Effects of Tezosentan on Symptoms and Clinical Outcomes in Patients With Acute Heart Failure

McMurray, John J.V.; Teerlink, John R.; Cotter, Gad; Bourge, Robert C.; Cleland, John G.F.; Jondeau, Guillaume; Krum, Henry; Metra, Marco; O’Connor, Christopher M.; Parker, John D.; Torre‐Amione, Guillermo; Veldhuisen, Dirk J. van; Lewsey, Jim; Frey, Aline; Rainisio, Maurizio; Kobrin, Isaac

doi:10.1001/jama.298.17.2009

Cited by 335 publications

(235 citation statements)

References 36 publications

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“…This is consistent with previous trials testing drugs acting on peripheral vessels and/or renal function in patients with AHF 29, 30. The prognosis of the patients with AHF was not found to be related to left ventricular ejection fraction31 and a similar benefit of serelaxin on clinical outcomes was observed in both patients with preserved and reduced ejection fraction 32.…”

Section: Discussionsupporting

confidence: 90%

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Teerlink

Voors

Ponikowski

et al. 2017

European J of Heart Fail

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Patients admitted for acute heart failure (AHF) experience high rates of in‐hospital and post‐discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin‐2, a hormone with vasodilatory and end‐organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX‐AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all‐cause and cardiovascular mortality by 37% through day 180. RELAX‐AHF‐2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX‐AHF‐2 is a multicentre, randomized, double‐blind, placebo‐controlled, event‐driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild‐to‐moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all‐cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in‐hospital length of stay during index AHF. The results from RELAX‐AHF‐2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.

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Section: Discussionsupporting

confidence: 90%

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Teerlink

Voors

Ponikowski

et al. 2017

European J of Heart Fail

Self Cite

105

103

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“…WHF by Day 7 during the index admission occurred in 26% of patients and, after adjustment for baseline characteristics, was associated with a mean increase in length of hospital stay (LOS) of 4.33 days ( P < 0.0001) and a hazard ratio (HR) for 30‐day HF readmission or death of 2.43 ( P < 0.0001; Figure 1A , 12). Any WHF within 7 days (during the index hospitalization or a re‐hospitalization) was associated with an HR for 90‐day mortality of 2.57 ( P < 0.0001) 12, 13. However, in‐hospital WHF was only modestly influenced by patients' baseline characteristics (such as severity of HF and end‐organ impairment) during the first day of admission, underlining the difficulty physicians encounter in early identification of patients at risk of poor outcomes.…”

Section: What Is the Clinical Relevance Of In‐hospital Worsening Hearmentioning

confidence: 98%

In‐hospital worsening heart failure: a clinically relevant endpoint?

et al. 2017

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Outcome measures used for the clinical evaluation of patients with acute heart failure differ between studies and may neither adequately address the characteristic presenting symptoms and signs nor reflect the pathophysiological processes involved. In‐hospital worsening of heart failure (WHF) is associated with poor outcomes and thus a potential endpoint conveying clinically meaningful prognostic information.Current definitions of WHF are based on the combination of worsening symptoms and signs and the intensification of treatment during admission. Definitions vary across studies and do not fully account for baseline therapy or circumstances in which there is failure to respond to treatment. Further, there are limited data to inform healthcare professionals as to which patients are most at risk of developing in‐hospital WHF.In this opinion piece, we review the definitions for WHF used in recent and ongoing clinical trials and propose a novel definition, which captures failure to respond to treatment as well as clinical worsening (deterioration of symptoms and signs) of the patient's condition. Such a definition, applied consistently across studies, would help clarify the characteristics of patients likely to develop in‐hospital WHF, allow comparative assessments of the effectiveness of interventions, and help guide appropriate patient management in order to improve outcomes.

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“…After title and abstract screening, 2,972 were excluded and 40 potentially relevant articles were retrieved for full text evaluation. In the end, 25 were excluded (Supplementary Table I) and 15 2,9,11,[14][15][16][17][18][20][21][22][23][24][25][26] RCTs that met the predetermined criteria were included in the present study. Major characteristics of the included RCTs are summarized in the Table. In general, the 15 studies, covering a total of 3,624 patients, were published between 1998 and 2013.…”

Section: Study Characteristicsmentioning

confidence: 99%

“…17,18) Hence, the effects of ERA for the management of HF remain to be clarified and there is lack of a complete overview. For this purpose, we performed a metaanalysis of RCTs to investigate the clinical and hemodynamic effects of ERA in patients with HF.…”

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confidence: 99%

Clinical and Hemodynamic Effects of Endothelin Receptor Antagonists in Patients With Heart Failure

et al. 2017

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SummaryThe clinical benefit of endothelin receptor antagonists (ERA) for the management of heart failure (HF) remains controversial. To examine this question, we performed a meta-analysis of randomized controlled trials (RCTs) to investigate the clinical and hemodynamic effects of ERA in HF patients.We searched the PubMed, Medline, Embase, and Cochrane Library from inception to March 20, 2016 to identify the pertinent studies. Risk ratio (RR) and weighted mean difference (WMD) were calculated using a fixed or random effect model.A total of 15 RCTs with 3,624 HF patients were included. Compared with control groups, ERA might not improve the mortality (RR 1.12, 95%CI 0.81 to 1.54, P = 0.51) or incidence of worsening HF or cardiovascular events (WHF/ CVE) (RR 1.06, 95%CI 0.94 to 1.19, P = 0.35) in HF patients. Subgroup analysis also suggested that neither nonselective nor selective ERAs had an impact on mortality and WHF/CVE. However, the hemodynamic variables of HF patients, including cardiac index (WMD 0.32, 95%CI 0.22 to 0.43, P < 0.01), pulmonary capillary wedge pressure (WMD -3.10, 95%CI -3.99 to -2.20, P < 0.01), mean pulmonary arterial pressure (WMD -4.42, 95%CI -5.50 to -3.33, P < 0.01), systemic vascular resistance (WMD -276.35, 95%CI -399.62 to -153.09, P < 0.01), and pulmonary vascular resistance (WMD -69.42, 95%CI -105.33 to -33.52, P < 0.01) were significantly improved by ERA.In conclusion, this meta-analysis suggests that ERA therapy could effectively improve cardiac output and pulmonary and systemic hemodynamics, but with less benefit to the clinical outcomes of HF patients. (Int Heart J 2017; 58: 400-408) Key words: Endothelin system, Systematic review H eart failure (HF) is a major public health problem, with a prevalence of more than 23 million worldwide. 1) Progression of HF is characterized by sustained deterioration in symptoms, cardiac function, and peripheral and pulmonary vascular resistance.2,3) Neurohormonal activation, an important factor of left ventricular (LV) remodeling, is likely to be a primary determinant for the progression. The roles of activation of the renin-angiotensin system (RAS) and sympathetic nervous system (SNS) in HF are well documented and inhibiting them with angiotensin-converting enzyme inhibitors (ACEI) and β blockers could effectively reverse the process of LV remodeling, relieve patient symptoms, and prolong life. [4][5][6] Furthermore, it has been demonstrated that local activation of the endothelin (ET) system might also be linked with HF progression. 7)ET-1 is thought to mediate potent vasoconstriction, proliferation of vascular smooth muscle, and myocardial hypertrophy through ET A receptors. 8) In contrast, activation of endothelial ET B receptors is primarily involved in vasodilation, antithrombotic, and antiproliferative effects. Moreover, ET-1 also has a potential to enhance the activity of RAS and SNS pathways and induce the production of other neurohormonal factors.9) Plasma levels of ET-1 and big ET-1 are elevated and can significantly predict mortalit...

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Effects of Tezosentan on Symptoms and Clinical Outcomes in Patients With Acute Heart Failure

Cited by 335 publications

References 36 publications

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

In‐hospital worsening heart failure: a clinically relevant endpoint?

Clinical and Hemodynamic Effects of Endothelin Receptor Antagonists in Patients With Heart Failure

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