[Show abstract][Hide abstract] ABSTRACT: We investigated the clinical profiles associated with serum uric acid (sUA) levels in a large cohort of patients hospitalized for worsening chronic heart failure with ejection fraction (EF) ≤40%, with specific focus on gender, race, and renal function based interactions. In 3,955 of 4,133 patients (96%) with baseline sUA data, clinical characteristics and outcomes were compared across sUA quartiles. The primary end points were all-cause mortality and a composite of cardiovascular mortality or heart failure hospitalization. Interaction analyses were performed for gender, race, and baseline renal function. Median follow-up was 9.9 months. Mean sUA was 9.1 ± 2.8 mg/dl and was higher in men than in women (9.3 ± 2.7 vs 8.7 ± 3.0 mg/dl, p <0.001) and in blacks than in whites (10.0 ± 2.7 vs 9.0 ± 2.8 mg/dl, p <0.001). Higher sUA was associated with lower systolic blood pressure and EF, higher natriuretic peptides, and more impaired renal function. After accounting for 24 baseline covariates, in patients with enrollment estimated glomerular filtration rate ≥30 ml/min/1.73 m(2), sUA was strongly associated with increased all-cause mortality (hazard ratio 1.44, 95% confidence interval 1.22 to 1.69, p <0.001) and the composite end point (hazard ratio 1.44, 95% confidence interval 1.26 to 1.64, p <0.001). However, in patients with estimated glomerular filtration rate <30 ml/min/1.73 m(2), sUA was not related with either end point (both p >0.4). Adjusted interaction analyses for gender, race, and admission allopurinol use were not significant. In conclusion, sUA is commonly elevated in patients hospitalized for worsening chronic heart failure and reduced EF, especially in men and blacks. The prognostic use of sUA differs by baseline renal function, suggesting different biologic and pathophysiologic significance of sUA among those with and without significant renal dysfunction.
The American Journal of Cardiology 09/2014; 114(11). DOI:10.1016/j.amjcard.2014.09.008 · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite the well-established benefits of mineralocorticoid receptor agonists (MRAs) in heart failure with reduced ejection fraction, safety concerns remain in patients with concomitant diabetes mellitus (DM) because of common renal and electrolyte abnormalities in this population. We analyzed all-cause mortality and composite cardiovascular mortality and HF hospitalization over a median 9.9 months among 1,998 patients in the placebo arm of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial by DM status and discharge MRA use. Of the 750 patients with DM, 59.2% were receiving MRAs compared with 62.5% in the non-DM patients. DM patients not receiving MRAs were older, more likely to be men, with an ischemic heart failure etiology and slightly worse renal function compared with those receiving MRAs. After adjustment for baseline risk factors, among DM patients, MRA use was not associated with either mortality (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.75 to 1.15) or the composite end point (HR 0.94; 95% CI 0.80 to 1.10). Similar findings were seen in non-DM patients (mortality [HR 1.01; 95% CI 0.84 to 1.22] or the composite end point [HR 0.98; 95% CI 0.85 to 1.13] [p >0.43 for DM interaction]). In conclusion, in-hospital initiation of MRA therapy was low (15% to 20%), and overall discharge MRA use was only 60% (with regional variation), regardless of DM status. There does not appear to be clear, clinically significant in-hospital hemodynamic or even renal differences between those on and off MRA. Discharge MRA use was not associated with postdischarge end points in patients hospitalized for worsening heart failure with reduced ejection fraction and co-morbid DM. DM does not appear to influence the effectiveness of MRA therapy.
The American Journal of Cardiology 06/2014; 114(5). DOI:10.1016/j.amjcard.2014.05.064 · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Angiotensin receptor antagonists (ARBs) improve outcomes in patients with heart failure (HF) with reduced left ventricular ejection fraction, but may induce hyperkalemia (HK) and/or a worsening of renal function (WRF).
The incidence and risk factors of HK and its inter-relationship with WRF, as well as associations with clinical outcome (death or admission for HF i.e. the primary outcome) in 3846 HF patients enrolled in the double blind HEAAL trial (losartan 150mg/d vs. 50mg/d) were assessed. Worsening of renal function was defined as a decrease in eGFR >20% from baseline and HK as serum K >5.5 or >5mmol/L. Higher dose of losartan increased serum potassium. Episodes of HK >5mmol/L or WRF occurred at least once in about half of the patients. WRF was associated with higher occurrence of HK (HR 1.19 (1.06-1.34)) and vice versa (HR 1.35 (1.19-1.53)), but preceded HK in only about half of the events. High dose losartan improved outcome despite more frequent WRF and HK, both being independently associated with adverse outcomes in multivariate analyses.
HK and WRF are common in HF patients. Both can be predicted from baseline risk factors and are therefore potentially preventable. Although associated with worse outcome, occurrence of any does not hinder the efficacy of high dose losartan. HK was associated with WRF and worse outcomes. Whether therapy targeting specifically HK may maximize the survival benefit derived from renin angiotensin aldosterone inhibitor use should be appropriately tested in future trials.
International journal of cardiology 02/2014; 173(3). DOI:10.1016/j.ijcard.2014.02.034 · 6.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
The purpose of this study was to characterize the relationship between heart rate and post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction (EF) in sinus rhythm.
A reduction in heart rate improves clinical outcomes in patients with chronic heart failure and in sinus rhythm, but the association between heart rate and post-discharge outcomes in patients with HHF is presently unclear.
This post-hoc analysis of the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) trial examined 1,947 patients with HHF and EF ≤40% not in atrial fibrillation/flutter or pacemaker dependent.
The median follow-up period was 9.9 months. At baseline, patients with a higher heart rate tended to be younger with lower EF and were more likely to have worse New York Heart Association functional class and higher natriuretic peptide levels. After adjustment for clinical risk factors, baseline heart rate was not predictive of all-cause mortality (p ≥ 0.066). However, at ≥70 beats/min, every 5-beat increase in 1-week post-discharge heart rate was independently associated with increased all-cause mortality (hazard ratio: 1.13 [95% confidence interval: 1.05 to 1.22]; p = 0.002). Similarly, every 5-beat increase ≥70 beats/min in 4-week post-discharge heart rate was predictive of all-cause mortality (hazard ratio: 1.12 [95% confidence interval: 1.05 to 1.19]; p = 0.001).
In this large cohort of patients with HHF with reduced EF and in sinus rhythm, baseline heart rate did not correlate with all-cause mortality. In contrast, at ≥70 beats/min, higher heart rate in the early post-discharge period was independently predictive of death during subsequent follow-up. Further study of post-discharge heart rate as a potential therapeutic target in this high-risk population is encouraged.
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. OBJECTIVE To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01132846.
JAMA The Journal of the American Medical Association 11/2013; 310(23). DOI:10.1001/jama.2013.282190 · 30.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Serum magnesium levels may be impacted by neurohormonal activation, renal function, and diuretics. The clinical profile and prognostic significance of serum magnesium level concentration in patients hospitalized for heart failure (HF) with reduced ejection fraction is unclear. In this retrospective analysis of the placebo group of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan trial, we evaluated 1,982 patients hospitalized for worsening HF with ejection fractions ≤40%. Baseline magnesium levels were measured within 48 hours of admission and analyzed as a continuous variable and in quartiles. The primary end points of all-cause mortality (ACM) and cardiovascular mortality or HF rehospitalization were analyzed using Cox regression models. Mean baseline magnesium level was 2.1 ± 0.3 mg/dl. Compared with the lowest quartile, patients in the highest magnesium level quartile were more likely to be older, men, have lower heart rates and blood pressures, have ischemic HF origin, and have higher creatinine and natriuretic peptide levels (all p <0.003). During a median follow-up of 9.9 months, every 1-mg/dl increase in magnesium level was associated with higher ACM (hazard ratio [HR] 1.77; 95% confidence interval [CI] 1.35 to 2.32; p <0.001) and the composite end point (HR 1.44; 95% CI 1.15 to 1.81; p = 0.002). However, after adjustment for known baseline covariates, serum magnesium level was no longer an independent predictor of either ACM (HR 0.94, 95% CI 0.69 to 1.28; p = 0.7) or the composite end point (HR 1.01, 95% CI 0.79 to 1.30; p = 0.9). In conclusion, despite theoretical concerns, baseline magnesium level was not independently associated with worse outcomes in this cohort. Further research is needed to understand the importance of serum magnesium levels in specific HF patient populations.
The American journal of cardiology 10/2013; 112(11). DOI:10.1016/j.amjcard.2013.07.020 · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
This study was designed to test the hypothesis of whether amlodipine reduces the risk for death in patients with heart failure due to a nonischemic cardiomyopathy.
A pre-specified subgroup analysis in an earlier, large-scale, placebo-controlled study suggested that amlodipine might reduce the risk for death in patients with heart failure due to a nonischemic cardiomyopathy.
To evaluate this hypothesis, 1654 patients with severe heart failure due to a nonischemic cardiomyopathy (ejection fraction <30%) were randomly assigned to amlodipine (target dose: 10 mg/d) or placebo added to conventional therapy for heart failure for a median of 33 months.
There were 278 deaths in the amlodipine group and 262 deaths in the placebo group (hazard ratio: 1.09; 95% confidence interval [CI]: 0.92 to 1.29; p = 0.33). The differences between the 2 groups in the risks for cardiovascular death and hospitalization were also not significant. When the results from patients with a nonischemic cardiomyopathy in both the earlier trial and in the current study were combined, there was no evidence of a favorable or unfavorable effect of amlodipine on mortality (hazard ratio: 0.97; 95% CI: 0.83 to 1.13; p = 0.66). Both trials, however, observed higher frequencies of peripheral edema and pulmonary edema and lower frequencies of uncontrolled hypertension and chest pain in patients treated with amlodipine.
These results of the current trial, viewed together with the results from the earlier study, indicate that amlodipine does not exert favorable effects on the clinical course of patients with heart failure, regardless of the presence or absence of underlying coronary artery disease. These findings indicate the need for great caution when striking benefits are observed in subgroups of patients or in trials not primarily designed to assess such effects.
[Show abstract][Hide abstract] ABSTRACT: Haemoconcentration has been studied as a marker of decongestion in patients with hospitalization for heart failure (HHF). We describe the relationship between haemoconcentration, worsening renal function, post-discharge outcomes, and clinical and laboratory markers of congestion in a large multinational cohort of patients with HHF.
In 1684 patients with HHF with ejection fraction (EF) ≤40% assigned to the placebo arm of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, absolute in-hospital haematocrit change was calculated as the change between baseline and discharge or day 7 (whichever occurred first). Patient characteristics, changes in renal function, and outcomes over a median follow-up of 9.9 months were compared by in-hospital haematocrit change. Overall, 26% of patients had evidence of haemoconcentration (i.e. ≥3% absolute increase in haematocrit). Patients with greater increases in haematocrit tended to have better baseline renal function. Haemoconcentration correlated with greater risk of in-hospital worsening renal function, but renal parameters generally returned to baseline within 4 weeks post-discharge. Patients with haemoconcentration were less likely to have clinical congestion at discharge, and experienced greater in-hospital decreases in body weight and natriuretic peptide levels. After adjustment for baseline clinical risk factors, every 5% increase of in-hospital haematocrit change was associated with a decreased risk of all-cause death [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.70-0.95]. Haematocrit change was also associated with decreased cardiovascular mortality or heart failure (HF) hospitalization at ≤100 days post-randomization (HR 0.73, 95% CI 0.71-0.76).
In this large cohort of patients with HHF with reduced EF, haemoconcentration was associated with greater improvements in congestion and decreased mortality and HF re-hospitalization despite an increased risk of in-hospital worsening renal function.
European Journal of Heart Failure 07/2013; 15(12). DOI:10.1093/eurjhf/hft110 · 6.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AIMS: Post-discharge morbidity and mortality for acute heart failure (AHF) patients remains high. Although the adverse effects of neurohormonal activation are well known in chronic HF, the prognostic significance of serum aldosterone in patients hospitalized for AHF has not been well studied.
METHODS AND RESULTS: A secondary analysis was carried out of the placebo arm (n = 1850) from the EVEREST trial which had aldosterone measured at baseline. All patients were hospitalized for worsening HF and had an LVEF <40%. The median follow-up was 9.9 months. The association between serum aldosterone levels at baseline and the independently adjudicated outcomes [all-cause mortality (ACM) and the combined outcome of cardiovascular mortality (CVM) and HF re-hospitalization] were explored with multivariable Cox models. Median aldosterone levels increased during the hospital stay from 11 ng/dL at baseline to 15 ng/dL at discharge (P < 0.001) and remained increased after discharge (16 ng/dL at 24 weeks, P < 0.001). After adjusting for potential confounders, higher baseline aldosterone levels were associated with an increased risk for ACM and CVM or HF re-hospitalization [hazard ratio (HR) 1.49, 95% confidence intrerval (CI) 1.11-1.99; and HR 1.40, 95% CI 1.11-1.78, respectively, in the highest quartile when compared with the lowest].
CONCLUSION: In patients with LVEF <40% hospitalized for AHF and receiving standard therapy, serum aldosterone levels correlated with worse post-discharge outcomes. Aldosterone levels increase during AHF hospitalization and remain increased long after discharge. These results suggest that further modulation of the renin-angiotensin-aldosterone system in patients admitted with worsening HF might favourably improve post-discharge outcomes.
European Journal of Heart Failure 06/2013; 15(11). DOI:10.1093/eurjhf/hft100 · 6.58 Impact Factor