Baseline and on-statin treatment lipoprotein(a) levels predict cardiovascular events: An individual-patient-data meta-analysis of statin outcome trials Article Type: Article

NHIBITION OF THE RENIN-ANGIOTENsin-aldosterone system (RAAS) has long been recognized as a lifeprolonging therapy for patients with chronic heart failure (HF) with reduced left ventricular ejection fraction (LVEF), 1 and angiotensinconverting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs) are recommended by all major national guidelines. 2,3 However, although the benefits of these treatments are undisputed, these agents induce a compensatory increase in renin and downstream RAAS intermediaries that may partially offset RAAS blocking effects. Based on this pathophysiological concept of "RAAS escape," multiple trials have demon-Author Affiliations are listed at the end of this article.

AimsWe evaluated the effect of (dual) renin -angiotensin -aldosterone system (RAAS) blockade with valsartan and an ACE inhibitor [92.7% of patients were treated with an ACE inhibitor in the Valsartan in Heart Failure Trial (Val-HeFT)] in patients with NYHA class II-IV heart failure (HF) and reduced EF on cardiovascular (CV) death and HF hospitalization by subgroups and by presence of early worsening of renal function (EWRF) and according to baseline estimated glomerular filtration rate (eGFR). Methods and resultsWe analysed the data from 5010 patients enrolled in the Val-HeFT study. A total of 2346 (46.8%) patients had baseline renal impairment (i.e. baseline eGFR ,60 mL/min/1.73 m 2 ). Further, 425 patients (8.6%) had EWRF (i.e. eGFR decrease .20% within 1 month after randomization), whereas 4503 patients (91.4%) had ≤ 20% decline in eGFR. Overall, the difference between valsartan and placebo on the composite endpoint of CV death and HF hospitalization was significant [P ¼ 0.0005; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.75-0.92)]. In patients with baseline renal impairment, the difference between the treatment groups was also significant (P ¼ 0.0002; HR 0.76, 95% CI 0.66-0.88). Patients with EWRF had higher risk of CV death and HF hospitalization vs. those without ERWF (P , 0.0001; HR 1.44, 95% CI 1.21-1.71), and within the EWRF group a significant difference was also observed between valsartan and placebo (P ¼ 0.0086; HR 0.63, 95% CI 0.45-0.89). However, the interaction between treatment and eGFR at Month 1 was not significant (P ¼ 0.1160). ConclusionBenefits were maintained in patients with renal dysfunction at baseline and those who experienced EWRF.--

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AimsThe objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in postdischarge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and resultsASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-Btype natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P ¼ 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64 -0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P ¼ 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P , 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P ¼ 0.07 for interaction). ConclusionThis pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without DM. Recently, the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) confirmed the high prevalence of DM among HHF patients with reduced left ventricular ejection fraction (LVEF). 6 In this study, the addition of aliskiren to standard therapy had no significant effect on CV death or heart failure (HF) rehospitalization within 6 or 12 months. Although the overall study results were neutral, pre-specified subgroup analysis found the effect of the study drug on all-cause death within 12 months to differ by the presence of comorbid DM, wit...