***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospect i ve , r and omized trial to improve survival . METHODS We conducted a 12-week prospect i ve , r and omized , multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol ( formerly called prostacyclin ) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension ( New York Heart Association functional class III or IV ) . RESULTS Exercise capacity was improved in the 41 patients treated with epoprostenol ( median distance walked in six minutes , 362 m at 12 weeks vs. 315 m at base line ) , but it decreased in the 40 patients treated with conventional therapy alone ( 204 m at 12 weeks vs. 270 m at base line ; P < 0.002 for the comparison of the treatment groups ) . Indexes of the quality of life were improved only in the epoprostenol group ( P < 0.01 ) . Hemodynamics improved at 12 weeks in the epoprostenol-treated patients . The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and + 3 percent , respectively ( difference in mean change , -6.7 mm Hg ; 95 percent confidence interval , -10.7 to -2.6 mm Hg ; P < 0.002 ) , and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and + 9 percent , respectively ( difference in mean change , -4.9 mm Hg/liter/min ; 95 percent confidence interval , -7.6 to -2.3 mm Hg/liter/min ; P < 0.001 ) . Eight patients died during the study , all of whom had been r and omly assigned to conventional therapy ( P = 0.003 ) . Serious complications included four episodes of catheter-related sepsis and one thrombotic event . CONCLUSIONS As compared with conventional therapy , the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement , as well as improved survival in patients with severe primary pulmonary hypertension Background — Eisenmenger syndrome is characterized by the development of pulmonary arterial hypertension with consequent intracardiac right-to-left shunt and hypoxemia in patients with preexisting congenital heart disease . Because Eisenmenger syndrome is associated with increased endothelin expression , patients may benefit from endothelin receptor antagonism . Theoretically , interventions that have some effect on the systemic vascular bed could worsen the shunt and increase hypoxemia . Methods and Results — The Bosentan R and omized Trial of Endothelin Antagonist Therapy-5 ( BREATHE-5 ) was a 16-week , multicenter , r and omized , double-blind , placebo-controlled study evaluating the effect of bosentan , a dual endothelin receptor antagonist , on systemic pulse oximetry ( primary safety end point ) and pulmonary vascular resistance ( primary efficacy end point ) in patients with World Health Organization functional class III Eisenmenger syndrome . Hemodynamics were assessed by right- and left-heart catheterization . Secondary end points included exercise capacity assessed by 6-minute walk distance , additional hemodynamic parameters , functional capacity , and safety . Fifty-four patients were r and omized 2:1 to bosentan  ( n=37 ) or placebo ( n=17 ) for 16 weeks . The placebo-corrected effect on systemic pulse oximetry was 1.0 % ( 95 % confidence interval , −0.7 to 2.8 ) , demonstrating that bosentan did not worsen oxygen saturation . Compared with placebo , bosentan reduced pulmonary vascular resistance index ( −472.0 dyne · s · cm−5 ; P=0.0383 ) . The mean pulmonary arterial pressure decreased ( −5.5 mm Hg ; P=0.0363 ) , and the exercise capacity increased ( 53.1 m ; P=0.0079 ) . Four patients discontinued as a result of adverse events , 2 ( 5 % ) in the bosentan group and 2 ( 12 % ) in the placebo group . Conclusions — In this first placebo-controlled trial in patients with Eisenmenger syndrome  , bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation Background In a previous study , 6-minute walk distance ( 6MWD ) improvement with sildenafil was not dose dependent at the 3 doses tested ( 20 , 40 , and 80 mg 3 times daily [ TID ] ) . This study assessed whether lower doses were less effective than the approved 20-mg TID dosage . Methods Treatment-naive patients with pulmonary arterial hypertension were r and omized to 12 weeks of double-blind sildenafil 1 , 5 , or 20 mg TID ; 12 weeks of open-label sildenafil 20 mg TID followed . Changes from baseline in 6-minute walk distance ( 6MWD ) for sildenafil 1 or 5 mg versus 20 mg TID were compared using a Williams test . Hemodynamics , functional class , and biomarkers were assessed . Results The study was prematurely terminated for non-safety reasons , with 129 of 219 planned patients treated . At week 12 , 6MWD change from baseline was significantly greater for sildenafil 20 versus 1 mg ( P = 0.011 ) but not versus 5 mg . At week 24 , 6MWD increases from baseline were larger in those initially r and omized to 20 versus 5 or 1 mg ( 74 vs 50 and 47 m , respectively ) . At week 12 , changes in hemodynamic parameters were generally small and variable between treatment groups ; odds ratios for improvement in functional class were not statistically significantly different . Improvements in B-type natriuretic peptide levels were significantly greater with sildenafil 20 versus 1 but not 5 mg . Conclusions Sildenafil 20 mg TID appeared to be more effective than 1 mg TID for improving 6MWD ;  sildenafil 5 mg TID appeared to have similar clinical and hemodynamic effects as 20 mg TID.Trial registration Clinical Trials.gov NCT00430716 ( Registration date : January 31 , 2007 ) BACKGROUND Pulmonary hypertension ( PH ) is a well-known independent prognostic factor in chronic obstructive pulmonary disease ( COPD ) and a sufficient criterion for lung transplant c and idacy . Limited data are currently available on the hemodynamic and clinical effect of phosphodiesterase 5 inhibitors in patients with severe PH associated with COPD . This study assessed the effect of sildenafil on pulmonary hemodynamics and gas exchange in severe PH associated with COPD . METHODS After screening , this multicenter , r and omized , placebo-controlled double-blind trial r and omized patients to receive 20 mg sildenafil or placebo 3 times a day ( ratio 2:1 ) for 16 weeks . The primary end point was the reduction in pulmonary vascular resistance . Secondary end points included BODE ( body mass index , airflow obstruction , dyspnea , and exercise capacity ) index , 6-minute walk test , and quality of life question naire . Changes in the partial pressure of arterial oxygen were evaluated as a safety parameter . RESULTS The final population included 28 patients , 18 in the sildenafil group and 10 in the placebo group . At 16 week , patients treated with sildenafil had a decrease in pulmonary vascular resistance ( mean difference with placebo -1.4 WU ; 95 % confidence interval , ≤ -0.05 ; p = 0.04 ) . Sildenafil also improved the BODE index , diffusion capacity of the lung for carbon monoxide percentage , and quality of life . Change from baseline in the partial pressure of arterial oxygen was not significantly different between the sildenafil and placebo groups . CONCLUSIONS This pilot study found that treatment with sildenafil  reduced pulmonary vascular resistance and improved the BODE index and quality of life , without a significant effect on gas exchange OBJECTIVES The purpose of this study was to assess the safety and efficacy of the oral prostacyclin analogue beraprost sodium during a 12-month double-blind , r and omized , placebo-controlled trial in patients with pulmonary arterial hypertension ( PAH ) . BACKGROUND Pulmonary arterial hypertension is a progressive disease that ultimately causes right heart failure and death . Despite the risks from its delivery system , continuous intravenous epoprostenol remains the most efficacious treatment currently available . METHODS A total of 116 patients with World Health Organization ( WHO ) functional class II or III primary pulmonary hypertension or PAH related to either collagen vascular diseases or congenital systemic to pulmonary shunts were enrolled . Patients were r and omized to receive the maximal tolerated dose of beraprost sodium ( median dose 120 microg four times a day ) or placebo for 12 months . The primary end point was disease progression ; i.e. , death , transplantation , epoprostenol rescue , or > 25 % decrease in peak oxygen consumption ( VO(2 ) ) . Secondary end points included exercise capacity assessed by 6-min walk test and peak VO(2 ) , Borg dyspnea score , hemodynamics , symptoms of PAH , and quality of life . RESULTS Patients treated with beraprost exhibited less evidence of disease progression at six months ( p = 0.002 ) , but this effect was not evident at either shorter or longer follow-up intervals . Similarly , beraprost-treated patients had improved 6-min walk distance at 3 months by 22 m from baseline and at 6 months by 31 m ( p = 0.010 and 0.016 , respectively ) compared with placebo , but not at either 9 or 12 months . Drug-related adverse events were common and were related to the disease and /or expected prostacyclin adverse events . CONCLUSIONS These data suggest that beneficial effects may occur during early phases of treatment with beraprost in WHO functional class II or III patients but that this effect attenuates with time BACKGROUND In a phase 2 trial , selexipag , an oral selective IP prostacyclin-receptor agonist , was shown to be beneficial in the treatment of pulmonary arterial hypertension . METHODS In this event-driven , phase 3 , r and omized , double-blind , placebo-controlled trial , we r and omly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses ( maximum dose , 1600 μg twice daily ) . Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist , a phosphodiesterase type 5 inhibitor , or both . The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period ( defined for each patient as 7 days after the date of the last intake of selexipag or placebo ) . RESULTS A primary end-point event occurred in 397 patients --41.6 % of those in the placebo group and 27.0 % of those in the selexipag group ( hazard ratio in the selexipag group as compared with the placebo group , 0.60 ; 99 % confidence interval , 0.46 to 0.78 ; P<0.001 ) . Disease progression and hospitalization accounted for 81.9 % of the events . The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline ( including those who were receiving a combination of two therapies ) . By the end of the study , 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause . Overall , 7.1 % of patients in the placebo group and 14.3 % of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events . The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin , including headache , diarrhea , nausea , and jaw pain . CONCLUSIONS Among patients with pulmonary arterial hypertension , the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo . There was no significant difference in mortality between the two study groups . ( Funded by Actelion Pharmaceuticals ; GRIPHON Clinical Trials.gov number , NCT01106014 . ) BACKGROUND Sildenafil inhibits phosphodiesterase type 5 , an enzyme that metabolizes cyclic guanosine monophosphate , thereby enhancing the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells , including those in the lung . METHODS In this double-blind , placebo-controlled study , we r and omly assigned 278 patients with symptomatic pulmonary arterial hypertension ( either idiopathic or associated with connective-tissue disease or with repaired congenital systemic-to-pulmonary shunts ) to placebo or sildenafil  
    Output:
    
In conclusion , no significant increase in RTI had been found in PAH-specific drug therapy when compared with placebo .