Rivaroxaban in Patients with Heart Failure, Sinus Rhythm, and Coronary Disease.

BACKGROUND: Heart failure is associated with activation of thrombin-related pathways, which predicts a poor prognosis. We hypothesized that treatment with rivaroxaban, a factor Xa inhibitor, could reduce thrombin generation and improve outcomes for patients with worsening chronic heart failure and underlying coronary artery disease. METHODS: In this double-blind, randomized trial, 5022 patients who had chronic heart failure, a left ventricular ejection fraction of 40% or less, coronary artery disease, and elevated plasma concentrations of natriuretic peptides and who did not have atrial fibrillation were randomly assigned to receive rivaroxaban at a dose of 2.5 mg twice daily or placebo in addition to standard care after treatment for an episode of worsening heart failure. The primary efficacy outcome was the composite of death from any cause, myocardial infarction, or stroke. The principal safety outcome was fatal bleeding or bleeding into a critical space with a potential for causing permanent disability. RESULTS: Over a median follow-up period of 21.1 months, the primary end point occurred in 626 (25.0%) of 2507 patients assigned to rivaroxaban and in 658 (26.2%) of 2515 patients assigned to placebo (hazard ratio, 0.94; 95% confidence interval [CI], 0.84 to 1.05; P=0.27). No significant difference in all-cause mortality was noted between the rivaroxaban group and the placebo group (21.8% and 22.1%, respectively; hazard ratio, 0.98; 95% CI, 0.87 to 1.10). The principal safety outcome occurred in 18 patients who took rivaroxaban and in 23 who took placebo (hazard ratio, 0.80; 95% CI, 0.43 to 1.49; P=0.48). CONCLUSIONS: Rivaroxaban at a dose of 2.5 mg twice daily was not associated with a significantly lower rate of death, myocardial infarction, or stroke than placebo among patients with worsening chronic heart failure, reduced left ventricular ejection fraction, coronary artery disease, and no atrial fibrillation. (Funded by Janssen Research and Development; COMMANDER HF ClinicalTrials.gov number, NCT01877915 .).

Effects of Elamipretide on Left Ventricular Function in Patients With Heart Failure With Reduced Ejection Fraction: The PROGRESS-HF Phase 2 Trial.

BACKGROUND: Elamipretide, a novel mitochondrial modulating agent, improves myocardial energetics; however, it is unknown whether this mechanistic benefit translates into improved cardiac structure and function in heart failure (HF) with reduced ejection fraction (HFrEF). The objective of this study was to evaluate the effects of multiple subcutaneous doses of elamipretide on left ventricular end systolic volume (LVESV) as assessed by cardiac magnetic resonance imaging. METHODS: We randomized 71 patients with HFrEF (LVEF ≤ 40%) in a double-blind, placebo-controlled trial in a 1:1:1 ratio to receive placebo, 4 mg or 40 mg elamipretide once daily for 28 consecutive days. RESULTS: The mean age (standard deviation) of the study population was 65 ± 10 years, 24% were females, and the mean EF was 31% ± 7%. The change in LVESV from baseline to week 4 was not significantly different between elamipretide 4 mg (89.4 mL to 85 mL; difference, -4.4 mL) or 40 mg (77.9 mL to 76.6 mL; difference, -1.2 mL) compared with placebo (77.7 mL to 74.6 mL; difference, -3.8 mL) (4 mg vs placebo: difference of means, -0.3; 95% CI, -4.6 to 4.0; P = 0.90; and 40 mg vs placebo: difference of means, 2.3; 95% CI, -1.9 to 6.5; P  =  0.28). Also, no significant differences in change in LVESV and LVEF were observed between placebo and either of the elamipretide groups. Rates of any study drug-related adverse events were similar in the 3 groups. CONCLUSIONS: Elamipretide was well tolerated but did not improve LVESV at 4 weeks in patients with stable HFrEF compared with placebo.

Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A Randomized Trial.

RATIONALE: Potential benefits of mesenchymal stem cell (MSC) therapy in heart failure may be related to paracrine properties and systemic effects, including anti-inflammatory activities. If this hypothesis is valid, intravenous administration of MSCs should improve outcomes in heart failure, an entity in which excessive chronic inflammation may play a pivotal role. OBJECTIVE: To assess the safety and preliminary efficacy of intravenously administered ischemia-tolerant MSCs (itMSCs) in patients with nonischemic cardiomyopathy. METHODS AND RESULTS: This was a single-blind, placebo-controlled, crossover, randomized phase II-a trial of nonischemic cardiomyopathy patients with left ventricular ejection fraction ≤40% and absent hyperenhancement on cardiac magnetic resonance imaging. Patients were randomized to intravenously administered itMSCs (1.5×106 cells/kg) or placebo; at 90 days, each group received the alternative treatment. Overall, 22 patients were randomized to itMSC (n=10) and placebo (n=12) at baseline. After crossover, data were available for 22 itMSC patients. No major differences in death, hospitalization, or serious adverse events were noted between the 2 treatments. Change from baseline in left ventricular ejection fraction and ventricular volumes was not significantly different between therapies. Compared with placebo, itMSC therapy increased 6-minute walk distance (+36.47 m, 95% confidence interval 5.98-66.97; P=0.02) and improved Kansas City Cardiomyopathy clinical summary (+5.22, 95% confidence interval 0.70-9.74; P=0.02) and functional status scores (+5.65, 95% confidence interval -0.11 to 11.41; P=0.06). The data demonstrated MSC-induced immunomodulatory effects, the magnitude of which correlated with improvement in left ventricular ejection fraction. CONCLUSIONS: In this pilot study of patients with nonischemic cardiomyopathy, itMSC therapy was safe, caused immunomodulatory effects, and was associated with improvements in health status and functional capacity. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02467387.

Dual Vasopressin V1a/V2 Antagonism: The Next Step in Neurohormonal Modulation in Patients With Heart Failure?

Stimulation of the V1a receptor for arginine vasopressin produces myocardial and vascular effects similar to those of angiotensin II while stimulation of the V2 receptor causes fluid retention. There are no data with sustained blockade of the V1a receptor while single-dose experiments suggest benefit. Acute and chronic administration of selective V2 receptor antagonists reliably relieves dyspnea and produces diuresis without adverse effects on renal function or neurohormonal stimulation, either as adjunctive or alternative therapy to loop diuretics, but has not been shown to improve outcomes as adjunctive therapy. Combined antagonism has been tried only in single-dose studies in stable patients or over the short-term in acute heart failure, with encouraging results. Based on the both the pathophysiologic rationale for additional neurohormonal blockade and these results, chronically blocking both receptors, particularly in more congested patients, may offer significant benefit either as adjunctive or alternative therapy to standard diuretics.

A Critical Appraisal of Short-Term End Points in Acute Heart Failure Clinical Trials.

The prevalence of heart failure continues to grow, and this is accompanied by an increase in hospitalization for acute heart failure. Hospitalization for heart failure results in a trajectory shift of the syndrome and is associated with worsening outcomes, increased mortality risk, and high costs. Numerous clinical trials over the past 2 decades have had limited success, with no single agent shown to improve mortality risk. The lack of success is multifactorial and in part related to inadequate targets and end points selected for intervention, underscoring the need to better understand and define the pathophysiology of acute heart failure. To better inform future drug development, this review critically explores the short-term end points and outcomes that previous phase III acute heart failure trials have examined.

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.

Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study.

Aims: To determine tolerability and the optimal dose regimen of the soluble guanylate cyclase stimulator vericiguat in patients with chronic heart failure and preserved ejection fraction (HFpEF). Methods and results: SOCRATES-PRESERVED was a prospective, randomized, placebo-controlled double-blind, Phase 2b dose-finding study in patients with HFpEF (ejection fraction ≥ 45%). Patients received vericiguat once daily at 1.25 or 2.5 mg fixed doses, or 5 or 10 mg titrated from a 2.5 mg starting dose, or placebo for 12 weeks. The two primary endpoints were change from baseline in log-transformed N-terminal pro-B-type natriuretic peptide (NT-ProBNP) and left atrial volume (LAV) at 12 weeks. Patients (N = 477; 48% women; mean age 73 ± 10 years; baseline atrial fibrillation 40%) were randomized within 4 weeks of HF hospitalization (75%) or outpatient treatment with intravenous diuretics for HF (25%) to vericiguat (n = 384) or placebo (n = 93). In the pooled three highest dose arms change in logNT-proBNP (vericiguat: +0.038 ± 0.782 log(pg/mL), n = 195; placebo: -0.098 ± 0.778 log(pg/mL), n = 73; one-sided P = 0.8991, two-sided P = 0.2017), and change in LAV [vericiguat: -1.7 ± 12.8 mL (n = 194); placebo: -3.4 ± 12.7 mL (n = 67), one-sided P = 0.8156, two-sided P = 0.3688] were not different from placebo. Vericiguat was well tolerated (adverse events: vericiguat 10 mg arm, 69.8%; placebo, 73.1%), with low discontinuation rates in all groups, and no changes in blood pressure at 10 mg compared with placebo. The pre-specified exploratory endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score improved in the vericiguat 10 mg arm by mean 19.3 ± 16.3 points [median 19.8 (interquartile range 10.4-30.7)] from baseline (mean difference from placebo 9.2 points). Conclusion: Vericiguat was well tolerated, did not change NT-proBNP and LAV at 12 weeks compared with placebo but was associated with improvements in quality of life in patients with HFpEF. Given the encouraging results on quality of life, the effects of vericiguat in patients with HFpEF warrant further study, possibly with higher doses, longer follow-up and additional endpoints.

Redefining the role of biomarkers in heart failure trials: expert consensus document.

Heart failure is a growing cardiovascular disease with significant epidemiological, clinical, and societal implications and represents a high unmet need. Strong efforts are currently underway by academic and industrial researchers to develop novel treatments for heart failure. Biomarkers play an important role in patient selection and monitoring in drug trials and in clinical management. The present review gives an overview of the role of available molecular, imaging, and device-derived digital biomarkers in heart failure drug development and highlights capabilities and limitations of biomarker use in this context.

Partial Adenosine A1 Agonist in Heart Failure.

Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels. Activation of myocardial adenosine A1Rs has been shown to modulate a variety of pathologies associated with ischemic cardiac injury, including arrhythmogenesis, coronary and ventricular dysfunction, apoptosis, mitochondrial dysfunction, and ventricular remodeling. Partial A1R agonists are agents that are likely to elicit favorable pharmacological responses in heart failure (HF) without giving rise to the undesirable cardiac and extra-cardiac effects observed with full A1R agonism. Preclinical data have shown that partial adenosine A1R agonists protect and improve cardiac function at doses that do not result in undesirable effects on heart rate, atrioventricular conduction, and blood pressure, suggesting that these compounds may constitute a valuable new therapy for chronic HF. Neladenoson bialanate (BAY1067197) is the first oral partial and highly selective A1R agonist that has entered clinical development for the treatment of HF. This review provides an overview of adenosine A1R-mediated signaling in the heart, summarizes the results from preclinical and clinical studies of partial A1R agonists in HF, and discusses the potential benefits of these drugs in the clinical setting.

Novel Endpoints for Heart Failure Clinical Trials.

PURPOSE OF REVIEW: With the growing prevalence of heart failure, there is a particular need to develop new pharmacologic treatments that can improve outcomes. While there are several approved therapies for heart failure with reduced ejection fraction, there is currently no approved agent for those with preserved ejection fraction. The current review aimed to explore the utility of alternate endpoints to mortality and hospitalization. RECENT FINDINGS: There is increased interest in the use of alternative endpoints such as functional status and quality of life for heart failure drug development to focus on patients feeling better in addition to improving outcomes. This should ideally be measured using objective as well as subjective parameters. While mortality and hospitalization remain important endpoints for clinical trials in heart failure, other more patient-centered outcomes are attractive alternatives yet how to best incorporate these in a trial setting remains to be elucidated.

A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.

AIMS: To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus. METHODS AND RESULTS: Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: NCT01807221). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7-10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg finerenone groups, respectively (P = 0.42-0.88). Except for the 2.5→5 mg finerenone group, the composite clinical endpoint occurred numerically less frequently in finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups. CONCLUSION: Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the finerenone 10→20 mg group should be further explored in a large outcomes trial.

Phenomapping for novel classification of heart failure with preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome in need of improved phenotypic classification. We sought to evaluate whether unbiased clustering analysis using dense phenotypic data (phenomapping) could identify phenotypically distinct HFpEF categories. METHODS AND RESULTS: We prospectively studied 397 patients with HFpEF and performed detailed clinical, laboratory, ECG, and echocardiographic phenotyping of the study participants. We used several statistical learning algorithms, including unbiased hierarchical cluster analysis of phenotypic data (67 continuous variables) and penalized model-based clustering, to define and characterize mutually exclusive groups making up a novel classification of HFpEF. All phenomapping analyses were performed by investigators blinded to clinical outcomes, and Cox regression was used to demonstrate the clinical validity of phenomapping. The mean age was 65±12 years; 62% were female; 39% were black; and comorbidities were common. Although all patients met published criteria for the diagnosis of HFpEF, phenomapping analysis classified study participants into 3 distinct groups that differed markedly in clinical characteristics, cardiac structure/function, invasive hemodynamics, and outcomes (eg, phenogroup 3 had an increased risk of HF hospitalization [hazard ratio, 4.2; 95% confidence interval, 2.0-9.1] even after adjustment for traditional risk factors [P<0.001]). The HFpEF phenogroup classification, including its ability to stratify risk, was successfully replicated in a prospective validation cohort (n=107). CONCLUSIONS: Phenomapping results in a novel classification of HFpEF. Statistical learning algorithms applied to dense phenotypic data may allow improved classification of heterogeneous clinical syndromes, with the ultimate goal of defining therapeutically homogeneous patient subclasses.

Utility of positron emission tomography for drug development for heart failure.

Only about 1 in 5,000 investigational agents in a preclinical stage acquires Food and Drug Administration approval. Among many reasons for this includes an inefficient transition from preclinical to clinical phases, which exponentially increase the cost and the delays the process of drug development. Positron emission tomography (PET) is a nuclear imaging technique that has been used for the diagnosis, risk stratification, and guidance of therapy. However, lately with the advance of radiochemistry and of molecular imaging technology, it became evident that PET could help novel drug development process. By using a PET radioligand to report on receptor occupancy during novel agent therapy, it may help assess the effectiveness, efficacy, and safety of such a new medication in an early preclinical stage and help design successful clinical trials even at a later phase. In this article, we explore the potential implications of PET in the development of new heart failure therapies and review PET's application in the respective pathophysiologic pathways such as myocardial perfusion, metabolism, innervation, inflammation, apoptosis, and cardiac remodeling.

Trends in Heart Failure Clinical Trials From 2001-2012.

BACKGROUND: A systematic assessment of the temporal trends in heart failure (HF) clinical trials is lacking. METHODS AND RESULTS: A total of 154 phase II-IV HF trials including 162,725 patients published from 2001 to 2012 in 8 high-impact-factor journals were reviewed. The median number of participants and sites per trial were 367 (interquartile range [IQR] 133-1450) and 38 (5-101), respectively. Median enrollment duration was 2.2 (1.5-3.3) years. The majority of studies investigated treatment for chronic HF (82.5%) and investigated HF with reduced ejection fraction (EF) (71.4%), whereas 27 trials (17.5%) enrolled patients with mixed EF and 9 (5.8%) enrolled HF with preserved EF patients alone. Enrollment rates did not significantly change over time (median 0.49 patients site(-1) month(-1), IQR 0.34-0.98; P = .53). Trials meeting their primary end point decreased over time from 73.5% in 2001-2003 to 52.5% in 2010-2012 (P = .08) and were more often smaller and used nonmortality end points. Industry trials were larger with shorter enrollment duration, more concentrated in North America, and more likely to be positive. Trials conducted exclusively outside North America and Western Europe had the highest enrollment rates (median 1.95 patients site(-1) month(-1), IQR 1.34-4.11). CONCLUSIONS: Contemporary HF clinical trials display slow enrollment rates and decreased rates of positive outcomes over time. Positive trials tended to be smaller size with a higher proportion of surrogate end points.

Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure.

Heart failure (HF) represents a global public health and economic problem associated with unacceptable rates of death, hospitalization, and healthcare expenditure. Despite available therapy, HF carries a prognosis comparable to many forms of cancer with a 5-year survival rate of ~50%. The current treatment paradigm for HF with reduced ejection fraction (EF) centers on blocking maladaptive neurohormonal activation and decreasing cardiac workload with therapies that concurrently lower blood pressure and heart rate. Continued development of hemodynamically active medications for stepwise addition to existing therapies carries the risk of limited tolerability and safety. Moreover, this treatment paradigm has thus far failed for HF with preserved EF. Accordingly, development of hemodynamically neutral HF therapies targeting primary cardiac pathologies must be considered. In this context, a partial adenosine A1 receptor (A1R) agonist holds promise as a potentially hemodynamically neutral therapy for HF that could simultaneous improve cardiomyocyte energetics, calcium homeostasis, cardiac structure and function, and long-term clinical outcomes when added to background therapies. In this review, we describe the physiology and pathophysiology of HF as it relates to adenosine agonism, examine the existing body of evidence and biologic rationale for modulation of adenosine A1R activity, and review the current state of drug development of a partial A1R agonist for the treatment of HF.

Serum insulin-like growth factor-1 and its binding protein-7: potential novel biomarkers for heart failure with preserved ejection fraction.

BACKGROUND: Insulin-like growth factor binding protein-7 (IGFBP-7) modulates the biological activities of insulin-like growth factor-1 (IGF-1). Previous studies demonstrated the prognostic value of IGFBP-7 and IGF-1 among patients with systolic heart failure (HF). This study aimed to evaluate the IGF1/IGFBP-7 axis in HF patients with preserved ejection fraction (HFpEF). METHODS: Serum IGF-1 and IGFBP-7 levels were measured in 300 eligible consecutive patients who underwent comprehensive cardiac assessment. Patients were categorized into 3 groups including controls with normal diastolic function (n = 55), asymptomatic left ventricular diastolic dysfunction (LVDD, n = 168) and HFpEF (n = 77). RESULTS: IGFBP-7 serum levels showed a significant graded increase from controls to LVDD to HFpEF (median 50.30 [43.1-55.3] vs. 54.40 [48.15-63.40] vs. 61.9 [51.6-69.7], respectively, P < 0.001), whereas IGF-1 levels showed a graded decline from controls to LVDD to HFpEF (120.0 [100.8-144.0] vs. 112.3 [88.8-137.1] vs. 99.5 [72.2-124.4], p < 0.001). The IGFBP-7/IGF-1 ratio increased from controls to LVDD to HFpEF (0.43 [0.33-0.56] vs. 0.48 [0.38-0.66] vs. 0.68 [0.55-0.88], p < 0.001). Patents with IGFB-7/IGF1 ratios above the median demonstrated significantly higher left atrial volume index, E/E' ratio, and NT-proBNP levels (all P ≤ 0.02). CONCLUSION: In conclusion, this hypothesis-generating pilot study suggests the IGFBP-7/IGF-1 axis correlates with diastolic function and may serve as a novel biomarker in patients with HFpEF. A rise in IGFBP-7 or the IGFBP-7/IGF-1 ratio may reflect worsening diastolic function, adverse cardiac remodeling, and metabolic derangement.

Trends in characteristics of cardiovascular clinical trials 2001-2012.

BACKGROUND: Efficient conduct of clinical trials is essential for the timely generation of critical medical knowledge. METHODS: We systematically assessed size, duration, enrollment rates, and geographic distribution of randomized cardiovascular trials published between 2001 and 2012 in the 8 highest-impact journals in general medicine and cardiology. RESULTS: Of the 1,224 trials, 27.0% were conducted in North America, 36.5% in Western Europe, and 7.7% in other countries, and 28.8% were multiregional. Trials enrolled a median of 452 patients (interquartile range 167-1,530) in 20 sites (2-76). Median duration was 2.1 (1.3-3.3) years, with an estimated enrollment rate of 1.1 (0.5-3.5) patients/site per month. Between 2001-2003 and 2009-2012, the proportion of North American trials decreased from 34.5% to 25.7% (P = .006), whereas that of multiregional trials (from 26.0% to 30.3%; P = .046) and trials conducted in other countries (from 4.6% to 10.3%; P = .012) increased. Over time, trials involved more patients (from 400 to 500 [median]; P = .032) and sites (from 20 to 22; P = .049), multiregional trials involved more countries (from 12 to 18; P = .031), and enrollment rate declined from 1.2 to 0.9 patients/site per month (P = .017). The proportion of trials meeting their primary end point ("positive") decreased from 69% to 57% (P < .001). Trials with higher enrollment rates were more likely to be positive (odds ratio 1.20 per doubling, 95% CI 1.12-1.29), as were industry-sponsored compared with government-sponsored trials (odds ratio 2.62, 95% CI 1.67-4.12). CONCLUSIONS: From 2001 to 2012, cardiovascular clinical trials have become larger, more global, and less likely to meet their primary end point. Enrollment rates have declined, requiring more sites and regions.

Improving cardiovascular clinical trials conduct in the United States: recommendation from clinicians, researchers, sponsors, and regulators.

Advances in medical therapies leading to improved patient outcomes are in large part related to successful conduct of clinical trials that offer critical information regarding the efficacy and safety of novel interventions. The conduct of clinical trials in the United States, however, continues to face increasing challenges with recruitment and retention. These trends are paralleled by an increasing shift toward more multinational trials where most participants are enrolled in countries outside the United States, bringing into question the generalizability of the results to the American population. This manuscript presents the perspectives and recommendations from clinicians, researchers, sponsors, and regulators who attended a meeting facilitated by the Food and Drug Administration to improve upon the current clinical trial trends in the United States.

Amino acids and derivatives, a new treatment of chronic heart failure?

Amino acids play a key role in multiple cellular processes. Amino acids availability is reduced in patients with heart failure (HF) with deleterious consequences on cardiac and whole-body metabolism. Several metabolic abnormalities have been identified in the failing heart, and many of them lead to an increased need of amino acids. Recently, several clinical trials have been conducted to demonstrate the benefits of amino acids supplementation in patients with HF. Although they have shown an improvement of exercise tolerance and, in some cases, of left ventricular function, they have many limitations, namely small sample size, differences in patients' characteristics and nutritional supplementations, and lack of data regarding outcomes. Moreover recent data suggest that a multi-nutritional approach, including also antioxidants, vitamins, and metals, may be more effective. Larger trials are needed to ascertain safety, efficacy, and impact on prognosis of such an approach in HF.