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1
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Ghofrani HA, Gomberg-Maitland M, Zhao L, Grimminger F. Mechanisms and treatment of pulmonary arterial hypertension. Nat Rev Cardiol 2025; 22:105-120. [PMID: 39112561 DOI: 10.1038/s41569-024-01064-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/04/2024] [Indexed: 11/28/2024]
Abstract
Substantial progress has been made in the management of pulmonary arterial hypertension (PAH) in the past 25 years, but the disease remains life-limiting. Established therapies for PAH are mostly limited to symptomatic relief by correcting the imbalance of vasoactive factors. The tyrosine kinase inhibitor imatinib, the first predominantly non-vasodilatory drug to be tested in patients with PAH, improved exercise capacity and pulmonary haemodynamics compared with placebo but at the expense of adverse events such as subdural haematoma. Given that administration by inhalation might reduce the risk of systemic adverse effects, inhaled formulations of tyrosine kinase inhibitors are currently in clinical development. Other novel therapeutic approaches for PAH include suppression of activin receptor type IIA signalling with sotatercept, which has shown substantial efficacy in clinical trials and was approved for use in the USA in 2024, but the long-term safety of the drug remains unclear. Future advances in the management of PAH will focus on right ventricular function and involve deep phenotyping and the development of a personalized medicine approach. In this Review, we summarize the mechanisms underlying PAH, provide an overview of available PAH therapies and their limitations, describe the development of newer, predominantly non-vasodilatory drugs that are currently being tested in phase II or III clinical trials, and discuss future directions for PAH research.
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Affiliation(s)
- Hossein-Ardeschir Ghofrani
- Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany.
| | - Mardi Gomberg-Maitland
- George Washington University School of Medicine and Health Sciences, Department of Medicine, Washington, DC, USA
| | - Lan Zhao
- National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK
| | - Friedrich Grimminger
- Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Institute for Lung Health (ILH), Cardio-Pulmonary Institute (CPI), German Center for Lung Research (DZL), Giessen, Germany
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2
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Tsai J, Malik S, Tjen-A-Looi SC. Pulmonary Hypertension: Pharmacological and Non-Pharmacological Therapies. Life (Basel) 2024; 14:1265. [PMID: 39459565 PMCID: PMC11509317 DOI: 10.3390/life14101265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/23/2024] [Accepted: 10/01/2024] [Indexed: 10/28/2024] Open
Abstract
Pulmonary hypertension (PH) is a severe and chronic disease characterized by increased pulmonary vascular resistance and remodeling, often precipitating right-sided heart dysfunction and death. Although the condition is progressive and incurable, current therapies for the disease focus on multiple different drugs and general supportive therapies to manage symptoms and prolong survival, ranging from medications more specific to pulmonary arterial hypertension (PAH) to exercise training. Moreover, there are multiple studies exploring novel experimental drugs and therapies including unique neurostimulation, to help better manage the disease. Here, we provide a narrative review focusing on current PH treatments that target multiple underlying biochemical mechanisms, including imbalances in vasoconstrictor-vasodilator and autonomic nervous system function, inflammation, and bone morphogenic protein (BMP) signaling. We also focus on the potential of novel therapies for managing PH, focusing on multiple types of neurostimulation including acupuncture. Lastly, we also touch upon the disease's different subgroups, clinical presentations and prognosis, diagnostics, demographics, and cost.
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Affiliation(s)
- Jason Tsai
- Susan Samueli Integrative Health Institute, College of Health Sciences, University of California-Irvine, Irvine, CA 92617, USA;
| | | | - Stephanie C. Tjen-A-Looi
- Susan Samueli Integrative Health Institute, College of Health Sciences, University of California-Irvine, Irvine, CA 92617, USA;
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Corboz MR, Nguyen TL, Stautberg A, Cipolla D, Perkins WR, Chapman RW. Current Overview of the Biology and Pharmacology in Sugen/Hypoxia-Induced Pulmonary Hypertension in Rats. J Aerosol Med Pulm Drug Deliv 2024; 37:241-283. [PMID: 39388691 PMCID: PMC11502635 DOI: 10.1089/jamp.2024.0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 07/03/2024] [Indexed: 10/12/2024] Open
Abstract
The Sugen 5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) demonstrates most of the distinguishing features of PAH in humans, including increased wall thickness and obstruction of the small pulmonary arteries along with plexiform lesion formation. Recently, significant advancement has been made describing the epidemiology, genomics, biochemistry, physiology, and pharmacology in Su/Hx challenge in rats. For example, there are differences in the overall reactivity to Su/Hx challenge in different rat strains and only female rats respond to estrogen treatments. These conditions are also encountered in human subjects with PAH. Also, there is a good translation in both the biochemical and metabolic pathways in the pulmonary vasculature and right heart between Su/Hx rats and humans, particularly during the transition from the adaptive to the nonadaptive phase of right heart failure. Noninvasive techniques such as echocardiography and magnetic resonance imaging have recently been used to evaluate the progression of the pulmonary vascular and cardiac hemodynamics, which are important parameters to monitor the efficacy of drug treatment over time. From a pharmacological perspective, most of the compounds approved clinically for the treatment of PAH are efficacious in Su/Hx rats. Several compounds that show efficacy in Su/Hx rats have advanced into phase II/phase III studies in humans with positive results. Results from these drug trials, if successful, will provide additional treatment options for patients with PAH and will also further validate the excellent translation that currently exists between Su/Hx rats and the human PAH condition.
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Yuchi Y, Suzuki R, Ishida N, Satomi S, Saito T, Teshima T, Matsumoto H. Comparative Study of Cardiovascular Effects of Selected Pulmonary Vasodilators in Canine Models of Mitral Valve Disease. BIOLOGY 2024; 13:311. [PMID: 38785793 PMCID: PMC11118215 DOI: 10.3390/biology13050311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/25/2024]
Abstract
Previous reports have shown that various oral pulmonary vasodilators are effective against canine pulmonary hypertension (PH). However, no studies have compared their hemodynamic effects. We aimed to compare the hemodynamic effects of 15 µg/kg beraprost sodium, 1.0 mg/kg sildenafil, and their combination, in dogs with experimentally induced mitral regurgitation. This experimental crossover study evaluated the hemodynamic and functional effects of oral pulmonary vasodilators by application of right-sided heart catheterization and echocardiography. Beraprost significantly decreased pulmonary and systemic vascular resistance. Additionally, beraprost increased right-ventricular stroke volume and left-ventricular cardiac output without worsening left-heart size and left-atrial pressure. The pulmonary vasodilatory effects of sildenafil were stronger, and its systemic vasodilatory effects were weaker than those of beraprost. However, sildenafil significantly increased the left-ventricular volume, left-atrial pressure indicator, and right-ventricular cardiac output. Combination therapy resulted in the strongest pulmonary and systemic vasodilating effects without worsening the left-heart size and left-atrial pressure indicators. Both beraprost and sildenafil were effective against canine PH; however, sildenafil was associated with the risk of worsening left-heart loading. Combination therapy with beraprost and sildenafil synergistically dilated pulmonary and systemic vessels, indicating a more potent treatment option for severe PH cases.
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Affiliation(s)
- Yunosuke Yuchi
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan; (Y.Y.); (S.S.); (T.S.); (T.T.); (H.M.)
- Garden Veterinary Hospital, Tokyo 153-0063, Japan
| | - Ryohei Suzuki
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan; (Y.Y.); (S.S.); (T.S.); (T.T.); (H.M.)
| | - Narumi Ishida
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan; (Y.Y.); (S.S.); (T.S.); (T.T.); (H.M.)
| | - Shuji Satomi
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan; (Y.Y.); (S.S.); (T.S.); (T.T.); (H.M.)
| | - Takahiro Saito
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan; (Y.Y.); (S.S.); (T.S.); (T.T.); (H.M.)
| | - Takahiro Teshima
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan; (Y.Y.); (S.S.); (T.S.); (T.T.); (H.M.)
| | - Hirotaka Matsumoto
- Laboratory of Veterinary Internal Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan; (Y.Y.); (S.S.); (T.S.); (T.T.); (H.M.)
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Matsuura T, Yoshimura A, Fukushima R. Effects of Beraprost with or without NOS Inhibition on Plasma Aldosterone and Hemodynamics in Healthy Cats. Vet Sci 2024; 11:155. [PMID: 38668422 PMCID: PMC11054574 DOI: 10.3390/vetsci11040155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/20/2024] [Accepted: 03/27/2024] [Indexed: 04/29/2024] Open
Abstract
OBJECTIVES The aim of the study was to evaluate the hemodynamic and RA system effects of the oral administration of the clinical dose of beraprost for feline CKD in healthy cats, and also to examine whether NOS inhibition reversed them. METHODS A placebo-controlled pharmacological sequential design study was carried out to assess the plasma aldosterone and renin concentrations (PAC and PRC), blood pressure, heart rate, and exploratorily to estimate renal plasma flow (RPF) and renal vascular resistance (RVR) with simplified methods. RESULTS Beraprost reduced PAC when compared to the placebo (p < 0.05); this was reversed when NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was added to the beraprost treatment (p < 0.01). No differences in the PRC or hemodynamic parameters were detected between beraprost and the placebo. The correlation ratios (η2) showed opposite relationships between beraprost and the added L-NAME effects on PAC, mean blood pressure (MBP), heart rate, estimated RPF (p < 0.001), estimated RVR (p < 0.01), and PRC (p < 0.05). CONCLUSIONS In healthy cats, the clinical dose of beraprost suppresses PAC, which can be reversed by the inhibition of NOS.
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Affiliation(s)
| | - Aritada Yoshimura
- Animal Medical Center, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
| | - Ryuji Fukushima
- Animal Medical Center, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
- Animal Medical Emergency Center, Tokyo University of Agriculture and Technology, Tokyo 184-8588, Japan
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Manzi G, Mariani MV, Filomena D, Recchioni T, Papa S, Scoccia G, Badagliacca R, Vizza CD. Comparative effectiveness of oral therapies targeting the prostacyclin pathway in pulmonary arterial hypertension: A systematic review and network meta-analysis. Vascul Pharmacol 2024; 154:107280. [PMID: 38309551 DOI: 10.1016/j.vph.2024.107280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 12/27/2023] [Accepted: 01/26/2024] [Indexed: 02/05/2024]
Abstract
BACKGROUND Oral prostanoids are recommended in patients with pulmonary arterial hypertension (PAH) and an unsatisfactory response to first-line therapy. OBJECTIVE To compare the effectiveness of oral therapies targeting the prostacyclin pathway in PAH patients. METHODS An online search of Medline, Cochrane Registry, Scopus and EMBASE libraries (from inception to May, 12,020) was conducted. Eight randomized controlled studies were included in the meta-analysis involving 3023 patients, with 828 receiving oral treprostinil, 607 patients receiving selexipag, 125 patients receiving beraprost, and 1463 patients receiving placebo. RESULTS Compared to placebo, oral treprostinil (WMD 9.05, 95% CI 3.0280-15.0839, p = 0.0032) and beraprost (WMD 21.98, 95% CI 5.0536-38.9063, p = 0.0109) were associated with a significant increase in 6-min walking distance (6MWD) at follow-up from baseline, whereas selexipag use was associated with a non-significant increase in 6MWD (WMD 15.41, 95% CI -0.6074; 31.4232, p = 0.0593). Compared to placebo, the risk of clinical worsening was significantly lowered by selexipag (RR 0.47, 95% CI 0.35-0.65, p < 0.001) and oral treprostinil (RR 0.65, 95% CI 0.46-0.90, p 0.012), whereas a non-significant reduction of the outcome was related to beraprost use (RR 0.70, 95% CI 0.36-1.38, p 0.31). No significant difference in 6MWD change and clinical worsening reduction were found among oral treprostinil and selexipag. Beraprost use less frequently caused adverse events as compared to selexipag and oral treprostinil. CONCLUSIONS No differences in 6MWD change, clinical worsening reduction and adverse events rates were found among oral treprostinil and selexipag, resulting in similar efficacy and safety profiles.
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Affiliation(s)
- Giovanna Manzi
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Marco Valerio Mariani
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Domenico Filomena
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Tommaso Recchioni
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Silvia Papa
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Gianmarco Scoccia
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Roberto Badagliacca
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy.
| | - Carmine Dario Vizza
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
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Farmakis IT, Baroutidou A, Patsiou V, Arvanitaki A, Doundoulakis I, Hobohm L, Zafeiropoulos S, Konstantinides SV, D'Alto M, Badagliacca R, Giannakoulas G. Contribution of pressure and flow changes to resistance reduction after pulmonary arterial hypertension treatment: a meta-analysis of 3898 patients. ERJ Open Res 2024; 10:00706-2023. [PMID: 38259812 PMCID: PMC10801731 DOI: 10.1183/23120541.00706-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/21/2023] [Indexed: 01/24/2024] Open
Abstract
Background Pulmonary arterial hypertension (PAH)-targeted therapies exert significant haemodynamic changes; however, systematic synthesis is currently lacking. Methods We searched PubMed, CENTRAL and Web of Science for studies evaluating mean pulmonary artery pressure (mPAP), cardiac index/cardiac output (CI/CO) and pulmonary vascular resistance (PVR) of PAH-targeted therapies either in monotherapy or combinations as assessed by right heart catheterisation in treatment-naïve PAH patients. We performed a random-effects meta-analysis with meta-regression. Results We included 68 studies (90 treatment groups) with 3898 patients (age 47.4±13.2 years, 74% women). In studies with small PVR reduction (<4 WU), CI/CO increase (R2=62%) and not mPAP reduction (R2=24%) was decisive for the PVR reduction (p<0.001 and p=0.36, respectively, in the multivariable meta-regression model); however, in studies with large PVR reduction (>4 WU), both CI/CO increase (R2=72%) and mPAP reduction (R2=35%) contributed significantly to the PVR reduction (p<0.001 and p=0.01, respectively). PVR reduction as a percentage of the pre-treatment value was more pronounced in the oral+prostanoid intravenous/subcutaneous combination therapy (mean difference -50.0%, 95% CI -60.8- -39.2%), compared to oral combination therapy (-41.7%, -47.6- -35.8%), prostanoid i.v./s.c. monotherapy (-31.8%, -37.6- -25.9%) and oral monotherapy (-21.6%, -25.4- -17.8%). Changes in haemodynamic parameters were significantly associated with changes in functional capacity of patients with PAH as expressed by the 6-min walking distance. Conclusion Combination therapies, especially with the inclusion of parenteral prostanoids, lead to remarkable haemodynamic improvement in treatment-naïve PAH patients and may unmask the contribution of mPAP reduction to the overall PVR reduction in addition to the increase in CO.
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Affiliation(s)
- Ioannis T. Farmakis
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
- Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Amalia Baroutidou
- Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Vasiliki Patsiou
- Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Alexandra Arvanitaki
- Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Doundoulakis
- Athens Heart Center, Athens Medical Center, Athens, Greece
- First Department of Cardiology, National and Kapodistrian University, “Hippokration” Hospital, Athens, Greece
| | - Lukas Hobohm
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
- Department of Cardiology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Stefanos Zafeiropoulos
- Elmezzi Graduate School of Molecular Medicine, Northwell Health, Manhasset, NY, USA
- Feinstein Institutes for Medical Research at Northwell Health, Manhasset, NY
| | - Stavros V. Konstantinides
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
- Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece
| | - Michele D'Alto
- Department of Cardiology, University “L. Vanvitelli”-Monaldi Hospital, Naples, Italy
| | - Roberto Badagliacca
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - George Giannakoulas
- Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Manzi G, Mariani MV, Filomena D, Papa S, Recchioni T, Scoccia G, Vizza CD, Badagliacca R. Comparative effectiveness of oral therapies targeting the prostacyclin pathway in pulmonary arterial hypertension: A systematic review and network meta-analysis. Int J Cardiol 2023:131691. [PMID: 38158135 DOI: 10.1016/j.ijcard.2023.131691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 12/22/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Oral prostanoids are recommended in patients with pulmonary arterial hypertension (PAH) and a unsatisfactory response to first-line therapy. OBJECTIVE To compare effectiveness of oral therapies targeting the prostacyclin pathway in PAH patients. METHODS An online search of Medline, Cochrane Registry, Scopus and EMBASE libraries (from inception to May, 12020) was performed. Eight randomized controlled studies were included in the meta-analysis involving 3023 patients, of whom 828 receiving oral treprostinil, 607 patients receiving selexipag, 125 patients receiving beraprost, and 1463 patients received placebo. RESULTS As compared to placebo, oral treprostinil (WMD 9.05, 95% CI 3.0280-15.0839, p = 0.0032) and beraprost (WMD 21.98, 95% CI 5.0536-38.9063, p = 0.0109) arms significantly increased 6 min walking distance (6MWD) at follow-up from baseline, whereas selexipag use was associated with a non-significant increase in 6MWD (WMD 15.41, 95% CI -0.6074; 31.4232, p = 0.0593). Compared to placebo, the risk of clinical worsening was significantly lowered by selexipag (RR 0.47, 95% CI 0.35-0.65, p < 0.001) and oral treprostinil (RR 0.65, 95% CI 0.46-0.90, p 0.012), whereas a non-significant reduction of the outcome was related to beraprost use (RR 0.70, 95% CI 0.36-1.38, p 0.31). No significant difference in 6MWD change and clinical worsening reduction were found among oral treprostinil and selexipag. Beraprost use less frequently caused adverse events as compared to selexipag and oral treprostinil. CONCLUSIONS No differences in 6MWD change, clinical worsening reduction and adverse events rates were found among oral treprostinil and selexipag, resulting in similar efficacy and safety profile.
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Affiliation(s)
- Giovanna Manzi
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Marco Valerio Mariani
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Domenico Filomena
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Silvia Papa
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Tommaso Recchioni
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Gianmarco Scoccia
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Carmine Dario Vizza
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy.
| | - Roberto Badagliacca
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Policlinico Universitario Umberto I, Sapienza University of Rome, 00161 Rome, Italy
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Zeng C, Liu J, Zheng X, Hu X, He Y. Prostaglandin and prostaglandin receptors: present and future promising therapeutic targets for pulmonary arterial hypertension. Respir Res 2023; 24:263. [PMID: 37915044 PMCID: PMC10619262 DOI: 10.1186/s12931-023-02559-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 10/09/2023] [Indexed: 11/03/2023] Open
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH), Group 1 pulmonary hypertension (PH), is a type of pulmonary vascular disease characterized by abnormal contraction and remodeling of the pulmonary arterioles, manifested by pulmonary vascular resistance (PVR) and increased pulmonary arterial pressure, eventually leading to right heart failure or even death. The mechanisms involved in this process include inflammation, vascular matrix remodeling, endothelial cell apoptosis and proliferation, vasoconstriction, vascular smooth muscle cell proliferation and hypertrophy. In this study, we review the mechanisms of action of prostaglandins and their receptors in PAH. MAIN BODY PAH-targeted therapies, such as endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, activators of soluble guanylate cyclase, prostacyclin, and prostacyclin analogs, improve PVR, mean pulmonary arterial pressure, and the six-minute walk distance, cardiac output and exercise capacity and are licensed for patients with PAH; however, they have not been shown to reduce mortality. Current treatments for PAH primarily focus on inhibiting excessive pulmonary vasoconstriction, however, vascular remodeling is recalcitrant to currently available therapies. Lung transplantation remains the definitive treatment for patients with PAH. Therefore, it is imperative to identify novel targets for improving pulmonary vascular remodeling in PAH. Studies have confirmed that prostaglandins and their receptors play important roles in the occurrence and development of PAH through vasoconstriction, vascular smooth muscle cell proliferation and migration, inflammation, and extracellular matrix remodeling. CONCLUSION Prostacyclin and related drugs have been used in the clinical treatment of PAH. Other prostaglandins also have the potential to treat PAH. This review provides ideas for the treatment of PAH and the discovery of new drug targets.
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Affiliation(s)
- Cheng Zeng
- Department of Cardiology, The Second Xiangya Hospital of Central South University, No.139, Middle Ren-min Road, Changsha, 410011, Hunan Province, People's Republic of China
| | - Jing Liu
- Department of Cardiology, The Second Xiangya Hospital of Central South University, No.139, Middle Ren-min Road, Changsha, 410011, Hunan Province, People's Republic of China
| | - Xialei Zheng
- Department of Cardiology, The Second Xiangya Hospital of Central South University, No.139, Middle Ren-min Road, Changsha, 410011, Hunan Province, People's Republic of China
| | - Xinqun Hu
- Department of Cardiology, The Second Xiangya Hospital of Central South University, No.139, Middle Ren-min Road, Changsha, 410011, Hunan Province, People's Republic of China.
| | - Yuhu He
- Department of Cardiology, The Second Xiangya Hospital of Central South University, No.139, Middle Ren-min Road, Changsha, 410011, Hunan Province, People's Republic of China.
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Bobhate P, Gupta RK, Karande T, Kulkarni S. Inhaled iloprost as an add-on therapy for advanced pulmonary arterial hypertension: An Indian perspective. THE NATIONAL MEDICAL JOURNAL OF INDIA 2023; 35:338-343. [PMID: 37167510 DOI: 10.25259/nmji_35_6_338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
Background Pulmonary arterial hypertension (PAH) is a progressive disease with high morbidity and mortality. Risk stratification and initiation of dual or triple combination therapy has a better clinical response, especially in high-risk patients. Unfortunately, prostacyclin analogues are not marketed in India; hence, the use of these medications is limited. We report the benefits and difficulties of using iloprost inhalation in patients with advanced PAH in India. Methods In this prospective observational study, we included patients with group 1 PAH. Inhaled iloprost was initiated as an add-on therapy for patients who had clinical, echocardiographic or laboratory deterioration on dual oral medications. Patients with clinical instability were excluded. All patients underwent thorough clinical evaluation, detailed echocardiogram and laboratory investigations. Patients were started on inhaled iloprost 2.5 μg six times daily and closely followed up. The dose was escalated if necessary. On follow-up, clinical echocardiographic and laboratory evaluation was done on all patients. Results Fourteen patients (11 women) with a median age of 32 years (2-66 years) with group 1 PAH were started on inhaled iloprost as an add-on therapy. Improvement in clinical parameters, WHO functional class, echocardiographic-derived right ventricular function, and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels were observed in 10 of 14 patients. A median increase of 31% (4.2, 106%) in the distance travelled during 6-minute walk test, a median increase of 45% (-20, 120%) in right ventricular fractional area change, a median increase of 27% (-16.7, 60%) in tricuspid annular peak systolic excursion and a median decrease of 36.7% (-69.6, 17.2%) in NT-pro-BNP levels were observed after initiation of medication. Three patients had progression of symptoms and were then referred for lung/heart-lung transplant. One patient developed progression of symptoms after an excellent initial response and transitioned to subcutaneous treprostinil. Improvement in clinical, echocardiographic and laboratory features allowed us to successfully perform surgical Potts shunt in 2 patients. The medications were well tolerated with minimal and transient side-effects. There were no deaths. Conclusion Inhaled iloprost can be used with acceptable benefits and minimal side-effects in patients with PAH.
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Affiliation(s)
- Prashant Bobhate
- Children's Heart Center, Kokilaben Dhirubhai Ambani Hospital and Research Centre, Rao Achyut Rao Patwardhan Marg, Four Bungalows, Andheri West, Mumbai 400053, Maharashtra, India
| | - Rajat Kumar Gupta
- Children's Heart Center, Kokilaben Dhirubhai Ambani Hospital and Research Centre, Rao Achyut Rao Patwardhan Marg, Four Bungalows, Andheri West, Mumbai 400053, Maharashtra, India
| | - Tanuja Karande
- Children's Heart Center, Kokilaben Dhirubhai Ambani Hospital and Research Centre, Rao Achyut Rao Patwardhan Marg, Four Bungalows, Andheri West, Mumbai 400053, Maharashtra, India
| | - Snehal Kulkarni
- Children's Heart Center, Kokilaben Dhirubhai Ambani Hospital and Research Centre, Rao Achyut Rao Patwardhan Marg, Four Bungalows, Andheri West, Mumbai 400053, Maharashtra, India
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11
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Papa S, Scoccia G, Serino G, Adamo FI, Jabbour JP, Caputo A, Boromei M, Filomena D, Laviola D, Maggio E, Manzi G, Mihai A, Recchioni T, Sabusco A, Valeri L, Vinciullo S, Vizza CD, Badagliacca R. Impact of Parenteral Prostanoids in Pulmonary Arterial Hypertension: The Relevance of Timing. J Clin Med 2023; 12:6840. [PMID: 37959305 PMCID: PMC10648828 DOI: 10.3390/jcm12216840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 10/19/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Parenteral prostanoids are being recommended in pulmonary arterial hypertension (PAH) treatment, but the prognostic relevance of delayed treatment initiation is still debated. This study assessed the impact of the timing of prostacyclin treatment initiation on reducing PVR and achieving a low-risk profile in PAH patients. The study enrolled 151 patients who started on parenteral prostanoids with different treatment strategies. All patients underwent right heart catheterization, clinical evaluation, and risk assessments at baseline and after 1-year follow-up. Patients with an upfront strategy including parenteral prostanoid plus one oral drug had -5.3 ± 6.2 WU (-50 ± 19%) reduction in PVR, patients with an upfront strategy including parenteral prostanoid plus double oral drug had -12.8 ± 5.9 WU (-68 ± 17%) reduction in PVR, while patients with an add-on strategy including parenteral prostanoid after oral drugs had -3.9 ± 3.5 WU (-23 ± 19%) reduction in PVR. An upfront strategy including parenteral prostanoids was independently associated with an increased likelihood of achieving the greater reduction of PVR compared with an add-on strategy. Additionally, the greater the severity of PH at the time of diagnosis, in terms of PVR and RV reverse remodeling, the higher the probability of treatment failure. An upfront strategy including a parenteral prostanoid is associated with the highest likelihood of achieving a low-risk profile and a greater reduction of PVR compared with parenteral prostanoid as an add-on to oral treatment.
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Affiliation(s)
- Silvia Papa
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Gianmarco Scoccia
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Giorgia Serino
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Francesca Ileana Adamo
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Jean Pierre Jabbour
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Annalisa Caputo
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Michela Boromei
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Domenico Filomena
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Domenico Laviola
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Enrico Maggio
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Giovanna Manzi
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Alexandra Mihai
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Tommaso Recchioni
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Alexandra Sabusco
- Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy;
| | - Livia Valeri
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Sara Vinciullo
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Carmine Dario Vizza
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
| | - Roberto Badagliacca
- Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy; (G.S.); (G.S.); (F.I.A.); (J.P.J.); (A.C.); (M.B.); (D.F.); (D.L.); (E.M.); (G.M.); (A.M.); (T.R.); (L.V.); (S.V.); (C.D.V.); (R.B.)
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12
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Alqarni AA, Aldhahir AM, Alghamdi SA, Alqahtani JS, Siraj RA, Alwafi H, AlGarni AA, Majrshi MS, Alshehri SM, Pang L. Role of prostanoids, nitric oxide and endothelin pathways in pulmonary hypertension due to COPD. Front Med (Lausanne) 2023; 10:1275684. [PMID: 37881627 PMCID: PMC10597708 DOI: 10.3389/fmed.2023.1275684] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 09/19/2023] [Indexed: 10/27/2023] Open
Abstract
Pulmonary hypertension (PH) due to chronic obstructive pulmonary disease (COPD) is classified as Group 3 PH, with no current proven targeted therapies. Studies suggest that cigarette smoke, the most risk factor for COPD can cause vascular remodelling and eventually PH as a result of dysfunction and proliferation of pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs). In addition, hypoxia is a known driver of pulmonary vascular remodelling in COPD, and it is also thought that the presence of hypoxia in patients with COPD may further exaggerate cigarette smoke-induced vascular remodelling; however, the underlying cause is not fully understood. Three main pathways (prostanoids, nitric oxide and endothelin) are currently used as a therapeutic target for the treatment of patients with different groups of PH. However, drugs targeting these three pathways are not approved for patients with COPD-associated PH due to lack of evidence. Thus, this review aims to shed light on the role of impaired prostanoids, nitric oxide and endothelin pathways in cigarette smoke- and hypoxia-induced pulmonary vascular remodelling and also discusses the potential of using these pathways as therapeutic target for patients with PH secondary to COPD.
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Affiliation(s)
- Abdullah A. Alqarni
- Department of Respiratory Therapy, Faculty of Medical Rehabilitation Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Respiratory Therapy Unit, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
| | - Abdulelah M. Aldhahir
- Respiratory Therapy Department, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Sara A. Alghamdi
- Respiratory Care Department, Al Murjan Hospital, Jeddah, Saudi Arabia
| | - Jaber S. Alqahtani
- Department of Respiratory Care, Prince Sultan Military College of Health Sciences, Dammam, Saudi Arabia
| | - Rayan A. Siraj
- Department of Respiratory Care, College of Applied Medical Sciences, King Faisal University, Al Ahsa, Saudi Arabia
| | - Hassan Alwafi
- Faculty of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia
| | - Abdulkareem A. AlGarni
- King Abdulaziz Hospital, The Ministry of National Guard Health Affairs, Al Ahsa, Saudi Arabia
- King Saud bin Abdulaziz University for Health Sciences, College of Applied Medical Sciences, Al Ahsa, Saudi Arabia
| | - Mansour S. Majrshi
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Respiratory Medicine, Royal Brompton Hospital, London, United Kingdom
| | - Saad M. Alshehri
- Department of Respiratory Therapy, King Fahad General Hospital, Jeddah, Saudi Arabia
| | - Linhua Pang
- Respiratory Medicine Research Group, Academic Unit for Translational Medical Sciences, University of Nottingham School of Medicine, Nottingham, United Kingdom
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13
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Boucly A, Gerges C, Savale L, Jaïs X, Jevnikar M, Montani D, Sitbon O, Humbert M. Pulmonary arterial hypertension. Presse Med 2023; 52:104168. [PMID: 37516248 DOI: 10.1016/j.lpm.2023.104168] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 07/17/2023] [Indexed: 07/31/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare and progressive disease characterised by remodelling of the pulmonary arteries and progressive narrowing of the pulmonary vasculature. This leads to a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure and, if left untreated, to right ventricular failure and death. A correct diagnosis requires a complete work-up including right heart catheterisation performed in a specialised centre. Although our knowledge of the epidemiology, pathology and pathophysiology of the disease, as well as the development of innovative therapies, has progressed in recent decades, PAH remains a serious clinical condition. Current treatments for the disease target the three specific pathways of endothelial dysfunction that characterise PAH: the endothelin, nitric oxide and prostacyclin pathways. The current treatment algorithm is based on the assessment of severity using a multiparametric risk stratification approach at the time of diagnosis (baseline) and at regular follow-up visits. It recommends the initiation of combination therapy in PAH patients without cardiopulmonary comorbidities. The choice of therapy (dual or triple) depends on the initial severity of the condition. The main treatment goal is to achieve low-risk status. Further escalation of treatment is required if low-risk status is not achieved at subsequent follow-up assessments. In the most severe patients, who are already on maximal medical therapy, lung transplantation may be indicated. Recent advances in understanding the pathophysiology of the disease have led to the development of promising emerging therapies targeting dysfunctional pathways beyond endothelial dysfunction, including the TGF-β and PDGF pathways.
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Affiliation(s)
- Athénaïs Boucly
- Université Paris-Saclay, Faculé de Médicine, Le Kremlin-Bicêtre, France; Service de Pneumologie et Soins Intensifs Respiratoires, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMRS-999, Le Kremlin-Bicêtre, France; National Heart and Lung Institute, Imperial College London, London, UK.
| | - Christian Gerges
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Laurent Savale
- Université Paris-Saclay, Faculé de Médicine, Le Kremlin-Bicêtre, France; Service de Pneumologie et Soins Intensifs Respiratoires, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMRS-999, Le Kremlin-Bicêtre, France
| | - Xavier Jaïs
- Université Paris-Saclay, Faculé de Médicine, Le Kremlin-Bicêtre, France; Service de Pneumologie et Soins Intensifs Respiratoires, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMRS-999, Le Kremlin-Bicêtre, France
| | - Mitja Jevnikar
- Université Paris-Saclay, Faculé de Médicine, Le Kremlin-Bicêtre, France; Service de Pneumologie et Soins Intensifs Respiratoires, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMRS-999, Le Kremlin-Bicêtre, France
| | - David Montani
- Université Paris-Saclay, Faculé de Médicine, Le Kremlin-Bicêtre, France; Service de Pneumologie et Soins Intensifs Respiratoires, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMRS-999, Le Kremlin-Bicêtre, France
| | - Olivier Sitbon
- Université Paris-Saclay, Faculé de Médicine, Le Kremlin-Bicêtre, France; Service de Pneumologie et Soins Intensifs Respiratoires, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMRS-999, Le Kremlin-Bicêtre, France
| | - Marc Humbert
- Université Paris-Saclay, Faculé de Médicine, Le Kremlin-Bicêtre, France; Service de Pneumologie et Soins Intensifs Respiratoires, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMRS-999, Le Kremlin-Bicêtre, France
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14
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Humbert M, Sitbon O, Guignabert C, Savale L, Boucly A, Gallant-Dewavrin M, McLaughlin V, Hoeper MM, Weatherald J. Treatment of pulmonary arterial hypertension: recent progress and a look to the future. THE LANCET. RESPIRATORY MEDICINE 2023; 11:804-819. [PMID: 37591298 DOI: 10.1016/s2213-2600(23)00264-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 07/03/2023] [Accepted: 07/06/2023] [Indexed: 08/19/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a severe but treatable form of pre-capillary pulmonary hypertension caused by pulmonary vascular remodelling. As a result of basic science discoveries, randomised controlled trials, studies of real-world data, and the development of clinical practice guidelines, considerable progress has been made in the treatment options and outcomes for patients with PAH, underscoring the importance of seamless translation of information from bench to bedside and, ultimately, to patients. However, PAH still carries a high mortality rate, which emphasises the urgent need for transformative innovations in the field. In this Series paper, written by a group of clinicians, researchers, and a patient with PAH, we review therapeutic approaches and treatment options for PAH. We summarise current knowledge of the cellular and molecular mechanisms of PAH, with an emphasis on emerging treatable pathways and optimisation of current management strategies. In considering future directions for the field, our ambition is to identify therapies with the potential to stall or reverse pulmonary vascular remodelling. We highlight novel therapeutic approaches, the important role of patients as partners in research, and innovative approaches to PAH clinical trials.
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Affiliation(s)
- Marc Humbert
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France; INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Department of Respiratory and Intensive Care Medicine, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, ERN-LUNG, Le Kremlin-Bicêtre, France.
| | - Olivier Sitbon
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France; INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Department of Respiratory and Intensive Care Medicine, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, ERN-LUNG, Le Kremlin-Bicêtre, France
| | - Christophe Guignabert
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France; INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Department of Respiratory and Intensive Care Medicine, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, ERN-LUNG, Le Kremlin-Bicêtre, France
| | - Laurent Savale
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France; INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Department of Respiratory and Intensive Care Medicine, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, ERN-LUNG, Le Kremlin-Bicêtre, France
| | - Athénaïs Boucly
- INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France; INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France; Department of Respiratory and Intensive Care Medicine, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, ERN-LUNG, Le Kremlin-Bicêtre, France
| | | | - Vallerie McLaughlin
- Department of Internal Medicine, Division of Cardiology, Frankel Cardiovascular Center University of Michigan Medical School, Ann Arbor, MI, USA
| | - Marius M Hoeper
- Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany; Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH), Hannover, Germany
| | - Jason Weatherald
- Department of Medicine, Division of Pulmonary Medicine, University of Alberta, Edmonton, AB, Canada
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Khan SL, Mathai SC. Scleroderma pulmonary arterial hypertension: the same as idiopathic pulmonary arterial hypertension? Curr Opin Pulm Med 2023; 29:380-390. [PMID: 37461869 PMCID: PMC11334969 DOI: 10.1097/mcp.0000000000001001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/03/2023]
Abstract
PURPOSE OF REVIEW Pulmonary arterial hypertension (PAH) is a common complication of systemic sclerosis (SSc), which confers significant morbidity and mortality. The current therapies and treatment strategies for SSc-associated PAH (SSc-PAH) are informed by those used to treat patients with idiopathic PAH (IPAH). There are, however, important differences between these two diseases that impact diagnosis, treatment, and outcomes. RECENT FINDINGS Both SSc-PAH and IPAH are incompletely understood with ongoing research into the underlying cellular biology that characterize and differentiate the two diseases. Additional research seeks to improve identification among SSc patients in order to diagnose patients earlier in the course of their disease. Novel therapies specifically for SSc-PAH such as rituximab and dimethyl fumarate are under investigation. SUMMARY Although patients with SSc-PAH and IPAH present with similar symptoms, there are significant differences between these two forms of PAH that warrant further investigation and characterization of optimal detection strategies, treatment algorithms, and outcomes assessment.
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Affiliation(s)
- Sarah L Khan
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Alqarni AA, Aldhahir AM, Bintalib HM, Alqahtani JS, Siraj RA, Majrshi M, AlGarni AA, Naser AY, Alghamdi SA, Alwafi H. Inhaled therapies targeting prostacyclin pathway in pulmonary hypertension due to COPD: systematic review. Front Med (Lausanne) 2023; 10:1217156. [PMID: 37706024 PMCID: PMC10496018 DOI: 10.3389/fmed.2023.1217156] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/08/2023] [Indexed: 09/15/2023] Open
Abstract
Background Pulmonary hypertension due to chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) is classified as group 3 pulmonary hypertension. Inhaled treprostinil, a prostaglandin I2 analogue also known as prostacyclin, has recently been approved as a first drug for patients with pulmonary hypertension secondary to ILD. However, due to a lack of evidence, no therapies are currently approved for those with COPD-associated pulmonary hypertension. Thus, this systematic review aims to summarise the current evidence to assess the impact of inhaled prostaglandin I2 analogue use on the pulmonary hemodynamics, exercise function, lung function, and gas exchange in patients with pulmonary hypertension due to COPD. Methods We systematically searched the electronic databases of Medline, Embase, Scopus and Cochrane from inception to 1 February 2023. Studies of adult patients with a confirmed diagnosis of COPD-associated pulmonary hypertension who received inhaled drugs targeting the prostacyclin pathway were included in the systematic review. Case reports, systematic reviews, conference abstracts with no full text, non-full-text articles, non-English manuscripts and book chapters were excluded from this systematic review. A risk-of-bias assessment was carried out for the studies included in this review, using two different Cochrane risk-of-bias tools for randomised and non-randomised clinical trials. Results A total of four studies met our inclusion criteria and were included in this systematic review. The results of one prospective clinical trial showed an improvement in the pulmonary hemodynamics (e.g., cardiac index, cardiac output and mean pulmonary artery pressure) in response to inhaled prostacyclin use in patients with pulmonary hypertension secondary to COPD. However, the severity of dyspnoea, lung function, exercise capacity and gas exchange were not affected when inhaled prostacyclin was used for patients with COPD-related pulmonary hypertension. Conclusion This systematic review demonstrated that although inhaled prostacyclin does not seem to improve COPD-related outcomes (e.g., lung function and exercise capacity), short-term use of inhaled prostacyclin has the potential to reduce mean pulmonary artery pressure and pulmonary vascular resistance without impairing ventilation-perfusion mismatch. Further studies with larger sample sizes are warranted. Systematic review registration CRD42022372803, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=372803.
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Affiliation(s)
- Abdullah A. Alqarni
- Department of Respiratory Therapy, Faculty of Medical Rehabilitation Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Respiratory Therapy Unit, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
| | - Abdulelah M. Aldhahir
- Respiratory Therapy Department, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Heba M. Bintalib
- Department of Respiratory Care, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Centre, Jeddah, Saudi Arabia
| | - Jaber S. Alqahtani
- Department of Respiratory Care, Prince Sultan Military College of Health Sciences, Dammam, Saudi Arabia
| | - Rayan A. Siraj
- Department of Respiratory Care, College of Applied Medical Sciences, King Faisal University, Al Ahsa, Saudi Arabia
| | - Mansour Majrshi
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- Respiratory Medicine, Royal Brompton Hospital, London, United Kingdom
| | - Abdulkareem A. AlGarni
- King Abdulaziz Hospital, The Ministry of National Guard Health Affairs, Al Ahsa, Saudi Arabia
- King Saud bin Abdulaziz University for Health Sciences, College of Applied Medical Sciences, Al Ahsa, Saudi Arabia
| | - Abdallah Y. Naser
- Department of Applied Pharmaceutical Sciences and Clinical Pharmacy, Faculty of Pharmacy, Isra University, Amman, Jordan
| | - Sara A. Alghamdi
- Respiratory Care Department, Mediclinic Almurjan Hospital, Jeddah, Saudi Arabia
| | - Hassan Alwafi
- Faculty of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia
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Auth R, Klinger JR. Emerging pharmacotherapies for the treatment of pulmonary arterial hypertension. Expert Opin Investig Drugs 2023; 32:1025-1042. [PMID: 37881882 DOI: 10.1080/13543784.2023.2274439] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 10/19/2023] [Indexed: 10/27/2023]
Abstract
INTRODUCTION Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Approved treatment options currently primarily target abnormal cell signaling pathways involved in vasoconstriction and proliferation, such as those mediated by prostacyclin, cyclic guanosine monophosphate, and endothelin. AREAS COVERED Recent advancements have led to new applications and modes of delivery of currently approved PAH medications. At the same time, novel drugs targeting specific molecular pathways involved in PAH pathogenesis have been developed and are being investigated in clinical trials. This review summarizes investigational drug trials for PAH gathered from a comprehensive search using PubMed and ClinicalTrials.gov between 2003 and 2023. It includes both currently approved medications studied at different doses or new administration forms and experimental drugs that have not yet been approved. EXPERT OPINION Approved treatments for PAH target imbalances in pulmonary vasoactive pathways that work primarily on enhancing pulmonary vasodilation with less salient effects on pulmonary vascular remodeling. The advent of more locally acting inhaled medications offers additional therapeutic options that may improve the ease of drug delivery and reduce adverse systemic effects. The more recent emphasis on developing and applying therapeutics that directly impact the aberrant signaling pathways implicated in PAH appears more likely to advance the treatment of this devastating disease.
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Affiliation(s)
- Roger Auth
- Division of Pulmonary, Sleep and Critical Care Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA
| | - James R Klinger
- Division of Pulmonary, Sleep and Critical Care Medicine, Rhode Island Hospital and the Alpert Medical School of Brown University, Providence, RI, USA
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Garcia MVF, Coz-Yataco A, Al-Jaghbeer MJ. Pulmonary arterial hypertension trials put to the test: Using the fragility index to assess trials robustness. Heart Lung 2023; 61:147-152. [PMID: 37271106 DOI: 10.1016/j.hrtlng.2023.05.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/29/2023] [Accepted: 05/30/2023] [Indexed: 06/06/2023]
Abstract
BACKGROUND Randomized clinical trials (RCTs) are considered the gold standard for evidence-based medicine. The Fragility Index (FI) is a tool to assess the robustness of RCT results. FI was validated for dichotomous outcomes and recent work expanded its use to continuous outcomes. Studying the robustness of RCTs in Pulmonary Arterial Hypertension (PAH) treatments is crucial due to the severity and mortality risks associated with this rare condition. OBJECTIVES Analyze FI and Fragility quotient (FQ) of significant primary outcomes in PAH RCTs and study FI correlation with sample size and journal impact factor. METHODS FI and FQ calculation followed by Spearman correlation to assess the correlation between FI and sample size, and FI and impact factor. RESULTS The median sample size of the 21 trials was 202 patients (IQR 106-267), with 6 trials reporting primary outcomes as dichotomous and 15 reporting continuous primary outcomes. The median FI was 10 (IQR 3-20), and the median FQ was 0.044 (0.026-0.097). A moderate correlation was found between FI and sample size, with r = 0.56; P = 0.008 and FI and journal impact factor (r=0.50; P=0.019). The FI for continuous outcomes was similar to that for dichotomous outcomes. CONCLUSIONS This study represents the first analysis of the FI and FQ of PAH treatment RCTs, and expands the use of FI to continuous outcomes in this context. The moderate correlation between FI and sample size suggests that increasing sample size alone is partially correlated to a higher FI. The similarity between FI for continuous and dichotomous outcomes supports the broader use of FI in PAH RCTs.
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Affiliation(s)
| | - Angel Coz-Yataco
- Cleveland Clinic Foundation, Fairview Hospital, 18101 Lorain Ave, Cleveland, OH 44111, United States; Respiratory Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Mohammed J Al-Jaghbeer
- Cleveland Clinic Foundation, Fairview Hospital, 18101 Lorain Ave, Cleveland, OH 44111, United States; Respiratory Institute, Cleveland Clinic Foundation, Cleveland, OH, United States; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States
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19
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Jin Q, Chen D, Zhang X, Zhang F, Zhong D, Lin D, Guan L, Pan W, Zhou D, Ge J. Medical Management of Pulmonary Arterial Hypertension: Current Approaches and Investigational Drugs. Pharmaceutics 2023; 15:1579. [PMID: 37376028 DOI: 10.3390/pharmaceutics15061579] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/02/2023] [Accepted: 05/13/2023] [Indexed: 06/29/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular syndrome characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, which eventually leads to right heart failure and even death. Although the exact mechanism of PAH is not fully understood, pulmonary vasoconstriction, vascular remodeling, immune and inflammatory responses, and thrombosis are thought to be involved in the development and progression of PAH. In the era of non-targeted agents, PAH had a very dismal prognosis with a median survival time of only 2.8 years. With the deep understanding of the pathophysiological mechanism of PAH as well as advances in drug research, PAH-specific therapeutic drugs have developed rapidly in the past 30 years, but they primarily focus on the three classical signaling pathways, namely the endothelin pathway, nitric oxide pathway, and prostacyclin pathway. These drugs dramatically improved pulmonary hemodynamics, cardiac function, exercise tolerance, quality of life, and prognosis in PAH patients, but could only reduce pulmonary arterial pressure and right ventricular afterload to a limited extent. Current targeted agents delay the progression of PAH but cannot fundamentally reverse pulmonary vascular remodeling. Through unremitting efforts, new therapeutic drugs such as sotatercept have emerged, injecting new vitality into this field. This review comprehensively summarizes the general treatments for PAH, including inotropes and vasopressors, diuretics, anticoagulants, general vasodilators, and anemia management. Additionally, this review elaborates the pharmacological properties and recent research progress of twelve specific drugs targeting three classical signaling pathways, as well as dual-, sequential triple-, and initial triple-therapy strategies based on the aforementioned targeted agents. More crucially, the search for novel therapeutic targets for PAH has never stopped, with great progress in recent years, and this review outlines the potential PAH therapeutic agents currently in the exploratory stage to provide new directions for the treatment of PAH and improve the long-term prognosis of PAH patients.
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Affiliation(s)
- Qi Jin
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Dandan Chen
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Xiaochun Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Feng Zhang
- Department of Cardiology, Jinshan Hospital, Fudan University, 1508 Longhang Road, Shanghai 201508, China
| | - Dongxiang Zhong
- Department of Cardiology, Shanghai East Hospital, Shanghai Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China
| | - Dawei Lin
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Lihua Guan
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Wenzhi Pan
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Daxin Zhou
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
- National Clinical Research Center for Interventional Medicine, 180 Fenglin Road, Xuhui District, Shanghai 200032, China
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20
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Fike CD, Aschner JL. Pharmacotherapy for Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Past, Present, and Future. Pharmaceuticals (Basel) 2023; 16:503. [PMID: 37111262 PMCID: PMC10141152 DOI: 10.3390/ph16040503] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/31/2023] Open
Abstract
Approximately 8-42% of premature infants with chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD), develop pulmonary hypertension (PH). Infants with BPD-PH carry alarmingly high mortality rates of up to 47%. Effective PH-targeted pharmacotherapies are desperately needed for these infants. Although many PH-targeted pharmacotherapies are commonly used to treat BPD-PH, all current use is off-label. Moreover, all current recommendations for the use of any PH-targeted therapy in infants with BPD-PH are based on expert opinion and consensus statements. Randomized Control Trials (RCTs) are needed to determine the efficacy of PH-targeted treatments in premature infants with or at risk of BPD-PH. Prior to performing efficacy RCTs, studies need to be conducted to obtain pharmacokinetic, pharmacodynamic, and safety data for any pharmacotherapy used in this understudied and fragile patient population. This review will discuss current and needed treatment strategies, identify knowledge deficits, and delineate both challenges to be overcome and approaches to be taken to develop effective PH-targeted pharmacotherapies that will improve outcomes for premature infants with or at risk of developing BPD-PH.
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Affiliation(s)
- Candice D. Fike
- Department of Pediatrics, University of Utah Health, Salt Lake City, UT 84108, USA
| | - Judy L. Aschner
- Department of Pediatrics, Joseph M. Sanzari Children’s Hospital at Hackensack University Medical Center, Hackensack, NJ 07601, USA
- Department of Pediatrics, Hackensack Meridian School of Medicine, Nutley, NJ 07110, USA
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21
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Anheyer D, Bugaj TJ, Lüdtke R, Appelbaum S, Trübel H, Ostermann T. No Placebo Effect beyond Regression to the Mean on the Six Minute Walk Test in Pulmonary Arterial Hypertension Trials. Int J Mol Sci 2023; 24:ijms24021069. [PMID: 36674584 PMCID: PMC9865257 DOI: 10.3390/ijms24021069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 01/09/2023] Open
Abstract
In drug studies, patients are often included when the disease activity is high. This will make any treatment appear to lessen disease activity, although the improvement is biased by selection. This effect is known as regression towards the mean (RTM). We aimed at investigating drug trials in Pulmonary Arterial Hypertension (PAH) using the 6-minute walking distance test (6MWD) as a primary outcome for the phenomenon of RTM. An existing registry of 43 open label studies and 23 randomized controlled trials conducted between 1990 and 2009 was used as the data source. Data analysis was carried out for 18 randomized controlled trials (RCTs) and 24 open label studies out of this registry. Data were analyzed for verum and placebo arms of the RCTs separately, as well as for the open label arms. In the verum arms, the overall effect given as 33.2 m (95% CI: 25.7; 40.6]); 6MWD was slightly lower than the effect in the observational studies, with 44.6 m (95% CI: [25.4; 63.8]). After studying and interpreting the data, we found that regression towards the mean plays only a minor role in PAH studies. In particular, placebo effects in the RCTs were negligibly small, with a mean 6MWD of -2.5 m (95% CI: [-9.8; 4.7]) in the placebo arm. Therefore, our analysis indicates that results of non-randomized observational studies can be regarded as valid tools for gaining valid clinical effects in patients with PAH.
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Affiliation(s)
- Dennis Anheyer
- Department for Psychology and Psychotherapy, Witten/Herdecke University, 58458 Witten, Germany
- Institute for General Practice and Interprofessional Care, University Hospital Tübingen, 72076 Tübingen, Germany
| | - Till Johannes Bugaj
- Department of General Internal Medicine and Psychosomatics, University of Heidelberg, Medical Hospital, 69120 Heidelberg, Germany
| | | | - Sebastian Appelbaum
- Department for Psychology and Psychotherapy, Witten/Herdecke University, 58458 Witten, Germany
| | - Hubert Trübel
- Department for Medicine, Witten/Herdecke University, 58458 Witten, Germany
| | - Thomas Ostermann
- Department for Psychology and Psychotherapy, Witten/Herdecke University, 58458 Witten, Germany
- Correspondence:
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22
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Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2023; 61:2200879. [PMID: 36028254 DOI: 10.1183/13993003.00879-2022] [Citation(s) in RCA: 812] [Impact Index Per Article: 406.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- Marc Humbert
- Faculty of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France, Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France
- INSERM UMR_S 999, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France
| | - Gabor Kovacs
- University Clinic of Internal Medicine, Division of Pulmonology, Medical University of Graz, Graz, Austria
- Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
| | - Marius M Hoeper
- Respiratory Medicine, Hannover Medical School, Hanover, Germany
- Biomedical Research in End-stage and Obstructive Lung Disease (BREATH), member of the German Centre of Lung Research (DZL), Hanover, Germany
| | - Roberto Badagliacca
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Roma, Italy
- Dipartimento Cardio-Toraco-Vascolare e Chirurgia dei Trapianti d'Organo, Policlinico Umberto I, Roma, Italy
| | - Rolf M F Berger
- Center for Congenital Heart Diseases, Beatrix Children's Hospital, Dept of Paediatric Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Margarita Brida
- Department of Sports and Rehabilitation Medicine, Medical Faculty University of Rijeka, Rijeka, Croatia
- Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton and Harefield Hospitals, Guys and St Thomas's NHS Trust, London, UK
| | - Jørn Carlsen
- Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Andrew J S Coats
- Faculty of Medicine, University of Warwick, Coventry, UK
- Faculty of Medicine, Monash University, Melbourne, Australia
| | - Pilar Escribano-Subias
- Pulmonary Hypertension Unit, Cardiology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
- CIBER-CV (Centro de Investigaciones Biomédicas En Red de enfermedades CardioVasculares), Instituto de Salud Carlos III, Madrid, Spain
- Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Pisana Ferrari
- ESC Patient Forum, Sophia Antipolis, France
- AIPI, Associazione Italiana Ipertensione Polmonare, Bologna, Italy
| | - Diogenes S Ferreira
- Alergia e Imunologia, Hospital de Clinicas, Universidade Federal do Parana, Curitiba, Brazil
| | - Hossein Ardeschir Ghofrani
- Department of Internal Medicine, University Hospital Giessen, Justus-Liebig University, Giessen, Germany
- Department of Pneumology, Kerckhoff Klinik, Bad Nauheim, Germany
- Department of Medicine, Imperial College London, London, UK
| | - George Giannakoulas
- Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - David G Kiely
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
- Sheffield Pulmonary Vascular Disease Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Insigneo Institute, University of Sheffield, Sheffield, UK
| | - Eckhard Mayer
- Thoracic Surgery, Kerckhoff Clinic, Bad Nauheim, Germany
| | - Gergely Meszaros
- ESC Patient Forum, Sophia Antipolis, France
- European Lung Foundation (ELF), Sheffield, UK
| | - Blin Nagavci
- Institute for Evidence in Medicine, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Karen M Olsson
- Clinic of Respiratory Medicine, Hannover Medical School, member of the German Center of Lung Research (DZL), Hannover, Germany
| | - Joanna Pepke-Zaba
- Pulmonary Vascular Diseases Unit, Royal Papworth Hospital, Cambridge, UK
| | | | - Göran Rådegran
- Department of Cardiology, Clinical Sciences Lund, Faculty of Medicine, Lund, Sweden
- The Haemodynamic Lab, The Section for Heart Failure and Valvular Disease, VO. Heart and Lung Medicine, Skåne University Hospital, Lund, Sweden
| | - Gerald Simonneau
- Faculté Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France
- Centre de Référence de l'Hypertension Pulmonaire, Hopital Marie-Lannelongue, Le Plessis-Robinson, France
| | - Olivier Sitbon
- INSERM UMR_S 999, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France
- Faculté Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France
- Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France
| | - Thomy Tonia
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - Mark Toshner
- Dept of Medicine, Heart Lung Research Institute, University of Cambridge, Royal Papworth NHS Trust, Cambridge, UK
| | - Jean-Luc Vachiery
- Department of Cardiology, Pulmonary Vascular Diseases and Heart Failure Clinic, HUB Hôpital Erasme, Brussels, Belgium
| | | | - Marion Delcroix
- Clinical Department of Respiratory Diseases, Centre of Pulmonary Vascular Diseases, University Hospitals of Leuven, Leuven, Belgium
- The two chairpersons (M. Delcroix and S. Rosenkranz) contributed equally to the document and are joint corresponding authors
| | - Stephan Rosenkranz
- Clinic III for Internal Medicine (Department of Cardiology, Pulmonology and Intensive Care Medicine), and Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne, Köln, Germany
- The two chairpersons (M. Delcroix and S. Rosenkranz) contributed equally to the document and are joint corresponding authors
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23
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Hashimoto H, Oka T, Nakanishi R, Mizumura S, Dobashi S, Hashimoto Y, Okamura Y, Ota K, Ikeda T. Evaluation of balloon pulmonary angioplasty using lung perfusion SPECT in patients with chronic thromboembolic pulmonary hypertension. J Nucl Cardiol 2022; 29:3392-3400. [PMID: 35474442 PMCID: PMC9834092 DOI: 10.1007/s12350-022-02971-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 03/15/2022] [Indexed: 01/22/2023]
Abstract
BACKGROUND The aim of this study was to evaluate the effect of balloon pulmonary angioplasty (BPA) using lung perfusion single-photon emission computed tomography (SPECT) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS 20 consecutive patients (64 ± 15 years) who were diagnosed with CTEPH and underwent BPA were included in this study. All patients underwent lung perfusion SPECT before and after BPA. The relationship between functional %volume of the lung calculated from the lung perfusion SPECT (FVL-LPSPECT), and other clinical parameters before and after BPA was assessed using the Wilcoxon signed-rank test. The correlation between each parameter and mean pulmonary artery pressure (mPAP) using the Spearman's correlation was performed. To determine predictors of mPAP for evaluating treatment effectiveness, significant parameters were included in multiple regression analysis. After BPA, world health organization functional classification, six-minute walk distance (6MWD), mPAP, and FVL-LPSPECT significantly improved. FVL-LPSPECT (r = - 0.728, P < 0.001) and 6MWD (r = - 0.571, P = 0.009) were significant correlation of mPAP. In the multiple regression analysis, FVL-LPSPECT was the most significant predictor of improvement in mPAP after BPA (P < 0.001). CONCLUSIONS This study demonstrated that the lung perfusion SPECT could be a potential measurement of the effectiveness of BPA in patients with CTEPH.
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Affiliation(s)
- Hidenobu Hashimoto
- Department of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ward, Tokyo, 143-8541, Japan.
| | - Takashi Oka
- Department of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ward, Tokyo, 143-8541, Japan
| | - Rine Nakanishi
- Department of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ward, Tokyo, 143-8541, Japan
| | - Sunao Mizumura
- Department of Radiology, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Shintaro Dobashi
- Department of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ward, Tokyo, 143-8541, Japan
| | - Yukiko Hashimoto
- Department of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ward, Tokyo, 143-8541, Japan
| | - Yuriko Okamura
- Department of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ward, Tokyo, 143-8541, Japan
| | - Kyoko Ota
- Department of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ward, Tokyo, 143-8541, Japan
| | - Takanori Ikeda
- Department of Cardiovascular Medicine, Department of Internal Medicine, Faculty of Medicine, Toho University, 6-11-1, Omorinishi, Ota-ward, Tokyo, 143-8541, Japan
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Otani N, Tomoe T, Kawabe A, Sugiyama T, Horie Y, Sugimura H, Yasu T, Nakamoto T. Recent Advances in the Treatment of Pulmonary Arterial Hypertension. Pharmaceuticals (Basel) 2022; 15:1277. [PMID: 36297387 PMCID: PMC9609229 DOI: 10.3390/ph15101277] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 10/10/2022] [Accepted: 10/12/2022] [Indexed: 09/29/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a disease in which stenosis or obstruction of the pulmonary arteries (PAs) causes an increase in PA pressure, leading to right-sided heart failure and death. Basic research has revealed a decrease in the levels of endogenous vasodilators, such as prostacyclin, and an increase in the levels of endogenous vasoconstrictors, such as endothelin, in patients with PAH, leading to the development of therapeutic agents. Currently, therapeutic agents for PAH target three pathways that are selective for PAs: the prostacyclin, endothelin, and nitric oxide pathways. These treatments improve the prognosis of PAH patients. In this review, we introduce new drug therapies and provide an overview of the current therapeutic agents.
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Affiliation(s)
| | | | | | | | | | | | | | - Takaaki Nakamoto
- Department of Cardiology, Dokkyo Medical University Nikkyo Medical Center, 632 Takatoku, Nikko 321-2593, Japan
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25
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Atsukawa M, Takano M, Omura J. Treatment pattern and clinical outcomes in portopulmonary hypertension: A database study in Japan. JGH OPEN 2022; 6:763-773. [DOI: 10.1002/jgh3.12820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/17/2022] [Accepted: 09/04/2022] [Indexed: 11/07/2022]
Affiliation(s)
- Masanori Atsukawa
- Division of Gastroenterology and Hepatology Nippon Medical School Tokyo Japan
| | - Masashi Takano
- Medical Affairs Division Janssen Pharmaceutical K.K. Tokyo Japan
| | - Junichi Omura
- Medical Affairs Division Janssen Pharmaceutical K.K. Tokyo Japan
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Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, Carlsen J, Coats AJS, Escribano-Subias P, Ferrari P, Ferreira DS, Ghofrani HA, Giannakoulas G, Kiely DG, Mayer E, Meszaros G, Nagavci B, Olsson KM, Pepke-Zaba J, Quint JK, Rådegran G, Simonneau G, Sitbon O, Tonia T, Toshner M, Vachiery JL, Vonk Noordegraaf A, Delcroix M, Rosenkranz S. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2022; 43:3618-3731. [PMID: 36017548 DOI: 10.1093/eurheartj/ehac237] [Citation(s) in RCA: 1746] [Impact Index Per Article: 582.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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27
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Pitre T, Su J, Cui S, Scanlan R, Chiang C, Husnudinov R, Khalid MF, Khan N, Leung G, Mikhail D, Saadat P, Shahid S, Mah J, Mielniczuk L, Zeraatkar D, Mehta S. Medications for the treatment of pulmonary arterial hypertension: a systematic review and network meta-analysis. Eur Respir Rev 2022; 31:31/165/220036. [PMID: 35948391 DOI: 10.1183/16000617.0036-2022] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/30/2022] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND There is no consensus on the most effective treatments of pulmonary arterial hypertension (PAH). Our objective was to compare effects of medications for PAH. METHODS We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrials.gov from inception to December 2021. We performed a frequentist random-effects network meta-analysis on all included trials. We rated the certainty of the evidence using the Grades of Recommendation, Assessment, Development, and Evaluation approach. RESULTS We included 53 randomised controlled trials with 10 670 patients. Combination therapy with endothelin receptor antagonist (ERA) plus phosphodiesterase-5 inhibitors (PDE5i) reduced clinical worsening (120.7 fewer events per 1000, 95% CI 136.8-93.4 fewer; high certainty) and was superior to either ERA or PDE5i alone, both of which reduced clinical worsening, as did riociguat monotherapy (all high certainty). PDE5i (24.9 fewer deaths per 1000, 95% CI 35.2 fewer to 2.1 more); intravenous/subcutaneous prostanoids (18.3 fewer deaths per 1000, 95% CI 28.6 fewer deaths to 0) and riociguat (29.1 fewer deaths per 1000, 95% CI 38.6 fewer to 8.7 more) probably reduce mortality as compared to placebo (all moderate certainty). Combination therapy with ERA+PDE5i (49.9 m, 95% CI 25.9-73.8 m) and riociguat (49.5 m, 95% CI 17.3-81.7 m) probably increase 6-min walk distance as compared to placebo (moderate certainty). CONCLUSION Current PAH treatments improve clinically important outcomes, although the degree and certainty of benefit vary between treatments.
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Affiliation(s)
- Tyler Pitre
- Division of Internal Medicine, McMaster University, Hamilton, ON, Canada.,Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
| | - Johnny Su
- Division of Internal Medicine, McMaster University, Hamilton, ON, Canada.,Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
| | - Sonya Cui
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
| | - Ryan Scanlan
- Division of Internal Medicine, McMaster University, Hamilton, ON, Canada.,Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
| | - Christopher Chiang
- Division of Internal Medicine, McMaster University, Hamilton, ON, Canada.,Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
| | - Renata Husnudinov
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
| | | | - Nadia Khan
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Gareth Leung
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - David Mikhail
- Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Pakeezah Saadat
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
| | - Shaneela Shahid
- Health Research Methods Evidence and Impact, McMaster University, Hamilton, ON, Canada
| | - Jasmine Mah
- Dept of Medicine, Dalhousie University, Halifax, NS, Canada
| | | | - Dena Zeraatkar
- Health Research Methods Evidence and Impact, McMaster University, Hamilton, ON, Canada.,Harvard Medical School, Harvard University, Boston, MA, USA.,D. Zeraatkar and S. Mehta contributed equally to this article as senior authors and supervised the work
| | - Sanjay Mehta
- Southwest Ontario PH Clinic, Division of Respirology, Dept of Medicine, Lawson Health Research Institute, London Health Sciences Centre, Schulich School of Medicine, Western University, London, ON, Canada.,PHA Canada, Vancouver, BC, Canada.,D. Zeraatkar and S. Mehta contributed equally to this article as senior authors and supervised the work
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28
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Tremblay É, Gosselin C, Mai V, Lajoie AC, Kilo R, Weatherald J, Lacasse Y, Bonnet S, Lega JC, Provencher S. Assessment of Clinical Worsening End Points as a Surrogate for Mortality in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Circulation 2022; 146:597-612. [PMID: 35862151 DOI: 10.1161/circulationaha.121.058635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Clinical worsening (CW) is a composite end point commonly used in pulmonary arterial hypertension (PAH) trials. We aimed to assess the trial-level surrogacy of CW for mortality in PAH trials, and whether the various CW components were similar in terms of frequency of occurrence, treatment-related relative risk (RR) reduction, and importance to patients. METHODS We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to December 2020) for trials evaluating the effects of PAH therapies on CW. The coefficient of determination between the RR for CW and mortality was assessed by regression analysis. The frequency of occurrence, RR reduction, and importance to patients of the CW components were assessed. RESULTS We included 35 independent cohorts (9450 patients). PAH therapies significantly reduced CW events (RR, 0.64 [95% CI, 0.55-0.73]), including PAH-related hospitalizations (RR, 0.61 [95% CI, 0.47-0.79]), treatment escalation (RR, 0.57 [95% CI, 0.38-0.84]) and symptomatic progression (RR, 0.58 [95% CI, 0.48-0.69]), and modestly reduced all-cause mortality when incorporating deaths occurring after a primary CW-defining event (RR, 0.860 [95% CI, 0.742-0.997]). However, the effects of PAH-specific therapies on CW only modestly correlated with their effects on mortality (R2trial, 0.35 [95% CI, 0.10-0.59]; P<0.0001), and the gradient in the treatment effect across component end points was large in the majority of trials. The weighted proportions of CW-defining events were hospitalization (33.5%) and symptomatic progression (32.3%), whereas death (6.7%), treatment escalation (5.6%), and transplantation/atrioseptostomy (0.2%) were infrequent. CW events were driven by the occurrence of events of major (49%) and mild-to-moderate (37%) importance to patients, with 14% of the events valued as critical. CONCLUSIONS PAH therapies significantly reduced CW events, but study-level CW is not a surrogate for mortality in PAH trials. Moreover, components of CW largely vary in frequency, response to therapy, and importance to patients and are thus not interchangeable. REGISTRATION URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42020178949.
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Affiliation(s)
- Élodie Tremblay
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Pulmonary Hypertension Research Group Quebec City, Canada (E.T., C.G., V.M., A.C.L., S.B., S.P.)
| | - Camille Gosselin
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Pulmonary Hypertension Research Group Quebec City, Canada (E.T., C.G., V.M., A.C.L., S.B., S.P.)
| | - Vicky Mai
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Pulmonary Hypertension Research Group Quebec City, Canada (E.T., C.G., V.M., A.C.L., S.B., S.P.)
| | - Annie C Lajoie
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Pulmonary Hypertension Research Group Quebec City, Canada (E.T., C.G., V.M., A.C.L., S.B., S.P.)
| | - Roubi Kilo
- Pôle De Santé Publique, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, F-69310, Pierre-Bénite, France (R.K.)
| | - Jason Weatherald
- Department of Medicine, Division of Respiratory Medicine, Libin Cardiovascular Institute, University of Calgary, Canada (J.W.)
| | - Yves Lacasse
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Department of Medicine (Y.L., S.B., S.P.), Université Laval, Quebec City, Canada
| | - Sebastien Bonnet
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Department of Medicine (Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Pulmonary Hypertension Research Group Quebec City, Canada (E.T., C.G., V.M., A.C.L., S.B., S.P.)
| | - Jean-Christophe Lega
- Université de Lyon, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Centre national de la recherche scientifique, F-69100, Groupe d'Etude Multidisciplinaire des Maladies Thrombotiques, Department of Internal and Vascular Medicine, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, F-69310, Lyon, France (J.-C.L.)
| | - Steeve Provencher
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Department of Medicine (Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Pulmonary Hypertension Research Group Quebec City, Canada (E.T., C.G., V.M., A.C.L., S.B., S.P.)
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Zhu HR, Kuang HY, Li Q, Ji XJ. Effects of oral targeted treatments in pulmonary arterial hypertension: A systematic review and meta-analysis. Front Cardiovasc Med 2022; 9:915470. [PMID: 35983180 PMCID: PMC9378982 DOI: 10.3389/fcvm.2022.915470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/08/2022] [Indexed: 11/26/2022] Open
Abstract
Background Although pulmonary arterial hypertension (PAH) is a fatal disease, specific drugs have been used to treat PAH. These drugs predominantly target these three pathobiological pathways: Endothelin receptor antagonist (ERA), nitric oxide (NO), and prostanoids pathways. In this review, we aimed to analyze the efficacy and safety of oral targeted treatments for PAH. Methods The national library of medicine (MEDLINE), excerpta medica database (EMBASE), and Cochrane Central Register of Controlled Trials databases were searched. Randomized controlled trials that compared the oral targeted drugs with placebos were selected. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) for variables with dichotomous outcomes, and standardized mean differences with continuous outcomes variables. Additionally, the mean of the differences for the 6-min walk distance (6MWD) was analyzed. Results In total, 23 studies involving 7,121 patients were included in this study. These studies show that orally PAH-specific drugs could decrease the risk of clinical worsening events, with an OR of 0.55 (p < 0.001). Furthermore, these drugs could improve exercise capacity, showing a 21.74-m increase in 6MWD (95% CI: 17.53–25.95 m) and cause a greater amelioration of functional class (OR = 0.60, 95% CI: 0.47–0.76). Additionally, subgroup analysis indicated that compared with placebo, ERAs, and drugs in the NO pathway were most effective and safe, which are associated with an improvement in exercise capacity, 6MWD, and worsening events-free survival rate. Conclusion Nitric oxide exhibited the most prominent clinical effect on exercise tolerance. However, in the subgroup analysis, oral targeted drugs of different pathways show applicability to different populations, which highlights the need for precise treatment in the clinical setting. Systematic Review Registration [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=297946], identifier [CRD 42022297946].
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Affiliation(s)
- Hui-ru Zhu
- National Clinical Research Center for Child Health and Disorders, Department of Ultrasound, Children’s Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
| | - Hong-yu Kuang
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiang Li
- Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Department of Cardiology, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Xiao-juan Ji
- Department of Ultrasound, Chongqing General Hospital, Chongqing, China
- *Correspondence: Xiao-juan Ji,
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30
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Rodríguez-Ramallo H, Báez-Gutiérrez N, Otero-Candelera R, Martín LAK. Subgroup Analysis in Pulmonary Hypertension-Specific Therapy Clinical Trials: A Systematic Review. J Pers Med 2022; 12:863. [PMID: 35743648 PMCID: PMC9224970 DOI: 10.3390/jpm12060863] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/18/2022] [Accepted: 05/23/2022] [Indexed: 12/20/2022] Open
Abstract
Pulmonary hypertension (PH) treatment decisions are driven by the results of randomized controlled trials (RCTs). Subgroup analyses are often performed to assess whether the intervention effect will change due to the patient's characteristics, thus allowing for individualized decisions. This review aimed to evaluate the appropriateness and interpretation of subgroup analyses performed in PH-specific therapy RCTs published between 2000 and 2020. Claims of subgroup effects were evaluated with prespecified criteria. Overall, 30 RCTs were included. Subgroup analyses presented: a high number of subgroup analyses reported, lack of prespecification, and lack of interaction tests. The trial protocol was not available for most RCTs; significant differences were found in those articles that published the protocol. Authors reported 13 claims of subgroup effect, with 12 claims meeting four or fewer of Sun's criteria. Even when most RCTs were generally at low risk of bias and were published in high-impact journals, the credibility and general quality of subgroup analyses and subgroup claims were low due to methodological flaws. Clinicians should be skeptical of claims of subgroup effects and interpret subgroup analyses with caution, as due to their poor quality, these analyses may not serve as guidance for personalized care.
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Affiliation(s)
- Héctor Rodríguez-Ramallo
- Hospital Pharmacy Department, Virgen del Rocio University Hospital, 41004 Seville, Spain; (H.R.-R.); (L.A.-k.M.)
| | - Nerea Báez-Gutiérrez
- Hospital Pharmacy Department, Reina Sofía University Hospital, 14004 Cordoba, Spain
| | | | - Laila Abdel-kader Martín
- Hospital Pharmacy Department, Virgen del Rocio University Hospital, 41004 Seville, Spain; (H.R.-R.); (L.A.-k.M.)
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31
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Suzuki R, Yuchi Y, Saito T, Teshima T, Matsumoto H, Koyama H. Investigation of Beraprost Sodium on Cardiac Function and Hemodynamics in Canine Models of Chronic Pulmonary Hypertension. Front Vet Sci 2022; 9:876178. [PMID: 35498754 PMCID: PMC9048895 DOI: 10.3389/fvets.2022.876178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/21/2022] [Indexed: 01/02/2023] Open
Abstract
Pulmonary hypertension (PH) is a life-threatening disease in dogs characterized by increased pulmonary arterial pressure (PAP) and/or pulmonary vascular resistance. No study has evaluated the utility of Beraprost sodium (BPS) in dogs with PH. This study aimed to evaluate the effect of BPS on cardiac function and hemodynamics and examine the optimal dose of BPS in canine models of chronic embolic PH. In this prospective crossover study, three doses of BPS (5, 15, and 25 μg/kg, twice a day) were examined in eight canine models of chronic embolic PH. All model dogs underwent invasive PAP measurement, echocardiography, and non-invasive systemic blood pressure measurement before and after continuous administration of oral BPS for 1 week. No side effects of BPS were observed in any dog during the study. All doses of BPS significantly decreased systolic PAP and pulmonary vascular impedance. Additionally, systemic vascular impedance significantly decreased with 15 and 25 μg/kg of BPS. The right ventricular stroke volume and longitudinal strain significantly decreased with all doses of BPS. The left ventricular stroke volume and circumferential strain decreased with 15 μg/kg BPS. BPS was well-tolerated in this study. A dose-dependent vasodilating effect on pulmonary vessels was observed in canine models of chronic PH. Additionally, 15 μg/kg BPS showed a balanced vasodilating effect on systemic and pulmonary vessels. Furthermore, with a decrease in systemic and pulmonary vascular impedance, the left and right ventricular functions were significantly improved. Our results suggest that BPS may be useful in the treatment of canine PH.
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Hocq C, Vanhoutte L, Guilloteau A, Massolo AC, Van Grambezen B, Carkeek K, Piersigilli F, Danhaive O. Early diagnosis and targeted approaches to pulmonary vascular disease in bronchopulmonary dysplasia. Pediatr Res 2022; 91:804-815. [PMID: 33674739 DOI: 10.1038/s41390-021-01413-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 01/25/2021] [Indexed: 01/31/2023]
Abstract
Pulmonary hypertension has emerged as a life-threatening disease in preterm infants suffering from bronchopulmonary dysplasia (BPD). Its development is closely linked to respiratory disease, as vasculogenesis and alveologenesis are closely interconnected. Once clinically significant, BPD-associated pulmonary hypertension (BPD-PH) can be challenging to manage, due to poor reversibility and multiple comorbidities frequently associated. The pulmonary vascular disease process underlying BPD-PH is the result of multiple innate and acquired factors, and emerging evidence suggests that it progressively develops since birth and, in certain instances, may begin as early as fetal life. Therefore, early recognition and intervention are of great importance in order to improve long-term outcomes. Based on the most recent knowledge of BPD-PH pathophysiology, we review state-of-the-art screening and diagnostic imaging techniques currently available, their utility for clinicians, and their applicability and limitations in this specific population. We also discuss some biochemical markers studied in humans as a possible complement to imaging for the detection of pulmonary vascular disease at its early stages and the monitoring of its progression. In the second part, we review pharmacological agents currently available for BPD-PH treatment or under preclinical investigation, and discuss their applicability, as well as possible approaches for early-stage interventions in fetuses and neonates. IMPACT: BPD-associated PH is a complex disease involving genetic and epigenetic factors, as well as environmental exposures starting from fetal life. The value of combining multiple imaging and biochemical biomarkers is emerging, but requires larger, multicenter studies for validation and diffusion. Since "single-bullet" approaches have proven elusive so far, combined pharmacological regimen and cell-based therapies may represent important avenues for research leading to future cure and prevention.
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Affiliation(s)
- Catheline Hocq
- Division of Neonatology, St-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium
| | - Laetitia Vanhoutte
- Division of Pediatric Cardiology, St-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium
| | - Axelle Guilloteau
- Division of Clinical Pharmacy, St-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium
| | - Anna Claudia Massolo
- Department of Surgical and Medical Neonatology, Bambino Gesù Children's Hospital, Rome, Italy
| | - Bénédicte Van Grambezen
- Division of Neonatology, St-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium
| | - Kate Carkeek
- Division of Neonatology, St-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium
| | - Fiammetta Piersigilli
- Division of Neonatology, St-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium
| | - Olivier Danhaive
- Division of Neonatology, St-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium. .,Department of Pediatrics, Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA.
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33
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Aisosa O, Osarenkhoe J. Pulmonary hypertension and exercise tolerance in heart failure patients. INTERNATIONAL JOURNAL OF THE CARDIOVASCULAR ACADEMY 2022. [DOI: 10.4103/ijca.ijca_7_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Fu W, He W, Li Y, Chen Y, Liang J, Lei H, Fu L, Chen Y, Ren N, Jiang Q, Shen Y, Ma R, Wang T, Wang X, Zhang N, Xiao D, Liu C. Efficacy and safety of novel-targeted drugs in the treatment of pulmonary arterial hypertension: a Bayesian network meta-analysis. Drug Deliv 2021; 28:1007-1019. [PMID: 34060401 PMCID: PMC8172220 DOI: 10.1080/10717544.2021.1927243] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/02/2021] [Accepted: 05/04/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Pulmonary arterial hypertension (PAH) is a severe and fatal clinical syndrome characterized by high blood pressure and vascular remodeling in the pulmonary arterioles, which is also a rapidly progressing disease of the lung vasculature with a poor prognosis. Although PAH medication made great advances in recent years, the efficacy and safety of the medication are unsatisfactory. Therefore, we aimed to update and expand previous studies to explore the efficacy and safety of PAH-targeted medications. Methods: Relevant articles were searched and selected from published or publicly available data in PubMed, Cochrane Library, CNKI, PsycInfo, and MEDLINE (from inception until October 1st, 2020). To assess the efficacy and safety of PAH therapies, five efficacy outcomes [6-minute walking distance (6MWD), mean pulmonary arterial pressure (mPAP), WHO functional class (WHO FC) improvement, clinical worsening, death] and two safety outcomes [adverse events (AEs), serious adverse events (SAEs)] were selected. And 6MWD was regarded as the primary efficacy outcome.Results: 50 trials included with 10 996participants were selected. In terms of efficacy, all targeted drugs were more effective than placebo. For 6MWD, Bosentan + Sildenafil, Sildenafil, Bosentan + Iloprost were better than others. Bosentan + Iloprost and Bosentan + Sildenafil were better for mPAP. Bosentan + Iloprost and Ambrisentan + Tadalafil were more effective in improving WHO FC. Bosentan + Tadalafil and Bosentan + Iloprost had the Ambrisentan probability to reduce the incidence of clinical worsening. It is demonstrated that Ambrisentan had clear benefits in reducing all-cause mortality. In terms of safety, no therapies had been shown to reduce the incidence of SAEs significantly, and Ambrisentan + Tadalafil significantly increased the incidence of AEs.Conclusions: Phosphodiesterase 5 inhibitor (PDE5i) + Endothelin Receptor Antagonists (ERA) seems to be better therapy for PAH. Prostacyclin analogs (ProsA) + ERA appear promising, though additional data is warranted.Registration PROSPERO CRD42020218818.
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Affiliation(s)
- Wenhai Fu
- Department of Medicine, First Clinical School, Guangzhou Medical University, Guangzhou, China
| | - Wenjun He
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Yuexin Li
- Department of Medicine, First Clinical School, Guangzhou Medical University, Guangzhou, China
| | - Yangxiao Chen
- Department of Medicine, First Clinical School, Guangzhou Medical University, Guangzhou, China
| | - Jingyi Liang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Hui Lei
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Lin Fu
- Department of Medicine, First Clinical School, Guangzhou Medical University, Guangzhou, China
| | - Yanghang Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Ni Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Qian Jiang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Yi Shen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Ran Ma
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Tao Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Xinni Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Nuofu Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Dakai Xiao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | - Chunli Liu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
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35
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Gupta S, Padhan P, Subhankar S, Singh P. Cardiovascular complications in patients with interstitial lung disease and their correlation with 6-minute walk test and spirometry: A single-center study. J Family Med Prim Care 2021; 10:3330-3335. [PMID: 34760753 PMCID: PMC8565147 DOI: 10.4103/jfmpc.jfmpc_350_21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 07/07/2021] [Accepted: 07/10/2021] [Indexed: 11/04/2022] Open
Abstract
Introduction Pulmonary hypertension and other cardiac complications occur frequently due to chronic hypoxia induced by interstitial lung diseases (ILD) or due to connective tissue disorder itself. Two-dimensional (2D) echocardiography is ideal for identifying abnormalities at a given time. In this study, we tried to detect cardiovascular complications in patients with ILD using 2D echocardiography and correlate them with a 6-minute walk test (6 MWT) and spirometry. Materials and Methods This study was carried out for 18 months including 100 consecutive cases of ILD. The diagnosis was made using the latest criteria as per the disease and high-resolution computed tomography (HRCT) thorax. All patients were evaluated with 2D echocardiography, 6 MWT, and spirometry along with routine investigations. Their results were analyzed using STATA 15.1 software. Result Cardiovascular involvement was detected in 68% of cases. Pulmonary hypertension predominated with a prevalence of 50%. In spirometry, mean Forced expiratory volume in first second (FEV1)and Forced vital capacity (FVC) were found to be 54.96 (L) and 53.49 (L), respectively, with a predominant restrictive pattern (89%). There was a significant correlation between baseline saturation of oxygen (SpO2) and pulmonary arterial systolic pressure (PASP) with a P value of <0.05. Baseline SpO2 and distance covered in 6 MWT had a significant correlation (P = 0.014). Conclusion A baseline or nighttime hypoxia is responsible for developing PAH. Pulmonary arterial hypertension should be suspected in patients unable to perform 6 MWT or having low baseline SpO2. A routine follow-up with a 6 MWT and baseline SpO2 should be performed in each visit to identify early deterioration of the disease.
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Affiliation(s)
- Saurabh Gupta
- Department of Pulmonary Medicine, Kalinga Institute of Medical Sciences, KIIT University, Patia, Bhubaneswar, Odisha, India
| | - Prasanta Padhan
- Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences, KIIT University, Patia, Bhubaneswar, Odisha, India
| | - Saswat Subhankar
- Department of Pulmonary Medicine, Kalinga Institute of Medical Sciences, KIIT University, Patia, Bhubaneswar, Odisha, India
| | - Pratima Singh
- Department of Pulmonary Medicine, Kalinga Institute of Medical Sciences, KIIT University, Patia, Bhubaneswar, Odisha, India
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Sung SH, Yeh WY, Chiang CE, Huang CJ, Huang WM, Chen CH, Cheng HM. The prognostic significance of the alterations of pulmonary hemodynamics in patients with pulmonary arterial hypertension: a meta-regression analysis of randomized controlled trials. Syst Rev 2021; 10:284. [PMID: 34717773 PMCID: PMC8556931 DOI: 10.1186/s13643-021-01816-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 09/15/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hemodynamic assessment in patients with pulmonary arterial hypertension (PAH) is essential for risk stratification and pharmacological management. However, the prognostic value of the hemodynamic changes after treatment is less well established. OBJECTIVES We investigated the prognostic impacts of the changes in hemodynamic indices, including mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), right atrial pressure (RAP), and cardiac output index (CI). We conducted this systematic review with meta-regression analysis on existing clinical trials. METHODS We searched and identified all relevant randomized controlled trials from multiple databases. An analogous R2 index was used to quantify the proportion of variance explained by each predictor in the association with PAH patients' prognosis. A total of 21 trials and 3306 individuals were enrolled. RESULTS The changes in mPAP, PVR, RAP, and CI were all significantly associated with the change in 6MWD (∆6MWD). The change in mPAP was with the highest explanatory power for ∆6MWD (R2 analog = 0.740). Additionally, the changes in mPAP, PVR, and CI were independently predictive of adverse clinical events. The change in mPAP had the highest explanatory power for the clinical events (R2 analog = 0.911). Furthermore, the change in PVR was with the highest explanatory power for total mortality of PAH patients (R2 analog = 0.612). CONCLUSION Hemodynamic changes after treatment, including mPAP, PVR, CI, and RAP, were significantly associated with adverse clinical events or mortality in treated PAH patients. It is recommended that further studies be conducted to evaluate the changes in hemodynamic indices to guide drug titration. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42019125157.
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Affiliation(s)
- Shih-Hsien Sung
- Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang Ming Chiao Tung University, School of Medicine, Taipei, Taiwan
| | - Wan-Yu Yeh
- Center for Evidence-based Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Beitou District, Taipei, Taiwan
| | - Chern-En Chiang
- Department of Medicine, National Yang Ming Chiao Tung University, School of Medicine, Taipei, Taiwan.,General Clinical Research Center, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chi-Jung Huang
- Center for Evidence-based Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Beitou District, Taipei, Taiwan
| | - Wei-Ming Huang
- Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang Ming Chiao Tung University, School of Medicine, Taipei, Taiwan
| | - Chen-Huan Chen
- Department of Medicine, National Yang Ming Chiao Tung University, School of Medicine, Taipei, Taiwan.,Institute of Public Health and Community Medicine Research Center, National Yang Ming Chiao Tung University, School of Medicine, Taipei, Taiwan.,Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hao-Min Cheng
- Department of Medicine, National Yang Ming Chiao Tung University, School of Medicine, Taipei, Taiwan. .,Center for Evidence-based Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Beitou District, Taipei, Taiwan. .,Institute of Public Health and Community Medicine Research Center, National Yang Ming Chiao Tung University, School of Medicine, Taipei, Taiwan. .,Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan.
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Genecand L, Wacker J, Beghetti M, Lador F. Selexipag for the treatment of pulmonary arterial hypertension. Expert Rev Respir Med 2020; 15:583-595. [PMID: 33382345 DOI: 10.1080/17476348.2021.1866990] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION : Pulmonary arterial hypertension (PAH) is a rare pulmonary vasculopathy. This review focuses on selexipag, a prostacyclin receptor agonist validated for the treatment of PAH. AREAS COVERED We review the structure, mechanisms of action, pharmacokinetics, and pharmacodynamics of selexipag. Clinical efficacy and tolerability are discussed using the main clinical trial published for selexipag (GRIPHON) and its post-hoc analysis. EXPERT OPINION Selexipag should be added as a triple oral combination therapy in case of insufficient response to oral combination therapy with endothelin receptor antagonist and phosphodiesterase 5 inhibitor. However, selexipag should not replace parenteral prostacyclin in high-risk patients.
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Affiliation(s)
- Léon Genecand
- Internal Medicine Department,Riviera Chablais Hospital, Rennaz, Switzerland.,Pulmonary Hypertension Program, Geneva University Hospitals, Geneva, Switzerland
| | - Julie Wacker
- Pulmonary Hypertension Program, Geneva University Hospitals, Geneva, Switzerland.,Paediatric Cardiology Unit, University Hospitals of Geneva, Switzerland; Centre Universitaire Romand De Cardiologie Et Chirurgie Cardiaque Pédiatrique, University of Geneva and Lausanne, Switzerland
| | - Maurice Beghetti
- Pulmonary Hypertension Program, Geneva University Hospitals, Geneva, Switzerland.,Paediatric Cardiology Unit, University Hospitals of Geneva, Switzerland; Centre Universitaire Romand De Cardiologie Et Chirurgie Cardiaque Pédiatrique, University of Geneva and Lausanne, Switzerland
| | - Frédéric Lador
- Pulmonary Hypertension Program, Geneva University Hospitals, Geneva, Switzerland.,Department of Medicine Specialties, Division of Pulmonary Diseases, Geneva University Hospitals, Geneva, Switzerland
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38
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Zheng W, Wang Z, Jiang X, Zhao Q, Shen J. Targeted Drugs for Treatment of Pulmonary Arterial Hypertension: Past, Present, and Future Perspectives. J Med Chem 2020; 63:15153-15186. [PMID: 33314936 DOI: 10.1021/acs.jmedchem.0c01093] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a devastating disease that can lead to right ventricular failure and premature death. Although approved drugs have been shown to be safe and effective, PAH remains a severe clinical condition, and the long-term survival of patients with PAH is still suboptimal. Thus, potential therapeutic targets and new agents to treat PAH are urgently needed. In recent years, a variety of related pathways and potential therapeutic targets have been found, which brings new hope for PAH therapy. In this perspective, not only are the marketed drugs used to treat PAH summarized but also the recently developed novel pharmaceutical therapies currently in clinical trials are discussed. Furthermore, the advances in natural products as potential treatment for PAH are also updated.
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Affiliation(s)
- Wei Zheng
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,School of Pharmacy, University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Zhen Wang
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xiangrui Jiang
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Qingjie Zhao
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jingshan Shen
- CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,School of Pharmacy, University of the Chinese Academy of Sciences, Beijing 100049, China
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39
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Simonneau G, Ghofrani HA, Corris PA, Rosenkranz S, Grünig E, White J, McLaughlin VV, Langleben D, Meier C, Busse D, Kleinjung F, Benza RL. Assessment of the REPLACE study composite endpoint in riociguat-treated patients in the PATENT study. Pulm Circ 2020; 10:2045894020973124. [PMID: 33354316 PMCID: PMC7734510 DOI: 10.1177/2045894020973124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/22/2020] [Indexed: 11/25/2022] Open
Abstract
The goal of treatment in patients with pulmonary arterial hypertension is to achieve a low risk status, indicating a favorable long-term outcome. The REPLACE study investigated the efficacy of switching to riociguat in patients with pulmonary arterial hypertension and an insufficient response to phosphodiesterase-5 inhibitors. In this post hoc analysis, we applied the REPLACE composite endpoint of clinical improvement to the placebo-controlled PATENT-1 study of riociguat in pulmonary arterial hypertension and its long-term extension, PATENT-2. Clinical improvement was defined as ≥2 of the following in patients who completed the study without clinical worsening: ≥10% or ≥30 m improvement in 6-minute walking distance; World Health Organization functional class I or II; ≥30% decrease in N-terminal prohormone of brain natriuretic peptide. At PATENT-1 Week 12, patients treated with riociguat were more likely to achieve the composite endpoint vs. placebo (P < 0.0001), with similar results in pretreated (P = 0.0189) and treatment-naïve (P < 0.0001) patients. Achievement of the composite endpoint at Week 12 was associated with a 45% reduction in relative risk of death and a 19% reduction in relative risk of clinical worsening in PATENT-2. Overall, these data suggest that use of the REPLACE composite endpoint in patients with pulmonary arterial hypertension is a valid assessment of response to treatment.
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Affiliation(s)
- Gérald Simonneau
- Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique, and INSERM Unité 999, Le Kremlin-Bicêtre, France
| | - Hossein-Ardeschir Ghofrani
- University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany, Department of Pneumology, Kerchoff Clinic, Bad Nauheim, Germany and Department of Medicine, Imperial College London, London, UK
| | - Paul A Corris
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Stephan Rosenkranz
- Department III of Internal Medicine, Cologne University Heart Center, Cologne, Germany
| | - Ekkehard Grünig
- Centre for Pulmonary Hypertension at Thoraxklinik Heidelberg, Heidelberg, Germany
| | - Jim White
- Division of Pulmonary and Critical Care Medicine and the Mary M. Parkes Center, University of Rochester Medical Center, Rochester, NY, USA
| | | | - David Langleben
- Center for Pulmonary Vascular Disease and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada
| | | | | | | | - Raymond L Benza
- Department of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
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40
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Nikkho S, Fernandes P, White RJ, Deng C(CQ, Farber HW, Corris PA. Clinical trial design in phase 2 and 3 trials for pulmonary hypertension. Pulm Circ 2020; 10:2045894020941491. [PMID: 33282181 PMCID: PMC7682228 DOI: 10.1177/2045894020941491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 06/17/2020] [Indexed: 11/15/2022] Open
Abstract
This article on clinical trial design incorporates the broad experience of members of the Pulmonary Vascular Research Institute's (PVRI) Innovative Drug Development Initiative (IDDI) as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. It is increasingly clear that the design of phase 2 and 3 trials in pulmonary hypertension will have to diversify from the traditional randomised double-blind design, given the anticipated need to trial novel therapeutic approaches in the immediate future. This article reviews a wide range of differing approaches and places these into context within the field of pulmonary hypertension.
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Affiliation(s)
| | | | - R. James White
- University of Rochester Medical Center, Rochester, NY, USA
| | | | | | - Paul A Corris
- Translational and Clinical Science Institute, Newcastle University, Newcastle upon Tyne, UK
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41
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Toshner M, Spiekerkoetter E, Bogaard H, Hansmann G, Nikkho S, Prins KW. Repurposing of medications for pulmonary arterial hypertension. Pulm Circ 2020; 10:2045894020941494. [PMID: 33282182 PMCID: PMC7682234 DOI: 10.1177/2045894020941494] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 06/20/2020] [Indexed: 12/18/2022] Open
Abstract
This manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. Drug repurposing, use of a drug in a disease for which it was not originally developed, in pulmonary arterial hypertension has been a remarkable success story, as highlighted by positive large phase 3 clinical trials using epoprostenol, bosentan, iloprost, and sildenafil. Despite the availability of multiple therapies for pulmonary arterial hypertension, mortality rates have modestly changed. Moreover, pulmonary arterial hypertension patients are highly symptomatic and frequently end up on parental therapy and lung transplant waiting lists. Therefore, an unmet need for new treatments exists and drug repurposing may be an important avenue to address this problem.
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Affiliation(s)
- Mark Toshner
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Edda Spiekerkoetter
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Harm Bogaard
- Department of Pulmonary Medicine, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Georg Hansmann
- Department of Pediatric Cardiology and Critical Care, Hannover Medical School, Hannover, Germany
| | - Sylvia Nikkho
- Bayer Pharmaceuticals, Clinical Development Pulmonology, Berlin, Germany
| | - Kurt W. Prins
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA
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42
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Papamichalis M, Xanthopoulos A, Papamichalis P, Skoularigis J, Triposkiadis F. Adult congenital heart disease with pulmonary arterial hypertension: mechanisms and management. Heart Fail Rev 2020; 25:773-794. [PMID: 31407139 DOI: 10.1007/s10741-019-09847-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Adult congenital heart disease (ACHD) encompasses a range of structural cardiac abnormalities present before birth attributable to abnormal foetal cardiac development. The pulmonary circulation of patients with ACHD and intracardiac or extracardiac defects is often exposed to increased blood flow and occasionally to systemic pressures. Depending on the location and magnitude of the defect as well as the time of surgical correction, the patient with ACHD is at risk of developing pulmonary arterial hypertension (PAH), which dramatically increases morbidity and mortality. It is encouraging that therapies applied in idiopathic PAH and significantly improve outcome are also effective in ACHD-related PAH (ACHD-PAH). This review summarizes the challenges encountered in the diagnosis and management of ACHD-PAH.
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Affiliation(s)
- Michail Papamichalis
- Department of Cardiology, Larissa University General Hospital, P.O. Box 1425, 411 10, Larissa, Greece
| | - Andrew Xanthopoulos
- Department of Cardiology, Larissa University General Hospital, P.O. Box 1425, 411 10, Larissa, Greece
| | | | - John Skoularigis
- Department of Cardiology, Larissa University General Hospital, P.O. Box 1425, 411 10, Larissa, Greece
| | - Filippos Triposkiadis
- Department of Cardiology, Larissa University General Hospital, P.O. Box 1425, 411 10, Larissa, Greece.
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Grundy JS, King CD, Adams JW, Cabell CH. Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate-release oral formulation in healthy volunteers. Pulm Circ 2020; 10:2045894020922814. [PMID: 32489643 PMCID: PMC7238799 DOI: 10.1177/2045894020922814] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/08/2020] [Indexed: 11/16/2022] Open
Abstract
Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single-center, randomized, double-blind, placebo-controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate-release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms. Eighty-two healthy subjects (single ascending dose (n = 32) and multiple ascending dose (n = 50)) completed the studies. No clinically significant safety issues were observed, except one serious adverse event of atrial fibrillation considered moderate in intensity. In the single ascending dose study, ralinepag was tolerated up to 100 µg (single dose), but not 200 µg due to nausea and vomiting. Dose proportional mean ralinepag plasma exposure measures were observed. Maximum plasma concentrations were reached within 1.0–1.5 h post-dose and mean terminal elimination half-life values from 20.5–26.4 h. In the multiple ascending dose study, ralinepag tolerability decreased with increasing QD or BID dose. Dose proportional steady-state plasma exposure measures were observed where evaluable, with mean steady-state peak-to-trough ratios ranging from 3.34–4.49 (QD dosing) and 1.95–2.36 (BID dosing). Mean effective half-life values ranged from 17.5–18.4 h, reflecting ∼1.7-fold (QD dosing) and ∼2.6-fold (BID dosing) accumulation in plasma exposure. Safety and tolerability of oral immediate-release ralinepag was generally consistent with expectations for this drug class, but more individualized dose escalation appears warranted. Ralinepag exhibited favorable pharmacokinetic properties, with BID dosing producing desired minimal steady-state peak-to-trough fluctuation. Overall, results supported further clinical investigation of ralinepag and guided development of an extended-release formulation to facilitate QD dosing.
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Affiliation(s)
- John S. Grundy
- Nonclinical Development & Clinical Pharmacology Department, Arena Pharmaceuticals, Inc., San Diego, CA, USA
- John S. Grundy, Arena Pharmaceuticals, Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
| | - Christopher D. King
- Nonclinical Development & Clinical Pharmacology Department, Arena Pharmaceuticals, Inc., San Diego, CA, USA
| | - John W. Adams
- Research Department, Arena Pharmaceuticals, Inc., San Diego, CA, USA
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Zolty R. Pulmonary arterial hypertension specific therapy: The old and the new. Pharmacol Ther 2020; 214:107576. [PMID: 32417272 DOI: 10.1016/j.pharmthera.2020.107576] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2020] [Indexed: 02/08/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a vascular disorder associated with high morbidity and mortality rate and is characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, ultimately resulting in right ventricular failure and death. Over the past few decades, significant advances in the understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary arterial hypertension have occured. This has led to the development of disease specific treatment including prostanoids, endothelin receptor antagonists, phosphodiesterase inhibitors, and soluble guanylate cyclase stimulators. These therapies significantly improve exercise capacity, quality of life, pulmonary hemodynamics, but none of the current treatments are actually curative and long-term prognosis remains poor. Thus, there is a clear need to develop new therapies. Several potential pharmacologic agents for the treatment of pulmonary arterial hypertension are under clinical development and some promising results with these treatments have been reported. These agents include tyrosine protein kinase inhibitors, rho-kinase inhibitors, synthetically produced vasoactive intestinal peptide, antagonists of the 5-HT2 receptors, and others. This article will review several of these promising new therapies and will discuss the current evidence regarding their potential benefit in pulmonary arterial hypertension.
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Affiliation(s)
- Ronald Zolty
- Cardiovascular Divisions, 982265 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198, United States of America.
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45
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Christiansen D, Porter S, Hurlburt L, Weiss A, Granton J, Wentlandt K. Pulmonary Arterial Hypertension: A Palliative Medicine Review of the Disease, Its Therapies, and Drug Interactions. J Pain Symptom Manage 2020; 59:932-943. [PMID: 31805363 DOI: 10.1016/j.jpainsymman.2019.11.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 11/24/2019] [Accepted: 11/26/2019] [Indexed: 01/13/2023]
Abstract
Pulmonary arterial hypertension (PAH) is often a progressive and ultimately fatal disease. It is characterized by an elevated mean pulmonary arterial pressure because of disease of the small pulmonary arterioles. PAH leads to a constellation of symptoms, including dyspnea, fatigue, syncope, chest discomfort, and peripheral edema. Disease-targeted therapies for PAH produce symptomatic and functional improvement, but long-term survival remains uncommon without lung transplantation. Palliative care is appropriate to support patients with advanced PAH who typically have a high symptom burden. However, palliative care has historically focused on supporting patients with malignant disease, rather than progressive chronic disease such as PAH. Our aim is to provide palliative care clinicians with a background in the classification, pathophysiology, and modern treatment of PAH. This review describes disease-targeted therapies and their effects on symptoms, physical functioning, and health-related quality of life. We also review the unique physiology of PAH and its implication for palliative interventions. Pharmacological interactions with, and precautions related to commonly used palliative care medications, are discussed.
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Affiliation(s)
- David Christiansen
- Department of Internal Medicine, Section of Respiratory Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Sandra Porter
- Department of Pharmacy, University Health Network, Toronto, Ontario, Canada
| | - Lindsay Hurlburt
- Division of Palliative Care, Department of Supportive Care, University Health Network, Toronto, Ontario, Canada; Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada
| | - Andrea Weiss
- Division of Palliative Care, Department of Supportive Care, University Health Network, Toronto, Ontario, Canada; Division of Palliative Care, Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
| | - John Granton
- Division of Respirology, Department of Medicine, University Health Network, Sinai Health System, University of Toronto, Toronto, Ontario, Canada
| | - Kirsten Wentlandt
- Division of Palliative Care, Department of Supportive Care, University Health Network, Toronto, Ontario, Canada; Division of Palliative Care, Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada.
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Abstract
Pulmonary arterial hypertension (PAH) is a rare disease in infants and children that is associated with significant morbidity and mortality. The disease is characterized by progressive pulmonary vascular functional and structural changes resulting in increased pulmonary vascular resistance and eventual right heart failure and death. In many pediatric patients, PAH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. PAH associated with developmental lung diseases such as bronchopulmonary dysplasia or congenital diaphragmatic hernia is increasingly more recognized in infants and children. Although treatment of the underlying disease and reversal of advanced structural changes have not yet been achieved with current therapy, quality of life and survival have improved significantly. Targeted pulmonary vasodilator therapies, including endothelin receptor antagonists, prostacyclin analogs, and phosphodiesterase type 5 inhibitors have resulted in hemodynamic and functional improvement in children. The management of pediatric PAH remains challenging as treatment decisions depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts. This article reviews the current drug therapies and their use in the management of PAH in children.
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Affiliation(s)
- Catherine M Avitabile
- Division of Cardiology, Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Erika E Vorhies
- Division of Pediatric Cardiology, Department of Pediatrics, University of Calgary Cumming School of Medicine, Alberta Children's Hospital, Calgary, Canada
| | - David Dunbar Ivy
- B100, Division of Pediatric Cardiology, Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, 13123 East 16th Avenue, Aurora, CO, 80045, USA.
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Rezus E, Burlui AM, Gafton B, Stratulat TA, Zota GR, Cardoneanu A, Rezus C. A patient-centered approach to the burden of symptoms in patients with scleroderma treated with Bosentan: A prospective single-center observational study. Exp Ther Med 2020; 19:1739-1746. [PMID: 32104228 PMCID: PMC7027142 DOI: 10.3892/etm.2019.8361] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 11/12/2019] [Indexed: 12/21/2022] Open
Abstract
Systemic sclerosis (SSc) is a rare and complex autoimmune disease associated with poor vital and functional outcomes. The functional hindrance in patients derives from various disease-specific manifestations, including Raynaud's phenomenon and digital ulcers (DUs). Bosentan is an endothelin receptor antagonist capable of preventing the appearance of new DUs in patients with scleroderma. The present study aimed to evaluate the effects of Bosentan on the severity of Raynaud's phenomenon, DU-related symptoms and functional impairment during the first year of treatment. A prospective study that included adult patients with SSc admitted to the Rheumatology Department between January 2016 and January 2017 that were candidates for Bosentan therapy, was performed. All patients were asked to evaluate the burden of symptoms secondary to Raynaud's and DUs using a visual analogue scale (VAS), whereas functional hindrance was assessed via Health Assessment Questionnaire Disability Index (HAQ-DI). The outcomes were assessed at baseline and every 3 months during 1 year of therapy. Among the 41 patients included initially, 2 participants discontinued the treatment after 1 month due to adverse events (elevation of liver enzymes). The study cohort exhibited a significant improvement in HAQ-DI, VAS-R and VAS-DU scores in response to Bosentan therapy over the 1-year follow-up period. Higher scores at baseline predicted a weaker treatment-related improvement, with the risk of a poor outcome being increased by 220% for VAS-R, 116% for VAS-DU, whereas no increase was observed for HAQ-DI. The post-treatment improvement in VAS-DU levels was associated with a better outcome for HAQ-DI (R=0.44; P=0.005). This association was not identified for VAS-R (R=0.24; P=0.137). Throughout the follow-up period, patients with dyspnea presented with significantly higher HAQ-DI scores compared with non-dyspneic patients. Bosentan therapy may indirectly influence functionality and quality of life in patients with scleroderma by reducing the burden of Raynaud's and DU-related symptoms. Nonetheless, patients with SSc with a decreased symptom burden at baseline exhibited improved outcomes.
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Affiliation(s)
- Elena Rezus
- Department of Rheumatology and Physiotherapy, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Alexandra Maria Burlui
- Department of Rheumatology and Physiotherapy, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Bogdan Gafton
- Department of Medical Oncology-Radiotherapy, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Teodora Alexa Stratulat
- Department of Medical Oncology-Radiotherapy, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Gabriela Rusu Zota
- Department of Pharmacology, Clinical Pharmacology and Algesiology, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Anca Cardoneanu
- Department of Rheumatology and Physiotherapy, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Ciprian Rezus
- Department of Internal Medicine, ‘Grigore T. Popa’ University of Medicine and Pharmacy, 700115 Iasi, Romania
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Petrovič M, Locatelli I. Comparative effectiveness of pulmonary arterial hypertension drugs in treatment-naive patients: a network meta-analysis. J Comp Eff Res 2020; 9:7-22. [PMID: 31845591 DOI: 10.2217/cer-2019-0037] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: No network meta-analysis has been conducted to study efficacy of drug therapies specific for treatment of pulmonary arterial hypertension in treatment-naive patients only. Methods: Randomized controlled trials on pulmonary arterial hypertension-specific drug therapies were searched and a Bayesian network meta-analysis was performed. The 6-min walking distance (6MWD) and all-cause mortality were efficacy outcomes, whereas discontinuation due to adverse events was a safety-related outcome. Results: Analysis included 3.713 patients from 21 trials. Combination of ambrisentan and tadalafil showed the greatest impact on 6MWD, followed by epoprostenol and intravenous treprostinil (high dose). The latter two demonstrated marked effect size on mortality, although not statistically significant. Conclusion: According to 6MWD, ambrisentan/tadalafil combination was considered as most effective among all comparisons. Prospero ID: CRD42019110832.
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Affiliation(s)
- Maja Petrovič
- Krka, d. d., Novo mesto, Šmarješka c. 6, 8501 Novo mesto, Slovenia
- University of Ljubljana, Faculty of Pharmacy, Department of Social Pharmacy, Aškerčeva c. 7, 1000 Ljubljana, Slovenia
| | - Igor Locatelli
- University of Ljubljana, Faculty of Pharmacy, Department of Social Pharmacy, Aškerčeva c. 7, 1000 Ljubljana, Slovenia
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Ntiloudi D, Qanud K, Tomaio JN, Giannakoulas G, Al-Abed Y, Zanos S. Pulmonary arterial hypertension: the case for a bioelectronic treatment. Bioelectron Med 2019; 5:20. [PMID: 32232109 PMCID: PMC7098229 DOI: 10.1186/s42234-019-0036-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/08/2019] [Indexed: 12/16/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease of unknown etiology that progresses to right ventricular failure. It has a complex pathophysiology, which involves an imbalance between vasoconstrictive and vasodilative processes in the pulmonary circulation, pulmonary vasoconstriction, vascular and right ventricular remodeling, systemic inflammation, and autonomic imbalance, with a reduced parasympathetic and increased sympathetic tone. Current pharmacological treatments for PAH include several classes of drugs that target signaling pathways in vascular biology and cardiovascular physiology, but they can have severe unwanted effects and they do not typically stop the progression of the disease. Pulmonary artery denervation has been tested clinically as a method to suppress sympathetic overactivation, however it is a nonspecific and irreversible intervention. Bioelectronic medicine, in particular vagus nerve stimulation (VNS), has been used in cardiovascular disorders like arrhythmias, heart failure and arterial hypertension and could, in principle, be tested as a treatment in PAH. VNS can produce pulmonary vasodilation and renormalize right ventricular function, via activation of pulmonary and cardiac vagal fibers. It can suppress systemic inflammation, via activation of fibers that innervate the spleen. Finally, VNS can gradually restore the balance between parasympathetic and sympathetic tone by regulating autonomic reflexes. Preclinical studies support the feasibility of using VNS in PAH. However, there are challenges with such an approach, arising from the need to affect a relatively small number of relevant vagal fibers, and the potential for unwanted cardiac and noncardiac effects of VNS in this sensitive patient population.
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Affiliation(s)
- Despοina Ntiloudi
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030 USA.,2Department of Cardiology, AHEPA University Hospital, Thessaloniki, Greece
| | - Khaled Qanud
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030 USA
| | - Jacquelyn-Nicole Tomaio
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030 USA
| | | | - Yousef Al-Abed
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030 USA
| | - Stavros Zanos
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030 USA
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Chaix MA, Gatzoulis MA, Diller GP, Khairy P, Oechslin EN. Eisenmenger Syndrome: A Multisystem Disorder-Do Not Destabilize the Balanced but Fragile Physiology. Can J Cardiol 2019; 35:1664-1674. [PMID: 31813503 DOI: 10.1016/j.cjca.2019.10.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 10/01/2019] [Indexed: 12/13/2022] Open
Abstract
Eisenmenger syndrome is the most severe and extreme phenotype of pulmonary arterial hypertension associated with congenital heart disease. A large nonrestrictive systemic left-to-right shunt triggers the development of pulmonary vascular disease, progressive pulmonary arterial hypertension, and increasing pulmonary vascular resistance at the systemic level, which ultimately results in shunt reversal. Herein, we review the changing epidemiological patterns and pathophysiology of Eisenmenger syndrome. Multiorgan disease is an integral manifestation of Eisenmenger syndrome and includes involvement of the cardiac, hematological, neurological, respiratory, gastrointestinal, urinary, immunological, musculoskeletal, and endocrinological systems. Standardized practical guidelines for the assessment, management, risk stratification, and follow-up of this very fragile and vulnerable population are discussed. Multidisciplinary care is the best clinical practice. An approach to the prevention and management of a broad spectrum of complications is provided. Relevant therapeutic questions are discussed, including anticoagulation, noncardiac surgery, physical activity, transplantation, and advanced-care planning (palliative care). Advanced pulmonary arterial hypertension therapies are indicated in patients with Eisenmenger syndrome and World Health Organization functional class II or higher symptoms to improve functional capacity, quality of life, and-less well documented-survival. Specific recommendations regarding monotherapy or combination therapy are provided according to functional class and clinical response. The ultimate challenge for all care providers remains early detection and management of intracardiac and extracardiac shunts, considering that Eisenmenger syndrome is a preventable condition.
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Affiliation(s)
- Marie-A Chaix
- Adult Congenital Centre, Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada
| | - Michael A Gatzoulis
- Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Gerhard-Paul Diller
- Department of Cardiology, Adult Congenital and Valvular Heart Disease, University Hospital Münster, Münster, Germany
| | - Paul Khairy
- Adult Congenital Centre, Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada
| | - Erwin N Oechslin
- Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
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