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Impact of vasodilators on diuretic response in patients with congestive heart failure: A mechanistic trial of cimlanod ( BMS ‐986231)
Abstract
Background
Cimlanod is a nitroxyl donor with vasodilator properties.
Methods
In this randomised, double‐blind, mechanistic, cross‐over trial, twenty‐one patients with left ventricular ejection fraction <45%, increased plasma concentrations of NT‐proBNP and receiving loop diuretics were given, on separate study days, either an eight‐hour intravenous (IV) infusion of cimlanod (12 μg/kg/min) or placebo. Furosemide was given as a 40 mg IV bolus four hours after the start of infusion. The primary endpoint was urine volume in the four hours after the bolus of furosemide during infusion of cimlanod compared with placebo.
Results
Median NT‐proBNP at baseline was 1,487 (IQR: 847–2,665) ng/L. Infusion of cimlanod increased cardiac output and reduced blood pressure without affecting cardiac power index consistent with a vasodilator effect. Urine volume in the 4 hours post‐furosemide was lower with cimlanod (1,032 ± 393 mL) versus placebo (1,481 ± 560 mL) ( P = 0.002), as were total sodium excretion (P = 0.004), fractional sodium excretion ( P = 0.016), systolic blood pressure (P < 0.001), estimated glomerular filtration rate (P = 0.012), and haemoglobin (P = 0.010), an index of plasma volume expansion.
Conclusions
For patients with heart failure and congestion, vasodilation with agents such as cimlanod reduces the response to diuretic agents, which may offset any benefit from acute reductions in cardiac preload and afterload.
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Document Reviewers: Rudolf A. de Boer (CPG Review Coordinator) (Netherlands), P. Christian Schulze (CPG Review Coordinator) (Germany), Magdy Abdelhamid (Egypt), Victor Aboyans (France), Stamatis Adamopoulos (Greece), Stefan D. Anker (Germany), Elena Arbelo (Spain), Riccardo Asteggiano (Italy), Johann Bauersachs (Germany), Antoni Bayes‐Genis (Spain), Michael A. Borger (Germany), Werner Budts (Belgium), Maja Cikes (Croatia), Kevin Damman (Netherlands), Victoria Delgado (Netherlands), Paul Dendale (Belgium), Polychronis Dilaveris (Greece), Heinz Drexel (Austria), Justin Ezekowitz (Canada), Volkmar Falk (Germany), Laurent Fauchier (France), Gerasimos Filippatos (Greece), Alan Fraser (United Kingdom), Norbert Frey (Germany), Chris P. Gale (United Kingdom), Finn Gustafsson (Denmark), Julie Harris (United Kingdom), Bernard Iung (France), Stefan Janssens (Belgium), Mariell Jessup (United States of America), Aleksandra Konradi (Russia), Dipak Kotecha (United Kingdom), Ekaterini Lambrinou (Cyprus), Patrizio Lancellotti (Belgium), Ulf Landmesser (Germany), Christophe Leclercq (France), Basil S. Lewis (Israel), Francisco Leyva (United Kingdom), AleVs Linhart (Czech Republic), Maja‐Lisa Løchen (Norway), Lars H. Lund (Sweden), Donna Mancini (United States of America), Josep Masip (Spain), Davor Milicic (Croatia), Christian Mueller (Switzerland), Holger Nef (Germany), Jens‐Cosedis Nielsen (Denmark), Lis Neubeck (United Kingdom), Michel Noutsias (Germany), Steffen E. Petersen (United Kingdom), Anna Sonia Petronio (Italy), Piotr Ponikowski (Poland), Eva Prescott (Denmark), Amina Rakisheva (Kazakhstan), Dimitrios J. Richter (Greece), Evgeny Schlyakhto (Russia), Petar Seferovic (Serbia), Michele Senni (Italy), Marta Sitges (Spain), Miguel Sousa‐Uva (Portugal), Carlo G. Tocchetti (Italy), Rhian M. Touyz (United Kingdom), Carsten Tschoepe (Germany), Johannes Waltenberger (Germany/Switzerland)
All experts involved in the development of these guidelines have submitted declarations of interest. These have been compiled in a report and published in a supplementary document simultaneously to the guidelines. The report is also available on the ESC website www.escardio.org/guidelines
For the Supplementary Data which include background information and detailed discussion of the data that have provided the basis for the guidelines see European Heart Journal online
Acute decompensated heart failure (ADHF) is one of the leading admission diagnoses worldwide, yet it is an entity with incompletely understood pathophysiology and limited therapeutic options. Patients admitted for ADHF have high in-hospital morbidity and mortality, as well as frequent rehospitalizations and subsequent cardiovascular death. This devastating clinical course is partly due to suboptimal medical management of ADHF with persistent congestion upon hospital discharge and inadequate predischarge initiation of life-saving guideline-directed therapies. While new drugs for the treatment of chronic HF continue to be approved, there has been no new therapy approved for ADHF in decades. This review will focus on the current limited understanding of ADHF pathophysiology, possible therapeutic targets, and current limitations in expanding available therapies in light of the unmet need among these high-risk patients.
Aims
Nitroxyl (HNO) provokes vasodilatation and inotropic and lusitropic effects in animals via post‐translational modification of thiols. We aimed to compare effects of the HNO donor cimlanod (BMS‐986231) with those of nitroglycerin (NTG) or placebo on cardiac function in patients with chronic heart failure with reduced ejection fraction (HFrEF).
Methods and Results
In a randomized, multicenter, double‐blind, crossover trial, 45 patients with stable HFrEF were given a 5‐h intravenous infusion of cimlanod, NTG, or placebo on separate days. Echocardiograms were done at the start and end of each infusion period and read in a core laboratory. The primary endpoint was stroke volume index (SVI) derived from the left ventricular outflow tract at the end of each infusion period. SVI with placebo was 30±7 ml/m² and was lower with cimlanod (29±9 ml/m²; p = 0.03) and NTG (28±8 ml/m²; p = 0.02). Transmitral E‐wave Doppler velocity on cimlanod or NTG was lower than on placebo and, consequently, E/e’ (p = 0.006) and E/A ratio (p = 0.003) were also lower. NTG had similar effects to cimlanod on these measurements. Blood pressure reduction was similar with cimlanod and NTG and greater than with placebo.
Conclusion
In patients with chronic HFrEF, the hemodynamic effects of cimlanod and NTG are similar. The effects of cimlanod may be explained by venodilatation and preload reduction without additional inotropic or lusitropic effects. Ongoing trials of cimlanod will further define its potential role in the treatment of heart failure.
Objectives
The primary objective was to identify well-tolerated doses of cimlanod in patients with acute heart failure (AHF). Secondary objectives were to identify signals of efficacy, including biomarkers, symptoms, and clinical events.
Background
Nitroxyl (HNO) donors have vasodilator, inotropic and lusitropic effects. Bristol-Myers Squibb-986231 (cimlanod) is an HNO donor being developed for acute heart failure (AHF).
Methods
This was a phase IIb, double-blind, randomized, placebo-controlled trial of 48-h treatment with cimlanod compared with placebo in patients with left ventricular ejection fraction ≤40% hospitalized for AHF. In part I, patients were randomized in a 1:1 ratio to escalating doses of cimlanod or matching placebo. In part II, patients were randomized in a 1:1:1 ratio to either of the 2 highest tolerated doses of cimlanod from part I or placebo. The primary endpoint was the rate of clinically relevant hypotension (systolic blood pressure <90 mm Hg or patients became symptomatic).
Results
In part I (n = 100), clinically relevant hypotension was more common with cimlanod than placebo (20% vs. 8%; relative risk [RR]: 2.45; 95% confidence interval [CI]: 0.83 to 14.53). In part II (n = 222), the incidence of clinically relevant hypotension was 18% for placebo, 21% for cimlanod 6 μg/kg/min (RR: 1.15; 95% CI: 0.58 to 2.43), and 35% for cimlanod 12 μg/kg/min (RR: 1.9; 95% CI: 1.04 to 3.59). N-terminal pro–B-type natriuretic peptide and bilirubin decreased during infusion of cimlanod treatment compared with placebo, but these differences did not persist after treatment discontinuation.
Conclusions
Cimlanod at a dose of 6 μg/kg/min was reasonably well-tolerated compared with placebo. Cimlanod reduced markers of congestion, but this did not persist beyond the treatment period. (Evaluate the Safety and Efficacy of 48-Hour Infusions of HNO (Nitroxyl) Donor in Hospitalized Patients With Heart Failure [STANDUP AHF]; NCT03016325)
Background:
Cardiac output (CO) assessment is a corner stone in advanced haemodynamic management, especially in critical ill patients. The present study was conducted to validate cardiac index and cardiac output by NICaS™ with the thermodilution technique using pulmonary artery catheter in post-operative cardiac surgical patients.
Materials and methods:
This was a prospective observational clinical study conducted at a tertiary care hospital. 23 adult patients in the age range of 18-65 years who had undergone for elective coronary artery bypass grafting were included in the study.
Results:
Spearman's correlation coefficient of cardiac index between continuous Thermodilution (cTD) and Non-Invasive Cardiac System (NICaS™) showed a good correlation (r = 0.765, 95% confidence interval 0.70 to 0.82, P < 0.0001). There was a good correlation between cTD and NICaS™ for cardiac output (r = 0.759, 95% confidence interval 0.69 to 0.81, P < 0.0001), Bland-Altman plot for cardiac index between cTD and NICaS™ showed a mean bias of -0.66 ± 0.6919 with limits of agreement being -2.02 to 0.6936. Bland-Altman plot for cardiac output between cTD and NICaS™ showed a mean bias of -1.0386 ± 1.17 with limits of agreement being -3.34 to + 1.26. Percentage error for cardiac index and cardiac output were 64.78% and 64% respectively. Polar plot analysis showed an angular bias of 6.32° with radial limits of agreement being -8.114° to 20.75° for cardiac index and angular bias of 5.6682° with radial limits of agreement being -9.1422° to 20.4784° for cardiac output.
Conclusion:
NICaS™ demonstrated a good trending ability for both CI and CO. However, NICaS™ derived parameters are not interchangeable with the values derived from continuous thermodilution technique.
Background:
Serelaxin 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.
Methods:
In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days.
Results:
A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups.
Conclusions:
In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).
Aims
To assess differences in diuretic dose requirements in patients treated with sacubitril/valsartan compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM‐HF) trial.
Methods and results
Overall, 8399 patients with New York Heart Association class II–IV heart failure and reduced LVEF were randomized to sacubitril/valsartan 200 mg bid or enalapril 10 mg twice daily. Loop diuretic doses were assessed at baseline, 6, 12, and 24 months, and furosemide dose equivalents were calculated via multiplication factors (2x for torsemide and 40x for bumetanide). Percentages of participants with reductions or increases in loop diuretic dose were determined. At baseline, 80.8% of participants were taking any diuretics (n = 6290 for loop diuretics, n = 496 for other diuretics); of those, recorded dosage data for loop diuretics were available on 5487 participants. Mean baseline furosemide equivalent doses were 48.2 mg for sacubitril/valsartan and 49.6 mg for enalapril (P = 0.25). Patients treated with sacubitril/valsartan were more likely to reduce diuretic dose and less likely to increase diuretic dose relative to those randomized to enalapril at 6, 12, 24 months post‐randomization, with an overall decreased diuretic use of 2.0% (P = 0.02), 4.1% (P < 0.001), and 6.1% (P < 0.001) at 6, 12, and 24 months, respectively, with similar findings in an on‐treatment analysis.
Conclusion
Treatment with sacubitril/valsartan was associated with more loop diuretic dose reductions and fewer dose increases compared with enalapril, suggesting that treatment with sacubitril/valsartan may reduce the requirement for loop diuretics relative to enalapril in patients with heart failure with reduced ejection fraction.
Nitroxyl (HNO) is a reactive nitrogen molecule that has potential therapeutic benefits for patients with acute heart failure. The results of the first‐in‐human study for BMS‐986231, a novel HNO donor, are reported. The aim of this sequential cohort study was to evaluate the safety, tolerability, and pharmacokinetic profile of BMS‐986231 after 24‐ and 48‐hour intravenous infusions in healthy volunteers. Eighty subjects were randomized and dosed. Seven cohorts (stratum A) received BMS‐986231 0.1, 0.33, 1, 3, 5, 10, and 15 μg/kg/min or placebo, infused over 24 hours. An additional cohort (stratum B) received 10 μg/kg/min or placebo, infused over 48 hours. Adverse events (AEs) were reported for 30 days after completion of infusion. Blood/urine samples were collected at regular intervals; other parameters (blood pressure, heart rate/rhythm, cardiac index) were also assessed. Headaches were the most commonly reported drug‐related AE (48%) in those who received BMS‐986231, although their severity was reduced by hydration. No other significant drug‐related AEs were noted. BMS‐986231 was associated with dose‐dependent and well‐tolerated reductions in systolic and diastolic blood pressure versus baseline; cardiac index, as measured noninvasively, was increased. BMS‐986231 had no clinically significant effect on heart rate/rhythm or laboratory parameters. Its mean elimination half‐life was 0.7‐2.5 hours. BMS‐986231 was safe and well‐tolerated for up to 24 hours (15 μg/kg/min) or 48 hours (10 μg/kg/min), with a favorable hemodynamic profile observed. Ongoing studies continue to evaluate the potential benefit of BMS‐986231 in patients with acute heart failure.
Aims
Even if treatment controls symptoms, patients with heart failure may still be congested. We aimed at assessing the prevalence and clinical relevance of congestion in outpatients with chronic heart failure.
Methods and results
We recorded clinical and ultrasound [lung B‐lines; inferior vena cava (IVC) diameter; internal jugular vein diameter before and after a Valsalva manoeuvre (JVD ratio)] features of congestion in heart failure patients during a routine check‐up. Of 342 patients who attended, predominantly in New York Heart Association class I or II (n = 257; 75%), 242 (71%) had at least one feature of congestion, either clinical (n = 139; 41%) or by ultrasound (n = 199; 58%). Amongst patients (n = 203, 59%) clinically free of congestion, 31 (15%) had ≥ 14 B‐lines, 57 (29%) had a dilated IVC (> 2.0 cm), 38 (20%) had an abnormal JVD ratio (< 4), 87 (43%) had at least one of these, and 27 (13%) had two or more. During a median follow‐up of 234 (interquartile range 136–351) days, 60 patients (18%) died or were hospitalized for heart failure. In univariable analysis, each clinical and ultrasound measure of congestion was associated with increased risk but, in multivariable models, only higher N‐terminal pro‐B‐type natriuretic peptide and IVC, and lower JVD ratio, were associated with the composite outcome.
Conclusions
Many patients with chronic heart failure with few symptoms have objective evidence of congestion and this is associated with an adverse prognosis. Whether using these measures of congestion to guide management improves outcomes requires investigation.
Background:
Diuretics are the mainstay of treatment for congestion but concerns exist that they adversely affect prognosis. We explored whether the relationship between loop diuretic use and outcome is explained by the underlying severity of congestion amongst patients referred with suspected heart failure.
Method and results:
Of 1190 patients, 712 had a left ventricular ejection fraction (LVEF) ≤50 %, 267 had LVEF >50 % with raised plasma NTproBNP (>400 ng/L) and 211 had LVEF >50 % with NTproBNP ≤400 ng/L; respectively, 72 %, 68 % and 37 % of these groups were treated with loop diuretics including 28 %, 29 % and 10 % in doses ≥80 mg furosemide equivalent/day. Compared to patients with cardiac dysfunction (either LVEF ≤50 % or NT-proBNP >400 ng/L) but not taking a loop diuretic, those taking a loop diuretic were older and had more clinical evidence of congestion, renal dysfunction, anaemia and hyponatraemia. During a median follow-up of 934 (IQR: 513-1425) days, 450 patients were hospitalized for HF or died. Patients prescribed loop diuretics had a worse outcome. However, in multi-variable models, clinical, echocardiographic (inferior vena cava diameter), and biochemical (NTproBNP) measures of congestion were strongly associated with an adverse outcome but not the use, or dose, of loop diuretics.
Conclusions:
Prescription of loop diuretics identifies patients with more advanced features of heart failure and congestion, which may account for their worse prognosis. Further research is needed to clarify the relationship between loop diuretic agents and outcome; imaging and biochemical measures of congestion might be better guides to diuretic dose than symptoms or clinical signs.
AimsWe studied the characteristics and clinical outcome related to diuretic response and the effects of serelaxin in patients hospitalized for acute heart failure (AHF).Methods and resultsRELAX-AHF was a double-blind, placebo-controlled trial, enrolling 1161 patients admitted to hospital for AHF who were randomized to 48 h i.v infusions of placebo or serelaxin (30 µg/kg per day) within 16 h from presentation. Diuretic response was defined as Δ weight kg/[(total i.v. dose)/40 mg] + [(total oral dose)/80 mg)] furosemide (or equivalent loop diuretic dose) up to day 5. Median diuretic response was −0.42 (−1.00, −0.14) kg/40 mg. A poor diuretic response was independently associated with Western-like region (Western Europe, North America, Israel, and Poland), lower diastolic blood pressure, the absence of oedema, higher blood urea nitrogen, and lower levels of aspartate aminotransferase and potassium (all P < 0.01). Randomization to serelaxin was associated with lower doses of i.v. loop diuretics and slightly less weight loss, resulting in a neutral effect on diuretic response. Worse diuretic response was independently associated both with less relief of dyspnoea, measured with a visual analogue scale (VAS) at day 5 (primary endpoint; P = 0.0002), and with a higher risk of cardiovascular death or rehospitalization for heart failure or renal failure through day 60 (secondary endpoint, P < 0.0001), but not with increased 180-day cardiovascular mortality (P = 0.507).Conclusions
In patients hospitalized for AHF, a poor diuretic response was associated with a poor in-hospital and early post-discharge clinical outcome. Serelaxin had a neutral effect on diuretic response.Trial registration: NCT00520806
Diminished diuretic response is common in patients with acute heart failure, although a clinically useful definition is lacking. Our aim was to investigate a practical, workable metric for diuretic response, examine associated patient characteristics and relationships with outcome.
We examined diuretic response (defined as Δ weight kg/40 mg furosemide) in 1745 hospitalized acute heart failure patients from the PROTECT trial. Day 4 response was used to allow maximum differentiation in responsiveness and tailoring of diuretic doses to clinical response, following sensitivity analyses. We investigated predictors of diuretic response and relationships with outcome. The median diuretic response was -0.38 (-0.80 to -0.13) kg/40 mg furosemide. Poor diuretic response was independently associated with low systolic blood pressure, high blood urea nitrogen, diabetes, and atherosclerotic disease (all P < 0.05). Worse diuretic response independently predicted 180-day mortality (HR: 1.42; 95% CI: 1.11-1.81, P = 0.005), 60-day death or renal or cardiovascular rehospitalization (HR: 1.34; 95% CI: 1.14-1.59, P < 0.001) and 60-day HF rehospitalization (HR: 1.57; 95% CI: 1.24-2.01, P < 0.001) in multivariable models. The proposed metric-weight loss indexed to diuretic dose-better captures a dose-response relationship. Model diagnostics showed diuretic response provided essentially the same or slightly better prognostic information compared with its individual components (weight loss and diuretic dose) in this population, while providing a less biased, more easily interpreted signal.
Worse diuretic response was associated with more advanced heart failure, renal impairment, diabetes, atherosclerotic disease and in-hospital worsening heart failure, and predicts mortality and heart failure rehospitalization in this post hoc, hypothesis-generating study.
Oedema is one of the fundamental features of heart failure, but the pathophysiology of oedema varies. Patients present along a spectrum ranging from acute pulmonary oedema to gross fluid retention and peripheral oedema (anasarca). In patients with pure pulmonary oedema, the problem is one of acute haemodynamic derangement; the patient does not have excess fluid, but pulmonary venous pressure rises such that the rate of fluid transudation into the interstitium of the lung exceeds the capacity of the pulmonary lymphatics to drain away the fluid. Conversely, in patients with peripheral oedema, the problem is one of fluid retention. Understanding the causes of oedema will enable straightforward, correct management of the condition. For patients with acute pulmonary oedema, vasodilatation is important to reduce cardiac filling pressures. For patients with fluid retention, removing the fluid, using either diuretics or mechanical means, is the most important consideration.
In the early 1990s, within three years of cloning of endothelin receptors, orally active endothelin receptor antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials - except those for pulmonary arterial hypertension and scleroderma-related digital ulcers - were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused.
Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent.
We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days.
Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11).
Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).
Aim
The “2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure” replaces the “2013 ACCF/AHA Guideline for the Management of Heart Failure” and the “2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure.” The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with heart failure.
Methods
A comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies, published through September 2021, were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021.
Structure
Heart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients’ interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments with high-quality published economic analyses.
Congestion, related to pressure and/or fluid overload, plays a central role in the pathophysiology, presentation and prognosis of heart failure and is an important therapeutic target. While symptoms and physical signs of fluid overload are required to make a clinical diagnosis of heart failure, they lack both sensitivity and specificity, which might lead to diagnostic delay and uncertainty. Over the last decades, new ultrasound methods for the detection of elevated intracardiac pressures and/or fluid overload have been developed that are more sensitive and specific, thereby enabling earlier and more accurate diagnosis and facilitating treatment strategies. Accordingly, we considered that a state‐of‐the‐art review of ultrasound methods for the detection and quantification of congestion was timely, including imaging of the heart, lungs (B‐lines), kidneys (intrarenal venous flow), and venous system (inferior vena cava and internal jugular vein diameter).
Importance
Acute heart failure (AHF) precipitates millions of hospital admissions worldwide, but previous registries have been country or region specific.
Objective
To conduct a prospective contemporaneous comparison of AHF presentations, etiologic factors and precipitants, treatments, and in-hospital outcomes among global regions through the International Registry to Assess Medical Practice with Longitudinal Observation for Treatment of Heart Failure (REPORT-HF).
Design, Setting, and Participants
A total of 18 553 adults were enrolled during a hospitalization for AHF. Patients were recruited from the acute setting in Western Europe (WE), Eastern Europe (EE), Eastern Mediterranean and Africa (EMA), Southeast Asia (SEA), Western Pacific (WP), North America (NA), and Central and South America (CSA). Patients with AHF were approached for consent and excluded only if there was recent participation in a clinical trial. Patients were enrolled from July 23, 2014, to March 24, 2017. Statistical analysis was conducted from April 18 to June 29, 2018; revised analyses occurred between August 6 and 29, 2019.
Main Outcomes and Measures
Heart failure etiologic factors and precipitants, treatments, and in-hospital outcomes among global regions.
Results
A total of 18 553 patients were enrolled at 358 sites in 44 countries. The median age was 67.0 years (interquartile range [IQR], 57-77), 11 372 were men (61.3%), 9656 were white (52.0%), 5738 were Asian (30.9%), and 867 were black (4.7%). A history of HF was present in more than 50% of the patients and 40% were known to have a prior left-ventricular ejection fraction lower than 40%. Ischemia was a common AHF precipitant in SEA (596 of 2329 [25.6%]), WP (572 of 3354 [17.1%]), and EMA (364 of 2241 [16.2%]), whereas nonadherence to diet and medications was most common in NA (306 of 1592 [19.2%]). Median time to the first intravenous therapy was 3.0 (IQR, 1.4-5.6) hours in NA; no other region had a median time above 1.2 hours (P < .001). This treatment delay remained after adjusting for severity of illness (P < .001). Intravenous loop diuretics were the most common medication administered in the first 6 hours of AHF management across all regions (65.4%-89.9%). Despite similar initial blood pressure across all regions, inotropic agents were used approximately 3 times more often in SEA, WP, and EE (11.3%-13.5%) compared with NA and WE (3.1%-4.3%) (P < .001). Older age (odds ratio [OR], 1.0; 95% CI, 1.00-1.02), HF etiology (ischemia: OR, 1.65; 95% CI, 1.11-2.44; valvular: OR, 2.10; 95% CI, 1.36-3.25), creatinine level greater than 2.75 mg/dL (OR, 1.85; 95% CI, 0.71-2.40), and chest radiograph signs of congestion (OR, 2.03; 95% CI, 1.39-2.97) were all associated with increased in-hospital mortality. Similarly, younger age (OR, −0.04; 95% CI, −0.05 to −0.02), HF etiology (ischemia: OR, 0.77; 95% CI, 0.26-1.29; valvular: OR, 2.01; 95% CI, 1.38-2.65), creatinine level greater than 2.75 mg/dL (OR, 1.16; 95% CI, 0.31-2.00), and chest radiograph signs of congestion (OR, 1.02; 95% CI, 0.57-1.47) were all associated with increased in-hospital LOS.
Conclusions and Relevance
Data from REPORT-HF suggest that patients are similar across regions in many respects, but important differences in timing and type of treatment exist, identifying region-specific gaps in medical management that may be associated with patient outcomes.
Importance
Short-term infusions of single vasodilators, usually given in a fixed dose, have not improved outcomes in patients with acute heart failure (AHF).
Objective
To evaluate the effect of a strategy that emphasized early intensive and sustained vasodilation using individualized up-titrated doses of established vasodilators in patients with AHF.
Design, Setting, and Participants
Randomized, open-label blinded-end-point trial enrolling 788 patients hospitalized for AHF with dyspnea, increased plasma concentrations of natriuretic peptides, systolic blood pressure of at least 100 mm Hg, and plan for treatment in a general ward in 10 tertiary and secondary hospitals in Switzerland, Bulgaria, Germany, Brazil, and Spain. Enrollment began in December 2007 and follow-up was completed in February 2019.
Interventions
Patients were randomized 1:1 to a strategy of early intensive and sustained vasodilation throughout the hospitalization (n = 386) or usual care (n = 402). Early intensive and sustained vasodilation was a comprehensive pragmatic approach of maximal and sustained vasodilation combining individualized doses of sublingual and transdermal nitrates, low-dose oral hydralazine for 48 hours, and rapid up-titration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril-valsartan.
Main Outcomes and Measures
The primary end point was a composite of all-cause mortality or rehospitalization for AHF at 180 days.
Results
Among 788 patients randomized, 781 (99.1%; median age, 78 years; 36.9% women) completed the trial and were eligible for primary end point analysis. Follow-up at 180 days was completed for 779 patients (99.7%). The primary end point, a composite of all-cause mortality or rehospitalization for AHF at 180 days, occurred in 117 patients (30.6%) in the intervention group (including 55 deaths [14.4%]) and in 111 patients (27.8%) in the usual care group (including 61 deaths [15.3%]) (absolute difference for the primary end point, 2.8% [95% CI, −3.7% to 9.3%]; adjusted hazard ratio, 1.07 [95% CI, 0.83-1.39]; P = .59). The most common clinically significant adverse events with early intensive and sustained vasodilation vs usual care were hypokalemia (23% vs 25%), worsening renal function (21% vs 20%), headache (26% vs 10%), dizziness (15% vs 10%), and hypotension (8% vs 2%).
Conclusions and Relevance
Among patients with AHF, a strategy of early intensive and sustained vasodilation, compared with usual care, did not significantly improve a composite outcome of all-cause mortality and AHF rehospitalization at 180 days.
Trial Registration
ClinicalTrials.gov Identifier: NCT00512759
Hospitalisation for acute heart failure remains a major public health problem with high prevalence, morbidity, mortality, and cost. Prior attempts to develop new therapies for this condition have not been successful. Nitroxyl (HNO) plays a unique role in cardiovascular physiology by direct post‐translational modification of thiol residues on target proteins, specifically SERCA2a, phospholamban, the ryanodine receptor and myofilament proteins in cardiomyocytes. In animal models, these biological effects lead to vasodilatation, increased inotropy and lusitropy, but without tachyphylaxis, pro‐arrhythmia or evidence of increased myocardial oxygen demand. BMS‐986231 is an HNO donor being developed as a therapy for heart failure, and initial studies in patients with heart failure support the potential clinical value of these physiological effects. In this manuscript, we describe the ongoing phase II development programme for BMS‐986231, which consists of three related randomised placebo‐controlled clinical trials, StandUP‐AHF, StandUP‐Imaging and StandUP‐Kidney, which are designed to provide evidence of tolerability and efficacy as well as confirm the anticipated physiological effects in patients with heart failure with reduced ejection fraction. These studies will set the stage for the further study of BMS‐986231 in future phase III clinical trials.
Some departures from the individual randomization protocol affecting a small subset of participants in the PREvención con DIeta MEDiterránea (PREDIMED) trial (at most 14%) have recently been reported in the re-publication of the main PREDIMED paper. For this reason, the authors wish to make the following clarifications and corrections to their original PREDIMED sub-study examining the effect of the Mediterranean diets (MedDiets), supplemented with extra-virgin olive oil (EVOO) or nuts, on the risk of heart failure. In the original sub-study, as reported in detail elsewhere,¹ some participants (n = 425, or 5.7% of the total sample) were directly allocated, since they were recruited, to the same arm of the trial as their relatives because a previous member of the same household (usually the spouse) was already randomized in the trial. Also, centre D, one of the 11 recruiting centres (n = 646, or 8.7% of the total sample), had allocated a subset of its participants by clusters (clinics), instead of using individual randomization (35 participants from centre D were also second household members). The authors have re-analysed the effect of the intervention on the incidence of heart failure after adjusting for propensity scores (built with 30 predictors of allocation to each intervention group) and using a robust estimate of the variance to correct for intra-cluster correlation, considering the members of the same household and the participants in the same clinics of centre D as clusters. The corrected Table and Figure (see below; all corrections are marked in bold characters) show the corrected estimates for the outcome, as compared with those reported in the original paper. In consistency with the published paper, the unadjusted hazard ratios (HR) did not indicate significant associations for the MedDiet + EVOO [HR 0.63; 95% confidence interval (CI) 0.38–1.04] and MedDiet + nuts (HR 0.91; 95% CI 0.55–1.50), compared with the control group. Results from the multivariate analyses (Table) also remained unchanged. 2 Incidence of heart failure during the trial period with active intervention (2003–2010) by intervention group (Table presented.) CI, confidence interval; EVOO, extra-virgin olive oil.*Models were stratified according to centre and history of diabetes and used robust variance estimators.†Models were stratified according to centre and history of diabetes.‡Models were stratified according to centre, sex and education (four categories).aModels used robust estimate of the variance adjusted for intra-cluster correlation, considering the members of the same household and the participants in the same clinics of centre D as clusters.bAdjusted for age, sex, education (four categories), smoking (three categories), waist-to-height ratio (continuous), physical activity (METS-min/d), dyspnea symptoms at baseline (three categories) and non-AF arrhythmias at baseline.cAdjusted for age, smoking (three categories), waist-to-height ratio (continuous), physical activity (METS-min/day), dyspnoea symptoms at baseline (three categories), non-atrial fibrillation arrhythmias at baseline and history of diabetes. Models used robust estimates of the variance adjusted for propensity scores and intra-cluster correlation, considering the members of the same household and the participants in the same clinics of centre D as clusters.dAdjusted for (b), history of hypertension, history of dyslipidaemia, family history of premature coronary heart disease and baseline prevalence of atrial fibrillation.eAdjusted for (c) and history of hypertension, history of dyslipidaemia, family history of premature coronary heart disease and baseline prevalence of atrial fibrillation. Models used robust estimates of the variance adjusted for propensity scores and intra-cluster correlation, considering the members of the same household and the participants in the same clinics of centre D as clusters.fAdjusted for (d) and baseline energy intake (kcal/day).gAdjusted for (e) and baseline energy intake (kcal/day). Models used robust estimates of the variance adjusted for propensity scores and intra-cluster correlation, considering the members of the same household and the participants in the same clinics of centre D as clusters. (Figure presented.) Kaplan–Meier estimates of the incidence of heart failure in the total study population (trial intervention period, 2003–2010). Hazard ratios were stratified by centre and history of diabetes (Cox model with robust estimates for the variance, adjusted for propensity scores and intra-cluster correlation, considering the members of the same household and the participants in the same clinics of centre D as clusters). CI, confidence interval; EVOO; extra-virgin olive oil; MedDiet, Mediterranean diet. As a sensitivity analysis, we also re-analysed the data after excluding participants from centre D and those who were members of the same household (Table). The new multivariate adjusted HRs for heart failure were 0.66 (95% CI 0.35–1.25) and 1.18 (95% CI 0.68–2.04) for the MedDiet + EVOO and the MedDiet + nuts groups, respectively, compared with the control group. Importantly, the key message from the original article does not change and the final conclusions remain the same. © 2019 The Authors. European Journal of Heart Failure
This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.
Background
Acute heart failure (AHF) is a heterogeneous disorder with most of the patients presenting with breathlessness along with varying degrees of peripheral edema. The presence of peripheral edema suggests that volume overload is the cause of decompensation leading to AHF, while breathlessness in the absence of edema may reflect a “vascular phenotype”. This analysis investigated the characteristics, therapeutic response and outcome of patients with AHF, with and without overt peripheral edema in the RELAX-AHF trial.
Methods
Physician-assessed edema scores at baseline were used to categorize the population into those with no /mild edema (score 0 or 1+) and moderate/severe edema (score 2+ or 3+). The effect of serelaxin versus placebo was assessed within each subgroup.
Results
Patients with moderate/severe edema (n = 583; 50.5%) were more likely to have severe dyspnea, orthopnea (>30 degrees), rales (≥1/3) and elevated jugular venous pressure (>6 cm) than the patients with little or no peripheral edema (n=571; 49.5%) The relative benefits of serelaxin in terms of reduction in breathlessness, lower diuretic requirements, decreased length of initial hospital stay and days in ICU/CCU, and improved prognosis (180-day cardiovascular and all-cause mortality) were generally similar for patients with or without peripheral edema. However, as patients with moderate/severe peripheral edema had worse outcomes, the absolute benefit was generally greater than in patients with no/mild edema.
Conclusions
Overall, patients with AHF and moderate/severe peripheral edema have a worse prognosis but appear to receive similar relative benefit and perhaps greater absolute benefit from serelaxin administration.
Background:
The ROSE AHF trial (Renal Optimization Strategies Evaluation in Acute Heart Failure) found that when compared with placebo, neither low-dose dopamine (2 µg/kg per minute) nor low-dose nesiritide (0.005 μg/kg per minute without bolus) enhanced decongestion or preserved renal function in AHF patients with renal dysfunction. However, there may be differential responses to vasoactive agents in AHF patients with reduced versus preserved ejection fraction (EF). This post hoc analysis examined potential interaction between treatment effect and EF (EF ≤40% versus >40%) on the ROSE AHF end points.
Methods and results:
ROSE AHF enrolled AHF patients (n=360; any EF) with renal dysfunction. The coprimary end points were cumulative urine volume and the change in serum cystatin-C in 72 hours. The effect of dopamine (interaction P=0.001) and nesiritide (interaction P=0.039) on urine volume varied by EF group. In heart failure with reduced EF, urine volume was higher with active treatment versus placebo, whereas in heart failure with preserved EF, urine volume was lower with active treatment. The effect of dopamine and nesiritide on weight change, sodium excretion, and incidence of AHF treatment failure also varied by EF group (interaction P<0.05 for all). There was no interaction between vasoactive treatment's effect and EF on change in cystatin-C. Compared with placebo, dopamine was associated with improved clinical outcomes in heart failure with reduced EF and worse clinical outcomes in heart failure with preserved EF. With nesiritide, there were no differences in clinical outcomes when compared with placebo in both heart failure with reduced EF and heart failure with preserved EF.
Conclusions:
In this post hoc analysis of ROSE AHF, the response to vasoactive therapies differed in patients with heart failure with reduced EF and heart failure with preserved EF. Investigations of AHF therapies should assess the potential for differential responses in AHF with preserved versus reduced EF.
Clinical trial registration:
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01132846.
Diuretic unresponsiveness often occurs during hospital admission for acute heart failure (AHF) and is associated with adverse outcome. This study aims to investigate determinants, clinical outcome, and the effects of nesiritide on diuretic response early after admission for AHF.
Diuretic response, defined as weight loss per 40 mg of furosemide or equivalent, was examined from hospital admission to 48 hours in 4,379 patients from the ASCEND-HF trial. As an additional analysis, a urinary diuretic response metric was investigated in 5,268 patients using urine volume from hospital admission to 24 hours per 40 mg of furosemide or equivalent.
Mean diuretic response was -0.42 kg/40 mg of furosemide (interquartile range -1.0, -0.05). Poor responders had lower blood pressure, more frequent diabetes, long-term use of loop diuretics, poorer baseline renal function, and lower urine output (all P < .01). Randomized nesiritide treatment was not associated with diuretic response (P = .987). Good diuretic response was independently associated with a significantly decreased risk of 30-day all-cause mortality or heart failure rehospitalization (odds ratio 0.44, 95% CI 0.29-0.65, highest vs lowest quintile, P < .001). Diuretic response based on urine output per 40 mg of furosemide showed similar results in terms of clinical predictors, association with outcome, and the absence of an effect of nesiritide.
Poor diuretic response early after hospital admission for AHF is associated with low blood pressure, renal impairment, low urine output, and an increased risk of death or rehospitalization early after discharge. Nesiritide had a neutral effect on diuretic response.
Copyright © 2015 Elsevier Inc. All rights reserved.
Pulmonary hypertension (PH) is associated with poor outcome in patients with chronic heart failure (CHF) and may be a therapeutic target. Our aims were to develop a non-invasive model for studying pulmonary vaso-reactivity in CHF and characterize sildenafil's acute cardiovascular effects.
In a cross-over study, 18 CHF patients participated 4 times [sildenafil (2x20mg)/or placebo (double-blind) while breathing air/or 15% oxygen] at rest and during exercise. Oxygen saturation (SaO2) and systemic vascular resistance (SVR) were recorded. Left and right ventricular (RV) function and trans-tricuspid systolic pressure gradient (RVTG) were measured echocardiographically.At rest, hypoxia caused SaO2(p=0.001) to fall and RVTG to rise(+5±4mmHg;p=0.001). Sildenafil reduced SaO2(-1±2%;p=0.043), SVR(-87±156dyn.s.cm;p=0.034) and RVTG(-2±5mmHg;p=0.05). Exercise caused cardiac output(+2.1±1.8L/min;p<0.001) and RVTG(+19±11mmHg;p<0.0001) to rise. The reduction in RVTG with sildenafil was not attenuated by hypoxia. The rise in RVTG with exercise was not substantially reduced by sildenafil.
Sildenafil reduces SaO2 at rest whilst breathing air, this was not exacerbated by hypoxia, suggesting increased ventilation-perfusion mismatching due to pulmonary vasodilation in poorly ventilated lung regions. Sildenafil reduces RVTG at rest and prevents increases caused by hypoxia but not by exercise. This study shows the usefulness of this model to evaluate new therapeutics in PH.
Plasma volume (PV) expansion hallmarks worsening chronic heart failure (CHF) but no non-invasive means of quantifying volume status exists. Because weight and haematocrit are related to PV, they can be used to calculate relative PV status (PVS). We tested the validity and prognostic utility of calculated PVS in CHF patients.
First, we evaluated the agreement between calculated actual PV (aPV) and aPV levels measured using (125) Iodine-human serum albumin. Second, we derived PVS as: [(calculated aPV - ideal PV)/ideal PV] × 100%. Third, we assessed the prognostic implications of PVS in 5002 patients from the Valsartan in Heart Failure Trial (Val-HeFT), and validated this in another 246 routine CHF outpatients. On analysis, calculated and measured aPV values correlated significantly in 119 normal subjects and 30 CHF patients. In the Val-HeFT cohort, mean (+SD) PVS was -9 ± 8% and related to volume biomarkers such as brain natriuretic peptide (BNP). Over 2 years, 977 (20%) patients died. Plasma volume status was associated with death and first morbid events in a 'J-shaped' fashion with the highest risk seen with a PVS > -4%. Stratification into PVS quartiles confirmed that a PVS > -4% was associated with increased mortality (unadjusted hazard ratio 1.65, 95% confidence interval 1.44-1.88, χ(2) = 54, P < 0.001) even after adjusting for 22 variables, including brain natriuretic peptide. These results were mirrored in the validation cohort.
Relative PVS calculated from simple clinical indices reflects the degree to which patients have deviated from their ideal PV and independently relates to outcomes. The utility of PVS-driven CHF management needs further evaluation.
© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.
AimsMany assume that most patients hospitalized with heart failure (HF) are short of breath at rest (SOBAR). The National HF Audit for England and Wales suggests that this assumption is false, which has profound implications for managementMethods and resultsA retrospective case-note review was carried out of patients hospitalized with HF to determine how many present with shortness of breath at rest or are comfortable at rest but breathless on slight exertion (CARBOSE). Vital signs were tracked for 24 h and mortality for 180 days. Of 311 patients, those who were SOBAR (42%) had higher median heart rate (HR) (100 vs. 85 b.p.m.; P < 0.001), systolic blood pressure (SBP) (141 vs. 122 mmHg; P < 0.001), and respiratory rate (RR) (24 vs. 18 breaths/min; P < 0.001) compared with those who were CARBOSE (56%). Vital signs changed little in those who were CARBOSE over the first 4–6 h, but SBP (141–128 mmHg; P < 0.001), HR (100–90 b.p.m.; P = 0.002), and RR (24–20 breaths/min; P < 0.001) fell in those who were SOBAR. At presentation, SBP was >125 mmHg in 73% of patients who were SOBAR and in 46% who were CARBOSE, dropping to 52% and 37%, respectively, by 4–6 h. Mortality amongst those who were SOBAR and those who were CARBOSE was, respectively, 19% and 34% (odds ratio 2.29; P = 0.005, 95% confidence interval 1.29–4.06).Conclusion
Many patients admitted with HF are CARBOSE. Shortness of breath at rest may be more alarming, but those who are CARBOSE have a worse prognosis, perhaps reflecting more severe right heart dysfunction. Clinical trials of hospitalized HF may inappropriately exclude patients if they focus on shortness of breath at rest rather than peripheral congestion.
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.
Most patients with heart failure have mild or moderate renal dysfunction. This reflects the combined impact of chronic renal parenchymal disease, renal artery disease, renal congestion and hypoperfusion, neuroendocrine and cytokine activation and the effects of treatments for heart failure. Remarkably, with good treatment, the average annual rate of decline in renal function is similar in patients with chronic heart failure and healthy people of a similar age. Urea appears to be a stronger marker of an adverse prognosis than creatinine-based measures of renal function. Recent evidence suggests that minor, transient increases in creatinine in the setting of acute heart failure are not prognostically important but persistent deterioration does indicate a higher mortality. The poor prognosis of patients with worsening renal function ensures that few require renal dialysis but this may change as methods to prevent sudden death improve and new ways are found to control fluid congestion. Reversing renal dysfunction and stopping its progression remain important targets for treatment of heart failure.
Nitroxyl (HNO) displays distinct pharmacology to its redox congener nitric oxide (NO(•)) with therapeutic potential in the treatment of heart failure. It remains unknown if HNO donors are resistant to tolerance development following chronic in vivo administration. Wistar-Kyoto rats received a 3-day subcutaneous infusion of one of the NO(•) donors, glyceryl trinitrate (GTN) or diethylamine/NONOate (DEA/NO), or the HNO donor Angeli's salt (AS). GTN infusion (10 μg/kg/min) resulted in significantly blunted depressor responses to intravenous bolus doses of GTN, demonstrating tolerance development. By contrast, infusion with AS (20 μg/kg/min) or DEA/NO (2 μg/kg/min) did not alter their subsequent depressor responses. Similarly, ex vivo vasorelaxation responses in isolated aortae revealed that GTN infusion elicited a significant 6-fold decrease in the sensitivity to GTN and reduction in the maximum response to acetylcholine (ACh). Chronic infusion of AS or DEA/NO had no effect on subsequent vasorelaxation responses to themselves or to ACh. No functional cross-tolerance between nitrovasodilators was evident, either in vivo or ex vivo, although an impaired ability of a nitrovasodilator to increase tissue cGMP content was not necessarily indicative of a reduced functional response. In conclusion, HNO donors may represent novel therapies for cardiovascular disease with therapeutic potential over clinically used organic nitrates.
In patients with heart failure, few data describe the neurohormonal response to nesiritide and furosemide either alone or in combination. This study systematically compared the effects of nesiritide, furosemide, and their combination on natriuresis/diuresis and plasma aldosterone in patients with chronic stable heart failure who were relatively diuretic resistant.
Natriuretic, diuretic, and neurohormonal responses to furosemide and nesiritide will differ when these agents are administered alone vs. in combination.
Twenty-eight subjects completed a multicenter, open-label, three-arm crossover study. Each subject received the following treatments in random order on alternate days: (1) furosemide, 40 mg intravenous bolus; (2) nesiritide, 2 microg/kg intravenous bolus followed by a 0.01 microg/kg/min infusion for 6 hours; (3) both furosemide and nesiritide, with furosemide given at least 15 minutes after initiation of nesiritide.
Plasma aldosterone increased by 2.2 +/- 1.6 ng/dL after furosemide alone, decreased by 3.9 +/- 1.6 ng/dL after nesiritide alone (P = 0.005 vs furosemide alone and P = 0.56 vs furosemide plus nesiritide), and decreased by 2.8 +/- 1.6 ng/dL after furosemide plus nesiritide (P = 0.02 vs furosemide alone).
Furosemide alone produced natriuresis/diuresis and a prompt rise in plasma aldosterone values. Nesiritide alone produced no significant natriuresis/diuresis, but decreased plasma aldosterone values. When furosemide was administered on a background of nesiritide infusion, the observed natriuresis/diuresis was similar to that seen with furosemide alone, without the anticipated increase in plasma aldosterone observed with furosemide alone.
Vasodilator therapy may be associated with reflex counter-regulatory responses, and these responses may play a role in the development of tolerance to nitroglycerin (GTN).
Standing systolic blood pressure, body weight, urinary sodium, and hormonal responses to continuous (n = 10) and intermittent (n = 10) transdermal GTN administration were studied in normal volunteers. There was rapid attenuation of the hypotensive response to transdermal GTN therapy in the continuous but not in the intermittent therapy group. Significant weight gain and sodium retention occurred during continuous but not during intermittent GTN therapy. This was accompanied by a greater decrease in hematocrit in the continuous group, a finding that suggests that plasma volume expansion occurred during continuous GTN therapy. Continuous GTN therapy was associated with increases in plasma norepinephrine, atrial natriuretic peptide, arginine, vasopressin, and plasma renin activity. A different pattern of neurohormonal response was seen during intermittent therapy, with values tending to return to baseline levels after the nitrate-free interval.
Continuous transdermal GTN therapy leads to counter-regulatory responses associated with sodium retention and probable plasma volume expansion. By contrast, intermittent transdermal GTN therapy is associated with a different pattern of hormonal response, the lack of sodium retention and no evidence of plasma volume expansion. It is likely that these counter-regulatory responses play an important role in the attenuation of nitrate effects.
We examined the mechanisms involved in the cardiovascular and renal response to prolonged infusion of atrial natriuretic factor (ANF) in patients with chronic heart failure. ANF infusion was titrated to produce a 30% decrease in pulmonary capillary wedge pressure or a 20% increase in cardiac output, and this dose (average, 75 +/- 4 ng/kg/min) was then administered for 20 hours. The short-term response to ANF included significant reductions in central filling pressures, increases in cardiac output, modest increases in diuresis and glomerular filtration rates, significant reduction in plasma aldosterone levels, and a 3.6-fold increase in plasma cyclic GMP levels. During prolonged infusion, plasma cGMP levels and cardiac output gradually returned to baseline. Similarly, the initially increased diuretic effects were completely abolished during prolonged ANF infusion, although plasma alpha-hANF levels remained consistently elevated above baseline values (control, 198 +/- 38; titration, 2,760 +/- 596; 20 hours, 3,499 +/- 659 pg/ml). Four hours after beginning the ANF infusion, marked increases in hematocrit levels were noted (42.5 +/- 1.0% versus 45.3 +/- 1.4%, control and infusion, respectively, p less than 0.05); during this time, no change in total plasma protein concentration occurred, indicating extravascular shift of fluid and plasma proteins. No evidence was noted for activation of vasoconstrictor hormones during prolonged ANF infusion, although mean arterial pressure was significantly reduced throughout the infusion period. Plasma pro-ANF (31-67) levels, determined as a marker for endogenous ANF secretion, were significantly suppressed as were the reductions of central filling pressures. After ANF discontinuation, heart rate and pulmonary capillary wedge pressure increased significantly above baseline values without evidence for sympathetic stimulation. We conclude that 1) prolonged infusion of ANF causes only transient increases in plasma cGMP levels but a sustained reduction of the cardiac release of ANF and that 2) the beneficial hemodynamic effects of ANF, that is, unloading of the ventricles, may be associated with or, in part, may be secondary to a shift of plasma constituents into the extravascular space. The latter may limit the therapeutic potential of ANF for long-term treatment.
To better understand the mechanism of nitrate tolerance in patients with congestive heart failure, 13 patients received a 24 h infusion of nitroglycerin (1.5 micrograms/kg body weight per min) with or without N-acetylcysteine (225 mg/kg per 24 h). The infusions were separated by a 24 h nitrate-free interval. By the end of the nitroglycerin infusion, mean arterial pressure had returned to baseline values and there was a significant increase in ventricular filling pressures and systemic vascular resistance compared with values after 1 h of treatment. The simultaneous infusion of N-acetylcysteine had no effect on these changes. Although a strict fluid restriction of 1.5 liters/day was maintained for 1 week before and throughout the study, after 24 h of nitroglycerin infusion there was a significant and similar degree of hemodilution whether nitroglycerin was infused alone (9.1 +/- 4.3%) or with N-acetylcysteine (8.7 +/- 4.1%). This hemodilution corresponded to an increase in intravascular volume of 745 +/- 382 ml, most of which occurred during the 1st h. Plasma renin activity increased and plasma atrial natriuretic peptide decreased during the infusion. The results of this study suggest that nitrate tolerance is multifactorial. In addition to the previously described pharmacologic tolerance to the effect of nitroglycerin on vascular smooth muscle, a capillary fluid shift from the extravascular to intravascular space appears to be involved, especially during the 1st h of the infusion. A third mechanism, reflex neurohumoral activation, also seems to contribute to the genesis of nitroglycerin tolerance.
The immediate haemodynamic effects of intravenous frusemide (1 mg/kg) and intravenous isosorbide dinitrate (50-200 micrograms/kg/h) were compared in a prospective, randomised, between-group study in 28 men with radiographic and haemodynamic evidence of left ventricular failure following acute myocardial infarction. The diuresis induced by frusemide reduced the left heart filling pressure and cardiac output and transiently raised systemic blood-pressure. In contrast, isosorbide dinitrate was accompanied by a reduction in systemic blood-pressure and peripheral resistance with the result that the cardiac output was not decreased despite a large fall in the pulmonary vascular and left heart filling pressures. These results indicate that reduction of excessive preload by venodilatation may be haemodynamically superior to that induced by diuresis in terms of both reducing myocardial oxygen consumption and maintaining peripheral perfusion. The influence of these contrasting treatments on the prognosis of these high-risk patients warrants further study.
The hemodynamic response to minoxidil, an orally active, potent vasodilator, was evaluated in 11 patients with severe chronic congestive heart failure (CHF). The hemodynamic response was determined following single doses of 10, 15, 20, 25, and 30 mg of minoxidil. The hemodynamic response was characterized by marked increases in cardiac index (+63%) and stroke volume index (+52%) and by decrease in systemic vascular resistance (-38%). There was also a slight decrease in pulmonary capillary wedge pressure from an average of 24 +/- 8 to 21 +/- 7 mm Hg. Although the average mean arterial pressure remained unchanged, one patient developed significant hypotension. Chronic minoxidil therapy (eight patients) was associated with fluid retention and weight gain. In four patients in whom fluid retention could be minimized with larger doses of diuretics, a sustained clinical and hemodynamic improvement was observed. These findings suggest that minoxidil has the potential to improve cardiac function and may be useful in chronic vasodilator therapy of CHF, provided fluid retention can be controlled.
Contrary to expectation, most studies have demonstrated that initiation of an angiotensin-converting enzyme (ACE) inhibitor in conventional doses in patients with heart failure reduces the diuretic efficacy of furosemide. Recently, it has been suggested that single low doses (1 mg) but not high doses (25 mg) of captopril enhance furosemide-induced diuresis. It is not known whether the interaction between diuretics and ACE inhibitors are altered during long-term dosing.
Eight patients with heart failure treated with diuretics and ACE inhibitors for at least 3 months were studied. All patients were established on captopril 12.5 mg three times daily for 2 weeks before the study. Sodium intake was fixed before the study, and usual medication was withheld on study days. Intravenous furosemide was given on each of 2 study days to maintain a moderate, constant diuresis. Renal plasma flow and glomerular filtration rate (GFR) were determined using clearance techniques, and urine was collected hourly over 4 hours. Captopril 12.5 mg or placebo was given in a randomized, single-blind fashion at the end of the first hour. Compared with placebo, captopril reduced plasma concentrations of angiotensin II (23 +/- 18 versus 4 +/- 3 pg/ml 1 hour after dosing, P < .02) and systolic (131 +/- 31 versus 122 +/- 29 mm Hg, P < .01) and diastolic (74 +/- 15 versus 67 +/- 13 mm Hg, P < .05) blood pressures. GFR fell (55 +/- 24 versus 51 +/- 22 mL/min, P < .02) and effective renal plasma flow rose during the first (198 +/- 76 versus 231 +/- 49 mL/min) and second hours after dosing (185 +/- 69 versus 247 +/- 74 mL/min, P < .02). Similarly, urine volumes, in response to furosemide, increased after captopril (238 +/- 90 versus 283 +/- 111 mL, P < .05, and 245 +/- 78 versus 311 +/- 92 mL, P < .01, 1 and 2 hours after dosing). Urinary electrolyte concentrations fell, but total urinary sodium (22 +/- 7 versus 28 +/- 12 mmol/hr, P < .01) and chloride (20 +/- 6 versus 25 +/- 11 mmol/hr, P < .05) excretion increased in the 2 hours after dosing, as did fractional excretion of sodium (urinary sodium/urinary creatinine) (61 +/- 27 versus 75 +/- 36 mmol/mumol, P < .01).
Intense although transient ACE inhibition with captopril enhances the diuretic effects of furosemide during long-term ACE inhibition.
Organic nitrates exert their effect by direct inhibition of vascular tone, resulting in decreased myocardial oxygen demand and improved oxygen supply. Less well known is the effect of nitrates on blood rheology. To evaluate the haemodiluting effect of intravenous nitroglycerin we studied 70 consecutive patients admitted to our coronary care unit. The study group consisted of 51 patients with acute chest pain who were treated with nitroglycerin intravenously in a dose between 1 and 5 mg. h⁻¹ during the first 24 h of admission; 19 patients without this treatment were used as controls. In the study group, values of haemoglobin, haematocrit, serum protein and serum albumin, as indirect parameters of haemodilution, all decreased significantly within 24 h, irrespective of the final diagnosis. Similar values were found in the control group. The mean decrease in the haemoglobin value was 0·92 (SD =0·55) mmol. 1⁻¹ vs controls −0·05 (SD=0.48) mmol. 1⁻¹, P<0·05; the mean decrease in haematocrit was 0·047 (SD=0·032) vs controls 0·000 (SD=0·023), P<0·05. Similar decreases were found in serum protein and albumin values.
It is concluded that intravenous nitroglycerin causes a significant decrease in haemoglobin and haematocrit values within 24 h of administration. This altered haemorrheologic state may, besides the well known direct vascular effects of nitroglycerin, contribute to the protective effect of nitroglycerin in acute myocardial ischaemia. The effects of nitroglycerin, and the possible mechanisms underlying the decrease in haemoglobin and haematocrit values, will be discussed.
Nitrates and furosemide, commonly administered in the treatment of pulmonary oedema, have not been compared in a prospective clinical trial. We compared the efficacy and safety of these drugs in a randomised trial of patients with severe pulmonary oedema and oxygen saturation below 90%.
Patients presenting to mobile emergency units with signs of congestive heart failure were treated with oxygen 10 L/min, intravenous furosemide 40 mg, and morphine 3 mg bolus. 110 patients were randomly assigned either to group A, who received isosorbide dinitrate (3 mg bolus administered intravenously every 5 min; n=56) or to group B, who received furosemide (80 mg bolus administered intravenously every 15 min, as well as isosorbide dinitrate 1 mg/h, increased every 10 min by 1 mg/h; n=54). Six patients were withdrawn on the basis of chest radiography results. Treatment was continued until oxygen saturation was above 96% or mean arterial blood pressure had decreased by 30% or to below 90 mm Hg. The main endpoints were death, need for mechanical ventilation, and myocardial infarction. The analyses were by intention to treat.
Mechanical ventilation was required in seven (13%) of 52 group-A patients and 21 (40%) of 52 group-B patients (p=0.0041). Myocardial infarction occurred in nine (17%) and 19 (37%) patients, respectively (p=0.047). One patient in group A and three in group B died (p=0.61). One or more of these endpoints occurred in 13 (25%) and 24 (46%) patients, respectively (p=0.041).
High-dose isosorbide dinitrate, given as repeated intravenous boluses after low-dose intravenous furosemide, is safe and effective in controlling severe pulmonary oedema. This treatment regimen is more effective than high-dose furosemide with low-dose isosorbide nitrate in terms of need for mechanical ventilation and frequency of myocardial infarction.
Cardiac output (CO) is measured but sparingly due to limitations in its measurement technique (ie, right-heart catheterization). Yet, in recent years it has been suggested that CO may be of value in the diagnosis, risk stratification, and treatment titration of cardiac patients, especially those with congestive heart failure (CHF). We examine the use of a new noninvasive, continuous whole-body bioimpedance system (NICaS; NI Medical; Hod-Hasharon, Israel) for measuring CO. The aim of the present study was to test the validity of this noninvasive cardiac output system/monitor (NICO) in a cohort of cardiac patients.
Prospective, double-blind comparison of the NICO and thermodilution CO determinations.
We enrolled 122 patients in three different groups: during cardiac catheterization (n = 40); before, during, and after coronary bypass surgery (n = 51); and while being treated for acute congestive heart failure (CHF) exacerbation (n = 31). MEASUREMENTS AND INTERVENTION: In all patients, CO measurements were obtained by two independent blinded operators. CO was measured by both techniques three times, and an average was determined for each time point. CO was measured at one time point in patients undergoing coronary catheterization; before, during, and after bypass surgery in patients undergoing coronary bypass surgery; and before and during vasodilator treatment in patients treated for acute heart failure.
Overall, 418 paired CO measurements were obtained. The overall correlation between the NICO cardiac index (CI) and the thermodilution CI was r = 0.886, with a small bias (0.0009 +/- 0.684 L) [mean +/- 2 SD], and this finding was consistent within each group of patients. Thermodilution readings were 15% higher than NICO when CI was < 1.5 L/min/m(2), and 5% lower than NICO when CI was > 3 L/min/m(2). The NICO has also accurately detected CI changes during coronary bypass operation and vasodilator administration for acute CHF.
The results of the present study indicate that whole-body bioimpedance CO measurements obtained by the NICO are accurate in rapid, noninvasive measurement and the follow-up of CO in a wide range of cardiac clinical situations.
Strategies to preserve renal function and enhance diuretic responsiveness during therapy for heart failure (HF) are needed. We hypothesized that brain natriuretic peptide (nesiritide) added to standard HF therapy would preserve renal function and enhance diuretic responsiveness.
Patients with HF with underlying renal dysfunction who were admitted with volume overload were randomized to standard therapy with nesiritide (2 mug/kg bolus; 0.01 mug/kg/min for 48 hours) or without nesiritide. Patients requiring intravenous vasodilator or inotropic therapy for rapid symptom relief were ineligible. In all patients, diuretics were administered according to a standardized dosing algorithm.
Patients (n = 72) had a mean creatinine level of 1.75 +/- 0.59 mg/dL. Patients receiving nesiritide had a lesser increase in creatinine (P = .048) and blood urea nitrogen (P = .02), but a greater reduction in blood pressure (P < .01). Nesiritide did not enhance diuretic responsiveness (P = .57) but increased 3'5' cyclic guanosine monophosphate and decreased endothelin more (P < .05 for both). There were no differences in the change in atrial natriuretic peptide, N-terminal pro-brain natriuretic peptide, plasma renin activity, angiotensin II, and aldosterone between groups.
When used as adjuvant "renal protective" therapy in patients with HF with renal dysfunction, the recommended dose of nesiritide reduced blood pressure, did not seem to worsen renal function, and suppressed endothelin but did not enhance diuretic responsiveness or prevent activation of the renin-angiotensin-aldosterone system.