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.     

Overview of the results of recent beta blocker trials

Results of the studies published or reported within the last 2 years provide convincing evidence that beta-blockers can decrease mortality in patients with chronic symptomatic heart failure because of left ventricular systolic dysfunction. The Cardiac Insufficiency Bisoprolol Study (CIBIS)-II and Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) trials showed a 34% reduction in all-cause death with bisoprolol and metoprolol therapy in patients with class II-III heart failure. Data from Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS), with a 35% mortality reduction, extended this benefit to class IV patients treated with carvedilol who do not require intravenous diuretics or positive inotropes. Ongoing beta-blocker studies address new topics, such as treatment of older patients, in whom diastolic heart failure may be more common, and direct comparison of different drugs. Although the use of beta-blockers for heart failure tends to increase, implementation of the knowledge from the trials in clinical practice still remains a challenge.     

Update of REACH-1 and MERIT-HF clinical trials in heart failure. Cardio.net Editorial Team

BACKGROUND: This article reviews the design and results of REACH-1 (Research on Endothelin Antagonism in Chronic Heart Failure) and MERIT (Metoprolol controlled and Extended release, Randomised Intervention Trial in congestive Heart Failure), two recently reported clinical trials that investigated, respectively, the role of a non-selective endothelin antagonist (bosentan) and of a beta-selective blocker for the treatment of heart failure. RESULTS: The REACH-1 trial demonstrated that initiation of bosentan therapy is associated with an increased risk of worsening heart failure. However, long-term therapy with bosentan may have improved symptoms and favourably altered the progression of heart failure. The MERIT-HF clinical trial indicated that beta-blockade using metoprolol confers a significant beneficial effect on total mortality in patients with stable chronic heart failure.     

Emerging role of pharmacogenomics in heart failure

PURPOSE OF REVIEW: The promise of pharmacogenomics is that it will one day result in targeted heart failure therapy that maximizes individual benefit and diminishes risk. Recent reports from the Beta Blocker Evaluation Survival and African American Heart Failure clinical trials provide a roadmap of how this promise may soon be realized. This review will discuss recent investigations of pharmacogenomics in heart failure, and the challenge of converting genomic heterogeneity into a usable clinical tool. RECENT FINDINGS: Genomic analysis from randomized clinical trials has been increasingly utilized to investigate genetic variables that affect drug response. Analysis from the Beta Blocker Evaluation Survival Trial, demonstrates the impact of beta-blockers on survival was primarily in patients with the beta-1 adrenergic receptor Arg389Arg genotype. The efficacy of angiotensin-converting enzyme inhibitors and the combination of isosorbide dinitrate and hydralazine differs in black and white heart failure cohorts. Initial reports from the African American Heart Failure Trial demonstrate the impact of aldosterone synthase polymorphism on left ventricle remodeling, outcomes and the impact of isosorbide dinitrate and hydralazine. Investigations from the African American Heart Failure Trial will continue to focus on determining the genomic bases for observed racial differences in therapeutic efficacy. An era of polygenic analysis, aided by Genome Wide Association Studies, should soon be upon us. SUMMARY: Modern clinical trials will increasingly have a pharmacogenetic component to allow more efficient targeting of therapeutics. Investigators are beginning to delineate the genomic basis for differences in drug efficacy between black and white heart failure cohorts. Pharmacogenomics will have an increasing role in the treatment of heart failure patients.     

Endothelial dysfunction and nitric oxide enhancing therapy: a new approach to the treatment of heart failure

Despite ethnic differences in heart failure prevalence, risk profiles, and outcomes, no clinical trials have been designed to prospectively examine the mechanisms responsible for these differences. The African-American Heart Failure Trial is the first prospective trial designed to test a novel therapy that enhances endothelial function and nitric oxide bioavailability in African-American patients with advanced heart failure.     

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.     

The impact of race on response to RAAS inhibition

Retrospective analyses of the Studies of Left Ventricular Dysfunction (SOLVD) and Vasodilator Heart Failure Trials (V-HeFT) have addressed the question of whether angiotensin-converting enzyme (ACE) inhibitors are equally efficacious in black patients and white patients with heart failure. In SOLVD, there was no ethnic difference in the efficacy of enalapril for reducing mortality and preventing the development of heart failure, but enalapril was more effective in whites in reducing hospitalizations. In V-HeFT II, enalapril was more efficacious than the combination of isosorbide dinitrate and hydralazine in whites in reducing mortality, but not in blacks. However, the combination of isosorbide dinitrate and hydralazine may be particularly advantageous in black patients as suggested by V-HeFT I and the recent African American Heart Failure Trial. In aggregate, the available data suggest that ACE inhibitors should remain a cornerstone of therapy for heart failure with a reduced ejection fraction in white patients and black patients.     

The impact of chronic heart failure on health-related quality of life data acquired in the baseline phase of the CARE-HF study

AIMS: To assess the quality of life of patients with heart failure, due to left ventricular dysfunction (NYHA class III or IV), taking optimal medical therapy using baseline quality of life assessments from the CArdiac REsynchronisation in Heart Failure (CARE-HF) trial, and to evaluate the appropriateness of using the EQ-5D in patients with heart failure. METHODS AND RESULTS: The quality of life of patients enrolled in CARE-HF was evaluated using the EQ-5D and Minnesota Living with Heart Failure Questionnaire. Response rates for the instruments were >90% and statistical modelling revealed an association between EQ-5D and Minnesota Living with Heart Failure scores. Heart failure is shown to have an important impact on all aspects of quality of life, but particularly on patients' mobility and usual activities, and leads to significant reductions in comparison with a representative sample of the UK population. CONCLUSIONS: The impact of heart failure varies amongst patients but the overall burden of disease appears to be comparable to other chronic conditions such as motor neurone or Parkinson's disease. The EQ-5D appears to be an acceptable valid measure for use in patients with heart failure although further evidence of the responsiveness of this measure in such patients is required.     

Rationale, design, and methods for a pivotal randomized clinical trial of continuous aortic flow augmentation in patients with exacerbation of heart failure: the MOMENTUM trial

BackgroundFor patients hospitalized with heart failure (HF) who are inadequately responsive to medical therapy, the options include ventricular assist devices and cardiac transplant. In animal models and patients, continuous aortic flow augmentation using the Orqis Medical Cancion System (Orqis Medical Corporation, Lake Forest, California), a percutaneously placed arterial-to-arterial circuit (continuous flow up to 1.5 L/min) with an extracorporeal, magnetic, centrifugal pump, improves hemodynamics and renal function with benefits persisting 24 hours after discontinuation.Methods and ResultsThe Multi-center Trial of the Orqis Medical Cancion System for the Enhanced Treatment of Heart Failure Unresponsive to Medical Therapy is enrolling patients hospitalized with HF who are randomized to continuous aortic flow augmentation or medical therapy alone. Entry requires persistent HF, elevated pulmonary capillary wedge pressure, reduced cardiac index, and impaired renal function or substantial diuretic requirement despite intravenous inotrope or vasodilator treatment. The primary efficacy end point is a composite including the components of 72- to 96-hour pulmonary capillary wedge pressure reduction and days alive out of hospital with no mechanical support for more than 35 days. Additional end points include changes in serum creatinine, N-terminal pro-B-type natriuretic peptide, and health-related quality of life.ConclusionsThe Multi-center Trial of the Orqis Medical Cancion System for the Enhanced Treatment of Heart Failure Unresponsive to Medical Therapy tests the hypothesis that continuous aortic flow augmentation improves the clinical status and outcomes in patients hospitalized with HF exacerbation who are inadequately responsive to medical therapy.     

Anemia in heart failure: To treat or not to treat?

Opinion statement  Anemia is a prevalent comorbidity in chronic heart failure (CHF). As studies have demonstrated close links between anemia and a poorer prognosis, there has been an interest in developing treatment strategies for this condition. Anemia is closely associated with disease severity and may be secondary to multiple modifiable causes; therefore, the initial strategies should always include a thorough search for etiology and should focus on optimizing heart failure treatment. Recently, more specific therapies have been assessed, namely erythropoiesis-stimulating agents and iron supplementation therapy. Studies evaluating erythropoietin in heart failure have demonstrated conflicting results to date, with smaller, singlecenter studies seeming to show a clinical benefit and larger, multicenter trials demonstrating no significant effect on clinical outcome aside from improvement in selected quality-of-life indices. Similarly, studies evaluating iron therapy alone in anemic patients with heart failure have so far shown promising results with regard to clinical and quality-of-life outcomes, but these studies are limited in that they involved small patient numbers. Ongoing studies such as the Reduction of Events With Darbepoetin Alfa in Heart Failure (RED-HF), Iron Supplementation in Heart Failure Patients With Anemia (IRON-HF), and Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure (FAIR-HF) trials will determine the value of darbepoetin alfa and intravenous iron replacement therapy in anemic CHF patients.     

A comparative analysis of the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS

BACKGROUND: Recent large randomized, controlled trials (BEST [Beta-blocker Evaluation of Survival Trial], CIBIS-II [Cardiac Insufficiency Bisoprolol Trial II], COPERNICUS [Carvedilol Prospective Randomized Cumulative Survival Study], and MERIT-HF [Metoprolol Randomized Intervention Trial in Congestive Heart Failure]) have addressed the usefulness of beta-blockade in the treatment of advanced heart failure. CIBIS-II, COPERNICUS, and MERIT-HF have shown that beta-blocker treatment with bisoprolol, carvedilol, and metoprolol XL, respectively, reduce mortality in advanced heart failure patients, whereas BEST found a statistically nonsignificant trend toward reduced mortality with bucindolol. We conducted a post hoc analysis to determine whether the response to beta-blockade in BEST could be related to differences in the clinical and demographic characteristics of the study populations. We generated a sample from BEST to resemble the patient cohorts studied in CIBIS-II and MERIT-HF to find out whether the response to beta-blocker therapy was similar to that reported in the other trials. These findings are further compared with COPERNICUS, which entered patients with more severe heart failure. METHODS: To achieve conformity with the entry criteria for CIBIS-II and MERIT-HF, the BEST study population was adjusted to exclude patients with systolic blood pressure <100 mm Hg, heart rate <60 bpm, and age >80 years (exclusion criteria employed in those trials). The BEST comparison subgroup (BCG) was further modified to more closely reflect the racial demographics reported for patients enrolled in CIBIS-II and MERIT-HF. The association of beta-blocker therapy with overall survival and survival free of cardiac death, sudden cardiac death, and progressive pump failure in the BCG was assessed. RESULTS: In the BCG subgroup, bucindolol treatment was associated with significantly lower risk of death from all causes (hazard ratio (HR)=0.77 [95% CI=0.65, 0.92]), cardiovascular death (HR=0.71 [0.58, 0.86]), sudden death (HR=0.77 [0.59, 0.999]), and pump failure death (HR=0.64 [0.45, 0.91]). CONCLUSIONS: Although not excluding the possibility of differences resulting from chance alone or to different properties among beta-blockers, this study suggests the possibility that different heart failure population subgroups may have different responses to beta-blocker therapy.     

Rationale and design of the Valsartan Heart Failure Trial: a large multinational trial to assess the effects of valsartan, an angiotensin-receptor blocker, on morbidity and mortality in chronic congestive heart failure.

BACKGROUND: To investigate the role of persistent angiotensin activity despite angiotensin-converting enzyme inhibitor therapy in the progression of heart failure, the Valsartan Heart Failure Trial has been designed to investigate the effect of the angiotensin-receptor blocker, valsartan, on morbidity and mortality. METHODS AND RESULTS: Nearly 5,000 patients with New York Heart Association classes II to IV heart failure, while receiving all standard therapy, are being randomized to treatment with valsartan, 160 mg twice daily, or placebo in a worldwide study. Follow-up will be continued until 906 deaths have been recorded. Additional end points will include the need for hospitalization, other major morbid events, quality--of life measurement, changes in neurohormone levels, and changes in left ventricular size and function. Substudies will explore exercise tolerance, arrhythmias, and magnetic resonance imaging. CONCLUSION: This study should help establish the role of angiotensin-receptor blockade in the treatment of heart failure.     

Early initiation of beta blockade in heart failure: issues and evidence

Despite clinical trials demonstrating that inhibitors of the renin-angiotensin and sympathetic nervous systems can reduce the mortality and morbidity risk associated with heart failure, these drugs have remained underutilized in general clinical practice. In particular, many patients with heart failure due to left ventricular systolic dysfunction fail to receive beta blockers, although this class of drugs, as well as other antihypertensive agents such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, are recommended as part of routine heart failure therapy by national expert consensus guidelines. In-hospital initiation of beta-blocker therapy may improve long-term utilization by physicians and compliance by patients through obviating many of the misperceived dangers associated with beta blockade. The following review of the clinical trial data from the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, the Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial, and the Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial on the efficacy, safety, and tolerability of beta blockers indicates that early initiation can be safely achieved and can improve patient outcomes.     

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.     

Early Initiation of β Blockade in Heart Failure: Issues and Evidence

Despite clinical trials demonstrating that inhibitors of the renin-angiotensin and sympathetic nervous systems can reduce the mortality and morbidity risk associated with heart failure, these drugs have remained underutilized in general clinical practice. In particular, many patients with heart failure due to left ventricular systolic dysfunction fail to receive β blockers, although this class of drugs, as well as other antihypertensive agents such as angiotensinconverting enzyme inhibitors or angiotensin receptor blockers, are recommended as part of routine heart failure therapy by national expert consensus guidelines. In-hospital initiation of β-blocker therapy may improve long-term utilization by physicians and compliance by patients through obviating many of the misperceived dangers associated with β blockade. The following review of the clinical trial data from the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, the Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial, and the Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial on the efficacy, safety, and tolerability of β blockers indicates that early initiation can be safely achieved and can improve patient outcomes.     

Hospital Management of Acute Decompensated Heart Failure

Heart failure (HF) is one of the leading causes of hospitalizations for elderly adults in the United States. One in 5 Americans will be >65 years of age by 2050. Because of the high prevalence of HF in this group, the number of Americans requiring hospitalization for this disorder is expected to rise significantly. We reviewed the most recent and ongoing studies and recommendations for the management of patients hospitalized due to decompensated HF. The Acute Decompensated Heart Failure National Registry, together with the 2013 American College of Cardiology Foundation and American Heart Association heart failure guidelines, earlier retrospective and prospective studies including the Diuretic Optimization Strategies Evaluation (DOSE), the Trial of Intensified vs Standard Medical Therapy in the Elderly Patients With Congestive Heart Failure (TIME-CHF), the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE–HF), the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT) and the Comparison of Medical, Pacing and Defibrillation Therapies in Heart Failure (COMPANION) trial were reviewed for current practices pertaining to these patients. Gaps in our knowledge of optimal use of patient-specific information (biomarkers and comorbid conditions) still exist.     

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.     

Clinical trials update from the European Society of Cardiology heart failure meeting 2009: CHANCE,B‐Convinced,CHAT, CIBIS‐ELD,and Signal‐HF

This paper provides information and a commentary on trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the annual meeting of the Heart Failure Association of the European Society of Cardiology held in Nice. The CHANCE study showed a substantial reduction in morbidity and mortality in a randomized controlled trial (RCT) of a multidisciplinary management programme for patients with chronic heart failure in Russia. Data from the B‐Convinced study, also an RCT, suggest that continuation of beta‐blocker (BB) therapy in patients hospitalized with worsening heart failure may be associated with improved outcomes when compared with treatment discontinuation. The CHAT study suggests that telephone support can improve prognosis in heart failure patients living in remote rural locations. CIBIS‐ELD showed that titration of BBs to target doses in older patients with heart failure is more difficult; but tolerance levels were similar for bisoprolol and carvedilol. Signal‐HF randomized elderly heart failure patients to treatment guided by NT‐proBNP levels or usual care, and showed no effect of NT‐proBNP‐guided treatment on outcomes.     

Clinical trials update from Heart Rhythm 2008 and Heart Failure 2008: ATHENA, URGENT, INH study, HEART and CK-1827452

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the Heart Rhythm Society meeting in San Francisco, USA and the Heart Failure Association meeting of the European Society of Cardiology which was held in Milan, Italy in June 2008. Unpublished reports should be considered as preliminary data, as analyses may change in the final publication. The ATHENA study showed that dronedarone reduced the incidence of the composite outcome of cardiovascular hospitalisation or death, in patients with atrial fibrillation or flutter, 29% of whom had a history of heart failure, compared with placebo. The URGENT study demonstrated that treatment of acute heart failure with standard therapy, including intravenous diuretics and nitrates, leads to a rapid resolution of breathlessness in the sitting position but that orthopnoea often persists. The INH study showed that a disease management programme could reduce mortality compared to usual care but not hospitalisation rates. The HEART study failed to recruit its planned number of patients, although it is the largest randomised trial of revascularisation in heart failure reported to date. At a median follow-up of 5 years no difference in mortality was observed but the study lacked power to provide a conclusive result. The selective myosin activator CK-1827452 produced a concentration dependent increase in systolic ejection time, stroke volume and fractional shortening in patients with heart failure compared to placebo.     

Contemporary treatment of heart failure: Is there adequate evidence to support a unique strategy for African-Americans? pro position

Clinical trials provide average effects of interventions but are not powered to identify differences in subgroup responses. African-Americans have been under-represented in most previous trials in patients with heart failure. Furthermore, physiologic differences have been demonstrated between African-Americans and whites in the mechanisms and response to therapy in hypertension. Review of previous heart failure trials reveals that African-Americans exhibit less benefit than whites from ACE inhibitors, angiotensin receptor blockers, and at least one β-blocker. In contrast, black patients experienced a greater benefit than white patients from the combination of nitrate and hydralazine. These data emphasize the need for trials in black patients to identify effective therapy. The first such trial, African-American Heart Failure Trial, is currently underway.