Incidence of, Risk Factors for, and Outcomes After Ascites in a Population-Based Cohort of Older Americans.

BACKGROUND: The incidence of, risk factors for, and outcomes after the development of ascites are poorly described for contemporary patients with cirrhosis. METHODS: We examined data for a 20% random sample of US Medicare enrollees with cirrhosis and Part D prescription coverage from 2008 to 2019, excluding patients with heart failure and diuretic use prior to cirrhosis. Among 63,364 persons with cirrhosis, we evaluated the incidence of ascites using an Aalen-Johansen estimator. We evaluated risk factors for ascites, mortality, and mortality after ascites using multistate modeling. We determined the associations with each outcome for an array of medication exposures including nonselective beta-blockers, antiviral therapy, statins, rifaximin, anticoagulants, and metformin. RESULTS: The cumulative incidence of ascites was 5.1%, 9.5%, and 10.7% and 1, 3, and 5 years overall. The corresponding data for ascites requiring paracentesis were 1%, 2.1%, and 2.4%. Persons aged < 65 years, with alcohol-related cirrhosis, varices, or HE, are most likely to develop ascites. The risk of ascites was higher for persons taking any NSBB (including carvedilol) but lower for those taking atorvastatin (but not other statins) and antiviral therapy for Hepatitis C. Incident ascites was associated with increased risk of death, HR 27.6 95%CI(21.7-35.1). Survival following ascites was 1.08 years (interquartile range, IQR, 0.26-2.75), 0.38 years (IQR0.1-1.3) for those requiring paracentesis. Lipophilic statins were the only medications associated with lower mortality after ascites requiring paracentesis. CONCLUSIONS: Ascites is associated with a high risk of death. Very few candidate therapies are associated with the reduction in the risk of ascites and mortality after ascites development.

Ex Ante Economic Evaluation of Arg389 Genetically Targeted Treatment with Bucindolol versus Empirical Treatment with Carvedilol in NYHA III/IV Heart Failure.

OBJECTIVE: The Beta-Blocker Evaluation Survival Trial showed no survival benefit for bucindolol in New York Heart Association (NYHA) class III/IV heart failure (HF) with reduced ejection fraction, but subanalyses suggested survival benefits for non-Black subjects and Arg389 homozygotes. We conducted an ex ante economic evaluation of Arg389 targeted treatment with bucindolol versus carvidolol, complementing a previous ex ante economic evaluation of bucindolol preceded by genetic testing for the Arg389 polymorphism, in which genetic testing prevailed economically over no testing. METHODS: A decision tree analysis with an 18-month time horizon was performed to estimate the cost effectiveness/cost utility of trajectories of 100%, 50%, and 0% of patients genetically tested for Arg389 and comparing bucindolol with empirical carvedilol treatment as per prior BEST subanalyses. Incremental cost-effectiveness/cost-utility ratios (ICERs/ICURs) were estimated. RESULTS: Race-based analyses for non-White subjects at 100% testing showed a loss of (0.04) life-years and (0.03) quality-adjusted life-years (QALYs) at an incremental cost of $2185, yielding a negative ICER of ($54,625)/life-year and ICUR of ($72,833)/QALY lost; at 50%, the analyses showed a loss of (0.27) life-years and (0.16) QALYs at an incremental cost of $1843, yielding a negative ICER of ($6826)/life-year and ICUR of ($11,519)/QALY lost; at 0%, the analyses showed a loss of (0.33) life-years and (0.30) QALYs at an incremental cost of $1459, yielding a negative ICER of ($4421)/life-year and ICUR of ($4863)/QALY lost. Arg389 homozygote analyses at 100% testing showed incremental gains of 0.02 life-years and 0.02 QALYs at an incremental cost of $378, yielding an ICER of 18,900/life-year and ICUR of $18,900/QALY gained; at 50%, the analyses showed a loss of (0.24) life-years and (0.09) QALYs at an incremental cost of $1039, yielding a negative ICER of ($4329)/life-year and ICUR of ($9336)/QALY lost; at 0%, the analyses showed a loss of (0.33) life-years and (0.30) QALYs at an incremental cost of $1459, yielding a negative ICER of ($4421)/life-year and ICUR of ($4863)/QALY lost. CONCLUSION: This independent ex ante economic evaluation suggests that genetically targeted treatment with bucindolol is unlikely to yield clinicoeconomic benefits over empirical treatment with carvedilol in NYHA III/IV HF.

Assessment of myocardial function in obstructive hypertrophic cardiomyopathy cats with and without response to medical treatment by carvedilol.

BACKGROUND: Inconsistency of treatment response in cats with obstructive hypertrophic cardiomyopathy is well recognized. We hypothesized that the difference in response to beta-blockers may be caused by myocardial functional abnormalities. This study was designed to compare myocardial function in cats with obstructive hypertrophic cardiomyopathy with and without response to beta-blockers. Twenty-one, client-owned, hypertrophic cardiomyopathy cats treated with carvedilol were analyzed. After carvedilol treatment, cats with decreased left ventricular outflow tract velocity were categorized as responders (n = 10); those exhibiting no response (no decrease in the left ventricular outflow tract velocity) were categorized as non-responders (n = 11). The cats were examined using layer-specific assessment of the myocardial function (whole, endocardial, and epicardial layers) longitudinally and circumferentially by two-dimensional speckle-tracking echocardiography, before and after carvedilol treatment. RESULTS: The non-responder cats had a significantly higher age, end-diastolic left ventricular posterior-wall thickness, peak velocity of left ventricular outflow tract, and dose of carvedilol than the responders (p = 0.04, p < 0.01, p < 0.01, and p < 0.01, respectively). The circumferential strain in the epicardial layer was lower and circumferential endocardial to epicardial strain ratio was higher in non-responders than responders (p < 0.001 and p = 0.006). According to the multivariate analysis, circumferential strain in the epicardial layer was the only independent correlate of treatment response with carvedilol. CONCLUSIONS: Myocardial function, assessed by two-dimensional speckle-tracking echocardiography, differed in cats with hypertrophic cardiomyopathy with and without response to beta-blockers. The determination of layer-specific myocardial function may facilitate detailed pathophysiologic assessment and treatment response in cats with hypertrophic cardiomyopathy.

Low Utilization of Beta-Blockers Among Medicare Beneficiaries Hospitalized for Heart Failure With Reduced Ejection Fraction.

BACKGROUND: The evidence-based beta-blockers carvedilol, bisoprolol, and metoprolol succinate reduce mortality and hospitalizations among patients with heart failure with reduced ejection fraction (HFrEF). Use of these medications is not well described in the general population of patients with HFrEF, especially among patients with potential contraindications. OBJECTIVES: Our goal was to describe the patterns of prescription fills for carvedilol, bisoprolol, and metoprolol succinate among Medicare beneficiaries hospitalized for HFrEF, as well as to estimate the associations between specific contraindications for beta-blocker therapy and those patterns. METHODS AND RESULTS: With the use of the cohort of 15,205 Medicare beneficiaries hospitalized for HFrEF from 2007 to 2013 in the 5% Medicare random sample, we described prescription fills (30 days after discharge) and dosage patterns (1 year after discharge) for beta-blockers. By means of of Fine and Gray competing risk models, we estimated the associations between potential contraindications (hypotension, chronic obstructive pulmonary disease [COPD], asthma, and syncope) and prescription fill and dosing patterns while adjusting for demographics, comorbidities, and health care utilization. For beneficiaries who did not die or readmitted to the hospital, 38% of hospitalizations were followed by a prescription fill for an evidence-based beta-blocker within 30 days, 12% were followed by prescription fills for at least 50% of the recommended dose of an evidence-based beta-blocker within 1 year, and 9% were followed by a prescription fill for an up-titrated dose of an evidence-based beta-blocker within 1 year. The prevalence of the contraindications were 21% for hypotension, 48% for COPD, 15% for asthma, and 12% for syncope. Among beneficiaries who did not fill a prescription for an evidence-based beta-blocker within 30 days, 67% had at least 1 of these contraindications. Hypotension, COPD, and syncope were each associated with a ∼10% lower risk of filling a prescription for an evidence-based beta-blocker. CONCLUSIONS: Prescription fill and up-titration rates for evidence-based beta-blockers are low among Medicare beneficiaries with HFrEF, but contraindications explain only a minor part of these low rates.

Assessment of clinical effect and treatment quality of immediate-release carvedilol-IR versus SLOW release carvedilol-SR in Heart Failure patients (SLOW-HF): study protocol for a randomized controlled trial.

BACKGROUND: Carvedilol is a non-selective, third-generation beta-blocker and is one of the cornerstones for treatment for patients with heart failure and reduced ejection fraction (HFrEF). However, due to its short half-life, immediate-release carvedilol (IR) needs to be prescribed twice a day. Recently, slow-release carvedilol (SR) has been developed. The aim of this study is to evaluate whether carvedilol-SR is non-inferior to standard carvedilol-IR in terms of its clinical efficacy in patients with HFrEF. METHODS/DESIGN: Patients with stable HFrEF will be randomly assigned in a 1:1 ratio to the carvedilol-SR group (160 patients) and the carvedilol-IR group (160 patients). Patients aged ≥ 20 years, with a left ventricular ejection fraction ≤ 40%, N-terminal pro B-natriuretic peptide (NT-proBNP) ≥ 125 pg/ml or BNP ≥ 35 pg/ml, who are clinically stable and have no evidence of congestion or volume retention, will be eligible. After randomization, patients will be followed up for 6 months. The primary endpoint is the change in NT-proBNP level from baseline to the study end. The secondary endpoints include the proportion of patients with NT-proBNP increment > 10% from baseline, composite of all-cause mortality and readmission, mortality rate, readmission rate, changes in blood pressure, quality of life, and drug compliance. DISCUSSIONS: The SLOW-HF trial is a prospective, randomized, open-label, phase-IV, multicenter study to evaluate the therapeutic efficacy of carvedilol-SR compared to carvedilol-IR in HFrEF patients. If carvedilol-SR proves to be non-inferior to carvedilol-IR, a once-daily prescription of carvedilol may be recommended for patients with HFrEF. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03209180 . Registered on 6 July 2017.

Avaliação da função diastólica do ventrículo esquerdo na miocardiopatia chagásica em três etapas de tratamento da insuficiência cardíaca: convencional, otimizada e associada ao emprego de carvedilol / Assessment of left ventricular diastolic function in Chagas' cardiomyopathy in three stages of heart failure treatment: conventional, optimized and associated with the use of carvedilol

A doença de Chagas é um dos principais problemas de saúde pública na América Latina. A cardiopatia crônica constitui a manifestação clínicamais importante da doença, e seu prognóstico depende tanto da funçãosistólica quanto diastólica do VE. Devido à carência de ensaios clínicosutilizando inibidores do SRAA e beta-bloqueadores como tratamento dacardiopatia chagásica, pouco se sabe sobre a eficácia desses medicamentos no grupo de pacientes chagásicos. Objetivo: O objetivo desse estudo foi o de determinar a eficácia dos inibidores do SRAA e do carvedilol na melhora da disfunção diastólica em pacientes com cardiopatia chagásica crônica. Paciente e Métodos: Realizou-se um estudo prospectivo em 41 pacientes com cardiopatia chagásica crônica. Todos os pacientes foram tratados com enalapril (dose máxima de 20 mg BID) e espironolactona (25 mg MID), durante 4 mêses. Subseqüentemente, os pacientes foram randomizados para o uso de placebo (n=20) ou carvedilol (n=19) por quatro meses, dose máxima de 25 mg BID. Os desfechos analisados foram mudanças nos parâmetros de função diastólica do VE analisados pela ecocardiografia transtorácica com Doppler após o uso dos inibidores de SRAA e após o uso de carvedilol, e mudanças nos níveis séricos de BNP, usado como um marcador da pressão de enchimento do VE. Resultados: Trinta e quatro pacientes foram categorizados de acordo com o grau de disfunção diastólica, e 37 tiveram suas análises realizadas pelos métodos de DT modo-M em cores. Trinta e nove pacientes tiveram a dosagem de BNP realizada. Otimização do tratamento de IC com inibidores do SRAA associou-se a uma melhora nos parâmetros de função diastólica do VE: aumento significativo do tempo de relaxamento isovolumétrico (TRIV) (137,47 ms vs. 151,55 ms, p=0,02), aumento da velocidade da onda E relacionada à parede inferior (6,55 cm/s vs. 7,30 cm/s, p=0,03) diminuição do índice E/E relacionado à parede inferior (9,23 vs. 8,36, p=0,065), e aumento da velocidade da onda A relacionada à parede ântero-lateral (6,05 vs. 6,78, p=0,02) e parede inferior (7,49 vs.8,61; p=0,006). A velocidade de propagação diminuiu na fase I do tratamento, observando-se seu aumento no grupo carvedilol na fase II (24,31cm/s vs. 30,60 cm/s, p=0,004). Houve diminuição significativa nos níveis do BNP [95,90 vs 32,55; P=0,026] na fase I. O emprego do carvedilol foi associado a uma tendência de preservação dos parâmetros da função diastólica: observou-se redução do valor de índice sistólico de fluxo da veia pulmonar no grupo placebo (0,52 vs. 0,48, p=0,029), sem alteração no grupo carvedilol, e diminuição da onda E da parede ínfero-lateral no grupo placebo(8,4 vs. 7,4, p=0,001). Não se observaram diferenças nos níveis de BNP entre os grupos carvedilol e placebo [86,95(123,05) vs. 31,40 (184,38); p=0,525] Conclusões: No grupo de pacientes estudados com cardiopatia chagásica crônica a otimização do tratamento com enalapril e espironolactona resultou em melhora significativa da função diastólica do VE e em diminuição dos níveis de BNP, enquanto o emprego do carvedilol associou-se a uma tendência de prevenção da piora da disfunção diastólica, sem mudanças nos níveis de BNP.Palavras chave: Doença de Chagas, cardiomiopatia chagásica, função ventricular esquerda, insuficiência cardíaca

Chronic Chagas cardiomyopathy causes substantial morbidity andmortality in Latin America and its prognosis is dependent on systolic anddiastolic left ventriclar (LV) function. Whether renin-angiotensin system(RAS) inhibitors and beta-blockers are safe and beneficial in this group ofpatients has been challenged because of the lack of formal trials.Objective: The objective of this study was to determine the efficacy ofrenin-angiotensin system (RAS) inhibitors and beta-blockers in improvingdiastolic dysfunction in chronic Chagas cardiomyopathy.Methods: We conducted a double-blind, placebo-controlled, andrandomized trial in 41 patients with Trypanosoma cruzi infection andcardiomyopathy. All patients received enalapril (up-titrated to 20 mg BID)and spironolactone (25 mg QD). Subsequently, the patients were randomly assigned to receive placebo (n=20) or carvedilol up-titrated to 25 mg BID (n=19). The end points were changes in LV diastolic function parameters evaluated by transthoracic Doppler echocardiography after RAS inhibition and that after the addition of carvedilol, and change in brain natriuretic peptide (BNP) levels, used as a surrogate marker of LV filling pressure. Results: Optimization of RAS inhibition was safe and associated with improvement in LV diastolic function parameters: isovolumic relaxation time (137.47 ms vs. 151.55 ms, p=0.02), increase of inferior wall E velocity (6.55 cm/s vs. 7.30 cm/s, p=0.03), decrease of inferior E/E index (9.23 vs. 8.36, p=0.065), and increase of antero-lateral wall A (6.05 vs. 6.78, p=0.02). BNP levels decreased significantly [95.90 vs 32.55; p=0.026]. Treatment with carvedilol was associated with a trend toward a preservation of diastolic parameters: decrease in systolic pulmonary venous flow index (0.52 vs. 0.48, p=0.029), and a decrease in inferolateral wall E velocity in placebo group (6.55 cm/s vs. 7.30 cm/s, p=0.03), both not observed in the carvedilol group. LV flow propagation velocity decreased in the first stage of treatment and increased after carvedilol association (24.31cm/s vs. 30.60 cm/s, p=0.004). There was no significant change in BNP levels [86.95 (123.05) vs. 31.40 (184.38); p=0.525]. Conclusions: In patients with chronic Chagas cardiomyopathy,optimizatin of treatment with enalapril and spironolactone was associated with significant benefits in LV diastolic cardiac function and a decrease of BNP levels, and subsequent addition of carvedilol was associated with a trend toward a prevention of worsening of diastolic dysfunction, without changes in BNP levels. Key Words: diastolic function, heart failure, Chagas cardiomyopathy, brain natriuretic peptide, echocardiography