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Cardiac glycosides are among the oldest medications in cardiovascular care, prized for their actions as positive inotropic agents and modulators of atrioventricular conduction. In heart failure with reduced ejection fraction, their mechanistic rationale was so convincing that digitalis became a mainstay of treatment long before the initiation of large-scale trials investigating the effects of cardiac glycosides on morbidity and mortality. Early mechanistic and hemodynamic studies of cardiac glycosides, together with trials that showed improved exercise capacity and quality of life, reinforced their use. This evidence was bolstered by randomized withdrawal trials, in which discontinuation of digoxin led to rapid clinical . . .

The effects of renin–angiotensin–aldosterone system blockers on angiotensin-converting enzyme 2 levels and activity in humans are uncertain. The authors hypothesize that ACE2 may be beneficial rather than harmful during lung injury and suggest that RAAS-inhibitor withdrawal may be harmful in some high-risk patients with known or suspected Covid-19.

For a study with an event time as the endpoint, its survival function contains all the information regarding the temporal, stochastic profile of this outcome variable. The survival probability at a specific time point, say t, however, does not transparently capture the temporal profile of this endpoint up to t. An alternative is to use the restricted mean survival time (RMST) at time t to summarize the profile. The RMST is the mean survival time of all subjects in the study population followed up to t, and is simply the area under the survival curve up to t. The advantages of using such a quantification over the survival rate have been discussed in the setting of a fixed-time analysis. In this article, we generalize this approach by considering a curve based on the RMST over time as an alternative summary to the survival function. Inference, for instance, based on simultaneous confidence bands for a single RMST curve and also the difference between two RMST curves are proposed. The latter is informative for evaluating two groups under an equivalence or noninferiority setting, and quantifies the difference of two groups in a time scale. The proposal is illustrated with the data from two clinical trials, one from oncology and the other from cardiology.

Patients with heart failure with preserved ejection fraction were assigned to receive sacubitril–valsartan or valsartan. At a median of 35 months, there was no significant between-group difference in the composite outcome of total hospitalizations for heart failure or death from cardiovascular causes.

In this randomized study, the addition of lixisenatide, a glucagon-like peptide 1–receptor agonist, to usual care in patients with type 2 diabetes and a recent cardiovascular event did not alter the rate of subsequent major cardiovascular or other serious adverse events. Randomized trials involving patients with new or established type 2 diabetes have shown that improved glucose control reduces the risk of microvascular complications, 1 – 3 with modest cardiovascular benefits suggested by meta-analyses and extended follow-up of clinical trials. 4 – 7 However, various studies indicate that, despite being effective in lowering the glucose and glycated hemoglobin levels, some hypoglycemic medications may increase, rather than reduce, the risk of cardiovascular events. 8 – 10 These unexpected findings prompted the reexamination of the regulatory approval processes for new antidiabetic therapies, which had been based primarily on the surrogate measure of glucose lowering with limited clinical-outcomes data. Since . . .

In a subgroup of TOPCAT participants assigned to spironolactone, the spironolactone metabolite canrenone was measured to assess adherence. Canrenone levels were undetectable in 30% of participants from Russia, as compared with only 3% from the United States and Canada. To the Editor: In the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, patients with heart failure and preserved ejection fraction were randomly assigned to receive either spironolactone or placebo. The investigators found that the incidence of the primary composite end point of death from cardiovascular causes, hospitalization for heart failure, or resuscitated cardiac arrest was not significantly lower in the spironolactone group than in the placebo group, but the incidence of hospitalization for heart failure was significantly lower in the spironolactone group. 1 However, significant differences in the clinical profiles, event rates, and responses to . . .

In a randomized trial, 5661 patients with acute myocardial infarction and a reduced left ventricular ejection fraction, pulmonary congestion, or both were assigned to receive either sacubitril–valsartan or ramipril. At a median of 22 months, there was no significant difference between the two groups in the incidence of death from cardiovascular causes or incident heart failure.

Increased excretion of albumin in urine might be a marker of the various pathophysiological changes that arise in patients with heart failure. Therefore our aim was to assess the prevalence and prognostic value of a spot urinary albumin to creatinine ratio (UACR) in patients with heart failure. UACR was measured at baseline and during follow-up of 2310 patients in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Programme. The prevalence of microalbuminuria and macroalbuminuria, and the predictive value of UACR for the primary composite outcome of each CHARM study—ie, death from cardiovascular causes or admission to hospital with worsening heart failure—and death from any cause were assessed. 1349 (58%) patients had a normal UACR, 704 (30%) had microalbuminuria, and 257 (11%) had macroalbuminuria. The prevalence of increased UACR was similar in patients with reduced and preserved left ventricular ejection fractions. Patients with an increased UACR were older, had more cardiovascular comorbidity, worse renal function, and a higher prevalence of diabetes mellitus than did those with normoalbuminuria. However, a high prevalence of increased UACR was still noted among patients without diabetes, hypertension, or renal dysfunction. Elevated UACR was associated with increased risk of the composite outcome and death even after adjustment for other prognostic variables including renal function, diabetes, and haemoglobin A 1c. The adjusted hazard ratio (HR) for the composite outcome in patients with microalbuminuria versus normoalbuminuria was 1·43 (95% CI 1·21–1·69; p<0·0001) and for macroalbuminuria versus normoalbuminuria was 1·75 (1·39–2·20; p<0·0001). The adjusted values for death were 1·62 (1·32–1·99; p<0·0001) for microalbuminuria versus normoalbuminuria, and 1·76 (1·32–2·35; p=0·0001) for macroalbuminuria versus normoalbuminuria. Treatment with candesartan did not reduce or prevent the development of excessive excretion of urinary albumin. Increased UACR is a powerful and independent predictor of prognosis in heart failure. AstraZeneca.

Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. This placebo-controlled trial randomly assigned such patients to receive darbepoetin alfa or placebo. The two composite end points were death or cardiovascular disease and death or end-stage renal disease. Darbepoetin alfa did not reduce either outcome and was associated with an increased risk of stroke. The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia did not reduce the risk of either of two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. Type 2 diabetes mellitus and chronic kidney disease frequently coexist, and each disease independently increases the risk of cardiovascular events and end-stage renal disease. 1 , 2 Intensive treatment of concomitant conventional risk factors such as hypertension and elevated levels of low-density lipoprotein reduces fatal and nonfatal cardiovascular complications and slows the progression of kidney disease. 3 – 8 Observational studies suggest that anemia can be considered another biomarker of risk, since a lower hemoglobin level is independently associated with a higher rate of cardiovascular and renal events, 9 – 11 especially among patients with diabetes. 12 , 13 Whether the use of erythropoiesis-stimulating agents (ESAs) to increase . . .

In this trial, 3445 patients with heart failure and a preserved ejection fraction were assigned to spironolactone or placebo. At a mean of 3.3 years, there was no significant difference in death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure. Many patients with heart failure have a normal or near-normal left ventricular ejection fraction. 1 – 4 Such patients share common signs and symptoms, as well as an impaired quality of life and a poor prognosis, with patients who have heart failure and a reduced ejection fraction. 5 – 8 However, the benefit of most medical therapies for heart failure is limited to those with a reduced ejection fraction, generally 40% or less. 1 , 2 , 9 The lack of favorable evidence from clinical-outcome trials involving patients with heart failure and a preserved left ventricular ejection fraction is reflected in current guidelines, which offer no specific . . .