Josep Masip

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.

Non-invasive pressure support ventilation versus conventional oxygen therapy in acute cardiogenic pulmonary oedema: a randomised trial

BACKGROUND Non-invasive pressure support ventilation (NIPSV) is an effective treatment for acute respiratory failure in patients with chronic obstructive pulmonary disease. We assessed the efficacy of this therapy in acute cardiogenic pulmonary oedema in a randomised comparison with conventional oxygen therapy. METHODS 40 patients were randomly assigned conventional oxygen therapy or NIPSV supplied by a standard ventilator through a face mask, with adjustment of tidal volume and pressure support in addition to a positive end-expiratory pressure of 5 cm water. Physiological measurements were obtained in the first 2 h and at 3 h, 4 h, and 10 h. The main endpoints were intubation rate and resolution time. Analyses were by intention to treat. FINDINGS Three patients were withdrawn on the basis of clinical and chest radiography results. Endotracheal intubation was required in one (5%) of 19 patients assigned NIPSV and in six (33%) of 18 assigned conventional oxygen therapy (p=0.037). Resolution time (defined as a clinical improvement with oxygen saturation of 96% or more and respiratory rate less than 30 breaths/min) was significantly shorter in the NIPSV group (median 30 [IQR 15-53] vs 105 [50-230] min, p=0.002). NIPSV led to a rapid improvement in oxygenation in the first 2 h. There were no differences in hospital length of stay or mortality. INTERPRETATION In this study of acute cardiogenic pulmonary oedema, NIPSV was superior to conventional oxygen therapy. Further studies should compare NIPSV with continuous positive airway pressure.

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.

Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergenc: Recommendations on pre-hospital & early hospital management of acute heart failure

Acute heart failure is a fatal syndrome. Emergency physicians, cardiologists, intensivists, nurses and other health care providers have to cooperate to provide optimal benefit. However, many treatment decisions are opinion‐based and few are evidenced‐based. This consensus paper provides guidance to practicing physicians and nurses to manage acute heart failure in the pre‐hospital and hospital setting. Criteria of hospitalization and of discharge are described. Gaps in knowledge and perspectives in the management of acute heart failure are also detailed. This consensus paper on acute heart failure might help enable contiguous practice.

Practical recommendations for prehospital and early in-hospital management of patients presenting with acute heart failure syndromes

Guideline recommendations for the prehospital and early in-hospital (first 6-12 hrs after presentation) management of acute heart failure syndromes are lacking. The American College of Cardiology/American Heart Association and European Society of Cardiology guidelines direct the management of these acute heart failure patients, but specific consensus on early management has not been published, primarily because few early management trials have been conducted. This article summarizes practical recommendations for the prehospital and early management of patients with acute heart failure syndromes; the recommendations were developed from a meeting of experts in cardiology, emergency medicine, and intensive care medicine from Europe and the United States. The recommendations are based on a unique clinical classification system considering the initial systolic blood pressure and other symptoms: 1) dyspnea and/or congestion with systolic blood pressure >140 mm Hg; 2) dyspnea and/or congestion with systolic blood pressure 100-140 mm Hg; 3) dyspnea and/or congestion with systolic blood pressure <100 mm Hg; 4) dyspnea and/or congestion with signs of acute coronary syndrome; and 5) isolated right ventricular failure. These practical recommendations are not intended to replace existing guidelines. Rather, they are meant to serve as a tool to facilitate guideline implementation where data are available and to provide suggested treatment approaches where formal guidelines and definitive evidence are lacking.

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.

Recommendations on pre-hospital and early hospital management of acute heart failure : a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine - short version

Despite several critical steps forward in the management of chronic heart failure (CHF), the area of acute heart failure (AHF) has remained relatively stagnant. As stated in the updated ESC HF guidelines, clinicians responsible for managing patients with AHF must frequently make treatment decisions without adequate evidence, usually on the basis of expert opinion consensus.2 Specifically, the treatment of acute HF remains largely opinion-based with little good evidence to guide therapy. Acute heart failure is a syndrome in which emergency physicians, cardiologists, intensivists, nurses, and other healthcare providers have to cooperate to provide ‘rapid’ benefit to the patients. We hereby would like to underscore the wider experience grown in different settings of the area of intensive care on acute heart failure, actually larger and more composite than that got in specialized Care Units. The distillate of such different experiences is discussed and integrated in the present document. Hence, the authors of this consensus paper believe a common working definition of AHF covering all dimensions and modes of presentations has to be made, with the understanding that most AHF presentations are either acute decompensations of chronic underlying HF or the abrupt onset of dyspnoea associated with significantly elevated blood pressure. Secondly, recent data show that, much like acute coronary syndrome, AHF might have a ‘time to therapy’ concept. Accordingly, ‘pre-hospital’ management is considered a critical component of care. Thirdly, most patients with AHF have normal or high blood pressure at presentation, and are admitted with symptoms and/or signs of congestion. This is in contradiction to the presentation where low cardiac output leads to symptomatic hypotension and signs/symptoms of hypoperfusion, a circumstance that is relatively rare, present in coronary care unit/intensive care unit (CCU/ICU) but associated with a particularly poor outcome. Hence, it is important to note that appropriate therapy requires appropriate identification of the specific AHF phenotype.3 The aim of the current paper is not to replace guidelines, but, to provide contemporary perspective for early hospital management within the context of the most recent data and to provide guidance, based on expert opinions, to practicing physicians and other healthcare professionals (Figure 1). We believe that the experience accrued in the different settings from the emergency department through to the ICU/CCU is collectivel valuable in determining how best to manage the patients with AHF. Herein, a shortened version mainly including group recommendations is provided. Full version of the consensus paper is provided as Supplementary material online.

Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology

Acute right ventricular (RV) failure is a complex clinical syndrome that results from many causes. Research efforts have disproportionately focused on the failing left ventricle, but recently the need has been recognized to achieve a more comprehensive understanding of RV anatomy, physiology, and pathophysiology, and of management approaches. Right ventricular mechanics and function are altered in the setting of either pressure overload or volume overload. Failure may also result from a primary reduction of myocardial contractility owing to ischaemia, cardiomyopathy, or arrhythmia. Dysfunction leads to impaired RV filling and increased right atrial pressures. As dysfunction progresses to overt RV failure, the RV chamber becomes more spherical and tricuspid regurgitation is aggravated, a cascade leading to increasing venous congestion. Ventricular interdependence results in impaired left ventricular filling, a decrease in left ventricular stroke volume, and ultimately low cardiac output and cardiogenic shock. Identification and treatment of the underlying cause of RV failure, such as acute pulmonary embolism, acute respiratory distress syndrome, acute decompensation of chronic pulmonary hypertension, RV infarction, or arrhythmia, is the primary management strategy. Judicious fluid management, use of inotropes and vasopressors, assist devices, and a strategy focusing on RV protection for mechanical ventilation if required all play a role in the clinical care of these patients. Future research should aim to address the remaining areas of uncertainty which result from the complexity of RV haemodynamics and lack of conclusive evidence regarding RV‐specific treatment approaches.

Acute heart failure and cardiogenic shock: a multidisciplinary practical guidance

PurposeAcute heart failure (AHF) causes high burden of mortality, morbidity, and repeated hospitalizations worldwide. This guidance paper describes the tailored treatment approaches of different clinical scenarios of AHF and CS, focusing on the needs of professionals working in intensive care settings.ResultsTissue congestion and hypoperfusion are the two leading mechanisms of end-organ injury and dysfunction, which are associated with worse outcome in AHF. Diagnosis of AHF is based on clinical assessment, measurement of natriuretic peptides, and imaging modalities. Simultaneously, emphasis should be given in rapidly identifying the underlying trigger of AHF and assessing severity of AHF, as well as in recognizing end-organ injuries. Early initiation of effective treatment is associated with superior outcomes. Oxygen, diuretics, and vasodilators are the key therapies for the initial treatment of AHF. In case of respiratory distress, non-invasive ventilation with pressure support should be promptly started. In patients with severe forms of AHF with cardiogenic shock (CS), inotropes are recommended to achieve hemodynamic stability and restore tissue perfusion. In refractory CS, when hemodynamic stabilization is not achieved, the use of mechanical support with assist devices should be considered early, before the development of irreversible end-organ injuries.ConclusionA multidisciplinary approach along the entire patient journey from pre-hospital care to hospital discharge is needed to ensure early recognition, risk stratification, and the benefit of available therapies. Medical management should be planned according to the underlying mechanisms of various clinical scenarios of AHF.

European Society of Cardiology-Acute Cardiovascular Care Association Position paper on acute heart failure: A call for interdisciplinary care

Acute heart failure (AHF) continues to have unacceptably high rates of mortality and morbidity. This position paper highlights the need for more intense interdisciplinary cooperation as one key element to overcome the challenges associated with fragmentation in the care of AHF patients. Additional aspects discussed include the importance of early diagnosis and treatment, options for initial treatment, referral bias as a potential cause for treatment preferences among experts, considerable uncertainty regarding patient disposition, the diagnosis of accompanying acute myocardial infarction, the need for antibiotic therapy, as well as assessment of intravascular volume status.