Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) – A subgroup analysis of the ARIES-E clinical trial

Fischer, Aryeh; Denton, Christopher P.; Matucci‐Cerinic, Marco; Gillies, Hunter; Blair, Christiana; Tislow, James; Nathan, Steven D.

doi:10.1016/j.rmed.2016.06.018

Cited by 31 publications

(27 citation statements)

References 28 publications

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“…Two large RCTs (ARIES 1 and 2) assessed the efficacy and safety of ambrisentan (2.5, 5, and 10 mg daily) in PAH. 38 Fischer et al 39 performed a subanalysis in patients with CTD-PAH (n ¼ 124) based on a combination of these trials (ARIES-C) and their open-label extensions (ARIES-E). The primary endpoint for both studies was change in 6MWT from baseline to week 12 compared to placebo.…”

Section: Endothelin Receptor Antagonistsmentioning

confidence: 99%

Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment

Zanatta

Polito

Famoso

et al. 2019

Exp Biol Med (Maywood)

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Pulmonary arterial hypertension (PAH) is a serious complication of connective tissue disorders (CTDs), and CTD-PAH is the second cause of PAH after the idiopathic form. PAH is characterized by increased pulmonary arterial pressure and pulmonary vascular resistance, which can lead to right heart failure and death. About 90% of CTD-PAH cases are associated with systemic sclerosis (SSc, 74%), mixed connective tissue disease (MCTD, 8%) or systemic lupus erythematosus (SLE, 8%). CTD-PAH has also been reported, albeit rarely, in Sjögren syndrome, inflammatory idiopathic myopathies and rheumatoid arthritis. As for idiopathic PAH, the impaired production of vasoactive mediators such as nitric oxide and prostacyclin, and the increased production of vasoconstrictors and proliferative mediators such as endothelin-1, affect the vascular tone and promote vascular remodeling. Moreover, there is growing evidence suggesting that inflammation and autoimmunity may contribute to the genesis and progression of CTD-PAH, especially in SLE and MCTD patients who require an early administration of corticosteroids and immunosuppressants in order to avoid irreversible pathologic changes in pulmonary vessels. Conversely, immunosuppressive agents are ineffective in SSc-PAH, which requires a timely and aggressive treatment with specific PAH therapies (combination therapy). In this review, we summarized the current data on the pathophysiology and treatment of CTD-PAH. Impact statement Our article focuses on the pathogenesis and treatment of CTD-PAH. In the latest ESC/ESR guidelines for PAH, the authors underline that although CTD-PAH should follow the same treatment protocol as idiopathic PAH, the therapeutic approach is more complex and difficult in the former. This review throws light on several peculiar aspects of CTD-PAH and the latest findings in the pathogenesis, namely, the role of inflammation in the maladaptive right ventricle remodeling in SSc-PAH where immunosuppressants are classically believed to be ineffective. Furthermore, we discuss the major critical points in the therapy of CTD-PAH which is one of the strengths of our article. To the best of our knowledge, there are no other reviews that exclusively focus on the pathogenesis and treatment of CTD-PAH patients, with an emphasis on the more critical issues. Thus, it is our contention that our work would be of interest to the readers.

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Section: Endothelin Receptor Antagonistsmentioning

confidence: 99%

Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment

Zanatta

Polito

Famoso

et al. 2019

Exp Biol Med (Maywood)

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“…Therapies have progressed from a time when only intravenous epoprostenol was available [144,145] and outcomes were very poor, to the current availability of multiple licensed treatments that can be used in combination ( Table 2). The early studies that led to the licensing of various PAH therapies, including bosentan and sildenafil, focused on short term gains in exercise capacity; in these studies, the response of patients with SSc-associated PAH or CTD-associated PAH was often less efficacious than patients with other forms of PAH, although most treatments seem to result in meaningful benefit in the majority of patients with SSc-associated PAH [146,147,148,149]. However, evidence in clinical practice suggests that these therapies have long-term benefits in SSc-associated PAH [142], which is supported by key eventdriven clinical trials published in the past 3 years [150,151,152]: the SERAPHIN trial (which tested the oral endothelin receptor antagonist macitentan), the GRIPHON trial (which tested the prostcyclinreceptor agonist selexipag) and the AMBITION trial (which tested a combination therapy of ambrisentan (endothelin receptor antagonist) and tadalafil (a PDE5 inhibitor)).…”

Section: [H2] Treatment Approaches For Lung Fibrosismentioning

confidence: 99%

Major lung complications of systemic sclerosis

2018

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Systemic sclerosis (SSc) is associated with high mortality owing to internal organ complications, and lung disease is the leading cause of SSc-associated death. The most notable lung complications in SSc are fibrosis and pulmonary arterial hypertension (PAH). A major challenge for the management of lung disease in SSc is detecting those patients with severe pathology and those patients who are likely to benefit from available treatments. In the past few years, strategies for managing lung fibrosis and pulmonary hypertension, including PAH, have greatly progressed. For lung fibrosis, the tools to assess risk of progression and severity of the disease have been refined. Clinical trial results support the use of immunosuppression, including high-intensity regimens with autologous stem cell transplantation. New trials are underway to test other potential therapies including treatments that are approved for use in idiopathic lung fibrosis. For PAH, identifying individuals at high risk of disease development is critical. In addition, individuals who have borderline elevation of pulmonary arterial pressure need to be appropriately managed and followed up. Many approved drugs targeting PAH are now available, and results from large-scale clinical trials provide robust evidence that various treatments for SSc-associated PAH are associated with good long-term outcomes.

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“…3 From included studies in F I G U R E 4 Forest plot comparing Combination vs Monotherapy A, 6 min walk distance; B, clinical failure endpoint our analysis, the pattern of frequency of AEs appears similar to that of the idiopathic subtype. 3,31 Vasodilatory AEs, such as peripheral edema, were more common with initial combination therapy compared to monotherapy. 3 Choosing…”

Section: Discussionmentioning

confidence: 99%

“…However, CTD-specific data from 3 of these studies were reported in 3 subsequent publications. 3,30,31 The final analysis included a total of 3100 PAH patients, of whom 784 belonged to the CTD-PAH subgroup (25.3%). Characteristics of the included studies are summarized in Table 1 Five studies compared various forms of combination therapy to monotherapy.…”

Section: Study Characteristicsmentioning

confidence: 99%

Effectiveness and safety of endothelin receptor antagonists, alone and in combination therapy, in the pulmonary arterial hypertension‐connective tissue disease subtype: A systematic review and meta‐analysis

et al. 2020

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Introduction: There is limited information regarding the effectiveness of endothelin receptor antagonists (ERA) in patients with connective tissue disease-pulmonary arterial hypertension (CTD-PAH), a condition that is characterized by poorer clinical outcomes compared to other PAH subtypes. Objective: To conduct a systematic review and meta-analysis of the effectiveness and safety of ERA in CTD-PAH. Methods: A literature search, using MEDLINE, COCHRANE, CINAHL and EMBASE databases was conducted, from inception to May 2019 to identify randomized control studies of ERA, as monotherapy or in combination with phosphodiesterase type 5 inhibitors (PDE5i), in CTD-PAH. A protocol was registered in PROSPERO (CRD42019136956). Efficacy outcomes, including the 6-minute walk distance (6MWD) and composite clinical failure endpoints (CFE), and safety outcomes were evaluated. Results: A total of 13 studies, including 784 CTD-PAH participants, were identified. ERA, as monotherapy, did not reduce the risk of CFE compared to placebo (odds ratio [OR] 0.77, 95% CI 0.50-1.19, P = .25). By contrast, combination therapy (ERA + PDE5i) significantly reduced the risk of developing CFE vs monotherapy (OR 0.54, 95% CI 0.32-0.90, P = .02). 6MWD did not improve when comparing monotherapy vs placebo (+17.41 m; 95% CI −19.83-54.66) P = .36) or combination therapy vs monotherapy (+13.17 m; 95% CI −16.44-42.78, P = .38). ERA-related adverse events rates in CTD-PAH and general PAH cohorts were comparable. Conclusions: ERA, when used in combination with PDE5is, are associated with reduced risk of CFE, but no significant changes in 6MWD, in CTD-PAH. This warrants further studies investigating early combination therapy as a standard of care in this group. | 1277 SHIVAKUMAR et Al.

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Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) – A subgroup analysis of the ARIES-E clinical trial

Cited by 31 publications

References 28 publications

Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment

Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment

Major lung complications of systemic sclerosis

Effectiveness and safety of endothelin receptor antagonists, alone and in combination therapy, in the pulmonary arterial hypertension‐connective tissue disease subtype: A systematic review and meta‐analysis

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