RESUMEN
BACKGROUND: Diabetes is a risk factor for heart failure, and both conditions are increasing. Identifying treatments that prevent both conditions will be clinically important. We previously reported that candesartan (an angiotensin receptor blocker) reduces cardiovascular mortality and heart failure hospitalizations in heart failure patients (CHARM: Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity Program). METHODS AND RESULTS: We assessed the impact of candesartan versus placebo on the development of diabetes, a predefined secondary outcome in a randomized, controlled, double-blind study involving 5436 of the 7601 patients with heart failure, irrespective of ejection fraction, who did not have a diagnosis of diabetes at entry into the trial. Patients received candesartan (target of 32 mg once daily) or matching placebo for 2 to 4 years. One hundred sixty-three (6.0%) individuals in the candesartan group developed diabetes, as compared with 202 (7.4%) in the placebo group (hazard ratio [HR], 0.78 with a 95% confidence interval [CI] of 0.64 to 0.96; P=0.020). The composite end point of death or diabetes occurred in 692 (25.2%) and 779 (28.6%), respectively, in the candesartan and placebo groups (HR, 0.86; 95% CI, 0.78 to 0.95; P=0.004). The results were not statistically heterogeneous in the various subgroups examined, although the apparent magnitude of benefit appeared to be smaller among those treated concomitantly with angiotensin-converting enzyme inhibitors at trial entry (HR, 0.88; 95% CI, 0.65 to 1.20) compared with those not receiving these drugs (HR, 0.71; 95% CI, 0.53 to 0.93; P for heterogeneity, 0.28). CONCLUSIONS: The angiotensin receptor blocker candesartan appears to prevent diabetes in heart failure patients, suggesting that the renin-angiotensin axis is implicated in glucose regulation.
Asunto(s)
Bencimidazoles/farmacología , Diabetes Mellitus Tipo 2/prevención & control , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Tetrazoles/farmacología , Adulto , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Antihipertensivos/farmacología , Compuestos de Bifenilo , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etiología , Método Doble Ciego , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infarto del Miocardio , Sistema Renina-AngiotensinaRESUMEN
BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been shown to attenuate left ventricular (LV) enlargement in association with reducing mortality after myocardial infarction (MI). Preclinical data suggest that angiotensin receptor blockers (ARBs) may have similar structural and functional effects after MI. The Valsartan in Acute Myocardial Infarction (VALIANT) Echo study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with captopril, could attenuate progressive LV enlargement or improve LV ejection fraction to a greater extent than captopril alone. METHODS AND RESULTS: Six hundred ten patients enrolled in the main VALIANT study who experienced MI and evidence of LV dysfunction, heart failure, or both were enrolled in the VALIANT Echo study. Patients were randomized to receive valsartan 160 mg PO BID, captopril 50 mg PO TID, or valsartan 80 mg PO BID plus captopril 50 mg PO TID between 1 and 10 days after MI. Six hundred three patients had echocardiograms of sufficient quality for quantitative analysis. Echocardiograms were digitized, and endocardial borders were traced manually from 2 short-axis and 2 apical views. Ventricular volumes, ejection fractions, combined areas, and infarct segment length were measured, and changes in echocardiographic measures from baseline to 20 months were compared between treatment groups. Baseline clinical and echocardiographic characteristics were similar in the 3 treatment arms. The changes from baseline to 20 months in all echocardiographic parameters were similar in all 3 treatment arms. Baseline echocardiographic measures of ejection fraction, end-diastolic volume, and infarct segment length were highly predictive of outcomes including total mortality, death or hospitalization for heart failure, or death or any cardiovascular event (heart failure, MI, stroke, resuscitated sudden death), even after adjustment for known covariates. CONCLUSIONS: Treatment with the ACE inhibitor captopril, valsartan, or the combination of captopril plus valsartan resulted in similar changes in cardiac volume, ejection fraction, and infarct segment length between baseline and 20 months after MI. Baseline echocardiographic measures were powerfully and independently predictive of all major outcomes.
Asunto(s)
Captopril/farmacología , Ventrículos Cardíacos/efectos de los fármacos , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Infarto del Miocardio/tratamiento farmacológico , Tetrazoles/farmacología , Valina/análogos & derivados , Disfunción Ventricular Izquierda/tratamiento farmacológico , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Captopril/administración & dosificación , Quimioterapia Combinada , Electrocardiografía , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Pronóstico , Volumen Sistólico/efectos de los fármacos , Tetrazoles/administración & dosificación , Resultado del Tratamiento , Valina/administración & dosificación , Valina/farmacología , ValsartánRESUMEN
BACKGROUND: Previous prospective outcome studies of statins have not provided any guidance on benefit-risk in patients with heart failure. AIM: The primary objective is to determine whether rosuvastatin (10 mg) reduces the combined endpoint of cardiovascular mortality, non-fatal myocardial infarction or non-fatal stroke (time to first event). The first secondary endpoint is all-cause mortality. METHODS: CORONA is a randomized, double-blind, placebo-controlled trial. Briefly, men and women, aged > or =60 years with chronic symptomatic systolic heart failure of ischemic aetiology and ejection fraction < or =0.40 (NYHA class III and IV) or < or =0.35 (NYHA class II) were eligible if they were not using or in need of cholesterol lowering drugs. RESULTS: Mean age was 73 years (n=5016; 24% women), with 37% in NYHA II and 62% in NYHA III, ejection fraction 0.31, total cholesterol 5.2 mmol/L. Sixty percent have a history of myocardial infarction, 63% hypertension, and 30% diabetes. Patients are well treated for heart failure with 90% on loop or thiazide diuretics, 42% aldosterone antagonists, 91% ACE inhibitor or AT-I blocker, 75% beta-blockers, and 32% digitalis. CONCLUSION: CORONA is important for three main reasons: (1) A positive result is very important because of the high risk of the population studied, the increasing prevalence of elderly patients with chronic symptomatic systolic heart failure in our society, and the health economic issues involved. (2) If negative, new mechanistic questions about heart failure have to be raised. (3) If neutral we can avoid unnecessary polypharmacy.
Asunto(s)
Fluorobencenos/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/mortalidad , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Factores de Edad , Anciano , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/diagnóstico , Humanos , Hipercolesterolemia/diagnóstico , Cooperación Internacional , Masculino , Persona de Mediana Edad , Probabilidad , Estudios Prospectivos , Medición de Riesgo , Rosuvastatina Cálcica , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: The VALsartan In Acute myocardial iNfarcTion (VALIANT) trial compared outcomes with: (1) angiotensin-converting enzyme inhibition (ACEI) with the reference agent captopril; (2) angiotensin-receptor blockade (ARB) with valsartan; or (3) both in patients with heart failure (HF) and/or left ventricular systolic dysfunction (LVSD) after myocardial infarction (MI). AIMS: a goal of this active-control trial was to simulate conditions that would lead current practitioners to use ACEIs. Thus, we compared characteristics of VALIANT patients with those of patients in placebo-controlled trials that established ACEIs as standard treatment. METHODS AND RESULTS: We collected demographic, clinical, medication and imaging information from 14703 patients in 24 countries. This high-risk population was a median 65.8 years old, and 31.1% were female. Most (51.8%) showed imaging evidence of LVSD at enrollment. Most (72%) had Killip class>/=II HF. Patients received evidence-based therapies at rates similar to those of contemporary MI trials and at an improved rate compared with prior placebo-controlled ACEI trials. CONCLUSION: VALIANT represents the largest globally representative cohort enrolled with HF and/or LVSD after MI. Patients were similar to those in placebo-controlled ACEI trials while reflecting improvements in evidence-based care. With enrollment complete, VALIANT is poised to define the optimal strategy for renin-angiotensin system blockade after MI to improve cardiovascular outcomes.