Upfront Combination Therapy With Ambrisentan and TadalafilIin Treatment Naive Patients With Pulmonary Arterial Hypertension (PAH): Subgroup Analyses by Functional Class (FC), Etiology, and Region From the AMBITION Study

CHEST Journal ◽  
2014 ◽  
Vol 146 (4) ◽  
pp. 339A ◽  
Author(s):  
Lewis Rubin ◽  
Joan Barbera ◽  
Adaani Frost ◽  
Hossein-Ardeschir Ghofrani ◽  
Marius Hoeper ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Functional Class ◽  
Subgroup Analyses ◽  
Treatment Naïve ◽  
Pulmonary Arterial

scholarly journals Recent advances in the management of pulmonary arterial hypertension

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2755 ◽  
Author(s):  
Halley Tsai ◽  
Yon K. Sung ◽  
Vinicio de Jesus Perez
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Right Heart Failure ◽  
New Drugs ◽  
Triple Combination Therapy ◽  
Treatment Naïve ◽  
Treatment Paradigm ◽  
Pulmonary Arterial

Over the past 20 years, there has been an explosion in the development of therapeutics to treat pulmonary arterial hypertension (PAH), a rare but life-threatening disorder associated with progressive elevation of pulmonary pressures and severe right heart failure. Recently, the field has seen the introduction of riociguat, a soluble guanylate cyclase stimulator, a new endothelin receptor antagonist (macitentan), and oral prostanoids (treprostinil and selexipag). Besides new drugs, there have been significant advances in defining the role of upfront combination therapy in treatment-naïve patients as well as proposed methods to deliver systemic prostanoids by use of implantable pumps. In this review, we will touch upon the most important developments in PAH therapeutics over the last three years and how these have changed the guidelines for the treatment of PAH. These exciting developments herald a new era in the treatment of PAH which will be punctuated by the use of more clinically relevant endpoints in clinical research trials and a novel treatment paradigm that may involve upfront double- or triple-combination therapy. We anticipate that the future will make use of these strategies to test the efficacy of upcoming new drugs that aspire to reduce disease progression and improve survival in patients afflicted with this devastating disease.

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.

scholarly journals The role of combination therapy in managing pulmonary arterial hypertension

2014 ◽  
Vol 23 (134) ◽  
pp. 469-475 ◽  
Author(s):  
Hossein-Ardeschir Ghofrani ◽  
Marc Humbert
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Treatment Algorithm ◽  
Supporting Evidence ◽  
Potential Clinical Benefit ◽  
Treatment Naïve ◽  
Sequential Combination ◽  
Pulmonary Arterial ◽  
Randomised Controlled

Pulmonary arterial hypertension (PAH) is a complex, progressive disease with several pathobiological mechanisms, including the endothelin, nitric oxide and prostacyclin pathways. Current treatments for PAH target one of these pathways and, in more severe cases or instances of disease worsening, may be combined with a view to target multiple pathways in parallel. Treatment combination is performed sequentially (as an intensification from initial monotherapy) or upfront (use of two or more therapies in treatment-naïve patients). Whilst combination therapy has been historically considered to be an option for the treatment of PAH, supporting evidence was typically limited to expert opinion, clinical experience and registry data.Data from randomised controlled trials on sequential combination therapy in particular has grown in recent years, resulting in a change in the level of recommendations in the latest update to the PAH treatment algorithm. However, short-term trials have shown inconsistent results, and have not been powered to assess morbidity/mortality outcomes. More recent data from long-term trials suggest a potential clinical benefit associated with sequential combination therapy.In this review we will introduce the concept of combination therapy, consider the latest evidence for both sequential and upfront combination therapy, and discuss additional considerations when initiating combination therapy in clinical practice.

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 Novel approach to classifying patients with pulmonary arterial hypertension using cluster analysis

2017 ◽  
Vol 7 (2) ◽  
pp. 486-493 ◽  
Author(s):  
Kishan S. Parikh ◽  
Youlan Rao ◽  
Tariq Ahmad ◽  
Kai Shen ◽  
G. Michael Felker ◽  
...  
Keyword(s):  
Cluster Analysis ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Patient Characteristics ◽  
Functional Class ◽  
Walking Distance ◽  
P Value ◽  
Novel Approach ◽  
Treatment Naïve ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) patients have distinct disease courses and responses to treatment, but current diagnostic and treatment schemes provide limited insight. We aimed to see if cluster analysis could distinguish clinical phenotypes in PAH. An unbiased cluster analysis was performed on 17 baseline clinical variables of PAH patients from the FREEDOM-M, FREEDOM-C, and FREEDOM-C2 randomized trials of oral treprostinil versus placebo. Participants were either treatment-naïve (FREEDOM-M) or on background therapy (FREEDOM-C, FREEDOM-C2). We tested for association of clusters with outcomes and interaction with respect to treatment. Primary outcome was 6-minute walking distance (6MWD) change. We included 966 participants with 12-week (FREEDOM-M) or 16-week (FREEDOM-C and FREEDOM-C2) follow-up. Four patient clusters were identified. Compared with Clusters 1 (n = 131) and 2 (n = 496), Clusters 3 (n = 246) and 4 (n = 93) patients were older, heavier, had worse baseline functional class, 6MWD, Borg Dyspnea Index, and fewer years since PAH diagnosis. Clusters also differed by PAH etiology and background therapies, but not gender or race. Mean treatment effect of oral treprostinil differed across Clusters 1–4 increased in a monotonic fashion (Cluster 1: 10.9 m; Cluster 2: 13.0 m; Cluster 3: 25.0 m; Cluster 4: 50.9 m; interaction P value = 0.048). We identified four distinct clusters of PAH patients based on common patient characteristics. Patients who were older, diagnosed with PAH for a shorter period, and had worse baseline symptoms and exercise capacity had the greatest response to oral treprostinil treatment.

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 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.

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