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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.

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.

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 . . .

Cardiac-resynchronization therapy is recommended for patients with advanced, symptomatic heart failure. This clinical trial found benefit in asymptomatic patients, but since the rate of death was not affected, it remains to be seen whether clinical guidelines will be modified to include asymptomatic patients. This clinical trial found benefit with cardiac-resynchronization therapy in asymptomatic patients, but since the rate of death was not affected, it remains to be seen whether clinical guidelines will be modified to include asymptomatic patients. Patients with cardiac disease and reduced left ventricular function are at increased risk for arrhythmia-related sudden death and heart failure. The placement of an implantable cardioverter–defibrillator (ICD) improves survival and reduces the risk of sudden death in appropriately selected patients with cardiac disease. 1 – 3 However, life-prolonging defibrillator therapy is associated with an increased risk of first and recurrent heart-failure events. 4 Cardiac-resynchronization therapy (CRT) with biventricular pacing is an effective adjunctive therapy to pharmacologic management in reducing the rate of hospitalization in symptomatic patients with advanced heart-failure symptoms (New York Heart Association [NYHA] class III or IV), an ejection fraction of . . .

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.

This study assessed the relationship between initial responsiveness to darbepoetin alfa and outcomes in patients with chronic kidney disease and type 2 diabetes mellitus. A poor initial hematopoietic response was associated with an increased risk of death or cardiovascular events. Erythropoiesis-stimulating agents (ESAs) have been credited with a reduced need for red-cell transfusion and improved quality of life for patients with end-stage kidney disease who have severe anemia. 1 In patients with chronic kidney disease who do not require dialysis and have moderate anemia, the use of ESAs remains substantial, despite little evidence of benefit and increased concern that these agents may confer harm. 2 – 4 Trials comparing lower and higher hemoglobin targets have been interpreted to suggest that targeting of a lower hemoglobin range would be a safer approach in these patients, 2 , 5 , 6 leading to recommendations for continued use of . . .

Statin therapy lowers not only low-density lipoprotein (LDL) cholesterol levels, but also levels of C-reactive protein (CRP), a marker of inflammation. This study examined the independent effects of decreasing LDL cholesterol and CRP levels on subsequent coronary risk in patients with acute coronary syndromes who were receiving pravastatin or atorvastatin. Lowering CRP levels reduced coronary risk irrespective of the extent of LDL cholesterol lowering. Patients with the lowest risk had the lowest levels of both LDL cholesterol and CRP after 30 days of statin therapy. This study examined the independent effects of decreasing LDL cholesterol and CRP levels on subsequent coronary risk in patients with acute coronary syndromes who were receiving statin therapy. Statin therapy lowers the risk of cardiovascular events by reducing plasma cholesterol levels, and practice guidelines for patients with known cardiovascular disease emphasize the importance of reaching target goals for low-density lipoprotein (LDL) cholesterol. 1 However, we have shown that statin therapy results in a greater clinical benefit when levels of the inflammatory biomarker C-reactive protein (CRP) are elevated 2 , 3 and that statins lower CRP levels in a manner largely independent of LDL cholesterol levels. 3 – 6 These findings, along with basic laboratory evidence, have led to the hypothesis that, in addition to being potent lipid-lowering agents, statins may also have antiinflammatory . . .

Background Compared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes. Methods We compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF. Results Among 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: − 0.24%, 95% CI − 0.33 to − 0.16%, P < 0.001). Numerically, new insulin treatment was initiated less often in the sacubitril/valsartan group than in the valsartan group, but the difference was not statistically significant (12.8% vs. 16.1%; HR: 0.80, 95% CI 0.62–1.02, P = 0.07). Hypoglycemia adverse event reports were low, but more frequent in those receiving sacubitril/valsartan than in the valsartan group (4.2% vs. 2.6%; HR: 1.64, 95% CI 1.05–2.56, P = 0.030). In a pooled analysis of PARAGON-HF and PARADIGM-HF, the effect of sacubitril/valsartan on change in HbA1c was not significantly modified by LVEF (P interaction  = 0.56). Across the spectrum of LVEF, sacubitril/valsartan reduced new insulin therapy (HR: 0.75, 95% CI 0.63–0.89, P = 0.001), compared with enalapril or valsartan. Conclusions Sacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia. Trial registration  ClinicalTrials.gov NCT01920711

Systematic reporting of estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) Study equation is recommended for detection of chronic kidney disease and prediction of cardiovascular (CV) risk. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is a newly developed and validated formula for eGFR that is more accurate at normal or near-normal eGFR. We aimed to assess the incremental prognostic accuracy of eGFR CKD-EPI versus eGFR MDRD in subjects at increased risk for CV disease. We performed a post hoc analysis of the VALIANT trial that enrolled 14,527 patients with acute myocardial infarction with signs and symptoms of heart failure and/or left ventricular systolic dysfunction. The eGFR MDRD and eGFR CKD-EPI were computed using age, gender, race, and baseline creatinine level. Patients were categorized according to their eGFR using each equation. To assess the incremental prognostic value of eGFR CKD-EPI, the net reclassification improvement was calculated for the composite end point of CV death, recurrent myocardial infarction, heart failure, or stroke. Twenty-four percent of the subjects were reclassified into a different eGFR category using eGFR CKD-EPI. The composite end point occurred in 33% of the subjects in this cohort. Based on eGFR CKD-EPI, subjects reclassified into a higher eGFR experienced fewer events than those reclassified into a lower eGFR (21% vs 43%). In unadjusted analyses, the composite end point risk in subjects with eGFR between 75 and 90 mL/min per 1.73 m 2 was comparable with the referent group (eGFR between 90 and 105) using eGFR MDRD (hazard ratio 1.1, 95% CI 0.9-1.2) but was significantly higher using eGFR CKD-EPI (hazard ratio 1.2, 95% CI 1.1-1.4). The net reclassification improvement for eGFR CKD-EPI over eGFR MDRD was 8.7%. The CKD-EPI equation provides more accurate risk stratification than the MDRD Study equation in patients at high risk for CV disease, including identification of increased risk at mildly decreased eGFR.

Despite increasing prevalence of heart failure (HF) in patients with preserved ejection fraction (PEF), there are no available therapies proven to reduce morbidity and mortality. Aldosterone, a potent stimulator of myocardial and vascular fibrosis, may be a key mediator of HF progression in this population and is therefore an important therapeutic target. The TOPCAT trial is designed to evaluate the effect of spironolactone, an aldosterone antagonist, on morbidity, mortality, and quality of life in patients with HF-PEF. Up to 3,515 patients with HF-PEF will be randomized in double-blind fashion to treatment with spironolactone (target dose 30 mg daily) or matching placebo. Eligible patients include those with age ≥50 years, left ventricular ejection fraction ≥45%, symptomatic HF, and either a hospitalization for HF within the prior year or an elevated natriuretic peptide level (B-type natriuretic peptide ≥100 pg/mL or N-terminal pro–B-type natriuretic peptide ≥360 pg/mL) within the 60 days before randomization. Patients with uncontrolled hypertension and those with known infiltrative or hypertrophic cardiomyopathy are excluded. The primary end point is the composite of cardiovascular death, hospitalization for HF, or aborted cardiac arrest. Key secondary end points include quality of life, nonfatal cardiovascular events, and new-onset atrial fibrillation. Ancillary studies of echocardiography, tonometry, and cardiac biomarkers will provide more insight regarding this understudied population and the effects of spironolactone therapy. TOPCAT is designed to assess definitively the role of spironolactone in the management of HF-PEF.