Challenges in Endpoint Development for Pulmonary Hypertension Trials in Children

2014 ◽  
Vol 13 (3) ◽  
pp. 125-128 ◽  
Author(s):  
Dunbar Ivy
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Drug Approval ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Hypoxemic Respiratory Failure ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Pulmonary Arterial ◽  
Phosphodiesterase Type

There are currently 12 medications approved for use in the treatment of pulmonary arterial hypertension (PAH) in adults. These include endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclins. However, in children there are no approved targeted PAH medications, with the exception of inhaled nitric oxide for treatment of hypoxemic respiratory failure in neonates. This review will address some of the challenges in the development of treatments for children, including lessons from recent trials, endpoints for clinical trials, and challenges with drug approval in children.

scholarly journals Pulmonary veno-occlusive disease in a patient with recently diagnosed systemic sclerosis

2019 ◽  
Vol 5 (2) ◽  
pp. NP1-NP4
Author(s):  
Nina M van Leeuwen ◽  
Sofia Ramiro ◽  
Maarten K Ninaber ◽  
Esther Nossent ◽  
Jeska K de Vries-Bouwstra
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Occlusive Disease ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Pulmonary Arterial ◽  
Phosphodiesterase Type ◽  
Worse Prognosis

Pulmonary veno-occlusive disease is a rare cause of pulmonary hypertension in patients with systemic sclerosis that can be misclassified as pulmonary arterial hypertension. Differentiation between pulmonary veno-occlusive disease and pulmonary arterial hypertension is challenging because of the similar clinical picture. Nevertheless, discrimination is important because pulmonary veno-occlusive disease has a worse prognosis. Vasodilators including phosphodiesterase type 5 inhibitors and endothelin receptor antagonists should be started with caution and often in combination with diuretics to prevent pulmonary edema.

scholarly journals Medication adherence, hospitalization, and healthcare resource utilization and costs in patients with pulmonary arterial hypertension treated with endothelin receptor antagonists or phosphodiesterase type-5 inhibitors

2020 ◽  
Vol 10 (1) ◽  
pp. 204589401988008 ◽  
Author(s):  
Robert P. Frantz ◽  
Jerrold W. Hill ◽  
Cassandra A. Lickert ◽  
Rolin L. Wade ◽  
Michele R. Cole ◽  
...  
Keyword(s):  
Medication Adherence ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Receptor Antagonists ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Proportion Of Days Covered ◽  
Pulmonary Arterial ◽  
Phosphodiesterase Type

Adherence to therapy for pulmonary arterial hypertension is essential to optimize patient outcomes, but data on real-world adherence to different pulmonary arterial hypertension drug classes are limited. This retrospective database analysis evaluated relationships between adherence, hospitalization, and healthcare costs in pulmonary arterial hypertension patients treated with endothelin receptor antagonists or phosphodiesterase type-5 inhibitors. From the IQVIA Adjudicated Health Plan Database, patients with pulmonary arterial hypertension were identified based on diagnostic codes and prescriptions for endothelin receptor antagonists (ambrisentan, bosentan, macitentan) or phosphodiesterase type-5 inhibitors (sildenafil, tadalafil) approved for pulmonary arterial hypertension. Patients were assigned to the class of their most recently initiated (index) pulmonary arterial hypertension therapy between 1 January 2009 and 30 June 2015. Medication adherence was measured by proportion of days covered; patients with proportion of days covered ≥80% were considered adherent. The proportion of adherent patients was higher for endothelin receptor antagonists (571/755; 75.6%) than for phosphodiesterase type-5 inhibitors (970/1578; 61.5%; P < 0.0001). In both groups, hospitalizations declined as proportion of days covered increased. Among adherent patients, those on endothelin receptor antagonists had a significantly lower hospitalization rate than those on phosphodiesterase type-5 inhibitors (23.1% versus 28.5%, P = 0. 0218), fewer hospitalizations (mean (standard deviation) 0.4 (0.8) versus 0.5 (0.9); P = 0.02), and mean hospitalization costs during the six-month post-index ($9510 versus $15,726, P = 0.0318). Increasing adherence reduced hospitalization risk more for endothelin receptor antagonists than for phosphodiesterase type-5 inhibitors (hazard ratio 0.176 versus 0.549, P = 0.001). Rates and numbers of rehospitalizations within 30 days post-discharge were similar between groups. Mean total costs were higher with endothelin receptor antagonists than phosphodiesterase type-5 inhibitors in all patients ($91,328 versus $72,401, P = 0.0003) and in adherent patients ($88,867 versus $56,300, P < 0.0001), driven by higher drug costs.

scholarly journals Pharmacological therapy for patients with chronic thromboembolic pulmonary hypertension

2015 ◽  
Vol 24 (136) ◽  
pp. 272-282 ◽  
Author(s):  
Marius M. Hoeper
Keyword(s):  
Pulmonary Hypertension ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Phase Iii ◽  
Current Evidence ◽  
Endothelin Receptor ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Thromboembolic Pulmonary Hypertension ◽  
Soluble Guanylate Cyclase Stimulator

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but life-threatening disease resulting from unresolved thromboembolic obstructions. Pulmonary endarterectomy (PEA) surgery is the gold-standard treatment as it is potentially curative; however, not all patients are deemed operable and up to one-third have persistent or recurrent CTEPH after the procedure. Pulmonary arterial hypertension (PAH) and CTEPH have similar clinical presentations and histopathological features, so agents shown to be effective in PAH have often been prescribed to patients with CTEPH in the absence of proven therapies. However, clinical evidence for this strategy is not compelling. A number of small uncontrolled trials have investigated endothelin receptor antagonists, prostacyclin analogues and phosphodiesterase type 5 inhibitors in CTEPH with mixed results, and a phase III study of the endothelin receptor antagonist bosentan met only one of its two co-primary end-points. Recently, however, the soluble guanylate cyclase stimulator, riociguat, was approved in the USA and Europe for the treatment of inoperable or persistent/recurrent CTEPH following positive results from the phase III CHEST study (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial). This article reviews the current evidence for the use of pharmacological therapies in CTEPH.

scholarly journals Pulmonary hypertension: reasonable selection of specific therapy

2018 ◽  
Vol 15 (1) ◽  
pp. 45-50
Author(s):  
N A Karoli ◽  
S I Sazhnova ◽  
A P Rebrov
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Structural Changes ◽  
Pulmonary Arteries ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Receptor Antagonists ◽  
Pulmonary Vasodilator ◽  
Pulmonary Arterial

Pulmonary hypertension is characterized with persistent increase in pulmonary vascular resistance leading to progressive worsening of right ventricular failure and death. The basis for pulmonary arterial hypertension is structural changes in pulmonary arteries and arterioles caused by endothelial dysfunction. Endothelin-1 is the main pathogenic trigger of pulmonary hypertension and potential target for therapeutic exposure. The efficacy of endothelin receptor antagonists is proved in various preclinical and clinical studies. In patients with pulmonary arterial hypertension, the efficacy of dual and selective endothelin receptor antagonists is comparable despite the varied activity against various receptors. Bosentan is the most widely used pulmonary vasodilator which improves exercise tolerance and decelerates disease progression.

scholarly journals Pulmonary Arterial Hypertension in Adults: Novel Drugs and Catheter Ablation Techniques Show Promise? Systematic Review on Pharmacotherapy and Interventional Strategies

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Salvatore Rosanio ◽  
Francesco Pelliccia ◽  
Carlo Gaudio ◽  
Cesare Greco ◽  
Abdul M. Keylani ◽  
...  
Keyword(s):  
Systematic Review ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Percutaneous Balloon ◽  
Novel Drugs ◽  
Pulmonary Arterial ◽  
Phosphodiesterase Type ◽  
Approved Drugs

This systematic review aims to provide an update on pharmacological and interventional strategies for the treatment of pulmonary arterial hypertension in adults. Currently US Food and Drug Administration approved drugs including prostanoids, endothelin-receptor antagonists, phosphodiesterase type-5 inhibitors, and soluble guanylate-cyclase stimulators. These agents have transformed the prognosis for pulmonary arterial hypertension patients from symptomatic improvements in exercise tolerance ten years ago to delayed disease progression today. On the other hand, percutaneous balloon atrioseptostomy by using radiofrequency perforation, cutting balloon dilatation, or insertion of butterfly stents and pulmonary artery catheter-based denervation, both associated with very low rate of major complications and death, should be considered in combination with specific drugs at an earlier stage rather than late in the progression of pulmonary arterial hypertension and before the occurrence of overt right-sided heart failure.

scholarly journals Methods of Pharmacological Treatment of Chronic Thromboembolic Pulmonary Hypertension Current Approaches to the Patients Management

Kardiologiia ◽  
2018 ◽  
Vol 58 (11) ◽  
pp. 82-93
Author(s):  
E. A. Ushkalova ◽  
S. K. Zyryanov ◽  
K. E. Zatolochina
Keyword(s):  
Pulmonary Hypertension ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Vasculature ◽  
The European Union ◽  
Pulmonary Thromboendarterectomy ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Thromboembolic Pulmonary Hypertension ◽  
Phosphodiesterase Type

In this paper we have discussed epidemiology, pathogenesis, and approaches to treatment of chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is a unique potentially curable form of pulmonary hypertension. The gold standard of CTEPH treatment is pulmonary thromboendarterectomy. However, about 40% of patients with CTEPH are inoperable due to distal surgically inaccessible lesions of the pulmonary vasculature, severe hemodynamic impairments, or other contraindications. In addition, nearly half of patients have persistent or recurrent pulmonary hypertension following surgery. Current guidelines support the use of pharmacotherapy in these patients. In the article we have presented results of main clinical studies of targeted drugs therapy (endothelin receptor antagonists, prostanoids, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators) of patients with CTEPH. The only drug that has demonstrated robust clinical efficacy in terms of improvment hemodynamic parameters, exercise capacity and patients’ quality of life is the stimulator of the soluble guanylate cyclase riociguat. The efficacy and safety of riociguat have been investigated in short-term and long-term studies with follow-up up to 6 years. Results of these studies have constituted the basis forits approval by the regulatory authorities of more than 50 countries for the treatment of inoperable CTEPH and persistent or recurrent CTEPH after pulmonary thromboendarterectomy. In the European Union, USA and many other countries, riociguat is the only pharmacological agent approved for these indications.

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