***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 — Safe , effective therapy is needed for pediatric pulmonary arterial hypertension . Methods and Results — Children ( n=235 ; weight ≥8 kg ) were r and omized 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[Combining Dot Above]O2 ) 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[Combining Dot Above]O2 for the 3 doses combined versus placebo was 7.7±4.0 % ( 95 % confidence interval , −0.2 % to 15.6 % ; P=0.056 ) . PV[Combining Dot Above]O2 , 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 r and omized to low- , medium- , or high-dose sildenafil . In STARTS-2 ( ongoing ) , increased mortality was observed with higher doses . Conclusions — Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension  . Percent change in PV[Combining Dot Above]O2 for the 3 sildenafil doses combined was only marginally significant ; however , PV[Combining Dot Above]O2 , 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 . Clinical Trial Registration — http://www . clinical trials.gov . Unique identifier : NCT00159913 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  ( 20 , 40 , or 80 mg ) orally three times daily for 12 weeks . The primary end point was the change from baseline to week 12 in the distance walked in six minutes . The change in mean pulmonary-artery pressure and World Health Organization ( WHO ) functional class and the incidence of clinical worsening were also assessed , but the study was not powered to assess mortality . Patients completing the 12-week r and omized study could enter a long-term extension study . RESULTS The distance walked in six minutes increased from baseline in all sildenafil groups ; the mean placebo-corrected treatment effects were 45 m ( + 13.0 percent ) , 46 m ( + 13.3 percent ) , and 50 m ( + 14.7 percent ) for 20 , 40 , and 80 mg of sildenafil , respectively ( P<0.001 for all comparisons ) . All sildenafil doses reduced the mean pulmonary-artery pressure ( P=0.04 , P=0.01 , and P<0.001 , respectively ) , improved the WHO functional class ( P=0.003 , P<0.001 , and P<0.001 , respectively ) , and were associated with side effects such as flushing , dyspepsia , and diarrhea . The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo . Among the 222 patients completing one year of treatment with sildenafil monotherapy , the improvement from baseline at one year in the distance walked in six minutes was 51 m. CONCLUSIONS Sildenafil improves exercise capacity , WHO functional class , and hemodynamics in patients with symptomatic pulmonary arterial hypertension Background — Treatment options for pulmonary arterial hypertension target the prostacyclin , endothelin , or nitric oxide pathways . Tadalafil , a phosphodiesterase type-5 inhibitor , increases cGMP , the final mediator in the nitric oxide pathway . Methods and Results — In this 16-week , double-blind , placebo-controlled study , 405 patients with pulmonary arterial hypertension ( idiopathic or associated ) , either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan  , were r and omized to placebo or tadalafil 2.5 , 10 , 20 , or 40 mg orally once daily . The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes . Changes in World Health Organization functional class , clinical worsening , and health-related quality of life were also assessed . Patients completing the 16-week study could enter a long-term extension study . Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner ; only the 40-mg dose met the prespecified level of statistical significance ( P<0.01 ) . Overall , the mean placebo-corrected treatment effect was 33 m ( 95 % confidence interval , 15 to 50 m ) . In the bosentan-naive group , the treatment effect was 44 m ( 95 % confidence interval , 20 to 69 m ) compared with 23 m ( 95 % confidence interval , −2 to 48 m ) in patients on background bosentan therapy . Tadalafil 40 mg improved the time to clinical worsening ( P=0.041 ) , incidence of clinical worsening ( 68 % relative risk reduction ; P=0.038 ) , and health-related quality of life . The changes in World Health Organization functional class were not statistically significant . The most common treatment-related adverse events reported with tadalafil  were headache , myalgia , and flushing . Conclusions — In patients with pulmonary arterial hypertension , tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening STUDY OBJECTIVE To determine the efficacy of continuous intravenous infusion of prostacyclin ( epoprostenol ) in primary pulmonary hypertension . DESIGN R and omized trial with 8-week treatment periods and nonr and omized treatment for up to 18 months . SETTING Four referral centers . PATIENTS Sequential sample of 24 patients with primary pulmonary hypertension . Nineteen patients completed the study . Four patients died and one left the study because of adverse effects ( pulmonary edema ) . INTERVENTIONS Continuous intravenous prostacyclin administered by portable infusion pump at doses determined by acute responses during baseline catheterization in ten patients . Nine patients were treated with anticoagulants , oral vasodilators , and diuretics . MEASUREMENTS AND MAIN RESULTS Starting with a baseline value for total pulmonary resistance of 21.6 units , there was a decrease of 7.9 units ( 95 % CI , -13.1 to -2.2 ; P = 0.022 ) in the prostacyclin-treated group after 8 weeks ; there was virtually no change in the conventional therapy group ( from 20.6 to 20.4 units , not significant ) . Six of ten prostacyclin-treated patients who completed the 8-week study period had reductions in mean pulmonary artery pressure of greater than 10 mm Hg , whereas only one of nine in the conventional treatment group had a similar response ( P = 0.057 ) . Nine patients receiving prostacyclin for up to 18 months have persistent hemodynamic effects , although dose requirements have increased with time . Complications have been attributable to the drug delivery system . CONCLUSIONS Prostacyclin produces substantial and sustained hemodynamic and symptomatic responses in severe primary pulmonary hypertension and may be useful in the management of some patients with this disease The efficacy and safety of combining bosentan , an orally active dual endothelin receptor antagonist and epoprostenol , a continuously infused prostagl and in , in the treatment of pulmonary arterial hypertension ( PAH ) was investigated . In this double-blind , placebo-controlled prospect i ve study , 33 patients with PAH started epoprostenol treatment ( 2 ng·kg−1min−1 starting dose , up to 14±2 ng·kg 
    Output:
    
All drug classes demonstrated increases in 6MWD when compared with placebo , and combination therapy showed improved 6MWD compared with monotherapy .
Although no studies were powered to detect a mortality reduction , monotherapy was associated with improved 6MWD and reduced hospitalization rates .
Our findings also suggest an improvement in 6MWD when a second drug is added to monotherapy