Reviews on Recent Clinical Trials - Volume 9, Issue 2, 2014

Heart failure remains the main cause of death in children with heart disease. In USA and Europe hospital mortality of children with heart failure is about 7% of children, nearly twice as high as in adults. In this review a group of authors report about their experience with beta-blockers in childhood heart failure. Most of them start to treat children with severe heart failure at a time - 20 years ago - when beta blockers seem to be contraindicated in this situation. The physicians and their patients and/or parents all are aware of the risk of this decision. However, unproven medical therapies for heart failure are the most important therapeutical dilemma in pediatric cardiology. The authors carefully observed a highly selected group of patients with the highest risk to die and had the patience to wait for the longtime follow up. Today - based upon this experience –we know that beta blockers are safe and may save the lives of many children with heart disease all over the world. Together with young colleagues who enthusiastically support this idea the authors now intend to break down the “wall of ignorance” for this promising therapy in pediatric cardiology.

Patients with chronic heart failure have prolonged sympathetic stimulation and subsequent worsening of the failing heart function. Beta-blockers (non-selective, cardio-selective, and non-selective with ancillary properties) counteract the effects of prolonged sympathetic stimulation. Beta-blocker therapy results in the improvement of the left ventricular systolic and diastolic function, reversal remodeling, heart rate control, effective prevention of the malignant arrhythmias, and lowering of the both cardiac afterload and preload in patients with chronic heart failure.

The prevalence of heart failure in patients with congenital heart disease, mainly due to large left to right shunts, is as high as 20%. Heart failure has a high impact on prognosis, growth and neurodevelopment. Prior to surgery or after palliative procedures children need a medical heart failure therapy. The traditional therapy with digoxin, diuretics and ACE-inhibitors is not supported by prospective randomized trials. Propranolol had a significant beneficial effect on the clinical heart failure score, neurohormonal activation, heart rate variability and cardiac remodeling in the prospective randomized trial CHF-Pro-Infant. Beta-blocker dosages depend on heart rate with a target between 100 and 110 bpm in infants and an average dose of 2mg/kg/day after a titration period of 2 to 3 weeks. Within the last 18 years after the first case the author treated only infants with severe heart failure and highly elevated Pro-BNP-levels (8879 pg/ml on average). However we never observed serious side effects due to worsening heart failure, severe bradycardia or pulmonary obstruction. Diuretics are given as low as necessary to prevent the activation of the renin-angiotensin-aldosterone system with its detrimental effect on cardiac remodeling.

Thanks to the enormous progress in the field of cardiac surgery and paediatric cardiology since the mid of 20th century, more and more children with congenital heart defects reach the adulthood. This on the other hand encounter physician and patients various problems due to late complications after the heart surgery like congestive heart failure, arrhythmia and sudden death. One of the challenging area is the medical management of heart failure in these patients with complex anatomy and hemodynamics. The lack of evidence of the effectiveness of the anti congestive medications in this population in from of large randomized controlled trials, makes it difficult to establish universally accepted therapy guidelines. In this article we will review the evidence of the beta-blockers in heart failure in patients with congenital heart disease. Also we will discuss the mechanisms of heart failure in this patient's cohort and will review the literature with respect to the use of neurohormonal antagonists in congenital heart disease. There is an urgent need to initiate well-designed clinical trials to prove if the positive results of neurohormonal blockade in acquired heart failure in adults can be translated in patients with congenital heart disease.

Background: Numerous prospective randomized clinical trials demonstrated favorable effect of beta-blockers in adults with chronic heart failure. However, effectiveness of beta blockers in pediatric patients with systemic ventricle systolic dysfunction was not recognized sufficiently. Limited number of pediatric patients might be the course of unrecognized carvediolol treatment benefit. Currently, no meta-analysis has examined the impact of carvedilol and conventional therapy on the clinical outcome in children with chronic heart failure due to impaired systemic ventricle systolic function. Materials and Methods: We have systematically searched the Medline/PubMed and Cochrane Library for the controlled clinical trials that examine carvedilol and standard treatment efficacy in pediatric patients with systemic ventricle systolic dysfunction. Mean differences for continuous variables, odds ratios for dichotomous outcomes, heterogeneity between studies and publication bias were calculated using Cochrane Review Manager (Rev Man 5.2). Results: Total of 8 prospective/observational studies met established criteria. Odds ratio for chronic heart failure related mortality/heart transplantation secondary to carvedilol was 0.52 (95% CI: 0.28-0.97, I2 = 0%). Our analysis showed that carvedilol could prevent 1 death/ heart transplantation by treating 14 pediatric patients with impaired systemic ventricle systolic function. Conclusion: Meta-analysis demonstrated clinical outcome benefit of carvedilol in children with chronic heart failure.

Respiratory failure and heart failure are inevitable complications in Duchenne muscular dystrophy (DMD). Respiratory failure and heart failure undergo simultaneously and affect each other. After dissemination of mechanical ventilation, heart failure is the main cause of death in DMD. Regular assessment of cardiopulmonary function, early introduction of cardioprotective therapy and intensive respiratory care are the key issues in medical managements of DMD. In DMD, angiotensin converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) are used as the first line drugs. Beta-blockers (BB) are usually added to ACEI/ARB, when they cannot achieve sufficient effects. Although high dose of BB might be required for functional improvements, even a low dose BB can reduce cardiac events. Recent meta-analyses reported heart rate reduction is more important than BB dose for reducing mortality. Thus heart rate monitoring is essential for titration of BB. Tachycardia under optimal respiratory care can also be an indicator of BB. Although the introduction of BB is relatively safe under gradual dose-escalation from a low dose, hospitalization during uptitration should be considered in advanced cases.

Congestive cardiac failure accounts for 36% of childhood deaths in hypertrophic cardiomyopathy, and in infants with heart failure symptoms before two years of age, the mortality is extremely high unless treatment with betareceptor antagonists is instituted. The mechanism of heart failure is not systolic dysfunction, but rather extreme diastolic dysfunction leading to high filling pressures. Risk factors for development of heart failure are a generalized pattern of hypertrophy with a left ventricular posterior wallto- cavity ratio >0.30, the presence of left ventricular outflow tract obstruction at rest, and the co-existence of syndromes in the Noonan/Leopard/Costello spectrum. The 5-year survival of high-risk patients is improved from 54% to 93% by highdose beta-blocker therapy (>4.5 mg/kg/day propranolol). The mechanism of the beneficial effect of beta-blockers is to improve diastolic function by lengthening of diastole, reducing outflow-obstruction, and inducing a beneficial remodelling resulting in a larger left ventricular cavity, and improved stroke volume. Hypertrophic cardiomyopathy is associated with increased activity of cardiac sympathetic nerves, and infants in heart failure with hypertrophic cardiomyopathy show signs of extreme sympathetic over-activity, and require exceptionally high doses of beta-blockers to achieve effective betablockade as judged by 24 h Holter recordings, often 8-24 mg/kg/day of propranolol or equivalent. Conclusion: Beta-blocker therapy is without doubt the treatment of choice for patients with heart failure caused by hypertrophic cardiomyopathy, but the dose needs to carefully titrated on an individual basis for maximum benefit, and the dose required is surprisingly large in infants with heart failure due to hypertrophic cardiomyopathy.

The exact prevalence of heart failure among children of developing countries is not known, as the data is limited. The relative frequency of different causes of pediatric heart failure varies widely across different countries and even among different parts of large countries like India. Children of developing countries face a double burden of etiologies. Conditions such us congenital heart disease, myocarditis and cardiomyopathies are common causes of pediatric of heart failure. In addition, diseases like rheumatic heart disease, nutritional deficiencies, and other tropical diseases also result in heart failure among children of the developing countries. However, most of the developing countries have low resources and hence management of pediatric heart failure becomes challenging. Advanced therapies for heart failure are rarely used in children of developing countries and cardiac transplant remains a distant dream.

Objective: Induction of labour for reasons that medical professionals do not consider “medically indicated” is a difficult subject, both for women requesting it, as well as the medical professionals involved in their care. There is often a prejudice that induction will increase risks for mothers and babies, and therefore they try to avoid it. We aimed to look at this group of patients who request induction for a number of “non-medical” or “social” reasons, to see if maternal and fetal outcomes were any different. Materials and Methods: Compare term women requesting induction over an eighteen-month period with women undergoing routine induction for post dates over the same period at a University NHS Foundation Trust. 74 women requesting induction were compared with 124 women undergoing routine induction for post dates. A retrospective review of the notes of the study and control groups was performed. The results were statistically analysed. Main outcomes were mode of delivery and any serious maternal or neonatal morbidity or mortality. Results: Women with a BMI of less than 30 are more to likely to achieve a vaginal birth in the maternal request group when compared to the control group. No significant differences were observed between other maternal and fetal outcomes. Conclusion: The results from this study add to the growing body of evidence that shows there is no increased risk of Caesarean section or other serious complications if women are induced for reasons thought to be not medically justified by medical professionals.

Indacaterol was introduced as an agent of the new generation of very long acting beta2-agonists (VLABA) that provides a 24-hour activity of bronchodilation and allows a once-daily OD dosing. The first trial showed a significantly higher efficacy of indacaterol vs. placebo in patients with chronic obstructive pulmonary disease (COPD). The following trials were aimed at evaluating its performance compared with other bronchodilators. The results can be summarized in a comparable efficacy of indacaterol, mainly assessed by the increase in FEV1 value but also by quality of life and other patient- reported outcomes (PROs), compared with the OD antimuscarinic tiotropium bromide, and in a slightly higher efficacy compared with the LABA formoterol and salmeterol administered twice-daily. No problems of safety and tolerability were reported in the trials as well as in specific studies, every kind of adverse event, including cardiovascular effects, being similarly frequent with indacaterol and with placebo. Concerning the real-life management, in respect to LABA, the OD dosing makes indacaterol more convenient for COPD patients and is likely to positively influence the patient’s adherence. Since adherence to medical treatment of chronic diseases, and particularly COPD is a crucial issue in medicine, such aspect should confer to indacaterol a valuable role in clinical practice. The recently approved combination of indacaterol with the antimuscarinic glycopyrronium [QVA149], based on the demonstration of positive effects on both lung function and PROs, is likely to be a further option for patients with severe COPD.

In recent years an increasing attention is focused on the potential effects of drugs on cancer incidence and/or cancer survival. Many medications of common use, developed for a variety of medical non-cancer situations, have been found to have potential anti- cancer effects. In this article, we performed an overview of the literature evidence for several commonly used non-cancer medications, such as aspirin, beta-blockers, metformin and other anti- diabetics, cardiac glycosides, anticoagulant heparin, statins, psychotropic drugs, vitamins, calcium and estrogens which have been shown to have anticancer effects, in observational and experimental studies. A huge amount of data supports the idea that a few of these commonly used medicines could decrease cancer death-rate, particularly aspirin, statins and metformin, crosswise different types of cancer. To date, no mature data are available from randomized and prospective trials; perhaps, the results of some studies underway will allow us to answer some questions on the possible use of these drugs in our clinical practice in primary and secondary prevention, or even in adjuvant setting.

Hepatitis C virus (HCV) chronically infects about 2% of the world’s population. Approximately a quarter of these patients will develop, during their life, liver cirrhosis, which entails a high risk of complications and death. Successful antiviral therapy can reduce the risk of disease progression, but it is feasible only in a minority of patients because it includes interferon which is contraindicated in the most advanced stages of the disease and in patients with severe impairment of other organs. Consequent to the launch of the first direct antiviral agents (DAA), namely the protease inhibitors telaprevir and boceprevir, several molecules are in an advanced phase of clinical development to be used in association with interferon or with other DAA (in interferon-free combinations). This review focuses on the mechanism of action, pharmacokinetics, efficacy, safety and resistance of dasabuvir, a non-nucleoside inhibitor of NS5B viral RNA-dependent RNA polymerase. Thanks to its pharmacokinetics, dasabuvir can be administered twice daily. In combinations with other oral DAAs, dasabuvir results in very high rates of SVR (about 95%) in patients with HCV genotype 1 infection with a good tolerability and safety. In conclusion, dasabuvir is a good agent to be used in interferon-free combinations for the treatment of chronic hepatitis C.