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In a randomized trial, 6545 patients with acute heart failure were assigned to either serelaxin or placebo in addition to standard care. There were no significant differences between the two groups in the incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).

Analyses of country or regional differences in cardiovascular (CV) trials are based on geographical subgroup analyses. However, apart from map location and related racial, ethnic, and genetic variations, identified differences may also depend on social structure and provision and access to health care, for which country income and income inequality are indicators. The aim of the study was to examine the association between country per capita income and income inequality and prognosis in patients with heart failure or an acute coronary syndrome in 3 international trials (EMPHASIS-HF, EPHESUS, and EXAMINE). Countries were classified into high income or low-middle income (LMICs) and into low, middle, or high inequality using the Gini index. The main outcome measures were all-cause and CV death. Patients from LMICs and countries with higher inequality were younger, were less often white, had fewer comorbid conditions, and were less often treated with guideline-recommended therapies, including devices. These patients had higher adjusted mortality rates (+15% to +70%) compared with patients from high-income countries and countries with less inequality. Patients from countries with the combination of greater inequality and low-middle income had particularly high mortality rates (+80% to +190%) compared with those that did not have both characteristics. Living in a country that is poor and has inequality had more impact on death rates than any comorbidity. These findings were reproduced in 3 trials. Patients from LMICs and countries with greater inequality had the highest mortality rates. The prognostic impact of income and inequality is substantial and should be considered when looking into subgroup differences in CV trials.

In this trial, 2737 patients with heart failure and LV systolic dysfunction were given eplerenone or placebo in addition to recommended therapy. Eplerenone significantly reduced the risk of the primary outcome, a composite of death or hospitalization. The activation of mineralocorticoid receptors by aldosterone and cortisol has deleterious effects in patients with cardiovascular disease. 1 In the placebo-controlled Randomized Aldactone Evaluation Study (RALES), 2 adding the mineralocorticoid-receptor antagonist spironolactone to recommended therapy in patients with systolic heart failure and moderate-to-severe symptoms (i.e., New York Heart Association [NYHA] functional class III or IV symptoms) decreased the rate of death from any cause and the risk of hospitalization for cardiovascular reasons. In the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), 3 the selective mineralocorticoid-receptor antagonist eplerenone, added to recommended medical therapy, reduced the rates of death from any . . .

Nesiritide was approved by the FDA on the basis of small clinical trials for the treatment of acute heart failure. In this large clinical trial, nesiritide did not improve outcomes in patients with acute heart failure, and it can no longer be recommended for this condition. Acute decompensated heart failure is a major health problem that is associated with several million hospitalizations worldwide each year, poor short-term outcomes, and high costs. 1 – 3 Despite the magnitude of the problem, rates of early death and rehospitalization have not improved over the past several decades. 3 Nesiritide, a recombinant B-type natriuretic peptide (BNP) with vasodilatory properties, 4 – 7 was approved in 2001 for use in patients with acute heart failure on the basis of studies showing a reduction in pulmonary-capillary wedge pressure and improvement in dyspnea at 3 hours. 5 , 6 , 8 However, subsequent pooled analyses of data from small, randomized trials . . .

Chronic heart failure is associated with high mortality and morbidity. Raised resting heart rate is a risk factor for adverse outcomes. We aimed to assess the effect of heart-rate reduction by the selective sinus-node inhibitor ivabradine on outcomes in heart failure. Patients were eligible for participation in this randomised, double-blind, placebo-controlled, parallel-group study if they had symptomatic heart failure and a left-ventricular ejection fraction of 35% or lower, were in sinus rhythm with heart rate 70 beats per min or higher, had been admitted to hospital for heart failure within the previous year, and were on stable background treatment including a β blocker if tolerated. Patients were randomly assigned by computer-generated allocation schedule to ivabradine titrated to a maximum of 7·5 mg twice daily or matching placebo. Patients and investigators were masked to treatment allocation. The primary endpoint was the composite of cardiovascular death or hospital admission for worsening heart failure. Analysis was by intention to treat. This trial is registered, number ISRCTN70429960. 6558 patients were randomly assigned to treatment groups (3268 ivabradine, 3290 placebo). Data were available for analysis for 3241 patients in the ivabradine group and 3264 patients allocated placebo. Median follow-up was 22·9 (IQR 18–28) months. 793 (24%) patients in the ivabradine group and 937 (29%) of those taking placebo had a primary endpoint event (HR 0·82, 95% CI 0·75–0·90, p<0·0001). The effects were driven mainly by hospital admissions for worsening heart failure (672 [21%] placebo vs 514 [16%] ivabradine; HR 0·74, 0·66–0·83; p<0·0001) and deaths due to heart failure (151 [5%] vs 113 [3%]; HR 0·74, 0·58–0·94, p=0·014). Fewer serious adverse events occurred in the ivabradine group (3388 events) than in the placebo group (3847; p=0·025). 150 (5%) of ivabradine patients had symptomatic bradycardia compared with 32 (1%) of the placebo group (p<0·0001). Visual side-effects (phosphenes) were reported by 89 (3%) of patients on ivabradine and 17 (1%) on placebo (p<0·0001). Our results support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of this disorder. Servier, France.

Raised resting heart rate is a marker of cardiovascular risk. We postulated that heart rate is also a risk factor for cardiovascular events in heart failure. In the SHIFT trial, patients with chronic heart failure were treated with the selective heart-rate-lowering agent ivabradine. We aimed to test our hypothesis by investigating the association between heart rate and events in this patient population. We analysed cardiovascular outcomes in the placebo (n=3264) and ivabradine groups (n=3241) of this randomised trial, divided by quintiles of baseline heart rate in the placebo group. The primary composite endpoint was cardiovascular death or hospital admission for worsening heart failure. In the ivabradine group, heart rate achieved at 28 days was also analysed in relation to subsequent outcomes. Analysis adjusted to change in heart rate was used to study heart-rate reduction as mechanism for risk reduction by ivabradine directly. In the placebo group, patients with the highest heart rates (≥87 beats per min [bpm], n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to <72 bpm, n=461, 92 events; hazard ratio [HR] 2·34, 95% CI 1·84–2·98, p<0·0001). Risk of primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes. Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17·4%, 95% CI 15·3–19·6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0·95, 0·85–1·06, p=0·352). Our analysis confirms that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure. Servier, France.

A global heart failure (HF) registry suggested that the inverse association between body mass index (BMI) and all-cause mortality differed by race, particularly stronger in Japanese patients at 1-year follow-up. Whether this finding was consistent across all East Asian populations was unknown. In a multicenter prospective study in Taiwan, we enrolled 1,301 patients hospitalized for systolic HF from 2013 to 2014 and followed up the mortality after their discharge for a median of 1-year period. Cox proportional hazard regression analyses were used to assess the association of BMI with all-cause mortality. The results showed that BMI was inversely associated with all-cause mortality (hazard ratio and 95% CI per 5-kg/m2 increase: 0.75 [0.62 to 0.91]) after adjusting for demographics, traditional risk factors, HF severity, and medications at discharge. Subsequently, we sought previous studies regarding the BMI association with mortality for East Asian patients with HF from Medline, and a random-effect meta-analysis was performed by the inverse variance method. The meta-analysis including 7 previous eligible studies (3 for the Chinese and 4 for the Japanese cohorts) and the present one showed similar results that BMI was inversely associated with all-cause mortality (hazard ratio 0.65 [0.58 to 0.73], I2 = 37%). In conclusion, our study in Taiwan and a collaborative meta-analysis confirmed a strong inverse BMI-mortality association consistently among East Asian patients with HF.

Both transposition of the great arteries (TGA) previously submitted to a Senning/Mustard procedure and congenitally corrected TGA (cc-TGA) have the systemic circulation supported by the morphological right ventricle, thereby rendering these patients to heart failure events risk. The aim of this study was to evaluate cardiopulmonary exercise test parameters for stratifying the risk of heart failure events in TGA patients. Retrospective evaluation of adult TGA patients with systemic circulation supported by the morphological right ventricle submitted to cardiopulmonary exercise test in a tertiary centre. Patients were followed up for at least 1 year for the primary endpoint of cardiac death or heart failure hospitalisation. Several cardiopulmonary exercise test parameters were analysed as potential predictors of the combined endpoint and their predictive power were compared (area under the curve). Cardiopulmonary exercise test was performed in 44 TGA patients (8 cc-TGA), with a mean age of 35.1 ± 8.4 years. The primary endpoint was reached by 10 (22.7%) patients, with a mean follow-up of 36.7 ± 26.8 months. Heart rate at anaerobic threshold had the highest area under the curve value (0.864), followed by peak oxygen consumption (pVO2) (0.838). Heart rate at anaerobic threshold ≤95 bpm and pVO2 ≤20 ml/kg/min had a sensitivity of 87.5 and 80.0% and a specificity of 82.4 and 76.5%, respectively, for the primary outcome. Heart rate at anaerobic threshold ≤95 bpm had the highest predictive power of all cardiopulmonary exercise test parameters analysed for heart failure events in TGA patients with systemic circulation supported by the morphological right ventricle.

Gliptins are a novel class of oral antihyperglycaemic agent that inhibit dipeptidyl peptidase 4. Professor Scheen describes the pleiotropic beneficial effects of these drugs, beyond basic glycaemic control in patients with type 2 diabetes mellitus, to emerging data and ongoing trials on cardiovascular protection in patients with ischaemic heart disease or congestive heart failure. Dipeptidyl peptidase 4 (DPP-4) inhibitors (commonly referred to as gliptins) are a novel class of oral antihyperglycaemic agents with demonstrated efficacy in the treatment of type 2 diabetes mellitus (T2DM). Preclinical data and mechanistic studies have indicated a possible beneficial action on blood vessels and the heart, via both glucagon-like peptide 1 (GLP-1)-dependent and GLP-1-independent effects. DPP-4 inhibition increases the concentration of many peptides with potential vasoactive and cardioprotective effects. Clinically, DPP-4 inhibitors improve several risk factors in patients with T2DM. They improve blood glucose control (mainly by reducing postprandial glycaemia), are weight neutral (or even induce modest weight loss), lower blood pressure, improve postprandial lipaemia, reduce inflammatory markers, diminish oxidative stress, and improve endothelial function. Some positive effects on the heart have also been described in patients with ischaemic heart disease or congestive heart failure, although their clinical relevance requires further investigation. Post-hoc analyses of phase II–III, controlled trials suggest a possible cardioprotective effect with a trend for a lower incidence of major cardiovascular events with gliptins than with placebo or active agents. However, the actual relationship between DPP-4 inhibition and cardiovascular outcomes remains to be proven. Major prospective clinical trials with predefined cardiovascular outcomes and involving various DPP-4 inhibitors are now underway in patients with T2DM and a high-risk cardiovascular profile. Key Points Dipeptidyl peptidase 4 (DPP-4) inhibitors (gliptins) are incretin-based drugs with a role in the management of type 2 diabetes mellitus; they improve glucose control without inducing hypoglycaemia or weight gain Gliptins not only increase the level of glucagon-like peptide 1, but also the concentration of other peptides that might exert vasoactive, and possibly cardioprotective, effects Gliptins exert pleiotropic actions in patients with type 2 diabetes, resulting in favourable effects on postprandial glycaemia and lipaemia, blood pressure, silent inflammation, oxidative stress, and endothelial dysfunction Post-hoc analyses of phase II–III, controlled trials showed no cardiovascular harm with gliptins compared with placebo or other antihyperglycaemic agents, and possibly indicated a cardiovascular protective effect Large, prospective trials involving >40,000 high-risk patients with type 2 diabetes are ongoing to test the noninferiority or superiority of gliptins (mostly compared with placebo), with prespecified, cardiovascular end points