Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH, but complicated ...administration requirements can limit the use of these therapies in patients with less severe disease. This study was designed to evaluate the safety and efficacy of the oral prostacyclin analogue treprostinil diolamine as initial treatment for de novo PAH.
Three hundred forty-nine patients (intent-to-treat population) not receiving endothelin receptor antagonist or phosphodiesterase type-5 inhibitor background therapy were randomized (treprostinil, n=233; placebo, n=116). The primary analysis population (modified intent-to-treat) included 228 patients (treprostinil, n=151; placebo, n=77) with access to 0.25-mg treprostinil tablets at randomization. The primary end point was change from baseline in 6-minute walk distance at week 12. Secondary end points included Borg dyspnea index, clinical worsening, and symptoms of PAH. The week 12 treatment effect for 6-minute walk distance (modified intent-to-treat population) was 23.0 m (P=0.0125). For the intent-to-treat population, 6-minute walk distance improvements were observed at peak (26.0 m; P=0.0001) and trough (17.0 m; P=0.0025) plasma study drug concentrations. Other than an improvement in the combined 6-minute walk distance/Borg dyspnea score, there were no significant changes in secondary end points. Oral treprostinil therapy was generally well tolerated; the most common adverse events (intent-to-treat) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%).
Oral treprostinil improves exercise capacity in PAH patients not receiving other treatment. Oral treprostinil could provide a convenient, first-line prostacyclin treatment option for PAH patients not requiring more intensive therapy.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00325403.
Registries of patients with pulmonary arterial hypertension (PAH) have been instrumental in characterizing the presentation and natural history of the disease and provide a basis for prognostication. ...Since the initial accumulation of data conducted in the 1980s, subsequent registry databases have yielded information about the demographic factors, treatment, and survival of patients and have permitted comparisons between populations in different eras and environments. Inclusion of patients with all subtypes of PAH has also allowed comparisons of these subpopulations. We describe herein the basic methodology by which PAH registries have been conducted, review key insights provided by registries, summarize issues related to interpretation and comparison of the results, and discuss the utility of data to predict survival outcomes. Potential sources of bias, particularly related to the inclusion of incident and/or prevalent patients and missing data, are addressed. A fundamental observation of current registries is that survival in the modern treatment era has improved compared with that observed previously and that outcomes among PAH subpopulations vary substantially. Continuing systematic clinical surveillance of PAH will be important as treatment evolves and as understanding of mechanisms advance. Considerations for future directions of registry studies include enrollment of a broader population of patients with pulmonary hypertension of all clinical types and severity and continued globalization and collaboration of registry databases.
Portal hypertension may have major consequences on the pulmonary vasculature due to the complex pathophysiological interactions between the liver and lungs. Portopulmonary hypertension (PoPH), a ...subset of group 1 pulmonary hypertension (PH), is a serious pulmonary vascular disease secondary to portal hypertension, and is the fourth most common subtype of pulmonary arterial hypertension. It is most commonly observed in cirrhotic patients; however, patients with noncirrhotic portal hypertension can also develop it. On suspicion of PoPH, the initial evaluation is by a transthoracic echocardiogram in which, if elevated pulmonary pressures are shown, patients should undergo right heart catheterization to confirm the diagnosis. The prognosis is extremely poor in untreated patients; therefore, management includes pulmonary arterial hypertension therapies with the aim of improving pulmonary hemodynamics and moving patients to orthotopic liver transplantation (OLT). In this article, we review in detail the epidemiology, pathophysiology, process for diagnosis, and most current treatments including OLT and prognosis in patients with PoPH. In addition, we present a diagnostic algorithm that includes the current criteria to properly select patients with PoPH who are candidates for OLT.
Eisenmenger syndrome describes congenital heart disease-associated severe pulmonary hypertension accompanied by right-to-left shunting. The multicenter, double-blind, randomized, placebo-controlled, ...16-week, phase III MAESTRO study (Macitentan in Eisenmenger Syndrome to Restore Exercise Capacity) evaluated the efficacy and safety of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome.
Patients with Eisenmenger syndrome aged ≥12 years and in World Health Organization functional class II-III were randomized 1:1 to placebo or macitentan 10 mg once daily for 16 weeks. Patients with complex cardiac defects, Down syndrome and background PAH therapy were eligible. The primary end point was change from baseline to week 16 in 6-minute walk distance. Secondary end points included change from baseline to week 16 in World Health Organization functional class. Exploratory end points included NT-proBNP (N-terminal pro-B-type natriuretic peptide) at end of treatment expressed as a percentage of baseline. In a hemodynamic substudy, exploratory end points included pulmonary vascular resistance index (PVRi) at week 16 as a percentage of baseline.
Two hundred twenty six patients (macitentan n=114; placebo n=112) were randomized. At baseline, 60% of patients were in World Health Organization functional class II and 27% were receiving phosphodiesterase type-5 inhibitors. At week 16, the mean change from baseline in 6-minute walk distance was 18.3 m and 19.7 m in the macitentan and placebo groups (least-squares mean difference, -4.7 m; 95% confidence limit (CL), -22.8, 13.5; P=0.612). World Health Organization functional class improved from baseline to week 16 in 8.8% and 14.3% of patients in the macitentan and placebo groups (odds ratio, 0.53; 95% CL, 0.23, 1.24). NT-proBNP levels decreased with macitentan versus placebo (ratio of geometric means, 0.80; 95% CL, 0.68, 0.94). In the hemodynamic substudy (n=39 patients), macitentan decreased PVRi compared with placebo (ratio of geometric means, 0.87; 95% CL, 0.73, 1.03). The most common adverse events with macitentan versus placebo were headache (11.4 versus 4.5%) and upper respiratory tract infection (9.6 versus 6.3%); a hemoglobin decrease from baseline of ≥2 g/dL occurred in 36.0% versus 8.9% of patients. Five patients (3 macitentan; 2 placebo) prematurely discontinued treatment and 1 patient died (macitentan group).
Macitentan did not show superiority over placebo on the primary end point of change from baseline to week 16 in exercise capacity in patients with Eisenmenger syndrome.
URL: https://www.clinicaltrials.gov . Unique identifier: NCT01743001.
Safe, effective therapy is needed for pediatric pulmonary arterial hypertension.
Children (n=235; weight ≥8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times ...daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PV(O(2))) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated mean±SE percent change in PV(O(2)) for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, -0.2% to 15.6%; P=0.056). PV(O(2)), functional class, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses.
Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV(O(2)) for the 3 sildenafil doses combined was only marginally significant; however, PV(O(2)), functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight.
http://www.clinicaltrials.gov. Unique identifier: NCT00159913.
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