167 results on '"Badesch DB"'
Search Results
2. Request to 'Update' the 2019 Update of Guidelines for Management of Pulmonary Arterial Hypertension Response
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Klinger JR, Elliott G, Levine DJ, Bossone E, Duvall L, Fagan K, Frantsve-Hawley J, Kawut SM, Ryan JJ, Rosenzweig EB, Sederstrom N, Steen VD, Badesch DB, Klinger, Jr, Elliott, G, Levine, Dj, Bossone, E, Duvall, L, Fagan, K, Frantsve-Hawley, J, Kawut, Sm, Ryan, Jj, Rosenzweig, Eb, Sederstrom, N, Steen, Vd, and Badesch, Db
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- 2019
3. Oral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients on Background Endothelin Receptor Antagonist and/or Phosphodiesterase Type 5 Inhibitor Therapy (The FREEDOM-C Study): A Randomized Controlled Trial
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Tapson VF, Torres F, Kermeen F, Keogh AM, Allen RP, Frantz RP, Badesch DB, Frost AE, Shapiro SM, Laliberte K, Sigman J, Arneson C, GALIE', NAZZARENO, Tapson VF, Torres F, Kermeen F, Keogh AM, Allen RP, Frantz RP, Badesch DB, Frost AE, Shapiro SM, Laliberte K, Sigman J, Arneson C, and Galiè N
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TREPOSTINIL ,pulmonary arterial hypertension ,RANDOMIZED CONTROLLED TRIAL - Abstract
Background: Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor. Methods: A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score. Results: Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P 5.07). Improvements in dyspnea fatigue index score (P 5.01) and combined 6MWD and Borg dyspnea score (P 5.01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m). Conclusions: The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies
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- 2012
4. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study
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Rubin LJ, Badesch DB, Fleming TR, Simonneau G, Ghofrani HA, Oakes M, Layton G, Serdarevic Pehar M, McLaughlin VV, Barst RJ, behalf of the SUPER 2 Study Group, GALIE', NAZZARENO, Rubin LJ, Badesch DB, Fleming TR, Galiè N, Simonneau G, Ghofrani HA, Oakes M, Layton G, Serdarevic-Pehar M, McLaughlin VV, Barst RJ, and behalf of the SUPER-2 Study Group.
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Adult ,Aged, 80 and over ,Male ,Adolescent ,Hypertension, Pulmonary ,Vasodilator Agents ,Administration, Oral ,Bosentan ,Middle Aged ,Piperazines ,Sildenafil Citrate ,Placebos ,Survival Rate ,Treatment Outcome ,Double-Blind Method ,Purines ,pulmonary arterial hypertension ,Humans ,Female ,Sulfones ,Aged ,Proportional Hazards Models - Abstract
Background: The long-term safety and tolerability of sildenafil treatment of pulmonary arterial hypertension (PAH) were assessed. Methods: Two hundred fifty-nine of 277 randomized and treated patients completed a 12-week, double-blind, placebo-controlled trial (SUPER-1 [Sildenafil Use in Pulmonary Arterial Hypertension]) of oral sildenafil in treatment-naive patients with PAH (96% functional class II/III) and entered an open-label uncontrolled extension study (SUPER-2) that continued until the last patient completed 3 years of sildenafil treatment. Patients titrated to sildenafil 80 mg tid; one dose reduction for tolerability was allowed during the titration phase. Results: The median duration of sildenafil treatment across SUPER-1 and SUPER-2 was 1,242 days (range, 1-1,523 days); 170 patients (61%) completed both studies, and 89 patients discontinued from SUPER-2. After 3 years, 87% of 183 patients on treatment were receiving sildenafil 80 mg tid. Of patients remaining under follow-up, 3%, 10%, and 18% were receiving a second approved PAH therapy at 1, 2, and 3 years, respectively. At 3 years post-SUPER-1 baseline, 127 patients had an increased 6-min walk distance (6MWD); 81 improved and 86 maintained functional class. Most adverse events were of mild or moderate severity. At 3 years, 53 patients had died (censored, n 5 37). Three-year estimated survival rate was 79%; if all censored patients were assumed to have died, 3-year survival rate was 68%. No deaths were considered to be treatment related. Conclusions: Long-term treatment of PAH initiated as sildenafil monotherapy was generally well tolerated. After 3 years, the majority of patients (60%) who entered the SUPER-1 trial improved or maintained their functional status, and 46% maintained or improved 6MWD.
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- 2011
5. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension
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Oudiz RJ, Olschewski H, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Harrison BC, Despain D, Dufton C, Rubin LJ, ARIES Study Group, GALIE', NAZZARENO, Oudiz RJ, Galiè N, Olschewski H, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Harrison BC, Despain D, Dufton C, Rubin LJ, and ARIES Study Group.
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Male ,medicine.medical_specialty ,hypertension ,Time Factors ,ambrisentan ,Ambrisentan ,pulmonary ,Hypertension, Pulmonary ,Administration, Oral ,law.invention ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,medicine ,Humans ,Pulmonary Wedge Pressure ,Pulmonary wedge pressure ,Survival rate ,Exercise Tolerance ,Dose-Response Relationship, Drug ,Phenylpropionates ,business.industry ,Endothelin receptor antagonist ,Middle Aged ,medicine.disease ,Pulmonary hypertension ,Confidence interval ,Surgery ,Discontinuation ,exercise capacity ,Pyridazines ,Survival Rate ,Treatment Outcome ,Cardiology ,Female ,endothelin ,Cardiology and Cardiovascular Medicine ,business ,long-term survival ,medicine.drug ,Follow-Up Studies - Abstract
Objectives This study evaluated the safety and efficacy of ambrisentan for a period of 2 years in patients with pulmonary arterial hypertension (PAH). Background Ambrisentan is an oral, once-daily endothelin receptor antagonist that is selective for the endothelin type A receptor. The ARIES-1 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies) and ARIES-2 trials were the pivotal 12-week, placebo-controlled studies that led to the regulatory approval of ambrisentan (5 and 10 mg) for the treatment of PAH. Methods In the ARIES-1 and -2 studies, and the subsequent long-term extension protocol, the ARIES-E study, 383 patients received ambrisentan (2.5, 5, or 10 mg). Efficacy and safety assessments are presented from the time of the first dose of ambrisentan for all patients with post-baseline data. Results After 2 years of ambrisentan exposure, the mean change from baseline in 6-min walk distance was improved for the 5-mg (+23 m; 95% confidence interval: 9 to 38 m) and 10-mg (+28 m; 95% confidence interval: 11 to 45 m) groups. Estimates of survival and freedom from clinical worsening for the combined dose group were 94% and 83%, respectively, at 1 year and 88% and 72%, respectively, at 2 years. The annualized risk of aminotransferase abnormalities >3× the upper limit of normal was ∼2% per year; most of these events were mild and did not lead to discontinuation of drug. Conclusions Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period. (A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 or AMB-321; NCT00578786 )
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- 2009
6. Sitaxsentan for the treatment of pulmonary arterial hypertension: a 1-year, prospective, open-label observation of outcome and survival
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Benza RL, Barst RJ, Frost A, Girgis RE, Highland KB, Strange C, Black CM, Badesch DB, Rubin L, Fleming TR, Naeije R., GALIE', NAZZARENO, Benza RL, Barst RJ, Galie N, Frost A, Girgis RE, Highland KB, Strange C, Black CM, Badesch DB, Rubin L, Fleming TR, and Naeije R.
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Adult ,Endothelin Receptor Antagonists ,Male ,Time Factors ,Adolescent ,Dose-Response Relationship, Drug ,Hypertension, Pulmonary ,Isoxazoles ,Thiophenes ,Middle Aged ,Drug Administration Schedule ,Survival Rate ,Treatment Outcome ,Humans ,Female ,Prospective Studies ,Aged ,Follow-Up Studies - Abstract
Despite advances in the management of pulmonary arterial hypertension (PAH), the mortality rate remains excessive. Long-term efficacy evaluations are needed to guide therapeutic management. The purpose of this study is to present 1-year observational data with two endothelin antagonists, sitaxsentan and bosentan, in a prospective, open-label study.The present study was a prospective, international, multicenter, randomized, open-label extension of the Sitaxsentan To Relieve Impaired Exercise-2 trial. All-cause mortality, time to discontinuation (all causes) from monotherapy, time to discontinuation due to adverse events, time to elevations in and time to discontinuation due to elevated hepatic transaminases, and time to first clinical worsening event were evaluated. Patients initially receiving sitaxsentan at 50 mg were excluded from the main analysis. The distributions of time-to-event variables are estimated using Kaplan-Meier methods, and treatment effects are evaluated using the Cox proportional hazards model.Patients treated with sitaxsentan at 100 mg had 96% overall survival and a 34% risk for a clinical worsening event by 1 year. In addition, there was a 6% risk of elevated aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels3 x upper limit of normal range (ULN) at 1 year and a 15% risk of discontinuation due to adverse events. Patients treated with bosentan had 88% overall survival and a 40% risk of a clinical worsening event by 1 year. In addition, there was a 14% risk for elevated AST and/or ALT levels3 x ULN at 1 year and a 30% risk of discontinuation due to adverse events.At 1 year, sitaxsentan therapy appears safe and efficacious for patients with PAH; reductions in mortality and the risk for clinical worsening events provide support for durability of efficacy.
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- 2008
7. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial
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Simonneau G, Rubin LJ, Barst RJ, Fleming TR, Frost AE, Engel PJ, Kramer MR, Burgess G, Collings L, Cossons N, Sitbon O, Badesch DB, GALIE', NAZZARENO, Simonneau G, Rubin LJ, Galiè N, Barst RJ, Fleming TR, Frost AE, Engel PJ, Kramer MR, Burgess G, Collings L, Cossons N, Sitbon O, and Badesch DB
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pulmonary hypertension, eoprostenol ,respiratory tract diseases - Abstract
Oral sildenafil and intravenous epoprostenol have independently been shown to be effective in patients with pulmonary arterial hypertension. OBJECTIVE: To investigate the effect of adding oral sildenafil to long-term intravenous epoprostenol in patients with pulmonary arterial hypertension. DESIGN: A 16-week, double-blind, placebo-controlled, parallel-group study. SETTING: Multinational study at 41 centers in 11 countries from 3 July 2003 to 27 January 2006. PATIENTS: 267 patients with pulmonary arterial hypertension (idiopathic, associated anorexigen use or connective tissue disease, or corrected congenital heart disease) who were receiving long-term intravenous epoprostenol therapy. INTERVENTION: Patients were randomly assigned to receive placebo or sildenafil, 20 mg three times daily, titrated to 40 mg and 80 mg three times daily, as tolerated, at 4-week intervals. Of 265 patients who received treatment, 256 (97%) patients (123 in the placebo group and 133 in the sildenafil group) completed the study. MEASUREMENTS: Change from baseline in exercise capacity measured by 6-minute walk distance (primary end point) and hemodynamic measurements, time to clinical worsening, and Borg dyspnea score (secondary end points). RESULTS: A placebo-adjusted increase of 28.8 meters (95% CI, 13.9 to 43.8 meters) in the 6-minute walk distance occurred in patients in the sildenafil group; these improvements were most prominent among patients with baseline distances of 325 meters or more. Relative to epoprostenol monotherapy, addition of sildenafil resulted in a greater change in mean pulmonary arterial pressure by -3.8 mm Hg (CI, -5.6 to -2.1 mm Hg); cardiac output by 0.9 L/min (CI, 0.5 to 1.2 L/min); and longer time to clinical worsening, with a smaller proportion of patients experiencing a worsening event in the sildenafil group (0.062) than in the placebo group (0.195) by week 16 (P = 0.002). Health-related quality of life also improved in patients who received combined therapy compared with those who received epoprostenol monotherapy. There was no effect on the Borg dyspnea score. Of the side effects generally associated with sildenafil treatment, the most commonly reported in the placebo and sildenafil groups, respectively, were headache (34% and 57%; difference, 23 percentage points [CI, 12 to 35 percentage points]), dyspepsia (2% and 16%; difference, 13 percentage points [CI, 7 to 20 percentage points]), pain in extremity (18% and 25%; difference, 8 percentage points [CI, -2 to 18 percentage points]), and nausea (18% and 25%; difference, 8 percentage points [CI, -2 to 18 percentage points]). LIMITATIONS: The study excluded patients with pulmonary arterial hypertension associated with other causes. There was an imbalance in missing data between groups, with 8 placebo recipients having no postbaseline walk assessment compared with 1 sildenafil recipient. These patients were excluded from the analysis. CONCLUSION: In some patients with pulmonary arterial hypertension, the addition of sildenafil to long-term intravenous epoprostenol therapy improves exercise capacity, hemodynamic measurements, time to clinical worsening, and quality of life, but not Borg dyspnea score. Increased rates of headache and dyspepsia occurred with the addition of sildenafil.
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- 2008
8. ARIES-3: Ambrisentan Therapy in a Diverse Population of Patients with Pulmonary Hypertension.
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Badesch, DB, primary, Feldman, J, additional, Keogh, A, additional, Mathier, MA, additional, Oudiz, RJ, additional, Shapiro, S, additional, Farber, H, additional, McGoon, M, additional, Frost, A, additional, and Rubin, LJ, additional
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- 2009
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9. Arginine Supplementation in Pulmonary Arterial Hypertension (PAH): Results of a Pilot RCT.
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Badesch, DB, primary, Fagan, KA, additional, McCollister, D, additional, Kittelson, J, additional, Tripputi, M, additional, Yaeger, T, additional, Weinberger, HD, additional, and Weil, JV, additional
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- 2009
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10. Depressive Symptoms in Pulmonary Arterial Hypertension: Prevalence and Impact on Functional Status.
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McCollister, DH, primary, Beutz, M, additional, McLaughlin, VV, additional, Rumsfeld, J, additional, Masoudi, F, additional, Tripputi, M, additional, Kittelson, J, additional, Yeager, T, additional, Weintraub, P, additional, and Badesch, DB, additional
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- 2009
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11. Results of the FREEDOM–C Study: A Pivotal Study of Oral Treprostinil Used Adjunctively with an ERA and/or PDE5-Inhibitor for the Treatment of PAH.
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Tapson, VF, primary, Torres, F, additional, Kermeen, F, additional, Keogh, A, additional, Allen, RP, additional, Frantz, RP, additional, Badesch, DB, additional, Frost, AE, additional, Shapiro, S, additional, Sigman, J, additional, Grover, R, additional, Laliberte, K, additional, Mottola, D, additional, Galie, N, additional, and Simonneau, G, additional
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- 2009
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12. Portopulmonary hypertension: a report from the US-based REVEAL Registry.
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Krowka MJ, Miller DP, Barst RJ, Taichman D, Dweik RA, Badesch DB, McGoon MD, Krowka, Michael J, Miller, Dave P, Barst, Robyn J, Taichman, Darren, Dweik, Raed A, Badesch, David B, and McGoon, Michael D
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Background: We evaluated survival and hospitalization rates in patients with group 1 portopulmonary hypertension (PoPH) in the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry).Methods: The REVEAL Registry is a multicenter, observational, US-based study evaluating demographics and management of patients with pulmonary arterial hypertension (PAH). Outcomes were examined using Kaplan-Meier time-to-event estimates and compared with patients with idiopathic PAH (IPAH) or familial PAH (FPAH).Results: One hundred seventy-four patients with PoPH were enrolled in the REVEAL Registry (IPAH/FPAH; n = 1,478) from March 2006 to December 2009. Mean age was 53 ± 10 years, 52% were female, 32% were newly diagnosed, and 6% were New York Heart Association/World Health Organization functional class IV. Outcome parameters were worse for PoPH vs IPAH/FPAH, respectively: 2-year survival from enrollment (67% vs 85%, P < .001), 5-year survival from time of diagnosis (40% vs 64%, P < .001), and 2-year freedom from all-cause hospitalization (49% vs 59%, P = .019). However, despite worse outcomes, hemodynamic parameters at diagnosis were better for PoPH vs IPAH/FPAH, respectively: mean pulmonary artery pressure (49 mm Hg vs 53 mm Hg, P < .001), mean right atrial pressure (9 mm Hg vs 10 mm Hg, P = .005), pulmonary vascular resistance (8 Wood units vs 12 Wood units, P < .001), and cardiac output (5 L/min vs 4 L/min, P < .001). Compared with patients with IPAH/FPAH, patients with PoPH were less likely to be on a PAH-specific therapy at enrollment (P < .001), suggesting potential delays in therapy for patients with PoPH.Conclusions: Patients with PoPH had significantly poorer survival and all-cause hospitalization rates compared with patients with IPAH/FPAH, despite having better hemodynamics at diagnosis. Further studies should investigate such outcomes and differences in treatment patterns.Trial Registry: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]- Published
- 2012
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13. The Changing Picture of Patients With Pulmonary Arterial Hypertension in the United States: How REVEAL Differs From Historic and Non-US Contemporary Registries.
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Frost AE, Badesch DB, Barst RJ, Benza RL, Elliott CG, Farber HW, Krichman A, Liou TG, Raskob GE, Wason P, Feldkircher K, Turner M, and McGoon MD
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REVEAL (The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) provides current demographics of patients with group 1 pulmonary arterial hypertension (PAH) in the United States. [ABSTRACT FROM AUTHOR]
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- 2011
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14. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype.
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Chung L, Liu J, Parsons L, Hassoun PM, McGoon M, Badesch DB, Miller DP, Nicolls MR, Zamanian RT, Chung, Lorinda, Liu, Juliana, Parsons, Lori, Hassoun, Paul M, McGoon, Michael, Badesch, David B, Miller, Dave P, Nicolls, Mark R, and Zamanian, Roham T
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Background: REVEAL (the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) is the largest US cohort of patients with pulmonary arterial hypertension (PAH) confirmed by right-sided heart catheterization (RHC), providing a more comprehensive subgroup characterization than previously possible. We used REVEAL to analyze the clinical features of patients with connective tissue disease-associated PAH (CTD-APAH).Methods: All newly and previously diagnosed patients with World Health Organization (WHO) group 1 PAH meeting RHC criteria at 54 US centers were consecutively enrolled. Cross-sectional and 1-year mortality and hospitalization analyses from time of enrollment compared CTD-APAH to idiopathic disease and systemic sclerosis (SSc) to systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis (RA).Results: Compared with patients with idiopathic disease (n = 1,251), patients with CTD-APAH (n = 641) had better hemodynamics and favorable right ventricular echocardiographic findings but a higher prevalence of pericardial effusions, lower 6-min walk distance (300.5 ± 118.0 vs 329.4 ± 134.7 m, P = .01), higher B-type natriuretic peptide (BNP) levels (432.8 ± 789.1 vs 245.6 ± 427.2 pg/mL, P < .0001), and lower diffusing capacity of carbon monoxide (Dlco) (44.9% ± 18.0% vs 63.6% ± 22.1% predicted, P < .0001). One-year survival and freedom from hospitalization were lower in the CTD-APAH group (86% vs 93%, P < .0001; 67% vs 73%, P = .03). Compared with patients with SSc-APAH (n = 399), those with other CTDs (SLE, n = 110; MCTD, n = 52; RA, n = 28) had similar hemodynamics; however, patients with SSc-APAH had the highest BNP levels (552.2 ± 977.8 pg/mL), lowest Dlco (41.2% ± 16.3% predicted), and poorest 1-year survival (82% vs 94% in SLE-APAH, 88% in MCTD-APAH, and 96% in RA-APAH).Conclusions: Patients with SSc-APAH demonstrate a unique phenotype with the highest BNP levels, lowest Dlco, and poorest survival of all CTD-APAH subgroups.Trial Registry: ClinicalTrials.gov; No.: NCT00370214; URL: clinicaltrials.gov. [ABSTRACT FROM AUTHOR]- Published
- 2010
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15. Predicting Survival in Pulmonary Arterial Hypertension: Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL)
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Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, and McGoon MD
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- 2010
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16. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry.
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Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, Barst RJ, Benza RL, Liou TG, Turner M, Giles S, Feldkircher K, Miller DP, McGoon MD, Badesch, David B, Raskob, Gary E, Elliott, C Greg, Krichman, Abby M, Farber, Harrison W, and Frost, Adaani E
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Background: The Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management (REVEAL Registry) was established to provide updated characteristics of patients with pulmonary arterial hypertension (PAH) and to improve diagnosis, treatment, and management.Methods: Fifty-four US centers enrolled consecutively screened patients with World Health Organization group I PAH who met expanded hemodynamic criteria of mean pulmonary arterial pressure (PAP) > 25 mm Hg at rest (30 mm Hg with exercise), pulmonary capillary wedge pressure (PCWP)or= 240 dynes x s x cm(-5). Patients meeting the traditional hemodynamic definition (PCWP Results: Between March 2006 and September 2007, 2,967 patients enrolled. Among 2,525 adults meeting traditional hemodynamic criteria, the mean age was 53 +/- 14 years, and 2,007 (79.5%) were women. The mean duration between symptom onset and diagnostic catheterization was 2.8 years, and 1,008 (41.3%) patients were treated with more than one pulmonary vascular-targeted medication. Compared with patients meeting the traditional hemodynamic definition of PAH, patients with a PCWP of 16 to 18 mm Hg were older, more obese, had a lower 6-min walk distance, and had a higher incidence of systemic hypertension, sleep apnea, renal insufficiency, and diabetes. Conclusions: Patients in the REVEAL Registry are older and more often female than in previous descriptions. Delays between symptom onset and diagnostic catheterization persist. Many treatment regimens are fundamentally empirical, and data will be required to determine outcomes, improve risk stratification, and develop and validate more precise prognostic tools. Patients with PCWP of 16 to 18 mm Hg differ in a number of important respects from those meeting the traditional hemodynamic definition of PAH. [ABSTRACT FROM AUTHOR]- Published
- 2010
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17. Longterm survival among patients with schleroderma-associated pulmonary arterial hypertension treated with intravenous epoprostenol.
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Badesch DB, McGoon MD, Barst RJ, Tapson VF, Rubin LJ, Wigley FM, Kral KM, Raphiou IH, and Crater GD
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- 2009
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18. Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease.
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Roberts KE, Fallon MB, Krowka MJ, Brown RS, Trotter JF, Peter I, Tighiouart H, Knowles JA, Rabinowitz D, Benza RL, Badesch DB, Taichman DB, Horn EM, Zacks S, Kaplowitz N, Kawut SM, Pulmonary Vascular Complications of Liver Disease Study Group, Roberts, Kari E, Fallon, Michael B, and Krowka, Michael J
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Rationale: Portopulmonary hypertension (PPHTN) occurs in 6% of liver transplant candidates. The pathogenesis of this complication of portal hypertension is poorly understood.Objectives: To identify genetic risk factors for PPHTN in patients with advanced liver disease.Methods: We performed a multicenter case-control study of patients with portal hypertension. Cases had a mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dynes.s(-1).cm(-5), and pulmonary capillary wedge pressure < or =15 mm Hg. Controls had a right ventricular systolic pressure < 40 mm Hg (if estimated) and normal right-sided cardiac morphology by transthoracic echocardiography. We genotyped 1,079 common single nucleotide polymorphisms (SNPs) in 93 candidate genes in each patient.Measurements and Main Results: The study sample included 31 cases and 104 controls. Twenty-nine SNPs in 15 candidate genes were associated with the risk of PPHTN (P < 0.05). Multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with the risk of PPHTN. The biological relevance of one of the aromatase SNPs was supported by an association with plasma estradiol levels.Conclusions: Genetic variation in estrogen signaling and cell growth regulators is associated with the risk of PPHTN. These biologic pathways may elucidate the mechanism for the development of PPHTN in certain patients with severe liver disease. [ABSTRACT FROM AUTHOR]- Published
- 2009
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19. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2.
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Galiè N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ, Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group, Galiè, Nazzareno, Olschewski, Horst, Oudiz, Ronald J, Torres, Fernando, and Frost, Adaani
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- 2008
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20. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease.
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Badesch DB, Hill NS, Burgess G, Rubin LJ, Barst RJ, Galiè N, Simonneau G, and SUPER Study Group
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- 2007
21. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension.
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McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst RJ, Hsu HH, and Rubin LJ
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RATIONALE: Small, open-label studies suggest that combinations of existing therapies may be effective for pulmonary arterial hypertension (PAH). OBJECTIVE: To evaluate the safety and efficacy of adding inhaled iloprost, a prostacyclin analog, to the endothelin receptor antagonist bosentan in patients with PAH. METHODS: In a randomized, multicenter, double-blind trial, inhaled iloprost (5 mug) or placebo was added to stable monotherapy with bosentan for 12 wk. Efficacy endpoints included change from baseline in 6-min-walk distance (6-MWD), modified New York Heart Association (NYHA) functional class, hemodynamic parameters, and time to clinical worsening. MEASUREMENTS AND MAIN RESULTS: A total of 67 patients with PAH (55% idiopathic PAH, 45% associated PAH, 94% NYHA class III, and mean baseline 6-MWD of 335 m) were randomized. At Week 12, patients receiving iloprost had a mean increase in 6-MWD of 30 m (p = 0.001); placebo patients had a mean 6-MWD increase of 4 m (p = 0.69), with a placebo-adjusted difference of +26 m (p = 0.051). NYHA status improved by one class in 34% of iloprost versus 6% of placebo patients (p = 0.002). Iloprost delayed the time to clinical worsening (p = 0.0219). Improvements were noted in postinhalation placebo-adjusted change in mean pulmonary artery pressure (-8 mm Hg; p < 0.001) and pulmonary vascular resistance (-254 dyn . s . cm(-5); p < 0.001). Combination therapy was well tolerated. CONCLUSIONS: Within the limitations of a relatively small sample size, results of this study demonstrate that the addition of inhaled iloprost in patients with PAH with reduced exercise capacity on bosentan monotherapy is safe and efficacious. [ABSTRACT FROM AUTHOR]
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- 2006
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22. Pulmonary arterial hypertension: future directions. Report of a National Heart, Lung and Blood Institute/Office of Rare Diseases workshop.
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Newman JH, Fanburg BL, Archer SL, Badesch DB, Barst RJ, Garcia JGN, Kao PN, Knowles JA, Loyd JE, McGoon MD, Morse JH, Nichols WC, Rabinovitch M, Rodman DM, Stevens T, Tuder RM, Voelkel NF, and Gail DB
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- 2004
23. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study.
- Author
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Sitbon O, Badesch DB, Channick RN, Frost A, Robbins IM, Simonneau G, Tapson VF, Rubin LJ, Sitbon, Olivier, Badesch, David B, Channick, Richard N, Frost, Adaani, Robbins, Ivan M, Simonneau, Gérald, Tapson, Victor F, and Rubin, Lewis J
- Abstract
Study Objectives: We report on the long-term safety and efficacy of bosentan treatment in patients with pulmonary arterial hypertension (PAH).Background: In a preceding study, bosentan was well tolerated and significantly improved the exercise capacity and hemodynamics of patients with PAH after 12 weeks of treatment.Design: The present study was an open-label extension to the preceding double-blind, placebo-controlled study of 32 patients with PAH (primary or associated with scleroderma) who received bosentan or placebo at 125 mg bid for 3 to 7 months.Patients: Twenty-nine of the original 32 patients received bosentan for an additional year (62.5 mg bid for 4 weeks and then 125 mg bid).Interventions: Study end points included long-term safety, 6-min walk distance at week 4, modified New York Heart Association (NYHA) functional class of PAH at month 12, and the occurrence of withdrawal due to clinical worsening. Additional exploratory analyses included a walk test at month 6 for 19 patients and hemodynamic assessment at month 12 for 11 patients.Results: At month 6, assessed patients continuing bosentan treatment maintained the improvement in walk distance observed at the end of the previous study (mean +/- SEM, 60 +/- 11 m), and patients starting bosentan treatment improved their walk distance by 45 +/- 13 m. Long-term treatment with bosentan for > 1 year was associated with an improvement in hemodynamic parameters and modified NYHA functional class. Overall, bosentan treatment was well tolerated. No patient underwent transplantation or died.Conclusions: Long-term treatment with bosentan is safe and has sustained benefits on exercise capacity and hemodynamics in patients with PAH. [ABSTRACT FROM AUTHOR]- Published
- 2003
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24. Bosentan therapy for pulmonary arterial hypertension.
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Rubin LJ, Badesch DB, Barst RJ, Galiè N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G, and Bosentan Randomized Trial of Endothelin Antagonist Therapy Study Group
- Published
- 2002
25. Thyrotoxicosis as a risk factor for pulmonary arterial hypertension.
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Ma RC, Chow CC, Rubin LJ, Badesch DB, Ma, Ronald C, and Chow, Chun Chung
- Published
- 2006
26. End points and clinical trial design in pulmonary arterial hypertension.
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McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galiè N, Gibbs JS, Kim NH, Oudiz RJ, Peacock A, Provencher S, Sitbon O, Tapson VF, Seeger W, McLaughlin, Vallerie V, Badesch, David B, Delcroix, Marion, Fleming, Thomas R, Gaine, Sean P, and Galiè, Nazzareno
- Abstract
New and emerging therapies might provide benefit in patients with pulmonary arterial hypertension. Their efficacy and safety will be compared with existing combination therapies in randomized clinical trials. Appropriate end points for these trials need to be identified: these will include exercise testing, the composite end point of time to clinical worsening, and hemodynamic markers, including advanced imaging modalities and biomarkers. Quality-of-life questionnaires are useful and important secondary end points; pulmonary arterial hypertension-specific questionnaires are currently being developed. Advantages and disadvantages of various trial designs, including placebo-controlled monotherapy or add-on trials, noninferiority studies, and withdrawal trials are also discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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27. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association.
- Author
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McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, and Varga J
- Published
- 2009
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28. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.
- Author
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Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, and Rubin LJ
- Published
- 2001
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29. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension.
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Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jobsis MM, Blackburn SD Jr., Shortino D, and Crow JW
- Published
- 1996
30. End Points and Clinical Trial Design in Pulmonary Arterial Hypertension
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Nick H. Kim, Olivier Sitbon, Nazzareno Galiè, Steeve Provencher, Marion Delcroix, Vallerie V. McLaughlin, Andrew J. Peacock, J. Simon R. Gibbs, Werner Seeger, Thomas R. Fleming, David B. Badesch, Victor F. Tapson, Sean Gaine, Ronald J. Oudiz, McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galiè N, Gibbs JS, Kim NH, Oudiz RJ, Peacock A, Provencher S, Sitbon O, Tapson VF, and Seeger W.
- Subjects
Research design ,medicine.medical_specialty ,Endpoint Determination ,Hypertension, Pulmonary ,MEDLINE ,law.invention ,Randomized controlled trial ,Quality of life ,law ,medicine ,end points ,Humans ,Intensive care medicine ,Randomized Controlled Trials as Topic ,Clinical Trials as Topic ,business.industry ,Clinical study design ,Hemodynamics ,PAH ,medicine.disease ,Pulmonary hypertension ,clinical trial design ,Respiratory Function Tests ,Clinical trial ,medicine.anatomical_structure ,Treatment Outcome ,Research Design ,Physical therapy ,Exercise Test ,Quality of Life ,business ,Cardiology and Cardiovascular Medicine ,Artery - Abstract
New and emerging therapies might provide benefit in patients with pulmonary arterial hypertension. Their efficacy and safety will be compared with existing combination therapies in randomized clinical trials. Appropriate end points for these trials need to be identified: these will include exercise testing, the composite end point of time to clinical worsening, and hemodynamic markers, including advanced imaging modalities and biomarkers. Quality-of-life questionnaires are useful and important secondary end points; pulmonary arterial hypertension-specific questionnaires are currently being developed. Advantages and disadvantages of various trial designs, including placebo-controlled monotherapy or add-on trials, noninferiority studies, and withdrawal trials are also discussed.
- Published
- 2009
- Full Text
- View/download PDF
31. Ambrisentan Therapy in Patients With Pulmonary Arterial Hypertension Who Discontinued Bosentan or Sitaxsentan Due to Liver Function Test Abnormalities
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Nazzareno Galiè, Michael J. Gerber, Lewis J. Rubin, Ronald J. Oudiz, David B. Badesch, Adaani E. Frost, Michael D. McGoon, Darrin Despain, Vallerie V. McLaughlin, Horst Olschewski, Chris Dufton, McGoon MD, Frost AE, Oudiz RJ, Badesch DB, Galie N, Olschewski H, McLaughlin VV, Gerber MJ, Dufton C, Despain DJ, and Rubin LJ.
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Adult ,Endothelin Receptor Antagonists ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Adolescent ,Ambrisentan ,SF-36 ,Hypertension, Pulmonary ,Thiophenes ,Critical Care and Intensive Care Medicine ,Gastroenterology ,Disease-Free Survival ,Young Adult ,Liver Function Tests ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,Child ,Antihypertensive Agents ,Transaminases ,Aged ,Sulfonamides ,Phenylpropionates ,medicine.diagnostic_test ,business.industry ,Bosentan ,Isoxazoles ,Middle Aged ,medicine.disease ,Pulmonary hypertension ,Discontinuation ,Surgery ,Pyridazines ,Treatment Outcome ,Female ,Liver function ,Cardiology and Cardiovascular Medicine ,business ,Liver function tests ,medicine.drug - Abstract
Background Some endothelin receptor antagonists (ERAs) are associated with liver function test (LFT) result abnormalities. However, ambrisentan has an incidence of serum aminotransferase levels more than three times the upper limit of normal (ULN), similar to that observed in PAH patients who are not receiving ERAs. Because ambrisentan may provide benefits in PAH patients who have discontinued ERA therapy due to LFT abnormalities, we evaluated the safety and efficacy of ambrisentan in this patient population. Methods Patients who previously discontinued bosentan and/or sitaxsentan due to LFT abnormalities received ambrisentan, 2.5 mg qd, for 4 weeks followed by 5 mg/d for 8 weeks. The primary end point was the incidence of aminotransferase levels more than three times ULN considered by the investigator to be related to ambrisentan and resulting in drug discontinuation. Secondary end points included aminotransferase levels more than five times ULN requiring drug discontinuation and more than three times ULN requiring dose reduction, as well as changes in 6-min walk distance (6MWD), Borg dyspnea index, World Health Organization functional class, and Short Form-36 health survey score. Patients continued treatment beyond the 12-week end point with monthly monitoring of LFTs. Results Thirty-six patients who previously discontinued bosentan (n = 31), sitaxsentan (n = 2), or both (n = 3) were enrolled. At baseline, 69.4% of patients were receiving prostanoid and/or sildenafil therapy. No patient had an aminotransferase level more than three times ULN that required ambrisentan discontinuation. One patient had a transient aminotransferase level more than three times ULN that resolved following a temporary dose reduction. No additional aminotransferase levels more than three times ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg qd in more than half of the patients. Significant improvements in 6MWD and other efficacy assessments were observed. Conclusions Ambrisentan treatment may be an option for patients who have discontinued bosentan and/or sitaxsentan therapy due to LFT result abnormalities. Trial registration Clinicaltrials.gov Identifier NCT00423592.
- Published
- 2009
32. Survival with first-line bosentan in patients with primary pulmonary hypertension
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Rj Barst, Gérald Simonneau, Olivier Sitbon, Vv Mclaughlin, Maurizio Rainisio, LJ Rubin, Carol Black, Db Badesch, Nazzareno Galiè, McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galie N, Rainisio M, Simonneau G, and Rubin LJ.
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Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Adolescent ,Hypertension, Pulmonary ,Hemodynamics ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Antihypertensive Agents ,Survival analysis ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Sulfonamides ,Exercise Tolerance ,Endothelin receptor antagonist ,Proportional hazards model ,business.industry ,Respiratory disease ,Bosentan ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Pulmonary hypertension ,Respiratory Function Tests ,respiratory tract diseases ,Surgery ,Treatment Outcome ,Female ,business ,Progressive disease ,medicine.drug - Abstract
The efficacy and safety of combining bosentan, an orally active dual endothelin receptor antagonist and epoprostenol, a continuously infused prostaglandin, in the treatment of pulmonary arterial hypertension (PAH) was investigated. In this double-blind, placebo-controlled prospective study, 33 patients with PAH started epoprostenol treatment (2 ng.kg(-1)min(-1) starting dose, up to 14+/-2 ng.kg(-1)min(-1) at week 16) and were randomised for 16 weeks in a 2:1 ratio to bosentan (62.5 mg b.i.d for 4 weeks then 125 mg b.i.d) or placebo. Haemodynamics, exercise capacity and functional class improved in both groups at week 16. In the combination treatment group, there was a trend for a greater (although nonsignificant) improvement in all measured haemodynamic parameters. There were four withdrawals in the bosentan/epoprostenol group (two deaths due to cardiopulmonary failure, one clinical worsening, and one adverse event) and one withdrawal in the placebo/epoprostenol group (adverse event). This study showed a trend but no statistical significance towards haemodynamics or clinical improvement due to the combination of bosentan and epoprostenol therapy in patients with pulmonary arterial hypertension. Several cases of early and late major complications were reported. Additional information is needed to evaluate the risk/benefit ratio of combined bosentan-epoprostenol therapy in pulmonary arterial hypertension.
- Published
- 2005
33. ARIES-1: A placebo-controlled, efficacy and safety study of ambrisentan in patients with pulmonary arterial hypertension
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Vallerie V. McLaughlin, Ronald J. Oudiz, Michael D. McGoon, David B. Badesch, Adaani E. Frost, Fernando Torres, Lewis J. Rubin, Horst Olschewski, Nazzareno Galiè, Oudiz RJ, Torres F, Frost AE, Badesch DB, Olchewski H, Galie N, McGoon MD, McLaughlin V, and Rubin LJ.
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Ambrisentan ,business.industry ,Respiratory System ,Critical Care and Intensive Care Medicine ,Placebo ,Critical Care Medicine ,Internal medicine ,Medicine ,In patient ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Ambrisentan is a high affinity, propanoic acid-class, ETA-selective endothelin receptor antagonist (ERA) with once-daily oral doses. Ambrisentan doses of 2.5 and 5 mg once-daily improved 6-minute walk distance (6MWD) and delayed clinical worsening in a placebo-controlled PAH study (ARIES-2), with no incidence of serum aminotransferases >3xULN. ARIES-1 evaluated ambrisentan doses of 5 and 10 mg once-daily, compared to placebo
- Published
- 2006
34. Survival in patients with class III idiopathic pulmonary arterial hypertension treated with first line oral bosentan compared with an historical cohort of patients started on intravenous epoprostenol
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Nazzareno Galiè, Gérald Simonneau, Maurizio Rainisio, David B. Badesch, Olivier Sitbon, Marc Humbert, Carol Black, Lewis J. Rubin, Robyn J. Barst, Vallerie V. McLaughlin, Sitbon O, McLaughlin VV, Badesch DB, Barst RJ, Black C, Galie N, Humbert M, Rainisio M, Rubin LJ, and Simonneau G.
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Proportional hazards model ,Endothelin receptor antagonist ,Hazard ratio ,medicine.disease ,Pulmonary hypertension ,Bosentan ,Surgery ,respiratory tract diseases ,Internal medicine ,Cohort ,medicine ,Cardiology ,business ,Survival analysis ,Cohort study ,medicine.drug - Abstract
Background: The oral dual endothelin receptor antagonist bosentan improves exercise capacity and delays clinical worsening in patients with pulmonary arterial hypertension, but its use could delay starting intravenous epoprostenol, a life saving treatment. Methods: Survival in patients with functional class III idiopathic pulmonary arterial hypertension (PAH) treated with bosentan in clinical trials was compared with historical data from similar patients treated with epoprostenol in the clinic. Statistical methods were used to adjust for possible underlying differences between the two groups. Results: Baseline factors for the 139 patients treated with bosentan and the 346 treated with epoprostenol suggested that the epoprostenol cohort had more severe disease—that is, a lower cardiac index (2.01 v 2.39 l/min/m2) and higher pressures and resistance. Kaplan-Meier survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan cohort and 91% and 84% in the epoprostenol cohort. Cox regression analyses adjusting for differences in baseline factors showed a greater probability of death in the epoprostenol cohort (hazard ratio 2.2 (95% confidence interval 1.2 to 4.0) in the model adjusted for haemodynamics). Alternative regression analyses and analyses to adjust for different data collection dates gave consistently similar results. When matched cohorts of 83 patients each were selected, survival estimates were similar. In the bosentan cohort 87% and 75% of patients followed for 1 and 2 years, respectively, remained on monotherapy. Conclusions: No evidence was found to suggest that initial treatment with oral bosentan, followed by or with the addition of other treatment if needed, adversely affected the long term outcome compared with initial intravenous epoprostenol in patients with class III idiopathic PAH.
- Published
- 2005
35. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease
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Badesch, D. B., Hill, N. S., Burgess, G., Rubin, L. J., Barst, R. J., Nazzareno Galie, Simonneau, G., Badesch DB., Hill NS., Burgess G., Rubin LJ., Barst RJ., Galiè N., and Simonneau G.
- Subjects
safety ,connective tissue disease ,pulmonary arterial hypertension ,sildenafil ,efficacy ,cardiovascular system ,respiratory tract diseases - Abstract
Objective. Pulmonary arterial hypertension associated with connective tissue disease (PAH-CTD) is difficult to manage, and has a poor prognosis. The phosphodiesterase-5 inhibitor sildenafil citrate enhances vasodilatation, has antiproliferative effects, and is effective in the treatment of PAH. We examined the efficacy and safety of oral sildenafil in patients with PAH-CTD. Methods. In a 12-week, double-blind study (SUPER-1), 278 patients with PAH were randomized to oral placebo, sildenafil 20 mg, sildenafil 40 mg, or sildenafil 80 mg 3 times daily (tid). In a post-hoc subgroup analysis of 84 patients with PAH-CTD, exercise capacity, hemodynamic measures, World Health Organization functional class, and tolerability were assessed. Results. Forty-five percent of the patients had scleroderma, 23% had systemic lupus erythematosus, and the rest (32%) were categorized as other. Patients were predominantly functional class II (38%) or III (61%) at baseline. Sildenafil-treated patients exhibited mean increases in 6-minute walk distance at Week 12 of 42 m (95% CI 20, 64) for 20 mg, 36 m (95% CI 14, 58) for 40 mg, and 15 m (95% CI -24, 54) for 80 mg, while placebo-treated patients exhibited a mean decrease of 13 m (95% CI -36, 10). Improvement of at least I functional class occurred in 29%-42% of sildenafil-treated patients, compared to 5% for placebo. Significant improvements in mean pulmonary arterial pressure and pulmonary vascular resistance were observed with sildenafil 20 mg, and sildenafil was generally well tolerated. Conclusion. In patients with PAH-CTD, sildenafil improves exercise capacity, hemodynamic measures (at the 20 mg dose), and functional class after 12 weeks of treatment.
36. Long-Term Effects of Sotatercept on Right Ventricular Function: Results From the PULSAR Study.
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Gomberg-Maitland M, McLaughlin VV, Badesch DB, Ghofrani HA, Hoeper MM, Humbert M, Preston IR, Souza R, Waxman AB, de Oliveira Pena J, Lu JT, Manimaran S, and Gibbs JSR
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- 2023
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37. Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial.
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Souza R, Badesch DB, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, McLaughlin VV, Preston IR, Waxman AB, Grünig E, Kopeć G, Meyer G, Olsson KM, Rosenkranz S, Lin J, Johnson-Levonas AO, de Oliveira Pena J, Humbert M, and Hoeper MM
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- Humans, Recombinant Fusion Proteins therapeutic use, Cardiac Catheterization, Familial Primary Pulmonary Hypertension, Hemodynamics, Heart
- Abstract
Background: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH)., Methods: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate., Results: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm
-5 ), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL-1 ·beat-1 ), PA compliance (0.58 mL·mmHg-1 ), cardiac efficiency (0.48 mL·beat-1 ·mmHg-1 ), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min-1 ). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg-1 ), end-systolic and end-diastolic RV areas (-4.39 cm2 and -5.31 cm2 , respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices., Conclusion: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function., Competing Interests: Conflict of interest: R. Souza has served as consultant for Acceleron Pharma, Inc., Bayer Healthcare Pharmaceuticals Inc. and Janssen Biotech, Inc. (fees paid to self). D.B. Badesch has received grants/contracts from Acceleron Pharma, Inc., Merck & Co., Inc. (Rahway, NJ, USA), Altavant and United Therapeutics (all paid to institution, clinical trial), received payment as consultant from Acceleron Pharma, Inc., Merck & Co., Inc. (Rahway, NJ, USA) and Aerovate Inc. (paid through institution), and the author's spouse or partner has stock in Johnson & Johnson Health Care Systems Inc. H.A. Ghofrani has served as consultant for Aerovate, Altavant, Bayer Healthcare, Gossamer Bio, Janssen Diagnostics, LLC, Merck & Co., Inc. (Rahway, NJ, USA) and Pfizer (fees paid to self), and is an employee of Justus Liebig University Giessen, Germany. J.S.R. Gibbs has served a consultant for Acceleron Pharma and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self), served in data and safety monitoring boards for Actelion Pharmaceuticals, Fundação Bial, GossamerBio and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self), served in end point review committee for Actelion Pharmaceuticals, Aerovate, Janssen Biotech, Pfizer Pharma GMBH and United Therapeutics Corporation (fees paid to self), and served as Chair of ERN-Lung Functional Committee Patient Reported Outcomes for ERN Lung. M. Gomberg-Maitland has served as a consultant for Acceleron Pharma and Merck & Co., Inc. (Rahway, NJ, USA), Aerami, Bayer HealthCare Pharmaceuticals Inc., Janssen Biotech, Keros and United Therapeutics Corporation (fees paid to self), has received grant/contract from Aerovate, Altavant, Acceleron Pharma and Merck & Co., Inc. (fees paid to institution), and the author's spouse is an employee of Intellia Therapeutics. V.V. McLaughlin has served as a consultant for Aerami, Aerovate, Altavant, Bayer Healthcare, Caremark, Corvista, Gossamer Bio, Janssen Biotech, Merck & Co., Inc. (Rahway, NJ, USA) and United Therapeutics (fees paid to self), received grants/contracts from Aerovate, Altavant, Gossamer Bio, Janssen Biotech, Merck & Co., Inc. (Rahway, NJ, USA) and Sonovie (paid to institution), served as fiduciary officer, board of directors, for Clene (fees paid to self), and is an employee of the University of Michigan. I.R. Preston has served as a steering committee member for Acceleron Pharma, Liquidia and United Therapeutics (fees paid to self), served as scientific advisory board member for Aerovate, Altavant and Gossamer (fees paid to self), served as consultant for Janssen Global Services, LLC and Respira Therapeutics (fees paid to self), and served as principal investigator for Janssen Global Services, LLC and United Therapeutics (fees paid to self). A.B. Waxman has served as consultant for ARIA-CV, Goassamer, Merck & Co., Inc. (Rahway, NJ, USA) and United Therapeutics Corporation (fees paid to self), received grants/contracts from AI Therapeutics, Inc. (fees paid to self), and served on a data and safety monitoring committee for Insmed, Inc. (fees paid to self). E. Grünig has served as consultant for Actelion Pharmaceuticals (fees paid to self), and served as speaker and/or consultant for Bayer Healthcare, Ferrer, GEBRO, GlaxoSmithKline, Janssen Biotech, Merck Sharp & Dohme (MSD) and OMT (fees paid to self). G. Kopeć has served as consultant for Acceleron Pharma, Inc. and Janssen Global Services, LLC, on a scientific advisory board (fees paid to self), served as PI in a clinical study for Acceleron Pharma, Inc., Bayer and Janssen Global Services, LLC (fees paid to self), served as a speaker for Bayer, Janssen Global Services, LLC and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self), served as investigator for Janssen Global Services, LLC (fees paid to self), and received travel fees from Janssen Global Services, LLC and Merck & Co., Inc. (Rahway, NJ, USA) (paid to self). G. Meyer has served as consultant for Bayer Healthcare and Janssen Biotech (fees paid to self), and received grants/contracts from Bayer Healthcare (paid to institution). K.M. Olsson has served as a consultant for Acceleron Pharma, Inc., Actelion Pharmaceuticals, AOP Orphan, Bayer, Ferrer Pharma, Janssen Global Services, LLC and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self). S. Rosenkranz has served as consultant for Abbott Fund, Acceleron Pharma, Inc., Actelion Pharmaceuticals, Aerovate, Altavant, AOP Orphan, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, Ferrer, Gossamer, Janssen, MSD and United Therapeutics (fees paid to self), and received grants/contracts from Actelion Pharmaceuticals, AstraZeneca, Bayer and Janssen (paid to institution). J. Lin, A.O. Johnson-Levonas and J. de Oliveira Pena are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock/stock shares in Merck & Co., Inc., Rahway, NJ, USA. M. Humbert has served as consultant for Acceleron Pharma, Inc., Aerovate, Altavant, AOP Orphan, Bayer, Chiesi Farmaceutici, Ferrer, Janssen Pharmaceuticals, Merck & Co., Inc. (Rahway, NJ, USA), MorphogenIX and United Therapeutics Corporation (fees paid to self). M.M. Hoeper has served as consultant for Acceleron Pharma, Inc., Actelion Pharmaceuticals, AOP Orphan, Bayer Healthcare, Ferrer, GossamerBio, Janssen Global Services, LLC and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self)., (Copyright ©The authors 2023.)- Published
- 2023
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38. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension.
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Hoeper MM, Badesch DB, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, McLaughlin VV, Preston IR, Souza R, Waxman AB, Grünig E, Kopeć G, Meyer G, Olsson KM, Rosenkranz S, Xu Y, Miller B, Fowler M, Butler J, Koglin J, de Oliveira Pena J, and Humbert M
- Subjects
- Adult, Humans, Double-Blind Method, Hypertension, Pulmonary drug therapy, Treatment Outcome, Vascular Resistance drug effects, Injections, Subcutaneous, Walk Test, Exercise Tolerance drug effects, Cardiovascular Agents administration & dosage, Cardiovascular Agents adverse effects, Cardiovascular Agents pharmacology, Cardiovascular Agents therapeutic use, Respiratory System Agents administration & dosage, Respiratory System Agents adverse effects, Respiratory System Agents pharmacology, Respiratory System Agents therapeutic use, Pulmonary Arterial Hypertension diagnosis, Pulmonary Arterial Hypertension drug therapy, Recombinant Fusion Proteins administration & dosage, Recombinant Fusion Proteins adverse effects, Recombinant Fusion Proteins pharmacology, Recombinant Fusion Proteins therapeutic use
- Abstract
Background: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension., Methods: We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit., Results: A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure., Conclusions: In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.)., (Copyright © 2023 Massachusetts Medical Society.)
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- 2023
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39. Impact of the COVID-19 pandemic on chronic disease management and patient reported outcomes in patients with pulmonary hypertension: The Pulmonary Hypertension Association Registry.
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Mayer M, Badesch DB, Nielsen KH, Kawut S, Bull T, Ryan JJ, Sager J, Mazimba S, Hemnes A, Klinger J, Runo J, McConnell JW, De Marco T, Chakinala MM, Yung D, Elwing J, Kaplan A, Argula R, Pomponio R, Peterson R, and Hountras P
- Abstract
To better understand the impact of the COVID-19 pandemic on the care of patients with pulmonary hypertension, we conducted a retrospective cohort study evaluating health insurance status, healthcare access, disease severity, and patient reported outcomes in this population. Using the Pulmonary Hypertension Association Registry (PHAR), we defined and extracted a longitudinal cohort of pulmonary arterial hypertension (PAH) patients from the PHAR's inception in 2015 until March 2022. We used generalized estimating equations to model the impact of the COVID-19 pandemic on patient outcomes, adjusting for demographic confounders. We assessed whether insurance status modified these effects via covariate interactions. PAH patients were more likely to be on publicly-sponsored insurance during the COVID-19 pandemic compared with prior, and did not experience statistically significant delays in access to medications, increased emergency room visits or nights in the hospital, or worsening of mental health metrics. Patients on publicly-sponsored insurance had higher healthcare utilization and worse objective measures of disease severity compared with privately insured individuals irrespective of the COVID-19 pandemic. The relatively small impact of the COVID-19 pandemic on pulmonary hypertension-related outcomes was unexpected but may be due to pre-established access to high quality care at pulmonary hypertension comprehensive care centers. Irrespective of the COVID-19 pandemic, patients who were on publicly-sponsored insurance seemed to do worse, consistent with prior studies highlighting outcomes in this population. We speculate that previously established care relationships may lessen the impact of an acute event, such as a pandemic, on patients with chronic illness., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)
- Published
- 2023
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40. Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension.
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Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Preston IR, Souza R, Waxman AB, Ghofrani HA, Escribano Subias P, Feldman J, Meyer G, Montani D, Olsson KM, Manimaran S, de Oliveira Pena J, and Badesch DB
- Subjects
- Adult, Humans, DEAE-Dextran, Treatment Outcome, Familial Primary Pulmonary Hypertension, Double-Blind Method, Pulmonary Arterial Hypertension
- Abstract
Background: In participants with pulmonary arterial hypertension, 24 weeks of sotatercept resulted in a significantly greater reduction from baseline in pulmonary vascular resistance than placebo. This report characterises the longer-term safety and efficacy of sotatercept in the PULSAR open-label extension. We report cumulative safety, and efficacy at months 18-24, for all participants treated with sotatercept., Methods: PULSAR was a phase 2, randomised, double-blind, placebo-controlled study followed by an open-label extension, which evaluated sotatercept on top of background pulmonary arterial hypertension therapy in adults. Participants originally randomised to placebo were re-randomised 1:1 to sotatercept 0.3 or 0.7 mg·kg
-1 (placebo-crossed group); those initially randomised to sotatercept continued the same sotatercept dose (continued-sotatercept group). Safety was evaluated in all participants who received ≥1 dose of sotatercept. The primary efficacy endpoint was change from baseline to months 18-24 in pulmonary vascular resistance. Secondary endpoints included 6-min walk distance and functional class. Two prespecified analyses, placebo-crossed and delayed-start, evaluated efficacy irrespective of dose., Results: Of 106 participants enrolled in the PULSAR study, 97 continued into the extension period. Serious treatment-emergent adverse events were reported in 32 (30.8%) participants; 10 (9.6%) reported treatment-emergent adverse events leading to study discontinuation. Three (2.9%) participants died, none considered related to study drug. The placebo-crossed group demonstrated significant improvement across primary and secondary endpoints and clinical efficacy was maintained in the continued-sotatercept group., Conclusion: These results support the longer-term safety and durability of clinical benefit of sotatercept for pulmonary arterial hypertension., Competing Interests: Conflict of interest: M. Humbert is a consultant and an advisory committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Aerovate, Altavant, AOP Orphan, Bayer, Ferrer, Janssen, Merck & Co., Inc., Rahway, NJ, USA, MorphogenIX and United Therapeutics, and has received research grants for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Janssen, and Merck & Co., Inc., Rahway, NJ, USA. V. McLaughlin is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Aerovate, Altavant, Bayer, Caremark LLC, CiVi Bioharma Inc., Corvista, Gossamer Bio, Janssen, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics, has received grant(s) from Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Janssen, Sonovie, United Therapeutics, is involved in CME programs for Impact PH and PHA, and on the board of directors for CiVi Biopharma Inc., and for Clene. J.S.R. Gibbs is a consultant and speaker for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Aerovate, Bayer, Complexa, Janssen, Merck & Co., Inc., Rahway, NJ, USA, MSD, Pfizer and United Therapeutics. M. Gomberg-Maitland is a consultant for Altavant, Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Janssen, and Entelligence Young for Janssen, is part of the advisory committee for United Therapeutics and the data safety monitoring board for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, has received grant(s) and/or reports GW with funds from Altavant, Bayer and United Therapeutics. M.M. Hoeper is a consultant and speaker for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. I.R. Preston is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Pfizer, Respira and United Therapeutics, a steering committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and has received grant(s) from Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, Complexa, Liquidia, PhaseBio, Tenax and United Therapeutics. R. Souza is an advisory committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA. A.B. Waxman is steering committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Altavant, Gossamer Bio, United Therapeutics, an investigator and/or principal investigator for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Aria-CV and United Therapeutics, and has received grant(s) from Acceleron, a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA. H-A. Ghofrani is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, Gossamer Bio, Jansson, MorphogenIX, MSD and Pfizer. P. Escribano Subias has received consulting fees from Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Janssen, MSD and Gossamer Bio, has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Janssen, MSD, Ferrer, Bayer and AOT, has received support for attending meetings from Janssen and MSD, has received equipment, materials, drugs, medical writing or other services from Janssen, and has participated on data safety monitoring or advisory boards for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway NJ, USA, Janssen, MSD and Gossamer Bio. J. Feldman reports consulting fees from Merck, Aerovate, Altavant, United Therapeutics, Liquidia, Corsair and Janssen. G. Meyer has received payment or honoraria for lectures, presentations, and speakers’ bureaus from Bayer and Janssen and has participated on advisory boards for Bayer and Janssen. D. Montani has received grant(s) from and is a consultant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, Chesi, GlaxoSmithKline, MSD and Pfizer. K.M. Olsson is a consultant and speaker for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. S. Manimaran and J. de Oliveira Pena are employees of Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA. D.B. Badesch is a consultant for Pfizer, is a consultant and advisory committee member for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Altavant, Arena, Bayer, Liquidia, Merck & Co., Inc., Rahway, NJ, USA, United Therapeutics, has received research grant for Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Actelion, Altavant, Arena, Belleraphon, Janssen, Liquidia, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics, sits on the data safety monitoring board for United Therapeutics, and is a long-term holder of common stock for Johnson and Johnson., (Copyright ©The authors 2023.)- Published
- 2023
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41. Corrigendum for health-related quality of life and hospitalizations in chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension: And analysis from the Pulmonary Hypertension Association Registry.
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Minhas J, Narasimmal SP, Bull TM, De Marco T, Mc Connell JW, Lammi MR, Thenappan T, Feldman JP, Sager JS, Badesch DB, Ryan JJ, Grinnan DC, Zwicke D, Horn EM, Elwing JM, Moss JE, Eggert M, Shlobin OA, Frantz RP, Bartolome SD, Mathai SC, Mazimba S, Pugliese SC, and Al-Naamani N
- Abstract
[This corrects the article DOI: 10.1177/20458940211053196.]., (© 2022 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)
- Published
- 2022
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42. Inference following multiple imputation for generalized additive models: an investigation of the median p-value rule with applications to the Pulmonary Hypertension Association Registry and Colorado COVID-19 hospitalization data.
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Bolt MA, MaWhinney S, Pattee JW, Erlandson KM, Badesch DB, and Peterson RA
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- Colorado, Hospitalization, Humans, Models, Statistical, Registries, COVID-19 epidemiology, Hypertension, Pulmonary diagnosis
- Abstract
Background: Missing data prove troublesome in data analysis; at best they reduce a study's statistical power and at worst they induce bias in parameter estimates. Multiple imputation via chained equations is a popular technique for dealing with missing data. However, techniques for combining and pooling results from fitted generalized additive models (GAMs) after multiple imputation have not been well explored., Methods: We simulated missing data under MCAR, MAR, and MNAR frameworks and utilized random forest and predictive mean matching imputation to investigate a variety of rules for combining GAMs after multiple imputation with binary and normally distributed outcomes. We compared multiple pooling procedures including the "D2" method, the Cauchy combination test, and the median p-value (MPV) rule. The MPV rule involves simply computing and reporting the median p-value across all imputations. Other ad hoc methods such as a mean p-value rule and a single imputation method are investigated. The viability of these methods in pooling results from B-splines is also examined for normal outcomes. An application of these various pooling techniques is then performed on two case studies, one which examines the effect of elevation on a six-minute walk distance (a normal outcome) for patients with pulmonary arterial hypertension, and the other which examines risk factors for intubation in hospitalized COVID-19 patients (a dichotomous outcome)., Results: In comparison to the results from generalized additive models fit on full datasets, the median p-value rule performs as well as if not better than the other methods examined. In situations where the alternative hypothesis is true, the Cauchy combination test appears overpowered and alternative methods appear underpowered, while the median p-value rule yields results similar to those from analyses of complete data., Conclusions: For pooling results after fitting GAMs to multiply imputed datasets, the median p-value is a simple yet useful approach which balances both power to detect important associations and control of Type I errors., (© 2022. The Author(s).)
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- 2022
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43. Mortality in Pulmonary Arterial Hypertension in the Modern Era: Early Insights From the Pulmonary Hypertension Association Registry.
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Chang KY, Duval S, Badesch DB, Bull TM, Chakinala MM, De Marco T, Frantz RP, Hemnes A, Mathai SC, Rosenzweig EB, Ryan JJ, and Thenappan T
- Subjects
- Adult, Familial Primary Pulmonary Hypertension, Female, Humans, Male, Middle Aged, Proportional Hazards Models, Registries, Survival Rate, United States epidemiology, Hypertension, Pulmonary, Pulmonary Arterial Hypertension diagnosis
- Abstract
Background Current mortality data for pulmonary arterial hypertension (PAH) in the United States are based on registries that enrolled patients prior to 2010. We sought to determine mortality in PAH in the modern era using the PHAR (Pulmonary Hypertension Association Registry). Methods and Results We identified all adult patients with PAH enrolled in the PHAR between September 2015 and September 2020 (N=935). We used Kaplan-Meier survival analysis and Cox proportional hazards models to assess mortality at 1, 2, and 3 years. Patients were stratified based on disease severity by 3 validated risk scores. In treatment-naïve patients, we compared survival based on initial treatment strategy. The median age was 56 years (44-68 years), and 76% were women. Of the 935 patients, 483 (52%) were ≤6 months from PAH diagnosis. There were 121 deaths (12.9%) during a median follow-up time of 489 days (281-812 days). The 1-, 2-, and 3-year mortality was 8% (95% CI, 6%-10%), 16% (95% CI, 13%-19%), and 21% (95% CI, 17%-25%), respectively. When stratified into low-, intermediate-, and high-risk PAH, the mortality at 1, 2, and 3 years was 1%, 4% to 6%, and 7% to 11% for low risk; 7% to 8%, 11% to 16%, and 18% to 20% for intermediate risk; and 12% to 19%, 22% to 38%, and 28% to 55% for high risk, respectively. In treatment-naïve patients, initial combination therapy was associated with better 1-year survival (adjusted hazard ratio, 0.43 [95% CI, 0.19-0.95]; P =0.037). Conclusions Mortality in the intermediate- and high-risk patients with PAH remains unacceptably high in the PHAR, suggesting the importance for early diagnosis, aggressive use of available therapies, and the need for better therapeutics.
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- 2022
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44. Surrogate Markers for Pulmonary Hypertension May Inform Prognosis in Lung Cancer.
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Forbes LM, Gu S, and Badesch DB
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- Biomarkers, Humans, Prognosis, Hypertension, Pulmonary diagnosis, Lung Neoplasms complications, Lung Neoplasms diagnosis
- Published
- 2021
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45. Sotatercept for the Treatment of Pulmonary Arterial Hypertension.
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Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Preston IR, Souza R, Waxman A, Escribano Subias P, Feldman J, Meyer G, Montani D, Olsson KM, Manimaran S, Barnes J, Linde PG, de Oliveira Pena J, and Badesch DB
- Subjects
- Adult, Dose-Response Relationship, Drug, Double-Blind Method, Exercise Tolerance drug effects, Female, Humans, Injections, Subcutaneous, Least-Squares Analysis, Male, Middle Aged, Natriuretic Peptide, Brain blood, Peptide Fragments blood, Pulmonary Arterial Hypertension blood, Pulmonary Arterial Hypertension physiopathology, Recombinant Fusion Proteins adverse effects, Recombinant Fusion Proteins pharmacology, Thrombocytopenia chemically induced, Walk Test, Pulmonary Arterial Hypertension drug therapy, Recombinant Fusion Proteins therapeutic use, Transforming Growth Factor beta antagonists & inhibitors, Vascular Resistance drug effects
- Abstract
Background: Pulmonary arterial hypertension is characterized by pulmonary vascular remodeling, cellular proliferation, and poor long-term outcomes. Dysfunctional bone morphogenetic protein pathway signaling is associated with both hereditary and idiopathic subtypes. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors in the attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways., Methods: In this 24-week multicenter trial, we randomly assigned 106 adults who were receiving background therapy for pulmonary arterial hypertension to receive subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo. The primary end point was the change from baseline to week 24 in pulmonary vascular resistance., Results: Baseline characteristics were similar among the three groups. The least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline to week 24 in pulmonary vascular resistance was -145.8 dyn · sec · cm
-5 (95% confidence interval [CI], -241.0 to -50.6; P = 0.003). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was -239.5 dyn · sec · cm-5 (95% CI, -329.3 to -149.7; P<0.001). At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline in 6-minute walk distance was 29.4 m (95% CI, 3.8 to 55.0). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was 21.4 m (95% CI, -2.8 to 45.7). Sotatercept was also associated with a decrease in N-terminal pro-B-type natriuretic peptide levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest., Conclusions: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension. (Funded by Acceleron Pharma; PULSAR ClinicalTrials.gov number, NCT03496207.)., (Copyright © 2021 Massachusetts Medical Society.)- Published
- 2021
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46. Clinical Differences and Outcomes between Methamphetamine-associated and Idiopathic Pulmonary Arterial Hypertension in the Pulmonary Hypertension Association Registry.
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Kolaitis NA, Zamanian RT, de Jesus Perez VA, Badesch DB, Benza RL, Burger CD, Chakinala MM, Elwing JM, Feldman J, Lammi MR, Mathai SC, McConnell JW, Presberg KW, Robinson JC, Sager J, Shlobin OA, Simon MA, Kawut SM, Glidden DV, Singer JP, and De Marco T
- Subjects
- Familial Primary Pulmonary Hypertension, Humans, Prospective Studies, Quality of Life, Registries, United States epidemiology, Hypertension, Pulmonary chemically induced, Hypertension, Pulmonary epidemiology, Methamphetamine adverse effects
- Abstract
Rationale: Single-center studies demonstrated that methamphetamine use is associated with pulmonary arterial hypertension (Meth-APAH). We used the Pulmonary Hypertension Association Registry to evaluate the national distribution of Meth-APAH and to compare its impact on patient-reported and clinical outcomes relative to idiopathic PAH. Objectives: To determine if patients with Meth-APAH differ from those with idiopathic PAH in demographics, regional distribution in the United States, hemodynamics, health-related quality of life, PAH-specific treatment, and health care use. Methods: The Pulmonary Hypertension Association Registry is a U.S.-based prospective cohort of patients new to care at a Pulmonary Hypertension Care Center. The registry collects baseline demographics, clinical parameters, and repeated measures of health-related quality of life, World Health Organization functional class, 6-minute walk distance, therapy, and health care use. Repeated measures of functional class, health-related quality of life, type of therapy, emergency department visits, and hospitalizations were compared using generalized estimating equations. Results: Of 541 participants included, 118 had Meth-APAH; 83% of Meth-APAH arose in the western United States. The Meth-APAH group was younger and had a poorer socioeconomic status and lower cardiac index than the idiopathic PAH group, despite no difference in mean pulmonary artery pressure or pulmonary vascular resistance. The Meth-APAH group had a more advanced functional class in longitudinal models (0.22 points greater; 95% confidence interval [CI], 0.07 to 0.37) and worse PAH-specific (emPHasis-10) health-related quality of life (-5.4; 95% CI, -8.1 to -2.8). There was no difference in dual combination therapy; however, participants with Meth-APAH were less likely to be initiated on triple therapy (odds ratio [OR], 0.43; 95% CI, 0.24 to 0.77) or parenteral therapy (OR, 0.10; 95% CI, 0.04 to 0.24). Participants with Meth-APAH were more likely to seek care in the emergency department (incidence rate ratio, 2.30; 95% CI, 1.71 to 3.11) and more likely to be hospitalized (incidence rate ratio, 1.42; 95% CI, 1.10 to 1.83). Conclusions: Meth-APAH represents a unique clinical phenotype of PAH, most common in the western United States. It accounts for a notable proportion of PAH in expert centers. Assessment for methamphetamine use is necessary in patients with PAH.
- Published
- 2021
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47. United States Pulmonary Hypertension Scientific Registry: Baseline Characteristics.
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Badlam JB, Badesch DB, Austin ED, Benza RL, Chung WK, Farber HW, Feldkircher K, Frost AE, Poms AD, Lutz KA, Pauciulo MW, Yu C, Nichols WC, and Elliott CG
- Subjects
- Adolescent, Adult, Aged, Cohort Studies, Female, Gonadal Steroid Hormones therapeutic use, Humans, Hypertension, Pulmonary complications, Hypertension, Pulmonary diagnosis, Male, Middle Aged, Mutation, Reproductive History, Symptom Assessment, United States epidemiology, Young Adult, Hypertension, Pulmonary epidemiology, Registries
- Abstract
Background: The treatment, genotyping, and phenotyping of patients with World Health Organization Group 1 pulmonary arterial hypertension (PAH) have evolved dramatically in the last decade., Research Question: The United States Pulmonary Hypertension Scientific Registry was established as the first US PAH patient registry to investigate genetic information, reproductive histories, and environmental exposure data in a contemporary patient population., Study Design and Methods: Investigators at 15 US centers enrolled consecutively screened adults diagnosed with Group 1 PAH who had enrolled in the National Biological Sample and Data Repository for PAH (PAH Biobank) within 5 years of a cardiac catheterization demonstrating qualifying hemodynamic criteria. Exposure and reproductive histories were collected by using a structured interview and questionnaire. The biobank provided genetic data., Results: Between 2015 and 2018, a total of 499 of 979 eligible patients with clinical diagnoses of idiopathic PAH (IPAH) or familial PAH (n = 240 [48%]), associated PAH (APAH; n = 256 [51%]), or pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis (n = 3 [1%]) enrolled. The mean age was 55.8 years, average BMI was 29.2 kg/m
2 , and 79% were women. Mean duration between symptom onset and diagnostic catheterization was 1.9 years. Sixty-six percent of patients were treated with more than one PAH medication at enrollment. Past use of prescription weight loss drugs (16%), recreational drugs (27%), and oral contraceptive pills (77%) was common. Women often reported miscarriage (37%), although PAH was rarely diagnosed within 6 months of pregnancy (1.9%). Results of genetic testing identified pathogenic or suspected pathogenic variants in 13% of patients, reclassifying 18% of IPAH patients and 5% of APAH patients to heritable PAH., Interpretation: Patients with Group 1 PAH remain predominately middle-aged women diagnosed with IPAH or APAH. Delays in diagnosis of PAH persist. Treatment with combinations of PAH-targeted medications is more common than in the past. Women often report pregnancy complications, as well as exposure to anorexigens, oral contraceptives, and/or recreational drugs. Results of genetic tests frequently identify unsuspected heritable PAH., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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48. Response.
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Klinger JR, Elliott G, Levine DJ, Bossone E, Duvall L, Fagan K, Frantsve-Hawley J, Kawut SM, Ryan JJ, Rosenzweig EB, Sederstrom N, Steen VD, and Badesch DB
- Subjects
- Familial Primary Pulmonary Hypertension, Humans, Thorax, Pulmonary Arterial Hypertension
- Published
- 2019
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49. Response.
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Frantz RP, Zhao C, Farber HW, Badesch DB, Elliott CG, Frost AE, McGoon MD, Mink DR, Selej M, and Benza RL
- Subjects
- Familial Primary Pulmonary Hypertension, Humans, Registries, Natriuretic Peptide, Brain
- Published
- 2018
- Full Text
- View/download PDF
50. Psychometric Validation of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Questionnaire: Results of the SYMPHONY Trial.
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Chin KM, Gomberg-Maitland M, Channick RN, Cuttica MJ, Fischer A, Frantz RP, Hunsche E, Kleinman L, McConnell JW, McLaughlin VV, Miller CE, Zamanian RT, Zastrow MS, and Badesch DB
- Subjects
- Adolescent, Adult, Aged, Antihypertensive Agents therapeutic use, Female, Humans, Hypertension, Pulmonary drug therapy, Male, Middle Aged, Prospective Studies, Psychometrics, Pyrimidines therapeutic use, Quality of Life, Sulfonamides therapeutic use, Young Adult, Hypertension, Pulmonary psychology, Surveys and Questionnaires standards
- Abstract
Background: Disease-specific patient-reported outcome (PRO) instruments are important in assessing the impact of disease and treatment. The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is the first instrument for quantifying pulmonary arterial hypertension (PAH) symptoms and impacts developed according to the 2009 US Food and Drug Administration PRO guidance; previous qualitative research in patients with PAH supported its initial content validity., Methods: Content finalization and psychometric validation were conducted by using data from A Study of Macitentan in Pulmonary Arterial Hypertension to Validate the PAH-SYMPACT (SYMPHONY), a single-arm, 16-week trial with macitentan 10 mg in US patients with PAH. Item performance, Rasch analysis, and factor analyses were used to select the final item content of the PRO and to define its domain structure. Internal consistency, test-retest reliability, known-group and construct validity, sensitivity to change, and influence of oxygen on item performance were evaluated., Results: Data from 278 patients (79% female; mean age: 60 years) were analyzed. Following removal of redundant/misfitting items, the final questionnaire has 11 symptom items across two domains (cardiopulmonary and cardiovascular symptoms) and 11 impact items across two domains (physical and cognitive/emotional impacts). Differential item function analysis confirmed that PRO scoring is unaffected by oxygen use. For all four domains, internal consistency reliability was high (Cronbach's alpha > 0.80), and scores were highly reproducible in stable patients (intraclass correlation coefficient: 0.84-0.94). Correlations with the Cambridge Pulmonary Hypertension Outcome Review questionnaire and the 36-item Medical Outcomes Study Short Form Survey were moderate to high ([r] = 0.34-0.80). The questionnaire differentiated well between patients with varying disease severity levels and was sensitive to improvements in clinician- and patient-reported disease severity., Conclusions: The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is a brief, disease-specific PRO instrument possessing good psychometric properties that can be administered in clinical practice and clinical studies., Trial Registry: ClinicalTrials.gov; No.: NCT01841762; URL: www.clinicaltrials.gov., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
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