Peter S. Pang

Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial

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.

Acute Heart Failure Syndromes

Heart failure resulting in hospitalization represents a significant and growing health care burden. Heterogeneity characterizes this group in terms of mode of presentation, pathophysiology, and prognosis. The vast majority of patients symptomatically improve during hospitalization; however, their early post-discharge rehospitalization and mortality rates continue to be high. Worsening signs and symptoms, neurohormonal, and renal abnormalities occurring soon after discharge may contribute to these high post-discharge event rates. Currently available assessment modalities combined with recent advances in cardiovascular therapies provide present-day opportunities to improve post-discharge outcomes. Further investigation into pathophysiologic targets and novel approaches to clinical trial design are needed. Improving post-discharge outcomes is the single most important goal in the management of acute heart failure syndromes.

Assessing and grading congestion in acute heart failure: a scientific statement from the Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine

Patients with acute heart failure (AHF) require urgent in‐hospital treatment for relief of symptoms. The main reason for hospitalization is congestion, rather than low cardiac output. Although congestion is associated with a poor prognosis, many patients are discharged with persistent signs and symptoms of congestion and/or a high left ventricular filling pressure. Available data suggest that a pre‐discharge clinical assessment of congestion is often not performed, and even when it is performed, it is not done systematically because no method to assess congestion prior to discharge has been validated. Grading congestion would be helpful for initiating and following response to therapy. We have reviewed a variety of strategies to assess congestion which should be considered in the care of patients admitted with HF. We propose a combination of available measurements of congestion. Key elements in the measurement of congestion include bedside assessment, laboratory analysis, and dynamic manoeuvres. These strategies expand by suggesting a routine assessment of congestion and a pre‐discharge scoring system. A point system is used to quantify the degree of congestion. This score offers a new instrument to direct both current and investigational therapies designed to optimize volume status during and after hospitalization. In conclusion, this document reviews the available methods of evaluating congestion, provides suggestions on how to properly perform these measurements, and proposes a method to quantify the amount of congestion present.

Effect of Serelaxin on Cardiac, Renal, and Hepatic Biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) Development Program Correlation With Outcomes

OBJECTIVES The aim of this study was to assess the effects of serelaxin on short-term changes in markers of organ damage and congestion and relate them to 180-day mortality in patients with acute heart failure. BACKGROUND Hospitalization for acute heart failure is associated with high post-discharge mortality, and this may be related to organ damage. METHODS The Pre-RELAX-AHF (Relaxin in Acute Heart Failure) phase II study and RELAX-AHF phase III study were international, multicenter, double-blind, placebo-controlled trials in which patients hospitalized for acute heart failure were randomized within 16 h to intravenous placebo or serelaxin. Each patient was followed daily to day 5 or discharge and at days 5, 14, and 60 after enrollment. Vital status was assessed through 180 days. In RELAX-AHF, laboratory evaluations were performed daily to day 5 and at day 14. Plasma levels of biomarkers were measured at baseline and days 2, 5, and 14. All-cause mortality was assessed as a safety endpoint in both studies. RESULTS Serelaxin reduced 180-day mortality, with similar effects in the phase II and phase III studies (combined studies: N = 1,395; hazard ratio: 0.62; 95% confidence interval: 0.43 to 0.88; p = 0.0076). In RELAX-AHF, changes in markers of cardiac (high-sensitivity cardiac troponin T), renal (creatinine and cystatin-C), and hepatic (aspartate transaminase and alanine transaminase) damage and of decongestion (N-terminal pro-brain natriuretic peptide) at day 2 and worsening heart failure during admission were associated with 180-day mortality. Serelaxin administration improved these markers, consistent with the prevention of organ damage and faster decongestion. CONCLUSIONS Early administration of serelaxin was associated with a reduction of 180-day mortality, and this occurred with fewer signs of organ damage and more rapid relief of congestion during the first days after admission.

Troponin Elevation in Heart Failure: Prevalence, Mechanisms, and Clinical Implications

Circulating biomarkers have become increasingly important in diagnosing and risk stratifying patients with heart failure (HF). While the natriuretic peptides have received much focus, there is increasing interest in the role of circulating cardiac troponin (cTn) in detecting myocardial injury (often subclinical) in those with HF. Accumulating evidence suggests that patients with chronic and acute HF may have measurable levels of circulating cTn, whose detection and magnitude may have prognostic implications. Furthermore, as new, more sensitive cTn assays are being developed, larger numbers of HF patients are found to have detectable cTn with a persistent relationship between magnitude and outcome. This knowledge improves our ability to understand the mechanism of worsening HF, improve risk stratification, and detect potential injury related to new therapeutics in HF. As investigators begin to understand the relationship of detectable cTn to HF outcomes, as well as temporal changes in its magnitude, and its relationship to other circulating biomarkers, more insight may be gained into the progressive nature of cardiac dysfunction and the transition from chronic compensated to acute decompensated HF. Ultimately, this information might allow physicians to guide therapy, choose appropriate therapeutics, and improve HF outcomes.

Acute Heart Failure Syndromes: Emergency Department Presentation, Treatment, and Disposition: Current Approaches and Future Aims A Scientific Statement From the American Heart Association

With a prevalence of 5 800 000 (≈2% of the entire populace) in 2009 and an estimated yearly incidence of 550 000, the burden of heart failure (HF) in the United States is tremendous.1 Although HF is largely a condition defined by chronic debility, virtually all patients experience, at some point, acute symptoms that trigger a visit to the emergency department (ED). These symptoms may vary in severity but, for the most part, they necessitate early intervention, often with intravenous medication and, less frequently, respiratory support. As shown by combined data from the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS), this is a common occurrence; there are nearly 658 000 annual ED encounters primarily for acute HF in the United States—a figure that represents almost 20% of the total HF-specific ambulatory care delivered each year.2 It is noteworthy that few settings other than the ED can offer open access to treatment or provide the level and intensity of care required to effectively manage the acute phase of decompensation, also referred to as episodes of acute heart failure syndromes (AHFS). Nearly 80% of those treated for AHFS in the ED are ultimately admitted to the hospital and, accordingly, the ED serves as the principal portal of entry for hospitalized AHFS patients.34 The ED therefore plays a unique role in the continuum of AHFS treatment, functioning for most patients as the initial point of definitive healthcare contact, the location where primary stabilization is achieved, and the site where disposition decisions are generally made.4 Whereas the ED is a pivotal place for the vast majority of hospitalized patients with acute HF, the evidence base on which this foundation of acute care is built is astonishingly thin. The purpose of this …

Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: Findings from the EVEREST trial

AIMS Signs and symptoms of congestion are the most common cause for hospitalization for heart failure (HHF). The clinical course and prognostic value of congestion during HHF has not been systemically characterized. METHODS AND RESULTS A post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 h of admission (median ~24 h) for worsening HF with an EF ≤ 40% and two or more signs or symptoms of fluid overload [dyspnoea, oedema, or jugular venous distension (JVD)] for a median follow-up of 9.9 months. Clinician-investigators assessed patients daily for dyspnoea, orthopnoea, fatigue, rales, pedal oedema, and JVD and rated signs and symptoms on a standardized 4-point scale ranging from 0 to 3. A modified composite congestion score (CCS) was calculated by summing the individual scores for orthopnoea, JVD, and pedal oedema. Endpoints were HHF, all-cause mortality (ACM), and ACM + HHF. Multivariable Cox regression models were used to evaluate the risk of CCS at discharge on outcomes at 30 days and for the entire follow-up period. The mean CCS obtained after initial therapy decreased from the mean ± SD of 4.07 ± 1.84 and the median (25th, 75th) of 4 (3, 5) at baseline to 1.11 ± 1.42 and 1 (0, 2) at discharge. At discharge, nearly three-quarters of study participants had a CCS of 0 or 1 and fewer than 10% of patients had a CCS >3. B-type natriuretic peptide (BNP) and amino terminal-proBNP, respectively, decreased from 734 (313, 1523) pg/mL and 4857 (2251, 9642) pg/mL at baseline to 477 (199, 1079) pg/mL, and 2834 (1218, 6075) pg/mL at discharge/Day 7. A CCS at discharge was associated with increased risk (HR/point CCS, 95% CI) for a subset of endpoints at 30 days (HHF: 1.06, 0.95-1.19; ACM: 1.34, 1.14-1.58; and ACM + HHF: 1.13, 1.03-1.25) and all outcomes for the overall study period (HHF: 1.07, 1.01-1.14; ACM: 1.16, 1.09-1.24; and ACM + HHF 1.11, 1.06-1.17). Patients with a CCS of 0 at discharge experienced HHF of 26.2% and ACM of 19.1% during the follow-up. CONCLUSION Among patients admitted for worsening signs and symptoms of HF and reduced EF, congestion improves substantially during hospitalization in response to standard therapy alone. However, patients with absent or minimal resting signs and symptoms at discharge still experienced a high mortality and readmission rate.

The impact of early standard therapy on dyspnoea in patients with acute heart failure: the URGENT-dyspnoea study

AIMS The vast majority of acute heart failure (AHF) trials to date have targeted dyspnoea. However, they enrolled patients relatively late and did not standardize their methods of dyspnoea measurement. URGENT Dyspnoea was designed to determine changes in dyspnoea in response to initial, standard therapy in patients presenting with AHF using a standardized approach. METHODS AND RESULTS URGENT Dyspnoea was an international, multi-centre, observational cohort study of AHF patients managed conventionally and enrolled within 1 h of first hospital medical evaluation. Patient-assessed dyspnoea was recorded in the sitting position at baseline and at 6 hours by Likert and visual analog scales. Less symptomatic patients were placed supine to determine whether this provoked worsening dyspnoea (orthopnoea). Of the 524 patients with AHF, the mean age was 68 years, 43% were women, and 83% received intravenous diuretics. On a 5-point Likert scale, dyspnoea improvement was reported by 76% of patients after 6 h of standard therapy. Supine positioning (orthopnoea test) led to worse dyspnoea in 47% of patients compared to sitting upright. CONCLUSION When sitting upright, dyspnoea in the sitting position improves rapidly and substantially in patients with AHF after administration of conventional therapy, mainly intra-venous diuretics. However, many patients remain orthopnoeic. Improving the methodology of clinical trials in AHF by standardizing the conditions under which dyspnoea is assessed could enhance their ability to identify effective treatments. Relief of orthopnoea is clinically valuable and may represent a useful goal for clinical trials.

Clinical Trials of Pharmacological Therapies in Acute Heart Failure Syndromes Lessons Learned and Directions Forward

Acute heart failure syndromes (AHFS) are characterized by a gradual or rapid onset of new or worsening signs and/or symptoms of heart failure (HF) requiring urgent therapy, usually resulting in hospitalization.1,2 The societal burden of AHFS is substantial, with >1 million hospitalizations annually in the United States and similar relative numbers in Europe.2–6 Ongoing epidemiological trends, such as the aging population, improved survival after myocardial infarction, and a decrease in sudden death due to defibrillator therapy, suggest that the prevalence of chronic HF resulting in hospitalization will continue to increase during the coming decades.7 The prognosis after hospitalization for AHFS remains bleak, with rates of death or recurrent hospitalization at 6 months approaching 50%,8–10 outcomes that have changed little in recent years despite improvements in the management of chronic HF.11 Hidden within these oft-cited statistics is a notable paradox—signs and symptoms of AHFS (dyspnea, edema, etc) are successfully treated in the majority of patients, but postdischarge outcomes remain dismal, and attempts to develop new short-term therapies for AHFS have largely been unsuccessful. Since our initial publication in 2005,1 4 large, international phase III development programs—tezosentan,12 levosimendan,13 tolvaptan,14 and rolofylline15—have failed to convincingly demonstrate the safety and efficacy of these agents in AHFS. Even for drugs approved for AHFS treatment (milrinone and nesiritide in the United States and levosimendan in parts of Europe), there have been persistent concerns about safety.16–18 Broadly speaking, the pharmacological armamentarium for AHFS—loop diuretics, vasodilators, and inotropes—is largely unchanged from the 1970s.19 Although substantial efforts in the last decade to develop improved AHFS therapies have yielded disappointing results, we believe that as a scientific community, we are now better equipped to conduct future studies. Hospitalization for AHFS is now recognized as a critical clinical …

Changes in renal function during hospitalization and soon after discharge in patients admitted for worsening heart failure in the placebo group of the EVEREST trial

AIM To provide an in-depth clinical characterization and analysis of outcomes of the patients hospitalized for heart failure (HF) who subsequently develop worsening renal function (WRF) during hospitalization or soon after discharge. METHODS AND RESULTS Of the 4133 patients hospitalized with worsening HF and reduced left ventricular ejection fraction (LVEF) (≤40%) in the EVEREST trial, 2072 were randomized to tolvaptan, a selective vasopressin-2 receptor antagonist, and 2061 were randomized to placebo, both in addition to standard therapy. This analysis included the 2021 (98%) patients in the placebo group with a complete set of renal function parameters. Renal function parameters and clinical variables were measured prospectively during hospitalization and after discharge. Worsening renal function was defined as an increase in sCr ≥0.3 mg/dL during the in-hospital (randomization to discharge or Day 7) and post-discharge (discharge or Day 7 to 4 weeks post-discharge) periods. Blood pressure (BP), body weight (BW), natriuretic peptides (NPs), and congestion score were correlated with WRF. The prognostic value of baseline renal function at admission and WRF during hospitalization and post-discharge on long-term outcomes were assessed using a Cox proportional hazards model adjusted for other baseline covariates. At randomization, 53.2% of patients had moderately or severely reduced estimated glomerular filtration rate (eGFR) (<60.0 mL/min/1.73 m2). Worsening renal function was observed in 13.8% in-hospital and 11.9% post-discharge. Worsening renal function during hospitalization and post-discharge was associated with greater reductions in BP, BW, and NPs. Baseline renal dysfunction as well as in-hospital and post-discharge WRF were predictive of a composite endpoint of cardiovascular (CV) mortality/HF rehospitalization. CONCLUSION The prevalence of renal dysfunction is high in patients hospitalized for HF with reduced LVEF. Worsening renal function may occur not only during hospitalization, but also in the early post-discharge period. Since worsening renal function during hospitalization is associated with a significant decrease in signs and symptoms of congestion, body weight and natriuretic peptides, which are good prognostic indicators, worsening renal function during hospitalization as an endpoint in clinical trials should be re-evaluated.