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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., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Background: Increased excretion of albumin in urine might be a marker of the various pathophysiological changes that arise in patients with heart failure. Therefore our aim was to assess the prevalence and prognostic value of a spot urinary albumin to creatinine ratio (UACR) in patients with heart failure., Methods: UACR was measured at baseline and during follow-up of 2310 patients in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Programme. The prevalence of microalbuminuria and macroalbuminuria, and the predictive value of UACR for the primary composite outcome of each CHARM study--ie, death from cardiovascular causes or admission to hospital with worsening heart failure--and death from any cause were assessed., Findings: 1349 (58%) patients had a normal UACR, 704 (30%) had microalbuminuria, and 257 (11%) had macroalbuminuria. The prevalence of increased UACR was similar in patients with reduced and preserved left ventricular ejection fractions. Patients with an increased UACR were older, had more cardiovascular comorbidity, worse renal function, and a higher prevalence of diabetes mellitus than did those with normoalbuminuria. However, a high prevalence of increased UACR was still noted among patients without diabetes, hypertension, or renal dysfunction. Elevated UACR was associated with increased risk of the composite outcome and death even after adjustment for other prognostic variables including renal function, diabetes, and haemoglobin A1c. The adjusted hazard ratio (HR) for the composite outcome in patients with microalbuminuria versus normoalbuminuria was 1.43 (95% CI 1.21-1.69; p<0.0001) and for macroalbuminuria versus normoalbuminuria was 1.75 (1.39-2.20; p<0.0001). The adjusted values for death were 1.62 (1.32-1.99; p<0.0001) for microalbuminuria versus normoalbuminuria, and 1.76 (1.32-2.35; p=0.0001) for macroalbuminuria versus normoalbuminuria. Treatment with candesartan did not reduce or prevent the development of excessive excretion of urinary albumin., Interpretation: Increased UACR is a powerful and independent predictor of prognosis in heart failure., Funding: AstraZeneca.

The Trial of Preventing Hypertension (TROPHY) demonstrated the feasibility of possibly reducing the incidence of hypertension with the angiotensin receptor blocker candesartan compared with placebo. The long-term benefits of pharmacologic therapy in high-normal blood pressure, or prehypertension are not known, and the long-term effect on health-related quality of life (HRQL) has not been determined. An analysis of covariance model was used to assess treatment differences from baseline in the HRQL scores using Short Form (SF)-36, and component measures at subsequent visits. Of the 809 randomized patients, 734 had both baseline and > or =1 HRQL follow-up assessment: 95% (379 of 397) of patients receiving candesartan and 91% (355 of 388) of patients receiving placebo. There were no statistically significant between-group differences in least-squares mean physical component survey and mental component survey scores or the individual scales at each scheduled visit relative to baseline values (P >.05). In TROPHY, patients with prehypertension had relatively high baseline HRQL, and HRQL was maintained with the angiotensin receptor blocker candesartan over both the 2-year treatment period and a total 4-year trial period.

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.