Advances in Therapeutic Interventions for Patients With Pulmonary Arterial Hypertension

Humbert, Marc; Lau, Edmund; Montani, David; Jaïs, Xavier; Sitbon, Olivier; Simonneau, Gérald

doi:10.1161/circulationaha.114.006974

Cited by 280 publications

(226 citation statements)

References 202 publications

(168 reference statements)

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“…Over the past three decades, there have been major advances in our understanding of the pathobiology of PAH, leading to the development of targeted therapies and improved patient outcomes [1].…”

Section: Introductionmentioning

confidence: 99%

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Hemnes

Humbert

2017

Eur Respir Rev

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The pathobiology of pulmonary arterial hypertension (PAH) is complex and incompletely understood. Although three pathogenic pathways have been relatively well characterised, it is widely accepted that dysfunction in a multitude of other cellular processes is likely to play a critical role in driving the development of PAH. Currently available therapies, which all target one of the three well-characterised pathways, provide significant benefits for patients; however, PAH remains a progressive and ultimately fatal disease. The development of drugs to target alternative pathogenic pathways is, therefore, an attractive proposition and one that may complement existing treatment regimens to improve outcomes for patients. Considerable research has been undertaken to identify the role of the less well-understood pathways and in this review we will highlight some of the key discoveries and the potential for utility as therapeutic targets.

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Section: Introductionmentioning

confidence: 99%

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Hemnes

Humbert

2017

Eur Respir Rev

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“…Medical therapies recommended for the treatment of PAH [4] target three distinct pathways (endothelin, nitric oxide and prostacyclin), [18] identified as pathologic. PAH specific therapies including endothelin receptor antagonists (ERA), phosphodiesterase type 5 (PDE-5) inhibitors, soluble guanylate cyclase (sGC) agonists, prostacyclin analogues, and prostacyclin receptor agonists are approved by the FDA for monotherapy or combination therapy for the treatment of PAH [4].…”

Section: Management Of Pahmentioning

confidence: 99%

Collaborative Care: A Defining Characteristic for a Pulmonary Hypertension Center

et al. 2017

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Introduction: Pulmonary hypertension (PH) is a complex, life-threatening disease. Development of pulmonary hypertension centers is recommended by pulmonary hypertension best practice guidelines and patient organizations to successfully care for patients. However, very little is published on the characteristics of these centers or the daily management required to care for this complex patient population. Methods: This article, written by nurses who have extensive experience in managing patients with pulmonary hypertension, details the collaboration and workflows needed at a

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“…There is ample evidence from published studies that add-on therapy to background monotherapy using sildenafil (PACES), inhaled treprostinil (TRIUMPH) and riociguat (PATENT) improve short-term end-points including exercise capacity and haemodynamics [1]. In addition, recently completed large-scale trial results have been presented demonstrating that initial combination therapy with ambrisentan plus tadalafil (AMBITION) reduced the time to clinical failure events [6], and the addition of macitentan (SERAPHIN) [7] or selexipag (GRIPHON) [8] reduced the time to morbidity and mortality events in both treatment-naïve subjects and those receiving background therapies.…”

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Navigating the uncharted waters of combination therapy in pulmonary arterial hypertension: COMPASS or dead-reckoning

Vachiéry

Rubin

2015

Eur Respir J

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@ERSpublications Two studies in this month's ERJ report results of combination therapy for PAH http://ow.ly/OlgID Despite substantial advances in the treatment of pulmonary arterial hypertension (PAH) over the past two decades, with 13 drugs approved by regulatory agencies worldwide, the responses to medical therapy are often incomplete or unsatisfactory [1]. As with other conditions with complex pathogenesis, PAH is probably the result of multiple stimuli, both genetic and epigenetic, whose interplay over the course of the disease is poorly understood. Combination therapy trials in cancer, heart failure and HIV infection have demonstrated the value of targeting multiple pathogenic pathways in complex diseases, and this strategy has become the therapeutic mainstay for these chronic conditions. Unlike these common diseases, however, PAH is considered an "orphan" disease, making large-scale clinical trials of multiple therapies more challenging, both logistically and practically [2,3]. Two articles in this issue of the European Respiratory Journal provide new information regarding the effects of adding a second approved oral medication to PAH patients who are not achieving a satisfactory clinical response to initial oral monotherapy [4,5].The COMPASS trial [4] enrolled 334 subjects over 6 years who were failing on first line therapy with sildenafil into a randomised trial to receive either the addition of bosentan 125 mg twice daily or placebo. The primary end-point was the time to first composite end-point of morbidity and mortality. There was no difference between the groups in the time to the primary end-point, and there were only modest differences in placebo-adjusted 6-min walk distance (+21 m) and N-terminal pro-brain natriuretic peptide (NT-ProBNP) in favour of the combination therapy group.The study reported by DARDI et al. [5] was an open label single-centre observational trial performed over 10 years in which subjects receiving first-line monotherapy with either sildenafil or bosentan then received the addition of the other drug if they failed to meet pre-specified treatment goals. While there was no pre-specified primary end-point of this study, the authors report the survival and describe improvements compared to baseline in exercise capacity, haemodynamics and symptoms in their cohort after treatment with combination therapy.Taken together, the results of these two studies leave us with a "cup half-full" feeling. Most disappointing is the COMPASS trial, which expended precious resources for a study that took far too long to complete enrolment -a problematic signal of design issues at the onset -and was underpowered to detect a meaningful treatment effect based on our current knowledge from larger time-to-clinical worsening end-point clinical trials in PAH. A likely important contributor to the negative outcome of COMPASS was the unproven primary end-point component of a patient self-assessment of status, although this has been

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Advances in Therapeutic Interventions for Patients With Pulmonary Arterial Hypertension

Cited by 280 publications

References 202 publications

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Collaborative Care: A Defining Characteristic for a Pulmonary Hypertension Center

Navigating the uncharted waters of combination therapy in pulmonary arterial hypertension: COMPASS or dead-reckoning

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