F. Kermeen

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

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 = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .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. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

Original ResearchPulmonary Vascular DiseaseFeaturedOral 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

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 = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .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. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

Human Metapneumovirus in Lung Transplant Recipients and Comparison to Respiratory Syncytial Virus

RATIONALE Human metapneumovirus is a newly described virus isolated in 2001 from children with acute respiratory viral infection. It has subsequently been reported globally, although there are limited data in lung transplant recipients. OBJECTIVES To prospectively analyze whether human metapneumovirus was circulating in our adult lung transplant community and assess the morbidity of this infection and to compare the clinical presentation and outcome after intravenous ribavirin of human metapneumovirus with that of respiratory syncytial virus (RSV). METHODS Lung transplant patients with clinical features of respiratory viral infection underwent nasopharyngeal aspirates. Patients with a positive specimen for RSV or human metapneumovirus by reverse transcriptase-polymerase chain reaction analysis and graft dysfunction received intravenous ribavirin and pulse steroid therapy. MEASUREMENTS AND MAIN RESULTS Eighty-nine patients had 199 visits for aspirate studies. A viral cause was determined for 62 visits in 47 patients (19 human metapneumovirus, 18 RSV, 13 parainfluenza, 9 influenza A, 2 adenovirus, and 1 influenza B). A significant percentage of patients with metapneumovirus (63%) and RSV (72%) developed graft dysfunction, with average declines in FEV(1) of 30 +/- 12.4% and 25.9 +/- 11.2%, respectively. In these patients, bronchiolitis obliterans syndrome onset or progression occurred in no patients with human metapneumovirus compared with 5 of 13 (38%) patients with RSV at 6 months. CONCLUSIONS Human metapneumovirus is a leading cause of acute respiratory tract illness in lung transplant recipients. The incidence and clinical spectrum at presentation are similar to RSV, although the latter seems to be associated with a higher risk of chronic rejection. We recommend testing of nasopharyngeal aspirates for human metapneumovirus with polymerase chain reaction to assess local epidemiologic patterns.

Survival after the initiation of combination therapy in patients with pulmonary arterial hypertension: an Australian collaborative report.

Background:  Several cellular pathways are implicated in the pathogenesis of pulmonary arterial hypertension (PAH) and attempts to arrest disease progression with a single drug would not be expected to succeed in the medium term. In clinical practice, combination therapy is often used in patients deteriorating on monotherapy, despite the absence of firm evidence from randomized controlled controls.

Time from symptoms to definitive diagnosis of idiopathic pulmonary arterial hypertension: The delay study

Survival rates for patients with idiopathic pulmonary arterial hypertension (IPAH) have improved with the introduction of PAH-specific therapies. However, the time between patient-reported onset of symptoms and a definitive diagnosis of IPAH is consistently delayed. We conducted a retrospective, multi-center, descriptive investigation in order to (a) understand what factors contribute to persistent diagnostic delays, and (b) examine the time from initial symptom onset to a definitive diagnosis of IPAH. Between January 2007 and December 2008, we enrolled consecutively diagnosed adults with IPAH from four tertiary referral centers in Australia. Screening of patient records and “one-on-one” interviews were used to determine the time from patient-described initial symptoms to a diagnosis of IPAH, confirmed by right heart catheterization (RHC). Thirty-two participants (69% female) were studied. Mean age at symptom onset was 56 ± 16.4 years and 96% reported exertional dyspnea. Mean time from symptom onset to diagnosis was 47 ± 34 months with patients subsequently aged 60 ± 17.3 years. Patients reported 5.3 ± 3.8 GP visits and 3.0 ± 2.1 specialist reviews before being seen at a pulmonary hypertension (PH) center. Advanced age, number of general practitioner (GP) visits, heart rate, and systolic blood pressure at the time of diagnosis were significantly associated with the observed delay. We found a significant delay of 3.9 years from symptom onset to a diagnosis of IPAH in Australia. Exertional dyspnea is the most common presenting symptom. Current practice within Australia does not appear to have the specific capacity for timely, multi-factorial evaluation of breathlessness and potential IPAH.

Improvement after angioplasty and stenting of pulmonary arteries due to sarcoid mediastinal fibrosis.

We describe a series of cases referred to our institution with working diagnoses of chronic thrombo-embolic pulmonary hypertension (CTEPH) for consideration of surgical pulmonary thrombo-endarterectomy (PTE). Investigations in two cases revealed extrinsic compression of the pulmonary arteries from massive mediastinal lymphadenopathy (mediastinal fibrosis) due to underlying sarcoidosis. Angioplasty and stenting of the pulmonary arteries were performed in all cases with sustained haemodynamic and functional improvement. This highlights the value of new imaging modalities in delineating causes of pulmonary hypertension, and demonstrates an interventional approach for selected cases.

Bosentan for the treatment of pulmonary arterial hypertension associated with congenital cardiac disease

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

Endothelin receptor antagonists are an effective long term treatment option in pulmonary arterial hypertension associated with congenital heart disease with or without trisomy 21.

INTRODUCTION Traditionally, treatment options for patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) are limited. Bosentan has been shown to improve pulmonary haemodynamics and exercise tolerance short term but long term clinical studies are lacking. AIM To report long term efficacy and safety data with endothelin receptor antagonists (ERA) in patients with PAH associated CHD. METHODS Prospective, open label, uncontrolled, single centre study of 53 patients (33 females, 17 Trisomy 21, mean age 34 ± 12 years) prescribed ERA (48 bosentan, 5 sitaxentan) from 2003 to August 2009. Outcome measurements of oxygen saturation (SaO2), WHO functional class, 6-minute walk test distance (6MWD) and adverse events were analysed. RESULTS Mean duration of therapy was 15 ± 13 months in 53 patients with CHD. Four patients failed ERA, seven died (five progressive RHF) and one delisted from transplantation. No abnormal liver transaminases occurred on bosentan, with one case on sitaxentan. After 3, 6, 12, 18 and 24 months of treatment a significant improvement was seen in WHO functional class (mean 3.15 vs 2.8 vs 2.5 vs 2.5 vs 2.4 vs 2.4; p<0.01) and 6MWD (344 ± 18 vs 392 ± 17 vs 411 ± 17 vs 420 ± 17 vs 442 ± 18 vs 417 ± 23: p<0.0005, p<0.01) compared with baseline. The Trisomy 21 and PAH-CHD showed a significant improvement in 6MWD at 6 and 12 months (263 ± 24 vs 348 ± 29 vs 360 ± 32, p<0.01, p<0.05) respectively. No changes in SaO2, BNP, RV or LV function were demonstrated during follow-up. CONCLUSION This large single centre study demonstrates that endothelin receptor antagonism is an effective and safe treatment in PAH associated CHD with or without Trisomy 21. The improvements in exercise tolerance are similar to reported benefits in other forms of PAH.

Erratum to: Prognostic value of right ventricular free wall strain in pulmonary hypertension patients with pseudo-normalized tricuspid annular plane systolic excursion values

Pulmonary hypertension (PH) is a progressively fatal disease having a significant impact on right ventricular (RV) function, a major determinant of longterm outcome in PH patients. In our clinic we frequently noticed the combination of PH and reduced RV function, but with discordant Tricuspid Annular Plane Systolic Excursion (TAPSE) values. The present study focuses on whether RV free wall strain measured using 2-dimensional speckle-tracking echocardiography is able to predict mortality in this subgroup of PH patients. 57 patients with PH and RV dysfunction (visual echocardiographic assessment of C2) and pseudo-normalized TAPSE values (defined as C16 mm) were retrospectively evaluated. Patients were divided by RV free -20 % as cut-off value. Follow-up data on all-cause mortality were registered after a median follow-up time of 27.9 ± 1.7 months. RV free of C-20 % was predictive of all-cause mortality after a median followup time of 27.9 ± 1.7 months (HR 3.76, 95 % CI 1.02–13.92, p = 0.05). RV free C-20 % remained a significant predictor of all-cause mortality (HR 4.30, 95 % CI 1.11–16.61, p = 0.04) after adjusting for PH-specific treatment. On the contrary, TAPSE was not a significant predictor of all-cause mortality. RV free wall strain provides prognostic information in patients with PH and RV dysfunction, but with normal TAPSE values. Future studies with larger cohorts, longer follow-up periods and inclusion of more echocardiographic parameters measuring LV and RV function could confirm the strength of RV free C-20 % as a predictor of mortality for this subgroup of patients with PH.

Congenital heart disease-associated pulmonary arterial hypertension: preliminary results from a novel registry.

Background/Aims:  Pulmonary arterial hypertension (PAH) frequently accompanies childhood congenital heart disease (CHD) and may persist into adult life. The advent of specific PAH therapies for PAH prompted formation of a national Australian and New Zealand registry in 2010 to document the incidence, demographics, presentation and outcomes for these patients.