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Background: Early initiation of pulmonary arterial hypertension (PAH) therapies is associated with improved long-term outcomes, yet data on the early use of prostacyclin pathway agents are limited. In these post hoc analyses of the Prostacyclin (PGI2) Receptor Agonist In Pulmonary Arterial Hypertension (GRIPHON) study, the largest randomized controlled trial for PAH to date, the prognostic value of time from diagnosis and its impact on treatment response were examined.Research Question: How does time from diagnosis impact morbidity/mortality events and response to selexipag treatment in patients with PAH?Study Design and Methods: The GRIPHON study randomly assigned 1,156 patients with PAH to selexipag or placebo treatment. Patients were categorized post hoc into a time from diagnosis of ≤ 6 months and > 6 months at randomization. Hazard ratios (selexipag vs placebo) were calculated for the primary end point of morbidity/mortality by time from diagnosis using Cox proportional hazard models.Results: Time from diagnosis was ≤ 6 months in 34.9% and > 6 months in 65.1% of patients. Time from diagnosis was prognostic of morbidity/mortality, with newly diagnosed patients having a poorer long-term outcome than patients diagnosed for longer. Compared with placebo, selexipag reduced the risk of morbidity/mortality in patients with a time from diagnosis of ≤ 6 months and > 6 months, with a more pronounced effect in newly diagnosed patients (hazard ratio, 0.45 [95% CI, 0.33-0.63] and 0.74 [95% CI, 0.57-0.96], respectively; P = .0219 for interaction).Interpretation: In the GRIPHON study, newly diagnosed PAH patients had a worse prognosis than patients with a longer time from diagnosis. The benefit of selexipag treatment on disease progression was more pronounced in patients treated earlier than in patients treated later.Trial Registry: ClinicalTrials.gov; No.: NCT01106014; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension (PAH) leads to reduced health-related quality of life (HRQoL). The objectives of this analysis were to evaluate the effect of macitentan on HRQoL in patients with PAH in the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) study. The association between baseline HRQoL and long-term outcomes was also investigated.Methods: Patients were randomized to placebo, macitentan 3 mg, or macitentan 10 mg once daily. Patients aged 14 years or older completed the 36-Item Short Form Survey (SF-36) at baseline, at month 6 and month 12, and at the end of treatment (EOT). The absolute change from baseline to month 6 in SF-36 scores was calculated. The time to a clinically meaningful deterioration in the SF-36 physical component summary and mental component summary (PCS and MCS) scores and associations between baseline PCS/MCS scores and time to morbidity/mortality events were also assessed.Results: At month 6, macitentan 10 mg significantly improved seven of eight SF-36 domains and the PCS and MCS scores vs placebo. Macitentan 10 mg significantly reduced the risk of a three-point or greater deterioration in PCS (hazard ratio [HR], 0.60; 95% CI, 0.47-0.76; P < .0001) and MCS scores (HR, 0.76; 95% CI, 0.61-0.95; P = .0173) until EOT vs placebo. Patients with a baseline PCS score greater than the median baseline value had a significantly reduced risk of morbidity/mortality compared with patients with a PCS score less than the median; a similar result was observed for the MCS score.Conclusions: Macitentan significantly improved HRQoL in patients with PAH compared with placebo and significantly reduced the risk of a clinically meaningful HRQoL deterioration. An association between better baseline HRQoL and improved long-term outcomes was shown.Trial Registry: ClinicalTrials.gov; No.: NCT00660179; URL: clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: The use of systemic prostanoids in severe pulmonary arterial hypertension (PAH) is often limited by patient/physician dissatisfaction with the delivery methods. Complications associated with external pump-delivered continuous therapy include IV catheter-related bloodstream infections and subcutaneous infusion site pain. We therefore investigated a fully implantable intravascular delivery system for treprostinil infusion.Methods: A multicenter, prospective, single-arm, clinical trial (DelIVery for Pulmonary Arterial Hypertension) was conducted by using an implantable intravascular delivery system. The implanted pumps were refilled percutaneously at least every 12 weeks. The primary end point was the rate of catheter-related complications using the new model 10642 catheter compared with a predefined objective performance criterion of 2.5 per 1,000 patient-days based on the literature.Results: Patients (n = 60) with severe PAH (World Health Organization group 1) receiving a stable dose of IV treprostinil for at least 4 weeks received an implant device and were followed up for 12.1 ± 4.4 months. Six catheter-related complications occurred, corresponding to a complication rate of 0.27 per 1,000 patient-days. The 97.5% upper one-sided confidence bound of 0.59 was less than the predefined criterion of 2.5 per 1,000 patient-days (P < .0001). Plasma treprostinil levels at 1 week postimplantation were highly correlated with baseline levels (r = 0.91; P < .0001). The delivery system management time as reported by the patients was 2.5 ± 1.7 hours per week preimplantation, and this time decreased to 0.6 ± 0.8 hour per week at 6 months' postimplantation (P < .0001). All patients rated overall satisfaction with the implantable system as good, very good, or excellent at 6 weeks and 6 months. There were no catheter-related bloodstream infections or catheter occlusions.Conclusions: The implantable intravascular delivery system delivered treprostinil to patients with PAH with a low rate of catheter-related complications and a high rate of patient satisfaction.Trial Registry: ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: Treprostinil is a stable prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) as parenteral or inhaled therapy. Treprostinil diolamine, a sustained-release oral formulation of treprostinil, was studied to determine whether it could provide a more convenient prostacyclin treatment option for patients with less severe PAH. The objective of this study was to evaluate the efficacy and safety of oral treprostinil in patients with PAH receiving stable background endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor (PDE-5I) therapy, or both.Methods: A 16-week, multicenter, double-blind, placebo-controlled study in 310 patients with PAH compared bid administration of oral treprostinil (n = 157) with placebo (n = 153). The primary end point was change in 6-min walk distance at week 16. Secondary efficacy end points were World Health Organization functional class, Borg dyspnea score, dyspnea-fatigue index, signs and symptoms of PAH, and clinical worsening.Results: One hundred thirty-two patients (84%) receiving oral treprostinil and 138 (90%) receiving placebo completed the study. The mean ± SD dose of oral treprostinil at week 16 was 3.1 ± 1.9 mg bid. The Hodges-Lehmann placebo-corrected median difference in 6MWD at week 16 was 10.0 m (95% CI, -2 to 22 m; P = .089). There were no significant changes in secondary end points. The most common adverse events associated with oral treprostinil were headache (71%), diarrhea (55%), nausea (46%), flushing (35%), and jaw pain (25%).Conclusions: The addition of oral treprostinil to background ERA and PDE-5I therapy did not result in a statistically significant improvement in exercise capacity. Side effects were common but tolerated by most subjects.Trial Registry: ClinicalTrials.gov; No.: NCT00887978; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: The Pulmonary Arterial Hypertension-Quality Enhancement Research Initiative (PAHQuERI) was created to help clinicians to implement a guidelines-based approach to the diagnosis and management of pulmonary arterial hypertension (PAH). Patients with PAH represent a heterogeneous population, and physician evaluation and treatment paradigms may vary considerably.Methods: Using an electronic data management system, participating physicians recorded data on diagnostic workup, disease management, and outcomes of patients with PAH. Queries were generated automatically following each follow-up visit if the tests recommended by the American College of Chest Physicians (ACCP) were not performed at least once.Results: Of 791 patients enrolled in PAH-QuERI, 77% were women; 64% received a diagnosis . 3 months prior to enrollment; 9% were in New York Heart Association functional class I, 39% in II, 48% in III, and 5% in IV; and the median age was 55 years (interquartile range, 45-66 years). At enrollment, all ACCP-recommended tests had been performed in only 6% of patients. The automated program generated 1,530 reminders for 642 patients (81%) with validated enrollment data. The proportion of recommended tests performed was 91% for CBC count, 91% for liver function test, 50% for connective tissue disease screen, 29% for HIV screen, 88% for chest radiograph, 82% for ECG, 97% for two-dimensional echocardiogram, 83% for pulmonary function tests, 41% for oximetry, 57% for ventilation/perfusion scan, 79% for 6-min walk distance, and 90% for right-sided heart catheterization. Regarding management, 78% of patients were on disease specific therapy, and the use of these therapies tended to increase with the functional disability of the patient. One hundred seventy patients were taking calcium channel blockers, 91 specifically for PAH. Only six of 91 patients (7%) who received calcium channel blockers specifically for PAH had met the current guideline for acute vasoreactivity.Conclusions: When comparing reported clinical practice with ACCP guidelines-recommended strategies, a diagnostic care gap is apparent such that certain essential and recommended diagnostic tests may be underused despite the availability of detailed guidelines and reminders. [ABSTRACT FROM AUTHOR]

The article explores the long-term safety and tolerability of sildenafil treatment of pulmonary arterial hypertension (PAH). Results reveal that, in general, long-term treatment of PAH initiated as sildenafil monotherapy was well tolerated. After three years, 60% of patients who entered the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER)-1 trial improved or maintained their functional status, and 46% kept or improved 6-min walk distance (6MWD).

The article presents a study on the health benefits of sitaxsentan on the treatment of pulmonary arterial hypertension. It aimed to provide 1-year observational data with the two endothelin antagonists sitaxsentan and bosentan. There were patients treated with sitaxsentan at 100 mg. who had 96% overall survival and a 34% risk for a clinical worsening event for 1 year.

Study objectives: To assess the efficacy and safety of continuous subcutaneous infusion of treprostinil, a stable prostacyclin analogue, for treating pulmonary arterial hypertension (PAH) in patients with connective tissue disease (CTD). Design: Two multicenter, randomized, double-blind, placebo-controlled, prospective trials of treprostinil vs placebo in 470 patients with PAH. Patients: A subset of 90 patients with PAH and CTD, including systemic lupus erythematosus, diffuse scleroderma, limited scleroderma, and mixed CTD/overlap syndrome. Interventions: Patients received either treprostinil (initiated at 1.25 ng/kg/min, and titrated upward) or placebo via continuous subcutaneous infusion. The maximum dose of treprostinil allowed was 22.5 ng/kg/min. Measurements: Six-minute walk (6MW) distance and dyspnea-fatigue scores were determined at baseline, and at 6 weeks and 12 weeks. Hemodynamic measures were obtained at baseline and at 12 weeks. Results: At baseline, most patients had New York Heart Association class III symptoms. The mean baseline 6MW distance was 289 m (range, 60 to 448 m). The mean dose of treprostinil at week 12 was 8.4 ng/kg/min (range, 1.25 to 17.5 ng/kg/min). After 12 weeks, the change in cardiac index from baseline was + 0.2 ± 0.08 L/min/m² in the treprostinil group and -0.07 ± 0.07 L/min/m² in the placebo group (p = 0.007). The pulmonary vascular resistance index decreased by 4 ± 2 U &time;s m² in the treprostinil group and increased by 1 ± 1 U × m² in the placebo group (p = 0.006). The placebo-corrected median improvement from baseline in 6MW distance was 25 m in treprostinil-treated patients (p = 0.055); this improvement appeared to be dose related. Dyspnea fatigue scores also improved in the treprostinil group compared with the placebo group (p = 0.014). Adverse events included infusion site pain and typical side effects related to prostaglandins, and were tolerated by most patients. Conclusions: Continuous subcutaneous infusion of treprostinil in patients with PAH associated with CTD improved exercise capacity, symptoms of PAH, and hemodynamics. [ABSTRACT FROM AUTHOR]

Discusses American College of Chest Physicians evidence-based clinical practice guidelines to diagnose and treat pulmonary arterial hypertension in the United States. Pathologic features of idiopathic pulmonary arterial hypertension; Evian nomenclature and classification of pulmonary hypertension; Functional assessment.

Background: IV epoprostenol treatment of pulmonary arterial hypertension (PAH) has been believed to require an indefinite duration of therapy. Objective: To describe the successful discontinuation of long-term epoprostenol therapy in four patients. Design: Case reports. Setting: Outpatient clinic, tertiary-care hospital. Patients: Four patients with acutely nonvasoreactive, World Health Organization (WHO) functional class IV PAH received long-term epoprostenol therapy. All patients subsequently demonstrated normalization of pulmonary arterial pressures on epoprostenol treatment. These patients were selected for epoprostenol withdrawal. Intervention: Down-titration and discontinuation of epoprostenol. Results: All four patients were safely transitioned from epoprosteuol to oral therapies and have maintained WHO functional class I-II for a mean of 11 months (range, 8 to 16 months). The duration of epoprostenol therapy prior to discontinuation averaged 5.7 years (range, 2.4 to 13.5 years). Conclusion: Epoprostenol may sufficiently reverse the pathogenic process in select patients with PAH to allow a transition to less complex and less invasive treatment modalities. [ABSTRACT FROM AUTHOR]

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]

Study objective: TXA[sub 2] (thromboxane A[sub 2]) is a lipid mediator believed to be produced primarily by platelets in normal subjects, although macrophages are capable of synthesis. There is increased production of TXA[sub 2] in patients with primary pulmonary hypertension (PPH), which may reflect augmented production by macrophages. The objective of this study was to determine if macrophages are activated in PPH and whether they contribute to the increased production of TXA[sub 2]. Study type: Case control. Setting: University hospital. Methods: We measured the urinary metabolites of three mediators that predominantly derive from different cell types in vivo: (1) TX-M (platelets and macrophages), a TXA[sub 2] metabolite; (2) prostaglandin D[sub 2] (PGD[sub 2]) metabolite (PGD-M); and (3) N-methylhistamine (mast cells), a histamine metabolite, in 12 patients with PPH and 11 normal subjects. Results: The mean (± SEM) excretion of beth TX-M and PGD-M at baseline was increased in PPH patients, compared to normal subjects (460 ± 50 pg/mg creatinine vs 236 ± 16 pg/mg creatinine [p = 0.0006], and 1,390 ± 221 pg/mg creatinine vs 637 ± 65 pg/mg creatinine [p = 0.005], respectively). N-methylhistamine excretion was not increased compared to normal subjects. There was a poor correlation between excretion of TX-M and PGD-M (r = 0.36) and between excretion of PGD-M and methylhistamine (r = 0.09) in individual patients. Conclusion: In patients with PPH, increased levels of PGD-M, without increased synthesis of N-methylhistamine, suggest that macrophages are activated. The lack of correlation between urinary metabolite levels of TXA[sub 2] and PGD[sub 2] implies that macrophages do not contribute substantially to elevated TXA[sub 2] production in patients with PPH. They may, however, have a role in the pathogenesis and/or maintenance of PPH, which warrants further investigation. [ABSTRACT FROM AUTHOR]

Editorial. Comments on an article regarding epoprostenol therapy as a bridge to pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension (CTEPH), published in the February 2003 issue of 'Chest.' Management of CTEPH patients requiring a skilled multidisciplinary team consisting of physicians to participate in preoperative assessment and postoperative care.

Pulmonary hypertension has been associated with ingestion of the appetite suppressant aminorex. A similar compound, 4-methyl-aminorex (street names, "U-4-E-uh" [pronounced euphoria] or "ice"), is a "designer" drug with central stimulant activity. This drug was discovered on the property of three individuals with diagnoses of pulmonary hypertension. The association between "recreational" aminorex manufacture and ingestion and the development of pulmonary hypertension is described. [ABSTRACT FROM AUTHOR]

An abstract of the study "Effect of Macitentan on Morbidity and Mortality in Pulmonary Arterial Hypertension (PAH): Results From the SERAPHIN Trial," by Lewis Rubin, Richard Channick and colleagues is presented.

An abstract of the study "Riociguat for the Treatment of Pulmonary Arterial Hypertension: A Randomized, Double-Blind, Placebo-Controlled Study (PATENT-1)" by Hossein Ghofrani et al. is presented.

An abstract of the article "FREEDOM-M: Efficacy and Safety of Oral Treprostinil Diethanolamine as Monotherapy in Patients With Pulmonary Arterial Hypertension" by Lewis Rubin et al. is presented.

An abstract of the article "Effect of Earlier Initiation of Inhaled Treprostinil (iTRE) on Long Term Outcomes in Patients with Pulmonary Arterial Hypertension (PAH)" by Raymond Benza, and colleagues is presented.

Presents a letter to the editor about a study on the use of epoprostenol and nesiritide in treating pulmonary hypertension by D.C. Kurian and colleagues.