Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The 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 post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT 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-B-type 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 = 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 = 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 = 0.07 for interaction). Conclusion This 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 D

Fluvastatin treatment is not associated with an increased incidence of cancer

Concerns regarding a potential link between statin treatment and increased risk of cancer were raised following the increased cancer incidence observed in patients treated with pravastatin in the Cholesterol and Recurrent Events and Pravastatin in Elderly Individuals at Risk of Vascular Disease studies. The aim of the present study was to investigate the risk of cancer associated with fluvastatin treatment in clinical trials. A pooled analysis of all available, randomised, placebo-controlled trials with fluvastatin with a minimum treatment period of 24 weeks was performed. The cancer incidences were compared in 3512 patients receiving fluvastatin, 20-80 mg/day, and 3289 patients receiving placebo. Overall, fewer patients were diagnosed with cancer in the fluvastatin group compared with the placebo group [220/3512 (6.3%) vs. 263/3289 (8.0%) respectively; p = 0.0309]. Cox regression analysis, adjusted for baseline covariates and stratified by study, revealed a hazard ratio for first cancer diagnosis of 0.812 [95% confidence interval (CI) 0.667-0.989; p = 0.037] for fluvastatin compared with placebo. No significant differences were observed in the incidence of cancers by site, with the exception of non-melanoma skin cancer (103 vs. 125 cases in the fluvastatin and placebo groups respectively; p = 0.047). Cox regression analysis showed that there was no association between baseline low-density lipoprotein cholesterol levels and the risk of developing cancer (hazard ratio 0.998, 95% CI 0.995-1.000; p = 0.107). In conclusion, fluvastatin treatment is not associated with an increased risk of cancer compared with placebo in clinical trials, independent of patient age, treatment duration and baseline cholesterol levels

Hepatorenal dysfunction identifies high-risk patients with acute heart failure: insights from the RELAX-AHF trial

Aims: Episodes of acute heart failure (AHF) may lead to end-organ dysfunction. In this post hoc analysis of the Relaxin in Acute Heart Failure trial, we used the MELD-XI (Model of End-Stage Liver Dysfunction) score to examine hepatorenal dysfunction in patients with AHF. Methods and results: On admission, the MELD-XI score was elevated (abnormal) in 918 (82%) patients, with 638 (57%) having isolated renal dysfunction (creatinine > 1 mg/dL), 73 (6.5%) isolated liver dysfunction (bilirubin > 1 mg/dL), and 207 (18.5%) coexisting dysfunction of the kidneys and the liver (both creatinine and bilirubin > 1 mg/dL). The percentage of patients with elevated MELD-XI score remained constant through a 60 day follow-up, as we observed a gradual decrease of liver dysfunction prevalence, counterbalanced by an increase in renal dysfunction. Serelaxin treatment was associated with a lower MELD-XI score on Day 2 and Day 5 (both P < 0.05), but this difference vs. placebo disappeared during longer follow-up. In the multivariable model, an elevated MELD-XI score on admission was associated with higher 180 day mortality: hazard ratios (95% confidence interval) for cardiovascular death were 3.10 (1.22–7.87), and for all-cause death 2.47 (1.19–5.15); both P < 0.05. The addition of the MELD-XI score to a prespecified prognostic model increased the discrimination of the model for all-cause death, but the increment in the C-index was only modest: 0.013 (P = 0.02). Conclusions: In patients with AHF, hepatorenal dysfunction is prevalent and related to poor outcome. The MELD-XI score is a useful prognosticator in AHF

Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: The ASTRONAUT randomized trial

IMPORTANCE: Hospitalizations for heart failure (HHF) represent a major health burden, with high rates of early postdischarge rehospitalization and mortality. OBJECTIVE: To investigate whether aliskiren, a direct renin inhibitor, when added to standard therapy, would reduce the rate of cardiovascular (CV) death or HF rehospitalization among HHF patients. DESIGN, SETTING, AND PARTICIPANTS: International, double-blind, placebo-controlled study that randomized hemodynamically stable HHF patients a median 5 days after admission. Eligible patients were 18 years or older with left ventricular ejection fraction (LVEF) 40% or less, elevated natriuretic peptides (brain natriuretic peptide [BNP] ≥ 400 pg/mL or N -terminal pro-BNP [NT-proBNP] ≥ 1600 pg/mL), and signs and symptoms of fluid overload. Patients were recruited from 316 sites across North and South America, Europe, and Asia between May 2009 and December 2011. The follow-up period ended in July 2012. INTERVENTION: All patients received 150 mg (increased to 300 mg as tolerated) of aliskiren or placebo daily, in addition to standard therapy. The study drug was continued after discharge for a median 11.3 months. MAIN OUTCOME MEASURES Cardiovascular death or HF rehospitalization at 6 months and 12 months. RESULTS: In total, 1639 patients were randomized, with 1615 patients included in the final efficacy analysis cohort (808 aliskiren, 807 placebo). Mean age was 65 years; mean LVEF, 28%; 41% of patients had diabetes mellitus, mean estimated glomerular filtration rate, 67 mL/min/1.73 m2. At admission and randomization, median NT-proBNP levels were 4239 pg/mL and 2718 pg/mL, respectively. At randomization, patients were receiving diuretics (95.9%), β-blockers (82.5%), angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (84.2%), and mineralocorticoid receptor antagonists (57.0%). In total, 24.9% of patients receiving aliskiren (77 CV deaths, 153 HF rehospitalizations) and 26.5% of patients receiving placebo (85 CV deaths, 166 HF rehospitalizations) experienced the primary end point at 6 months (hazard ratio [HR], 0.92; 95% CI, 0.76-1.12; P = .41). At 12 months, the event rates were 35.0% for the aliskiren group (126 CV deaths, 212 HF rehospitalizations) and 37.3% for the placebo group (137 CV deaths, 224 HF rehospitalizations; HR, 0.93; 95% CI, 0.79-1.09; P = .36). The rates of hyperkalemia, hypotension, and renal impairment/renal failure were higher in the aliskiren group compared with placebo. CONCLUSION AND RELEVANCE: Among patients hospitalized for HF with reduced LVEF, initiation of aliskiren in addition to standard therapy did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge

Cause of Death in Patients With Acute Heart Failure: Insights From RELAX-AHF-2

Objectives: This study sought to better understand the discrepant results of 2 trials of serelaxin on acute heart failure (AHF) and short-term mortality after AHF by analyzing causes of death of patients in the RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF-2) trial. Background: Patients with AHF continue to suffer significant short-term mortality, but limited systematic analyses of causes of death in this patient population are available. Methods: Adjudicated cause of death of patients in RELAX-AHF-2, a randomized, double-blind, placebo-controlled trial of serelaxin in patients with AHF across the spectrum of ejection fraction (EF), was analyzed. Results: By 180 days of follow-up, 11.5% of patients in RELAX-AHF-2 died, primarily due to heart failure (HF) (38% of all deaths). Unlike RELAX-AHF, there was no apparent effect of treatment with serelaxin on any category of cause of death. Older patients (≥75 years) had higher rates of mortality (14.2% vs. 8.8%) and noncardiovascular (CV) death (27% vs. 19%) compared to younger patients. Patients with preserved EF (≥50%) had lower rates of HF-related mortality (30% vs. 40%) but higher non-CV mortality (36% vs. 20%) compared to patients with reduced EF. Conclusions: Despite previous data suggesting benefit of serelaxin in AHF, treatment with serelaxin was not found to improve overall mortality or have an effect on any category of cause of death in RELAX-AHF-2. Careful adjudication of events in the serelaxin trials showed that older patients and those with preserved EF had fewer deaths from HF or sudden death and more deaths from other CV causes and from noncardiac causes. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778

Effects of serelaxin in patients with acute heart failure

49siSerelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure.openopenMetra M.; Teerlink J.R.; Cotter G.; Davison B.A.; Felker G.M.; Filippatos G.; Greenberg B.H.; Pang P.S.; Ponikowski P.; Voors A.A.; Adams K.F.; Anker S.D.; Arias-Mendoza A.; Avendano P.; Bacal F.; Bohm M.; Bortman G.; Cleland J.G.F.; Cohen-Solal A.; Crespo-Leiro M.G.; Dorobantu M.; Echeverria L.E.; Ferrari R.; Goland S.; Goncalvesova E.; Goudev A.; Kober L.; Lema-Osores J.; Levy P.D.; McDonald K.; Manga P.; Merkely B.; Mueller C.; Pieske B.; Silva-Cardoso J.; Spinar J.; Squire I.; Stepinska J.; Van Mieghem W.; Von Lewinski D.; Wikstrom G.; Yilmaz M.B.; Hagner N.; Holbro T.; Hua T.A.; Sabarwal S.V.; Severin T.; Szecsody P.; Gimpelewicz C.Metra, M.; Teerlink, J. R.; Cotter, G.; Davison, B. A.; Felker, G. M.; Filippatos, G.; Greenberg, B. H.; Pang, P. S.; Ponikowski, P.; Voors, A. A.; Adams, K. F.; Anker, S. D.; Arias-Mendoza, A.; Avendano, P.; Bacal, F.; Bohm, M.; Bortman, G.; Cleland, J. G. F.; Cohen-Solal, A.; Crespo-Leiro, M. G.; Dorobantu, M.; Echeverria, L. E.; Ferrari, R.; Goland, S.; Goncalvesova, E.; Goudev, A.; Kober, L.; Lema-Osores, J.; Levy, P. D.; Mcdonald, K.; Manga, P.; Merkely, B.; Mueller, C.; Pieske, B.; Silva-Cardoso, J.; Spinar, J.; Squire, I.; Stepinska, J.; Van Mieghem, W.; Von Lewinski, D.; Wikstrom, G.; Yilmaz, M. B.; Hagner, N.; Holbro, T.; Hua, T. A.; Sabarwal, S. V.; Severin, T.; Szecsody, P.; Gimpelewicz, C