Clinical trials update from the American Heart Association meeting 2010: EMPHASIS-HF, RAFT, TIM-HF, Tele-HF, ASCEND-HF, ROCKET-AF, and PROTECT

This article provides information and a commentary on key trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the annual meeting of the American Heart Association held in Chicago in 2010. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. In patients with mild heart failure (HF), EMPHASIS-HF showed that the addition of eplerenone to standard therapy was well tolerated and reduced both the risk of death and hospitalization. The addition of cardiac resynchronization therapy to implantable cardioverter defibrillator (ICD) therapy reduced the incidence of all-cause mortality and HF hospitalizations in patients with NYHA class II-III HF compared with ICD alone in RAFT. Telemonitoring failed to improve outcome compared with a high standard of conventional care in patients with chronic HF (TIM-HF study) and a telephone-based interactive voice response system failed to improve outcome in patients recently hospitalized for HF (Tele-HF study). ASCEND-HF suggested that nesiritide was ineffective but safe in patients with acute decompensated HF. ROCKET-AF suggests that the factor-Xa inhibitor rivaroxaban may be as effective as warfarin in patients with atrial fibrillation. The PROTECT study provided more data to suggest that amino-terminal B-type natriuretic peptide guided therapy may be beneficial in patients with left ventricular systolic dysfunction.     

Clinical trials update from the American Heart Association 2007: CORONA, RethinQ, MASCOT, AF-CHF, HART, MASTER, POISE and stem cell therapy

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the American Heart Association 2007. These should be considered as preliminary data, as analyses may change in the final publication. Rosuvastatin did not reduce mortality compared to placebo in patients with heart failure and left ventricular systolic dysfunction due to ischaemic heart disease in the CORONA study. Results of RethinQ provide equivocal evidence of benefit from CRT in patients with heart failure, echocardiographic dyssynchrony and QRS interval <130 ms. In the MASCOT study, the addition of atrial overdrive pacing did not reduce the incidence of permanent atrial fibrillation in patients receiving CRT. The AF-CHF study failed to show a benefit of rhythm control over rate control in patients with heart failure and atrial fibrillation. Self-management skills training and education had no benefit on the combined outcome of death or heart failure hospitalisation, compared with education alone in heart failure patients in the HART study. Microvolt T-wave alternans testing failed to identify patients at increased risk of life-threatening ventricular arrhythmias in the MASTER study. POISE suggests that initiating metoprolol therapy shortly prior to non-cardiac surgery increases the risk of hypotension, stroke and death, despite reducing the risk of myocardial infarction. Three trials of stem cell therapy in post-MI patients gave conflicting results.     

Acute decompensated heart failure: best evidence and current practice

Heart failure (HF) is one of the leading cardiovascular health problems in Europe and the United States. Acute decompensated HF remains a lethal diagnosis with a morbidity and mortality that often exceeds neoplastic or infective diseases. The incidence of HF continues to increase despite an intensive effort to increase education and delivery of healthcare to these affected patients. Yet, current guidelines in the United States do not address the management of acute decompensated HF, and focus predominantly on chronic stable systolic HF as well as patients with left ventricular dysfunction. Although the European Society of Cardiology has established some parameters for the management of acute HF, these guidelines are largely established by expert opinion, and are predominantly devoid of prospective randomized data in this cohort of patients. Current pharmacotherapies for acute decompensated HF include diuretics, neurohormonal antagonists, vasodilators, and inotropes. Regrettably, all of these drugs have their limitations in acute HF. Neurohormonal antagonists reduce morbidity and mortality, but may be inadequate to achieve and maintain the necessary hemodynamic relief required in advanced HF; while, bolus diuretics, a mainstay of initial symptomatic relief, may be maladaptive and up-regulate adverse neurohormonal regulatory mechanisms longterm with no positive impact on longterm mortality. Today, for those advanced HF patients who remain symptomatic despite optimal conventional therapy, limited treatments exist; but as newer therapies evolve, the options will expand to include more than palliative care, heart transplant and ventricular assist devices for these patients.     

Aspirin, clopidogrel, and warfarin use and outcomes in a cohort of 580 patients discharged after hospitalization for decompensated heart failure

The benefits of taking of aspirin, clopidogrel, and warfarin in relation to cardiovascular mortality and re-hospitalization in chronic heart failure (HF) patients have been called into question. We examined the outcomes (cardiac mortality and/or HF re-hospitalization) in patients discharged from our hospital between January 2003 and July 2009 after hospitalization for chronic decompensated HF. Of 580 HF patients (mean age, 63?±?13?years; mean ejection fraction, 26?±?9%, 63% with coronary disease and 37% without coronary disease), 207 patients (36%) died due to cardiovascular reasons, and 313 (54%) required HF re-hospitalization for decompensated HF during a 39?±?14?month follow-up period. 101 (17%) patients were taking clopidogrel during enrollment in the study. When comparing patients who were on clopidogrel treatment with those who were not, clopidogrel was found to have a beneficial effect on cardiac mortality (27 vs. 38%, P?=?0.04). In conclusion, in this observational prospective study, patients who used clopidogrel showed decreased cardiac mortality [HR, 0.566 (95% CI 0.332-0.964), P?=?0.036] compared to patients who did not take clopidogrel. Clopidogrel had a beneficial effect on the survival of chronic HF patients in the long term.     

Clinical trials update from European Society of Cardiology meeting 2008: TIME‐CHF,BACH, BEAUTIFUL,GISSI‐HF,and HOME‐HF

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure presented at the European Society of Cardiology meeting which was held in Munich, Germany from 30th August to 3rd September 2008. Unpublished reports should be considered as preliminary, as analyses may change in the final publication. The TIME‐CHF study failed to show that BNP guided therapy was superior to usual care in patients with heart failure. The BACH study suggested that a new biomarker, MR‐proANP, was as good as BNP for the diagnosis of heart failure in patients presenting with breathlessness. Ivabradine failed to reduce the incidence of cardiovascular events in patients with coronary artery disease and left ventricular systolic dysfunction in the BEAUTIFUL study, but patients with higher heart rates might have benefited. In GISSI‐HF, n–3 PUFA reduced mortality and cardiovascular hospitalisation by a small amount compared to placebo in patients with chronic heart failure, but rosuvastatin had no effect on clinical outcomes. In the HOME‐HF study, telemonitoring support failed to reduce the time to first re‐hospitalisation or death, or days alive and out of hospital, compared with usual care.     

Urgent cardiac resynchronization therapy in patients with decompensated chronic heart failure receiving inotropic therapy. A case series

BACKGROUND: It remains unknown whether patients with severe decompensated class IV heart failure (HF) receiving intravenous inotropic treatment benefit from cardiac resynchronization therapy (CRT). METHODS: We identified patients who underwent urgent CRT implantation due to decompensated class IV HF necessitating intravenous inotropic therapy. RESULTS: Of 10 patients with chronic ischemic cardiomyopathy (median QRS duration of 170 ms), CRT implantation was associated with symptomatic improvement in 8 patients. The mortality rate was 50% during a median follow-up of 9.5 months, with a median CRT-to-death duration of 6 months. CONCLUSIONS: CRT was feasible among class IV patients receiving inotropic treatment and was associated with clinical improvement.     

Neurohormonal Intervention to Reduce Sudden Cardiac Death in Heart Failure: What is the Optimal Pharmacologic Strategy?

Sudden cardiac death (SCD) accounts for up to 50% of deaths in patients with heart failure (HF), depending on severity of symptomatic impairment and left ventricular dysfunction. Neurohormonal therapy directed at the renin-angiotensin-aldosterone system may reduce the propensity to SCD through improved hemodynamic responsiveness, reduced sympathetic tone in the myocardium and inhibition of cardiac remodelling. Angiotensin converting enzyme (ACE) inhibitors reduce overall mortality in chronic HF, the greatest benefit appearing to arises from reduction of HF progression rather than SCD. In HF patients who experience myocardial infarction (MI) reduced incidence in SCD may make a more marked contribution to the mortality benefits of ACE inhibition. Addition of beta-blocker therapy to ACE inhibition has consistently resulted in a reduction in SCD in patients with either mild-to-moderate or severe HF, and in the presence or absence of MI; the reduction in SCD is of the order of one-third versus placebo. Aldosterone blockade reduces the risk of SCD in advanced chronic heart failure (when added to ACE inhibitor) and in HF associated with acute MI (when given in addition to both ACE inhibitor and beta blocker). The evidence base suggests that for maximal SCD risk reduction in HF, beta-blocker therapy is advisable in combination with standard ACE inhibitor therapy, with addition of aldosterone blockade to this regimen for particular groups of heart failure patients.     

Neurohormonal intervention to reduce sudden cardiac death in heart failure: what is the optimal pharmacologic strategy?

Sudden cardiac death (SCD) accounts for up to 50% of deaths in patients with heart failure (HF), depending on severity of symptomatic impairment and left ventricular dysfunction. Neurohormonal therapy directed at the renin-angiotensin-aldosterone system may reduce the propensity to SCD through improved hemodynamic responsiveness, reduced sympathetic tone in the myocardium and inhibition of cardiac remodelling. Angiotensin converting enzyme (ACE) inhibitors reduce overall mortality in chronic HF, the greatest benefit appearing to arises from reduction of HF progression rather than SCD. In HF patients who experience myocardial infarction (MI) reduced incidence in SCD may make a more marked contribution to the mortality benefits of ACE inhibition. Addition of beta-blocker therapy to ACE inhibition has consistently resulted in a reduction in SCD in patients with either mild-to-moderate or severe HF, and in the presence or absence of MI; the reduction in SCD is of the order of one-third versus placebo. Aldosterone blockade reduces the risk of SCD in advanced chronic heart failure (when added to ACE inhibitor) and in HF associated with acute MI (when given in addition to both ACE inhibitor and beta blocker). The evidence base suggests that for maximal SCD risk reduction in HF, beta-blocker therapy is advisable in combination with standard ACE inhibitor therapy, with addition of aldosterone blockade to this regimen for particular groups of heart failure patients.     

Clinical trials update from the European Society of Cardiology Heart Failure Meeting 2010: TRIDENT 1, BENEFICIAL,CUPID, RFA‐HF,MUSIC, DUEL,handheld BNP,phrenic nerve stimulation,CHAMPION and CABG with CRT study

This article provides information and a commentary on key trials relevant to the pathophysiology, prevention and treatment of heart failure (HF) presented at the annual meeting of the Heart Failure Association of the European Society of Cardiology held in Berlin. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. Tonapofylline failed to show efficacy and was associated with an approximately 1% increased risk of seizures in patients with acute decompensated heart failure (ADHF) and renal dysfunction in TRIDENT. Results from BENEFICIAL do not support the use of alagebrium, an advanced glycation end‐product breaker, in clinically stable patients with relatively mild HF symptoms. CUPID showed encouraging preliminary results for augmentation of SERCA2a enzyme activity by gene transfection in patients with severe HF. The RFA‐HF study did not provide convincing evidence for the use of radiofrequency ablation for atrial fibrillation but was underpowered. A wearable, multi‐sensor patch showed potential for detecting impending HF decompensation in MUSIC. A comparison of low‐intensity oral diuretic therapy in patients hospitalized with ADHF suggested that torasemide was superior to furosemide in DUEL. The use of point‐of‐care B‐type natriuretic peptide and echocardiography failed to improve the rate of correct HF diagnosis in primary care. Phrenic nerve stimulation improved symptoms of sleep apnoea in a small study of patients with HF and central sleep apnoea. The use of a novel implantable pulmonary artery pressure monitoring system to guide patient management improved outcomes in the CHAMPION study. A study to evaluate a combined coronary artery bypass grafting (CABG) and epicardial cardiac resynchronization therapy implantation procedure reduced mortality compared with CABG alone.     

Cardio-renal syndrome: an entity cardiologists and nephrologists should be dealing with collegially

Heart failure may lead to acute kidney injury and viceversa. Chronic kidney disease may affect the clinical outcome in terms of cardiovascular morbidity and mortality while chronic heart failure may cause CKD. All these disorders contribute to the composite definition of cardio-renal syndromes. Renal impairment in HF patients has been increasingly recognized as an independent risk factor for morbidity and mortality; however, the most important clinical trials in HF tend to exclude patients with significant renal dysfunction. The mechanisms whereby renal insufficiency worsens the outcome in HF are not known, and several pathways could contribute to the “vicious heart/kidney circle.” Traditionally, renal impairment has been attributed to the renal hypoperfusion due to reduced cardiac output and decreased systemic pressure. The hypovolemia leads to sympathetic activity, increased renin-angiotensin-aldosterone pathways and arginine-vasopressin release. All these mechanisms cause fluid and sodium retention, peripheral vasoconstriction and an increased congestion as well as cardiac workload. Therapy addressed to improve renal dysfunction, reduce neurohormonal activation and ameliorate renal blood flow could lead to a reduction in mortality and hospitalization in patients with cardio-renal syndrome.     

Aging and heart failure: changing demographics and implications for therapy in the elderly

The elderly population (age ≥65) is increasing and with it morbidity, hospitalizations, costs and mortality due to heart failure (HF). HF is a progressive disorder that is superimposed on an on-going aging process. The two broad categories of HF, HF with left ventricular (LV) systolic dysfunction or low ejection fraction (HF/low-EF) and HF with preserved ejection fraction (HF/PEF) are equally prevalent in the elderly. Trials of therapy for HF/low-EF in primarily non-elderly patients showed mortality benefit in elderly patients. In contrast, trials for HF/PEF have not shown mortality benefit in elderly or non-elderly patients. HF pharmacotherapy in the elderly is challenging and needs to be individualized and consider several aging-related changes. More research into the biology of aging and more clinical trials in elderly patients are needed to improve morbidity and mortality in elderly HF patients.     

Clinical trials update from the American College of Cardiology meeting: CARE-HF and the remission of heart failure, Women's Health Study, TNT, COMPASS-HF, VERITAS, CANPAP, PEECH and PREMIER

This article provides information and a commentary on landmark trials presented at the American College of Cardiology meeting held in March 2005, relevant to the pathophysiology, prevention and treatment of heart failure. All reports should be considered as preliminary data, as analyses may change in the final publication. CARE-HF showed that Cardiac Re-synchronisation Therapy, administered in addition to expert pharmacological management, reduced all cause mortality and CV hospitalisation in patients with moderate or severe heart failure and cardiac dyssynchrony. The Women's Health Study showed no benefit of vitamin E supplementation or aspirin in the primary prevention of CV disease. The TNT study showed that reducing LDL cholesterol to levels lower than currently recommended, produced a 22% reduction in the incidence of major cardiovascular events. In COMPASS, an implantable device that continuously monitors intra-cardiac pressures was shown to be safe and to improve care in patients with chronic heart failure. Tezosentan failed to show benefit in patients with acute heart failure in the VERITAS study. The CANPAP study failed to show a benefit of continuous positive airway pressure on mortality and heart transplantation in heart failure patients with central sleep apnoea. EECP therapy improved exercise capacity but had no effect on peak VO2 in heart failure patients in the PEECH study. In the PREMIER study the matrix metalloproteinase inhibitor PG-116800 failed to prevent LV remodelling following myocardial infarction.     

Inotropic Therapy for End-Stage Heart Failure Patients

Positive inotropic agents play an important role in the management of acute decompensated heart failure (HF) patients with reduced cardiac output and poor end-organ perfusion. However, despite their acute hemodynamic benefits, the role of inotropes in the management of chronic advanced HF remains limited. Although digoxin has demonstrated the ability to improve symptoms in HF patients, numerous small, mostly nonrandomized studies have shown that patients with advanced HF improve symptomatically when administered continuous or intermittent intravenous β-agonists or phosphodiesterase inhibitors. However, this improvement occurs at the expense of an increased risk of cardiac arrhythmias, sudden cardiac death, and mortality. Similarly, several oral inotropes have been developed and studied in larger randomized clinical trials. The PROMISE study found that oral milrinone is associated with increased mortality, whereas the ESSENTIAL study showed that oral enoximone does not result in any significant improvement in symptoms, exercise capacity, or survival. The calcium-sensitizing inotrope levosimendan has shown some promise in the management of acute HF patients, but the PERSIST trial showed no improvement in survival or hospitalization rates with chronic oral therapy. This agent is still under investigation and is not available in the United States. Istaroxime, an inotrope with lusitropic properties, is also being investigated for its potential use in advanced HF patients. The current American College of Cardiology/American Heart Association, European Society of Cardiology, and Heart Failure Society of America guidelines indicate that, other than digoxin, inotropic agents should be reserved for patients presenting with acute decompensated HF and low-output states and reduced end-organ perfusion, who typically are admitted to an intensive care unit. These agents also are of benefit in advanced HF patients as a bridge to transplantation to optimize end-organ function and may be used in the outpatient setting, usually in patients with an implantable cardioverter–defibrillator. Finally, inotropes should be used to palliate symptoms in end-stage HF patients who have severe symptoms and are not candidates for heart transplantation or mechanical circulatory support.     

Surgical treatment of heart failure in the elderly

Heart failure (HF) in elderly patients who may benefit from surgical therapy is usually secondary to ischemic or valvular heart disease. When referring such patients for surgery, life expectancy, along with the expectations of the patient and family with regard to the surgical treatment, must be considered. The goals of cardiac surgery in this patient population are to maintain or improve cardiac function, decrease HF episodes, reduce hospital admissions, and improve functional class. Safer surgical techniques developed during the last two decades have allowed high-risk patients well into their 80s to undergo complex cardiac operations with decreasing morbidity and mortality. Successful surgical intervention often leads to a more productive and independent life for elderly patients who have HF.     

Surgical treatment of heart failure in the elderly

Heart failure (HF) in elderly patients who may benefit from surgical therapy is usually secondary to ischemic or valvular heart disease. When referring such patients for surgery, life expectancy, along with the expectations of the patient and family with regard to the surgical treatment, must be considered. The goals of cardiac surgery in this patient population are to maintain or improve cardiac function, decrease HF episodes, reduce hospital admissions,and improve functional class. Safer surgical techniques developed during the last two decades have allowed high-risk patients well into their 80s to undergo complex cardiac operations with decreasing morbidity and mortality. Successful surgical intervention often leads to a more productive and independent life for elderly patients who have HF.     

Percutaneous mechanical devices in the management of decompensated heart failure

Heart failure is the only cardiovascular disease diagnosis increasing in prevalence in the United States. A number of drugs have been shown to reduce morbidity and mortality in patients with chronic heart failure. Despite these advances, the frequency of hospitalization for heart failure has continued to increase, and clinical trial data are lacking in demonstrable benefit of drug therapy for patients hospitalized with acute, decompensated heart failure. A number of percutaneous devices have been developed and are in various stages of investigation and use to improve symptoms and clinical outcomes in patients hospitalized with heart failure. These include “add-on” devices, such as continuous aortic flow augmentation and ultrafiltration devices, and “rescue” devices to be used in patients who are rapidly deteriorating despite medical therapy. In addition to the intra-aortic balloon pump, newer approaches include percutaneous ventricular assist devices that are available for short-term use to stabilize patients until recovery can occur or as “bridges” to longer-term assist or cardiac transplantation. In the coming years, expanded clinical investigation is likely to explore the potential for devices to normalize underlying cardiac function and thereby improve long-term clinical outcomes.     

Strategies to reduce length of stay and costs associated with decompensated heart failure

Heart failure (HF) is a major medical problem in the United States, imposing significant economic burden on the health care system. Despite therapeutic advances, HF-associated morbidity and mortality continue to increase. Compliance with therapeutic guidelines for the management of chronic HF is far from ideal, increasing the likelihood that patients will experience multiple episodes of acute decompensated heart failure (ADHF) during the course of HF disease. Prevention, streamlined inpatient care, effective vasoactive therapy, and initiation of proven long-term therapies, including angiotensin-converting enzyme (ACE) inhibitors and beta-blockers, are all targets for improvement. Because of the chronic nature of heart failure, a successful disease management program for ADHF must also include effective outpatient care.     

Théorie hormonale de l’insuffisance cardiaque à fonction systolique altérée

Heart failure (HF) is a major cause of morbidity and mortality in the developed countries. Hospital discharges and deaths from HF are regularly increasing. Therapies initially aimed at reversing hemodynamic abnormalities in HF, increasing cardiac output, decreasing intracardiac pressures, and blocking vasoconstriction. However, none of these therapies improved survival and some actually increased mortality. Now therapies for HF related to left ventricular systolic dysfunction have focused on counteracting compensatory neurohormonal activation. Several neurohormonal activations are present in HF supporting hemodynamics, but they appear to be deleterious in the long term on the myocardium, increasing progression of the HF and mortality. Blocking the renin–angiotensin–aldosterone system and the sympathetic system are now the mainstay of medical therapy in HF related to systolic dysfunction as they decrease mortality, hospitalisation rate and improve quality of life. Hence, the approach to patient with chronic heart failure should differ from that of patient with acute heart failure.     

Use of traditional and biventricular implantable cardiac devices for primary and secondary prevention of sudden death

Sudden cardiac death is the leading cause of cardiac mortality, particularly among high-risk populations with known left ventricular systolic dysfunction. Multiple randomized clinical trials demonstrated a significant mortality benefit of the implantable cardioverter defibrillator (ICD) compared with antiarrhythmic drug therapy or standard medical care. Initial ICD trials showed a mortality improvement for patients who previously had experienced aborted sudden cardiac death or sustained ventricular tachycardia (secondary prevention). Primary prevention trials in selected high-risk patients who had both ischemic and nonischemic cardiomyopathy also demonstrated a mortality benefit associated with ICD treatment. More recently, cardiac resynchronization therapy with or without defibrillator capability has been shown to reduce morbidity and mortality among advanced heart failure patients with a prolonged QRS duration.     

Heart rate turbulence and death due to cardiac decompensation in patients with chronic heart failure

BACKGROUND: As treatment strategies for patients with chronic heart failure (HF) become more sophisticated, identifying patients at high risk of death and predicting mode of death is important. The aim of this study was to explore the potential utility of heart rate turbulence (HRT) to identify patients with HF at high risk of death. METHODS AND RESULTS: In a prospective study, 553 ambulant outpatients age 63+/-10 with symptoms of HF and evidence of cardiac dysfunction were recruited. All patients underwent 24-h Holter ECG recordings, which were analysed for arrhythmias, heart rate variability and HRT a measurement that is thought to quantify cardiac autonomic regulatory mechanisms. Baseline chest radiograph, biochemistry and 12-lead electrocardiograms were also obtained. In patients with HRT measurements at 5 years follow up, 146 patients had died, 59 due to decompensated HF. Independent predictors of death from decompensated HF at 5-year follow up (Cox proportional hazard model) were HRT slope (HR for 10% increment 0.84, 95% CI 0.77-0.91), serum sodium (HR for 10% increment 0.75, 95% CI 0.62-0.91) and serum creatinine (for 10% increment HR 1.14, 95% CI 1.08-1.19) all P<0.01. These 3 variables combined had excellent discrimination between patients dying of decompensated HF and other patients, C-statistic=0.82. CONCLUSIONS: In patients with mild-to-moderate HF, HRT slope is an independent predictor of death due to decompensated HF. HRT may have the potential to help tailor therapy in this patient group.