A review of phase II acute heart failure syndromes clinical trials

Hospitalization for acute heart failure syndromes (AHFS) is a growing health care burden. Over 1 million hospitalizations occur annually, with a postdischarge mortality and rehospitalization rate of ~45% by 90 days and a financial cost greater than $20 billion. Attempts to improve outcomes through novel therapies have largely failed, suggesting new approaches are needed. We review phase II studies in AHFS to identify opportunities for future development programs.     

The potential role of cardiac resynchronization therapy in acute heart failure syndromes

Cardiac resynchronization therapy (CRT) has been demonstrated to improve mortality and morbidity in patients with chronic, stable heart failure who have reduced left ventricular ejection fraction and prolonged QRS duration. Patients with acute heart failure syndromes (AHFS) have been excluded from major CRT trials. The potential benefits and risks of implementation of these devices in the AHFS setting are largely unknown. In this review, we discuss the role that early implementation of CRT may have in improving postdischarge outcomes. In addition, we also discuss the potential adverse consequences of inserting these devices in patients who are in the tenuous clinical state of AHFS.     

Sex-based differences in cardiac resynchronization therapy and implantable cardioverter defibrillator therapies: effectiveness and use

With the rapid advancements in heart failure device therapy, many physicians now use these devices in everyday clinical practice. However, questions remain regarding the clinical benefit of these therapies in different patient subgroups. Since the majority of patients enrolled in device trials are white men, extrapolating the data to specific patient subpopulations becomes important. Specifically, the question of clinical outcomes in women with implantable device therapy for prevention of sudden cardiac death and management of heart failure is an important clinical issue. In this article, we review the data on survival and clinical outcomes with heart failure device therapy (implantable cardioverter defibrillators [ICDs] and cardiac resynchronization therapy [CRT]) and analyze the results from clinical trials for any differences in outcomes based on gender. Even though women are a significantly under-represented population with regard to clinical investigation and utilization of heart failure devices, they still derive the same morbidity and mortality benefits compared to men. Specifically, ICD devices confer the same rates of sudden cardiac death prevention, and CRT devices improve CHF morbidity and mortality at rates comparable to those found in men. These results support equal use of ICDs and CRT in men and women.     

Acute heart failure syndromes and coronary perfusion

Acute heart failure syndromes (AHFS), with a high post-discharge mortality and rehospitalization rate, represent a significant public health burden. The treatment of patients hospitalized with AHFS often includes the use of vasoactive medications such as inotropes and vasodilators. Although such agents are frequently used, their safety and efficacy remain controversial. A significant number of patients with heart failure have underlying coronary artery disease and may be at greater risk from hemodynamic alterations that can diminish coronary perfusion. In AHFS, the relationship among vasoactive medications, coronary perfusion, and potential myocardial injury needs further investigation. Newer techniques now available to evaluate coronary perfusion should provide guidance for the evaluation of existing and future vasoactive therapies for AHFS.     

Clinical development of pharmacologic agents for acute heart failure syndromes: a proposal for a mechanistic translational phase

Hospitalization for acute heart failure syndromes (AHFS) predicts a poor prognosis, with postdischarge mortality and rehospitalization rates reaching 45% within 60 to 90 days. Despite the use of evidence-based therapies and adherence to national process measures, these event rates have largely remained the same over the past decade. Given the current and growing burden of AHFS, there exists a substantial unmet need for novel therapies that improve outcomes. However, attempts to improve symptoms and/or reduce postdischarge events have failed to produce positive results, either because of safety and/or efficacy. These negative results may be related to the drug itself, the protocol in terms of patient selection and/or end points, and/or the trial execution. Although experts may not agree on the exact reasons to explain the lack of success to date of phase III trials in AHFS, there is agreement that clinical benefits observed in phase II trials were not reproduced in phase III trials. A different approach may be needed. In November of 2009, a meeting was held at the Food and Drug Administration with the primary purpose of identifying the reasons why benefits observed during phase II did not translate into benefits in phase III to improve future trial design. Although multiple domains of trial design were discussed, the participants identified a lack of in-depth understanding of novel molecules before pivotal trials in AHFS as a possible contributor to the disappointing results of recent large trials. In this brief report, we outline the T1 or translational phase of research for AHFS clinical development as an important first step toward greater success in AHFS clinical trials.     

Expanded algorithm for managing patients with acute decompensated heart failure

Heart failure is a complex disease process, the manifestation of various cardiac and noncardiac abnormalities. General treatment approaches for heart failure have remained the same over the past decades despite the advent of novel therapies and monitoring modalities. In the same vein, the readmission rates for heart failure patients remain high and portend a poor prognosis for morbidity and mortality. In this context, development and implementation of improved algorithms for assessing and treating HF patients during hospitalization remains an unmet need. We propose an expanded algorithm for both monitoring and treating patients admitted for acute decompensated heart failure with the goal to improve post-discharge outcomes and decrease rates of rehospitalizations.     

A comprehensive, longitudinal description of the in-hospital and post-discharge clinical, laboratory, and neurohormonal course of patients with heart failure who die or are re-hospitalized within 90?days: analysis from the EVEREST trial

Hospitalization for worsening chronic heart failure results in high post-discharge mortality, morbidity, and cost. However, thorough characterization, soon after discharge of patients with early post-discharge events has not been previously performed. The objectives of this study were to describe the baseline, in-hospital, and post-discharge clinical, laboratory, and neurohormonal profiles of patients hospitalized for worsening heart failure with reduced ejection fraction (EF) who die or are re-admitted for cardiovascular (CV) causes within 90 days of initial hospitalization. Retrospective analysis of 4,133 patients hospitalized for worsening heart failure with EF ≤40% in the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial, which randomized patients to tolvaptan or placebo, both in addition to standard therapy. Clinical and laboratory parameters were obtained within 48?h of admission, during hospitalization, and post-discharge weeks 1, 4, 8, and every 8?weeks thereafter for a median of 9.9?months. Patients with events within 90?days were compared with those with later/no events. All-cause mortality (ACM) and CV re-hospitalization were independently adjudicated. Within 90?days of admission, 395 patients (9.6%) died and 801 patients (19.4%) were re-hospitalized for CV causes. Significant baseline and longitudinal differences were seen between groups with early versus later (>90?days) or no events at 12?months post-randomization. Post-discharge outcomes were similar in the tolvaptan and placebo groups. Patients with early post-discharge events experienced clinically significant worsening in signs and symptoms, laboratory values, and neurohormonal parameters soon after discharge. Identifying these abnormalities may facilitate efforts to reduce post-discharge mortality and re-hospitalization.     

Why,when, and how to assess pulmonary congestion in heart failure: pathophysiological,clinical, and methodological implications

Acute heart failure syndrome (AHFS) is a major public health problem. It is defined as gradual or rapid change in heart failure (HF) signs and symptoms, which often results in an unplanned hospitalization and a need for urgent therapy. Many evidence-based pharmacologic, device, and surgical treatment for HF are available or under development. Despite these new treatments and improvement in survival, hospitalizations in HF have steadily increased over the last 30 years, and the post-discharge prognosis of patients hospitalized with AHFS remains poor (Gheorghiade et al. Circulation 112:3958–3968, 2005; Fonarow et al. Rev Cardiovasc Med 4:S21–30, 2003). Most hospitalizations for AHFS are related to “congestion” rather than to low cardiac output. The definition, identification, quantification, and monitoring of congestion are therefore essential in AHFS. The purpose of this article is: (1) to characterize the different types of hemodynamic, clinical, and pulmonary congestion in AHFS; (2) to focus on the different possible ways to assess pulmonary congestion (probably the most important, and up to now the most diagnostically elusive of the three types of congestions); (3) to propose new possible ways to implement objective and user-friendly measures of pulmonary congestion in clinical and scientific decision-making in AHFS in the near future.     

Cardiac resynchronization therapy in patients with a narrow QRS

Although cardiac resynchronization therapy (CRT) is indicated in patients with moderate to severe heart failure with a wide QRS complex (> 120 ms), current guidelines exclude many heart failure patients with a narrow QRS. Detecting mechanical dyssynchrony on echocardiography has become a promising tool in selecting patients with a narrow QRS who may respond to CRT. Several small single-center studies identified patients with a narrow QRS (using echocardiography-based dyssynchrony criteria) who responded favorably to CRT; however, the results of two recent pilot studies remain elusive. The results of the RethinQ study do not provide necessary evidence for making clinical treatment decisions in this population. The lack of definitive evidence is the strongest rationale for conducting an adequately powered, long-term, end point-driven, randomized controlled trial to investigate whether CRT therapy can improve morbidity and mortality outcomes in heart failure patients with a narrow QRS. Such a trial, the EchoCRT trial, has recently been launched.     

Acute heart failure syndromes: clinical scenarios and pathophysiologic targets for therapy

Acute heart failure syndromes (AHFS) represent the most common discharge diagnosis in patients over age 65 years, with an exceptionally high mortality and readmission rates at 60–90 days. Recent surveys and registries have generated important information concerning the clinical characteristics of patients with AHFS and their prognosis. Most patients with AHFS present either with normal systolic blood pressure or elevated blood pressure. Patients who present with elevated systolic blood pressure usually have pulmonary congestion, a relatively preserved left ventricular ejection fraction (LVEF), are often elderly women, and their symptoms develop typically and abruptly. Patients with normal systolic blood pressure present with systemic congestion, reduced LVEF, are usually younger with a history of chronic HF, and have symptoms that develop gradually over days or weeks. In addition to the abnormal hemodynamics (increase in pulmonary capillary wedge pressure and/or decrease in cardiac output) that characterize patients with AHFS, myocardial injury, which may be related to a decrease in coronary perfusion and/or further activation of neurohormones and renal dysfunction, probably contributes to short-term and post-discharge cardiac events. Patients with AHFS also have significant cardiac and noncardiac underlying conditions that contribute to the pathogenesis of AHFS, including coronary artery disease (ischemia, hibernating myocardium, and endothelial dysfunction), hypertension, atrial fibrillation, and type 2 diabetes mellitus. Therefore, the targets of therapy for AHFS should be not only to improve symptoms and hemodynamics but also to preserve or improve renal function, prevent myocardial damage, modulate neurohumoral and inflammatory activation, and to manage other comorbidities that may cause and/or contribute to the progression of this syndrome.     

Hyponatremia in acute heart failure syndromes: A potential therapeutic target

Mild hyponatremia is common in patients hospitalized for worsening heart failure, and it is a major predictor of post-discharge mortality and morbidity irrespective of left ventricular ejection fraction. Recent data also suggest that standard therapy for heart failure does not improve or normalize serum sodium concentration during hospitalization. There are conclusive data that vasopressin antagonists improve or normalize serum sodium in this patient population. However, it is not known if this improvement or normalization in serum sodium is associated with an improvement in post-discharge outcomes. Future trials with vasopressin antagonists in patients hospitalized with worsening heart failure and hyponatremia are in order.     

Why should we care about CARE-HF?

Previous trials of cardiac resynchronization therapy (CRT) have suggested that this therapy can significantly improve functional class and exercise capacity during short-term follow-up. The impact of this therapy on morbidity and mortality has only recently been reported. The Cardiac Resynchronization-Heart Failure (CARE-HF) study has definitively shown that CRT significantly reduces mortality (36%, p < 0.002) in patients with NYHA functional class III and IV heart failure and ventricular dyssynchrony. This study also shows that CRT reverses ventricular remodeling and improves myocardial performance progressively for at least 18 months. In heart failure patients, the CARE-HF and Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) (the earlier major morbidity/mortality trial) studies together show the unequivocal benefit for CRT therapy and CRT therapy with back-up defibrillation to significantly reduce mortality and hospitalization compared with optimal medical therapy. Both studies suggest the benefit of adding the implantable cardiac defibrillator to CRT devices, as over one-third of deaths in the CRT-pacemaker arm of both the COMPANION and CARE-HF studies were sudden.     

Cardiac resynchronization therapy

Left ventricular (LV) dysynchrony, generally defined as the effect of intraventricular conduction defects or bundle branch block to produce nonsynchronous ventricular activation, places the failing heart at a further mechanical disadvantage. The deleterious effects of ventricular dysynchrony include suboptimal ventricular filling, paradoxical septal wall motion, reduced LV contractility, increased mitral regurgitation, and poor clinical outcomes (eg, increased hospitalization and mortality). The clinical and mechanical manifestations of ventricular dysynchrony can be treated by simultaneously pacing both the right and left ventricles usually in association with right atrial sensing, resulting in atrial-synchronized biventricular pacing or cardiac resynchronization therapy (CRT). The weight of evidence supporting the routine use of CRT in patients with heart failure with ventricular dysynchrony is now quite substantial. More than 4000 patients have been evaluated in randomized controlled trials of CRT, and several thousand additional patients have been assessed in observational studies and in registries. Data from these studies have consistently demonstrated the safety and efficacy of CRT in patients with New York Heart Association class III and IV heart failure. Cardiac resynchronization therapy has been shown to significantly improve LV structure and function, New York Heart Association functional class, exercise tolerance, quality of life, and morbidity and mortality.     

Why Should We Care About CARE-HF?

Previous trials of cardiac resynchronization therapy (CRT) have suggested that this therapy can significantly improve functional class and exercise capacity during short-term follow-up. The impact of this therapy on morbidity and mortality has only recently been reported. The Cardiac Resynchronization-Heart Failure (CARE-HF) study has definitively shown that CRT significantly reduces mortality (36%, p < 0.002) in patients with NYHA functional class III and IV heart failure and ventricular dyssynchrony. This study also shows that CRT reverses ventricular remodeling and improves myocardial performance progressively for at least 18 months. In heart failure patients, the CARE-HF and Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) (the earlier major morbidity/mortality trial) studies together show the unequivocal benefit for CRT therapy and CRT therapy with back-up defibrillation to significantly reduce mortality and hospitalization compared with optimal medical therapy. Both studies suggest the benefit of adding the implantable cardiac defibrillator to CRT devices, as over one-third of deaths in the CRT-pacemaker arm of both the COMPANION and CARE-HF studies were sudden.     

The Rationale for an Acute Heart Failure Syndromes Clinical Trials Network

BackgroundClinical trials involving novel therapies treating acute heart failure syndromes (AHFS) have shown limited success with regard to both efficacy and safety. As a direct result, outcomes have changed little over time and AHFS remains a disease process associated with largely no change in hospitalization rates (80%), hospital length of stay (median 4.5 days), and in-hospital (4-7%) and 60-day mortality (10%). Despite extensive emergency department (ED) involvement during the initial phase of AHFS management, clinical trials have enrolled patients after the ED phase of management, up to 48 hours after initial therapy, long after many patients have experienced significant beneficial effects of standard therapy. As standard therapy has provided symptomatic improvement in up to 70% of patients in these trials, it is not surprising that investigational agents started after 24 to 48 hours of standard therapy have shown limited clinical efficacy when compared with standard therapy.Methods and ResultsThe ability to screen, enroll, and randomize in the emergency setting is fundamental. The unique environment, the ethical complexities of enrollment in emergency-based research, and the need for rapid and standardized study-compliant care represent key challenges to active recruitment in AHFS studies. Specifically, the ability to identify and enroll a large cohort of AHFS patients early (<6 hours) in their presentation has been cited as the primary barrier to the appropriate design of clinical trials that includes this early window.ConclusionsIn response, we have created a network of dedicated academic physicians with experience in clinical trials and acute management of heart failure who together can surmount this barrier and provide a framework for conducting early trials in AHFS.     

Influence of Left Ventricular Lead Location on Outcomes in the COMPANION Study

Introduction: There are no randomized controlled trial data that evaluate mortality and hospitalization rates in cardiac resynchronization therapy (CRT) recipients based on left ventricular (LV) lead location. We analyzed the event-driven outcomes of mortality and hospitalization as well as functional outcomes including Functional Class, Quality-of-Life, and 6-minute walk distance in 1,520 patients enrolled in the COMPANION study of CRT versus optimal medical therapy.
Methods and Results: Over a mean follow-up after implantation of 16.2 months, patients randomized to CRT, regardless of lead location, experienced benefit compared with optimized pharmacologic therapy (OPT), with respect to all-cause mortality or heart failure hospitalization. All but a posterior location showed benefit with respect to the all-cause mortality or all-cause hospitalization outcome. Mortality benefit in CRT-D patients was indifferent to LV lead position. All functional outcomes including 6-minute walk distance, Quality-of-Life (QOL) and Functional Class improved with CRT, regardless of LV lead location.
Conclusion: LV lead location was not a major determinant of multiple measures of response to CRT therapy in the COMPANION Trial. While acute data indicate that a left lateral LV lead location results in the most favorable hemodynamic response, these chronic data suggest that positioning an LV lead in an anterior rather than a lateral or posterior LV location has similar benefit.     

Use of cardiac resynchronization therapy to optimize beta-blocker therapy in patients with heart failure and prolonged QRS duration

A retrospective analysis was performed on 52 patients with heart failure to determine the change in beta-blocker therapy after cardiac resynchronization therapy (CRT). After 6 months of CRT, the number of patients receiving beta-blocker therapy increased from 36 to 44, with improved clinical outcomes and larger beta-blocker doses, indicating that these 2 therapies may work together to improve outcomes by allowing the use of larger doses of beta blockers while correcting ventricular dyssynchrony.     

Cardiac resynchronization therapy

Cardiac resynchronization therapy (CRT) addresses abnormal left ventricular (LV) activation that produces detrimental effects on cardiac systolic and diastolic function. CRT improves symptoms and ventricular performance, promotes reverse remodeling, and decreases mortality and hospitalization in patients with congestive heart failure (CHF). Atrial-synchronized biventricular stimulation reverses many of the temporal delays in mechanical activation associated with LV dysfunction and conduction system disease. The therapy evolved from anecdotal application through surgical implantation of LV pacing leads to transvenous delivery of LV pacing leads for use with dedicated CRT devices. The controlled clinical trials included specific patient groups, and provided data leading to widely adopted indications for the therapy. Current indications exclude the use of CRT in patients with permanent atrial fibrillation, although small series suggest a benefit of the therapy in these patients. The role of cardiac imaging with echocardiography to detect cardiac dyssynchrony promises to improve patient selection by not only excluding likely nonresponders, but also extending the therapy to those with dyssynchrony in the absence of QRS prolongation. Expanded indications under evaluation include the role of CRT in patients with mildly symptomatic CHF, mild to moderate LV dysfunction, dyssynchrony in the absence of QRS prolongation, and dyssynchrony induced by right ventricular pacing.     

Overview of emerging pharmacologic agents for acute heart failure syndromes

BACKGROUND: Several therapies commonly used for the treatment of acute heart failure syndromes (AHFS) present some well-known limitations and have been associated with an early increase in the risk of death. There is, therefore, an unmet need for new pharmacologic agents for the early management of AHFS that may improve both short- and long-term outcomes. AIM: To review the recent evidence on emerging pharmacologic therapies in AHFS. METHODS: A systematic search of peer-reviewed publications was performed on MEDLINE, EMBASE and Clinical Trials.gov from January 1990 to August 2007. The results of unpublished or ongoing trials were obtained from presentations at national and international meetings and pharmaceutical industry releases. Bibliographies from these references were also reviewed, as were additional articles identified by content experts. RESULTS: Cumulative data from large studies and randomised trials suggest that therapies with innovative mechanisms of action may safely and effectively reduce pulmonary congestion or improve cardiac performance in AHFS patients. CONCLUSION: Some investigational agents for the management of AHFS are able to improve haemodynamics and/or clinical status. In spite of these promising findings, no new agent has demonstrated a clear benefit in terms of long-term clinical outcomes compared to placebo or conventional therapies.     

Device therapy in heart failure patients with chronic kidney disease

Heart failure (HF) and chronic kidney disease (CKD) both carry significant risk for sudden cardiac death, hospitalization, and mortality; when combined, however, they markedly increase the risk of morbidity and mortality. Device therapies such as implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) are treatments proven to have significant benefit on clinical outcomes in select patients with HF. However, the majority of studies supporting the use of these devices have limited data on patients with CKD or end-stage renal disease. In this review, we discuss the intersection of HF and CKD as it relates to progressive HF and the risk of sudden death. Although these disorders are common and have a poor prognosis, the evidence available for guiding treatment decisions for the use of ICD and CRT devices in these patients is lacking. Given this lack of clear evidence, pragmatic clinical trials and comparative effectiveness studies are needed to help identify the appropriate use of ICD and CRT devices in this high-risk population of patients with HF and CKD.