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.     

Use of pulmonary artery catheters in advanced heart failure

PURPOSE OF REVIEW: Randomized trials have demonstrated that use of the pulmonary artery catheter does not improve outcomes in patients with critical illness. Despite this, pulmonary artery catheters continue to be used, especially in heart failure. This review addresses recent clinical trials evaluating the safety and efficacy of the pulmonary artery catheter. It also offers guidelines on when pulmonary artery catheter use could be considered in patients with advanced heart failure. RECENT FINDINGS: A meta-analysis demonstrated that use of the pulmonary artery catheter in critically ill patients had no significant impact on morbidity or mortality. In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial, the addition of the pulmonary artery catheter to careful clinical assessment also had neutral impact. The results of the study are limited, however, by the patient population that was selected for the study, and there still may be a role for the pulmonary artery catheter in advanced heart failure. SUMMARY: Based on the results of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial and the meta-analysis, there is no indication for routine use of pulmonary artery catheters to adjust therapy during hospitalization for decompensation of chronic heart failure. There remain many specific clinical situations in heart failure in which the pulmonary artery catheter may be useful, however.     

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.     

Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE): design and rationale

BACKGROUND: There is little information about how to adjust pharmacologic agents in the treatment of patients with advanced congestive heart failure (CHF). Some studies have suggested that use of pulmonary artery catheterization to guide reductions in filling pressures may improve outcomes for patients with heart failure who are hospitalized with evidence of elevated filling pressures. However, there is no consensus regarding the true utility of this strategy. A randomized clinical trial is needed to test the safety, efficacy, and treatment benefit of pulmonary artery catheterization in patients with advanced CHF. STUDY DESIGN: The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial is a multicenter, randomized trial designed to test the long-term safety and efficacy of treatment guided by hemodynamic monitoring and clinical assessment versus that guided by clinical assessment alone in patients hospitalized with New York Heart Association class IV CHF. Five hundred patients will be randomly assigned to receive either medical therapy guided by a combination of clinical assessment and hemodynamic monitoring (PAC arm) or medical therapy guided by clinical assessment alone (CLIN arm). The primary end point of ESCAPE will be the number of days that patients are hospitalized or die during the 6-month period after randomization. Secondary end points will include changes in mitral regurgitation, peak oxygen consumption, and natriuretic peptide levels. Other secondary end points will be pulmonary artery catheter-associated complications, resource utilization, quality of life measures, and patient preferences regarding survival. IMPLICATIONS: The primary goal of ESCAPE will be to provide information about the utility of the pulmonary artery catheter in patients with advanced heart failure, independent of various treatment approaches used by individual physicians. In addition, this study will define current outcomes for this severely compromised population.     

Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE

This article provides information and a commentary on trials presented at the American Heart Association meeting held in November 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. In REPAIR-AMI an improvement in ejection fraction was observed in post-MI patients following infusion of bone marrow stem cells. However, the ASTAMI study showed no benefit of stem cell implantation in a similar patient cohort. The JELIS study reported a reduction in major coronary events in patients receiving statins plus fish oil compared to statins alone. MEGA showed that low dose statins in a low risk population reduce the incidence of major cardiovascular events. Two studies of levosimendan in acute heart failure gave conflicting results, in the REVIVE-II study levosimendan was reported to have a superior effect on the composite primary outcome compared to placebo, however, in SURVIVE despite a trend to early benefit with levosimendan, there was no difference in effect on long-term outcome versus dobutamine. The PROACTIVE study showed encouraging results for the use of pioglitazone in post-myocardial infarction patients with concomitant type 2 diabetes.     

Effect of late revascularization of a totally occluded coronary artery after myocardial infarction on mortality rates in patients with renal impairment

Renal dysfunction is an independent predictor of cardiovascular events and a negative prognostic indicator after myocardial infarction (MI). Randomized data comparing percutaneous coronary intervention to medical therapy in patients with MI with renal insufficiency are needed. The Occluded Artery Trial (OAT) compared optimal medical therapy alone to percutaneous coronary intervention with optimal medical therapy in 2,201 high-risk patients with occluded infarct arteries >24 hours after MI with serum creatinine levels ≤2.5 mg/dl. The primary end point was a composite of death, MI, and class IV heart failure (HF). Analyses were carried out using estimated glomerular filtration rate (eGFR) as a continuous variable and by eGFR categories. Long-term follow-up data (maximum 9 years) were used for this analysis. Lower eGFR was associated with development of the primary outcome (6-year life-table rates of 16.9% for eGFR >90 ml/min/1.73 m(2), 19.2% for eGFR 60 to 89 ml/min/1.73 m(2), and 34.9% for eGFR <60 ml/min/1.73 m(2); p <0.0001), death, and class IV HF, with no difference in rates of reinfarction. On multivariate analysis, eGFR was an independent predictor of death and HF. There was no effect of treatment assignment on the primary end point regardless of eGFR, and there was no significant interaction between eGFR and treatment assignment on any outcome. In conclusion, lower eGFR at enrollment was independently associated with death and HF in OAT participants. Despite this increased risk, the lack of benefit from percutaneous coronary intervention in the overall trial was also seen in patients with renal dysfunction and persistent occlusion of the infarct artery in the subacute phase after MI.     

Implantable cardioverter defibrillator therapy in patients with prior coronary revascularization in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)

Introduction: We conducted this study to examine the effect of the ICD on the outcomes of patients with prior coronary revascularization enrolled in the Sudden Cardiac Death in Heart Failure Trial (SCD‐HeFT) and to assess the association of time from coronary revascularization to enrollment with death and sudden cardiac death (SCD). Methods and Results: We included in this analysis patients with ischemic heart disease not randomized to the amiodarone arm. Cox proportional hazards models were used to examine the association of prior CABG and of prior PCI with each outcome. Interactions between randomized treatment and each revascularization type and time were tested in each model. Of the 882 patients who met these inclusion criteria, 255 (29%) had no prior revascularization, 178 (20%) had prior PCI only, 284 (32%) had prior CABG only, and 165 (19%) had prior PCI and CABG. There was no significant difference in ICD benefit across the revascularization subgroups (all P > 0.1). There was a trend toward improved survival with an ICD in patients who had their CABG > 2 years before randomization (HR [CI]= 0.71 [0.49, 1.04]) that was not observed in patients who had their CABG ≤ 2 years before randomization (HR [CI]= 1.40 [0.61, 3.24]). Conclusion: In SCD‐HeFT, there was no significant difference in ICD benefit across the revascularization subgroups. Patients who had their CABG > 2 years before randomization showed a trend toward improved survival with an ICD that was not observed in patients who had their CABG ≤ 2 years before randomization.     

Clinical trials update: highlights of the scientific sessions of the American Heart Association year 2000: Val HeFT, COPERNICUS, MERIT, CIBIS-II, BEST, AMIOVIRT, V-MAC, BREATHE, HEAT, MIRACL, FLORIDA, VIVA and the first human cardiac skeletal muscle myoblast transfer for heart failure

This article continues a series of reports summarising recent research developments pertinent to the topic of heart failure. This is a summary of presentations made at scientific sessions of the American Heart Association in November 2000. Clinical studies of particular interest to people caring for patients with heart failure include Val-HeFT, AMIOVIRT and V-MAC. New data from beta-blockers trials are reviewed, highlights from some important developments in post-infarction care, including MIRACL and FLORIDA, discussed and results of some early studies of gene therapy reported.     

Azimilide decreases recurrent ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators

OBJECTIVES: This study evaluated the effects of azimilide dihydrochloride (AZ) on anti-tachycardia pacing (ATP) and shock-terminated events in patients with implantable cardioverter defibrillators (ICDs). BACKGROUND: Animal studies have shown the effectiveness of AZ for therapy of supraventricular and ventricular tachycardia (VT). Azimilide dihydrochloride was investigated as adjunctive treatment for reducing the frequency of VT and, thus, the need for ICD therapies, including ATP and cardioversion/defibrillation (ICD shocks) in patients with inducible monomorphic VT. METHODS: A total of 172 patients were randomized to daily treatment with placebo, 35 mg, 75 mg, or 125 mg of oral AZ in this dose-ranging pilot study of patients with ICDs. The majority of patients had a history of documented remote myocardial infarction and congestive heart failure New York Heart Association class II or III. RESULTS: The frequency of appropriate shocks and ATP were significantly decreased among AZ-treated patients compared with placebo patients. The incidence of ICD therapies per patient-year among the placebo group was 36, and it was 10, 12, and 9 among 35 mg, 75 mg, and 125 mg AZ patients, respectively (hazard ratio = 0.31, p = 0.0001). Azimilide dihydrochloride was generally well tolerated and did not affect left ventricular ejection fraction or minimal energy requirements for defibrillation or pacing. CONCLUSIONS: Azimilide dihydrochloride may be a safe and effective drug for reducing the frequency of VT and ventricular fibrillation in patients with implanted ICDs.     

Usefulness of revascularization of patients with multivessel coronary artery disease before elective vascular surgery for abdominal aortic and peripheral occlusive disease

The Coronary Artery Revascularization Prophylaxis (CARP) study showed no survival benefit with preoperative coronary artery revascularization before elective vascular surgery. The generalizability of the trial results to all patients with multivessel coronary artery disease (CAD) has been questioned. The objective of this study was to determine the impact of prophylactic coronary revascularization on long-term survival in patients with multivessel CAD. Over a 4-year period, 1,048 patients underwent coronary angiography before vascular surgery during screening into the CARP trial. The cohort was composed of registry (n = 586) and randomized (n = 462) patients, and their survival was determined at 2.5 years after vascular surgery. High-risk coronary anatomy without previous bypass surgery included 2-vessel disease (n = 204 [19.5%]), 3-vessel disease (n = 130 [12.4%]), and left main coronary artery stenosis >/=50% (n = 48 [4.6%]). By log-rank test, preoperative revascularization was associated with improved survival in patients with a left main coronary artery stenoses (0.84 vs 0.52, p <0.01) but not those with either 2-vessel (0.80 vs 0.79, p = 0.83) or 3-vessel (0.79 vs 0.71, p = 0.15) disease. In conclusion, unprotected left main coronary artery disease was present in 4.6% of patients who underwent coronary angiography before vascular surgery, and this was the only subset of patients showing a benefit with preoperative coronary artery revascularization.     

Clinical trials update from the European Society of Cardiology: CHARM, BASEL, EUROPA and ESTEEM

This article contains a series of reports on recent research developments in the field of heart failure. Reports of key presentations made at the European Society of Cardiology meeting, held in Vienna, Austria, between 30 August and 3 September 2003 are reported. In the CHARM study, candesartan reduced cardiovascular deaths and hospital admissions for heart failure, both in patients who were already taking an ACE-inhibitor and in those who were ACE intolerant. However, results in patients with preserved left ventricular function were less conclusive. The BASEL study supports the use of B-type natriuretic peptide testing to confirm the diagnosis of heart failure in patients presenting with acute dyspnoea. In EUROPA, the largest ever study of secondary prevention of coronary artery disease, long-term treatment with perindopril reduced the incidence of cardiovascular death, myocardial infarction (MI) and cardiac arrest. The ESTEEM study showed that the oral thrombin inhibitor ximelagatran plus aspirin was more effective than aspirin alone in the prophylaxis of major cardiovascular events following MI.     

The efficacy of azimilide in the treatment of atrial fibrillation in the presence of left ventricular systolic dysfunction: results from the Azimilide Postinfarct Survival Evaluation (ALIVE) trial

OBJECTIVES: The purpose of this study was to assess the effect of oral azimilide dihydrochloride (AZ) 100 mg versus placebo on the onset, termination, and prevalence of atrial fibrillation (AF) in a subpopulation of patients in the Azimilide Postinfarct Survival Evaluation (ALIVE) trial. BACKGROUND: Previous clinical trials have demonstrated the antiarrhythmic effects of AZ in patients with AF. Azimilide was investigated for its effects on mortality in patients with depressed left ventricular (LV) function after recent myocardial infarction (MI) and in a subpopulation of patients with AF. METHODS: A total of 3,381 post-MI patients with depressed LV function were enrolled in this randomized, placebo-controlled, double-blind study of AZ 100 mg on all-cause mortality. A total of 93 patients had AF on the baseline 12-lead electrocardiogram (ECG). An additional 27 patients developed AF after initially being in sinus rhythm at randomization. These patients were identified through 12-lead ECGs obtained during routine visits at week 2, months 1, 4, 8, and 12. RESULTS: Patients with AF at baseline had a higher mortality than those without AF (p = 0.0006). Among AF patients, there was no difference in mortality between AZ patients and placebo patients (p = 0.82). Fewer AZ patients developed AF than placebo patients (p = 0.04). More AZ patients than placebo patients converted to sinus rhythm, but this difference did not achieve statistical significance (p = 0.076). Over one-year follow-up, more AZ patients were in sinus rhythm than placebo patients (p = 0.04). CONCLUSIONS: Azimilide was safe and effective AF therapy in patients with depressed LV function after an MI.     

Clinical trials update from the Heart Failure Society of America and the American Heart Association meetings in 2008: SADHART-CHF,COMPARE, MOMENTUM,thyroid hormone analogue study,HF-ACTION,I-PRESERVE, β-interferon study,BACH, and ATHENA

This article provides information and a commentary on trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the Heart Failure Society of America and the American Heart Association meetings in 2008. Unpublished reports should be considered as preliminary, as analyses may change in the final publication. (i) SADHART-CHF showed no difference in outcome for heart failure patients with depression treated with sertraline compared with placebo. (ii) A controlled release carvedilol formulation showed similar LV haemodynamic effects to the standard carvedilol formulation in the COMPARE study. (iii) A post hoc analysis of the MOMENTUM study suggested that patients with less severe heart failure may be more likely to benefit from a continuous aortic flow augmentation device. (iv) A thyroid hormone analogue was poorly tolerated in patients with heart failure. (v) HF-ACTION showed that exercise training is safe and offers modest clinical benefits in patients with heart failure. (vi) Irbesartan failed to improve outcomes in patients with preserved ejection fraction in the I-PRESERVE study. (vii) A phase II study of beta-interferon administration in patients with dilated cardiomyopathy showed encouraging results. (viii) The BACH study showed that mid-regional pro-adrenomedullin was more accurate than BNP or NT-proBNP at predicting outcome at 90 days in patients with acute heart failure. (ix) A secondary analysis from ATHENA showed a reduction in cardiovascular hospitalizations and strokes for patients with atrial fibrillation receiving dronedarone compared with placebo.     

Clinical trials update from the Heart Failure Society of America meeting: FIX-CHF-4, selective cardiac myosin activator and OPT-CHF

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the Heart Failure Society of America meeting held in Seattle in September 2006. All reports should be considered as preliminary data, as analyses may change in the final publication. Devices designed to improve cardiac contractility may have improved exercise tolerance and quality of life in the FIX-CHF-4 study; however, uncertainties in trial interpretation exist. The results of a study reporting the first administration of the selective myosin activator CK-1827452 to human volunteers, support the initiation of clinical trials in heart failure patients. In OPT-CHF, oxypurinol failed to show benefit compared to placebo for the treatment of heart failure, although a retrospective subgroup analysis suggests that it may be beneficial in patients with elevated serum uric acid levels.     

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.     

Statins in the prevention of heart failure after myocardial infarction

Statin therapy has demonstrated clear reductions in the risk of death and recurrent cardiac events in patients with acute coronary syndrome (ACS) and coronary artery disease. Heart failure after myocardial infarction (MI) is associated with increased in-hospital mortality and worse long-term prognosis. Some controversy exists about the effects of statin therapy on heart failure, although the favorable effects of statin therapy likely reduce the risk of heart failure development after MI and ACS. This article reviews data on statin therapy and the incidence of heart failure after MI, discussing mechanisms, safety, and outcomes.     

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.     

Coronary artery surgery for ischemic heart failure: risks, benefits, and the importance of assessment of myocardial viability

Heart failure and left ventricular dysfunction are common and are most often caused by myocardial ischemia/infarction secondary to occlusive coronary artery disease. Although recent refinements in medical therapy have resulted in improved survival, morbidity and mortality remain high in patients with advanced heart failure. Heart transplantation remains an option for selected patients, and implantable left ventricular assist devices may soon provide another treatment strategy for such patients. However, patients with established postischemic heart failure, significant myocardial viability, and coronary artery anatomy amenable to surgical revascularization can derive significant functional and survival benefit after coronary artery surgery, albeit with an increased perioperative risk. We discuss the role of coronary artery surgery in ischemic heart failure and review the evidence for such an approach.     

Clinical trials update from the European Society of Cardiology: SENIORS, ACES, PROVE-IT, ACTION, and the HF-ACTION trial

This article provides information and a commentary on landmark trials presented at the European Society of Cardiology Congress in August 2004, relevant to the pathophysiology, prevention or treatment of heart failure. The SENIORS trial suggests that nebivolol is well tolerated and effective in older patients with heart failure, even if left ventricular systolic function is not markedly depressed. However, patients aged >75 years appeared to gain less benefit. Further data on the effects of nebivolol on symptoms and quality of life are awaited. Two new trials of long-term antibiotic prophylaxis after myocardial infarction (ACES and PROVE-IT) showed no benefit. The ACTION trial showed no reduction in serious cardiovascular events with nifedipine GITS in patients with chronic stable angina, despite a substantial reduction in blood pressure. The HF-ACTION trial announced that the first 700 patients of a projected 3000 had been randomised to either an exercise program or encouragement to exercise but without a formal program. The primary outcome measure is death or hospitalisation for any reason.     

Clinical trials update from the European Society of Cardiology Heart Failure meeting and the American College of Cardiology: darbepoetin alfa study, ECHOS, and ASCOT-BPLA

This article provides information and a commentary on landmark trials presented at the European Society of Cardiology Heart Failure meeting held in June 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. The erythropoiesis stimulating protein, darbepoetin alfa, increased haemoglobin levels, improved quality of life and showed a trend for improved exercise duration in anaemic patients with symptomatic chronic heart failure. In the ECHOS study, the selective dopamine agonist nolomirole (CHF1035) showed no benefit in heart failure patients. Preliminary results of the ASCOT-BPLA study, which were reported at the American College of Cardiology meeting in March 2005, showed that in hypertensive patients, treatment with a calcium antagonist plus an ACE inhibitor was more effective at reducing cardiovascular outcomes than atenolol plus a diuretic.