Risk Related to Pre-Diabetes Mellitus and Diabetes Mellitus in Heart Failure With Reduced Ejection Fraction: Insights From Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial

BACKGROUND: The prevalence of pre-diabetes mellitus and its consequences in patients with heart failure and reduced ejection fraction are not known. We investigated these in the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. METHODS AND RESULTS: We examined clinical outcomes in 8399 patients with heart failure and reduced ejection fraction according to history of diabetes mellitus and glycemic status (baseline hemoglobin A1c [HbA1c]: /=6.5% [>/=48 mmol/mol; diabetes mellitus]), in Cox regression models adjusted for known predictors of poor outcome. Patients with a history of diabetes mellitus (n=2907 [35%]) had a higher risk of the primary composite outcome of heart failure hospitalization or cardiovascular mortality compared with those without a history of diabetes mellitus: adjusted hazard ratio, 1.38; 95% confidence interval, 1.25 to 1.52; P6.5%) and known diabetes mellitus compared with those with HbA1c<6.0% was 1.39 (1.17-1.64); P<0.001 and 1.64 (1.43-1.87); P<0.001, respectively. Patients with pre-diabetes mellitus were also at higher risk (hazard ratio, 1.27 [1.10-1.47]; P<0.001) compared with those with HbA1c<6.0%. The benefit of LCZ696 (sacubitril/valsartan) compared with enalapril was consistent across the range of HbA1c in the trial. CONCLUSIONS: In patients with heart failure and reduced ejection fraction, dysglycemia is common and pre-diabetes mellitus is associated with a higher risk of adverse cardiovascular outcomes (compared with patients with no diabetes mellitus and HbA1c <6.0%). LCZ696 was beneficial compared with enalapril, irrespective of glycemic status. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

BACKGROUND: -Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. METHODS AND RESULTS: -We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensinconverting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-Btype natriuretic peptide and troponin) versus enalapril. CONCLUSIONS: -Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255

Comparison of the efficacy of rosuvastatin versus atorvastatin in reducing apolipoprotein B/apolipoprotein A-1 ratio in patients with acute coronary syndrome: Results of the CENTAURUS study

Background. The mechanism underlying statin-induced event reduction in patients with acute coronary syndrome remains unclear. Aims. To assess the efficacy of rosuvastatin 20 mg versus atorvastatin 80 mg in reducing the apolipoprotein B/apolipoprotein A-1 (apoB/apoA-1) ratio at 3 months. Non-inferiority of rosuvastatin 20 mg versus atorvastatin 80 mg in reducing low-density lipoprotein cholesterol at 1 and 3 months was also assessed. Methods. Patients with non-ST-elevation acute coronary syndrome were enrolled into this randomized, double blind, parallel-group trial. Results. In total, 753 patients (369, rosuvastatin 20 mg; 384, atorvastatin 80 mg) were included in the intention-to-treat analysis; 478 patients (226, rosuvastatin 20 mg; 252, atorvastatin 80 mg) were included in the per-protocol analysis. Rosuvastatin 20 mg was more effective than atorvastatin 80 mg in decreasing apoB/apoA-1 ratio at 1 month (-44.4% vs -42.9%, p = 0.02) but not at 3 months (both -44.4%, p = 0.87). Low-density lipoprotein cholesterol decreased by similar to 50% after 1 and 3 months in both groups. Non-inferiority of rosuvastatin 20 mg versus atorvastatin 80 mg was demonstrated at 1 month (difference, -0.3% [95% confidence interval, -2.7; +2.1]), but not at 3 months (+1.0% [-1.6; 3.5]) (intention-to-treat analysis). In the per-protocol analysis, non-inferiority of rosuvastatin 20 mg was demonstrated at both 1 (-0.7% [-3.5; 2.0]) and 3 (-0.5% [-3.5; 2.5]) months. Conclusion. In patients with non-ST-elevation acute coronary syndrome, rosuvastatin 20 mg decreased apoB/apoA-1 ratio at 1 month more than atorvastatin 80 mg. No difference could be shown at 3 months; thus, the primary endpoint was not met. (C) 2010 Published by Elsevier Masson SAS