Quality of life and prognosis in heart failure: results of the Beta-Blocker Evaluation of Survival Trial (BEST)

BackgroundQuality of life (QOL) was a prespecified secondary end point in the Beta-Blocker Evaluation of Survival Trial. The Beta-Blocker Evaluation of Survival Trial used four QOL questionnaires to evaluate patient health status over time in response to treatment with placebo or bucindolol. The goal of the current study was to determine the relationship between the different questionnaires, assess the effect of treatment on health status, and evaluate the association between changes in health status and prognosis.MethodsThe San Diego Heart Failure (SDHF), Minnesota Living with Heart Failure (MLHF), Patient Global Assessment (PGA), and Physician Global Assessment (PhyGA) questionnaires were measured at baseline through 48 months of follow-up. For SDHF and MLHF, changes from baseline were calculated. Spearman correlation was used to assess relationships, and Cox Proportional Hazards regression was used to predict time to all-cause mortality, and mortality or heart failure hospitalization, bivariately and multivariately. To determine whether beta-blocker treatment affected QOL, the Wilcoxon rank-sum test was used to compare treatment groups.ResultsAt 12 months, SDHF (r = +0.56, P = .0001), PGA (r = +0.36, P = .0001), and PhyGA (r = +0.37, P = .0001) correlated with MLHF. SDHF (P = .0001), MLHF (P = .0004), PGA (P = .0001), and PhyGA (P = .0001) were all strongly associated with all-cause mortality, with low values of each associated with a lower hazard. For the combined end point of all-cause mortality or heart failure hospitalization, change in QOL with each instrument had a P value of .0001. At 12 months, bucindolol-treated patients had improvement in both PhyGA and PGA compared with placebo; neither the SDHF nor the MLWF instrument distinguished between the two treatment groups unless a worst-rank assignment was used for patients who died.ConclusionThe four instruments correlate with each other and predict clinical end points, suggesting that each is a valid measure of health status. According to the PGA and the PhyGA, bucindolol improves QOL.     

Effect of statin therapy on survival in patients with nonischemic dilated cardiomyopathy (from the Beta-blocker Evaluation of Survival Trial [BEST])

To determine whether statin therapy improves survival in patients with heart failure (HF) secondary to nonischemic dilated cardiomyopathy (non-IDC), data from 1,024 patients with non-IDC (New York Heart Association functional class III and IV HF) and left ventricular ejection fraction < or =0.35 who were enrolled in the BEST were analyzed. The association of statin therapy at the initial screening visit with all-cause and cardiovascular mortality was evaluated using multivariate Cox proportional hazards models. After adjusting for age, gender, race, systolic blood pressure, total cholesterol, New York Heart Association functional class IV, estimated glomerular filtration rate, current cigarette smoking, left ventricular ejection fraction, angiotensin-converting enzyme inhibitor use, antiplatelet therapy, diabetes mellitus, treatment group (beta blocker or placebo), and hypertension, statin use was independently associated with decreased all-cause mortality (hazard ratio 0.38, confidence interval 0.18 to 0.82, p = 0.0134) and also with decreased cardiovascular death (hazard ratio 0.42, confidence interval 0.18 to 0.95, p = 0.037). In conclusion, in patients with moderate or severe HF due to non-IDC entered into BEST, statin therapy at entry was independently associated with a decrease in all-cause and cardiovascular mortality.     

Hot summers and heart failure: seasonal variations in morbidity and mortality in Australian heart failure patients (1994-2005)

BACKGROUND: There are minimal reports of seasonal variations in chronic heart failure (CHF)-related morbidity and mortality beyond the northern hemisphere. AIMS AND METHODS: We examined potential seasonal variations with respect to morbidity and all-cause mortality over more than a decade in a cohort of 2961 patients with CHF from a tertiary referral hospital in South Australia subject to mild winters and hot summers. RESULTS: Seasonal variation across all event-types was observed. CHF-related morbidity peaked in winter (July) and was lowest in summer (February): 70 (95% CI: 65 to 76) vs. 33 (95% CI: 30 to 37) admissions/1000 at risk (p<0.005). All-cause admissions (113 (95% CI: 107 to 120) vs. 73 (95% CI 68 to 79) admissions/1000 at risk, p<0.001) and concurrent respiratory disease (21% vs. 12%, p<0.001) were consistently higher in winter. 2010 patients died, mortality was highest in August relative to February: 23 (95% CI: 20 to 27) vs. 12 (95% CI: 10 to 15) deaths per 1000 at risk, p<0.001. Those aged 75 years or older were most at risk of seasonal variations in morbidity and mortality. CONCLUSION: Seasonal variations in CHF-related morbidity and mortality occur in the hot climate of South Australia, suggesting that relative (rather than absolute) changes in temperature drive this global phenomenon.     

Predictors of mortality and morbidity in patients with chronic heart failure.

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.     

Markers of oxidative damage and antioxidant enzyme activities as predictors of morbidity and mortality in patients with chronic heart failure

BackgroundAlthough the majority of previous findings unequivocally confirmed the existence of systemic oxidative stress in chronic heart failure (CHF) patients, data on prognostic potential of biomarkers of oxidative lipid and protein damage are limited. We aimed to address the relation of oxidative stress markers to severity and prognosis in CHF secondary to ischemic cardiomyopathy.Methods and ResultsPlasma malondialdehyde (MDA), protein thiol groups (P-SH), reactive carbonyl derivatives (RCD), together with glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were determined in 120 CHF patients and 69 healthy controls. Increased lipid peroxidation (MDA) and oxidation of plasma proteins (RCD; P-SH) s well as downregulated GSH-Px activity were found in CHF patients compared with controls. Significant correlation was obtained only for RCD content and remodeling indices (LVEDV: r = 0.469, P = .008; LVESV: r = 0.452; P = .011). Cox regression analysis demonstrated only MDA (HR = 3.33; CI: 1.55–7.12; P = .002) as independent predictor of death, whereas SOD was associated with unstable angina pectoris (HR = 2.09; CI: 1.16–3.78; P = .011).ConclusionsIn the course of CHF progression, carbonyl stress is implicated in the LV remodeling. Malondialdehyde level might be a useful parameter for monitoring and planning management of CHF patients.     

Beta-blocker therapy in advanced heart failure: clinical characteristics and long-term outcomes

AIMS: To evaluate the clinical characteristics and long-term outcomes of advanced heart failure patients (NYHA Class IIIb-IV) receiving beta-blocker therapy vs. those patients not receiving beta-blockers at randomization in the FIRST trial, a randomized, double-blind, placebo-controlled trial of epoprostenol vs. usual care in advanced heart failure. METHODS AND RESULTS: The patient population consisted of 471 patients enrolled in FIRST with Class IIIb-IV heart failure, left ventricular ejection fraction (LVEF) of <30%, advanced hemodynamic abnormalities, and standard pharmacologic treatment of ACE-inhibitor, diuretics, and/or digoxin. The study cohort consisted of 448 patients not receiving beta-blockers and 23 patients receiving beta-blockers at randomization for the FIRST trial. Patients in the beta-blocker group had decreased rates of any clinical event (P = 0.03), worsening heart failure (P = 0.001), and death or worsening heart failure (P = 0.0008) than patients not receiving beta-blockers. After adjusting for prognostically important variables, the favorable effect of beta-blockers on worsening heart failure (P = 0.02) and death or worsening heart failure (P = 0.02) persisted. CONCLUSION: Patients with advanced heart failure who receive beta-blocker therapy have a lower rate of hospitalization and are less likely to experience worsening heart failure or death at 6 months than patients who are not treated with beta-blockers. These observational data contribute to the growing body of data demonstrating a favorable effect of beta-blockers on clinical outcomes in heart failure.     

Baseline and serial neurohormones in patients with congestive heart failure treated with and without bucindolol: results of the neurohumoral substudy of the Beta-Blocker Evaluation of Survival Study (BEST)

BackgroundSerial neurohormones may serve as markers of efficacy of congestive heart failure (CHF) therapy. We measured serial plasma big-endothelin (Big-ET), ET-1, N-terminal atrial natriuretic peptide, and brain natriuretic peptide (BNP) in 206 patients randomized to bucindolol or placebo in Beta-Blocker Evaluation of Survival Trial (BEST).Methods and ResultsNeurohormones were measured at baseline and 3 and 12 months. At baseline, BNP and Big-ET levels were greater in New York Heart Association (NYHA) Class IV than in Class III patients (median 122 pg/mL versus 447 pg/mL, P = .001; and 20.0 pg/mL versus 9.9 pg/mL, P = .003), and in patients with left ventricular ejection fraction (LVEF) ≤20% compared with LVEF >20% (median 211 pg/mL versus 99.1 pg/mL; and 12.9 pg/mL versus 8.0 pg/mL, both P = .003). Big-ET and BNP were the strongest predictors of the composite end point of CHF hospitalization or death. LVEF at 12 months correlated inversely with 12-month BNP levels (r = −0.41, P = .0001). Bucindolol had no effect on neurohormones except that bucindolol treated patients had lower Big-ET levels at 3 months than patients receiving placebo (median 9.1 pg/mL versus 10.9 pg/mL, P = .05). A decline in ET-1 was associated with increased risk of the composite endpoint.ConclusionsLack of effect of bucindolol on natriuretic peptide levels appears consistent with its overall lack of efficacy in BEST.     

Beta-blocker therapy in elderly patients with renal dysfunction and heart failure

OBJECTIVE To assess the role of beta-blockers(BB)in patients with chronic kidney disease(CKD)aged≥75 years.METHODS AND RESULTS From January 2008 to July 2014,we included 390 consecutive patients≥75 years of age with ejection fraction≤35%and glomerular filtration rate(GFR)≤60 m L/min per 1.73 m^2.We analyzed the relationship between treatment with BB and mortality or cardiovascular events.The mean age of our population was 82.6±4.1 years.Mean ejection fraction was 27.9%±6.5%.GFR was 60-45 m L/min per 1.73 m^2 in 50.3%of patients,45-30 m L/min per 1.73 m^2 in 37.4%,and<30 m L/min per 1.73 m^2 in 12.3%.At the conclusion of follow-up,67.4%of patients were receiving BB.The median follow-up was28.04(IR:19.41-36.67)months.During the study period,211 patients(54.1%)died and 257(65.9%)had a major cardiovascular event(death or hospitalization for heart failure).BB use was significantly associated with a reduced risk of death(HR=0.51,95%CI:0.35-0.74;P<0.001).Patients receiving BB consistently showed a reduced risk of death across the different stages of CKD:stage IIIa(GFR=30-45 m L/min per 1.73 m^2;HR=0.47,95%CI:0.26-0.86,P<0.0001),stage IIIb(GFR 30-45 m L/min per 1.73 m^2;HR=0.55,95%CI:0.26-1.06,P=0.007),and stages IV and V(GFR<30 m L/min per 1.73 m~2;HR=0.29,95%CI:0.11-0.76;P=0.047).CONCLUSIONS The use of BB in elderly patients with HFr EF and renal impairment was associated with a better prognosis.Use of BB should be encouraged when possible.     

Gender-related differences in patients with acute heart failure: Management and predictors of in-hospital mortality

Aim and methods

Gender-related differences in clinical phenotype, in-hospital management and prognosis of acute heart failure (AHF) patients have been previously reported in European and US registries. The ALARM-HF survey is the first to include a cohort of 4953 patients hospitalized for AHF in 666 hospitals in 6 European countries, Mexico and Australia.

Results

Women accounted for 37% of the study population, were older and had higher rates of de novo heart failure (45% vs 36%, p < 0.001) than men. An acute coronary syndrome (ACS) was the predominant precipitating factor in both genders, but to a lesser extent in females (30% vs 42%, p < 0.001). Between genders comparison showed higher incidence of atrial fibrillation, valvular heart disease, diabetes, obesity, anemia and depression in women (p < 0.05). Similarly, women had higher left ventricular ejection fraction (LVEF) on admission (42 ± 15% vs 36 ± 13%, p < 0.001) and systolic blood pressure (135 ± 40 mm Hg vs 131 ± 39 mm Hg, p = 0.001) than men. On the other hand, men had more often coronary artery disease, renal failure and chronic obstructive pulmonary disease (p < 0.05). Importantly, in-hospital mortality was similar in both genders (11.1% in females vs 10.5% in males, p = 0.475), and its common predictors were: systolic blood pressure at admission, creatinine > 1.5 mg/dL and diabetes. Furthermore, recent ACS, valvular heart disease and dementia contributed to prognosis in women, while LVEF, hypertension and anemia were independent predictors in men.

Conclusion

Among patients with AHF, there are significant differences in co-morbidities, precipitating factors and predictors of in-hospital mortality between genders. Nevertheless, in-hospital mortality remains similar between genders.     

Beta-blocker treatment in heart failure patients with atrial fibrillation: challenges and perspectives

Heart failure (HF) and atrial fibrillation (AF) are common conditions that share similar clinical phenotype and frequently coexist. The classification of HF in patients with preserved ejection fraction (> 50%, HFpEF), mid-range reduced EF (40%−49%, HFmrEF) and reduced EF (< 40%, HFrEF) are crucial for optimising the therapeutic approach, as each subgroup responds differently. Beta-blocker constitute an important component of our pharmacological regimen for chronic HF. Beta-blocker administration is reccomended in patients with HF with reduced ejection fraction in stable sinus rhythm, due to improvement of symptoms, the better long term-outcome and survival. The beneficial role of beta-blocker use in patients with preserved EF still remain unclear, as no treatment showed a positive impact, regarding morbidity or mortality reduction. The presence of AF in HF patients increases as the disease severity evolves and is associated with a higher rate of cardiovascular morbidity and mortality. But more question is the use of betablocker in HF patients irrespective of EF and concomitant AF. There are many conflicting data and publications, regarding the beta blocker benefit in this population. Generally, it is supported an attenuation of beta-blockers beneficial effect in HF patients with AF. A design of more randomised trials/studies with HF patients and concomitant AF may improve our clinical approach of beta-blockers use and identify the patients with HF, who mostly profit from an invasive approach.

Atrial fibrillation (AF) and heart failure (HF) with or without systolic dysfunction constitute common cardiac conditions, that frequently coexist and overlap.^[1] These entities share multiple risk factors such as age, hypertension, diabetes, obesity, as well as cardiac substrates as valvular, ischemic, and non ischemic structural heart disease.^{[1, 2]} Their coexistence can be partially explained by the presence of the common risk factors.^[3]The definition of heart failure revised in 2016, based on the measurement of left ventricular ejection fraction (EF).^[4] Especially, HF can be divided in three groups: heart failure with preserved EF(> 50%, HFpEF), mid-range reduced EF (40%−49%, HFmrEF) and reduced EF (< 40%, HFrEF).^[4] Interestingly, up to 50% of chronic HF patients present normal or only mildly impaired left ventricular EF.^[5] The prevalence of AF in HF patients increases as the disease severity evolves.^[6] Specifically, in patients with New York Heart Association (NYHA) I−II is typically about 5%, NYHA III approximately 26% and NYHA IV is presented up to 50%.^[6] According to the data from randomized clinical trials and registries, the presence of AF in HFpEF patients ranges between 15% and 41%.^[7] Patients with HFpEF are more likely to demonstrate prevalent AF or AF at any time up to twice, compared with those with HFrEF.^[7] Data from the natiowide Swedish heart failure registry reported the prevelance of AF among LVEF ranges, specifically 53% in HFrEF, 60% HFmrEF, and 65% inHFpEF.^[8] The presence of AF in HFrEF patients was 27% in an anaylsis of ESC-HF long term registry.^[9] Notably, AF occurs in 24%−44% of patients in the setting of acute HF and in one third of those with chronic HF.^{[10, 11]} Atrial fibrillation is also found in more than half (57%) of patients with new onset of HF.^[12] Furthermore, HF is present in 33%, 44% and 56% of ambulatory patients with paroxysmal, persistent and permanent AF, respectively and in more than one third (37%) of those with new onset AF.^{[12, 13]}     

The effect of diabetes on outcomes of patients with advanced heart failure in the BEST trial

OBJECTIVES: This was a retrospective analysis to determine the effect of diabetes on outcome in patients with advanced heart failure (HF), and to determine the effect of beta-blockade in patients with HF with and without diabetes mellitus. BACKGROUND: In chronic HF the impact on clinical outcomes and therapeutic response of the prevalent comorbid condition diabetes mellitus has not been extensively investigated. METHODS: We assessed the impact of diabetes on prognosis and effectiveness of beta-blocker therapy with bucindolol in patients with HF enrolled in the Beta-Blocker Evaluation of Survival Trial (BEST). We conducted a retrospective analysis to examine the prognosis of patients with advanced HF with and without diabetes, and the effect of beta-blocker therapy on mortality and HF progression or myocardial infarction (MI). The database was the 2,708 patients with advanced HF (36% with diabetes and 64% without diabetes) who were randomized to the beta-blocker bucindolol or placebo in BEST and followed for mortality, hospitalization, and MI for an average of two years. RESULTS: Patients with diabetes had more severe chronic HF and more coronary risk factors than patients without diabetes. Diabetes was independently associated with increased mortality in patients with ischemic cardiomyopathy (adjusted hazard ratio 1.33, 95% confidence interval 1.12 to 1.58, p = 0.001), but not in those with a nonischemic etiology (adjusted hazard ratio 0.98, 95% confidence interval 0.74 to 1.30, p = 0.89). Compared with patients without diabetes, in diabetic patients beta-blocker therapy was at least as effective in reducing death or HF hospitalizations, total hospitalizations, HF hospitalizations, and MI. Ventricular function and physiologic responses to beta-blockade were similar in patients with and without diabetes. CONCLUSIONS: Diabetes worsens prognosis in patients with advanced HF, but this worsening appears to be limited to patients with ischemic cardiomyopathy. In advanced HF beta-blockade is effective in reducing major clinical end points in patients with and without diabetes.     

Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme

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.     

Gender differences in advanced heart failure: insights from the BEST study

OBJECTIVES: The goal of this study was to determine the influence of gender on baseline characteristics, response to treatment, and prognosis in patients with heart failure (HF) and impaired left ventricular ejection fraction (LVEF). BACKGROUND: Under-representation of women in HF clinical trials has limited our understanding of gender-related differences in patients with HF. METHODS: The impact of gender was assessed in the Beta-Blocker Evaluation of Survival Trial (BEST) which randomized 2,708 patients with New York Heart Association class III/IV and LVEF < or =0.35 to bucindolol versus placebo. Women (n = 593) were compared with men (n = 2,115). Mean follow-up period was two years. RESULTS: Significant differences in baseline clinical and laboratory characteristics were found. Women were younger, more likely to be black, had a higher prevalence of nonischemic etiology, higher right and left ventricular ejection fraction, higher heart rate, greater cardiothoracic ratio, higher prevalence of left bundle branch block, lower prevalence of atrial fibrillation, and lower plasma norepinephrine level. Ischemic etiology and measures of severity of HF were found to be predictors of prognosis in women and men. However, differences in the predictive values of various variables were noted; most notably, coronary artery disease and LVEF appear to be stronger predictors of prognosis in women. In the nonischemic patients, women had a significantly better survival rate compared with men. CONCLUSIONS: In HF patients with impaired LVEF, significant gender differences are present, and the prognostic predictive values of some variables vary in magnitude between women and men. The survival advantage of women is confined to patients with nonischemic etiology.     

Echocardiographic predictors of exercise capacity in patients with heart failure and systolic dysfunction: role of mitral regurgitation

Introduction and objectives

Patients with heart failure and similar left ventricular systolic dysfunction have differing exercise capacity. The aim of this study was to identify echocardiographic predictors of exercise capacity in patients with heart failure and systolic dysfunction.

Methods

We included 150 patients with class II (70%) or III (30%) heart failure with left ventricular ejection fraction below 40%. Six-minute walking test and cardiac color Doppler-echo, including tissue Doppler of mitral and tricuspid rings, were performed. Moderate and severe mitral regurgitation were considered as significant. Two groups were divided according to the median walking distance (290 m): Group 1, <290 m and Group 2, ≥290 m.

Results

Mitral regurgitation was detected in 112 patients (75%), which was significant in 40 (27%). Group 1 showed more significant mitral regurgitation (35 vs 18%), increased left atrium area (27±1 vs 24±1 cm²), mitral E amplitude (88±5 vs 72±3 cm/s) and systolic pulmonary pressure (37±1 vs 32±1 mmHg, all P<.05). By logistic regression analysis, only the presence of significant mitral regurgitation was independently associated with less walked distance (odds ratio: 3.44 95% confidence interval 1.02-11.66, P<.05). By multiple linear regression, the only independent predictor of walked distance was left atrium area (r=0.25, beta coefficient: −6.52 ± 2, P<.01).

Conclusions

In patients with class II-III heart failure and left ventricular systolic dysfunction, the main echocardiographic predictors of exercise capacity are related to the presence of significant mitral regurgitation.Full English text available from:www.revespcardiol.org