Search

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.)

Aims: Heart failure (HF) and chronic obstructive pulmonary disease are common partners. Bronchodilators are associated with adverse cardiovascular outcomes in patients with pulmonary disease. The outcome of patients with HF prescribed bronchodilators is poorly defined., Methods and Results: The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme randomized 7599 patients with symptomatic HF to receive candesartan or placebo. The relative risk conveyed by bronchodilator therapy was examined using a multivariable Cox proportional hazards model. The prevalence of bronchodilator therapy was similar in patients with reduced and preserved systolic function (respectively, 8.7 vs. 9.2%, P = 0.46). Beta-blocker utilization was markedly lower in patients receiving bronchodilators compared with those without (overall 31.9 vs. 57.6%, P < 0.0001). Bronchodilator use was associated with increased all-cause mortality [HR 1.26 (1.09-1.45), P = 0.0015], cardiovascular death [HR 1.21 (1.03-1.42), P = 0.0216], HF hospitalization [HR 1.49 (1.29-1.72), P < 0.0001], and major adverse cardiovascular events [HR 1.32 (1.17-1.76), P < 0.0001]. The adverse outcomes were consistent in patients with reduced and preserved systolic function. No significant interaction was observed between bronchodilators and beta-blockade with respect to outcomes., Conclusion: Bronchodilator use is a powerful independent predictor of worsening HF and increased mortality in a broad spectrum of patients with HF. Whether this relates to a toxic effect of bronchodilators, underlying pulmonary disease, or both is unclear and warrants further investigation.

Aims: Although many patients with heart failure have incomplete adherence to prescribed medications, predisposing factors remain unclear. This analysis investigates factors associated with adherence, with particular emphasis on age and sex., Methods and Results: A multivariable regression analysis of 7599 heart failure patients from the CHARM trial was done to evaluate factors associated with adherence. Adherence was measured as the proportion of time patients took more than 80% of study medication. The mean age was 66 years (SD 11) and 31.5% (n = 2400) were women. Women were slightly less adherent than men (87.3 vs. 89.8%, P = 0.002), even in adjusted, multivariable models (treatment, P = 0.006; placebo P = 0.004; and overall P < 0.001). However, all-cause mortality was lower in women (21.5%) than in men (25.3%) (adjusted hazard ratio, 0.77; 95% CI, 0.69-0.86; P < 0.001), but patients with a low adherence regardless of sex had a higher mortality. Age, severity of heart failure, number of medications, and smoking status were not associated with adherence., Conclusion: Women, particularly those <75 years of age, were less likely to be adherent in this large sample of patients with symptomatic heart failure. Understanding factors associated with adherence may provide opportunities for intervention.

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.

Objectives: This study sought to investigate the efficacy and tolerability of candesartan, according to baseline blood pressure (BP), in the 4,576 patients with a low ejection fraction (EF) (or=141 mm Hg) and 4 DBP categories (or=81 mm Hg)., Results: Low SBP and DBP were associated with worse clinical outcomes. Baseline BP did not modify the effects of candesartan on clinical outcomes: the interaction p value between SBP category and treatment was 0.38 (0.22 for DBP category). For both placebo and candesartan, study drug discontinuation for adverse effects (especially hypotension) was highest in patients in the lowest baseline BP categories. However, the relative risk of discontinuation for hypotension, renal dysfunction, and hyperkalemia in the candesartan compared with placebo group was not increased in patients with a low baseline BP., Conclusions: In patients with low EF heart failure, the relative risks and benefits of candesartan treatment were similar in patients with a low BP compared to those with a higher BP.

Aims: The curiosity that leanness is associated with poor survival in patients with chronic heart failure (CHF) needs further insight by investigating the impact of weight loss on prognosis in a large sample of patients across a broad spectrum of both reduced and preserved left ventricular (LV) systolic function., Methods and Results: We investigated the change in weight over 6 months in 6933 patients in the Candesartan in Heart failure: Reduction in Mortality and morbidity (CHARM) programme, and its association with subsequent mortality (1435 deaths) over a median 32.9 months follow-up using Cox proportional hazard models to account for the impact of body mass index and other risk predictors. We then used time-updated Cox models to relate each patient's ongoing data on annual weight change to their mortality hazard. The percentage weight loss over 6 months had a highly significant monotonically increasing association with excess mortality, both for cardiovascular and for other causes of death. Patients with 5% or greater weight loss in 6 months had over a 50% increase in hazard compared with those with stable weight. Weight loss carried a particularly high risk in patients who were already lean at study entry. Findings were similar in the presence of dependent oedema, preserved or reduced LV ejection fraction, and treatment with candesartan, although weight loss was significantly less common on candesartan. The time-updated analyses revealed an even stronger link between weight loss and short-term risk of dying, i.e. risk increased more than four-fold for patients whose last recorded annual weight loss exceeded 10%. Weight gain had a more modestly increased short-term mortality risk. Weight loss accelerates in the year prior to death., Conclusions: Weight loss and leanness are important predictors of poor prognosis in CHF. Being lean and losing weight is particularly bad. The detection of weight change, and particularly weight loss, should be considered as an adverse sign prompting further evaluation.

More than 40% of patients hospitalized with heart failure have preserved left ventricular ejection fraction (HF-PLVEF) and are at high risk for cardiovascular (CV) events. The purpose of this study was to determine the value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and brain natriuretic peptide (BNP) in predicting CV outcomes in patients with HF-PLVEF. Participants with an ejection fraction >40% in the prospective CHARM Echocardiographic Substudy were included in this analysis. Plasma NT-proBNP levels were measured, and 2 cut-offs were selected prospectively at 300 pg/ml and 600 pg/ml. BNP cut-off was set at 100 pg/ml. Clinical characteristics were recorded, and systolic and diastolic function were evaluated by echocardiography. The primary substudy outcome was the composite of CV mortality, hospitalization for heart failure, and myocardial infarction or stroke. A total of 181 patients were included, and there were 17 primary CV events (9.4%) during a median follow-up time of 524 days. In a model including clinical characteristics, echocardiographic measures, and BNP or NT-proBNP, the composite CV event outcome was best predicted by NT-proBNP >300 pg/ml (hazard ratio 5.8, 95% confidence intervals [CI] 1.3 to 26.4, p = 0.02) and moderate or severe diastolic dysfunction on echocardiography. When NT-proBNP >600 pg/ml was used in the model, it was the sole independent predictor of primary CV events (hazard ratio 8.0, 95% CI 2.6 to 24.8, p = 0.0003) as was BNP >100 pg/ml (hazard ratio 3.1, 95% CI 1.2 to 8.2, p = 0.02) in the BNP model. In conclusion, both elevated NT-proBNP and BNP are strong independent predictors of clinical events in patients with HF-PLVEF.

Aims: To determine whether the risk of adverse cardiovascular (CV) outcomes associated with diabetes differs in patients with low and preserved ejection fraction (EF) heart failure (HF)., Methods and Results: We analysed outcomes in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme which randomized 7599 patients with symptomatic HF and a broad range of EF. The prevalence of diabetes was 28.3% in patients with preserved EF (>40%) and 28.5% in those with low EF (

Background: We wished to test previous hypotheses that sex-related differences in mortality and morbidity may be due to differences in the cause of heart failure or in left ventricular ejection fraction (LVEF) by comparing fatal and nonfatal outcomes in women and men with heart failure and a broad spectrum of left ventricular ejection fraction., Methods and Results: We compared outcomes in 2400 women and 5199 men randomized in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program using multivariable regression analyses. A total of 1188 women (50%) had a low LVEF (< or = 0.40), and 1212 had a preserved LVEF (> 0.40). Among the men, 3388 (65%) had a low LVEF, and 1811 had a preserved LVEF. A total of 1216 women (51%) and 3465 men (67%) had an ischemic cause of their heart failure. All-cause mortality was 21.5% in women and 25.3% in men (adjusted hazard ratio [HR], 0.77; 95% CI, 0.69 to 0.86; P<0.001). Fewer women (30.4%) than men (33.3%) experienced cardiovascular death or heart failure hospitalization (adjusted HR, 0.83; 95% CI, 0.76 to 0.91; P<0.001). The risks of sudden death (HR, 0.70; 95% CI, 0.58 to 0.85) and death due to worsening heart failure (HR, 0.72; 95% CI, 0.58 to 0.89) were reduced to a comparable extent. The adjusted risk of cardiovascular hospitalization was also lower in women (HR, 0.88; 95% CI, 0.82 to 0.95), mainly because of a reduced risk of heart failure hospitalization (HR, 0.87; 95% CI, 0.78 to 0.97). Women had a lower risk of death irrespective of cause of heart failure or LVEF., Conclusions: Among patients with heart failure, women have lower risks of most fatal and nonfatal outcomes that are not explained, as previously suggested, by LVEF or origin of the heart failure.

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.

Objectives: 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., Background: 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., Methods: 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)., Results: 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)., Conclusions: 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.

Although in the developed world the incidence of and mortality from coronary heart disease (CHD) and stroke have been declining over the last 15 years, heart failure is increasing in incidence, prevalence and overall mortality, despite advances in the diagnosis and management of the condition. Hypertension, alone or in combination with CHD, precedes the development of heart failure in the majority of both men and women. Whilst there have been improvements in the overall management of hypertension, as reflected in rates of diagnosis, awareness, treatment and control of blood pressure (BP), there are still many patients with hypertension who remain undiagnosed or untreated and of those who do receive treatment many fail to achieve current targets for BP control. Placebo-controlled trials in hypertension, largely based on diuretic and beta-blocker-based regimens, have unequivocally demonstrated that the treatment of hypertension can significantly reduce the incidence of heart failure. Newer treatment strategies offer theoretical and proven practical advantages over established antihypertensive therapy. In particular, AT1-receptor blockers appear to provide benefits beyond BP control and are effective in the treatment of both hypertension and heart failure. Thus, the primary prevention of heart failure in hypertensive patients should be based upon strategies that provide tight and sustained BP control necessitating the use of multiple drugs. However, there is now compelling evidence to suggest that this therapy should include an antihypertensive agent that inhibits the reninangiotensin- aldosterone system (RAAS).

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: Whether an angiotensin receptor blocker is of benefit when added to a full dose of angiotensin-converting enzyme (ACE) inhibitor in heart failure (HF) is uncertain., Methods: The effect of candesartan, compared with placebo, in 2548 patients randomized in the CHARM-Added trial was analyzed according to (i) ACE inhibitor dose at baseline, (ii) ACE inhibitor dose during follow-up, and (iii) combination treatment with ACE inhibitor and beta-blocker at baseline. The main outcome was the composite of cardiovascular death or HF hospitalization., Results: The benefit of candesartan was not modified by the dose of ACE inhibitor. In all patients (n = 2548), the candesartan/placebo hazard ratio (HR) for the primary outcome was 0.85 (95% CI 0.75-0.96). In patients taking a guideline recommended dose of ACE inhibitor at baseline (n = 1291), this HR was 0.79 (95% CI 0.67-0.95; interaction P value .26). In patients taking a Food and Drug Administration-designated maximum dose of ACE inhibitor (n = 529), this HR was 0.75 (95% CI 0.57-0.98; interaction P value .29). The benefit of candesartan was preserved in patients taking beta-blockers in addition to a higher dose of ACE inhibitor and in patients maintaining a high dose of ACE inhibitor throughout follow-up., Conclusions: These clinical findings support the pharmacologic evidence that ACE inhibitors and angiotensin receptor blockers have distinct mechanisms of action and show that their combined use improves outcomes in patients with HF more than an evidence-based dose of ACE inhibitor alone.

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.

Background: We wished to determine the prevalence of, potential mechanistic associations of, and clinical outcomes related to anemia in patients with heart failure and a broad spectrum of left ventricular ejection fraction (LVEF)., Methods and Results: In multivariable analyses, we examined the associations between hemoglobin and baseline characteristics, laboratory variables, and outcomes in 2653 patients randomized in the CHARM Program in the United States and Canada. Anemia was equally common in patients with preserved (27%) and reduced (25%) LVEF but was more common in black and older patients. Anemia was associated with ethnicity, diabetes, low body mass index, higher systolic and lower diastolic blood pressure, and recent heart failure hospitalization. More than 50% of anemic patients had a glomerular filtration rate <60 mL.min(-1).1.73 m(-2) compared with <30% of nonanemic patients. Despite an inverse relationship between hemoglobin and LVEF, anemia was associated with an increased risk of death and hospitalization, a relationship observed in patients with both reduced and preserved LVEF. There were 133 versus 69 deaths and 527 versus 352 hospitalizations per 1000 patient-years of follow-up in anemic versus nonanemic patients (both P<0.001). The effect of candesartan in reducing outcomes was independent of hemoglobin., Conclusions: Anemia was common in heart failure, regardless of LVEF. Lower hemoglobin was associated with higher LVEF yet was an independent predictor of adverse mortality and morbidity outcomes. In heart failure, the causes of anemia and the associations between anemia and outcomes are probably multiple and complex.

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: We aimed to develop prognostic models for patients with chronic heart failure (CHF)., Methods and Results: We evaluated data from 7599 patients in the CHARM programme with CHF with and without left ventricular systolic dysfunction. Multi-variable Cox regression models were developed using baseline candidate variables to predict all-cause mortality (n=1831 deaths) and the composite of cardiovascular (CV) death and heart failure (HF) hospitalization (n=2460 patients with events). Final models included 21 predictor variables for CV death/HF hospitalization and for death. The three most powerful predictors were older age (beginning >60 years), diabetes, and lower left ventricular ejection fraction (EF) (beginning <45%). Other independent predictors that increased risk included higher NYHA class, cardiomegaly, prior HF hospitalization, male sex, lower body mass index, and lower diastolic blood pressure. The model accurately stratified actual 2-year mortality from 2.5 to 44% for the lowest to highest deciles of predicted risk., Conclusion: In a large contemporary CHF population, including patients with preserved and decreased left ventricular systolic function, routine clinical variables can discriminate risk regardless of EF. Diabetes was found to be a surprisingly strong independent predictor. These models can stratify risk and help define how patient characteristics relate to clinical course.

Context: Angiotensin-converting enzyme (ACE) inhibitors reduce the risk of myocardial infarction (MI), but it is not known whether angiotensin receptor blockers have the same effect., Objective: To assess the impact of the angiotensin receptor blocker candesartan on MI and other coronary events in patients with heart failure., Design, Setting, and Participants: The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program, a randomized, placebo-controlled study enrolling patients (mean age, 66 [SD, 11] years) with New York Heart Association class II to IV symptoms who were randomly allocated to receive candesartan (target dose, 32 mg once daily) or matching placebo given in addition to optimal therapy for heart failure. Patients were enrolled from March 1999 through March 2001. Of 7599 patients allocated, 4004 (53%) had experienced a previous MI, and 1808 (24%) currently had angina. At baseline, 3125 (41%) were receiving an ACE inhibitor; 4203 (55%), a beta-blocker; 3153 (42%), a lipid-lowering drug; 4246 (56%), aspirin; and 6286 (83%), a diuretic., Main Outcome Measure: The primary outcome of the present analysis was the composite of cardiovascular death or nonfatal MI in patients with heart failure receiving candesartan or placebo., Results: During the median follow-up of 37.7 months, the primary outcome of cardiovascular death or nonfatal MI was significantly reduced in the candesartan group (775 patients [20.4%]) vs the placebo group (868 [22.9%]) (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96; P = .004; number needed to treat [NNT], 40). Nonfatal MI alone was also significantly reduced in the candesartan group (116 [3.1%]) vs the placebo group (148 [3.9%]) (HR, 0.77; 95% CI, 0.60-0.98; P = .03; NNT, 118). The secondary outcome of fatal MI, sudden death, or nonfatal MI was significantly reduced with candesartan (459 [12.1%]) vs placebo (522 [13.8%]) (HR, 0.86; 95% CI, 0.75-0.97; P = .02; NNT, 59). Risk reductions in cardiovascular death or nonfatal MI were similar across predetermined subgroups and the component CHARM trials. There was no impact on hospitalizations for unstable angina or coronary revascularization procedures with candesartan., Conclusion: In patients with heart failure, candesartan significantly reduces the risk of the composite outcome of cardiovascular death or nonfatal MI.

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.

Aims: To evaluate the effect of the angiotensin receptor blocker candesartan on patients' perception of symptoms, using the McMaster Overall treatment evaluation (OTE), in a broad spectrum of patients with chronic heart failure (CHF)., Methods and Results: Patients with symptomatic CHF, randomised in the CHARM Programme in North America (n=2498), were studied. OTE was assessed at baseline, at 6, 14 and 26 months and the patient's final or closing visit. Patient's status was classified as "improved (score +1 to +7)", "unchanged (score 0)" or "deteriorated (score -1 to -7)" at the end of the study compared to baseline. Both a simple "last visit carried forward" (LVCF) analysis and "worst rank carried forward" (WRCF) analysis (where patients who died were allocated the worst OTE score) were used. In the LVCF analysis, compared to placebo, more candesartan patients improved (37.7% versus 33.5%) and fewer worsened (10.8% versus 12.0%) in OTE (p=0.017). The WRCF analysis also showed better overall OTE scores with candesartan compared to placebo (p=0.029). There was no heterogeneity in the response to candesartan between the CHARM component trials or across four exploratory sub-groups (age, sex, NYHA class and beta-blocker)., Conclusions: Candesartan was shown to be better than placebo, when using the McMaster OTE to measure patient perception of treatment. More patients treated with candesartan reported improvement and fewer reported deterioration. This benefit was obtained when candesartan was added to extensive background therapy and is consistent with the benefits of candesartan on NYHA class, hospital admission for worsening heart failure and mortality.

Candesartan is a selective angiotensin II Type I (AT(1)) receptor blocker which binds tightly to, and dissociates slowly from the receptor. It is an effective, long-acting antihypertensive agent with few or no side effects, when compared to placebo in hypertension trials. Several studies indicate that candesartan might prevent diabetes. A research programme of three prospective randomised outcome trials (the CHARM [Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity] programme) has shown that candesartan is of clinical value in a broad spectrum of patients with symptomatic heart failure, regardless of background therapy and ventricular function. There is a clear benefit of candesartan in patients unable to tolerate an angiotensin-converting enzyme inhibitor (ACEI) and this benefit is of a similar magnitude to that obtained with an ACEI. CHARM-Added shows that symptoms, morbidity and cardiovascular mortality are further reduced if an AT(1)-receptor blocker is added to an ACEI. This benefit is not only statistically significant but also clinically important. CHARM-Preserved indicate that candesartan can reduce hospital admission for heart failure in patients with preserved systolic function.

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 beta 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 beta 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.

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 angiotensin-converting-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.

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 angiotensin-receptor 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.

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. Analysis 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%.