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Background Angiotensin II type 1 receptor blockers have favourable effects on haemodynamic measurements, neurohumoral activity, and left-ventricular remodelling when added to angiotensin-converting-enzyme (ACE) inhibitors in patients with chronic heart failure (CHF). We aimed to find out whether these drugs improve clinical outcome. Methods Between March, 1999, and November, 1999, we enrolled 2548 patients with New York Heart Association functional class II--IV CHF and left-ventricular ejection fraction 40% or lower, and who were being treated with ACE inhibitors. We randomly assigned patients candesartan (n=1276, target dose 32 mg once daily) or placebo (n=1272). At baseline, 55% of patients were also treated with blockers and 17% with spironolactone. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was done by intention to treat. Findings The median follow-up was 41 months. 483 (38%) patients in the candesartan group and 538 (42%) in the placebo group experienced the primary outcome (unadjusted hazard ratio 0.85 [95% CI 0.75--0.96], p=0.011; covariate adjusted p=0.010). Candesartan reduced each of the components of the primary outcome significantly, as well as the total number of hospital admissions for CHF. The benefits of candesartan were similar in all predefined subgroups, including patients receiving baseline blocker treatment. Interpretation The addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients with CHF and reduced left-ventricular ejection fraction. [ABSTRACT FROM AUTHOR]

Background Half of patients with chronic heart failure (CHF) have preserved left-ventricular ejection fraction (LVEF), but few treatments have specifically been assessed in such patients. In previous studies of patients with CHF and low LVEF or vascular disease and preserved LVEF, inhibition of the renin-angiotensin system is beneficial. We investigated the effect of addition of an angiotensin-receptor blocker to current treatments. Methods Between March, 1999, and July, 2000, we randomly assigned 3023 patients candesartan (n=1514, target dose 32 mg once daily) or matching placebo (n=1509). Patients had New York Heart Association functional class II--IV CHF and LVEF higher than 40%. The primary outcome was cardiovascular death or admission to hospital for CHF. Anaysis was done by intention to treat. Findings Median follow-up was 36.6 months. 333 (22%) patients in the candesartan and 366 (24%) in the placebo group experienced the primary outcome (unadjusted hazard ratio 0.89 [95% CI 0.77--1.03], p=0.118; covariate adjusted 0.86 [0.74--1.0], p=0.051). Cardiovascular death did not differ between groups (170 vs 170), but fewer patients in the candesartan group than in the placebo group were admitted to hospital for CHF once (230 vs 279, p=0.017) or multiple times. Composite outcomes that included non-fatal myocardial infarction and non-fatal stroke showed similar results to the primary composite (388 vs 429; unadjusted 0.88 [0.77--1.01], p=0.078; covariate adjusted 0.86 [0.75--0.99], p=0.037). Interpretation Candesartan has a moderate impact in preventing admissions for CHF among patients who have heart failure and LVEF higher than 40%. [ABSTRACT FROM AUTHOR]

Background Angiotensin-converting-enzyme (ACE) inhibitors improve outcome of patients with chronic heart failure (CHF). A substantial proportion of patients, however, experience no benefit from ACE inhibitors because of previous intolerance. We aimed to find out whether candesartan, an angiotensinreceptor blocker, could improve outcome in such patients not taking an ACE inhibitor. Methods Between March, 1999, and March, 2001, we enrolled 2028 patients with symptomatic heart failure and left-ventricular ejection fraction 40% or less who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg once daily) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was by intention to treat. Findings The most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%). During a median follow-up of 33.7 months, 334 (33%) of 1013 patients in the candesartan group and 406 (40%) of 1015 in the placebo group had cardiovascular death or hospital admission for CHF (unadjusted hazard ratio 0.77 [95% CI 0.67--0.89], p=0.0004; covariate adjusted 0.70 [0.60--0.81], p<0.0001). Each component of the primary outcome was reduced, as was the total number of hospital admissions for CHF. Study-drug discontinuation rates were similar in the candesartan (30%) and placebo (29%) groups. Interpretation Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors. [ABSTRACT FROM AUTHOR]

Background Patients with chronic heart failure (CHF) are at high risk of cardiovascular death and recurrent hospital admissions. We aimed to find out whether the use of an angiotensin- receptor blocker could reduce mortality and morbidity. Methods In parallel, randomised, double-blind, controlled, clinical trials we compared candesartan with placebo in three distinct populations. We studied patients with left-ventricular ejection fraction (LVEF) 40% or less who were not receiving angiotensin-converting-enzyme inhibitors because of previous intolerance or who were currently receiving angiotensinconverting- enzyme inhibitors, and patients with LVEF higher than 40%. Overall, 7601 patients (7599 with data) were randomly assigned candesartan (n=3803, titrated to 32 mg once daily) or matching placebo (n=3796), and followed up for at least 2 years. The primary outcome of the overall programme was all-cause mortality, and for all the component trials was cardiovascular death or hospital admission for CHF. Analysis was by intention to treat. Findings Median follow-up was 37.7 months. 886 (23%) patients in the candesartan and 945 (25%) in the placebo group died (unadjusted hazard ratio 0.91 [95% CI 0.83--1.00], p=0.055; covariate adjusted 0.90 [0.82--0.99], p=0.032), with fewer cardiovascular deaths (691 [18%] vs 769 [20%], unadjusted 0.88 [0.79--0.97], p=0.012; covariate adjusted 0.87 [0.78--0.96], p=0.006) and hospital admissions for CHF (757 [20%] vs 918 [24%], p<0.0001) in the candesartan group. There was no significant heterogeneity for candesartan results across the component trials. More patients discontinued candesartan than placebo because of concerns about renal function, hypotension, and hyperkalaemia. Interpretation Candesartan was generally well tolerated and significantly reduced cardiovascular deaths and hospital admissions for heart failure. Ejection fraction or treatment at baseline did not alter these effects. [ABSTRACT FROM AUTHOR]