Clinical Trials of Carvedilol in Heart Failure

Carvedilol is a non-selective ₁ and -adrenergic antagonist with antioxidant properties. This novel, competitive antagonist has been studied in 8 placebo-controlled clinical trials involving over 1800 heart failure patients with systolic dysfunction in varying degrees of severity. Overall, carvedilol is well-tolerated in heart failure patients, with a predictable reduction in heart rate and favorable hemodynamic actions. The overall incidence of side effects including hypotension, dizziness, bradycardia and worsening heart failure are no worse than placebo, and can be minimized with careful titration. Improvement in left ventricular ejection fraction has been observed with carvedilol in all studies. A significant reduction in the risks of dying or being hospitalized has also been demonstrated. Some studies have demonstrated improvements in clinical parameters such as symptom status and exercise tolerance, but these benefits have been more difficult to demonstrate conclusively. These clinical trials have established an important role of carvedilol in the management of heart failure. The results from the recent survival trials of beta-adrenergic antagonists have confirmed the mortality benefit of this class of drug in the management of patients with heart failure.     

The Current Focus of Heart Failure Clinical Trials

Background

Heart failure (HF) is a major global health problem. Clinical trials test efficacy, effectiveness, and safety of novel and emerging therapies in HF. We sought to determine the salient features of ongoing interventional clinical trials in HF.

Pentoxifylline prevents pig serum‐induced rat liver fibrosis by inhibiting interleukin‐6 production

Background/Aim: Pig serum‐induced rat liver fibrosis is a model of liver fibrosis in the absence of obvious hepatocyte injury. Penoxifylline (PTX), a xanthine derivative, which is a well‐known suppressor of tumor necrosis factor‐α (TNF‐α) production from inflammatory cells, has also been shown to inhibit the growth of hepatic stellate cells and to inhibit collagen synthesis in these cells in vitro. We investigated the effect of PTX on pig serum‐induced liver fibrosis in vivo, and assessed the mechanisms of prevention of fibrogenesis by this drug. Methods: Male Wistar rats were given intraperitoneal injections of 0.5 ml normal pig serum twice a week for 10 weeks with or without concomitant oral administration of PTX (20 mg/kg). Results: Rats that received pig serum showed significant liver fibrosis, and their serum interleukin‐6 (IL‐6) and hyaluronic acid levels were significantly increased. The serum levels of IL‐6 were well correlated with the serum levels of hyaluronic acid, and increased as the liver fibrosis progressed. Penoxifylline prevented the development of fibrosis in this animal model and reduced the serum levels of IL‐6 in a dose‐dependent manner. In vitro, by the addition of PTX to the culture medium of the rat hepatic stellate cells (HSCs), the proliferation of the HSCs was significantly inhibited and IL‐6 in the culture supernatant was also reduced significantly. Exogenous addition of IL‐6 partially restored the proliferation. Conclusion: Penoxifylline prevents pig serum‐induced rat liver fibrosis by inhibiting the proliferation of HSCs and by inhibiting the production of IL‐6 from HSCs.     

A Meta‐Analysis of Temperament in Eating Disorders

Although suggested as an important contributor to the development and maintenance of eating disorders, temperament has not previously been studied adopting a meta‐analytical approach. We therefore pooled data (N = 14 studies; N = 3315 cases, N = 3395 controls) on Cloninger's temperament traits (novelty seeking, harm avoidance, reward dependence and persistence) in anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED) and eating disorders not otherwise specified. Persistence was significantly higher than in the controls in all eating disorders except for BED the highest levels being observed in AN. Correspondingly, the highest effect sizes for harm avoidance were seen in AN. Novelty seeking was significantly elevated relative to the controls only in BN. Harm avoidance was significantly lower, and reward dependence was significantly higher in individuals who had recovered from AN than in those who remained ill. Future studies with a longitudinal design are needed to explore the temporal relationships between eating disorders and temperament traits. Copyright © 2014 John Wiley & Sons, Ltd and Eating Disorders Association.     

Apnea‐Related Heart Rate Variability and Its Clinical Utility in Congestive Heart Failure Outpatients

Background: Cheyne‐Stokes breathing (CSB) is an abnormal cyclical pattern of respiratory fluctuations observed during sleep in congestive heart failure (CHF) of poor prognosis. We examined the clinical usefulness of CSB screening using the heart rate variability (HRV) data from the ambulatory electrocardiogram. Methods: We monitored ambulatory electrocardiograms and respiration simultaneously in 86 heart disease patients of both sexes, aged 57 ± 1 years. HRV was analyzed by the maximum entropy method during the sleeping period (11 PM—S AM). The 43 CHF patients underwent a 1‐year follow‐up study. Results: In the power spectra of the HRV, peaks were observed within the CSB band (0.005 to 0.03 Hz). Statistically significant differences in HRV were observed between CSB patients and CSB‐free patients in very low frequency (VLF) (P = 0.04), VLF/total frequency (TF) (P = 0.02), CSB (P = 0.01), CSB/TF (P = 0.003), and CSB/VLF (P < 0.0001). Cardiac events occurred in 23% of patients, including cardiac death in two, and rehospitalization for aggravated CHF in eight. In a multivariate Cox regression analysis in which age, sex, ejection fraction, NYHA functional class, beta blocker use, and basic heart disease were included, absence of ACE inhibitor use (RR 5.5, 95% Cl 1.0–31) and CSB/VLF ≧ 80% (RR 4.2, 95% Cl 1.1–17) remained significant predictors of cardiac events. Conclusions: HRV can act as an indicator of the presence of CSB in CHF patients, and could therefore be used, under outpatient conditions, to identify a CHF patients with a poor prognosis. A.N.E. 2002;7(2):127–132     

曲美他嗪联合美托洛尔治疗冠心病心力衰竭的Meta分析

目的系统评价曲美他嗪联合美托洛尔治疗冠心病心力衰竭的临床疗效与安全性。方法计算机检索中国期刊全文数据库(CNKI)、万方数据库、维普数据库(VIP)、PubMed、Cochrane Library等数据库,检索年限为2008年1月—2018年1月。按照纳入和排除标准提取数据,应用RevMan5.3软件对纳入文献进行质量评价与Meta分析。结果纳入12项随机对照试验(RCT),涉及 1 271例病人。Meta分析结果显示,与对照组相比,曲美他嗪联合美托洛尔治疗冠心病心力衰竭能提高临床疗效[RR=1.16,95% CI (1.12,1.21), P <0.000 01],增加左室射血分数[MD=6.14,95% CI (5.41,6.88), P <0.000 01],降低血浆B型钠尿肽水平[MD=- 3.10,95% CI (-3.80,-2.41), P <0.000 01],延长6 min步行距离[SMD=0.74,95% CI (0.57,0.92), P <0.000 01]。结论曲美他嗪联合美托洛尔治疗冠心病心力衰竭可以明显改善临床疗效、提高左室射血分数、降低血浆B型钠尿肽水平、延长6 min步行距离,且安全性好。     

The Role of Anti-Cytokine Therapy in the Failing Heart

The understanding of the role of neurohormones in the progression of heart failure has led to the utilization of agents that antagonize the activation of neurohormonal systems as effective therapy in patients with heart failure. As more evidence emerges linking proinflammatory cytokines to disease progression in heart failure, there is an increasing interest in developing anti-cytokine strategies that might be used as adjunctive therapy in patients with heart failure. Accordingly, the focus of the present review is to summarize the experimental and clinical studies that have attempted to modulate the effects of cytokines in heart failure. Strategies have been employed to either suppress cytokine production or to prevent their toxic effects by interfering with the binding of cytokines to their cognate receptors.     

Effective Exercise for the Prevention of Falls: A Systematic Review and Meta‐Analysis

OBJECTIVES: To determine the effects of exercise on falls prevention in older people and establish whether particular trial characteristics or components of exercise programs are associated with larger reductions in falls. DESIGN: Systematic review with meta‐analysis. Randomized controlled trials that compared fall rates in older people who undertook exercise programs with fall rates in those who did not exercise were included. SETTING: Older people. PARTICIPANTS: General community and residential care. MEASUREMENTS: Fall rates. RESULTS: The pooled estimate of the effect of exercise was that it reduced the rate of falling by 17% (44 trials with 9,603 participants, rate ratio (RR)=0.83, 95% confidence interval (CI)=0.75–0.91, P<.001, I²=62%). The greatest relative effects of exercise on fall rates (RR=0.58, 95% CI=0.48–0.69, 68% of between‐study variability explained) were seen in programs that included a combination of a higher total dose of exercise (>50 hours over the trial period) and challenging balance exercises (exercises conducted while standing in which people aimed to stand with their feet closer together or on one leg, minimize use of their hands to assist, and practice controlled movements of the center of mass) and did not include a walking program. CONCLUSION: Exercise can prevent falls in older people. Greater relative effects are seen in programs that include exercises that challenge balance, use a higher dose of exercise, and do not include a walking program. Service providers can use these findings to design and implement exercise programs for falls prevention.     

Determinants of Diuretic Responsiveness and Associated Outcomes During Acute Heart Failure Hospitalization: An Analysis From the NHLBI Heart Failure Network Clinical Trials

Background

Poor response to loop diuretic therapy is a marker of risk during heart failure hospitalization. We sought to describe baseline determinants of diuretic response and to further explore the relationship between this response and clinical outcomes.