Statins and chronic heart failure: do we need a large-scale outcome trial?

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are of proven clinical benefit in coronary heart disease, at least in those patients who do not have overt chronic heart failure (CHF). However, as there have been no prospective clinical trials of statins in CHF patients, the question arises as to whether the benefits observed in the absence of CHF can be necessarily inferred in those patients in whom CHF is established. In this review, the evidence base stating support of the use of statins in CHF is presented, as well as theoretical considerations as to why these agents may not necessarily be of benefit in this setting. The beneficial potential of statins clearly relates to their plaque stabilization properties and associated improvements in endothelial function, which together should reduce the risk of further infarction and, perhaps, the ischemic burden on the failing ventricle. Furthermore, these agents may have beneficial effects independent of lipid lowering. These include actions on neoangiogenesis, downregulation of AT(1) receptors, inhibition of proinflammatory cytokine activity and favorable modulation of the autonomic nervous system. The potential adverse effects of statins in CHF include reduction in levels of coenzyme Q10 (which may further exacerbate oxidative stress in CHF) and loss of the protection that lipoproteins may provide through binding and detoxifying endotoxins entering the circulation via the gut. In support of these possibilities are epidemiologic data linking a lower serum cholesterol with a poorer prognosis in CHF. These uncertainties indicate the need for a definitive outcome trial to assess the efficacy and safety of statins in CHF, despite their current widespread, non-evidence based use in this population.     

Heart failure and statins--why do we need a clinical trial?

Summary The effect of statins to reduce mortality and morbiditiy in primary and secondary prevention as well as in acute coronary syndroms is well established. Recent data show that pleiotropic effects might also have direct effects on the myocardial cell. However, in chronic heart failure the outcome is inversely related to LDL-plasma concentrations and other pleiotropic effects might impair mitochondrial function. Since there are no safety data on the use of statins in chronic heart failure, a controlled randomized and placebo-controlled trial is urgently needed.     

Electrical devices for left ventricular dysfunction and heart failure: do we need revised guidelines?

Three recent trials have demonstrated the benefit of cardiac resynchronization therapy (CRT) in the New York Heart Association (NYHA) class II patients with heart failure (HF) with ischemic or nonischemic cardiomyopathy as well as in NYHA class I (asymptomatic) patients mostly with ischemic cardiomyopathy. Earlier intervention with CRT in asymptomatic or minimally symptomatic patients improves survival and reduces HF hospitalizations. The reduction or the prevention of HF hospitalizations is of paramount importance because the HF episodes seem to alter the natural history of disease and are associated with deterioration of left ventricular (LV) function and a marked increase in mortality. The CRT benefit is greatest in patients with a QRS ≥ 150 ms. At this time, it would seem prudent to consider CRT-D (D = ICD) therapy for class I NYHA patients with a QRS ≥ 150 ms and an LV ejection fraction ≤ 30% regardless of etiology. Although the data for NYHA class I patients with nonischemic cardiomyopathy are scanty, the recommendation for class I patients is justified because CRT achieves a much greater degree of LV reverse remodeling in nonischemic compared to ischemic patients. With regard to lone ICDs, there is no evidence that they prevent sudden cardiac death more efficiently in symptomatic than in asymptomatic patients. Cardiomyopathy should be the primary target for device therapy regardless of symptoms for both CRT and lone ICD therapy. New guidelines are needed to address the role of CRT in hospitalized NYHA class IV HF patients or those who depend on inotropic therapy or an LV assist device because randomized CRT trials have not included these patients. CRT in these patients remains controversial. The mortality of such patients even with CRT is very high despite the occasional positive response. The role of CRT in patients waiting for cardiac transplantation also needs guidelines. With the expansion of CRT indications to minimally symptomatic or asymptomatic patients, the benefit of device therapy must be carefully weighed against the potential risk of lifelong device complications.     

Biologics and heart failure in rheumatoid arthritis: are we any wiser?

PURPOSE OF REVIEW: To summarize the recent literature concerning the role of TNF-alpha in heart failure, epidemiology of heart failure in rheumatoid arthritis and risk of heart failure associated with biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. RECENT FINDINGS: TNF-alpha has been implicated in the pathogenesis of heart failure. It has direct deleterious effects on the myocardium in the setting of acute injury or chronic heart failure. In animal models, TNF-alpha is important in cardiac remodeling, leading to cardiac dysfunction following acute injury. Both incident and worsening heart failure have been reported in patients with rheumatoid arthritis who are treated with anti-TNF-alpha therapy. Recent cohort studies, however, have shown no increased risk and, in some, a protective effect on the risk of heart failure. Certain traditional cardiovascular risk factors have a relatively lesser contribution to cardiovascular morbidity and mortality in patients with rheumatoid arthritis, suggesting that disease-related perturbations of the cytokine network may contribute to the excess risk of heart failure in these patients. SUMMARY: Overall mortality in rheumatoid arthritis has remained stagnant despite advances in rheumatoid arthritis and heart failure management and improved cardiovascular mortality in the general population. Heart failure prevalence is increased in patients with rheumatoid arthritis and leads to greater mortality. Despite current expert consensus contraindicating the use of anti-TNF-alpha agents in patients with moderate to severe heart failure, epidemiological studies in rheumatoid arthritis have not consistently substantiated this association.     

Stem cell therapy in heart failure: where do we stand and where are we heading?

Heart failure is a multifactorial and complex debilitating disease facing limitations in available pharmacological therapeutics. To cure such a disease, cardiac regeneration has been envisioned using stem cells. A few clinical trials using bone marrow-derived stem cells have been carried out without conclusive results. Stem cells of other origins should therefore be considered for future trials. In this article, the advantages and disadvantages of the most promising stem cells to be used in cell therapy are reviewed. The remaining challenges of cell therapy of heart failure are also presented.     

Contemporary management and research directions in advanced heart failure: where are we going?

Advanced heart failure (AHF) is not a uniform disorder, but is rather a heterogeneous group of patients with varying clinical presentations and definitions. It is growing in magnitude and represents a major public health problem. Herein we describe contemporary care of the patient with AHF, novel medical therapies, and mechanical circulatory assist devices. We speculate where progress has been made and where the major gaps in knowledge remain. Clearly, there is ample opportunity for research and discovery to further advance the care of these very sick patients.     

Cardiorenal anemia syndrome: do erythropoietin and iron therapy have a place in the treatment of heart failure?

The cardiorenal anemia syndrome in congestive heart failure (CHF) is an independent risk factor for vascular morbidity and mortality. Several factors play a role in the pathogenesis of anemia in CHF, including inflammation, impaired renal function, use of certain antihypertensive or cardioprotective agents, and gastrointestinal or urinary losses of essential hemopoietic factors. Several trials evaluated the effects of administering erythropoietin (EPO) and/or iron to patients with CHF. Even though most of them were uncontrolled studies, their results suggest that EPO treatment might be beneficial in CHF. Nevertheless, more studies are needed and certain issues should be resolved, particularly the optimal hemoglobin level, before EPO can become part of the treatment of patients with CHF.     

Are angiotensin-converting enzyme inhibitors and β-blockers making an impact on the epidemiology of heart failure?

With the advent of the 21st century, heart failure has emerged as a major component of the massive public health problem of cardiovascular disease. Currently over 5 million Americans suffer from the syndrome of heart failure with significant direct treatment costs estimated to be in excess of $22 billion per year. Unfortunately, assuming present demographic and medical trends continue, these bleak statistics are expected to worsen substantially over the next two decades. Epidemiologic studies have furthered our mechanistic understanding of heart failure pathophysiology by demonstrating that many patients with this syndrome have preserved systolic function by standard indices. In a positive turn, major advances have occurred in the treatment of heart failure based on the development of clinically effective pharmacologic antagonists of the renin-angiotensin-aldosterone and sympathetic nervous systems. These agents are capable of substantially reducing the morbidity and mortality associated with heart failure. However, the importance of enhanced physician and public awareness of heart failure remains critical in the future.     

Vitamin D insufficiency in congestive heart failure: Why and what to do about it?

This article gives an overview of the current knowledge on vitamin D status in patients with congestive heart failure (CHF). A serum 25-hydroxyvitamin D level below 50 nmol/l (20 ng/ml) is generally regarded as insufficient. Available data indicate that the majority of CHF patients have 25-hydroxyvitamin D levels in the insufficiency range. Skin synthesis of vitamin D after solar ultraviolet B exposure is the most important vitamin D source for humans. However, CHF patients have relatively low outdoor activities. Consequently, a disease-related sedentary lifestyle is an important cause for the insufficient vitamin D status in CHF patients. There is also evidence from a recently performed case-controlled study that indicators of ultraviolet B exposure are already reduced in CHF patients during childhood, adolescence, and early adulthood compared to healthy controls. We present results indicating that an insufficient vitamin D status may contribute to the etiology/pathogenesis of CHF. Data include a vitamin D-mediated reduction of elevated blood pressure as well as a vitamin D-mediated prevention of enhanced parathyroid hormone levels, a pathophysiological state that contributes to cardiovascular disease. Based on population attributable risks, hypertension and cardiovascular disease have a high impact, accounting for the majority of CHF events. Theoretically, vitamin D status can be improved by adequate skin synthesis of vitamin D and/or adequate oral vitamin D intake. At present, daily oral intake of 50–100μ g vitamin D seems to be the most effective way to improve vitamin D status in CHF patients.     

Are all outcomes in chronic heart failure rated equally? An argument for a patient-centred approach to outcome assessment

Chronic heart failure (CHF) is a multi-dimensional and complex syndrome. Outcome measures are important for determining both the efficacy and quality of care and capturing the patient’s perspective in evaluating the outcomes of health care delivery. Capturing the patient’s perspective via patient-reported outcomes is increasingly important; however, including objective measures such as mortality would provide more complete account of outcomes important to patients. Currently, no single measure for CHF outcomes captures all dimensions of the quality of care from the patient’s perspective. To describe the role of outcome measures in CHF from the perspective of patients, a structured literature review was undertaken. This review discusses the concepts and methodological issues related to measurement of CHF outcomes. Outcome assessment at the level of the patient, provider and health care system were identified as being important. The perspectives of all stakeholders should be considered when developing an outcomes measurement suite to inform CHF health care. This paper recommends that choice of outcome measures should depend on their ability to provide a comprehensive, comparable, meaningful and accurate assessment that are important to patient.     

Are angiotensin II receptor blockers more efficacious than placebo in heart failure? Implications of ELITE-2. Evaluation of Losartan In The Elderly

In the light of the recent randomized controlled trials in chronic heart failure, it is now commonly assumed that treatment with an angiotensin-receptor blocker (ARB) is equivalent to treatment with an angiotensin-converting enzyme (ACE) inhibitor. We performed an imputed placebo analysis using previous placebo-ACE inhibitor trials and the current ACE inhibitor-ARB comparison studies, which shows that ARBs may not even be superior to placebos, let alone an ACE inhibitor.