scholarly journals Relevance of Angiopoietin-2 and Soluble P-Selectin Levels in Patients with Pulmonary Arterial Hypertension Receiving Combination Therapy with Oral Treprostinil: A FREEDOM-C2 Biomarker Substudy

2016 ◽  
Vol 6 (4) ◽  
pp. 516-523 ◽  
Author(s):  
Manuel J. Richter ◽  
Ralph Schermuly ◽  
Werner Seeger ◽  
Youlan Rao ◽  
Hossein A. Ghofrani ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Additional Treatment ◽  
Functional Class ◽  
Operating Characteristics ◽  
Biomarker Analysis ◽  
Pulmonary Arterial ◽  
Soluble P ◽  
Angiopoietin 2

Studies have suggested roles for angiopoietin-2 (Ang-2) and soluble P-selectin (sP-selectin) as biomarkers of disease severity and treatment response in pulmonary arterial hypertension (PAH), but additional data are required for validation. We evaluated these biomarkers using data from FREEDOM-C2, in which patients with PAH receiving stable monotherapy or combination therapy were randomized to receive additional treatment with oral treprostinil (up-titrated from 0.25 mg twice daily) or placebo for 16 weeks. Biomarker analysis was optional in FREEDOM-C2. We measured plasma Ang-2 and sP-selectin levels at baseline and at week 16, and we assessed their association with predefined outcomes (6-minute walk distance [6MWD] change from baseline >40 m, 6MWD >380 m, functional class I/II, and/or N-terminal pro-brain natriuretic peptide [NT-proBNP] <1,800 pg/mL at week 16) using Spearman correlation, receiver operating characteristics, and logistic regression. Biomarker data were available for 83 of 157 and 95 of 153 patients in the oral treprostinil and placebo groups, respectively. In the oral treprostinil group, baseline Ang-2 levels correlated with week 16 NT-proBNP levels ( P < 0.0001). Baseline Ang-2 ≥12 ng/mL was associated with a reduced likelihood of having NT-proBNP <1,800 pg/mL at week 16 (multivariate odds ratio: 0.08; 95% confidence interval: 0.02–0.32). However, Ang-2 showed no significant association with the other assessed outcomes, and sP-selectin was not associated or correlated with any of the outcomes. These data suggest that Ang-2 and sP-selectin are not associated with response to oral treprostinil in patients already receiving stable PAH therapy. Trial registration: Clinicaltrials.gov identifier NCT00887978.

scholarly journals Triple combination therapy with macitentan, riociguat, and selexipag in a patient with idiopathic pulmonary arterial hypertension (functional class III)

Kardiologiia ◽  
2021 ◽  
Vol 61 (10) ◽  
pp. 104-107
Author(s):  
A. A. Proshkina ◽  
N. A. Tsareva ◽  
G. V. Nekludova ◽  
S. N. Avdeev
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Clinical Manifestations ◽  
Functional Class ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Triple Combination ◽  
Class Iii ◽  
Triple Combination Therapy ◽  
Pulmonary Arterial

The article presents a clinical case of successful triple combination therapy in a female patient with functional class III idiopathic pulmonary arterial hypertension. Supplementing the previous macitentan and riociguat treatment with selexipag reduced the severity of clinical manifestations of pulmonary hypertension. Also, the treatment efficacy was demonstrated by improvement of laboratory and instrumental indexes. Time-related changes were evaluated at 3 months after initiation of the selexipag treatment.

scholarly journals Clinical outcomes stratified by baseline functional class after initial combination therapy for pulmonary arterial hypertension

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
R. James White ◽  
Anton Vonk-Noordegraaf ◽  
Stephan Rosenkranz ◽  
Ronald J. Oudiz ◽  
Vallerie V. McLaughlin ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Confidence Interval ◽  
Arterial Hypertension ◽  
Functional Class ◽  
Hazard Ratio ◽  
Clinical Failure ◽  
Initial Combination Therapy ◽  
Pulmonary Arterial ◽  
Initial Combination

Abstract Background Initial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy. Previous studies in PAH have demonstrated greater treatment benefits in more symptomatic participants. Methods AMBITION was an event-driven, double-blind study in which participants were randomized 2:1:1 to once-daily initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg, ambrisentan 10 mg plus placebo, or tadalafil 40 mg plus placebo. In this pre-specified subgroup analysis, we compared the efficacy data between those with functional class (FC) II vs. FC III symptoms at baseline. Results This analysis included 500 participants in the previously defined primary analysis set (n = 155 FC II, n = 345 FC III). Comparing combination therapy to pooled monotherapy, the risk of clinical failure events was reduced by 79% (hazard ratio, 0.21 [95% confidence interval: 0.071, 0.63]) for FC II patients and 42% (hazard ratio, 0.58 [95% confidence interval: 0.39, 0.86]) for FC III patients. In a post-hoc analysis, the risk of first hospitalization for worsening PAH was also reduced by combination therapy, particularly for FC II patients (0 combination vs. 11 [14%] pooled monotherapy). Adverse events were frequent but comparable between the subgroups. Conclusions Treatment benefit from initial combination therapy appeared at least as great for FC II as for FC III participants. Hospitalizations for worsening PAH were not observed in FC II participants assigned to combination. The present data support an initial combination strategy for newly diagnosed patients even when symptoms are less severe. Funded by Gilead Sciences, Inc. and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.

Combination Pharmacotherapy in the Treatment of Pulmonary Arterial Hypertension

2013 ◽  
Vol 26 (1) ◽  
pp. 18-28 ◽  
Author(s):  
Kimberly L. Tackett ◽  
Gregory V. Stajich
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Therapeutic Option ◽  
Symptom Control ◽  
Right Ventricular Dysfunction ◽  
Functional Class ◽  
Current Therapy ◽  
Therapeutic Benefits ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a disorder of the small pulmonary arteries characterized by progressive fibrotic and proliferative changes that result in an increased pulmonary vascular resistance. It is a progressive and debilitating disease that leads to right ventricular dysfunction, impairment in activity tolerance and eventually right-sided heart failure, and premature death. The treatment goals for PAH include improvement in symptoms, improvement in functional class and exercise class, decreased morbidity, and preventing mortality. Combination therapy in the treatment of PAH is an emerging therapeutic option. Combining therapies with differing mechanisms of action will maximize therapeutic benefits such as symptom control and increased rate of survival. The updated 2007 American College of Chest Physicians evidence-based clinical practice guidelines recommend combination therapy in functional classes III and IV if there is no improvement with current therapy or if there is deterioration in class. PAH monotherapy has been shown to improve symptoms, but the patients’ hemodynamic parameters may not be normalized, leading to further pulmonary vascular remodeling. Combination therapy offers an additional option for those patients who are unable to stabilize on monotherapy.

scholarly journals Dasatinib-Induced Pulmonary Arterial Hypertension Treated with Upfront Combination Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-5 ◽  
Author(s):  
Makoto Nishimori ◽  
Tomoyuki Honjo ◽  
Kenji Kaihotsu ◽  
Naohiko Sone ◽  
Sachiko Yoshikawa ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Rare Complication ◽  
Functional Class ◽  
World Health ◽  
First Line Therapy ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Arterial ◽  
Health Organization

Pulmonary arterial hypertension (PAH) is a rare complication of dasatinib that was approved as a first-line therapy for chronic myelocytic leukemia (CML). A 24-year-old man presenting dyspnea at rest and leg edema was admitted to our hospital. He had been diagnosed with CML and prescribed dasatinib for 4 years. Chest X-ray showed significant bilateral pleural effusion and heart enlargement. Echocardiography revealed interventricular septal compression and elevated peak tricuspid regurgitation pressure gradient of 66.7 mmHg indicating severe pulmonary hypertension. After the other specific diseases to provoke PAH were excluded, he was diagnosed with dasatinib-induced PAH. Despite discontinuation of dasatinib and intravenous administration of diuretic for two weeks, World Health Organization (WHO) functional class was still II and mean pulmonary arterial pressure (PAP) was high at 37 mmHg. Therefore, we administered sildenafil and bosentan together as an upfront combination therapy three weeks after dasatinib discontinuation. Six months later, his symptoms improved to WHO functional class I and mean PAP was decreased to 31 mmHg. Although PAH is a rare complication of dasatinib, symptomatic patients prescribed with dasatinib should have an echocardiogram for PAH screening. Moreover, the upfront combination therapy would be a useful option for symptomatic patients after discontinuation of dasatinib.

scholarly journals Addition of Sildenafil in Patients with Pulmonary Arterial Hypertension with Inadequate Response to Bosentan Monotherapy

2008 ◽  
Vol 15 (8) ◽  
pp. 427-430 ◽  
Author(s):  
Nancy R Porhownik ◽  
Hassan Al-Sharif ◽  
Zoheir Bshouty
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Exercise Tolerance ◽  
Nyha Class ◽  
Heart Association ◽  
Functional Class ◽  
Inadequate Response ◽  
Nyha Classification ◽  
Pulmonary Arterial

BACKGROUND: Pulmonary arterial hypertension (PAH) remains a progressive disease despite improvement when using one of three medication classes: prostanoids, endothelin receptor antagonists or phosphodiesterase-5 inhibitors. Combination therapy has been proposed for patients with unsatisfactory response to monotherapy.OBJECTIVES: To examine the effect of adding sildenafil to bosentan on 6 min walk distance (6MWD) and New York Heart Association (NYHA) classification in patients with PAH who achieved inadequate improvement with bosentan monotherapy.METHODS: Patients with idiopathic PAH or connective tissue disease-associated PAH, and who had either self-reported inadequate improvement in exercise tolerance or a decline in 6MWD after initial improvement, were included in the study (n=10). Data on 6MWD and NYHA class at baseline (before initiation of bosentan), three and six months after baseline, second baseline (before initiation of combination therapy with sildenafil), and three and six months after second baseline were analyzed for any changes.RESULTS: Mean time from initiation of bosentan monotherapy to initiation of combination therapy was 558 days (range 150 to 900 days). Six months after initiation of bosentan, 6MWD increased by 57.2 m above the baseline of 314.4 m. Six months after combination therapy, 6MWD was 62.80 m higher than the baseline before initiation of combination therapy of 339 m (P<0.02). The overall increase in 6MWD six months after combination therapy was higher than the first baseline by 87.4 m (P not significant). NYHA functional class did not improve with combination therapy in all patients.DISCUSSION: Initiating combination therapy in patients who achieve an inadequate improvement in exercise tolerance with mono-therapy may result in further improvement in exercise tolerance.

scholarly journals 15 years journey of idiopathic pulmonary arterial hypertension with BMPR2 mutation

2019 ◽  
Vol 25 (1) ◽  
Author(s):  
Kyung Jin Ahn ◽  
Albert Youngwoo Jang ◽  
Su Jung Park ◽  
Wook-Jin Chung
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Clinical Symptoms ◽  
Functional Class ◽  
Class Iii ◽  
Insurance Policy ◽  
Loss To Follow Up ◽  
Pulmonary Arterial ◽  
The Government

Abstract Pulmonary arterial hypertension (PAH) is known as one of diseases with the worst prognosis. Recently, targeted PAH drugs have been developed and approved for use; therefore, the treatment strategy and goals have changed, and the prognosis has improved over two decades. We reviewed the case of a female who showed the natural disease course of heritable PAH in treatment with the targeted PAH drugs under the Korean Health Insurance policy. At the age of 15, she visited the outpatient clinic for dyspnea on exertion that occurred 3 years ago. At that time, severe pulmonary hypertension was revealed by an echocardiography and there was no evidence of significant shunt lesion or embolism. After 4 years of loss to follow-up, her performance was WHO functional class III and she still suffered from dyspnea. The initial monotherapy using an endothelin receptor antagonist was started in 2008. After 2 years, BMPR 2 mutation was detected. Her clinical symptoms gradually worsened because of poor compliance. To escalate therapy, combination therapy was given, and finally, triple maximal therapy was maintained. The next step is to consider intravenous prostanoids. Various combinations of targeted therapy have been tried, and several trials have been confirmed that improve the prognosis. Initial upfront combination therapy and a more enthusiastic approach make good a better prognosis. In this area, active support of the government insurance policy is indispensable in Korea.

scholarly journals Initial dual oral combination therapy in pulmonary arterial hypertension

2016 ◽  
Vol 47 (6) ◽  
pp. 1727-1736 ◽  
Author(s):  
Olivier Sitbon ◽  
Caroline Sattler ◽  
Laurent Bertoletti ◽  
Laurent Savale ◽  
Vincent Cottin ◽  
...  
Keyword(s):  
New York ◽  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Single Agent ◽  
Survival Rates ◽  
Heart Association ◽  
Functional Class ◽  
Class Iii ◽  
Pulmonary Arterial

Treatment for pulmonary arterial hypertension (PAH) has been underpinned by single-agent therapy to which concomitant drugs are added sequentially when pre-defined treatment goals are not met.This retrospective analysis of real-world clinical data in 97 patients with newly diagnosed PAH (86% in New York Heart Association functional class III−IV) explored initial dual oral combination treatment with bosentan plus sildenafil (n=61), bosentan plus tadalafil (n=17), ambrisentan plus tadalafil (n=11) or ambrisentan plus sildenafil (n=8).All regimens were associated with significant improvements in functional class, exercise capacity, dyspnoea and haemodynamic indices after 4 months of therapy. Over a median follow-up period of 30 months, 75 (82%) patients were still alive, 53 (71%) of whom received only dual oral combination therapy. Overall survival rates were 97%, 94% and 83% at 1, 2 and 3 years, respectively, and 96%, 94% and 84%, respectively, for the patients with idiopathic PAH, heritable PAH and anorexigen-induced PAH. Expected survival rates calculated from the French equation for the latter were 86%, 75% and 66% at 1, 2 and 3 years, respectively.Initial combination of oral PAH-targeted medications may offer clinical benefits, especially in PAH patients with severe haemodynamic impairment.

Longterm Efficacy and Safety of Monotherapy versus Combination Therapy in Systemic Sclerosis–associated Pulmonary Arterial Hypertension: A Retrospective RESCLE Registry Study

2019 ◽  
Vol 47 (1) ◽  
pp. 89-98 ◽  
Author(s):  
Melani Pestaña-Fernández ◽  
Manuel Rubio-Rivas ◽  
Carles Tolosa-Vilella ◽  
Alfredo Guillén-Del-Castillo ◽  
Mayka Freire ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Protective Factor ◽  
Sequential Therapy ◽  
Functional Class ◽  
Combination Group ◽  
Sequential Combination ◽  
Pulmonary Arterial

Objective.Monotherapy is an option as first-line therapy for pulmonary arterial hypertension (PAH). However, combination therapy is a beneficial alternative. Our objective was to evaluate the efficacy of monotherapy versus combination therapy in patients with systemic sclerosis (SSc)–associated PAH.Methods.All patients with SSc-associated PAH from the Spanish Scleroderma Registry (RESCLE) were reviewed. Patients were split into 3 groups: monotherapy versus sequential combination versus upfront combination therapy. The primary endpoint was death from any cause at 1, 3, and 5 years from PAH diagnosis.Results.Seventy-six patients (4.2%) out of 1817 had SSc-related PAH. Thirty-four patients (45%) were receiving monotherapy [endothelin receptor antagonist (n = 22; 29%) or phosphodiesterase-5 inhibitors (n = 12; 16%)], 25 (33%) sequential combination, and 17 (22%) upfront combination therapy. A lower forced vital capacity/DLCO in the sequential combination group was reported (2.9 ± 1.1 vs 1.8 ± 0.4 vs 2.3 ± 0.8; p = 0.085) and also a higher mean pulmonary arterial pressure in combination groups (37.2 ± 8.7 mmHg vs 40.8 ± 8.8 vs 46 ± 15.9; p = 0.026) at baseline. Treatment regimen (p = 0.017) and functional class (p = 0.007) were found to be independent predictors of mortality. Sequential combination therapy was found to be an independent protective factor (HR 0.11, 95% CI 0.03–0.51; p = 0.004), while upfront combination therapy showed a trend (HR 0.68, 95% CI 0.23–1.97; p = 0.476). Survival from PAH diagnosis among monotherapy, sequential, and upfront combination groups was 78% versus 95.8% versus 94.1% at 1 year, 40.7% versus 81.5% versus 51.8% at 3 years, and 31.6% versus 56.5% versus 34.5% at 5 years (p = 0.007), respectively. Side effects were not significantly different among groups.Conclusion.Combination sequential therapy improved survival in our cohort.

Short term effect of Selexipag in comparison to parenteral prostacyclin analogues in pulmonary arterial hypertension patients started on double-combination therapy with ERA and PDE-5 inhibitors

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F Dardi ◽  
E Zuffa ◽  
M Palazzini ◽  
F Pasca ◽  
A De Lorenzis ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Right Heart Catheterization ◽  
Functional Class ◽  
Rank Test ◽  
Heart Catheterization ◽  
Double Blind ◽  
Pulmonary Arterial ◽  
Prostacyclin Analogues

Abstract Background The event-driven, phase 3, randomized, double-blind, placebo-controlled GRIPHON trial demonstrated that Selexipag reduces the risk of a composite end point of death or morbidity events in patients with pulmonary arterial hypertension (PAH). Despite the advantage of a per os formulation, its efficacy in comparison to parenteral prostacyclin analogues in patients already on oral double-combination therapy with endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5-I) is not known. Purpose The aim of this study was to compare the effects of Selexipag (S) vs subcutaneous Treprostinil (T) vs intravenous Epoprostenol (E) in PAH patients initially started with double-combination therapy with ERA and PDE5-I. Methods We enrolled patients on double combination therapy with ERA + PDE5-I starting S, T or E. Drugs were gradually uptitrated to the maximum tolerated/approved dose. All patients were systematically assessed with WHO-functional class (FC), six minute walk test (6MWT) and right heart catheterization before treatment and 3 months after reaching a stable dose of the drug. Baseline characteristics and changes in 6MWT and haemodynamic parameters were analyzed using Wilcoxon signed-rank test and compared between the 3 drugs with Kruskal-Wallis test. Results One hundred and seventy-one patients with PAH were enrolled. Results are shown in the Table. Patients with a complete re-evaluation were 61% of S, 85% of T, 79% with E. Conclusions S was prescribed to the oldest and least severe PAH patients. E was prescribed to the youngest and most severe PAH patients and led to the strongest improvement of exercise capacity and haemodynamic profile. T has intermediate characteristics. Table 1 Funding Acknowledgement Type of funding source: None

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