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

No detrimental effect on renal function during long-term use of fluvastatin in renal transplant recipients in the Assessment of Lescol in Renal Transplantation (ALERT) study

Alert studien er den eneste og den største randomiserte kontrollerte studie hos nyretransplanterte pasienter med nyre og hjertekar hendelser, hvor 2102 pasienter ble fulgt i inntil 8 år. Andelen hjertedød ble redusert med 26% med bruk av det kolesterol senkende middelet fluvastatin. Funnene fra Alert førte til at fluvastatin er blitt rutine behandling hos disse pasienter verden over. Alert materialet er det eneste prospektive materiale som gir mulighet til å vurdere betydningen av potensielle risikofaktorer for disse hendelser. I sin avhandling ”Risikofaktorer for kardiale og renale endepunkter hos nyretransplanterte pasienter” undersøkte Sadollah Abedini og medarbeiderne fire viktige problemstillinger som tidligere ikke er undersøkt hos nyretransplanterte i en prospektiv studie. • Det har vært reist tvil om tryggheten ved statin behandling hos nyre transplanterte mht negativ effekt på transplantat funksjonen. Studien viste at det var trygt å bruke fluvastatin uten negativ virkning på transplantat funksjonen. • Forekomsten og risikofaktorene for slag er også dårlig belyst hos nyretransplanterte. Abedini og medarbeiderne fant at slag forekommer hyppig, og at risikofaktorer varierer i henhold til type slag. • IL-6 og spesielt hsCRP er inflammasjonsmarkører som er etablert risikofaktor for hjertekarsykdom hos ikke-transplanterte, men betydningen hos nyretransplanterte er ukjent. Resultatene fra denne avhandling viser at inflammasjon markørene IL-6 og hsCRP er uavhengig assosiert med hjertekar hendelser og dødelighet. • Asymmetrical DiMethylArginine (ADMA) er en relativ ny aktør som risikofaktor. Studien i denne avhandlingen viser for første gang at ADMA er en uavhengigrisikofaktor for hjertekar hendelser, slag, dødelighet og nedsatt transplantat funksjon hos nyretransplanterte

Disconnect between the effects of serelaxin on renal function and outcome in acute heart failure

Background: We aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes. Methods: We included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure. Results: Improvement in renal function was more frequently observed with serelaxin when compared with placebo [OR 1.88 (95% CI 1.64–2.15, p &lt; 0.0001)], but was not associated with subsequent clinical outcomes. WRF occurred less frequent with serelaxin [OR 0.70 (95% CI 0.60–0.83, p &lt; 0.0001)] and was associated with increased risk of ACM, worsening HF and the composite of CVD and HF or renal failure hospitalization. Improvement in renal function did not mediate the treatment effect of serelaxin [CVD HR 1.01 (0.99–1.04), ACM HR 1.01 (0.99–1.03), HF/renal failure hospitalization HR 0.99 (0.97–1.00)]. Conclusions: Despite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF. </p

Beneficial effect of early initiation of lipid-lowering therapy following renal transplantation

Background. Renal transplant recipients have a significantly reduced life expectancy, largely due to premature cardiovascular disease. The aim of the current analysis was to investigate the importance of time of initiation of therapy after transplantation, on the benefits of statin therapy. Methods. 2102 renal transplant recipients with total cholesterol levels of 4.0-9.0 mmol/l were randomly assigned to treatment with fluvastatin (n = 1050) or placebo (n = 1052) and followed for a mean time of 5.1 years. The end-points were major cardiac events. The average median time from transplantation to randomization was 4.5 years (range: 0.5-29 years). Results. In patients starting treatment with fluvastatin 6 years, respectively. The risk reduction for patients initiating therapy with fluvastatin at years 0-2 (compared with >6 years) following transplantation was 59% (RR: 0.41; 95% CI: 0.18-0.92; P = 0.0328). This is also reflected in total time on renal replacement therapy: in patients in the first quartile (120 months) (P = 0.033). Conclusions. Our data support an early introduction of fluvastatin therapy in a population of transplant recipients at high risk of premature coronary heart diseas

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 &gt; 1 mg/dL), 73 (6.5%) isolated liver dysfunction (bilirubin &gt; 1 mg/dL), and 207 (18.5%) coexisting dysfunction of the kidneys and the liver (both creatinine and bilirubin &gt; 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 &lt; 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 &lt; 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. © 2019 The Authors. ESC Heart Failure published by John Wiley &amp; Sons Ltd on behalf of the European Society of Cardiology

Day vs night: Does time of presentation matter in acute heart failure? A secondary analysis from the RELAX-AHF trial

Background Signs and symptoms of heart failure can occur at any time. Differences between acute heart failure (AHF) patients who present at nighttime vs daytime and their outcomes have not been well studied. Our objective was to determine if there are differences in baseline characteristics and clinical outcomes between AHF patients presenting during daytime vs nighttime hours within an international, clinical trial. Methods This is a post hoc analysis of the RELAX AHF trial, which randomized 1,161 AHF patients to serelaxin vs placebo, both in addition to usual AHF therapy. Prespecified end points of the primary trial were used: dyspnea, 60-day heart failure/renal failure rehospitalization or cardiovascular (CV) death, and 180-day CV death. Both unadjusted and adjusted analyses for outcomes stratified by daytime vs nighttime presentation were performed. Results Of the 1,161 RELAX-AHF patients, 775 (66.8%) patients presented during daytime and 386 (33.2%) at nighttime. Baseline characteristics were largely similar, although daytime patients were more likely to be male, have greater baseline body weight, have higher New York Heart Association class, have history of atrial fibrillation, and have more peripheral edema compared with nighttime patients. No differences in dyspnea relief or 60-day outcomes were observed. However, daytime presentation was associated with greater risk for 180-day CV death after adjustment (hazard ratio 2.28, 95% CI 1.34-3.86; c statistic = 0.82, 95% CI 0.78-0.86). Conclusion In this secondary analysis of the RELAX-AHF trial, baseline characteristics suggest that daytime-presenting patients may have more gradual worsening of chronic HF. Patients with AHF who presented at night had less risk for 180-day CV death, but similar risk for 60-day CV death or rehospitalization and symptom improvement for patients who presented during the daytime. © 2017 Elsevier Inc