Clinical trials update and cumulative meta-analyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO-Lipids and cardiac resynchronisation therapy in heart failure

This article continues a series of reports on recent research developments in the field of heart failure. Key presentations made at the American College of Cardiology meeting, held in New Orleans, Louisiana, USA in March 2004 are reported. These new data have been added to existing data in cumulative meta-analyses. The WATCH study randomised 1587 patients with heart failure and left ventricular systolic dysfunction to warfarin, aspirin or clopidogrel. The study showed no difference between the effects of these agents on mortality or myocardial infarction, but hospitalisations for heart failure were higher on aspirin (22.2%) compared to warfarin (16.1%). The SCD-HeFT study showed that ICD therapy reduced all-cause mortality at 5 years by 23% in patients with predominantly NYHA class II heart failure and left ventricular systolic dysfunction, but amiodarone was ineffective. The DINAMIT study showed that ICD therapy was not beneficial in patients with left ventricular dysfunction after a recent MI, even in those with risk factors for arrhythmic death. In CASINO, levosimendan improved survival compared with dobutamine or placebo in patients with decompensated heart failure. INSPIRE showed that SPECT imaging can be used to assess risk early after acute MI safely and accurately. Rimonabant was shown to be safe and effective in treating the combined cardiovascular risk factors of smoking and obesity. An overview of new developments in cardiac resynchronisation therapy (CRT) in heart failure is also reported.     

Kardiale Resynchronisationstherapie—immer mit ICD?

Sudden cardiac death is responsible for about 50% of all deaths in heart failure. In studies on primary and secondary prevention of sudden cardiac death, the implantable cardioverter defibrillator (ICD) has proven superior to antiarrhythmic drug therapy mainly in patients with coronary artery disease and reduced left ventricular function. Thus, in recent years the question arose whether prophylactic ICD treatment can reduce mortality as well in an unselected patient group with heart failure of any etiology. This is even more important for patients that are candidates for cardiac resynchronization therapy because, first, presence of an intraventricular conduction delay indicates an increased risk of sudden death and, second, the additional operative morbidity of ICD implantation is minimal compared to implant of a biventricular pacemaker. Recent studies have proven the benefit of conventional ICD treatment in patients with heart failure as well as the benefit of biventricular pacing in heart failure patients with ventricular conduction delay. In the present article, these studies and their influence on the system choice in cardiac resynchronization therapy are discussed.     

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 2006: OAT, SALT 1 and 2, MAGIC, ABCD, PABA-CHF, IMPROVE-CHF, and percutaneous mitral annuloplasty

This article provides information and a commentary on trials presented at the American Heart Association meeting held in November 2006, 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. The OAT study failed to show a benefit of PCI over optimal medical therapy in patients with persistent total occlusion of the infarct related artery following a myocardial infarction. In SALT 1 and 2, tolvaptan was found to correct hyponatraemia of various aetiologies; however, whether this has an impact on heart failure prognosis requires further evaluation. A placebo controlled study of myocardial implantation of skeletal myoblasts in patients with moderate to severe LVSD (MAGIC) showed equivocal/uncertain effects, long term follow-up data are awaited. The ABCD study which compared the ability of an invasive and a non-invasive test to identify patients at risk of arrhythmic events prior to ICD implantation, suggested that the two strategies were comparable, although the practical value of either test remains uncertain and the study had many major flaws. The PABA-CHF study hinted that pulmonary vein antrum isolation might be more effective than AV node ablation with bi-ventricular pacing for the treatment of patients with heart failure in atrial fibrillation. In IMPROVE-CHF, an NT-pro BNP guided treatment strategy was found to reduce the cost of managing patients with acute breathlessness.     

Clinical trials update from the American College of Cardiology 2007: ALPHA, EVEREST, FUSION II, VALIDD, PARR-2, REMODEL, SPICE, COURAGE, COACH, REMADHE, pro-BNP for the evaluation of dyspnoea and THIS-diet

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the American College of Cardiology meeting in March 2007. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication. The ALPHA study suggested that patients with heart failure (HF) due to idiopathic dilated cardiomyopathy who have a negative T-wave alternans test have a good prognosis and are unlikely to benefit from ICD therapy. EVEREST provides some evidence of short-term symptom benefit of tolvaptan in patients with acute decompensated HF but no clinically important long-term benefit. FUSION II failed to show a benefit of nesiritide in patients with chronic decompensated HF. Reducing blood pressure in hypertensive patients improved diastolic dysfunction in VALIDD. Eplerenone did not improve left ventricular remodelling in mild to moderate chronic HF. Selecting HF patients for revascularisation using FDG-PET imaging did not significantly improve outcome. Crataegus extract added to standard HF therapy did not reduce morbidity or mortality in SPICE. The COURAGE study, conducted in patients without HF or major cardiac dysfunction, showed that PCI did not reduce cardiac morbidity or mortality and can be safely deferred in patients with stable coronary disease on optimal medical therapy. The COACH study failed to show that HF nurse-intervention could reduce hospitalisations but did show trends to lower mortality, especially amongst patients with reduced ejection fraction; however, the smaller REMADHE study suggested striking benefits on morbidity and mortality. A large study of BNP provided additional information on its ability to distinguish cardiac and pulmonary breathlessness. The importance of dietary intervention in post-MI patients was highlighted by the findings of THIS-diet study.     

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.     

Clinical trials update from the European Society of Cardiology Heart Failure meeting: SHAPE, BRING-UP 2 VAS, COLA II, FOSIDIAL, BETACAR, CASINO and meta-analysis of cardiac resynchronisation therapy

This article continues a series of reports on recent research developments in the field of heart failure. Key presentations made at the European Society of Cardiology Heart Failure Update meeting, held in Wroclaw, Poland, in June 2004 are reported. The SHAPE study identified a need to educate general practitioners (GPs) in order to optimise treatment of heart failure in primary care. BRING-UP 2 VAS showed that cognitive impairment is very common in elderly heart failure patients and that these patients require specialist care. Carvedilol was shown to be well tolerated and effective in elderly heart failure patients in the observational COLA II study. In the FOSIDIAL study of patients with end-stage renal disease, fosinopril showed no benefit over placebo in reducing the incidence of cardiovascular events in these high-risk patients. The BETACAR study showed that carvedilol and metoprolol produced a similar effect on left ventricular ejection fraction (+13.1% and +12.0%, respectively). Revised mortality data for the CASINO study and a meta-analysis of the effects of cardiac resynchronisation therapy on mortality in the light of the recently published COMPANION study are reported.     

Implantable device therapy

Sudden cardiac death (SCD) accounts for two-thirds of fatal events related to heart disease. Coronary heart disease and non-ischemic cardiomyopathy are the most common causes of SCD. Data from major randomized trials have consistently shown that therapy with an implantable cardioverter defibrillator (ICD) results in a significant and meaningful effect on survival through a reduction in the risk of SCD in these population. These data have resulted in a marked increase in the application of implantable device therapy in the past 2 decades from secondary prevention with an implantable cardioverter/defibrillator (ICD) in survivors of a cardiac arrest to primary prevention of SCD in asymptomatic patients with ischemic and non-ischemic left ventricular dysfunction, and prevention of symptomatic heart failure progression and death with cardiac resynchronization therapy (CRT), and devices that combine CRT and ICD therapies (CRT-D). However, there are still areas of uncertainty regarding device therapy that include inconsistent benefit in risk-subgroups of patients with low ejection fraction; increased risk of heart failure after life-prolonging ICD therapy, and a considerable rate of device malfunction despite increasing sophistication. In the present review we focus on current data regarding the clinical indications as well as the safety and efficacy of implantable device therapy, including ICD, CRT, and CRT-D.     

Biventricular pacing and defibrillator use in chronic heart failure

Since the 1970s when the implantable cardioverter defibrillator (ICD) was developed, multiple clinical trials have documented survival benefits in certain high-risk subsets of heart failure patients. Over the past decade, cardiac resynchronization therapy (CRT) emerged as an important therapy in carefully selected patients with ongoing symptoms despite optimized pharmacological therapy. ICDs should be considered first-line therapy for survivors of life-threatening ventricular arrhythmic events. Subsets of patients with both ischemic and nonischemic dilated cardiomyopathy appear to have a survival benefit from primary ICD therapy. CRT has resulted in substantial symptomatic improvement and survival benefits in a subgroup of chronic heart failure patients. CRT should be considered in heart failure patients undergoing ICD implantation who have evidence of ventricular dyssynchrony.     

Clinical trials update from the Heart Failure Society of America: EMOTE, HERB-CHF, BEST genetic sub-study and RHYTHM-ICD

This article summarises key presentations relevant to the pathophysiology, prevention or treatment of heart failure, from the Heart Failure Society of America annual meeting held in Toronto, Canada. Data from the EnoxiMone in intravenous inOTropE-dependent subjects (EMOTE) study suggest that the oral PDE-3 inhibitor enoximone may be effective for weaning severe heart failure patients from intravenous inotropic therapy. Hawthorn Extract Randomised Blinded Trial in CHF (HERB-CHF) failed to show a benefit of hawthorn extract added to conventional heart failure therapy. A genetic sub-group analysis of the Blocker Evaluation of Survival Trial (BEST) study showed that bucindolol reduced mortality and hospitalisations in patients who were homozygous for the Arg389 variant of the beta(1) adrenoceptor. In the Resynchronisation Hemodynamic Treatment for Heart Failure Management (RHYTHM-ICD) study, patients randomised to cardiac resynchronisation therapy (CRT) showed an improvement in symptoms and functional capacity compared to the control group.     

Implantable cardioverter-defibrillators: a new preventive medical option

Implantable cardioverter-defibrillator (ICD or defibrillator) therapy has revolutionized the fields of cardiology and electrophysiology. Hundreds of thousands of patients at risk for sudden cardiac death receive them each year. The devices are not much larger than a pacemaker, and they have full pacemaker capabilities in addition to being able to shock patients out of life-threatening ventricular arrhythmias. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) in 1996 was a landmark trial that showed for the first time a mortality benefit of ICD therapy over medications in patients at high risk for sudden death. Multicenter Automatic Defibrillator Implantation Trial II, published in 2002, extended these results to all patients with ischemic heart failure with depressed heart function. Candidates for ICD implantation include most patients with an ejection fraction of <30%, especially those with coronary artery disease. More work needs to be done to define those patients with nonischemic cardiomyopathies who will benefit from ICDs and biventricular pacing for heart failure.     

Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001

This is a synopsis of presentations made at the American College of Cardiology (ACC) in 2001 summarising recent research developments relating to heart failure. Clinical studies of particular interest to physicians with an interest in heart failure and its prevention are reviewed. The COPERNICUS trial lends further support to the use of the beta-blocker, carvedilol, in severe heart failure and the CAPRICORN trial to its use in patients with post-infarction left ventricular systolic dysfunction. The MIRACLE study reinforces the evidence from three smaller trials that cardiac resynchronisation therapy is an effective treatment for the relief of symptoms in patients with severe heart failure and cardiac dyssynchrony. The STAF trial casts further doubt on the wisdom of cardioversion as a routine strategy for the management of chronic atrial fibrillation. The RITZ-2 trial suggests that an intravenous, non-selective endothelin antagonist is effective in improving haemodynamics and symptoms and possibly in reducing morbidity in severe heart failure. Observational studies in heart failure suggest that a moderate excess of body fat and elevated blood cholesterol may be desirable in patients with heart failure, challenging the current non-evidenced-based vogue for cholesterol lowering therapy in heart failure. The RENAISSANCE and RECOVER outcome studies of etanercept, a tumour necrosis factor (TNF) receptor analogue that blocks the effect of TNF, were stopped because of lack of evidence of benefit shortly after the ACC.     

New indications for implantable defibrillator therapy

Implantable cardioverter Defibrillator (ICD) therapy has been extensively evaluated in patients at high risk of sudden cardiac death. Most recently, the Sudden Cardiac Death in Heart Failure Trial found that patients with moderate symptoms of congestive heart failure, whether due to an ischemic or a nonischemic cause, have reduced mortality compared with patients treated only with conventional medical therapy for heart failure. The results of this trial confirm those of earlier trials finding a benefit of ICD therapy in patients with coronary artery disease and reduced left ventricular systolic function, and extend the indications for ICD therapy to those without coronary artery disease.     

Clinical trials update from the American Heart Association meeting: ACORN-CSD, primary care trial of chronic disease management, PEACE, CREATE, SHIELD, A-HeFT, GEMINI, vitamin E meta-analysis, ESCAPE, CARP, and SCD-HeFT cost-effectiveness study

This article provides information and a commentary on landmark trials presented at the American Heart Association meeting held in November 2004, relevant to the pathophysiology, prevention, and treatment of heart failure. An open trial of the ACORN Cardiac Support Device (CSD) showed encouraging preliminary results in patients with severe heart failure. The PEACE (Prevention of Events with Angiotensin-Converting Enzyme inhibition) study supports data from previous studies showing that ACE inhibitors reduce vascular events in patients at increased risk. The CREATE (clinical trial of metabolic modulation in acute MI treatment evaluation) study of patients with acute myocardial infarction (MI) showed no mortality benefit of a glucose/insulin/potassium regimen, but treatment with reviparin reduced the incidence of death, MI, or stroke. Azimilide was not associated with a significant reduction in shocks, but reduced the shocks or episodes of markedly symptomatic ventricular tachycardia terminated by pacing in the SHIELD (Shock Inhibition Evaluation with Azimilide) study. The addition of isosorbide dinitrate plus hydralazine to standard therapy improved survival in black heart failure patients in the A-HeFT (African-American Heart Failure Trial) study. In an investigation of hypertensive patients with diabetes, carvedilol had fewer adverse effects on diabetic control than metoprolol. A meta-analysis of high-dose vitamin E supplementation suggested an association with increased mortality. The ESCAPE (Evaluation Study of CHF and Pulmonary Artery Catheterisation Effectiveness) study showed no benefit of pulmonary artery catheterisation over clinical management in patients with severe heart failure. Routine prophylactic coronary revascularisation for stable coronary disease prior to major vascular surgery showed no benefit in the CARP (Coronary Artery Revascularization Prophylaxis) study. Analysis of data from SCD-HeFT supports the cost-effectiveness of ICDs in heart failure, although overall cost implications may be prohibitive.     

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.     

Cardiac resynchronization therapy: which device to implant?

Cardiac resynchronization therapy is now a validated treatment for patients with moderate to severe heart failure despite optimal drug treatment with left ventricular systolic dysfunction and cardiac dyssynchrony defined by wide QRS greater than 120 ms. Once an indication for cardiac resynchronization therapy has been confirmed the choice of the most appropriate device (pacemaker or intracardiac cardioverter defibrillator (ICD)) needs to be made. In heart failure patients the risk of sudden death, mainly but not always related to arrhythmic cause is high. Previous studies of primary prevention of sudden cardiac death in patients with a poor left ventricular function have shown that ICD therapy significantly reduces overall mortality and arrhythmic mortality. However patients candidates to cardiac resynchronization therapy are different from those included in the ICDs trials because they are older and have more comorbidities. The choice of the devices has to consider the potential benefit of the therapy, the comorbidities, the life expectancy but also the cost-effectiveness and the potential complications related to the device. Now, new devices provide information about the hemodynamic status of this heart failure population and thus provide an early detection of heart failure decompensation. The development of home monitoring should alert very early the physicians of the occurrence of a heart failure decompensation and thus to avoid recurrent hospitalisations for heart failure decompensation.     

Sudden Cardiac Death in Dilated Cardiomyopathy – Therapeutic Options

BACKGROUND: Despite routine use of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and spironolactone in patients with heart failure due to dilated cardiomyopathy (DCM), these patients still have a considerable annual mortality rate of 5-10%. Sudden unexpected death accounts for up to 50% of all deaths and is most often due to rapid ventricular tachycardia or ventricular fibrillation and less often due to bradyarrhythmias or asystole. THERAPEUTIC OPTIONS: The use of beta-blockers in patients with heart failure has been shown to improve overall mortality considerably. This survival benefit has been demonstrated for bisoprolol, metoprolol and carvedilol. Therefore, one of these three beta-blocking agents should be administered routinely starting with low doses in all patients with New York Heart Association (NYHA) class II or III heart failure in addition to ACE inhibitors, unless there is a contraindication to beta-blocker use. In addition, NYHA class IV heart failure patients have been shown to benefit from carvedilol therapy, if tolerated. The conflicting results of GESICA and CHF-STAT studies do not support a strategy of "prophylactic" amiodarone therapy in patients with DCM in order to prevent sudden cardiac death. Despite growing evidence that implantable cardioverter defibrillator (ICD) therapy results in improved overall survival py preventing sudden cardiac death in patients at high risk for serious arrhythmic events, arrhythmia risk stratification with regard to prophylactic ICD implantation remains highly controversial in patients with DCM. CONCLUSION: This review describes potential arrhythmia mechanisms in DCM and summarizes the results of antiarrhythmic drug trials and of prophylactic ICD trials in patients with heart failure as well as our knowledge concerning arrhythmia risk stratification in patients with DCM.     

Ethical Challenges of Deactivation of Cardiac Devices in Advanced Heart Failure

More than 23 million adults worldwide have heart failure (HF). Although survival after heart failure diagnosis has improved over time, mortality from heart failure remains high. At the end of life, the chronic HF patient often becomes increasingly symptomatic, and may have other life-limiting comorbidities as well. Multiple trials have shown a clear mortality benefit with the use of implantable cardioverter defibrillators (ICDs) in patients with cardiomyopathy and ventricular arrhythmia. However, patients who have an ICD may be denied the chance of a sudden cardiac death, and instead are committed to a slower terminal decline, with frequent DC shocks that can be painful and decrease the quality of life, greatly contributing to their distress and that of their families during this period. While patients with ICDs are routinely counseled with regard to the benefits of ICDs, they have a poor understanding of the options for device deactivation and related ethical and legal implications. Deactivating an ICD or not performing a generator change is both legal and ethical, and is supported by guidelines from both sides of the Atlantic. Patient autonomy is paramount, and no patient is committed to any therapy that they no longer wish to receive. Left ventricular assist devices (LVADs) were initially used as bridge in patients awaiting heart transplantation, but they are currently implanted as destination therapy (DT) in patients with end-stage heart failure who have failed to respond to optimal medical therapy and who are ineligible for cardiac transplantation. The decision-making process for initiation and deactivation of LVAD is becoming more and more ethically and clinically challenging, particularly for elderly patients.     

Current role of device therapy to reduce sudden cardiac death in heart failure

Sudden cardiac death (SCD) continues to be a major contributor to mortality in patients with heart failure (HF) despite recent advances in medical therapy. Device therapy, including the implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT), serves as an adjunct in reducing HF mortality. Several clinical trials support the prophylactic use of the ICD in reducing mortality in certain HF populations and have established the clinical benefits of CRT in advanced HF. More recently, the Comparison of Medical Therapy Pacing and Defibrillation in Heart Failure trial was the first study to demonstrate a survival benefit of CRT alone or in conjunction with an ICD. This article reviews the most pertinent data regarding the role of device therapy in reducing SCD in HF and addresses future challenges faced by device manufacturers and clinicians.     

Implantable cardioverter-defibrillator efficacy in patients with heart failure and left ventricular dysfunction (from the MADIT II population)

The Multicenter Automatic Defibrillator Implantation Trial II demonstrated a significant 31% reduction in the risk of mortality in postinfarction patients with low ejection fraction (EF < or =30%). Recently, results from the Sudden Death in Heart Failure Trial indicated that a subgroup of patients with New York Heart Association (NYHA) class III heart failure had less benefit from an implantable cardioverter-defibrillator (ICD) than patients with less advanced heart failure. This study evaluates the association between NYHA class, EF, and blood urea nitrogen (BUN) levels as measures of heart failure and left ventricular dysfunction, and ICD benefit in reducing mortality as well as the association of these parameters with ICD therapy for ventricular tachyarrhythmias. NYHA class I was identified in 442 patients (36%), class II in 425 (35%), and class III in 350 patients (29%). EF < or =20% was present in 472 patients (38%), EF of 21% to 25% in 359 patients (29%), and EF of 26% to 30% in 401 patients (33%). BUN < or =25 mg/dl was present in 850 patients (70%) and >25 mg/dl in 368 patients (30%). Patients with higher NYHA class and BUN had higher mortality (34%) and a higher risk of arrhythmic events (33% to 35%) than patients in lower functional groups (16% to 20%). EF did not differentiate the risk. There was no evidence for significant interactions between mortality, ICD therapy, and tested parameters. In conclusion, patients with more advanced heart failure have a higher risk of mortality and arrhythmic events than patients with less severe disease. However, there is no significant difference in the benefit from ICD therapy among the above subgroups of patients in the Multicenter Automatic Defibrillator Implantation Trial.