1,720,991 research outputs found
Clinical worsening in trials of pulmonary arterial hypertension: results and implications.
No full textPurpose of review: Time to clinical worsening (TTCW) can be used to assess disease progression associated with pulmonary arterial hypertension (PAH). As a consequence, it is highly relevant to patients, clinicians, and regulatory agencies. The majority of clinical trials of PAH-specific drug therapies have included TTCW as a secondary endpoint; this article summarizes the results of randomized controlled clinical trials in PAH, specifically with respect to the clinical worsening endpoint. Recent findings: Some trials have demonstrated a treatment-related delay in TTCW and others have not. Recent results suggest that TTCW shows particular promise in detecting disease progression, even in mildly affected patients. Definitions of clinical worsening have also varied across clinical trials; although all have agreed on the inclusion of all-cause death and hospitalization due to PAH in the definition, the inclusion of additional parameters defining 'disease progression' has differed. Summary: There is a need for a clear and uniform definition of TTCW that can be tailored to the study population being investigated; the endpoint may require adaptation for patients in different functional classes and with different causes. Consistency of event reporting within a trial may be improved by employing a committee to adjudicate events. Trials are beginning to include TTCW as a primary endpoint; the results will be important in establishing the validity of whether this parameter should become the endpoint of choice in PAH trials in the futur
Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease.
No full textSTUDY 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/m(2) in the treprostinil group and - 0.07 +/- 0.07 L/min/m(2) in the placebo group (p = 0.007). The pulmonary vascular resistance index decreased by 4 +/- 2 U x m(2) in the treprostinil group and increased by 1 +/- 1 U x m(2) 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
Therapy with subcutaneous treprostinil improves survival in patients with pulmonary arterial hypertension: four-year follow-up
No full textLong-term outcome in pulmonary arterial hypertension patients treated with treprostinil.
No full textPulmonary arterial hypertension (PAH) is fatal if untreated. Intravenous
epoprostenol improves exercise capacity and hemodynamics in PAH, and increases
survival in idiopathic PAH (IPAH). To evaluate the effects of subcutaneous (SC)
treprostinil, a longer acting prostacyclin analogue, followed by the addition of
other PAH therapies if needed, we followed 860 PAH patients treated with SC
treprostinil for up to 4 years.Survival is reported as Kaplan-Meier estimates;
for 332 IPAH patients with baseline hemodynamics, observed survival is also
compared with predicted survival, using the NIH formula.Of the total 860
patients, 199 (23%) discontinued due to AEs, 136 (16%) died, 117 (14%)
discontinued due to deterioration, 29 (3%) withdrew consent and 11 (1%)
underwent transplantation. 97 patients (11%) switched from SC treprostinil to an
alternative prostacyclin analogue; bosentan was added in 105 patients (12%) and
sildenafil in 25 patients (3%).Survival was 87%-68% over 1-4 years for all 860
patients and 88%-70% over 1-4 years with SC treprostinil monotherapy. For the
IPAH subset with baseline hemodynamics (n=332), 91%-72% over 1-4 years; in
contrast, predicted survival was 69%-38% over 1-4 years. The safety profile for
long-term SC treprostinil was consistent with previous short-term trials with no
unexpected AEs
Sitaxsentan improves time to clinical worsening in patients with pulmonary arterial hypertension
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Survival with first-line bosentan in patients with primary pulmonary hypertension.
No full textThe 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
Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2.
No full textThe 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 hypertensio
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.
No full textBACKGROUND: 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
Sitaxsentan, a selective endothelin-A receptor antagonist, improves exercise capacity in pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD)
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