions after an index heart failure (HF) hospitalization are a major contemporary health care problem. OBJECTIVE: To evaluate the feasibility and efficacy of an intensive telemonitoring strategy in the vulnerable period after an HF hospitalization. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted in 30 HF clinics in Brazil. Patients with left ventricular ejection fraction less than 40% and access to mobile phones were enrolled up to 30 days after an HF admission. Data were collected from July 2019 to July 2022. INTERVENTION: Participants were randomly assigned to a telemonitoring strategy or standard care. The telemonitoring group received 4 daily short message service text messages to optimize self-care, active engagement, and early intervention. Red flags based on feedback messages triggered automatic diuretic adjustment and/or a telephone call from the health care team. MAIN OUTCOMES AND MEASURES: The primary end point was change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to 180 days. A hierarchical win-ratio analysis incorporating blindly adjudicated clinical events (cardiovascular deaths and HF hospitalization) and variation in NT-proBNP was also performed. RESULTS: Of 699 included patients, 460 (65.8%) were male, and the mean (SD) age was 61.2 (14.5) years. A total of 352 patients were randomly assigned to the telemonitoring strategy and 347 to standard care. Satisfaction with the telemonitoring strategy was excellent (net promoting score at 180 days, 78.5). HF self-care increased significantly in the telemonitoring group compared with the standard care group (score difference at 30 days, -2.21; 95% CI, -3.67 to -0.74; P = .001; score difference at 180 days, -2.08; 95% CI, -3.59 to -0.57; P = .004). Variation of NT-proBNP was similar in the telemonitoring group compared with the standard care group (telemonitoring: baseline, 2593 pg/mL; 95% CI, 2314-2923; 180 days, 1313 pg/mL; 95% CI, 1117-1543; standard care: baseline, 2396 pg/mL; 95% CI, 2122-2721; 180 days, 1319 pg/mL; 95% CI, 1114-1564; ratio of change, 0.92; 95% CI, 0.77-1.11; P = .39). Hierarchical analysis of the composite outcome demonstrated a similar number of wins in both groups (telemonitoring, 49 883 of 122 144 comparisons [40.8%]; standard care, 48 034 of 122 144 comparisons [39.3%]; win ratio, 1.04; 95% CI, 0.86-1.26). CONCLUSIONS and relevance: An intensive telemonitoring strategy applied in the vulnerable period after an HF admission was feasible, well-accepted, and increased scores of HF self-care but did not translate to reductions in NT-proBNP levels nor improvement in a composite hierarchical clinical outcome.

Age-dependent impairment in antibody responses elicited by a homologous CoronaVac booster dose.

The emergence of the SARS-CoV-2 Omicron sublineages resulted in increased transmission rates and reduced protection from vaccines. To counteract these effects, multiple booster strategies were used in different countries, although data comparing their efficiency in improving protective immunity remain sparse, especially among vulnerable populations, including older adults. The inactivated CoronaVac vaccine was among the most widely distributed vaccine worldwide and was essential in the early control of SARS-CoV-2-related hospitalizations and deaths. However, it is not well understood whether homologous versus heterologous booster doses in those fully vaccinated with CoronaVac induce distinct humoral responses or whether these responses vary across age groups. We analyzed plasma antibody responses from CoronaVac-vaccinated younger or older individuals who received a homologous CoronaVac or heterologous BNT162b2 or ChAdOx1 booster vaccine. All three evaluated boosters resulted in increased virus-specific IgG titers 28 days after the booster dose. However, we found that both IgG titers against SARS-CoV-2 Spike or RBD and neutralization titers against Omicron sublineages were substantially reduced in participants who received homologous CoronaVac compared with the heterologous BNT162b2 or ChAdOx1 booster. This effect was specifically prominent in recipients >50 years of age. In this group, the CoronaVac booster induced low virus-specific IgG titers and failed to elevate neutralization titers against any Omicron sublineage. Our results point to the notable inefficiency of CoronaVac immunization and boosting in mounting protective antiviral humoral immunity, particularly among older adults, during the Omicron wave. These observations also point to benefits of heterologous regimens in high-risk populations fully vaccinated with CoronaVac.

The impact of the COVID-19 pandemic on heart failure management: Global experience of the OPTIMIZE Heart Failure Care network.

During the COVID-19 pandemic, reductions in heart failure (HF) hospitalizations have been widely reported, and there is an urgent need to understand how HF care has been reorganized in countries with different infection levels, vaccination rates and healthcare services. The OPTIMIZE Heart Failure Care program has a global network of investigators in 42 countries, with first-hand experience of the impact of the pandemic on HF management in different care settings. The national coordinators were surveyed to assess: 1) the challenges of the COVID-19 pandemic for continuity of HF care, from both a hospital and patient perspective; 2) the organizational changes enacted to ensure continued HF care; and 3) lessons learned for the future of HF care. Contributions were obtained from 37 national coordinators in 29 countries. We summarize their input, highlighting the issues raised and using the example of three very different settings (Italy, Brazil, and Taiwan) to illustrate the similarities and differences across the OPTIMIZE program.

Registry of transthyretin amyloidosis in the state of São Paulo (REACT-SP) / Registro em amiloidose transtirretina do estado de São Paulo (REACT-SP)

BACKGROUND: Amyloidosis is a systemic disease that involves multiple organs, characterized by the deposition of amyloid fibrils. Knowledge regarding the epidemiological, clinical, and genetic profile of the population affected by amyloidosis throughout the country is of fundamental importance for establishing diagnostic and therapeutic strategies. OBJECTIVE: To evaluate the epidemiological, clinical, laboratory, imaging, and treatment variables of patients with TTR cardiac amyloidosis. MATERIALS AND METHODS: A multicenter, retrospective, prospective, and observational study based on collection of data on the natural history of patients with TTR amyloidosis, followed in the state of São Paulo. RESULTS: To make it possible to map the regional distribution of the disease, increasing knowledge about the disease among clinicians and specialists in different areas. To evaluate patients with hereditary and wild-type TTR amyloidosis, in addition to following individuals with positive genotype and negative phenotype.

FUNDAMENTO: A amiloidose é uma doença sistêmica com envolvimento de diversos órgãos caracterizada pela deposição de fibrilas amiloides. O conhecimento do perfil epidemiológico, clínico e genético da população acometida por amiloidose no país é de fundamental importância em estratégias para estabelecer o diagnóstico bem como as estratégias terapêuticas. OBJETIVO: Avaliar as variáveis epidemiológicas, clínicas, laboratoriais, de imagem e tratamento dos pacientes com amiloidose cardíaca por transtirretina (TTR). MATERIAL E MÉTODOS: Estudo multicêntrico, retrospectivo, prospectivo e observacional baseado na coleta de dados da história natural dos pacientes com amiloidose TTR seguidos no estado de São Paulo. RESULTADOS: Permitir um mapa da distribuição regional da doença, aumentando o conhecimento da doença entre clínicos e especialistas nas diversas especialidades. Avaliar pacientes com amiloidose por TTR formas familiar e selvagem além de acompanhar indivíduos com genótipo positivo e fenótipo negativo. CONCLUSÃO: As informações coletadas poderão evidenciar uma maior conscientização da doença, criação de novos fluxogramas diagnósticos e de tratamento com impacto direto no conhecimento da história natural da doença e prognóstico dos pacientes.

Glucose-lowering Drugs and Hospitalization for Heart Failure: A Systematic Review and Additive-effects Network Meta-analysis With More Than 500 000 Patient-years.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2is) prevent hospitalization resulting from heart failure (HHF). However, patients with type 2 diabetes mellitus use multiple antihyperglycemic drugs to achieve glycosylated hemoglobin (HbA1c) targets. In these drug combinations, the risk of HHF is unpredictable and so is the parallel effect of glucose-lowering. PURPOSE: To examine the impact of antihyperglycemic drugs and their association on HHF. DATA SOURCES: Forty randomized controlled trials (RCTs) reporting HHF. STUDY SELECTION: Published RCTs were the data source. DATA EXTRACTION: Incidence rates of HHF. DATA SYNTHESIS: Random additive-effects network meta-analysis showed that metformin (P = 0.55), sulfonylureas (P = 0.51), glucagon-like peptide-1 receptor-agonist (P = 0.16), and dipeptidyl peptidase 4 inhibitors (DPP4is; P = 0.54) were neutral on the risk of HHF. SGLT2is and SGLT2is + DPP4is reduced the risk of HHF with a hazard ratio (HR) of 0.68 (95% CI, 0.60-0.76; P < 0.0001) and 0.70 (95% CI, 0.60-0.81; P < 0.0001), respectively. Increased risk of HHF was associated with thiazolidinediones (TZDs) as monotherapy or in combination with DPP4is (HR: 1.45; 95% CI, 1.18-1.78; P = 0.0004) and 1.49 (95% CI, 1.18-1.88; P = 0.0008), respectively. Regardless of the therapy, a 1% reduction in HbA1c reduced the risk of HHF by 31.3% (95% CI, 9-48; P = 0.009). LIMITATIONS: There are no data to verify drug combinations available for clinical use and to discriminate the effect of drugs within each of the therapeutic classes. CONCLUSIONS: The risk of HHF is reduced by SGLT2is as monotherapy or in combination with DPP4is and increased by TZDs as monotherapy or in combination. Glucose-lowering provides an additive effect of reducing HHF.

Serum potassium levels provide prognostic information in symptomatic heart failure beyond traditional clinical variables.

AIMS: Despite of recent advances in the pharmacological treatment, heart failure (HF) maintains significant morbidity and mortality rates. While serum potassium disorders are common and associated with adverse outcomes, the exact recommended potassium level for patients with HF are not entirely established. We aimed to investigate the prognostic role of potassium levels on a cohort of patients with symptomatic chronic HF. METHODS AND RESULTS: Patients with symptomatic chronic HF were identified at the referral to 6 min walking test (6MWT) and were prospectively followed up for cardiovascular events. Clinical and laboratorial data were retrospectively obtained. The primary endpoint was the composite of cardiovascular death, hospitalization due to HF, and heart transplantation. The cohort included 178 patients with HF with the mean age of 51 ± 12.76 years, 39% were female, 85% of non-ischaemic cardiomyopathy, and 38% had New York Heart Association Class III with a relatively high Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score (12.91 ± 6.6). The mean left ventricular ejection fraction was 39.98 ± 15.79%, and the mean 6MWT distance was 353 ± 136 m. After a median follow-up of 516 days, there were 22 major cardiovascular events (4 cardiovascular deaths, 13 HF admissions, and 5 heart transplants). Patients were stratified according to cut-point level of serum potassium of 4.7 mmol/L to predict combined cardiac events based on receiver operating characteristic analysis. Individuals with higher potassium levels had worse renal function (glomerular filtration rate, K ≤ 4.7: 102.8 ± 32.2 mL/min/1.73 m2 vs. K > 4.7: 85.42 ± 36.2 mL/min/1.73 m2 , P = 0.004), higher proportion of New York Heart Association Class III patients (K ≤ 4.7: 28% vs. K > 4.7: 48%, P = 0.0029), and also higher MAGGIC score (K ≤ 4.7: 12.08 ± 5.7 vs. K > 4.7: 14.9 ± 7.9, P = 0.0089), without significant differences on the baseline pharmacological HF treatment. Both potassium levels [hazard ratio (HR) 4.26, 95% confidence interval (CI) 1.59-11.421, P = 0.003] and 6MWT distance (HR 0.99, 95% CI 0.993-0.999, P = 0.01) were independently associated with the primary outcome. After adjustments for MAGGIC score and 6MWT distance, potassium levels > 4.7 mmol/L maintained a significant association with outcomes (HR 3.57, 95% CI 1.305-9.807, P = 0.013). Patients with K > 4.7 mmol/L were more likely to present clinical events during the follow-up (log rank = 0.005). Adding potassium levels to the model including 6MWT and MAGGIC significantly improved the prediction of events over 2 years (integrated discrimination index 0.105, 95% CI 0.018-0.281, P = 0.012 and net reclassification index 0.447, 95% CI 0.077-0.703, P = 0.028). CONCLUSIONS: Potassium levels were independently associated with worse outcomes in patients with chronic symptomatic HF, also improving the accuracy model for prognostic prediction when added to MAGGIC score and 6MWT distance. The potassium levels above 4.7 mmol/L might identify those patients at an increased risk of cardiovascular events.