Glucocorticoids For Decompensated Heart Failure

Heart failure can be defined as a syndrome caused by an abnormality of cardiac structure or function leading to failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues, despite increased filling pressures. Patients with heart failure frequently present with diuretic resistance and hyperuricemia due to diuretic use and worsening of renal function. Recent clinical evidence also shows that corticosteroids can improve renal function, potentiate diuretics’ effects and lower serum uric acid levels in heart failure. Therefore, corticosteroids could also be a potentially ideal treatment option for such patients in heart failure. Therefore, we designed this study to determine the effects of glucocorticoids on diuretic and uric acid lowering in decompensated heart failure. We also tried to clearfy its mechanisms to lower serum uric acid in such patients. Part one The effectiveness and Safety of glucocorticoids in decompensated heart failure- Meta-Analysis of Randomized Controlled TrialsObjective: Heart failure is a leading cause of cardiovascular morbidity and mortality in the world. Most patients with decompensated heart failure are admitted with overt volume overload or pulmonary congestion. Recent evidence appears to confirm that glucocorticoids may help to overcome diuretic resistance to loop diuretics and increase renal responsiveness to diuretics. The objective of this systematic review was to evaluate the effects of glucocorticoids in people with decompensated heart failure compared to standard medical therapy or placebo on mortality, renal function, New York Heart Association(NYHA) functional class, and their potential adverse effects(that is fluid retention)。Methods:1 We searched CENTRAL(Cochrane Central Register of Controlled Trials) on The Cochrane Library, MEDLINE(Ovid), EMBASE(Ovid) from their inception to 23 March 2015, searched the reference section of retrieved articles and clinical trials registers. We applied no language restrictions.2 Selection criteria: we included randomised controlled trials(RCTs) involving patients with decompensated heart failure.3 Data collection and analysis: four authors independently selected studies, assessed study quality and extracted data.Results: We included 10 RCTs involving 1239 participants. Study quality was high only in 2 large scale RCTs and relatively low in the other 8 trials due to no blinding measures. Most of participants in the trials were treated with glucocorticoids in short term(less than two weeks). 1 Glucocorticoid treatment did not increase short-term mortality(Odds ratio [OR] 0.50, 95% CI 0.24 to 1.07, random effects model), medium-term mortality(OR 0.65, 95% CI 0.41 to 1.04, random effects model) and long-term mortality(OR 0.47, 95% CI 0.21 to 1.06) in patients with decompensated heart failure. 2 The pooled data showed glucocorticoid treatment improved renal function and NYHA functional class. 3 Six RCTs documented the effect of glucocorticoid therapy on urine output. All of them showed that glucocorticoid therapy potentiated diuresis in patients with decompensated heart failure. The evidence did not show glucocorticoid treatment caused fluid retention in patients with decompensated heart failure. 4 One small trial reported the effect of glucocorticoids on infection, which did not show that glucocorticoids increased infection rate. 5 The trend shows glucocorticoids may increase odds of hyperglycemia and sleep disorder. 6 Other adverse effects, such as hyperactivity, osteoporosis, and muscle wasting, were not reported in the trials included in the review.。 Part two The Effect of Corticosteroid on Renal Water and Sodium Excretion in Symptomatic Heart Failure: Prednisone for Renal Function Improvement Evaluation StudyObjective: Heart failure(HF) is a complex clinical hemodynamic disorder characterized by progressive pump failure, and water and sodium retention. Most patients with decompensated HF are admitted with overt volume overload or pulmonary congestion. Although the effect of diuretics on survival remains unclear, their indisputable efficacy in relieving congestive symptoms makes them an essential component of decompensated HF management. However, they induce diuretic effects at the cost of activating the renin-angiotensin-aldosterone system(RAAS) and worsening the renal function. Therefore, new therapeutic strategies for patients with HF are needed. Newly emerging evidence shows that corticosteroids do not cause water and sodium retention. Rather, they can produce a potent diuretic effect and improve renal function in decompensated HF. The purpose of this study was to determine whether the effect of prednisone, a corticosteroid, on renal water and sodium excretion, is dose-dependent and to explore the underlying mechanisms by which it increases renal responsiveness to diuretics in HF.Methods:1 Trial design: Prednisone for Renal Function Improvement Evaluation Study was a prospective, open-label, none-blinded, randomized, parallel-group, dose-comparison study.2 Participants: Inclusion criteria included patients hospitalized for symptomatic HF, dyspnea at rest or with minimal activity, NT-proBNP >1000 pg/ml, LVEF ≤ 40%. Exclusion criteria included any condition, other than HF, that could limit the use of prednisone, such as active myocarditis, obstructive or restrictive cardiomyopathy, cardiac surgery within the previous 3 months, acute decompensated HF, and acute coronary syndrome.3 Interventions: Participants were randomized to receive either low-dose(15 mg/day, approximately 3 to 4 times daily cortisol secretion), medium-dose(30 mg/day) or high-dose(60 mg/day) prednisone, for 10 days. It was then tapered off, over 3 days, depending on whether the patients could tolerate it. Control: Participants randomized to the control group received only standard HF care.4 Outcomes: Primary outcome measures were daily urine output during 10 days and change from baseline in the 24-hour urinary sodium excretion, assessed at day 5 and day 10. Secondary outcome measures were serum creatinine(SCr).Results: 1 There was a remarkable increase in diuresis in patients receiving prednisone treatment, i.e., the combined prednisone treatment group compared with that of the control group. However, there was no difference in diuresis between the three prednisone-treated groups. Compared with that of the control group, i.e., standard HF care, only patients given low-dose prednisone induced a dramatic increase in diuresis. There was only a trend that medium-dose or high-dose prednisone may induce an increase in diuresis(P = 0.08 in the medium-dose prednisone group, P = 0.09 in the high-dose prednisone group). 2 At the end of the study the body weight reduction was 1.5 ± 1.1 kg in the standard care group, 3.0 ± 1.8 kg in the low-dose prednisone group, 3.9 ± 3.2 kg in the medium-dose prednisone group, and 4.1 ± 2.8 kg in high-dose prednisone group, favoring prednisone treatment. 3 The effect of prednisone on the 24-hour urinary sodium: Patients receiving prednisone induced an increase in the 24-hour urinary sodium compared with that in the control group. 4 Change from baseline in the 24-hour urinary sodium was significantly higher in the high-dose prednisone group than in the control group. There was no difference between the control group and the prednisone-treated groups in SCr and GFR. However, the trend favored prednisone. Part three Elevation in serum uric acid is associated with impaired renal uric acid clearance in patients with symptomatic heart failure and reduced ejection fractionObjective: Patients with at the end stage of heart failure(HF) frequently present with an elevation in serum uric acid(SUA). SUA elevation is a strong, independent predictor of mortality in patients with HF. Uric acid(UA) is the final product of purine degradation with xanthine oxidase. Approximately, two third of the uric acid is excreted through the kidneys and one third of the UA is excreted through the gastrointestinal tract. Either overproduction or reduced renal UA clearance can result in an elevation in SUA. It is well recognized that HF, as a state of tissue hypoxia, is associated with impaired oxidative metabolism that depletes adenosine triphosphate and activates the purine nucleotide degradation pathway to UA, leading to UA overproduction. However, at the end stage of HF, persistent gut venous congestion and aggressive diuretic treatment increase renin–angiotensin–aldosterone system(RAAS) activity and cause lipopolysaccharide(LPS) triggered inflammation activation and cytokine generation, leading to a reduction in renal blood flow, and an impairment of renal function. Renal function impairment secondary to RAAS and inflammatory activation may also play a more important role in the SUA elevation in HF. However, the above notion is based on the theoretical postulation, not on clinical data. Furthermore, the relations between SUA elevation and RAAS, inflammation, renal UA clearance and renal creatinine clearance(CCr) in patients with symptomatic heart failure and reduced ejection fraction(HFr EF) remain undetermined. Thus, we designed this study to assess the potential relations between SUA and renal UA clearance, CCr, inflammation activation, and RAAS in symptomatic HFrEF.Methods:This cross-sectional study was approved by the institutional ethics committee and conducted in adherence with local guidelines for good clinical practice. We reviewed the medical record of 131 patients with HFrEF from two studies, i.e. PRIME study and push-path 2 study conducted by our institute. Inclusion Criteria: adult patients with HFrEF(18-80 years), NYHA Class II-IV, and left ventricular ejection fraction(LVEF) ≤ 45%. Patients were excluded from the analysis when the patients received treatment with the xanthine oxidase inhibitor allopurinol or an uricosuric agent, or when a coexisting renal disease was present, or when the kidney function was severely impaired(e.g. serum creatinine levels >200 μmol/L, i.e. 2.26mg/dL). The Pearson correlation coefficients were derived. Variables, such as CCr, renal UA clearance were indexed to the BSA.Results: 1 There was a statistically significant linear inverse relationship between concentrations of SUA and renal UA clearance. 2 Also, there was a statistically significant linear inverse relationship between concentrations of SUA and CCr. 3 It is noteworthy that UA clearance highly correlated CCr. 4 The data did not show there was a correlation between SUA and hs-CPR. 5 There was also no correlation between RAAS and hs-CRP. 6 The data showed that plasma angiotensin II concentrations correlated with plasma aldosterone concentrations. However, there was no correlation between SUA and RAAS. Also, there was no correlation between hs-CRP and RAAS and CCr. Part four Prednisone lowers serum uric acid levels in patients with decompensated heart failure by increasing renal uric acid clearanceObjective: Uric acid(UA) is the final product of purine degradation with xanthine oxidase. Approximately two third of UA is excreted through the kidneys and the remainder through the gastrointestinal tract. At the end stage of heart failure(HF), the serum UA(SUA) level is usually elevated. SUA elevation is a strong and independent predictor of mortality in patients with HF. In such patients, venous congestion and diuretic treatment in HF can worsen renal function, reduce renal blood flow, and impair glomerular filtration and UA tubular excretion. Recently, several clinical studies documented that large doses of prednisone(1 mg/kg/day with a maximum dose of 60 mg/day), a commonly used anti-inflammatory agent, could not only improve renal responsiveness to diuretics, but also lower SUA in patients with decompensated HF. Newly published HF guidelines also recommend using prednisone to treat HF patients with gout. However, the optimal dose of prednisone and mechanisms underlying the hypouricemic effects of prednisone in HF are unclear. We therefore carried out this study to verify our hypothesis, i.e., prednisone lowers UA levels by increasing renal UA clearance.Methods:Thirty-eight patients with decompensated HF were randomized to receive standard HF care alone(n = 10) or with low-dose(15 mg/d, n = 8), medium-dose(30 mg/d, n = 10), or high-dose prednisone(60 mg/d, n = 10), for 10 days. Patients with New York Heart Association(NYHA) functional class III or IV, left ventricle ejection fraction of ≤40%, and N-terminal pro-brain natriuretic peptide of >1000 pg/ml were randomized to receive either prednisone or standard HF care for 10 days. All patients were started on a 2 liter per day fluid restriction and 5 gm of sodium chloride per day. No dietary recommendations for high uric acid patients were given during the study period. Participants randomized to prednisone groups were treated with low-dose(15 mg/d, n = 8), medium-dose(30 mg/d, n = 10), or high-dose prednisone(60 mg/d, n = 10), for 10 days. Prednisone was then tapered off over 3 days, depending on whether the patients could tolerate withdrawal of the medication. Participants randomized to the control group received only standard HF care alone. Primary outcome measures were SUA levels at the end of study. Secondary outcome measures were changes in renal UA clearance and renal fractional excretion of uric acid(FEUa).Results: 1 At the end of the study, change from baseline(CFB) in SUA only favored high-dose of prednisone treatment(-3.55 ± 1.02 mg/dL in the high-dose of prednisone group versus-0.01 ± 0.49 mg/dL in the standard HF care group, P < 0.05). 2 At the end of the study, CFB in renal UA clearance again only favored the group receiving high-dose prednisone therapy(4.30 ± 1.38 ml/min in the high-dose of prednisone group versus-0.54 ± 0.83 ml/min in the standard HF care group, P < 0.05). 3 Despite there is a trend that high-dose of prednisone may increase FEUa compared with that of standard care at the end of study, the increase in FEUa induced by prednisone was not statistically significant.Conclusions:1 Glucocorticoids are safe in decompensated heart failure. They do not increase short-term, medium-term and long-term mortality in patients with deompensated heart failure.2 Glucocorticoids do not cause fluid retention in patients with heart failure. Rather, they can increase renal sensitivity to diuretics and induce potent diuretic effects in such patients.3 There is a clear association between reduced renal uric acid clearance and increased serum uric acid levels in heart failure patients with reduced lefte ventricular ejection fraction. Glucocorticoids can lower serum uric acid levels in such patients by increasing renal uric acid clearance.