Ularitide as treatment of refractory ascites in cirrhosis- a study protocol for a randomised trial.

INTRODUCTION Ascites is a frequent complication to cirrhosis. When ascites becomes refractory to standard diuretic pharmacotherapy, patients are facing a median survival of less than one year and most likely a need for frequent hospitalisations due to large-volume paracentesis or complications. An unmet need exists for new and improved treatments of refractory ascites and the present study investigates the potential of the natriuretic peptide ularitide for this indication. METHODS We aim to investigate the effects, safety and tolerability of ularitide as treatment of refractory ascites in cirrhosis patients in a randomised, double-blind, placebo-controlled trial. Participants receive ularitide or placebo as a continuous intravenous infusion during hospitalisation as an add-on to any diuretic treatment. Clinical end points include increase in diuresis and natriuresis, reduction in body weight and waist circumference, safety end points, as well as changes in plasma concentrations of renal and systemic response biomarkers and hormones. CONCLUSION This study will provide evidence concerning the potential of ularitide in treating cirrhosis patients with refractory ascites. FUNDING This investigator-initiated trial is supported by ADS AIPHIA Development Services AG. TRIAL REGISTRATION Clinicaltrials.gov (NCT04311489) and EU Drug Regulating Authorities Clinical Trials (EudraCT: 2019-002268-28). The trial will be conducted in accordance with good clinical practice, the Declaration of Helsinki and applicable demands from Danish authorities.

Treatments targeting inotropy.

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.

Interaction of Left Ventricular Size and Sex on Outcome of Cardiac Resynchronization Therapy Among Patients With a Narrow QRS Duration in the EchoCRT Trial.

BACKGROUND: Longer QRS duration (QRSd) improves, but increased left ventricular (LV) end-diastolic volume (LVEDV) reduces, efficacy of cardiac resynchronization therapy (CRT). QRSd/LVEDV ratios differ between sexes. We hypothesized that in the EchoCRT (Echocardiography Guided Cardiac Resynchronization Therapy) trial enrolling patients with heart failure with QRSd <130 ms, those with larger LVEDV would deteriorate but those with the highest QRSd/LVEDV would improve with CRT. METHODS AND RESULTS: Primary outcome in patients (n=787, 72% men, 93% New York Heart Association class III, QRSd <130 ms, LV ejection fraction ≤35%, LV dilation and dyssynchrony) randomized to CRT-ON or CRT-OFF and followed up for 19 months was compared according to LVEDV (height indexed) or QRSd/LVEDV ratio, in multivariable analysis. Structural remodeling was assessed echocardiographically 6 months after implantation. Patients with baseline LVEDV higher than or equal to median worsened with CRT (death/heart failure hospitalization: CRT-ON versus CRT-OFF, 35.2% versus 24.5% [hazard ratio, 1.64; 95% confidence interval, 1.11-2.42; P=0.012]), but those with LVEDV lower than median remained unaffected. Patients with the highest QRSd/LVEDV ratio improved with CRT (death/heart failure hospitalization in top quartile: 20.9% in CRT-ON [n=91] versus 28.3% in CRT-OFF [n=106] [hazard ratio, 0.64; 95% confidence interval, 0.34-1.24; P=0.188], versus the remaining quartiles: 31.7% in CRT-ON [n=300] versus 24.8% in CRT-OFF [n=290] [hazard ratio, 1.47; 95% confidence interval, 1.07-2.02; P=0.016], test for interaction P=0.046). QRSd and dyssynchrony were similar between groups. The 3-way test for interaction indicated no sex-specific effects. However, numerically, men with LVEDV higher than or equal to median accounted for worse outcomes of CRT-ON. Women, with the highest QRSd/LVEDV ratio exhibited significant reverse remodeling. CONCLUSION: CRT has opposite effects among patients with heart failure with QRSd <130 ms according to LV size: worsening outcomes in patients with larger LV, but inducing beneficial effects in those with smaller LV. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00683696.

Cardiac Resynchronization Therapy in Patients With Heart Failure and Narrow QRS Complexes.

BACKGROUND: Cross correlation analysis (CCA) using tissue Doppler imaging has been shown to be associated with outcome after cardiac resynchronization therapy (CRT) in patients with heart failure (HF) with wide QRS. However, its significance in patients with narrow QRS treated with CRT is unknown. OBJECTIVES: The aim of the current study was to investigate the association of mechanical activation delay by CCA with study outcome in patients with HF enrolled in the EchoCRT trial. METHODS: Baseline CCA could be performed from tissue Doppler imaging in the apical views in 807 of 809 (99.7%) enrolled patients, and 6-month follow-up could be performed in 610 of 635 (96%) patients with available echocardiograms. Patients with a pre-specified maximal activation delay ≥35 ms were considered to have significant delay. The study outcome was HF hospitalization or death. RESULTS: Of 807 patients, 375 (46%) did not have delayed mechanical activation at baseline by CCA. Patients without delayed mechanical activation who were randomized to CRT-On compared with CRT-Off had an increased risk of poor outcome (hazard ratio: 1.70; 95% confidence interval: 1.13 to 2.55; p = 0.01) with a significant interaction term (p = 0.04) between delayed mechanical activation and device randomization for the endpoint. Among patients with paired baseline and follow-up data with no events before 6-month follow-up (n = 541), new-onset delayed mechanical activation in the CRT-On group showed a significant increase in unfavorable events (hazard ratio: 3.73; 95% confidence interval: 1.15 to 12.14; p = 0.03). CONCLUSIONS: In the EchoCRT population, absence of delayed mechanical activation by CCA was significantly associated with poor outcomes, possibly due to the onset of new delayed mechanical activation with CRT pacing. (Echocardiography Guided Cardiac Resynchronization Therapy [EchoCRT] Trial; NCT00683696).

Corrigendum to "Falls and Fractures in the Elderly with Sinus Node Disease: The Impact of Pacemaker Implantation".

[This corrects the article DOI: 10.1155/2012/498102.].

Effect of Ularitide on Cardiovascular Mortality in Acute Heart Failure.

BACKGROUND: In patients with acute heart failure, early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and, potentially, myocardial injury, thereby favorably affecting patients' long-term prognosis. METHODS: In this double-blind trial, we randomly assigned 2157 patients with acute heart failure to receive a continuous intravenous infusion of either ularitide at a dose of 15 ng per kilogram of body weight per minute or matching placebo for 48 hours, in addition to accepted therapy. Treatment was initiated a median of 6 hours after the initial clinical evaluation. The coprimary outcomes were death from cardiovascular causes during a median follow-up of 15 months and a hierarchical composite end point that evaluated the initial 48-hour clinical course. RESULTS: Death from cardiovascular causes occurred in 236 patients in the ularitide group and 225 patients in the placebo group (21.7% vs. 21.0%; hazard ratio, 1.03; 96% confidence interval, 0.85 to 1.25; P=0.75). In the intention-to-treat analysis, there was no significant between-group difference with respect to the hierarchical composite outcome. The ularitide group had greater reductions in systolic blood pressure and in levels of N-terminal pro-brain natriuretic peptide than the placebo group. However, changes in cardiac troponin T levels during the infusion did not differ between the two groups in the 55% of patients with paired data. CONCLUSIONS: In patients with acute heart failure, ularitide exerted favorable physiological effects (without affecting cardiac troponin levels), but short-term treatment did not affect a clinical composite end point or reduce long-term cardiovascular mortality. (Funded by Cardiorentis; TRUE-AHF ClinicalTrials.gov number, NCT01661634 .).

Prognostic implications of left ventricular global longitudinal strain in heart failure patients with narrow QRS complex treated with cardiac resynchronization therapy: a subanalysis of the randomized EchoCRT trial.

AIM: Left ventricular (LV) global longitudinal strain (GLS) reflects LV systolic function and correlates inversely with the extent of LV myocardial scar and fibrosis. The present subanalysis of the Echocardiography Guided CRT trial investigated the prognostic value of LV GLS in patients with narrow QRS complex. METHODS AND RESULTS: Left ventricular (LV) global longitudinal strain (GLS) was measured on the apical 2-, 4- and 3-chamber views using speckle tracking analysis. Measurement of baseline LV GLS was feasible in 755 patients (374 with cardiac resynchronization therapy (CRT)-ON and 381 with CRT-OFF). The median value of LV GLS in the overall population was 7.9%, interquartile range 6.2-10.1%. After a mean follow-up period of 19.4 months, 95 patients in the CRT-OFF group and 111 in the CRT-ON group reached the combined primary endpoint of all-cause mortality and heart failure hospitalization. Each 1% absolute unit decrease in LV GLS was independently associated with 11% increase in the risk to reach the primary endpoint (Hazard ratio 1.11; 95% confidence interval 95% 1.04-1.17, P < 0.001), after adjusting for ischaemic cardiomyopathy and randomization treatment among other clinically relevant variables. When categorizing patients according to quartiles of LV GLS, the primary endpoint occurred more frequently in patients in the lowest quartile (<6.2%) treated with CRT-ON vs. CRT-OFF (45.6% vs. 28.7%, P = 0.009) whereas, no differences were observed in patients with LV GLS ≥6.2% treated with CRT-OFF vs. CRT-ON (23.7% vs. 24.5%, respectively; P = 0.62). CONCLUSION: Low LV GLS is associated with poor outcome in heart failure patients with QRS width <130 ms, independent of randomization to CRT or not. Importantly, in the group of patients with the lowest LV GLS quartile, CRT may have a detrimental effect on clinical outcomes.

Rationale for and design of the TRUE-AHF trial: the effects of ularitide on the short-term clinical course and long-term mortality of patients with acute heart failure.

The TRUE-AHF is a randomized, double-blind, parallel-group, placebo-controlled trial which is evaluating the effects of a 48-h infusion of ularitide (15 ng/kg/min) on the short- and long-term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long-term follow-up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event-driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in-hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE-AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure. TRIAL REGISTRATION: NCT01661634.

Effect of cardiac resynchronization therapy in patients with diabetes randomized in EchoCRT.

AIMS: As patients with heart failure (HF) and concomitant diabetes carry a poor prognosis, this post-hoc subgroup analysis aimed to compare the outcomes of patients with and without diabetes randomized in the Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) study. METHODS AND RESULTS: EchoCRT randomized patients with a QRS duration <130 ms and echocardiographic evidence of left ventricular dyssynchrony to CRT turned on (CRT=ON) vs. off (CRT=OFF) following device implantation. At study entry, 328 patients (40.5%) had diabetes. The primary outcome (all-cause death or first hospitalization for worsening HF) occurred more frequently in patients with than without diabetes (32.6% vs. 23%, P = 0.003). A significant treatment interaction was observed for the primary outcome indicating a higher risk for CRT=ON vs. CRT-OFF in patients without [26.5% vs. 19.8%, hazard ratio (HR) 1.58, 95% confidence interval (CI) 1.08-2.31] vs. with diabetes (31.4% vs. 34%; HR 0.86, 95% CI 0.58-1.27; P for interaction 0.041). This effect was mainly driven by a lower rate in HF hospitalizations, but was only of borderline significance after multivariate adjustment (P = 0.063). The most pronounced effect was observed in patients with non-ischaemic cardiomyopathy, where a significantly reduced risk of reaching the primary endpoint for CRT=ON vs. CRT-OFF was observed in patients with (HR 0.27, P = 0.003) vs. patients without diabetes (HR 1.79, P = 0.038; P for interaction 0.005). No treatment interaction by diabetes diagnosis was found for mortality endpoints. CONCLUSION: In EchoCRT, HF patients with a narrow QRS complex and coexisting diabetes demonstrated a signal for less harm caused by CRT compared with patients without diabetes, which was driven by differences in hospitalizations owing to HF.

Effect of Gender on Outcomes After Cardiac Resynchronization Therapy in Patients With a Narrow QRS Complex: A Subgroup Analysis of the EchoCRT Trial.

BACKGROUND: In EchoCRT, a randomized controlled trial evaluating the effect of cardiac resynchronization therapy (CRT) in patients with a QRS duration of <130 ms and echocardiographic evidence of left ventricular dyssynchrony, the primary outcome (death from any cause or first hospitalization for worsening heart failure) occurred more frequently in the CRT-ON when compared with the control group. In this prespecified subgroup analysis, we evaluated the effect of sex on clinical outcome in EchoCRT. METHODS AND RESULTS: In EchoCRT, 585 (72%) of included patients were men. At baseline, male patients had a higher incidence of ischemic cardiomyopathy and longer QRS duration. On uni- and multivariable analysis, no significant interaction was observed regarding sex for the primary or any of the secondary end points. Numerically, a higher all-cause mortality was observed in male patients randomized to CRT-ON versus CRT-OFF on univariable analysis (hazard ratio, 1.83; 95% confidence interval, 1.08-3.12); however, no statistically significant interaction compared with females randomized to CRT-ON versus CRT-OFF was noted (hazard ratio, 0.99; P interaction, 0.56). There was no difference in the primary safety end point of system-related complications, including CRT system- and implantation-related events. CONCLUSIONS: The largest hazard for all-cause mortality in EchoCRT was observed in men randomized to CRT-ON; the comparison with women did not reach statistical significance, which may be because of the premature termination of the trial and the limited data. These results suggest that male sex may be a risk factor for harm by CRT in patients with narrow QRS width, an observation which deserves further investigation. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00683696.

Association of persistent or worsened echocardiographic dyssynchrony with unfavourable clinical outcomes in heart failure patients with narrow QRS width: a subgroup analysis of the EchoCRT trial.

AIMS: EchoCRT was a randomized trial of cardiac resynchronization therapy (CRT) in severely symptomatic heart failure (HF) patients with narrow QRS width <130 ms, ejection fraction ≤35%, and echocardiographic dyssynchrony. All received CRT implants which were then randomized to CRT-On or CRT-Off. While the trial showed no benefit of CRT to these patients, the aim of this subgroup analysis was to test the hypothesis that persistent or worsening dyssynchrony is associated with unfavourable clinical outcomes. METHODS AND RESULTS: We studied 614 EchoCRT patients with baseline and 6-month echocardiograms. Baseline dyssynchrony required for study inclusion was either tissue Doppler imaging longitudinal velocity delay ≥80 ms or speckle-tracking radial strain delay ≥130 ms. Persistent dyssynchrony at 6 months was observed similarly in both groups (77% in CRT-On; 76% in CRT-Off). Persistent dyssynchrony was associated with a significantly higher primary end point of death or HF hospitalization (HR = 1.54, 95% CI 1.03-2.30, P = 0.03), and in particular secondary endpoint of HF hospitalization (HR = 1.66, 95% CI 1.07-2.57, P = 0.02). HF hospitalizations were also associated with worsening longitudinal dyssynchrony (HR = 1.45, 95% CI 1.02-2.05, P = 0.037), and worsening radial dyssynchrony (HR = 1.81, 95% CI 1.16-2.81, P = 0.008). Associations of persistent or worsening dyssynchrony with outcomes were similar in CRT-Off and CRT-On groups. CONCLUSIONS: Persistent or worsening echocardiographic dyssynchrony in HF patients with narrow QRS width was a marker for unfavourable clinical outcomes unaffected by CRT. In particular, echocardiographic dyssynchrony on follow-up was strongly associated with HF hospitalizations and appears to be a prognostic marker of disease severity.

Ularitide: a natriuretic peptide candidate for the treatment of acutely decompensated heart failure.

Treatment for acutely decompensated heart failure (ADHF) has not changed much in the last two decades. Currently available therapies have variable efficacy and can be associated with adverse outcomes. Natriuretic peptides properties include diuresis, natriuresis, vasorelaxation, inhibition of renin-angiotensin-aldosterone system, and are thus chosen in the treatment of ADHF. Two forms of natriuretic peptides are currently available for the treatment of ADHF. Urodilatin (INN: ularitide) represents another member of the natriuretic peptide family with a unique molecular structure that may provide distinct benefits in the treatment of ADHF. Early clinical exploratory and Phase II studies have demonstrated that ularitide has potential cardiovascular and renal benefits. Ularitide is currently being tested in the Phase III TRUE-AHF clinical study. TRUE-AHF has features that may be different when compared with other recent outcome studies in ADHF. These distinct differences aim to maximize clinical effects and minimize potential adverse events of ularitide. However, whether this rationale translates into a better outcome needs to be awaited.

Agents with vasodilator properties in acute heart failure: how to design successful trials.

Agents with vasodilator properties (AVDs) are frequently used in the treatment of acute heart failure (AHF). AVDs rapidly reduce preload and afterload, improve left ventricle to aorta and right ventricle to pulmonary artery coupling, and may improve symptoms. Early biomarker changes after AVD administration have suggested potentially beneficial effects on cardiac stretch, vascular tone, and renal function. AVDs that reduce haemodynamic congestion without causing hypoperfusion might be effective in preventing worsening organ dysfunction. Existing AVDs have been associated with different results on outcomes in randomized clinical trials, and observational studies have suggested that AVDs may be associated with a clinical outcome benefit. Lessons have been learned from past AVD trials in AHF regarding preventing hypotension, selecting the optimal endpoint, refining dyspnoea measurements, and achieving early randomization and treatment initiation. These lessons have been applied to the design of ongoing pivotal clinical trials, which aim to ascertain if AVDs improve clinical outcomes. The developing body of evidence suggests that AVDs may be a clinically effective therapy to reduce symptoms, but more importantly to prevent end-organ damage and improve clinical outcomes for specific patients with AHF. The results of ongoing trials will provide more clarity on the role of AVDs in the treatment of AHF.

The effect of QRS duration on cardiac resynchronization therapy in patients with a narrow QRS complex: a subgroup analysis of the EchoCRT trial.

AIMS: In EchoCRT, a randomized trial evaluating the effect of cardiac resynchronization therapy (CRT) in patients with a QRS duration of <130 ms and echocardiographic evidence of left ventricular dyssynchrony, the primary outcome occurred more frequently in the CRT when compared with the control group. According to current heart failure guidelines, CRT is recommended in patients with a QRS duration of ≥120 ms. However, there is some ambiguity from clinical trial data regarding the benefit of patients with a QRS duration of 120-130 ms. METHODS AND RESULTS: The main EchoCRT trial was prematurely terminated due to futility. For the current subgroup analysis we compared data for CRT-ON vs. -OFF in patients with QRS < 120 (n = 661) and QRS 120-130 ms (n = 139). On uni- and multivariable analyses, no significant interaction was observed between the two groups and randomized treatment for the primary or any of the secondary endpoints. On multivariable analysis, a higher risk for the primary endpoint was observed in patients with a QRS duration of 120-130 ms randomized to CRT-ON vs. CRT-OFF (hazard ratio 2.18, 95% CI 1.02-4.65; P = 0.044). However, no statistically significant interaction, compared with patients with QRS < 120 ms randomized to CRT-ON vs. CRT-OFF, was noted (P-interaction = 0.160). CONCLUSIONS: In this pre-specified subgroup analysis of EchoCRT, no benefit of CRT was evident in patients with a QRS duration of 120-130 ms. These data further question the usefulness of CRT in this patient population.

Cardiac resynchronization therapy in heart failure patients with less severe left ventricular dysfunction.

Cardiac resynchronization therapy is beneficial in heart failure patients with LVEF ≤35% and electrical dyssynchrony. However, its effects among patients with less severe LV dysfunction have not been established. Recent post-hoc analyses of landmark CRT trials suggest that CRT benefit may be present in patients with LVEF >35% and is associated with improvement in cardiac reverse remodelling, all-cause mortality, and need for heart failure hospitalizations. This review summarizes the currently available literature regarding the potential impact of CRT in patients with more modest reductions in LVEF.

Long-term performance of modern coronary sinus leads in cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) has become an important pillar of contemporary heart failure therapy. The efficacy of CRT, however, critically relies on proper LV lead placement and performance, which is why data regarding the long-term performance of CS leads are of considerable interest. Available studies are limited by a restricted variety of lead vendors, earlier lead models and / or very short follow-up periods. In the current study, we therefore investigated the long-term performance of modern LV leads in a large "real world" cohort of patients undergoing CRT implantation. METHODS AND RESULTS: All 193 patients who had successfullyundergone CRT implantation at the University Hospital Zurich between September 2003 and January 2010 were included in the study. An overall stable course of stimulation energy was observed over time; neither ischemic etiology, lead configuration, or severely reduced EF had an influence on the evolution of energy thresholds over time. Interestingly, patients with a high energy threshold at baseline experienced a significant reduction during follow-up. In contrast, a significant drop in impedance was seen following implantation, followed by a steady course for the rest of the observation period. Only 15 patients (9.7%) showed an impedance > 1000 Ohm at any time during their follow-up. Seven lead dislocations were observed during follow up. CONCLUSION: The current comprehensive analysis of long-term performance of modern coronary sinus leads demonstrates excellent stability, performance and safety. These data may have important implications for physicians involved in biventricular pacemaker implantations and in the follow-up care of these patients.

Comprehensive cardiac resynchronization therapy optimization in the real world.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients suffering from chronic heart failure (CHF). Optimal device programming is crucial for maximum patient benefit. The goal of the present study was to assess device settings from CHF patients undergoing CRT optimization in a "real world" setting, and to delineate parameters most frequently requiring adjustment. METHODS: All patients who underwent CRT device implantation in the Cardiology Clinicat the University Hospital Zurich between January 2011 and September 2012 and in whom follow-up was available were included in this analysis. RESULTS: A total of 170 CHF patients were included in this analysis. True biventricular pacing was present in 44% of all patients, while QRS fusion was detected in 49.9%. The majority of the patients presented with suboptimal atrioventricular (AV) delays requiring adjustment. AV delays were therefore shortened due to the presence of QRS fusion in 53.3% and 38.1% of patients (sAV and pAV, respectively) or prolonged because of truncation of the A wave in the left ventricular inflow pulse wave Doppler measurement (17.5% and 28.4% for sAV and pAV, respectively). In contrast, interventricular delay (VV delay) was rarely changed (11.9%). CONCLUSIONS: In our "real world" cohort, a substantial proportion of patients presented to their first post-operative consultation with suboptimal device settings. Our data indicate that the opportunity to optimize device settings is frequently wasted in the "real world", underlining the necessity for expert device follow-up to deliver optimal care to this challenging group of heart failure patients.

Cardiac-resynchronization therapy in heart failure with a narrow QRS complex.

BACKGROUND: Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in chronic systolic heart failure with a wide QRS complex. Mechanical dyssynchrony also occurs in patients with a narrow QRS complex, which suggests the potential usefulness of CRT in such patients. METHODS: We conducted a randomized trial involving 115 centers to evaluate the effect of CRT in patients with New York Heart Association class III or IV heart failure, a left ventricular ejection fraction of 35% or less, a QRS duration of less than 130 msec, and echocardiographic evidence of left ventricular dyssynchrony. All patients underwent device implantation and were randomly assigned to have CRT capability turned on or off. The primary efficacy outcome was the composite of death from any cause or first hospitalization for worsening heart failure. RESULTS: On March 13, 2013, the study was stopped for futility on the recommendation of the data and safety monitoring board. At study closure, the 809 patients who had undergone randomization had been followed for a mean of 19.4 months. The primary outcome occurred in 116 of 404 patients in the CRT group, as compared with 102 of 405 in the control group (28.7% vs. 25.2%; hazard ratio, 1.20; 95% confidence interval [CI], 0.92 to 1.57; P=0.15). There were 45 deaths in the CRT group and 26 in the control group (11.1% vs. 6.4%; hazard ratio, 1.81; 95% CI, 1.11 to 2.93; P=0.02). CONCLUSIONS: In patients with systolic heart failure and a QRS duration of less than 130 msec, CRT does not reduce the rate of death or hospitalization for heart failure and may increase mortality. (Funded by Biotronik and GE Healthcare; EchoCRT ClinicalTrials.gov number, NCT00683696.).