ANTECEDENTES: La insuficiencia cardíaca crónica (ICC) es una carga creciente a la asistencia sanitaria. El tratamiento farmacológico con inhibidores de la enzima convertidora de angiotensina (IECA) y los bloqueadores beta mejora la supervivencia y reducir las hospitalizaciones en pacientes con fracción de eyección ventricular izquierda baja (FEVI). A pesar de estas terapias, la morbilidad y mortalidad sigue siendo problemática. Por otra parte, 30% a 50% de los pacientes con CHF tiene una FEVI conservada. No se sabe si los tratamientos son de beneficio en este grupo.
DISEÑO: El candesartán en insuficiencia cardiaca-Evaluación de la reducción de la mortalidad y morbilidad (CHARM) es un programa diseñado investigar la utilidad clínica de la angiotensina de acción prolongada de tipo II bloqueador de receptor 1, candesartán cilexetilo, en un amplio espectro de pacientes con cardiaca sintomática fracaso. Los pacientes con disfunción sistólica, tolerante o intolerante a un inhibidor de la ECA, y los pacientes con función sistólica conservada se incluyen. Específicamente, el programa CHARM consta de 3 paralelo, estudios independientes, controlados con placebo en pacientes con (1) la FEVI menor o igual a 40%, tratada inhibidor de la ECA (n = 2300); (2) la FEVI menor o igual a 40%, inhibidor de la ECA intolerantes (n = 1700); (3) FEVI mayor que 40%, no tratada con inhibidores de la ECA (n = 2500). se combinarán los 3 estudios para evaluar el efecto de candesartán cilexetilo en la mortalidad por todas las causas en el amplio espectro de la insuficiencia cardiaca sintomática. El objetivo principal en cada ensayo es evaluar los efectos sobre el criterio de valoración combinado de mortalidad cardiovascular o la hospitalización por ICC. Otros objetivos incluyen los efectos sobre el infarto de miocardio, hospitalización por todas las causas, y la utilización de recursos. CHARM se pretende asignar al azar a 6.500 pacientes con insuficiencia cardíaca sintomática de 26 países de Europa, Estados Unidos, Canadá, África del Sur y Australia. El programa CHARM comenzó a reclutar pacientes para marzo de 1999. El periodo de seguimiento es de un mínimo de 2 años. Se espera que el estudio para terminar en el tercer trimestre de 2002.
ANTECEDENTES: Los pacientes con insuficiencia cardíaca crónica (ICC) tienen un alto riesgo de muerte cardiovascular y los ingresos recurrentes del hospital. El objetivo fue determinar si el uso de un bloqueador del receptor de angiotensina podría reducir la mortalidad y la morbilidad.
MÉTODOS: En paralelos, aleatorizados, doble ciego, ensayos clínicos controlados, se comparó candesartán con placebo en tres poblaciones distintas. Se estudiaron pacientes con fracción de eyección del ventrículo izquierdo (FEVI) 40% o menos que no estaban recibiendo inhibidores de la enzima convertidora de la angiotensina debido a la intolerancia previa o que estaban recibiendo convertidora de la angiotensina-inhibidores de la enzima, y los pacientes con fracción de eyección superior al 40% . En general, 7601 pacientes (7599 con los datos) fueron asignados al azar candesartán (n = 3803, ajustada a 32 mg una vez al día) o placebo (n = 3796), y un seguimiento durante al menos 2 años. El resultado primario del programa global fue de mortalidad por cualquier causa, y para todos los ensayos de los componentes fue la muerte cardiovascular u hospitalización por ICC. El análisis fue por intención de tratar.
RESULTADOS: La mediana de seguimiento fue de 37,7 meses. 886 (23%) pacientes en el candesartán y 945 (25%) en el grupo placebo murieron (razón de riesgo ajustada 0.91 [IC 95% 0,83-1,00], p = 0,055; covariable ajustada 0,90 [0,82-0,99], p = 0,032 ), con un menor número de muertes de origen cardiovascular (691 [18%] frente a 769 [20%], no ajustados 0,88 [0,79-0,97], p = 0,012; covariable ajustada 0,87 [0,78-0,96], p = 0,006) y los ingresos hospitalarios por ICC ( 757 [20%] frente a 918 [24%], p <0,0001) en el grupo de candesartán. No hubo heterogeneidad significativa para los resultados de candesartán a través de los ensayos de componentes. Más pacientes abandonaron candesartán que con placebo debido a las preocupaciones acerca de la función renal, hipotensión y la hiperpotasemia.
INTERPRETACIÓN: El candesartán fue generalmente bien tolerado y redujo significativamente la mortalidad por enfermedades cardiovasculares y las hospitalizaciones por insuficiencia cardiaca. La fracción de eyección o el tratamiento al inicio del estudio no alteró estos efectos.
OBJETIVOS: Describir las características clínicas y el tratamiento contemporáneo de un amplio espectro de pacientes con insuficiencia cardíaca crónica (ICC) asignó al azar en el candesartán en Insuficiencia cardíaca-Evaluación de la Reducción en el programa de morbilidad (CHARM) Mortalidad y, que consta de tres estudios componentes compararon con placebo a candesartán.
Métodos y resultados: CHARM alternativo, encanto añadido y el encanto de conservas inscribieron 2028 pacientes intolerantes baja fracción de eyección ventricular izquierda (FEVI) inhibidores de la ECA, 2.548 inhibidor de la ECA FEVI baja trataron a los pacientes y 3025 pacientes conservan la FEVI, respectivamente. Los pacientes en CHARM preservada eran más a menudo femenina. La proporción de mujeres en CHARM en conserva fue del 40% frente al 32% en CHARM Alternativa y 21% en el encanto añadido. Los pacientes en CHARM en conserva también fueron más a menudo hipertensos que en los otros dos ensayos (64% vs. 50% y 48%, respectivamente). Los síntomas y signos (con la excepción de un tercer ruido cardíaco) fueron similares en los tres grupos de pacientes. Los bloqueadores beta se utilizan en más de la mitad de los pacientes en los tres grupos. Digoxina y espironolactona se utilizan con menos frecuencia y los antagonistas del calcio con mayor frecuencia en CHARM preservado. La espironolactona se utiliza con mayor frecuencia en CHARM alternativo, es decir, en pacientes que no toleran inhibidores de la ECA.
CONCLUSIONES: El Programa CHARM ofrece la mayor y más detallada respecto a la fecha de los pacientes de bajo y FEVI conservada CHF. También se describen las causas de intolerancia a IECA en una gran cohorte de pacientes y el otro trato que reciben estos pacientes.
ANTECEDENTES: La mitad de los pacientes con insuficiencia cardíaca crónica (ICC) se han conservado a la izquierda, fracción de eyección ventricular izquierda (FEVI), pero pocos tratamientos han sido específicamente evaluados en estos pacientes. En estudios previos de pacientes con ICC y FEVI baja o enfermedad vascular y la FEVI conservada, la inhibición del sistema renina-angiotensina es beneficioso. Se investigó el efecto de la adición de un bloqueador del receptor de angiotensina a los tratamientos actuales. MÉTODOS: Entre marzo de 1999 y julio de 2000, se asignó aleatoriamente a 3.023 pacientes con candesartán (n = 1514, objetivo de dosis 32 mg una vez al día) o placebo (n = 1509). Los pacientes tenían New York Heart Association en clase funcional II-IV de la ICC y FEVI superior al 40%. El resultado primario fue muerte cardiovascular u hospitalización por insuficiencia cardíaca congestiva. El análisis se realizó por intención de tratar. RESULTADOS: La mediana de seguimiento fue de 36,6 meses. 333 (22%) pacientes en el candesartán y 366 (24%) en el grupo placebo experimentaron el resultado primario (razón de riesgo ajustada 0.89 [IC 95% 0,77-1,03], p = 0,118; covariable ajustada 0.86 [0.74-1.0], p = 0,051). La muerte cardiovascular no difirió entre los grupos (170 vs 170), pero un menor número de pacientes en el grupo tratado con candesartán que en el grupo de placebo fueron hospitalizados por ICC, una vez (230 vs 279, p = 0,017) o varias veces. Los resultados de compuestos que incluyen no fatal infarto de miocardio y accidente cerebrovascular no fatal, mostró resultados similares al compuesto principal (388 vs 429; no ajustada 0,88 [0,77-1,01], p = 0,078; covariable ajustada 0,86 [0,75-0,99], p = 0,037 ). INTERPRETACIÓN: El candesartán tiene un impacto moderado en la prevención de hospitalizaciones por ICC en pacientes con insuficiencia cardiaca y fracción de eyección superior al 40%.
ANTECEDENTES: Los pacientes con insuficiencia cardíaca sintomática crónica (ICC) y la fracción de eyección ventricular izquierda reducida (FEVI) tienen un alto riesgo de muerte y hospitalización por empeoramiento CHF pesar de las terapias con la enzima convertidora de angiotensina (IECA), bloqueadores beta, e incluso un antagonista de la aldosterona. Para determinar si el bloqueador del receptor de angiotensina (ARB) candesartán reduce la mortalidad cardiovascular, la morbilidad y mortalidad por cualquier causa en pacientes con ICC y FEVI deprimida, un análisis pre-especificado del candesartán combinado en la Evaluación de Insuficiencia Cardiaca de la reducción de la mortalidad y la morbilidad (CHARM ) se llevó a cabo ensayos de baja FEVI. CHARM es un estudio doble ciego, multicéntrico, controlado con placebo,, programa de ensayo aleatorio, internacional.
Métodos y resultados: New York Heart Association (NYHA) clase II a través de pacientes con ICC IV con una FEVI <o = 40% fueron asignados al azar al candesartán o placebo en 2 ensayos paralelos complementarios (CHARM-Alternativo, para los pacientes que no toleran los inhibidores de la ECA, y CHARM-Añadido, para los pacientes que recibían inhibidores de la ECA). La mortalidad y la morbilidad se determinaron en 4.576 pacientes de baja FEVI (2289 candesartán y 2287 con placebo), valoradas según la tolerancia a una dosis objetivo de 32 mg una vez al día, y se observaron durante 2 a 4 años (mediana, 40 meses). El resultado primario (tiempo hasta el primer evento por intención de tratar) fue muerte cardiovascular u hospitalización CHF para cada ensayo, con la mortalidad por cualquier causa un punto final secundario en el análisis conjunto de los ensayos de baja FEVI. De los pacientes en el grupo de candesartán, 817 (35,7%) experimentaron muerte cardiovascular o una hospitalización por ICC en comparación con 944 (41,3%) en el grupo placebo (HR 0,82; IC 95% 0,74-0,90; p <0,001) con un menor riesgo para ambas muertes cardiovasculares (521 [22,8%] frente a 599 [26,2%]; HR [IC 95% 0,75 a 0,95] 0,84; P = 0,005) y las hospitalizaciones CHF (516 [22,5%] frente a 642 [28,1%]; HR 0,76 [IC 95% 0,68-0,85]; p <0,001). Es importante señalar que todas las causas de mortalidad también se redujo significativamente por candesartán (642 [28,0%] frente a 708 [31,0%]; HR [IC del 95%: 0,79 a 0,98] 0,88; P = 0,018). No heterogeneidad significativa para los efectos beneficiosos de candesartán se encontró en todos los subgrupos pre-especificados y posteriormente identificadas incluyendo el tratamiento con inhibidores de la ECA, bloqueadores beta, un antagonista de la aldosterona, o sus combinaciones. El fármaco del estudio se suspendió debido a los efectos adversos por el 23,1% de los pacientes en el grupo de candesartán y el 18,8% en el grupo placebo; las razones incluyen aumento de la creatinina (7,1% versus 3,5%), hipotensión (4,2% versus 2,1%), y la hiperpotasemia (2,8% versus 0,5%), respectivamente (todos P <0,001).
CONCLUSIONES: El candesartán reduce significativamente mortalidad por cualquier causa, muerte cardiovascular y las hospitalizaciones por insuficiencia cardiaca en pacientes con ICC y FEVI <o = 40% cuando se añade a las terapias estándar, incluyendo inhibidores de la ECA, bloqueadores beta, y un antagonista de la aldosterona. El monitoreo rutinario de la presión arterial, creatinina sérica, y el potasio sérico se justifica.
BACKGROUND: Patients with heart failure are at increased risk of sudden death and death attributed to progressive pump failure. We assessed the effect of candesartan on cause-specific mortality in patients enrolled in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program.
METHODS AND RESULTS: The CHARM program consisted of 3 component trials that enrolled patients with symptomatic heart failure: CHARM-Alternative (n=2028; LVEF<=40% [corrected] and ACE intolerant), CHARM-Added (n=2548; LVEF<=40%, [corrected] already on ACE inhibitors), and CHARM-Preserved (n=3023; LVEF >40%). Patients were randomized to candesartan, titrated to 32 mg QD, or placebo and were followed up for a median of 37.7 months. All deaths were reviewed by a blinded adjudication committee and categorized according to prespecified definitions on the basis of a narrative and source documentation. The number and rate of deaths by cause were calculated for each of the component trials and the overall program. Of all the patients, 8.5% died suddenly, and 6.2% died of progressive heart failure. Candesartan reduced both sudden death (HR 0.85 [0.73 to 0.99], P=0.036) and death from worsening heart failure (HR 0.78 [0.65 to 0.94], P=0.008). These reductions were most apparent in the patients with LVEF<=40% [corrected].
CONCLUSIONS: Candesartan reduced sudden death and death from worsening heart failure in patients with symptomatic heart failure, although this reduction was most apparent in patients with systolic dysfunction.
BACKGROUND: Decreased renal function has been found to be an independent risk factor for cardiovascular outcomes in patients with chronic heart failure (CHF) with markedly reduced left ventricular ejection fraction (LVEF). The aim of this analysis was to evaluate the prognostic importance of renal function in a broader spectrum of patients with CHF.
METHODS AND RESULTS: The Candesartan in Heart Failure:Assessment of Reduction in Mortality and Morbidity (CHARM) program consisted of three component trials that enrolled patients with symptomatic CHF, based on use of ACE inhibitors and reduced (< or =40%) or preserved LVEF (>40%). Entry baseline creatinine was required to be below 3.0 mg/dL (265 micromol/L). Routine baseline serum creatinine assessments were done in 2680 North American patients. An analysis of the estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease equation and LVEF on risk of cardiovascular death or hospitalization for heart failure, as well as on all-cause mortality, was conducted on these 2680 patients. The proportion of patients with eGFR <60 mL/min per 1.73 m2 was 36.0%; 42.6% for CHARM-Alternative, 33.0% for CHARM-Added, and 34.7% for CHARM-Preserved. During the median follow-up of 34.4 months (total 6493 person-years), the primary outcome of cardiovascular death or hospital admission for worsening CHF occurred in 950 of 2680 subjects. Both reduced eGFR and lower LVEF were found to be significant independent predictors of worse outcome after adjustment for major confounding baseline clinical characteristics. The risk for cardiovascular death or hospitalization for worsening CHF as well as the risk for all-cause mortality increased significantly below an eGFR of 60 mL/min per 1.73 m2 (adjusted hazard ratio, 1.54 for 45 to 60 mL/min per 1.73 m2 and 1.86 for <45 mL/min per 1.73 m2 for the primary outcome, both P<0.001, and hazard ratio of 1.50, P=0.006, and 1.91, P=0.001, respectively, for all-cause mortality). The prognostic value of eGFR was not significantly different among the three component trials. There was no significant interaction between renal function, the effect of candesartan, and clinical outcome.
CONCLUSIONS: Impaired renal function is independently associated with heightened risk for death, cardiovascular death, and hospitalization for heart failure in patients with CHF with both preserved as well as reduced LVEF. There was no evidence that the beneficial effect of candesartan was modified by baseline eGFR.
AIMS: More treatments are needed to improve clinical outcomes in chronic heart failure (HF). It is, however, important that treatments for a condition as common as HF are affordable. We have carried out a prospective economic analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme.
METHODS AND RESULTS: Patients with NYHA class II-IV HF and LVEF < or =0.40 were randomized to CHARM-Alternative if intolerant of an ACE-inhibitor or to CHARM-Added if taking an ACE-inhibitor. Patients with a LVEF >0.40 were randomized in CHARM-Preserved. Each trial compared the effect of candesartan to placebo on the primary outcome of cardiovascular death or HF hospitalization. Detailed information was prospectively collected on hospital admissions, procedures/operations and drugs. A cost-consequence analysis was performed for France, Germany and the UK for CHARM-Overall and a cost-effectiveness analysis for the low LVEF trials. The cost of candesartan was substantially offset by a reduction in hospital admissions, especially for HF. In the cost-consequence analysis, candesartan was cost-saving in most scenarios for CHARM-Alternative and Added but the marginal annual net cost per patient was upto 372 euros per year in CHARM-Preserved, in which candesartan did not reduce the primary outcome significantly. In the cost-effectiveness analysis of patients with a LVEF < or = 0.40, candesartan was cost-saving in some scenarios and in the others the maximum cost per life year gained was 3881 euros.
CONCLUSION: Candesartan improves functional class, reduces the risk of hospital admission, and increases survival in patients with a HF and a LVEF < or =0.40 at an acceptable cost.
BACKGROUND: Randomized clinical trials in patients with chronic heart failure and reduced left ventricular ejection fraction (LVEF) have demonstrated the life-saving and symptomatic benefits of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and, in more selected patients, spironolactone. Despite these major advancements, the prevalence of heart failure continues to increase mainly as a consequence of aging populations. The development of angiotensin II type 1 receptor blockers (ARBs) provides a pharmacologically distinct mechanism of inhibiting the renin-angiotensin-aldosterone system. ARBs offer the potential to produce further clinical improvements for patients with heart failure above and beyond ACE inhibitors, as well as an alternative for those intolerant to an ACE inhibitor. METHODS: The Candesartan in Heart failure--Assessment of Reduction in Mortality and morbidity (CHARM) programme was designed as three parallel, randomized, double-blind, placebo-controlled clinical trials comparing candesartan with placebo in three different but complementary populations of patients with symptomatic heart failure. RESULTS: In patients with intolerance to an ACE inhibitor and an LVEF of 40% or less (the CHARM-Alternative trial), candesartan reduced cardiovascular mortality and hospitalizations for heart failure by 23% (P < 0.001). In patients with an LVEF of 40% or less treated with an ACE inhibitor (the CHARM-Added trial), candesartan reduced cardiovascular death and hospitalization for chronic heart failure by 15% (P = 0.011). In patients with a LVEF greater than 40% (the CHARM-Preserved trial), hospitalizations for heart failure and new-onset diabetes were significantly reduced. CONCLUSION: The CHARM programme, together with evidence from mechanistic studies and from other large trials with ARBs, constitutes a firm basis for including an ARB in the therapeutic arsenal in the treatment for chronic heart failure.
<b>OBJECTIVES: </b>We tested the hypothesis that diastolic dysfunction (DD) was an important predictor of cardiovascular (CV) death or heart failure (HF) hospitalization in a subset of patients (ejection fraction [EF] >40%) in the CHARM-Preserved study. <b>BACKGROUND: </b>More than 40% of hospitalized patients with HF have preserved systolic function (HF-PSF), suggesting that DD may be responsible for the clinical manifestations of HF. <b>METHODS: </b>Patients underwent Doppler echocardiographic examination that included assessment of pulmonary venous flow or determination of plasma NT-pro-brain natriuretic peptide > or months after randomization to candesartan or placebo. The patients were classified into 1 of 4 diastolic function groups: normal, relaxation abnormality (mild dysfunction), pseudonormal (moderate dysfunction), and restrictive (severe dysfunction). <b>RESULTS: </b>There were 312 patients in the study, mean age was 66 +/- 11 years, EF was 50 +/- 10%, and 34% were women. The median follow-up was 18.7 months. Diastolic dysfunction was found in 67% of classified patients (n = 293), and moderate and severe DD were identified in 44%. Moderate and severe DD had a poor outcome compared with normal and mild DD (18% vs. 5%, p < 0.01). Diastolic dysfunction, age, diabetes, previous HF, and atrial fibrillation were univariate predictors of outcome. In multivariate analysis, moderate (hazard ratio [HR] 3.7, 95% confidence interval [CI] 1.2 to 11.1) and severe DD (HR 5.7, 95% CI 1.4 to 24.0) remained the only independent predictors (p = 0.003). <b>CONCLUSIONS: </b>Objective evidence of DD was found in two-thirds of HF-PSF patients. Moderate and severe DD, which were found in less than one-half of the patients, were important predictors of adverse outcome. The results demonstrate the prognostic significance and need for objective evidence of DD in HF-PSF patients.
BACKGROUND: Bundle branch block (BBB) is a powerful independent predictor of cardiovascular mortality in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). The prognostic implications in HF with preserved systolic function (HF-PSF) are less well understood.
METHODS: The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme randomised 7599 patients with symptomatic HF to receive candesartan or placebo. The primary outcome comprised cardiovascular death or HF hospitalisation. The relative risk conveyed by BBB relative to a normal electrocardiogram was examined.
RESULTS: The prevalence of BBB was significantly lower in patients with preserved compared with reduced systolic function (CHARM-Preserved 14.4%, Alternative 29.6%, Added 30.5%), p<0.0001. Overall, the adjusted hazard ratio for the primary outcome was 1.48 (95% confidence interval 1.22-1.78), p<0.0001, reflecting increased risk in patients with reduced LVEF (1.72 [1.28-2.31], p=0.0003). The apparently more modest risk among patients with HF-PSF was significant in unadjusted (1.80 [1.37-2.37], p<0.0001) but not adjusted analysis (1.16 [0.88-1.54], p=0.2897). However, no formal statistical difference was observed between the two cohorts, and interpretation is limited by the unknown prevalence of left and right BBB morphologies in each. Comparing BBB presence with absence yielded qualitatively similar results.
CONCLUSION: The simple clinical finding of BBB is a powerful independent predictor of worse clinical outcomes in patients with HF and reduced LVEF. It is less frequent, with a more modest predictive effect, in patients with preserved systolic function.
Chronic heart failure (HF) is a major cause of morbidity and mortality particularly in the elderly and a growing healthcare burden in Italy. The objective was to assess the cost-effectiveness of candesartan cilexetil, an angiotensin II type 1 receptor blocker (ARB) for the treatment of HF. A pre-specified economic evaluation was conducted on resource utilization (cardiovascular drug treatment, cardiovascular and non-cardiovascular hospital admission, cardiovascular procedures/operations) prospectively collected alongside the CHARM program, a series of parallel randomized clinical trials comparing candesartan with placebo (standard therapy) in patients with NYHA Class II-IV HF: CHARM-Alternative (LVEF < or =40% patients not receiving ACE inhibitors because of previous intolerance); CHARM-Added (LVEF < or =40% patients currently receiving ACE inhibitors); or CHARM-Preserved (LVEF > or =40% patients). The primary outcome for the component trials was the composite of cardiovascular death or worsening hospital admission for HF and of the overall program all-cause mortality. Adjunctive treatment with candesartan in CHARM-Alternative and CHARM-Added led to clinical benefits and to either cost-savings or a small additional cost, depending on the trial. The less certain clinical benefit in CHARM-Preserved was obtained at modest extra cost. The incremental cost-effectiveness ratios (ICERs) were estimated to range from euro713 per life year gained for CHARM-Alternative to dominant for CHARM-Added and the pooled reduced LVEF trials.
OBJECTIVE: The purpose of this study was to identify predictors of incident diabetes during follow-up of nondiabetic patients with chronic heart failure (CHF) in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program.
RESEARCH DESIGN AND METHODS: A total of 1,620 nondiabetic patients had full baseline datasets. We compared baseline demographic, medication, and laboratory data for patients who did or did not develop diabetes and conducted logistic regression and receiver operator characteristic curve analyses.
RESULTS: Over a median period of 2.8 years, 126 of the 1,620 patients (7.8%) developed diabetes. In multiple logistic regression analysis, the following baseline characteristics were independently associated with incident diabetes in decreasing order of significance by stepwise selection: higher A1C (odds ratio [OR] 1.78 per 1 SD increase; P < 0.0001), higher BMI (OR 1.64 per 1 SD increase; P < 0.0001), lipid-lowering therapy (OR 2.05; P = 0.0005), lower serum creatinine concentration (OR 0.68 per 1 SD increase; P = 0.0018), diuretic therapy (OR 4.81; P = 0.003), digoxin therapy (OR 1.65; P = 0.022), higher serum alanine aminotransferase concentration (OR 1.15 per 1 SD increase; P = 0.027), and lower age (OR 0.81 per 1 SD increase; P = 0.048). Using receiver operating characteristic curve analysis, A1C and BMI yielded areas under the curve of 0.723 and 0.712, respectively, increasing to 0.788 when combined. Addition of other variables independently associated with diabetes risk minimally improved prediction of diabetes.
CONCLUSIONS: In nondiabetic patients with CHF in CHARM, A1C and BMI were the strongest predictors of the development of diabetes. Other minor predictors in part reflected CHF severity or drug-associated diabetes risk. Identifying patients with CHF at risk of diabetes through simple criteria appears possible and could enable targeted preventative measures.
BACKGROUND: Conventional composite outcomes in heart failure (HF) trials, for example, time to cardiovascular death or first HF hospitalization, have recognized limitations. We propose an alternative outcome, days alive and out of hospital (DAOH), which incorporates mortality and all hospitalizations into a single measure. A refinement, the patient journey, also uses functional status (New York Heart Association [NYHA] class) measured during follow-up. The CHARM program is used to illustrate the methodology.
METHODS: CHARM randomized 7,599 patients with symptomatic HF to placebo or candesartan, with median follow-up of 38 months. We related DAOH and percent DAOH (ie, percentage of time spent alive and out of hospital) to treatment using linear regression adjusting for follow-up time.
RESULTS: Mean increase in DAOH for patients on candesartan versus placebo was 24.1 days (95% CI 9.8-38.3 days, P < .001). The corresponding mean increase in percent DAOH was 2.0% (95% CI 0.8%-3.1%, P < .001). These findings were dominated by reduced mortality (23 days) but enhanced by reduced time in hospital (1 day). Percent time spent in hospital because of HF was reduced by 0.10% (95% CI 0.04%-0.14%, P < .001). The patient journey analysis showed that patients in the candesartan group spent more follow-up time in NYHA classes I and II and less in NYHA class IV.
CONCLUSIONS: Days alive and out of hospital, especially percent DAOH, provide a valuable tool for summarizing the overall absolute treatment effect on mortality and morbidity. In future HF trials, percent DAOH can provide a useful alternative perspective on the effects of treatment.
AIMS: Heart failure is characterized by recurrent hospitalizations, but often only the first event is considered in clinical trial reports. In chronic diseases, such as heart failure, analysing all events gives a more complete picture of treatment benefit. We describe methods of analysing repeat hospitalizations, and illustrate their value in one major trial.
METHODS AND RESULTS: The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study compared candesartan with placebo in 3023 patients with heart failure and preserved systolic function. The heart failure hospitalization rates were 12.5 and 8.9 per 100 patient-years in the placebo and candesartan groups, respectively. The repeat hospitalizations were analysed using the Andersen-Gill, Poisson, and negative binomial methods. Death was incorporated into analyses by treating it as an additional event. The win ratio method and a method that jointly models hospitalizations and mortality were also considered. Using repeat events gave larger treatment benefits than time to first event analysis. The negative binomial method for the composite of recurrent heart failure hospitalizations and cardiovascular death gave a rate ratio of 0.75 [95% confidence interval (CI) 0.62-0.91, P = 0.003], whereas the hazard ratio for time to first heart failure hospitalization or cardiovascular death was 0.86 (95% CI 0.74-1.00, P = 0.050).
CONCLUSIONS: In patients with preserved EF, candesartan reduces the rate of admissions for worsening heart failure, to a greater extent than apparent from analysing only first hospitalizations. Recurrent events should be routinely incorporated into the analysis of future clinical trials in heart failure.
BACKGROUND: Hospitalization for acute heart failure (HF) is associated with high rates of subsequent mortality and readmission. We assessed the influence of the time interval between previous HF hospitalization and randomization in the Candesartan in Heart failure: Reduction in Mortality and morbidity (CHARM) trials on clinical outcomes in patients with both reduced and preserved ejection fraction.
METHODS AND RESULTS: CHARM enrolled 7599 patients with New York Heart Association class II to IV HF, of whom 5426 had a history of previous HF hospitalization. Cox proportional hazards regression models were used to assess the association between time from previous HF hospitalization and randomization and the primary outcome of cardiovascular death or unplanned admission to hospital for the management of worsening HF during a median of 36.6 months. For patients with HF and reduced or preserved ejection fraction, rates of cardiovascular mortality and HF hospitalization were higher among patients with previous HF hospitalization than those without. The risk for mortality and hospitalization varied inversely with the time interval between hospitalization and randomization. Rates were higher for patients with HF and reduced ejection fraction within each category. Event rates for those with HF with preserved ejection fraction and a HF hospitalization in the 6 months before randomization were comparable with the rate in patients with HF and reduced ejection fraction with no previous HF hospitalization.
CONCLUSIONS: Rates of cardiovascular death or HF hospitalization are greatest in those who have been previously hospitalized for HF. Independent of EF, rates of death and readmission decline as time from HF hospitalization to trial enrollment increased. Recent HF hospitalization identifies a high-risk population for future clinical trials in HF and reduced ejection fraction and HF with preserved ejection fraction.
CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00634400.
BACKGROUND: Noncardiovascular (non-CV) comorbidities may contribute to hospitalizations in patients with heart failure (HF). We examined the incidence of mortality following hospitalization for cardiovascular (CV) versus non-CV reasons in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program.
METHODS AND RESULTS: First hospitalizations for CV or non-CV reasons during the CHARM trial (N=7599) were related to subsequent risk of all-cause death using time-updated proportional hazards models. Over median 37.7 month follow-up, 2816 subjects (37.1%) were not hospitalized, 2893 (38.1%) were first hospitalized for CV reasons, and 1890 (24.9%) for non-CV reasons. The death rate (per 100 patient-years) among those not hospitalized was 2.8 compared with 17.8 after CV and 16.5 after non-CV hospitalization (both P<0.001 versus not hospitalized). Mortality at 30 days was higher after CV than non-CV hospitalization; however, among 30-day survivors of CV and non-CV hospitalization, rates of subsequent mortality were similar (14.5 versus 14.6 per 100 patient-years; P=0.62). Rates of CV hospitalization were higher for those with ejection fraction (EF) ≤40% than those with EF >40% (P<0.001), but rates of non-CV hospitalization did not vary by EF. Low EF patients had higher risk for mortality than preserved EF patients after any hospitalization, but within each EF subgroup, mortality in 30-day survivors of CV versus non-CV hospitalization was similar.
CONCLUSIONS: Non-CV hospitalization is frequent in patients with symptomatic heart failure and associated with risk of subsequent mortality similar to CV hospitalization across the spectrum of EF. These findings may have implications for developing strategies to prevent readmissions.
CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00634309 (CHARM-Added), NCT00634712 (CHARM-Preserved), NCT00634400 (CHARM-Alternative).
AIMS: We tested the hypothesis that candesartan improves outcomes in heart failure (HF) with mid-range ejection fraction [HFmrEF; ejection fraction (EF) 40-49%].
METHODS AND RESULTS: In 7598 patients enrolled in the CHARM Programme (HF across the spectrum of EF), we assessed characteristics, outcomes and treatment effect of candesartan according to EF. Patients with HFmrEF (n = 1322, 17%) were similar to those with HF with reduced EF (HFrEF; n = 4323, 57%) with respect to some characteristics, and intermediate between HFrEF and HF with preserved EF (HFpEF; n = 1953, 26%) with respect to others. Over a mean follow-up of 2.9 years, the incidence rates for the primary outcome of cardiovascular death or HF hospitalization were 15.9, 8.5 and 8.9 per 100 patient-years in HFrEF, HFmrEF and HFpEF. In adjusted analyses, the rates of the primary outcome declined with increasing EF up to 50%. For treatment effect, the incidence rates for the primary outcome for candesartan vs. placebo were 14.4 vs. 17.5 per 100 patient-years in HFrEF [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75-0.91; P < 0.001], 7.4 vs. 9.7 per 100 patient-years in HFmrEF (HR 0.76, 95% CI 0.61-0.96; P = 0.02), and 8.6 vs. 9.1 per 100 patient-years in HFpEF (HR 0.95, 95% CI 0.79-1.14; P = 0.57). For recurrent HF hospitalization, the incidence rate ratios were 0.68 in HFrEF (95% CI 0.58-0.80; P < 0.001), 0.48 in HFmrEF (95% CI 0.33-0.70; P < 0.001), and 0.78 in HFpEF (95% CI 0.59-1.03; P = 0.08). With EF as a continuous spline variable, candesartan significantly reduced the primary outcome until EF well over 50% and recurrent HF hospitalizations until EF well over 60%.
CONCLUSION: Candesartan improved outcomes in HFmrEF to a similar degree as in HFrEF. ClinicalTrials.gov: CHARM Alternative NCT00634400, CHARM Added NCT00634309, CHARM Preserved NCT00634712.
La insuficiencia cardíaca crónica (ICC) es una carga creciente a la asistencia sanitaria. El tratamiento farmacológico con inhibidores de la enzima convertidora de angiotensina (IECA) y los bloqueadores beta mejora la supervivencia y reducir las hospitalizaciones en pacientes con fracción de eyección ventricular izquierda baja (FEVI). A pesar de estas terapias, la morbilidad y mortalidad sigue siendo problemática. Por otra parte, 30% a 50% de los pacientes con CHF tiene una FEVI conservada. No se sabe si los tratamientos son de beneficio en este grupo.
DISEÑO:
El candesartán en insuficiencia cardiaca-Evaluación de la reducción de la mortalidad y morbilidad (CHARM) es un programa diseñado investigar la utilidad clínica de la angiotensina de acción prolongada de tipo II bloqueador de receptor 1, candesartán cilexetilo, en un amplio espectro de pacientes con cardiaca sintomática fracaso. Los pacientes con disfunción sistólica, tolerante o intolerante a un inhibidor de la ECA, y los pacientes con función sistólica conservada se incluyen. Específicamente, el programa CHARM consta de 3 paralelo, estudios independientes, controlados con placebo en pacientes con (1) la FEVI menor o igual a 40%, tratada inhibidor de la ECA (n = 2300); (2) la FEVI menor o igual a 40%, inhibidor de la ECA intolerantes (n = 1700); (3) FEVI mayor que 40%, no tratada con inhibidores de la ECA (n = 2500). se combinarán los 3 estudios para evaluar el efecto de candesartán cilexetilo en la mortalidad por todas las causas en el amplio espectro de la insuficiencia cardiaca sintomática. El objetivo principal en cada ensayo es evaluar los efectos sobre el criterio de valoración combinado de mortalidad cardiovascular o la hospitalización por ICC. Otros objetivos incluyen los efectos sobre el infarto de miocardio, hospitalización por todas las causas, y la utilización de recursos. CHARM se pretende asignar al azar a 6.500 pacientes con insuficiencia cardíaca sintomática de 26 países de Europa, Estados Unidos, Canadá, África del Sur y Australia. El programa CHARM comenzó a reclutar pacientes para marzo de 1999. El periodo de seguimiento es de un mínimo de 2 años. Se espera que el estudio para terminar en el tercer trimestre de 2002.
