Aims
We evaluated the added prognostic value of a multi‐time point‐based multimarker panel of biomarkers in patients with acute heart failure (AHF).
Methods and results
Seven circulating biomarkers ...NT‐proBNP, high sensitivity cardiac troponin T (hs‐cTnT), soluble ST2 (sST2), growth differentiation factor 15 (GDF‐15), cystatin‐C, galectin‐3, and high sensitivity C‐reactive protein (hs‐CRP) were measured at baseline and on days 2, 5, 14, and 60 in 1161 patients enrolled in the RELAX‐AHF trial. Patients with BNP ≥350 ng/L or NT‐proBNP ≥1400 ng/L, mild to moderate renal impairment, and systolic blood pressure >125 mmHg were included in the trial. Time‐dependent Cox regression analysis was utilized to evaluate the incremental value of serial measurement of biomarkers. Added value of individual biomarkers and their combination, on top of a pre‐specified baseline model, was quantified with the gain in the C‐index. Serial biomarker evaluation showed incremental predictive value over baseline measurements alone for the prediction of 180‐day cardiovascular mortality except for galectin‐3. While a repeat measurement as early as day 2 was adequate for NT‐proBNP and cystatin‐C in terms of maximizing discriminatory accuracy, further measurements on days 14 and 60 provided added value for hs‐cTnT, GDF‐15, sST2, and hs‐CRP. Individual biomarker additions on top of the baseline model showed additional prognostic value. The greatest prognostic gain was, however, attained with the combination of NT‐proBNP, hs‐cTnT, GDF‐15, and sST2, which yielded 0.08 unit absolute increment in the C‐index to 0.87 (95% confidence interval 0.83–0.91.
Conclusion
In patients with AHF and mild to moderate renal impairment, a multimarker approach based on a panel of serially evaluated biomarkers provides the greatest prognostic improvement unmatched by a single time point‐based single marker strategy.
Summary Background Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with ...positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo. Methods RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov , NCT00520806. Findings 1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120–775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients 26%; serelaxin, 156 27%; p=0·70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events 60-day Kaplan-Meier estimate, 13·0%; serelaxin, 76 events 13·2%; hazard ratio HR 1·02 0·74–1·41, p=0·89 or days alive out of the hospital up to day 60 (placebo, 47·7 SD 12·1 days; serelaxin, 48·3 11·6; p=0·37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42–0·93; p=0·019). Interpretation Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality. Funding Corthera, a Novartis affiliate company.
Background
Growth differentiation factor 15 (GDF‐15) was found to be upregulated in patients with chronic heart failure (HF) and associated with disease severity, however, data on patients with acute ...heart failure (AHF) is lacking.
Methods and results
Levels of GDF‐15 were measured at pre‐specified time‐points (baseline and at days 2, 5, 14, and 60) in patients enrolled in the placebo‐controlled RELAXin in Acute Heart Failure (RELAX‐AHF) study, which examined the effect of serelaxin in 1161 patients with AHF, systolic blood pressure >125 mmHg, and mild to moderate renal impairment. Neither baseline nor changes in GDF‐15 were associated with the degree of dyspnoea or dyspnoea relief. After adjustment for baseline characteristics, baseline GDF‐15 was not associated with the composite endpoint of heart failure or renal failure (HF/RF) readmission at 60 days/cardiovascular (CV) death or CV death at 180 days. In contrast, larger increases in GDF‐15 levels at days 2 and 14 were associated with a greater risk of 60‐day HF/RF rehospitalizations/CV death and CV death at 180 days. Serelaxin treatment was associated with significantly larger decreases of GDF‐15 at days 2 and 5 than placebo.
Conclusions
In AHF patients enrolled in the RELAX‐AHF study, increases in GDF‐15 levels, but not baseline measurements, were associated with a greater likelihood of adverse outcomes. Serelaxin administration was associated with greater decreases in GDF‐15 compared with placebo.
Patients admitted for acute heart failure (AHF) experience high rates of in‐hospital and post‐discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin‐2, a ...hormone with vasodilatory and end‐organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX‐AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all‐cause and cardiovascular mortality by 37% through day 180. RELAX‐AHF‐2 (
ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX‐AHF‐2 is a multicentre, randomized, double‐blind, placebo‐controlled, event‐driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild‐to‐moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all‐cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in‐hospital length of stay during index AHF. The results from RELAX‐AHF‐2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.
Background
Data on the prevalence and disease management of chronic urticaria (CU) and chronic spontaneous urticaria (CSU) in the pediatric population are scarce. This study assessed the prevalence ...of CU and CSU, and disease management among pediatric patients (0‐17 years).
Methods
A physician‐based online survey was conducted in 5 European countries (United Kingdom, Germany, Italy, France, and Spain) assessing the annual diagnosed prevalence, disease characteristics, and treatment patterns in the target population. Results are based on physician responses and analyzed using descriptive statistics. Prevalence estimates were calculated based on the number of CU/CSU pediatric patients diagnosed, seen, and treated by the respondents and extrapolated to the total pediatric population from each country.
Results
Across 5 European countries, the one‐year diagnosed prevalence of CU and CSU in pediatric patients was 1.38% (95% CI, 0.94‐1.86) and 0.75% (95% CI, 0.44‐1.08), respectively. Angioedema was reported in 6%‐14% of patients. A large proportion of CSU pediatric patients (40%‐60%) were treated with H1‐antihistamines at approved dose and 16%‐51% received H1‐antihistamines at higher doses. Approximately 1/3 of pediatric CSU patients remained uncontrolled with H1‐antihistamines at approved/higher doses. Other prescribed treatments were oral corticosteroids (10%‐28%) and topical creams (15%‐26%).
Conclusions
This study revealed a prevalence of CSU among pediatric population comparable to adults and also suggested an unmet need for approved treatments for inadequately controlled pediatric CSU patients. It is truly of concern that harmful (oral steroids) or insufficient (topical creams) treatments were frequently used despite better and guideline‐recommended alternatives.
Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and ...practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all‐cause mortality, cause‐specific mortality, relevant non‐fatal morbidity (e.g. all‐cause and cause‐specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient‐reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA‐ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12–13 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the group's recommendations for achieving common views on heart failure endpoints in clinical trials.
Aims
Although left ventricular ejection fraction (LVEF) is routinely used to categorize patients with heart failure (HF), whether it predicts outcomes after hospitalization for acute heart failure ...(AHF) is uncertain. Consequently, we assessed the relationship between LVEF and cardiovascular (CV) outcomes in a large, well characterized cohort of patients hospitalized for
AHF.
Methods and results
The 6128 patients from the RELAX‐AHF‐2 trial who had LVEF measured during AHF hospitalization were separated into LVEF quartiles and the relationship between LVEF and a composite of CV mortality and rehospitalization for HF or renal failure through 180 days was assessed. We found progressively lower risk for this composite outcome as LVEF increased (hazard ratio 0.95, 95% confidence interval 0.93–0.98 per 5% LVEF increase, P < 0.001) that was driven predominantly by decreased risk for rehospitalization. The smoothed spline curve depicting risk remained stable as LVEF decreased until reaching approximately 40%, at which point risk increased progressively with further reductions in LVEF. Significant differences between LVEF quartiles for post‐discharge CV risk were seen in patients with an ischaemic aetiology or with a history of HF preceding index hospitalization, but were less robust in patients with non‐ischaemic aetiology and absent in those with de novo
HF.
Conclusion
In patients hospitalized with AHF, CV events over 180 days were more frequent in patients with lower LVEF. This was due predominantly to a significant increase in risk for HF/renal failure rehospitalization but not in either CV or all‐cause mortality. LVEF had greater prognostic value in patients with ischaemic aetiology or pre‐existing
HF.
Previous studies have suggested that the neutrophil-to-lymphocyte ratio (NLR) is a novel yet readily evaluable inflammatory biomarker that may be useful for determining cardiovascular prognosis ...during acute episodes. The study investigated the role of NLR in predicting cardiovascular (CV) outcomes in patients with acute heart failure (HF). Individual patient data from the BLAST-AHF (phase 2b study of the biased ligand of the angiotensin 2 type 1 receptor, TRV027), Pre-RELAX-AHF (phase 2b study of recombinant human relaxin-2, serelaxin), and RELAX-AHF (phase 3 study of serelaxin) randomized, placebo-controlled studies for patients with acute HF were pooled for analysis. Dyspnea visual analog scale area under the curve through day 5, worsening HF through day 5, 30-day all-cause mortality, 60-day HF/renal failure rehospitalizations or CV death, 180-day all-cause mortality, and 180-day CV death were assessed. There were several differences in the baseline characteristics of the patients divided by NLR tertile, with patients in the higher NLR having worse clinical characteristics. NLR was an independent predictor of 30-day all-cause mortality (adjusted hazard ratio HR per log2 NLR increment: 1.66 1.22 to 2.25, p = 0.001), 60-day HF/renal failure rehospitalizations or CV death: 1.33 1.12 to 1.57, p = 0.001), 180-day all-cause mortality (adjusted HR 1.27 1.08 to 1.50, p = 0.003), and 180-day CV death (adjusted HR 1.24 1.04 to 1.49, p = 0.018). NLR, a readily available inflammatory biomarker, was associated with independent risk for short- and long-term adverse outcomes in acute HF, surpassing traditional markers, such as natriuretic peptides.
Little is known about mode of death after acute heart failure (AHF) hospitalization. In the RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) study, serelaxin, the ...recombinant form of human relaxin-2, reduced post-discharge mortality at 180 days in selected patients with AHF.
The goal of this study was to assess the effect of serelaxin on specific modes of death in patients with AHF.
The RELAX-AHF study randomized 1,161 patients with AHF to 48 h of therapy with intravenous serelaxin or placebo. Patients were followed for vital status through 180 days. A blinded clinical events committee reviewed all deaths and adjudicated a cause of death on the basis of pre-specified criteria. Cox proportional hazard models were used to assess the effect of serelaxin on each mode of death, on the basis of pre-specified groupings of mode of death.
There were 107 deaths (9.3%): 37 (35%) due to HF, 25 (23%) due to sudden death, 15 (14%) due to other cardiovascular (CV) causes, 19 (18%) due to non-CV causes, and 11 (10%) classified as unknown. The treatment effect of serelaxin was most pronounced on other CV deaths (hazard ratio HR: 0.29; 95% CI: 0.12 to 0.73; p = 0.005) and sudden death (HR: 0.46; 95% CI: 0.20 to 1.07; p = 0.065). There was no apparent impact of serelaxin treatment on HF deaths or non-CV deaths.
In the RELAX-AHF study, the effects of serelaxin on mortality were primarily driven by reduction in mortality from other CV causes and sudden death, without apparent impact on HF deaths. (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure RELAX-AHF; NCT00520806).
Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes ...hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension.
To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 μg/kg/d and then 60 min at 30 μg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study's main limitations were the relatively small sample size and stable, well-compensated population.
Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required.
ClinicalTrials.gov NCT01640964.
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