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Advanced Therapeutic Options in Acute Heart Failure
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Tiffany Dong, Aditi Nayak, Alanna Morris
Novel vasodilators include serelaxin and ularitide. Serelaxin is a recombinant form of relaxin, which releases nitric oxide allowing for cardiovascular and renal adaptations during pregnancy. In the RELAX-AHF trial, which enrolled 1,161 patients with ADHF, the serelaxin arm attained the primary endpoint of relief of dyspnea by day five but not day one.12 A follow-up study with 6,800 patients with ADHF (RELAX-AHF-2), failed to show cardiovascular mortality benefit or improvement in heart failure by day 5.13 Ularitide is a synthetic form of urodilatin, which is spliced into atrial natriuretic peptide, thus promoting natriuresis by the distal tubules and the collecting duct.14 In the SIRIUS II trial, patients who were randomized to a 24-h infusion of ularitide had dose-dependent reductions in pulmonary capillary wedge pressure (PCWP) and in dyspnea score at six hours. Patients on higher doses also had lower systemic vascular resistance and increased cardiac index that persisted 24 hours after starting ularitide.15 Despite these promising results, ularitide failed to improve cardiovascular mortality and clinical outcomes after 48-hours in a study of 2,157 patients.16
Hypertensive Emergencies and Urgencies
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Maria Lorenza Muiesan, Anna Paini, Claudia Agabiti Rosei, Fabio Bertacchini, Massimo Salvetti
Clevidipine is a third-generation calcium antagonist inhibiting selectively extracellular calcium influx through the L-type channel, relaxing smooth muscle of small arteries and reducing peripheral vascular resistance. The advantages of clevidipine are the blood metabolism, the very short (1-minute) half-life and the rapid titration (42,47) with minimal effects on stroke volume, cardiac output or heart rate. In the PRONTO study (48) clevidipine reduced SBP and improved dyspnoea more effectively than standard treatment did, with a reduction in the need of additional IV antihypertensive drugs and in the total dose of furosemide. In AHF, several other promising drugs including ularitide, an analogue of urodilatin, and serelaxin, a recombinant version of human relaxin-2, are currently under investigation (18).
Heart failure with reduced ejection fraction in older adults
Published in Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich, Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
Although elevated levels of blood vasopressin are common in ADHF, the vasopressin antagonist tolvaptan did not reduce hospital stay or mortality in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial (179). Similarly, the synthetic natriuretic peptide nesiritide had no significant effect on mortality, 30-day rehospitalization, or renal dysfunction in 7141 patients (mean age 67 years) in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial (180). In the RELAXin in Acute Heart Failure (RELAXAHF) trial (mean age 72 years), therapy with serelaxin, recombinant human relaxin-2, improved dyspnea, was safe and well tolerated, and reduced 180-day mortality, but had no effect on hospital readmissions or CV death (181). This is the only large RCT to date that has shown clinical benefit of a novel pharmacotherapy in older patients with acute HF.
The subset of patients with acute heart failure able to secrete relaxin-2 at pregnancy concentrations could have a longer survival: a pilot study
Published in Biomarkers, 2018
Òscar Miró, Pablo Herrero-Puente, Belén Prieto, María García-García, Pablo García-Hernández, Francisco J. Martín-Sánchez, Javier Jacob, José Ríos, Rodolfo Romero, Víctor Gil, Étienne Gayat, Pere Llorens, Alexandre Mebazaa
A second finding of this study was that although only a small proportion of patients presented high relaxin-2 concentrations, the long-term outcome of these patients was better compared to the rest of patients, and the difference was statistically significant on adjustment for the differences between the two groups of patients. It is of note that after adjusting our model for six variables, many of which had shown to influence the prognosis of patients with AHF (Metra et al.2010; Mebazaa et al.2013; Farmakis 2015; Miró et al.2017; Aguirre Tejedo and Miró 2017; Nozaki et al.2017), the relationship between relaxin-2 hypersecretion and long-term prognosis was even more evident. A few previous studies have analysed the potential role of relaxin-2 as a prognostic marker (Fisher et al.2003a; Kupari et al.2005; Herrero Puente et al.2017), but none have demonstrated any direct relationship. Unfortunately, they did not investigate the subset of patients with the highest relaxin-2 concentrations, and thus, we cannot compare our results with those of others. In the study by Fisher et al. (2003a), the authors divided 87 patients with AHF according to the presence of relaxin-2 levels greater than or less than 89 pg/mL (the median value of that study) and they found no differences in survival at one year. However, this cut-off is far from the concentrations achieved by pregnant women (>500 pg/mL) and, in fact, only 1 of the 87 patients of this study achieved this cut-off value. Accordingly, it seems that very high levels of relaxin-2 are needed in order to find a significant relationship with the prognosis of patients with AHF. Moreover, it was remarkable that the better prognosis found in the patients of the PLG was achieved at long term. In this sense, short-term secondary endpoints did not differ between the two groups of patients, thereby indicating that the potential pathophysiological benefits of relaxin-2 in AHF patients occur by very slow, and chronic adaptive mechanisms. Therefore, if relaxin-2 is used in the future as a therapeutic drug, our results suggest that it should be administered in a continuous, maybe daily schedule. This was not the case in the RELAX-AHF trials, in which serelaxin (a recombinant form of human relaxin-2) was only given during 48 h (Teerlink et al.2013; Novartis Media Relations, 2017); otherwise, this daily administration is very difficult to obtain unless an oral formulation is available.
Proportional pulse pressure relates to cardiac index in stabilized acute heart failure patients
Published in Clinical and Experimental Hypertension, 2018
Colin J. Petrie, Piotr Ponikowski, Marco Metra, Veselin Mitrovic, Mikhail Ruda, Alberto Fernandez, Alexander Vishnevsky, Gad Cotter, Olga Milo, Ute Laessing, Yiming Zhang, Marion Dahlke, Robert Zymlinski, Adriaan A. Voors
We performed a post-hoc evaluation of the relationship between invasively measured CI and brachial PPP with data obtained in patients with decompensated AHF and elevated pulmonary capillary wedge pressure (PCWP). These patients had been part of a study to assess haemodynamic effects of serelaxin in AHF; details of which have been previously published (11). In brief, patients hospitalized for AHF were randomized within 48 h of presentation. Mean (SD) time from AHF to start of study drug infusion was 29.0 h (11.2). AHF was defined as new onset or worsening of signs and symptoms of heart failure, requiring urgent therapy. Intravenous furosemide was given with no planned change in diuretic dose/use of i.v. vasodilator from 4 h prior to study drug initiation till 8 h thereafter. Central haemodynamic monitoring had to be initiated at least 1 h before randomization, with a mean PCWP ≥18 mmHg. Key exclusion criteria were SBP <115 mmHg or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (calculated using the simplified Modification of Diet in Renal Disease equation); history of acute coronary syndrome; significant valvular disease, significant arrhythmia; acute myocarditis; or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy; or planned treatment with inotropic agents, vasopressors, or mechanical support. Haemodynamic measurements were carried out at baseline and at 0.5, 2, 4, 6, 8, 20, 21, 22, and 24 h after initiation of study drug infusion, which covered the 20 h infusion period and the 4 h post-infusion (washout) period. Complete demographic and haemodynamic data were available for 63 patients. Baseline PCWP was calculated as the mean of the last three measurements taken at least 15 min apart immediately prior to randomization, which were required to be stable (within 15% of each other). Cardiac output (CO) was determined by the thermodilution technique. Triplicate CO measurements were obtained (six taken for those in atrial fibrillation) at all time points, except at 0.5, 2, and 6 h at which only single measurements were taken. CO measurements had to be stable (within 15% or no > 0.5 L/min of each other) and were averaged. CI (l/min/m2) was calculated by dividing CO by body surface area (BSA). BSA was calculated as 0.007184 × weight 0.425 × length 0.725. Brachial systolic and diastolic BP and pulse rate were measured using the A-Pulse CASPro ® device (Health STATS International, Singapore) during haemodynamic measurements. Unless otherwise stated PP was calculated from the brachial artery (not centrally derived). N-terminal pro-brain natriuretic peptide (NT- pro-BNP) levels were analyzed (Roche Diagnostics GmbH Mannheim, Germany) at baseline and at 8, 20, and 44 h after study treatment initiation.