|
1
|
Das BB. Novel Therapies for Right Ventricular Failure. Curr Cardiol Rep 2025; 27:26. [PMID: 39825962 DOI: 10.1007/s11886-024-02157-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/22/2024] [Indexed: 01/20/2025]
Abstract
PURPOSE OF REVIEW Traditionally viewed as a passive player in circulation, the right ventricle (RV) has become a pivotal force in hemodynamics. RV failure (RVF) is a recognized complication of primary cardiac and pulmonary vascular disorders and is associated with a poor prognosis. Unlike treatments for left ventricular failure (LVF), strategies such as adrenoceptor signaling inhibition and renin-angiotensin system modulation have shown limited success in RVF. This review aims to reassure about the progress in RVF treatment by exploring the potential of contemporary therapies for heart failure, including angiotensin receptor and neprilysin inhibitors, sodium-glucose co-transporter 2 inhibitors, and soluble guanylate cyclase stimulators, which may be beneficial for treating RV failure, particularly when associated with left heart failure. Additionally, it examines novel therapies currently in the pipeline. RECENT FINDINGS Over the past decade, a new wave of RVF therapies has emerged, both pharmacological and device-centered. Novel pharmacological interventions targeting metabolism, calcium homeostasis, oxidative stress, extracellular matrix remodeling, endothelial function, and inflammation have shown significant promise in preclinical studies. There is also a burgeoning interest in the potential of epigenetic modifications as therapeutic targets for RVF. Undoubtedly, a deeper understanding of the mechanisms underlying RV failure, both with and without pulmonary hypertension, is urgently needed. This knowledge is not just a theoretical pursuit, but a crucial step that could lead to the development of pharmacological and cell-based therapeutic options that directly target the RV and pulmonary vasculature, aligning with the principles of precision medicine.
Collapse
Affiliation(s)
- Bibhuti B Das
- Pediatric Advanced Heart Failure and Heart Transplant Program, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS, USA.
| |
Collapse
|
|
2
|
Das BB. A Review of Contemporary and Future Pharmacotherapy for Chronic Heart Failure in Children. CHILDREN (BASEL, SWITZERLAND) 2024; 11:859. [PMID: 39062308 PMCID: PMC11276462 DOI: 10.3390/children11070859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/10/2024] [Accepted: 07/13/2024] [Indexed: 07/28/2024]
Abstract
This review delves into the most recent therapeutic approaches for pediatric chronic heart failure (HF) as proposed by the International Society for Heart and Lung Transplantation (ISHLT), which are not yet publicly available. The guideline proposes an exhaustive overview of the evolving pharmacological strategies that are transforming the management of HF in the pediatric population. The ISHLT guidelines recognize the scarcity of randomized clinical trials in children, leading to a predominance of consensus-based recommendations, designated as Level C evidence. This review article aims to shed light on the significant paradigm shifts in the proposed 2024 ISHLT guidelines for pediatric HF and their clinical ramifications for pediatric cardiology practitioners. Noteworthy advancements in the updated proposed guidelines include the endorsement of angiotensin receptor-neprilysin inhibitors (ARNIs), sodium-glucose cotransporter 2 inhibitors (SGLT2is), and soluble guanylate cyclase (sGC) stimulators for treating chronic HF with reduced ejection fraction (HFrEF) in children. These cutting-edge treatments show potential for enhancing outcomes in pediatric HFrEF. Nonetheless, the challenge persists in validating the efficacy of therapies proven in adult HFrEF for the pediatric cohort. Furthermore, the proposed ISHLT guidelines address the pharmacological management of chronic HF with preserved ejection fraction (HFpEF) in children, marking a significant step forward in pediatric HF care. This review also discusses the future HF drugs in the pipeline, their mechanism of actions, potential uses, and side effects.
Collapse
Affiliation(s)
- Bibhuti B Das
- Department of Pediatrics, Heart Center, Mississippi Children's Hospital, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
| |
Collapse
|
|
3
|
Gantzel RH, Møller EE, Aagaard NK, Watson H, Jepsen P, Grønbæk H. Randomized clinical trial on safety of the natriuretic peptide ularitide as treatment of refractory cirrhotic ascites. Hepatol Commun 2024; 8:e0481. [PMID: 38934679 PMCID: PMC11213594 DOI: 10.1097/hc9.0000000000000481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 05/16/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Sodium and water retention is a mainstay of the pathophysiology leading to ascites formation in patients with advanced cirrhosis. Refractory ascites denotes the most severe ascites status with limited treatment options and a poor prognosis. We investigated the efficacy and safety of the natriuretic peptide ularitide in patients with refractory cirrhotic ascites. METHODS We conducted a randomized placebo-controlled trial investigating ularitide to manage refractory ascites. Until trial termination after interim analyses, we randomized 17 participants in a 2:1 ratio between ularitide (n=11) and placebo (n=6). While hospitalized, the participants received treatment for up to 48 hours. The primary efficacy endpoint was a change in renal water excretion, and secondary end points included changes in renal sodium excretion rate and body weight. The starting dose was 30 ng/kg/min, though later reduced to 20 for safety reasons. RESULTS In contrast to the study hypothesis, the mean urine production decreased after 24 hours of ularitide treatment compared with the baseline level (22.8 vs. 47.5 mL/h, p=0.04) and decreased more in participants randomized to ularitide than placebo (24.7 vs. -6.2 mL/h, p=0.05). Ularitide did not increase the renal sodium excretion rate or reduce the weight gain. The incidence rate ratio of adverse reactions in ularitide versus placebo was 8.5 (95% CI: 2-35, p=0.003). Participants treated with ularitide developed serious blood pressure reductions, impacting their renal responsiveness. CONCLUSIONS Ularitide in doses of 20-30 ng/kg/min did not benefit urine production and renal sodium excretion rate in patients with refractory ascites. The participants randomized to ularitide overall developed more adverse reactions than placebo. EudraCT no. 2019-002268-28.
Collapse
Affiliation(s)
- Rasmus H. Gantzel
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Medicine, Regional Hospital Gødstrup, Herning, Denmark
| | - Emilie E. Møller
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Niels K. Aagaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Hugh Watson
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
- Medical Development and Translational Sciences, Evotec ID, Lyon, France
| | - Peter Jepsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| |
Collapse
|
|
4
|
Lukoschewitz JD, Miger KC, Olesen ASO, Caidi NOE, Jørgensen CK, Nielsen OW, Hassager C, Hove JD, Seven E, Møller JE, Jakobsen JC, Grand J. Vasodilators for Acute Heart Failure - A Systematic Review with Meta-Analysis. NEJM EVIDENCE 2024; 3:EVIDoa2300335. [PMID: 38804781 DOI: 10.1056/evidoa2300335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
BACKGROUND Acute heart failure is a public health concern. This study systematically reviewed randomized clinical trials (RCTs) to evaluate vasodilators in acute heart failure. METHODS The search was conducted across the databases of Medline, Embase, Latin American and the Caribbean Literature on Health Sciences, Web of Science, and the Cochrane Central Register of Controlled Trials. Inclusion criteria consisted of RCTs that compared vasodilators versus standard care, placebo, or cointerventions. The primary outcome was all-cause mortality; secondary outcomes were serious adverse events (SAEs), tracheal intubation, and length of hospital stay. Risk of bias was assessed in all trials. RESULTS The study included 46 RCTs that enrolled 28,374 patients with acute heart failure. Vasodilators did not reduce the risk of all-cause mortality (risk ratio, 0.95; 95% confidence interval [CI], 0.87 to 1.04; I2=9.51%; P=0.26). No evidence of a difference was seen in the risk of SAEs (risk ratio, 1.01; 95% CI, 0.97 to 1.05; I2=0.94%) or length of hospital stay (mean difference, -0.10; 95% CI, -0.28 to 0.08; I2=69.84%). Vasodilator use was associated with a lower risk of tracheal intubation (risk ratio, 0.54; 95% CI, 0.30 to 0.99; I2=51.96%) compared with no receipt of vasodilators. CONCLUSIONS In this systematic review with meta-analysis of patients with acute heart failure, vasodilators did not reduce all-cause mortality.
Collapse
Affiliation(s)
- Jasmin D Lukoschewitz
- Department of Cardiology, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen
| | - Kristina C Miger
- Department of Cardiology, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen
| | - Anne Sophie O Olesen
- Department of Cardiology, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen
| | - Nora O E Caidi
- Department of Cardiology, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen
| | - Caroline K Jørgensen
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen
- Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Olav W Nielsen
- Department of Cardiology, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen
| | - Christian Hassager
- Department of Cardiology, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen
- Department of Cardiology, The Heart Center, Copenhagen University Hospital Rigshospitalet, Copenhagen
| | - Jens D Hove
- Department of Cardiology, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen
| | - Ekim Seven
- Department of Cardiology, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen
| | - Jacob E Møller
- Department of Cardiology, The Heart Center, Copenhagen University Hospital Rigshospitalet, Copenhagen
- Department of Clinical Medicine, University of Southern Denmark, Odense, Denmark
- Department of Cardiology, University of Southern Denmark, Odense, Denmark
| | - Janus Christian Jakobsen
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen
- Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Johannes Grand
- Department of Cardiology, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen
| |
Collapse
|
|
5
|
Haryani A, Sangwan A. New Pharmacotherapeutic Classes for the Management of Heart Failure: A Narrative Review. Cureus 2024; 16:e57180. [PMID: 38681432 PMCID: PMC11056082 DOI: 10.7759/cureus.57180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2024] [Indexed: 05/01/2024] Open
Abstract
Heart failure (HF) is a syndrome characterized by the heart failing to pump blood to the body at a rate proportional to its needs. HF is a public health burden globally and one of the leading causes of hospitalizations in adults. While many classes of drugs have been introduced for the treatment of HF, not every drug may be well-tolerated by patients. In this narrative review, we describe a few of the newer classes of medications proposed to be efficacious in treating acute and chronic HF. We focus on vericiguat, omecamtiv mecarbil, ularitide, and serelaxin, and thoroughly examine their efficacy and safety profiles while summarizing the clinical trials of the drugs. There is a need for more long-term studies comparing the efficacy of these medications to the conventional ones.
Collapse
|
|
6
|
Costa L, Sousa E, Fernandes C. Cyclic Peptides in Pipeline: What Future for These Great Molecules? Pharmaceuticals (Basel) 2023; 16:996. [PMID: 37513908 PMCID: PMC10386233 DOI: 10.3390/ph16070996] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 07/06/2023] [Accepted: 07/08/2023] [Indexed: 07/30/2023] Open
Abstract
Cyclic peptides are molecules that are already used as drugs in therapies approved for various pharmacological activities, for example, as antibiotics, antifungals, anticancer, and immunosuppressants. Interest in these molecules has been growing due to the improved pharmacokinetic and pharmacodynamic properties of the cyclic structure over linear peptides and by the evolution of chemical synthesis, computational, and in vitro methods. To date, 53 cyclic peptides have been approved by different regulatory authorities, and many others are in clinical trials for a wide diversity of conditions. In this review, the potential of cyclic peptides is presented, and general aspects of their synthesis and development are discussed. Furthermore, an overview of already approved cyclic peptides is also given, and the cyclic peptides in clinical trials are summarized.
Collapse
Affiliation(s)
- Lia Costa
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal;
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
| | - Emília Sousa
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal;
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
| | - Carla Fernandes
- Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal;
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
| |
Collapse
|
|
7
|
Abstract
PURPOSE OF REVIEW The distinction between 'acute' and 'chronic' heart failure persists. Our review aims to explore whether reclassifying heart failure decompensation more accurately as an event within the natural history of chronic heart failure has the potential to improve outcomes. RECENT FINDINGS Although hospitalisation for worsening heart failure confers a poor prognosis, much of this reflects chronic disease severity. Most patients survive hospitalisation with most deaths occurring in the post-discharge 'vulnerable phase'. Current evidence supports four classes of medications proven to reduce cardiovascular mortality for those who have heart failure with a reduced ejection fraction, with recent trials suggesting worsening heart failure events are opportunities to optimise these therapies. Abandoning the term 'acute heart failure' has the potential to give greater priority to initiating proven pharmacological and device therapies during decompensation episodes, in order to improve outcomes for those who are at the greatest risk.
Collapse
|
|
8
|
Gantzel RH, Kjær MB, Jepsen P, Aagaard NK, Watson H, Gluud LL, Grønbæk H. Effects and safety of natriuretic peptides as treatment of cirrhotic ascites: A systematic review and meta-analysis. World J Hepatol 2022; 14:827-845. [PMID: 35646272 PMCID: PMC9099106 DOI: 10.4254/wjh.v14.i4.827] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 11/22/2021] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Natriuretic peptides are involved in the cascade of pathophysiological events occurring in liver cirrhosis, counterbalancing vasoconstriction and anti-natriuretic factors. The effects of natriuretic peptides as treatment of cirrhotic ascites have been investigated only in small studies, and definitive results are lacking. AIM To examine the effects and safety of natriuretic peptides in cirrhosis patients with ascites. METHODS We searched MEDLINE, Web of Science, Scopus, Cochrane Library and Embase for all available studies applying intravenous administration of any natriuretic peptide to patients suffering from cirrhotic ascites. Inclusion was not limited by treatment duration or dose, or by follow-up duration. Both randomised controlled trials and non-randomised studies were eligible for inclusion. The primary outcome was change in renal sodium excretion. Secondary outcomes included safety measures and changes in renal water excretion, plasma aldosterone concentration, and plasma renin activity. RESULTS Twenty-two studies were included. Atrial natriuretic peptide (ANP) was the only intensively studied treatment. Sodium excretion increased in response to continuous ANP infusion and was more pronounced when infusion rates of > 30 ng/kg/min were administered compared with ≤ 30 ng/kg/min (P < 0.01). Moreover, natriuresis was significantly higher in study subgroups with mild/moderate ascites compared with moderate/severe and refractory ascites (P < 0.01). ANP infusions increased renal water excretion, although without reaching a statistically significant dose-response gradient. Plasma aldosterone concentration and plasma renin activity were significantly lower at baseline in study subgroups achieving a negative sodium balance in response to an ANP administration compared with treatment non-responders (P < 0.01). Blood pressure decreases occurred less frequently when ANP doses ≤ 30 ng/kg/min were applied. The quality of evidence for a natriuretic response to ANP was low, mainly due to small sample sizes and considerable between-study heterogeneity. Data were sparse for the other natriuretic peptides; B-type natriuretic peptide and urodilatin. CONCLUSION Intravenous ANP infusions increase sodium excretion in patients with cirrhotic ascites. Continuous infusion rates > 30 ng/kg/min are the most effective. However, safety increases with infusion rates ≤ 30 ng/kg/min.
Collapse
Affiliation(s)
- Rasmus Hvidbjerg Gantzel
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N 8200, Denmark
| | - Mikkel Breinholt Kjær
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N 8200, Denmark
| | - Peter Jepsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N 8200, Denmark
| | - Niels Kristian Aagaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N 8200, Denmark
| | - Hugh Watson
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N 8200, Denmark
| | - Lise Lotte Gluud
- Gastroenterology Unit, Copenhagen University Hospital, Hvidovre 2650, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N 8200, Denmark.
| |
Collapse
|
|
9
|
Weisert M, Su JA, Menteer J, Shaddy RE, Kantor PF. Drug Treatment of Heart Failure in Children: Gaps and Opportunities. Paediatr Drugs 2022; 24:121-136. [PMID: 35084696 DOI: 10.1007/s40272-021-00485-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/08/2021] [Indexed: 12/11/2022]
Abstract
Medical therapy for pediatric heart failure is based on a detailed mechanistic understanding of the underlying causes, which are diverse and unlike those encountered in most adult patients. Diuresis and improved perfusion are the immediate goals of care in the child with acute decompensated heart failure. Conversion to maintenance oral therapy for heart failure is based on the results of landmark studies in adults, as well as recent pediatric clinical trials and heart failure guidelines. There will continue to be an important role for newer drugs, some of which are in active trials in adults, and some of which are already approved for use in children. The need to plan for clinical trials in children during drug development for heart failure is emphasized.
Collapse
Affiliation(s)
- Molly Weisert
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Division of Cardiology, Heart Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Jennifer A Su
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Division of Cardiology, Heart Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Jondavid Menteer
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Division of Cardiology, Heart Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Robert E Shaddy
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Division of Cardiology, Heart Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Paul F Kantor
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Division of Cardiology, Heart Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
| |
Collapse
|
|
10
|
Gidlöf O. Toward a New Paradigm for Targeted Natriuretic Peptide Enhancement in Heart Failure. Front Physiol 2021; 12:650124. [PMID: 34721050 PMCID: PMC8548580 DOI: 10.3389/fphys.2021.650124] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 09/21/2021] [Indexed: 12/11/2022] Open
Abstract
The natriuretic peptide system (NPS) plays a fundamental role in maintaining cardiorenal homeostasis, and its potent filling pressure-regulated diuretic and vasodilatory effects constitute a beneficial compensatory mechanism in heart failure (HF). Leveraging the NPS for therapeutic benefit in HF has been the subject of intense investigation during the last three decades and has ultimately reached widespread clinical use in the form of angiotensin receptor-neprilysin inhibition (ARNi). NPS enhancement via ARNi confers beneficial effects on mortality and hospitalization in HF, but inhibition of neprilysin leads to the accumulation of a number of other vasoactive peptides in the circulation, often resulting in hypotension and raising potential concerns over long-term adverse effects. Moreover, ARNi is less effective in the large group of HF patients with preserved ejection fraction. Alternative approaches for therapeutic augmentation of the NPS with increased specificity and efficacy are therefore warranted, and are now becoming feasible particularly with recent development of RNA therapeutics. In this review, the current state-of-the-art in terms of experimental and clinical strategies for NPS augmentation and their implementation will be reviewed and discussed.
Collapse
Affiliation(s)
- Olof Gidlöf
- Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden
| |
Collapse
|
|
11
|
Loss KL, Shaddy RE, Kantor PF. Recent and Upcoming Drug Therapies for Pediatric Heart Failure. Front Pediatr 2021; 9:681224. [PMID: 34858897 PMCID: PMC8632454 DOI: 10.3389/fped.2021.681224] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 10/01/2021] [Indexed: 12/23/2022] Open
Abstract
Pediatric heart failure (HF) is an important clinical condition with high morbidity, mortality, and costs. Due to the heterogeneity in clinical presentation and etiologies, the development of therapeutic strategies is more challenging in children than adults. Most guidelines recommending drug therapy for pediatric HF are extrapolated from studies in adults. Unfortunately, even using all available treatment, progression to cardiac transplantation is common. The development of prospective clinical trials in the pediatric population has significant obstacles, including small sample sizes, slow recruitment rates, challenging endpoints, and high costs. However, progress is being made as evidenced by the recent introduction of ivabradine and of sacubitril/valsartan. In the last 5 years, new drugs have also been developed for HF with reduced ejection fraction (HFrEF) in adults. The use of well-designed prospective clinical trials will be fundamental in the evaluation of safety and efficacy of these new drugs on the pediatric population. The aim of this article is to review the clinical presentation and management of acute and chronic pediatric heart failure, focusing on systolic dysfunction in patients with biventricular circulation and a systemic left ventricle. We discuss the drugs recently approved for children and those emerging, or in use for adults with HFrEF.
Collapse
Affiliation(s)
- Karla L Loss
- Division of Cardiology, Department of Pediatrics, Keck School of Medicine at University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, United States
| | - Robert E Shaddy
- Division of Cardiology, Department of Pediatrics, Keck School of Medicine at University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, United States
| | - Paul F Kantor
- Division of Cardiology, Department of Pediatrics, Keck School of Medicine at University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, United States
| |
Collapse
|
|
12
|
Belletti A, Landoni G, Lomivorotov VV, Oriani A, Ajello S. Adrenergic Downregulation in Critical Care: Molecular Mechanisms and Therapeutic Evidence. J Cardiothorac Vasc Anesth 2019; 34:1023-1041. [PMID: 31839459 DOI: 10.1053/j.jvca.2019.10.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 09/09/2019] [Accepted: 10/10/2019] [Indexed: 02/08/2023]
Abstract
Catecholamines remain the mainstay of therapy for acute cardiovascular dysfunction. However, adrenergic receptors quickly undergo desensitization and downregulation after prolonged stimulation. Moreover, prolonged exposure to high circulating catecholamines levels is associated with several adverse effects on different organ systems. Unfortunately, in critically ill patients, adrenergic downregulation translates into progressive reduction of cardiovascular response to exogenous catecholamine administration, leading to refractory shock. Accordingly, there has been a growing interest in recent years toward use of noncatecholaminergic inotropes and vasopressors. Several studies investigating a wide variety of catecholamine-sparing strategies (eg, levosimendan, vasopressin, β-blockers, steroids, and use of mechanical circulatory support) have been published recently. Use of these agents was associated with improvement in hemodynamics and decreased catecholamine use but without a clear beneficial effect on major clinical outcomes. Accordingly, additional research is needed to define the optimal management of catecholamine-resistant shock.
Collapse
Affiliation(s)
- Alessandro Belletti
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Giovanni Landoni
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Vladimir V Lomivorotov
- Department of Anesthesiology and Intensive Care, E. Meshalkin National Medical Research Center, Novosibirsk, Russia; Novosibirsk State University, Novosibirsk, Russia
| | - Alessandro Oriani
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Silvia Ajello
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| |
Collapse
|
|
13
|
|
|
14
|
Antohi EL, Ambrosy AP, Collins SP, Ahmed A, Iliescu VA, Cotter G, Pang PS, Butler J, Chioncel O. Therapeutic Advances in the Management of Acute Decompensated Heart Failure. Am J Ther 2019; 26:e222-e233. [PMID: 30839371 PMCID: PMC6404761 DOI: 10.1097/mjt.0000000000000919] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Acute decompensated heart failure (ADHF) is the most common presenting phenotype of acute heart failure (AHF). The main goal of this article was to review the contemporary management strategies in these patients and to describe how future clinical trials may address unmet clinical needs. AREAS OF UNCERTAINTY The current pathophysiologic understanding of AHF is incomplete. The guideline recommendations for the management of ADHF are based only on algorithms provided by expert consensus guided by blood pressure and/or clinical signs of congestion or hypoperfusion. The lack of adequately conducted trials to address the unmet need for evidence therapy in AHF has not yet been surpassed, and at this time, there is no evidence-based strategy for targeted decongestive therapy to improve outcomes. The precise time point for initiation of guideline-directed medical therapies (GDMTs), as respect to moment of decompensation, is also unknown. DATA SOURCES The available data informing current management of patients with ADHF are based on randomized controlled trials, observational studies, and administrative databases. THERAPEUTIC ADVANCES A major step-forward in the management of ADHF patients is recognizing congestion, either clinical or hemodynamic, as a major trigger for heart failure (HF) hospitalization and most important target for therapy. However, a strategy based exclusively on congestion is not sufficient, and at present, comprehensive assessment during hospitalization of cardiac and noncardiovascular substrate with identification of potential therapeutic targets represents "the corner-stone" of ADHF management. In the last years, substantial data have emerged to support the continuation of GDMTs during hospitalization for HF decompensation. Recently, several clinical trials raised hypothesis of "moving to the left" concept that argues for very early implementation of GDMTs as potential strategy to improve outcomes. CONCLUSIONS The management of ADHF is still based on expert consensus documents. Further research is required to identify novel therapeutic targets, to establish the precise time point to initiate GDMTs, and to identify patients at risk of recurrent hospitalization.
Collapse
Affiliation(s)
- Elena-Laura Antohi
- University of Medicine Carol Davila, Bucharest; Emergency Institute for Cardiovascular Diseases-”Prof. C.C.Iliescu”, Bucharest, Romania
| | - Andrew P Ambrosy
- Division of Cardiology, Duke University Medical Center, Durham, NC, USA; Duke Clinical Research Institute, Durham, NC, USA
| | - Sean P Collins
- Department of Emergency Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Ali Ahmed
- Veteran Affairs Medical Center and George Washington University, Washington DC, USA
| | - Vlad Anton Iliescu
- University of Medicine Carol Davila, Bucharest; Emergency Institute for Cardiovascular Diseases-”Prof. C.C.Iliescu”, Bucharest, Romania
| | | | - Peter S Pang
- Department of Emergency Medicine and Indianapolis EMS, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Javed Butler
- Department of Medicine, University of Mississippi School of Medicine, Jackson, MI, USA
| | - Ovidiu Chioncel
- University of Medicine Carol Davila, Bucharest; Emergency Institute for Cardiovascular Diseases-”Prof. C.C.Iliescu”, Bucharest, Romania
| |
Collapse
|
|
15
|
Jobs A, Abdin A, de Waha-Thiele S, Eitel I, Thiele H, de Wit C, Vonthein R. Angiotensin-converting-enzyme inhibitors in hemodynamic congestion: a meta-analysis of early studies. Clin Res Cardiol 2019; 108:1240-1248. [DOI: 10.1007/s00392-019-01456-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 03/13/2019] [Indexed: 02/08/2023]
|
|
16
|
|
|
17
|
Machaj F, Dembowska E, Rosik J, Szostak B, Mazurek-Mochol M, Pawlik A. New therapies for the treatment of heart failure: a summary of recent accomplishments. Ther Clin Risk Manag 2019; 15:147-155. [PMID: 30774351 PMCID: PMC6348963 DOI: 10.2147/tcrm.s179302] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Despite continuous efforts to prevent cardiovascular diseases (CVDs), heart failure prevails as the number one cause of death in developed countries. To properly treat CVDs, scientists had to take a closer look at the factors that contribute to their pathogenesis and either modernize current pharmaceuticals or develop brand new treatments. Enhancement of current drugs, such as tolvaptan and omecamtiv mecarbil, sheds new light on already-known therapies. Tolvaptan, a vasopressin antagonist, could be adopted in heart failure therapy as it reduces pre- and afterload by decreasing systolic blood pressure and blood volume. Omecamtiv mecarbil, which is a myosin binding peptide, could aid cardiac contractility. The next generation vasodilators, serelaxin and ularitide, are based on naturally occurring peptides and they reduce peripheral vascular resistance and increase the cardiac index. In combination with their anti-inflammatory properties, they could turn out to be extremely potent drugs for heart failure treatment. Cardiotrophin has exceeded many researchers’ expectations, as evidence suggests that it could cause sarcomere hypertrophy without excessive proliferation of connective tissue. Rapid progress in gene therapy has caused it to finally be considered as one of the viable options for the treatment of CVDs. This novel therapeutic approach could restore stable heart function either by restoring depleted membrane proteins or by balancing the intracellular calcium concentration. Although it has been set back by problems concerning its long-term effects, it is still highly likely to succeed.
Collapse
Affiliation(s)
- Filip Machaj
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland,
| | - Elżbieta Dembowska
- Department of Periodontology, Pomeranian Medical University, Szczecin, Poland
| | - Jakub Rosik
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland,
| | - Bartosz Szostak
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland,
| | | | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, Szczecin, Poland,
| |
Collapse
|
|
18
|
Mitrovic V, Forssmann W, Schnitker J, Felix SB. Randomized double-blind clinical studies of ularitide and other vasoactive substances in acute decompensated heart failure: a systematic review and meta-analysis. ESC Heart Fail 2018; 5:1023-1034. [PMID: 30246939 PMCID: PMC6300812 DOI: 10.1002/ehf2.12349] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 07/18/2018] [Indexed: 01/08/2023] Open
Abstract
AIMS Acute decompensated heart failure (ADHF) has a poor prognosis and limited treatment options. No direct comparisons between ularitide-a synthetic natriuretic peptide being evaluated in ADHF-and other vasoactive substances are available. The aim of this meta-analysis was to determine haemodynamic effect sizes from randomized double-blind trials in ADHF. METHODS AND RESULTS Eligible studies enrolled patients with ADHF requiring hospitalization and haemodynamic monitoring. Patients received 24-48 h of infusion with a vasoactive substance or comparator. Primary outcome measure was pulmonary artery wedge pressure (PAWP). Treatment effects were quantified as changes from baseline using mean differences between study drug and comparator. Results were analysed using random-effects (primary analysis) and fixed-effects meta-analyses. Twelve randomized, double-blind studies were identified with data after 3, 6, and 24 h of treatment (n = 622, 644, and 644, respectively). At 6 h, significant PAWP benefits for ularitide over placebo were seen (Hedges' g effect size, -0.979; P < 0.0001). On meta-analysis, treatment difference between ularitide and pooled other agents was statistically significant (-0.501; P = 0.0303). Effect sizes were numerically higher with ularitide than other treatments at 3 and 24 h. After 6 h, a significant difference in effect size between ularitide and all other treatments was observed for right atrial pressure (Hedges' g, -0.797 for ularitide and -0.304 for other treatments; P = 0.0274). CONCLUSIONS After 6 h, ularitide demonstrated high effect sizes for PAWP and right atrial pressure. Improvements in these parameters were greater with ularitide vs. pooled data for other vasoactive drugs.
Collapse
Affiliation(s)
- Veselin Mitrovic
- Kerckhoff‐Klinik Forschungsgesellschaft mbHKüchlerstrasse 1061231Bad NauheimGermany
| | - Wolf‐Georg Forssmann
- Department of Internal Medicine, Clinic of Immunology, Division of Peptide ResearchHannover Medical School (MHH)HannoverGermany
| | - Jan Schnitker
- Institute of Applied Statistics (IAS) LtdBielefeldGermany
| | - Stephan B. Felix
- Department of Internal Medicine BUniversity Medicine Greifswald and DZHK (German Centre for Cardiovascular Research), partner site GreifswaldGreifswaldGermany
| |
Collapse
|
|
19
|
Yandrapalli S, Khan MH, Rochlani Y, Aronow WS. Sacubitril/valsartan in cardiovascular disease: evidence to date and place in therapy. Ther Adv Cardiovasc Dis 2018; 12:217-231. [PMID: 29921166 PMCID: PMC6041873 DOI: 10.1177/1753944718784536] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Accepted: 06/01/2018] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular (CV) disease is a major cause of morbidity and mortality in the developing and the developed world. Mortality from CV disease had plateaued in the recent years raising concerning alarms about the sustained efficacy of available preventive and treatment options. Heart failure (HF) is among the major contributors to the CV-related health care burden, a persisting concern despite the use of clinically proven guideline-directed therapies. A requirement for more efficient medical therapies coupled with recent advances in bio-innovation led to the creation of sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), which demonstrated substantial CV benefit when compared with the standard of care, enalapril, in patients with HF and reduced ejection fraction. Further investigations of this novel combination ARNI at the tissue level shed light into the anti-remodeling and cardioprotective effects of sacubitril/valsartan, while clinical studies in the phenotypes of HF with preserved ejection fraction, hypertension and subsets, coronary outcomes, postmyocardial infarction, and renal disease suggested that this combination could be beneficial across a wide spectrum of CV disease. Sacubitril/valsartan is a much-needed therapeutic advance in the avenue of CV disease.
Collapse
Affiliation(s)
- Srikanth Yandrapalli
- Department of Internal Medicine, New York Medical College at Westchester Medical Center, Valhalla, NY, USA
| | - Mohammed Hasan Khan
- Division of Cardiology, New York Medical College at Westchester Medical Center, Valhalla, NY, USA
| | - Yogita Rochlani
- Division of Cardiology, New York Medical College at Westchester Medical Center, Valhalla, NY, USA
| | - Wilbert S. Aronow
- Professor of Medicine, Cardiology Division, New York Medical College at Westchester Medical Center, Macy Pavilion, Room 141, Valhalla, NY 10595, USA
| |
Collapse
|
|
20
|
Singh A, Laribi S, Teerlink JR, Mebazaa A. Agents with vasodilator properties in acute heart failure. Eur Heart J 2018; 38:317-325. [PMID: 28201723 DOI: 10.1093/eurheartj/ehv755] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Revised: 12/14/2015] [Accepted: 12/22/2015] [Indexed: 01/05/2023] Open
Abstract
Millions of patients worldwide are admitted for acute heart failure (AHF) each year and physicians caring for these patients are confronted with the short-term challenges of reducing symptoms while preventing end organ dysfunction without causing additional harm, and the intermediate-term challenges of improving clinical outcomes such as hospital readmission and survival. There are limited data demonstrating the efficacy of any currently available therapies for AHF to meet these goals. After diuretics, vasodilators are the most common intravenous therapy for AHF, but neither nitrates, nitroprusside, nor nesiritide have robust evidence supporting their ability to provide meaningful effects on clinical outcomes, except perhaps early symptom improvement. Recently, a number of novel agents with vasodilating properties have been developed for the treatment of AHF. These agents include serelaxin, natriuretic peptides (ularitide, cenderitide), β-arrestin-biased angiotensin II type 1 receptor ligands (TRV120027), nitroxyl donors (CXL-1020, CXL-1427), soluble guanylate cyclase modulators (cinaciguat, vericiguat), short-acting calcium channel blockers (clevidipine), and potassium channel activators (nicorandil). These development programmes range from the stage of early dose-finding studies (e.g. TRV120027, CXL-1427) to large, multicentre mortality trials (e.g. serelaxin, ularitide). There is an urgent need for agents with vasodilating properties that will improve both in-hospital and post-discharge clinical outcomes, and these novel approaches may provide opportunities to address this need.
Collapse
Affiliation(s)
- Abhishek Singh
- Section of Cardiology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.,School of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Saïd Laribi
- INSERM, UMRS 942, Biomarkers and cardiac diseases, Paris, France.,Emergency Department, APHP, Saint Louis-Lariboisière Hospitals, Paris, France
| | - John R Teerlink
- Section of Cardiology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.,School of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Alexandre Mebazaa
- INSERM, UMRS 942, Biomarkers and cardiac diseases, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,Department of Anesthesiology and Critical Care, APHP, Saint Louis-Lariboisière Hospitals, Paris, France
| |
Collapse
|
|
21
|
Teneggi V, Sivakumar N, Chen D, Matter A. Drugs’ development in acute heart failure: what went wrong? Heart Fail Rev 2018; 23:667-691. [DOI: 10.1007/s10741-018-9707-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
|
|
22
|
Travessa AM, Menezes Falcão L. Vasodilators in acute heart failure - evidence based on new studies. Eur J Intern Med 2018; 51:1-10. [PMID: 29482882 DOI: 10.1016/j.ejim.2018.02.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 02/04/2018] [Accepted: 02/21/2018] [Indexed: 12/28/2022]
Abstract
Acute heart failure (AHF) contributes largely to the worldwide burden of heart failure (HF) and is associated with high mortality, poor prognosis and high rehospitalization rate. The pharmacologic therapy of AHF includes diuretics and vasodilators, which are a keystone when fluid overload and congestion are present. However, vasodilators are mainly focused on controlling symptoms, and drugs that also improve long-term mortality and morbidity seem to be in high demand. In this review, we summarize the existing evidence on mortality benefits of IV vasodilators in AHF. There is lack of evidence on the mortality benefits of IV vasodilators in AHF, as well as well-designed and large-scale trials for some of them. The existing trials on nitrates have conflicting results and are insufficient to establish definitive conclusions. Other vasodilators, such as enalaprilat, clevidipine, carperitide, and ularitide, have been evaluated only in a few trials assessing mortality. Levosimendan, nesititide and carperitide are approved by some regulatory agencies; however, data regarding mortality are also conflicting and large-scale post-marketing studies would be important. Serelaxin is a recent therapy with a novel mechanism of action and seemed to be promising; although serelaxin was safe and well tolerated in earlier trials, the results of a larger phase III trial failed to meet the primary endpoints of reduction in cardiovascular death at day 180 and reduction of worsening heart failure at day 5. The absence of definitive mortality benefits and high-quality and large-scale data not allow firm conclusions to be drawn about the role of IV vasodilators in AHF. Well-designed studies are needed to clarify the role of these drugs in the long-term outcome of AHF, as well as new therapies entering the clinical investigation.
Collapse
Affiliation(s)
- André M Travessa
- Centro Hospitalar Lisboa Norte, Lisbon, Portugal; Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - L Menezes Falcão
- Centro Hospitalar Lisboa Norte, Lisbon, Portugal; Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
| |
Collapse
|
|
23
|
Ularitide in Acute Heart Failure. CURRENT EMERGENCY AND HOSPITAL MEDICINE REPORTS 2018. [DOI: 10.1007/s40138-018-0150-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
|
24
|
Fu S, Ping P, Wang F, Luo L. Synthesis, secretion, function, metabolism and application of natriuretic peptides in heart failure. J Biol Eng 2018; 12:2. [PMID: 29344085 PMCID: PMC5766980 DOI: 10.1186/s13036-017-0093-0] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 12/21/2017] [Indexed: 12/11/2022] Open
Abstract
As a family of hormones with pleiotropic effects, natriuretic peptide (NP) system includes atrial NP (ANP), B-type NP (BNP), C-type NP (CNP), dendroaspis NP and urodilatin, with NP receptor-A (guanylate cyclase-A), NP receptor-B (guanylate cyclase-B) and NP receptor-C (clearance receptor). These peptides are genetically distinct, but structurally and functionally related for regulating circulatory homeostasis in vertebrates. In humans, ANP and BNP are encoded by NP precursor A (NPPA) and NPPB genes on chromosome 1, whereas CNP is encoded by NPPC on chromosome 2. NPs are synthesized and secreted through certain mechanisms by cardiomyocytes, fibroblasts, endotheliocytes, immune cells (neutrophils, T-cells and macrophages) and immature cells (embryonic stem cells, muscle satellite cells and cardiac precursor cells). They are mainly produced by cardiovascular, brain and renal tissues in response to wall stretch and other causes. NPs provide natriuresis, diuresis, vasodilation, antiproliferation, antihypertrophy, antifibrosis and other cardiometabolic protection. NPs represent body's own antihypertensive system, and provide compensatory protection to counterbalance vasoconstrictor-mitogenic-sodium retaining hormones, released by renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS). NPs play central roles in regulation of heart failure (HF), and are inactivated through not only NP receptor-C, but also neutral endopeptidase (NEP), dipeptidyl peptidase-4 and insulin degrading enzyme. Both BNP and N-terminal proBNP are useful biomarkers to not only make the diagnosis and assess the severity of HF, but also guide the therapy and predict the prognosis in patients with HF. Current NP-augmenting strategies include the synthesis of NPs or agonists to increase NP bioactivity and inhibition of NEP to reduce NP breakdown. Nesiritide has been established as an available therapy, and angiotensin receptor blocker NEP inhibitor (ARNI, LCZ696) has obtained extremely encouraging results with decreased morbidity and mortality. Novel pharmacological approaches based on NPs may promote a therapeutic shift from suppressing the RAAS and SNS to re-balancing neuroendocrine dysregulation in patients with HF. The current review discussed the synthesis, secretion, function and metabolism of NPs, and their diagnostic, therapeutic and prognostic values in HF.
Collapse
Affiliation(s)
- Shihui Fu
- Department of Geriatric Cardiology, Chinese People’s Liberation Army General Hospital, Beijing, 100853 China
- Department of Cardiology and Hainan Branch, Chinese People’s Liberation Army, General Hospital, Beijing, China
| | - Ping Ping
- Department of Pharmaceutical Care, Chinese People’s, Liberation Army General Hospital, Beijing, China
| | - Fengqi Wang
- Department of Cardiology and Hainan Branch, Chinese People’s Liberation Army, General Hospital, Beijing, China
| | - Leiming Luo
- Department of Geriatric Cardiology, Chinese People’s Liberation Army General Hospital, Beijing, 100853 China
| |
Collapse
|
|
25
|
Yandrapalli S, Jolly G, Biswas M, Rochlani Y, Harikrishnan P, Aronow WS, Lanier GM. Newer hormonal pharmacotherapies for heart failure. Expert Rev Endocrinol Metab 2018; 13:35-49. [PMID: 30063443 DOI: 10.1080/17446651.2018.1406799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Heart failure (HF) is characterized by maladaptive neurohormonal activation of the cardiovascular and renal systems resulting in circulatory inadequacy and frequent acute exacerbations. The increasing burden of HF prompted investigation of underlying pathophysiological mechanisms and the design of pharmacotherapeutics that would target these pathways. AREAS COVERED A MEDLINE search for relevant original investigations and review articles of newer hormonal drugs for HF since the year 2005 till October 2017 provided us with necessary literature. Major trials and relevant clinical investigations were discussed. EXPERT COMMENTARY A multitude of hormonal pathways central to HF were identified, including the natriuretic peptide system and neurohormones such as relaxin, arginine vasopressin, and endothelin. However, drugs targeting these novel pathways (aliskiren, tolvaptan, ularitide, serelaxin, bosentan, macitentan) failed to show mortality benefit. This emphasizes a tremendous unmet need in the pharmacotherapy for HF, especially for the subtypes of acute HF and HF with preserved ejection fraction. Sacubitril/valsartan demonstrated substantial mortality benefit in chronic systolic HF population and is endorsed by international HF guidelines. If proven to be efficacious in larger outcome trials, finerenone can be a valuable addition baseline HF therapy. More basic, translational, and phenotype specific clinical research is warranted to improve HF pharmacotherapy.
Collapse
Affiliation(s)
- Srikanth Yandrapalli
- a Department of Internal Medicine , New York Medical College at Westchester Medical Center , Valhalla , NY , USA
| | - George Jolly
- a Department of Internal Medicine , New York Medical College at Westchester Medical Center , Valhalla , NY , USA
| | - Medha Biswas
- b Division of Cardiology , New York Medical College at Westchester Medical Center , Valhalla , NY , USA
| | - Yogita Rochlani
- b Division of Cardiology , New York Medical College at Westchester Medical Center , Valhalla , NY , USA
| | - Prakash Harikrishnan
- b Division of Cardiology , New York Medical College at Westchester Medical Center , Valhalla , NY , USA
| | - Wilbert S Aronow
- b Division of Cardiology , New York Medical College at Westchester Medical Center , Valhalla , NY , USA
| | - Gregg M Lanier
- b Division of Cardiology , New York Medical College at Westchester Medical Center , Valhalla , NY , USA
| |
Collapse
|
|
26
|
Shah P, Pellicori P, Cuthbert J, Clark AL. Pharmacological and Non-pharmacological Treatment for Decompensated Heart Failure: What Is New? Curr Heart Fail Rep 2017; 14:147-157. [PMID: 28421408 PMCID: PMC5423987 DOI: 10.1007/s11897-017-0328-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF THE REVIEW Acute heart failure (AHF) is a life-threatening clinical condition that requires prompt medical attention. The aim of the current review is to summarise the results of recent clinical trials conducted in patients with AHF. RECENT FINDINGS Several novel compounds have apparently beneficial acute effects on cardiovascular haemodynamics and patients' symptoms, but their administration has not yet translated into improved survival and has been deleterious in some cases. The management of patients with AHF is challenging and reflects the heterogeneity of patient's presentation, the complexity and severity of a multi-organ syndrome, and the limited therapeutic options, usually restricted to a combination of diuretics and vasodilators. Ongoing trials of novel treatments may provide evidence of an effect on outcomes.
Collapse
Affiliation(s)
- Parin Shah
- Department of Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Cottingham, Kingston upon Hull, HU16 5JQ, UK.
| | - Pierpaolo Pellicori
- Department of Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Cottingham, Kingston upon Hull, HU16 5JQ, UK
| | - Joseph Cuthbert
- Department of Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Cottingham, Kingston upon Hull, HU16 5JQ, UK
| | - Andrew L Clark
- Department of Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Cottingham, Kingston upon Hull, HU16 5JQ, UK
| |
Collapse
|
|
27
|
McDonald MA, Ashley EA, Fedak PW, Hawkins N, Januzzi JL, McMurray JJ, Parikh VN, Rao V, Svystonyuk D, Teerlink JR, Virani S. Mind the Gap: Current Challenges and Future State of Heart Failure Care. Can J Cardiol 2017; 33:1434-1449. [DOI: 10.1016/j.cjca.2017.08.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 08/30/2017] [Accepted: 08/30/2017] [Indexed: 11/24/2022] Open
|
|
28
|
The evolution of heart failure with reduced ejection fraction pharmacotherapy: What do we have and where are we going? Pharmacol Ther 2017; 178:67-82. [DOI: 10.1016/j.pharmthera.2017.03.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
|
|
29
|
Rigopoulos AG, Bakogiannis C, de Vecchis R, Sakellaropoulos S, Ali M, Teren M, Matiakis M, Tschoepe C, Noutsias M. Acute heart failure. Herz 2017; 44:53-55. [DOI: 10.1007/s00059-017-4626-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 09/01/2017] [Accepted: 09/01/2017] [Indexed: 01/12/2023]
|
|
30
|
Tita C, Gilbert EM, Van Bakel AB, Grzybowski J, Haas GJ, Jarrah M, Dunlap SH, Gottlieb SS, Klapholz M, Patel PC, Pfister R, Seidler T, Shah KB, Zieliński T, Venuti RP, Cowart D, Foo SY, Vishnevsky A, Mitrovic V. A Phase 2a dose-escalation study of the safety, tolerability, pharmacokinetics and haemodynamic effects of BMS-986231 in hospitalized patients with heart failure with reduced ejection fraction. Eur J Heart Fail 2017; 19:1321-1332. [PMID: 28677877 PMCID: PMC6607490 DOI: 10.1002/ejhf.897] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 04/25/2017] [Accepted: 04/26/2017] [Indexed: 12/28/2022] Open
Abstract
Aims This study was designed to evaluate the safety, tolerability and haemodynamic effects of BMS‐986231, a novel second‐generation nitroxyl donor with potential inotropic, lusitropic and vasodilatory effects in patients hospitalized with decompensated heart failure and reduced ejection fraction (HFrEF). Methods and results Forty‐six patients hospitalized with decompensated HFrEF were enrolled into four sequential dose‐escalation cohorts in this double‐blind, randomized, placebo‐controlled Phase 2a study. Patients with baseline pulmonary capillary wedge pressure (PCWP) of ≥20 mmHg and a cardiac index of ≤2.5 L/min/m2 received one 6‐h i.v. infusion of BMS‐986231 (at 3, 5, 7 or 12 µg/kg/min) or placebo. BMS‐986231 produced rapid and sustained reductions in PCWP, as well as consistent reductions in time‐averaged pulmonary arterial systolic pressure, pulmonary arterial diastolic pressure and right atrial pressure. BMS‐986231 increased non‐invasively measured time‐averaged stroke volume index, cardiac index and cardiac power index values, and decreased total peripheral vascular resistance. There was no evidence of increased heart rate, drug‐related arrhythmia or symptomatic hypotension with BMS‐986231. Analyses of adverse events throughout the 30‐day follow‐up did not identify any toxicities specific to BMS‐986231, with the potential exception of infrequent mild‐to‐moderate headaches during infusion. There were no treatment‐related serious adverse events. Conclusions BMS‐986231 demonstrated a favourable safety and haemodynamic profile in patients hospitalized with advanced heart failure. Based on preclinical data and these study's findings, it is possible that the haemodynamic benefits may be mediated by inotropic and/or lusitropic as well as vasodilatory effects. The therapeutic potential of BMS‐986231 should be further assessed in patients with heart failure.
Collapse
Affiliation(s)
- Cristina Tita
- Division of Cardiovascular Medicine, Department of Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Edward M Gilbert
- Division of Cardiology, Faculty of Medicine, University of Utah, Salt Lake City, UT, USA
| | - Adrian B Van Bakel
- Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Jacek Grzybowski
- Department of Cardiomyopathy, Institute of Cardiology, Warsaw, Poland
| | - Garrie J Haas
- Division of Cardiology and Vascular Medicine, Faculty of Medicine, Ohio State University, Columbus, OH, USA
| | - Mohammad Jarrah
- Department of Cardiology, King Abdullah University Hospital, Irbid, Jordan
| | - Stephanie H Dunlap
- Division of Cardiology, Faculty of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Stephen S Gottlieb
- Division of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Marc Klapholz
- Division of Cardiology, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Parag C Patel
- Department of Transplant, Mayo Clinic, Jacksonville, FL, USA
| | - Roman Pfister
- Department III of Internal Medicine, Heart Centre, University Hospital of Cologne, Cologne, Germany
| | - Tim Seidler
- Division of Cardiology and Pulmonology, Medical University of Göttingen, Göttingen, Germany
| | - Keyur B Shah
- Department of Cardiology, Faculty of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Tomasz Zieliński
- Department of Heart Failure and Transplantology, Institute of Cardiology, Warsaw, Poland
| | - Robert P Venuti
- formerly of Cardioxyl Pharmaceuticals, Inc., Chapel Hill, NC, USA
| | - Douglas Cowart
- formerly of Cardioxyl Pharmaceuticals, Inc., Chapel Hill, NC, USA
| | - Shi Yin Foo
- formerly of Cardioxyl Pharmaceuticals, Inc., Chapel Hill, NC, USA
| | - Alexander Vishnevsky
- Intensive Care Unit, Cardiology Department, Pokrovskaya City Hospital, St Petersburg, Russia
| | - Veselin Mitrovic
- Department of Cardiology, Kerckhoff-Klinik, Bad Nauheim, Germany
| |
Collapse
|
|
31
|
Abo El gheit RE. Effect of the renal natriuretic peptide, ularitide, alone or combined with Vasopeptidase inhibitor, Omapatrilat, on experimental volume overload-induced congestive heart failure in rats (Ularitide/Omapatrilat in Congestive Heart Failure). ALEXANDRIA JOURNAL OF MEDICINE 2017. [DOI: 10.1016/j.ajme.2016.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
|
|
32
|
Affiliation(s)
- Paul J Hauptman
- From the Department of Medicine (Cardiology), Saint Louis University School of Medicine, St. Louis
| |
Collapse
|
|
33
|
Packer M, O'Connor C, McMurray JJV, Wittes J, Abraham WT, Anker SD, Dickstein K, Filippatos G, Holcomb R, Krum H, Maggioni AP, Mebazaa A, Peacock WF, Petrie MC, Ponikowski P, Ruschitzka F, van Veldhuisen DJ, Kowarski LS, Schactman M, Holzmeister J. Effect of Ularitide on Cardiovascular Mortality in Acute Heart Failure. N Engl J Med 2017; 376:1956-1964. [PMID: 28402745 DOI: 10.1056/nejmoa1601895] [Citation(s) in RCA: 246] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND In patients with acute heart failure, early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and, potentially, myocardial injury, thereby favorably affecting patients' long-term prognosis. METHODS In this double-blind trial, we randomly assigned 2157 patients with acute heart failure to receive a continuous intravenous infusion of either ularitide at a dose of 15 ng per kilogram of body weight per minute or matching placebo for 48 hours, in addition to accepted therapy. Treatment was initiated a median of 6 hours after the initial clinical evaluation. The coprimary outcomes were death from cardiovascular causes during a median follow-up of 15 months and a hierarchical composite end point that evaluated the initial 48-hour clinical course. RESULTS Death from cardiovascular causes occurred in 236 patients in the ularitide group and 225 patients in the placebo group (21.7% vs. 21.0%; hazard ratio, 1.03; 96% confidence interval, 0.85 to 1.25; P=0.75). In the intention-to-treat analysis, there was no significant between-group difference with respect to the hierarchical composite outcome. The ularitide group had greater reductions in systolic blood pressure and in levels of N-terminal pro-brain natriuretic peptide than the placebo group. However, changes in cardiac troponin T levels during the infusion did not differ between the two groups in the 55% of patients with paired data. CONCLUSIONS In patients with acute heart failure, ularitide exerted favorable physiological effects (without affecting cardiac troponin levels), but short-term treatment did not affect a clinical composite end point or reduce long-term cardiovascular mortality. (Funded by Cardiorentis; TRUE-AHF ClinicalTrials.gov number, NCT01661634 .).
Collapse
Affiliation(s)
- Milton Packer
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Christopher O'Connor
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - John J V McMurray
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Janet Wittes
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - William T Abraham
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Stefan D Anker
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Kenneth Dickstein
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Gerasimos Filippatos
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Richard Holcomb
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Henry Krum
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Aldo P Maggioni
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Alexandre Mebazaa
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - W Frank Peacock
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Mark C Petrie
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Piotr Ponikowski
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Frank Ruschitzka
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Dirk J van Veldhuisen
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Lisa S Kowarski
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Mark Schactman
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| | - Johannes Holzmeister
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.)
| |
Collapse
|
|
34
|
Cunningham L, Misra A. Serelaxin in the Treatment of Acute Heart Failure in the Emergency Department. CURRENT EMERGENCY AND HOSPITAL MEDICINE REPORTS 2017. [DOI: 10.1007/s40138-017-0136-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
35
|
Sabbah HN. Silent disease progression in clinically stable heart failure. Eur J Heart Fail 2017; 19:469-478. [PMID: 27976514 PMCID: PMC5396296 DOI: 10.1002/ejhf.705] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 10/21/2016] [Accepted: 11/02/2016] [Indexed: 12/11/2022] Open
Abstract
Heart failure with reduced ejection fraction (HFrEF) is a progressive disorder whereby cardiac structure and function continue to deteriorate, often despite the absence of clinically apparent signs and symptoms of a worsening disease state. This silent yet progressive nature of HFrEF can contribute to the increased risk of death-even in patients who are 'clinically stable', or who are asymptomatic or only mildly symptomatic-because it often goes undetected and/or undertreated. Current therapies are aimed at improving clinical symptoms, and several agents more directly target the underlying causes of disease; however, new therapies are needed that can more fully address factors responsible for underlying progressive cardiac dysfunction. In this review, mechanisms that drive HFrEF, including ongoing cardiomyocyte loss, mitochondrial abnormalities, impaired calcium cycling, elevated LV wall stress, reactive interstitial fibrosis, and cardiomyocyte hypertrophy, are discussed. Additionally, limitations of current HF therapies are reviewed, with a focus on how these therapies are designed to counteract the deleterious effects of compensatory neurohumoral activation but do not fully prevent disease progression. Finally, new investigational therapies that may improve the underlying molecular, cellular, and structural abnormalities associated with HF progression are reviewed.
Collapse
|
|
36
|
Nieminen MS, Fonseca C, Brito D, Wikström G. The potential of the inodilator levosimendan in maintaining quality of life in advanced heart failure. Eur Heart J Suppl 2017; 19:C15-C21. [PMID: 29249906 PMCID: PMC5932556 DOI: 10.1093/eurheartj/sux003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Maintaining adequate quality of life (QoL) is an important therapeutic objective for patients with advanced heart failure and, for some patients, may take precedence over prolonging life. Achieving good QoL in this context may involve aspects of patient care that lie outside the familiar limits of heart failure treatment. The inodilator levosimendan may be advantageous in this setting, not least because of its sustained duration of action, ascribed to a long-acting metabolite designated OR-1896. The possibility of using this drug in an outpatient setting is a notable practical advantage that avoids the need for patients to attend a clinic appointment. Intermittent therapy can be integrated into a wider system of outreach and patient monitoring. Practical considerations in the use of levosimendan as part of a palliative or end-of-life regimen focused on preserving QoL include the importance of starting therapy at low doses and avoiding bolus administration unless immediate effects are required and patients have adequate baseline arterial blood pressure.
Collapse
Affiliation(s)
- Markku S Nieminen
- Heart and Lung Center, Helsinki University Hospital, Meilahti Tower Hospital, PL 340, 00029 HUS Helsinki, Finland
| | - Cândida Fonseca
- Heart Failure Unit, Department of Internal Medicine, Hospital Sao Francisco Xavier, Centro Hospitalar Lisboa Ocidental, Estrada do Forte do Alto do Duque, 1449-005 Lisboa, Portugal
| | - Dulce Brito
- Department of Cardiology, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal
| | - Gerhard Wikström
- Department of Cardiology, Institute of Medical Sciences, Uppsala University, Akademiska sjukhuset, Ing.40, 5 tr, 751 85 Uppsala, Sweden
| |
Collapse
|
|
37
|
Mullens W, Verbrugge FH, Nijst P, Tang WHW. Renal sodium avidity in heart failure: from pathophysiology to treatment strategies. Eur Heart J 2017; 38:1872-1882. [DOI: 10.1093/eurheartj/ehx035] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 01/16/2017] [Indexed: 01/10/2023] Open
|
|
38
|
Unemori E. Serelaxin in clinical development: past, present and future. Br J Pharmacol 2017; 174:921-932. [PMID: 28009437 DOI: 10.1111/bph.13695] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 11/18/2016] [Accepted: 12/05/2016] [Indexed: 12/15/2022] Open
Abstract
The availability of highly purified recombinant human relaxin, serelaxin, has allowed clinical trials to be conducted in several indications and the elucidation of its pharmacology in human subjects. These studies have demonstrated that serelaxin has unique haemodynamic properties that are likely to contribute to organ protection and long-term outcome benefits in acute heart failure. Clinical observations support its consideration for therapeutic use in other patient populations, including those with chronic heart failure, coronary artery disease, portal hypertension and acute renal failure. LINKED ARTICLES This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.
Collapse
|
|
39
|
Díez J, Bayés-Genis A. What is on the horizon for improved treatments for acutely decompensated heart failure? Eur Heart J Suppl 2016. [DOI: 10.1093/eurheartj/suw043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
|
|
40
|
Hamo CE, Butler J, Gheorghiade M, Chioncel O. The bumpy road to drug development for acute heart failure. Eur Heart J Suppl 2016. [DOI: 10.1093/eurheartj/suw045] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
|
|
41
|
Packer M, Holcomb R, Abraham WT, Anker S, Dickstein K, Filippatos G, Krum H, Maggioni AP, McMurray JJV, Mebazaa A, O'Connor C, Peacock F, Ponikowski P, Ruschitzka F, van Veldhuisen DJ, Holzmeister J. Rationale for and design of the TRUE-AHF trial: the effects of ularitide on the short-term clinical course and long-term mortality of patients with acute heart failure. Eur J Heart Fail 2016; 19:673-681. [PMID: 27862700 DOI: 10.1002/ejhf.698] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 10/21/2016] [Accepted: 10/27/2016] [Indexed: 12/16/2022] Open
Abstract
The TRUE-AHF is a randomized, double-blind, parallel-group, placebo-controlled trial which is evaluating the effects of a 48-h infusion of ularitide (15 ng/kg/min) on the short- and long-term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long-term follow-up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event-driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in-hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE-AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure. TRIAL REGISTRATION NCT01661634.
Collapse
Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA
| | | | | | - Stefan Anker
- Innovative Clinical Trials, Department of Cardiology & Pneumology, University Medical Center Göttingen (UMG), Göttingen, Germany
| | | | - Gerasimos Filippatos
- National and Kapodistrian University of Athens, School of Medicine, Attikon Athens University Hospital, Department of Cardiology, Athens, Greece
| | - Henry Krum
- Monash University, Centre of Cardiovascular Research & Education in Therapeutics, Melbourne, Australia
| | - Aldo P Maggioni
- Centro Studi ANMCO, Fondazione 'per il Tuo cuore' HCF ONLUS, Firenze, Italy
| | - John J V McMurray
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Alexandre Mebazaa
- University of Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaire Saint Louis Lariboisière, Paris, France
| | | | | | | | | | | | - Johannes Holzmeister
- Cardiology, University Hospital Zurich, Zurich, Switzerland.,Cardiorentis AG, Zug, Switzerland
| | | |
Collapse
|
|
42
|
Affiliation(s)
- Jalal K Ghali
- a Division of Cardiology, Department of Medicine , Mercer University School of Medicine , Macon , GA USA
| |
Collapse
|
|
43
|
Abstract
Despite advances in therapy, patients with heart failure (HF) continue to experience unacceptably high rates of hospitalization and death, as well as poor quality of life. As a consequence, there is an urgent need for new treatments that can improve the clinical course of the growing worldwide population of HF patients. Serelaxin and ularatide, both based on naturally occurring peptides, have potent vasodilatory as well as other effects on the heart and kidneys. For both agents, phase 3 studies that are designed to determine whether they improve outcomes in patients with acute HF have completed enrollment. TRV027, a biased ligand for the type 1 angiotensin receptor with effects that extend beyond traditional angiotensin-receptor blockers is also being studied in the acute HF population. Omecamtiv mecarbil, an inotropic agent that improves myocardial contractility by a novel mechanism, and vericiguat, a drug that stimulates soluble guanylate cyclase, are both being developed to treat patients with chronic HF. Finally, despite the negative results of the CUPID study, gene transfer therapy continues to be explored as a means of improving the function of the failing heart. The basis for the use of these drugs and their current status in clinical trials are discussed. (Circ J 2016; 80: 1882-1891).
Collapse
|
|
44
|
Similar hemodynamic decongestion with vasodilators and inotropes: systematic review, meta-analysis, and meta-regression of 35 studies on acute heart failure. Clin Res Cardiol 2016; 105:971-980. [PMID: 27314418 DOI: 10.1007/s00392-016-1009-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 06/08/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND Acute heart failure (AHF) with reduced left-ventricular ejection fraction (LVEF) is often a biventricular congested state. The comparative effect of vasodilators and inotropes on the right- and/or left-sided congestion is unknown. METHODS AND RESULTS A systematic review, meta-analysis, and meta-regression of AHF studies using pulmonary artery catheter were performed using PubMed, Embase, and Cochrane library. Data from 35 studies, including 3016 patients, were studied. Included patients had a weighted mean age of 60 years, left-ventricular ejection fraction (LVEF) of 24 %, and plasma B-type natriuretic peptide (BNP) of 892 pg/ml. Both the left- and right-ventricular filling pressures were elevated: weighted mean pulmonary artery wedge pressure (PAWP) was 25 mmHg (range 17-31 mmHg) and right atrial pressure (RAP) 12 mmHg (range 7-18 mmHg). Vasodilators and inotropes had similar beneficial effects on PAWP [-6.3 mmHg (95 % CI -7.4 to -5.2 mmHg) and -5.8 mmHg (95 % CI -7.6 to -4.0 mmHg), respectively] and RAP [-2.9 mmHg (95 % CI -3.8 to -2.1 mmHg) and -2.8 mmHg (95 % CI -3.8 to -1.7 mmHg), respectively]. Among inotropes, inodilators, such as levosimendan, have greater beneficial effect on the left-ventricular filling pressure than dobutamine. Drug-induced improvement of PAWP tightly paralleled that of RAP with all studied drugs (r 2 = 0.90, p < 0.001). Vasodilators and inotropes had no short-term effect of renal function. CONCLUSION The left- and right-sided filling pressures are similarly improved by vasodilators or inotropes, in AHF with reduced LVEF.
Collapse
|
|
45
|
Tran HA, Lin F, Greenberg BH. Potential new drug treatments for congestive heart failure. Expert Opin Investig Drugs 2016; 25:811-26. [DOI: 10.1080/13543784.2016.1181749] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
|
|
46
|
Wong LL, Wang J, Liew OW, Richards AM, Chen YT. MicroRNA and Heart Failure. Int J Mol Sci 2016; 17:502. [PMID: 27058529 PMCID: PMC4848958 DOI: 10.3390/ijms17040502] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 03/18/2016] [Accepted: 03/23/2016] [Indexed: 12/12/2022] Open
Abstract
Heart failure (HF) imposes significant economic and public health burdens upon modern society. It is known that disturbances in neurohormonal status play an important role in the pathogenesis of HF. Therapeutics that antagonize selected neurohormonal pathways, specifically the renin-angiotensin-aldosterone and sympathetic nervous systems, have significantly improved patient outcomes in HF. Nevertheless, mortality remains high with about 50% of HF patients dying within five years of diagnosis thus mandating ongoing efforts to improve HF management. The discovery of short noncoding microRNAs (miRNAs) and our increasing understanding of their functions, has presented potential therapeutic applications in complex diseases, including HF. Results from several genome-wide miRNA studies have identified miRNAs differentially expressed in HF cohorts suggesting their possible involvement in the pathogenesis of HF and their potential as both biomarkers and as therapeutic targets. Unravelling the functional relevance of miRNAs within pathogenic pathways is a major challenge in cardiovascular research. In this article, we provide an overview of the role of miRNAs in the cardiovascular system. We highlight several HF-related miRNAs reported from selected cohorts and review their putative roles in neurohormonal signaling.
Collapse
Affiliation(s)
- Lee Lee Wong
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, #08-01, MD6 Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
| | - Juan Wang
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, #08-01, MD6 Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
| | - Oi Wah Liew
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, #08-01, MD6 Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
| | - Arthur Mark Richards
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, #08-01, MD6 Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
- Cardiac Department, National University Health System, Tower Block Level 9, 1E Kent Ridge Road, Singapore 119228, Singapore.
- Christchurch Heart Institute, Department of Medicine, University of Otago, PO Box 4345, Christchurch 8014, New Zealand.
| | - Yei-Tsung Chen
- Cardiovascular Research Institute, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, #08-01, MD6 Centre for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore.
| |
Collapse
|
|
47
|
Lemm H, Dietz S, Janusch M, Buerke M. [Modern drug therapy in cardiovascular intensive care medicine]. Internist (Berl) 2016; 56:702, 704-8, 710-2. [PMID: 26054838 DOI: 10.1007/s00108-015-3717-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Vasoactive drugs and inotropes are important in the hemodynamic management of patients with cardiogenic shock despite modest volume administration. Currently, the concept of cardiac relief is pursued in the treatment of acute heart failure. In this article we present the use of different drugs in the intensive care unit for acute heart failure and cardiogenic shock. In acute heart failure catecholamines are only used during the transition from heart failure to cardiogenic shock. Here, the therapeutic concept of ventricular unloading is more sought after. This can be achieved by the use of diuretics, nitrates, levosimendan (inodilatator), or in the future serelaxin. The hemodynamic management in cardiogenic shock occurs after moderate volume administration with dobutamine to increase inotropy. If no adequate perfusion pressures are achieved, norepinephrine can be administered as a vasopressor. If there is still no sufficient increase in cardiac output, the inodilatator levosimendan can be used. Levosimendan instead of phosphodiesterase inhibitors in this case is preferable. The maxim of hemodynamic management in cardiogenic shock is the transient use of inotropes and vasopressors in the lowest dose possible and only for as long as necessary. This means that one should continuously check whether the dose can be reduced. There are no mortality data demonstrating the utility of hemodynamic monitoring based on objective criteria—but it makes sense to use inotropes and vasopressors sparingly.
Collapse
Affiliation(s)
- H Lemm
- Medizinische Klinik II - Kardiologie, Angiologie, Internistische Intensivmedizin, St. Marienkrankenhaus Siegen, Kampenstr. 51, 57072, Siegen, Deutschland
| | | | | | | |
Collapse
|
|
48
|
Wang G, Wang P, Li Y, Liu W, Bai S, Zhen Y, Li D, Yang P, Chen Y, Hong L, Sun J, Chen J, Wang X, Zhu J, Hu D, Li H, Wu T, Huang J, Tan H, Zhang J, Liao Z, Yu L, Mao Y, Ye S, Feng L, Hua Y, Ni X, Zhang Y, Wang Y, Li W, Luan X, Sun X, Wang S. Efficacy and Safety of 1-Hour Infusion of Recombinant Human Atrial Natriuretic Peptide in Patients With Acute Decompensated Heart Failure: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Medicine (Baltimore) 2016; 95:e2947. [PMID: 26945407 PMCID: PMC4782891 DOI: 10.1097/md.0000000000002947] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 01/11/2016] [Accepted: 02/08/2016] [Indexed: 11/29/2022] Open
Abstract
The aim of the study was to evaluate the efficacy and safety of 1-h infusion of recombinant human atrial natriuretic peptide (rhANP) in combination with standard therapy in patients with acute decompensated heart failure (ADHF). This was a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients with ADHF were randomized to receive a 1-h infusion of either rhANP or placebo at a ratio of 3:1 in combination with standard therapy. The primary endpoint was dyspnea improvement (a decrease of at least 2 grades of dyspnea severity at 12 h from baseline). Reduction in pulmonary capillary wedge pressure (PCWP) 1 h after infusion was the co-primary endpoint for catheterized patients. Overall, 477 patients were randomized: 358 (93 catheterized) patients received rhANP and 118 (28 catheterized) received placebo. The percentage of patients with dyspnea improvement at 12 h was higher, although not statistically significant, in the rhANP group than in the placebo group (32.0% vs 25.4%, odds ratio=1.382, 95% confidence interval [CI]: 0.863-2.212, P = 0.17). Reduction in PCWP at 1 h was significantly greater in patients treated with rhANP than in patients treated with placebo (-7.74 ± 5.95 vs -1.82 ± 4.47 mm Hg, P < 0.001). The frequencies of adverse events and renal impairment within 3 days of treatment were similar between the 2 groups. Mortality at 1 month was 3.1% in the rhANP group vs 2.5% in the placebo group (hazard ratio = 1.21, 95% CI: 0.34-4.26; P > 0.99). 1-h rhANP infusion appears to result in prompt, transient hemodynamic improvement with a small, nonsignificant, effect on dyspnea in ADHF patients receiving standard therapy. The safety of 1-h infusion of rhANP seems to be acceptable. (WHO International Clinical Trials Registry Platform [ICTRP] number, ChiCTR-IPR-14005719.).
Collapse
Affiliation(s)
- Guogan Wang
- From the Department of Cardiology (G. Wang, P. Wang, J. Huang, H. Tan, J. Zhang, Z. Liao, L. Yu, Y. Mao, S. Ye, L. Feng, Y. Hua, X. Ni, Y. Zhang, X. Luan, X. Sun, S. Wang), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College; Heart Center (P. Wang), First Hospital of Tsinghua University; Key Laboratory of Cardiovascular Drugs of Ministry of Health (Y. Li), Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Department of Cardiology (W. Liu, S. Bai), Beijing Anzhen Hospital, The Capital University Medical Sciences, Beijing; Department of Cardiology (Y. Zhen), The First Hospital of Jilin University, Changchun; Department of Cardiology (D. Li), The Affiliated Hospital of Xuzhou Medical College, Xuzhou; Department of Cardiology (P. Yang, Y. Chen), China-Japan Friendship Hospital, Jilin University, Changchun; Department of Cardiology (LH), Jiangxi Provincial People's Hospital, Nanchang; Department of Cardiology (J. Sun), The First People's Hospital of Changzhou, Changzhou; Department of Cardiology (J. Chen), First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou; Department of Cardiology (X. Wang), Beijing Military General Hospital; Department of Cardiology (J. Zhu, D. Hu), Peking University People's Hospital, Beijing; Department of Cardiology (H. Li), The 254 Hospital of People's Liberation Army, Tianjin; Department of Cardiology (T. Wu), Guangzhou Red Cross Hospital, Guangzhou; and Medical Research & Biometrics Center (Y. Wang, W. Li), National Center for Cardiovascular Diseases, Beijing, China
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Tolppanen H, Logeart D. Nouveaux médicaments dans l’insuffisance cardiaque aiguë. MEDECINE INTENSIVE REANIMATION 2016. [DOI: 10.1007/s13546-015-1167-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
|
|
50
|
Abstract
Although the period from 1953 to 2001 resulted in the approval of more than 30 medications currently used to treat heart failure (HF), few novel drugs have been approved in the last decade. However, the investigational pipeline for HF medications once again appears promising. In patients with chronic heart failure with reduced ejection fraction (HFrEF), ivabradine and valsartan/sucubitril (LCZ696) were recently approved by the US Food and Drug Administration. Both agents have been shown to reduce the risk of cardiovascular death and HF hospitalization. In the treatment of acute HF, serelaxin and ularitide are the farthest along in development. Both agents have demonstrated favorable effects on surrogate end points and preliminary data suggest a possible mortality benefit with serelaxin. Consequently, phase 3 trials are ongoing to evaluate the effect of serelaxin and ularitide on clinical outcomes. Given the poor history of recent investigational acute HF drugs that have advanced to phase 3/4 studies, enthusiasm for both serelaxin and ularitide must be tempered until these trials are completed.
Collapse
Affiliation(s)
- Sarah Hanigan
- Department of Pharmacy, University of Michigan Health System, Ann Arbor, MI, USA
| | - Robert J. DiDomenico
- Department of Pharmacy Practice, Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago College of Pharmacy, Chicago, IL, USA
| |
Collapse
|