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In this randomized, placebo-controlled trial, investigators evaluated the effects of the sodium–glucose cotransporter 2 inhibitor dapagliflozin in patients with heart failure and a reduced ejection fraction with or without type 2 diabetes. The risk of worsening heart failure or cardiovascular death was lower among those who received dapagliflozin, regardless of the presence or absence of diabetes.

In patients with reduced ejection fraction, mild heart failure, and prolonged QRS duration, CRT with a defibrillator improved survival, as compared with defibrillator therapy alone. The survival benefit was limited to patients with left bundle-branch block. The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) showed the safety and effectiveness of cardiac-resynchronization therapy (CRT) with a defibrillator (CRT-D) in patients with asymptomatic or mildly symptomatic heart failure, a reduced ejection fraction, and a prolonged QRS duration. 1 The study showed that treatment with CRT-D was associated with a 34% relative reduction in the risk of nonfatal heart-failure events or death from any cause, as compared with implantable cardioverter–defibrillator (ICD) therapy alone over a median follow-up period of 2.4 years. The benefit of CRT-D in the trial was primarily driven by a significant relative reduction of . . .

Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor approved for the treatment of adult heart failure (HF); however, the benefit of sacubitril/valsartan in pediatric HF patients is unknown. This global multi-center study will use an adaptive, seamless two-part design. Part 1 will assess the pharmacokinetics/pharmacodynamics of single ascending doses of sacubitril/valsartan in pediatric (1 month to <18 years) HF patients with systemic left ventricle and reduced left ventricular systolic function stratified into 3 age groups (Group 1: 6 to <18 years; Group 2: 1 to <6 years; Group 3: 1 month to <1 year). Part 2 is a 52-week, efficacy and safety study where 360 eligible patients will be randomized to sacubitril/valsartan or enalapril. A novel global rank primary endpoint derived by ranking patients (worst-to-best outcome) based on clinical events such as death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores), and patient-reported HF symptoms will be used to assess efficacy. The PANORAMA-HF study, which will be the largest prospective pediatric HF trial conducted to date and the first to use a global rank primary endpoint, will determine whether sacubitril/valsartan is superior to enalapril for treatment of pediatric HF patients with reduced systemic left ventricular systolic function. Design of the two-stage, seamless, adaptive PANORAMA-HF study assessing the PK/PD, safety, and efficacy of sacubitril/valsartan versus enalapril in pediatric heart failure patients with systemic left ventricle and reduced left ventricular systolic function. bid, twice-weekly; m, month; mg, milligram; kg, kilogram; PD, pharmacodynamics; PK, pharmacokinetics. [Display omitted]

Ivabradine specifically inhibits the I f current in the sinoatrial node to lower heart rate, without affecting other aspects of cardiac function. We aimed to test whether lowering the heart rate with ivabradine reduces cardiovascular death and morbidity in patients with coronary artery disease and left-ventricular systolic dysfunction. Between December, 2004, and December, 2006, we screened 12 473 patients at 781 centres in 33 countries. We enrolled 10 917 eligible patients who had coronary artery disease and a left-ventricular ejection fraction of less than 40% in a randomised, double-blind, placebo-controlled, parallel-group trial. 5479 patients received 5 mg ivabradine, with the intention of increasing to the target dose of 7·5 mg twice a day, and 5438 received matched placebo in addition to appropriate cardiovascular medication. The primary endpoint was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure. We analysed patients by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00143507. Mean heart rate at baseline was 71·6 (SD 9·9) beats per minute (bpm). Median follow-up was 19 months (IQR 16–24). Ivabradine reduced heart rate by 6 bpm (SE 0·2) at 12 months, corrected for placebo. Most (87%) patients were receiving β blockers in addition to study drugs, and no safety concerns were identified. Ivabradine did not affect the primary composite endpoint (hazard ratio 1·00, 95% CI 0·91–1·1, p=0·94). 1233 (22·5%) patients in the ivabradine group had serious adverse events, compared with 1239 (22·8%) controls (p=0·70). In a prespecified subgroup of patients with heart rate of 70 bpm or greater, ivabradine treatment did not affect the primary composite outcome (hazard ratio 0·91, 95% CI 0·81–1·04, p=0·17), cardiovascular death, or admission to hospital for new-onset or worsening heart failure. However, it did reduce secondary endpoints: admission to hospital for fatal and non-fatal myocardial infarction (0·64, 95% CI 0·49–0·84, p=0·001) and coronary revascularisation (0·70, 95% CI 0·52–0·93, p=0·016). Reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater. Servier, France.

Current guidelines on the use of β-blockers in post–acute myocardial infarction (MI) patients without reduced left ventricular ejection fraction (LVEF) are based on studies before the implementation of modern reperfusion and secondary prevention therapies. It remains unknown whether β-blockers will reduce mortality and recurrent MI in contemporary revascularized post-MI patients without reduced LVEF. BETAMI is a prospective, randomized, open, blinded end point multicenter study in 10,000 MI patients designed to test the superiority of oral β-blocker therapy compared to no β-blocker therapy. Patients with LVEF ≥40% following treatment with percutaneous coronary intervention or thrombolysis and/or no clinical signs of heart failure are eligible to participate. The primary end point is a composite of all-cause mortality or recurrent MI obtained from national registries over a mean follow-up period of 3 years. Safety end points include rates of nonfatal MI, all-cause mortality, ventricular arrhythmias, and hospitalizations for heart failure obtained from hospital medical records 30 days after randomization, and from national registries after 6 and 18 months. Key secondary end points include recurrent MI, heart failure, cardiovascular and all-cause mortality, and clinical outcomes linked to β-blocker therapy including drug adherence, adverse effects, cardiovascular risk factors, psychosocial factors, and health economy. Statistical analyses will be conducted according to the intention-to-treat principle. A prespecified per-protocol analysis (patients truly on β-blockers or not) will also be conducted. The results from the BETAMI trial may have the potential of changing current clinical practice for treatment with β-blockers following MI in patients without reduced LVEF. EudraCT number 2018-000590-75.

Cardiac resynchronization improves left ventricular function and functional status in patients who have left ventricular systolic dysfunction and interventricular dyssynchrony due to a conduction delay. In a randomized trial comparing medical therapy alone with medical therapy plus cardiac resynchronization, combined therapy was associated with a significant reduction in the risk of death from any cause. In a randomized trial comparing medical therapy alone with medical therapy plus cardiac resynchronization, combined therapy was associated with a significant reduction in the risk of death from any cause. Despite improvements in pharmacologic treatment, many patients with heart failure have severe and persistent symptoms, and their prognosis remains poor. 1 , 2 Such patients commonly have regions of delayed myocardial activation and contraction, leading to cardiac dyssynchrony. In a series of trials lasting up to six months, cardiac resynchronization decreased symptoms and improved exercise capacity, the quality of life, and ventricular function. 3 – 7 The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial showed that cardiac-resynchronization therapy alone or combined with an implantable defibrillator reduced the composite end point of death from any cause or hospitalization during a . . .

The BEAUTIFUL study assessed the morbidity and mortality benefits of the heart rate-lowering agent ivabradine. The placebo arm of the BEAUTIFUL trial was a large cohort of patients with stable coronary artery disease and left-ventricular dysfunction. We did a subanalysis of this placebo group to test the hypothesis that elevated resting heart rate at baseline is a marker for subsequent cardiovascular death and morbidity. The association of baseline resting heart rate with cardiovascular outcomes was analysed using Cox proportional hazard models for groups with a heart rate of 70 beats per min (bpm) or greater (2693 patients) versus less than 70 bpm (2745 patients). Additional analyses were done with finer categorisation of heart rate, and with heart rate as a continuous variable. After adjustment for baseline characteristics, patients with heart rates of 70 bpm or greater had increased risk for cardiovascular death (34%, p=0·0041), admission to hospital for heart failure (53%, p<0·0001), admission to hospital for myocardial infarction (46%, p=0·0066), and coronary revascularisation (38%, p=0·037). For every increase of 5 bpm, there were increases in cardiovascular death (8%, p=0·0005), admission to hospital for heart failure (16%, p<0·0001), admission to hospital for myocardial infarction (7%, p=0·052), and coronary revascularisation (8%, p=0·034). The analysis of fine-groupings of heart rate suggests that the increase in mortality and heart failure outcomes rises continuously above 70 bpm, whereas the relation is less pronounced for coronary outcomes. For heart failure outcomes, the predictive value of resting heart rate was stronger for earlier events than for later events. In patients with coronary artery disease and left-ventricular systolic dysfunction, elevated heart rate (70 bpm or greater) identifies those at increased risk of cardiovascular outcomes, with a differential effect on outcomes associated with heart failure and outcomes associated with coronary events. Servier, France.

PurposeTo compare the effect of liraglutide, sitagliptin and insulin glargine added to standard therapy on left ventricular function in post-ischemic type-2 diabetes mellitus patients.MethodsWe evaluated 32 type-2 diabetes mellitus Caucasians with history of post-ischemic chronic heart failure NYHA class II/III and/or left ventricular ejection fraction ≤45 %. Participants underwent laboratory determinations, electrocardiogram, echocardiogram, Minnesota Living with Heart Failure questionnaire and 6 min walking test at baseline and following 52 weeks treatment. Patients were treated with standard therapy for chronic heart failure and were randomized to receive liraglutide, sitagliptin and glargine in addition to metformin and/or sulfonylurea.ResultsLiraglutide treatment induced an improvement in left ventricular ejection fraction from 41.5 ± 2.2 to 46.3 ± 3 %; P = 0.001). On the contrary, treatment with sitagliptin and glargine induced no changes in left ventricular ejection fraction (41.8 ± 2.6 vs. 42.5 ± 2.5 % and 42 ± 1.5 vs. 42 ± 1.6 %, respectively; P = NS). Indexed end-systolic LV volume was reduced only in liraglutide-treated patients (51 ± 9 vs. 43 ± 8 ml/m2; P < 0.05). Liraglutide treatment induced also a significant increase in the anterograde stroke volume (39 ± 9 vs. 49 ± 11 ml; P < 0.05), whereas no differences were observed in the other two groups. Cardiac output and cardiac index showed a significant increase only in liraglutide-treated patients (4.4 ± 0.5 vs. 5.0 ± 0.6 L/min; P < 0.05 and 1.23 ± 0.26 vs. 1.62 ± 0.29 L/m2; P = 0.005, respectively).Liraglutide treatment was also associated with an improvement of functional capacity and an improvement of quality of life.ConclusionsThese data provide evidence that treatment with liraglutide is associated with improvement of cardiac function and functional capacity in failing post-ischemic type-2 diabetes mellitus patients.

Low systolic blood pressure (SBP) was previously suggested to be a marker for heart failure and mortality in patients with low left ventricular ejection fraction. We aimed to explore the association of SBP on risk of ventricular tachyarrhythmias (VTA) and atrial arrhythmias as well as appropriate and inappropriate Implantable Cardioverter Defibrillator (ICD) therapy. The study population comprised 1,481 of 1,500 (99%) patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial – Reduce Inappropriate Therapy trial. Multivariate Cox proportional hazards regression modeling was used to identify the association of baseline SBP (recorded prior to ICD implantation) with the risk of VTA > 170 beats/min during follow-up (primary end point) and atrial arrhythmia, appropriate and inappropriate ICD therapy, hospitalization and death (secondary end points). SBP was dichotomized at 120 mm Hg (approximate mean and median) and was also assessed as a continuous measure. Multivariate analysis showed that each 10 mm Hg decrement in SBP was associated with corresponding 11% increased risk for VTA (p = 0.008). Low SBP (≤120 mm Hg) was associated with a significant 58% (p = 0.002) increased risk for VTA ≥170 beats/min; 53% (p = 0.019) increased risk for VTA ≥200 beats/min; and 65% (p = 0.001) increased risk for appropriate ICD therapy, as compared with SBP >120 mm Hg. Low SBP was not associated with increased risk of atrial arrhythmias, and inappropriate ICD therapy. In conclusion, in MADIT-RIT, SBP (≤120 mm Hg) predicted higher rates of VTA. These findings suggest that SBP may be utilized for VTA risk stratification in candidates for primary ICD therapy.

Some patients with chronic heart failure have intraventricular conduction delays, which cause asynchronous contraction of the left ventricle. This large clinical trial confirmed that biventricular pacing to restore synchronous contraction has significant benefits in such patients. The addition of an implantable defibrillator further reduces mortality. Resynchronization therapy may have clinical benefit, especially when combined with an implantable defibrillator. Intraventricular conduction delays are associated with dyssynchronous left ventricular contraction caused by regional delays in the electrical activation of the chamber. 1 , 2 This phenomenon, which occurs in 15 to 30 percent 3 – 5 of patients with heart failure due to dilated cardiomyopathy, reduces systolic function and increases systolic volume. 6 – 8 In patients with primary or secondary dilated cardiomyopathies characterized by intraventricular conduction delays, biventricular stimulation synchronizes the activation of the intraventricular septum and left ventricular free wall and thus improves left ventricular systolic function. 6 – 8 In short-term studies, cardiac-resynchronization therapy in the form of biventricular stimulation improved symptoms, 9 – 12 improved the . . .