Clinical efficacy and safety of switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension

2017 ◽  
Vol 28 (4) ◽  
pp. 542-547 ◽  
Author(s):  
Ebru Aypar ◽  
Dursun Alehan ◽  
Tevfik Karagöz ◽  
Hayrettin Hakan Aykan ◽  
İlker Ertugrul
Keyword(s):  
Young Adults ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Clinical Efficacy ◽  
Efficacy And Safety ◽  
Walk Distance ◽  
Children And Young Adults ◽  
Pulmonary Arterial ◽  
Minute Walk Distance ◽  
Minute Walk

AbstractBackgroundMacitentan is an orally active, potent, dual endothelin receptor antagonist and is the only registered treatment for pulmonary arterial hypertension that significantly reduced morbidity and mortality in a long-term event-driven study.AimFew studies compared the clinical efficacy and safety of switch from bosentan to macitentan only in adult patients with pulmonary arterial hypertension. We aimed to evaluate the clinical efficacy and safety of switch from bosentan to macitentan in children and young adults.MethodsThis is a single-institution, 24-week prospective study. Patients ⩾12 years of age with idiopathic/heritable pulmonary arterial hypertension or related to CHD or residual pulmonary arterial hypertension due to repaired congenital systemic-to-pulmonary shunts and on bosentan therapy were included. Concomitant treatment with oral phosphodiesterase type 5 inhibitors and inhaled prostanoids was allowed. Outcome measures included change from baseline to week 24, in the 6-minute walk distance, functional class, oxygen saturation at rest/after 6-minute walk distance test, systolic pulmonary artery pressure estimated by echocardiography, and brain natriuretic peptide levels. Safety end points included adverse events laboratory abnormalities.ResultsA total of 13 patients – 5 male and 8 female – completed the study. The mean age was 20.3±6.5 years (12–35) and weight was 54.0±14.5 kg (27–75). Five patients were ⩽18 years of age. Macitentan improved 6-minute walk distance from baseline (mean: 466±35 m (300–590)), at 12 weeks (mean: 494±78 m (325–590), +28 m) (p<0.05), and at 24 weeks (mean: 507±58 m (325–625), +41 m) (p<0.05). Macitentan did not significantly change functional class, oxygen saturation at rest/after 6-minute walk distance test, brain natriuretic levels, and systolic pulmonary artery pressure (p>0.05). None of the patients had anaemia, hepatotoxicity, and peripheral oedema.ConclusionsOur study is the first study that showed that switch from bosentan to macitentan significantly improved exercise capacity in children and young adults with pulmonary arterial hypertension and is well tolerated without any adverse events.

Clinical efficacy and safety of switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension: extended study results

2020 ◽  
Vol 30 (5) ◽  
pp. 681-685
Author(s):  
Ebru Aypar ◽  
Dursun Alehan ◽  
Tevfik Karagöz ◽  
Hakan Aykan ◽  
İlker Ertugrul
Keyword(s):  
Young Adults ◽  
Pulmonary Arterial Hypertension ◽  
Adverse Events ◽  
Arterial Hypertension ◽  
Prospective Study ◽  
Functional Class ◽  
Walk Distance ◽  
Children And Young Adults ◽  
Pulmonary Arterial ◽  
Minute Walk Distance

AbstractBackground:Macitentan is an orally active, potent, dual endothelin receptor antagonist and is the only registered treatment for pulmonary arterial hypertension that significantly reduced morbidity and mortality in a long-term study.Aim:We have recently reported that switch from bosentan to macitentan significantly improved exercise capacity in children and young adults with pulmonary arterial hypertension in a 24-week prospective study and well tolerated without adverse events. We now aimed to evaluate clinical efficacy, safety of switch in a larger patient population, in a 24-month prospective study.Methods:This is a single-institution, 24-month prospective study. Patients ≥12 years with idiopathic/heritable, pulmonary arterial hypertension, or related to CHD or residual pulmonary arterial hypertension due to repaired congenital systemic-to-pulmonary shunts and on bosentan treatment were included. Concomitant treatment with oral phosphodiesterase type 5 inhibitors/inhaled prostanoids was allowed. Outcome measures included change from baseline to 24 months, in the 6-minute walk distance, functional class, oxygen saturation at rest/after walk distance test, and natriuretic peptide levels. Safety end points included adverse events, laboratory abnormalities.Results:Twenty-seven patients (19 adults/8 children, mean age: 21.1 ± 6.3 years (12–36), weight: 53.1 ± 15.7 kgs (26–87)) were included. Mean duration of macitentan treatment: 22.3 ± 3.9 months (9–24). Six-minute walk distance significantly improved from baseline (mean: 458 ± 79 m (300–620)) at 6 months (mean: 501 ± 73 m (325–616) + 43 m) (p < 0.05), at 12 months (mean: 514 ± 82 m (330–626) + 56 m) (p < 0.05), and at 24 months (mean: 532 ± 85 m (330–682) + 74 m) (p < 0.05). We observed a significant improvement during the first 6 months but no incremental improvement after 6 months (p > 0.05). Macitentan did not significantly change functional class, oxygen saturation, and natriuretic levels (p > 0.05). None of the patients had anaemia, hepatotoxicity, and peripheral edema.Conclusions:Our study is the first study which showed that switch from bosentan to macitentan improved exercise capacity in children and young adults with pulmonary arterial hypertension significantly in the first 6 months and compared to baseline in 24 months and well tolerated without adverse events.

scholarly journals Novel dose–response analyses of treprostinil in pulmonary arterial hypertension and its effects on six-minute walk distance and hospitalizations

2020 ◽  
Vol 10 (3) ◽  
pp. 204589402092395
Author(s):  
Gautam Ramani ◽  
Steven Cassady ◽  
Eric Shen ◽  
Meredith Broderick ◽  
Allie Wasik ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Dose Response ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Walk Distance ◽  
Pulmonary Arterial ◽  
Higher Doses ◽  
Minute Walk Distance ◽  
Minute Walk

Treprostinil is a prostacyclin analogue approved for the treatment of pulmonary arterial hypertension. Apart from the inhaled formulation, there is neither a target dose nor a ceiling dose to guide clinicians using treprostinil; doses are individualized for each patient based upon tolerability and clinical improvement. Using combined data from the pivotal subcutaneous and oral treprostinil studies, we evaluated the effect of treprostinil dose on hospitalization and exercise capacity to better define the treprostinil dose–response relationship. Data from the pivotal subcutaneous and oral treprostinil studies were combined by converting oral doses to weight-based continuous doses (ng/kg/min) accounting for patient weight and bioavailability. Patients were divided into dose tertiles (lowest, middle, highest 33%) and retrospectively analyzed. Analysis 1 assessed the effect of dose on pulmonary arterial hypertension-related and all-cause hospitalizations. Analysis 2 evaluated the effects of dose on six-minute walk distance, Borg dyspnea score, and World Health Organization functional class. Results showed that, in Analysis 1, higher doses of treprostinil were associated with significantly longer times to first pulmonary arterial hypertension-related and all-cause hospitalization. In Analysis 2, there was a trend toward improvements in six-minute walk distance with higher doses. In patients with pulmonary arterial hypertension on systemic treprostinil therapy, higher doses were associated with significantly longer time to first pulmonary arterial hypertension-related and all-cause hospitalization. There was a trend toward improvements in six-minute walk distance. Collectively, these results underscore the importance of managing prostacyclin adverse events in order to achieve appropriate dose titration. Further studies are required to confirm these findings and to better characterize the dose–response relationship of treprostinil.

scholarly journals Do Changes of 6-Minute Walk Distance Predict Clinical Events in Patients With Pulmonary Arterial Hypertension?

2012 ◽  
Vol 60 (13) ◽  
pp. 1192-1201 ◽  
Author(s):  
Gianluigi Savarese ◽  
Stefania Paolillo ◽  
Pierluigi Costanzo ◽  
Carmen D'Amore ◽  
Milena Cecere ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Walk Distance ◽  
Clinical Events ◽  
Pulmonary Arterial ◽  
Minute Walk Distance ◽  
Minute Walk

scholarly journals Long-term study of oral treprostinil to treat pulmonary arterial hypertension: dosing, tolerability, and pharmacokinetics

2020 ◽  
Vol 10 (4) ◽  
pp. 204589401986633 ◽  
Author(s):  
R. James White ◽  
Keyur Parikh ◽  
Roblee Allen ◽  
Jeremy Feldman ◽  
Carlos Jerjez-Sanchez ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Adverse Events ◽  
Arterial Hypertension ◽  
Total Daily Dose ◽  
Walk Distance ◽  
Long Term Study ◽  
Pulmonary Arterial ◽  
One Year ◽  
Minute Walk Distance ◽  
Minute Walk

Oral treprostinil may be an option for low- and intermediate-risk patients with pulmonary arterial hypertension, a rare lung vascular disease. This open-label extension study collected data on participants who completed previously reported, placebo-controlled oral treprostinil studies. Eligible participants had completed the prospective parent studies and took increasing doses of oral treprostinil twice daily; some later transitioned to three times daily dosing. Investigators measured 6-minute walk distance at Month 12 as the sole efficacy measure but collected adverse events throughout the study. A single center measured pharmacokinetics in 13 subjects who changed dosing from twice daily to three times daily. Eight hundred and ninety-four participants enrolled and 71% completed one year of therapy, with a median total daily dose of 7 mg and a median 6-minute walk distance increase of 22 m (interquartile range, −14 to 67 m). Subjects achieving higher doses had larger increases in 6-minute walk distance; 42% of participants completed three years of therapy. Adverse events were typical for prostacyclin class therapy, but prostacyclin-type adverse events may have been better tolerated with three times daily dosing in 105 participants. In 13 participants transitioned to three times daily dosing with pharmacokinetic measurements before and after, trough drug levels were higher with three times daily dosing. Oral treprostinil is associated with modest but durable, dose-responsive effects on exercise tolerance for those who remained on therapy at one year in this prospective, uncontrolled study. Three times daily dosing was associated with higher trough levels and better tolerability. The recently completed Freedom-EV study will provide further insights into the utility of oral treprostinil ( https://clinicaltrials.gov/show/NCT01560624 ).

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