Summary 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.
Left ventricular function is a principal determinant of cardiovascular risk in patients with heart failure. The growing number of patients with preserved systolic function heart failure underscores ...the importance of understanding the relationship between ejection fraction and risk.
We studied 7599 patients with a broad spectrum of symptomatic heart failure enrolled in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Program. All patients were randomized to candesartan at a target dose of 32 mg once daily or matching placebo and followed up for a median of 38 months. We related left ventricular ejection fraction (LVEF), measured before randomization at the sites, to cardiovascular outcomes and causes of death. Mean LVEF in patients enrolled in CHARM was 38.8+/-14.9% (median LVEF 36%). Patients with lower LVEF tended to have higher baseline New York Heart Association class. The hazard ratio for all-cause mortality increased by 39% for every 10% reduction in ejection fraction below 45% (hazard ratio 1.39, 95% CI 1.32 to 1.46), with adjustment for baseline covariates. All-cause mortality, cardiovascular death, and all components of cardiovascular death declined with increasing ejection fraction until an ejection fraction of 45%, after which the risk of these outcomes remained relatively stable with increasing LVEF. The absolute change in rate per 100 patient-years for each 10% reduction in LVEF was greatest for sudden death and heart failure-related death. The effect of candesartan in reducing cardiovascular outcomes was consistent across LVEF categories.
LVEF is a powerful predictor of cardiovascular outcome in heart failure patients across a broad spectrum of ventricular function. Nevertheless, once elevated to a range above 45%, ejection fraction does not further contribute to assessment of cardiovascular risk in heart failure patients.
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 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.
Objectives The aim of this study was to explore the relationship between baseline resting heart rate and outcomes in patients with chronic heart failure (HF) according to baseline left ventricular ...ejection fraction (LVEF) and cardiac rhythm. Background Elevated resting heart rate is associated with worse outcomes in patients with HF and reduced LVEF. Whether this association is also found in patients with HF and preserved LVEF is uncertain, as is the predictive value of heart rate in patients in atrial fibrillation (AF). Methods Patients enrolled in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) Program were divided into groups by tertiles of baseline heart rate. Cox proportional hazard models were used to investigate the association between heart rate and pre-specified outcomes in the overall population as well as in subgroups defined according to LVEF (≤40% vs. >40%) and presence (or absence) of AF at baseline. Results After adjusting for predictors of poor prognosis, patients in the highest heart rate tertile had worse outcomes when compared with those in the lowest heart rate group (e.g., for the composite of cardiovascular death or HF hospital stay hazard ratio: 1.23, 95% confidence interval: 1.11 to 1.36, p < 0.001). The relationship between heart rate and outcomes was similar across LVEF categories and was not influenced by beta-blocker use (p value for interaction >0.10 for both endpoints). However, amongst patients in AF at baseline, heart rate had no predictive value (p value for interaction <0.001). Conclusions Resting heart rate is an important predictor of outcome in patients with stable chronic HF without AF, regardless of LVEF or beta-blocker use.
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.
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.
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.
The goal of this study was to identify potentially novel laboratory markers of risk in chronic heart failure patients.
Although a variety of prognostic markers have been described in heart failure, a ...systematic assessment of routine laboratory values has not been reported.
All 2,679 symptomatic chronic heart failure patients from the North American CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) program had a wide range of laboratory measures performed at a core facility, enabling us to assess the relationship between routine blood tests and outcomes using a Cox proportional hazards model. We then replicated our findings in a cohort of 2,140 heart failure patients from the Duke Databank.
Among 36 laboratory values considered in the CHARM program, higher red cell distribution width (RDW) showed the greatest association with morbidity and mortality (adjusted hazard ratio 1.17 per 1-SD increase, p < 0.001). Higher RDW was among the most powerful overall predictors, with only age and cardiomegaly showing a better independent association with outcome. This finding was replicated in the Duke Databank, in which higher RDW was strongly associated with all-cause mortality (adjusted hazard ratio 1.29 per 1 SD, p < 0.001), second only to age as a predictor of outcome.
In 2 large contemporary heart failure populations, RDW was found to be a very strong independent predictor of morbidity and mortality. Understanding how and why this marker is associated with outcome may provide novel insights into heart failure pathophysiology.
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).
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 (<or=40%). Diabetes was associated with a greater relative risk of CV death or HF hospitalization in patients with preserved EF hazard ratio (HR) 2.0 (1.70-2.36) than in patients with low EF HR 1.60 (1.44-1.77); interaction test P = 0.0009. For all-cause mortality, the risk conferred by diabetes was similar in both low and preserved EF groups. The effect of candesartan in reducing CV morbidity and mortality outcomes was not modified by having diabetes at baseline (P = 0.09 test for interaction).
Diabetes was an independent predictor of CV morbidity and mortality in patients with HF, regardless of EF. The relative risk of CV death or HF hospitalization conferred by diabetes was significantly greater in patients with preserved when compared with those with low EF HF.
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.
The aim of this study was to explore the relationship between baseline resting heart rate and outcomes in patients with chronic heart failure (HF) according to baseline left ventricular ejection ...fraction (LVEF) and cardiac rhythm.
Elevated resting heart rate is associated with worse outcomes in patients with HF and reduced LVEF. Whether this association is also found in patients with HF and preserved LVEF is uncertain, as is the predictive value of heart rate in patients in atrial fibrillation (AF).
Patients enrolled in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) Program were divided into groups by tertiles of baseline heart rate. Cox proportional hazard models were used to investigate the association between heart rate and pre-specified outcomes in the overall population as well as in subgroups defined according to LVEF (≤ 40% vs. >40%) and presence (or absence) of AF at baseline.
After adjusting for predictors of poor prognosis, patients in the highest heart rate tertile had worse outcomes when compared with those in the lowest heart rate group (e.g., for the composite of cardiovascular death or HF hospital stay hazard ratio: 1.23, 95% confidence interval: 1.11 to 1.36, p < 0.001). The relationship between heart rate and outcomes was similar across LVEF categories and was not influenced by beta-blocker use (p value for interaction >0.10 for both endpoints). However, amongst patients in AF at baseline, heart rate had no predictive value (p value for interaction <0.001).
Resting heart rate is an important predictor of outcome in patients with stable chronic HF without AF, regardless of LVEF or beta-blocker use.
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