Follow-Up Functional Class and 6-Minute Walk Distance Identify Long-Term Survival in Pulmonary Arterial Hypertension

Aims:Bosentan is efficacious in idiopathic pulmonary arterial hypertension, and the variants associated with connective tissue disease, but not currently approved for treatment of pulmonary arterial hypertension due to Eisenmenger's syndrome. We sought to evaluate its effect in adults with Eisenmenger's syndrome.Methods:We administered bosentan on the basis of compassionate use in 23 patients with Eisenmenger's syndrome, aged 37 plus or minus 14 years. Of the patients, 17 had never received specific treatment for pulmonary arterial hypertension, five were transitioned from treprostinil, and one from beraprost to bosentan. We measured functional class, saturation of oxygen, haemoglobin levels and six-minute walk distance at baseline, one, six months and at most recent follow-up.Results:Baseline functional class was IV in three, III in fifteen, and II in five patients. At follow-up, with a mean of 15 plus or minus 10 months, 13 of the 23 patients (57%) had improved by at least one functional class, from a median baseline of III to II (p equal to 0.016), mean saturation of oxygen at rest had increased from 81% to 84% (p equal to 0.001), and levels of haemoglobin had decreased from 178 plus or minus 26 grams per litre to 167 plus or minus 19 grams per litre (p equal to 0.001). Overall, the six-minute walk distance did not change from baseline of 335 metres. The distance walked by those not previously receiving specific therapy, however, improved from 318 plus or minus 129 to 345 plus or minus 123 metres (p equal to 0.03).Conclusion:Treatment of adults with Eisenmenger's syndrome using bosentan significantly improved functional class, saturation of oxygen at rest, and decreased levels of haemoglobin. Treatment with bosentan was associated with improvement in six-minute walk distance in those not previously receiving specific therapy. In patients already in receipt of specific therapy, transition to bosentan resulted in no clinical deterioration.

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Association between six-minute walk distance and long-term outcomes in patients with pulmonary arterial hypertension: Data from the randomized SERAPHIN trial

PLoS ONE ◽

10.1371/journal.pone.0193226 ◽

2018 ◽

Vol 13 (3) ◽

pp. e0193226 ◽

Cited By ~ 9

Author(s):

Rogério Souza ◽

Richard N. Channick ◽

Marion Delcroix ◽

Nazzareno Galiè ◽

Hossein-Ardeschir Ghofrani ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Long Term Outcomes ◽

Walk Distance ◽

Pulmonary Arterial ◽

Minute Walk Distance ◽

Minute Walk

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Effect of Bosentan on Exercise Capacity and Clinical Worsening in Patients with Dual down and Eisenmenger Syndrome

Clinical Medicine Insights Cardiology ◽

10.4137/cmc.s10237 ◽

2013 ◽

Vol 7 ◽

pp. CMC.S10237 ◽

Cited By ~ 12

Author(s):

Giorgio Serino ◽

Marco Guazzi ◽

Angelo Micheletti ◽

Carlo Lombardi ◽

Rossella Danesi ◽

...

Keyword(s):

Doppler Echocardiography ◽

Laboratory Tests ◽

Functional Class ◽

Walk Distance ◽

Pulmonary Arterial ◽

Minute Walk Distance ◽

Minute Walk ◽

Clinical Worsening

This single-center, retrospective analysis evaluated long-term bosentan treatment in adult patients (n = 7) with both Down and Eisenmenger syndromes (DS-ES). Laboratory tests, 6-minute walk distance (6MWD), functional class, and Doppler echocardiography were assessed at baseline and during 2 years' follow-up. Improvements or maintenance of 6MWD were observed (68 m improvement from baseline at month 12) after bosentan initiation. 6MWD was maintained up to year 2. Overall, 6 patients experienced a significant improvement in functional class during 2 years' therapy ( P = 0.01). There were no significant changes in parameters measured by Doppler echocardiography. None of the patients required either hospitalization or additional pulmonary arterial hypertension (PAH) therapy because of PAH progression. Bosentan treatment was generally well tolerated; no liver function abnormalities or serious adverse drug reactions were noted. In this DS-ES cohort, bosentan seemed to be well tolerated and clinically effective.

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Faculty Opinions recommendation of Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717963542.793465451 ◽

2012 ◽

Author(s):

Luke Howard

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Walk Distance ◽

End Point ◽

Pulmonary Arterial ◽

Minute Walk Distance ◽

Minute Walk

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Early Decline in Six-Minute Walk Distance from the Time of Diagnosis Predicts Clinical Worsening in Pulmonary Arterial Hypertension

Respiration ◽

10.1159/000370124 ◽

2015 ◽

Vol 89 (5) ◽

pp. 365-373 ◽

Cited By ~ 3

Author(s):

Julie Huang ◽

Sanjay Mehta ◽

Marco Mura

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Walk Distance ◽

Pulmonary Arterial ◽

Minute Walk Distance ◽

Minute Walk ◽

Clinical Worsening

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

Pulmonary Circulation ◽

10.1177/2045894020923956 ◽

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.

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

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2012.01.083 ◽

2012 ◽

Vol 60 (13) ◽

pp. 1192-1201 ◽

Cited By ~ 148

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

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

Pulmonary Circulation ◽

10.1177/2045894019866335 ◽

2020 ◽

Vol 10 (4) ◽

pp. 204589401986633 ◽

Cited By ~ 1

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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