***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: Objective The Pulmonary Arterial hyperTENsion sGC-stimulator Trial-1 ( PATENT-1 ) was a r and omised , double-blind , placebo-controlled phase III trial evaluating riociguat in patients with pulmonary arterial hypertension ( PAH ) . PATENT-2 was an open-label long-term extension to PATENT-1 . Here , we explore the efficacy and safety of riociguat in the subgroup of patients with persistent/recurrent PAH after correction of congenital heart disease ( PAH-CHD ) from the PATENT studies . Methods In PATENT-1 , patients received riociguat ( maximum 2.5 or 1.5 mg three times daily ) or placebo for 12 weeks ; efficacy assessment s included change from baseline to study end in 6-min walking distance ( 6MWD ; primary ) , pulmonary vascular resistance ( PVR ) , N-terminal of the prohormone of brain natriuretic peptide ( NT-proBNP ) , WHO functional class ( WHO FC ) and time to clinical worsening . In PATENT-2 , eligible patients from PATENT-1 received long-term riociguat ( maximum 2.5 mg three times daily ) ; the primary assessment was safety and tolerability . All PAH-CHD patients had a corrected cardiac defect . Results In PATENT-1 , riociguat  increased mean±SD 6MWD from baseline to week 12 by 39±60 m in patients with PAH-CHD versus 0±42 m for placebo . Riociguat also improved several secondary variables versus placebo , including PVR ( −250±410 vs −66±632 dyn·s/cm5 ) , NT-proBNP ( −164±317 vs −46±697 pg/mL ) and WHO FC ( 21%/79%/0 % vs 8%/83%/8 % improved/stabilised/worsened ) . One patient experienced clinical worsening ( riociguat 1.5 mg group ) . Riociguat was well tolerated . In PATENT-2 , riociguat  showed sustained efficacy and tolerability in patients with PAH-CHD at 2 years . Conclusions Riociguat was well tolerated in patients with PAH-CHD and improved clinical outcomes including 6MWD , PVR , WHO FC and NT-proBNP . Trial registration number The clinical trials numbers are NCT00810693 for PATENT-1 and NCT00863681 for PATENT-2 Background : The beneficial effects of parasympathetic stimulation have been reported in left heart failure , but whether it would be beneficial for pulmonary arterial hypertension ( PAH ) remains to be explored . Here , we investigated the relationship between parasympathetic activity and right ventricular ( RV ) function in patients with PAH , and the potential therapeutic effects of pyridostigmine ( PYR ) , an oral drug stimulating the parasympathetic activity through acetylcholinesterase inhibition , in experimental pulmonary hypertension ( PH ) . Methods : Heart rate recovery after a maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity . RV ejection fraction was assessed in 112 patients with PAH . Expression of nicotinic ( & agr;-7 nicotinic acetylcholine receptor ) and muscarinic ( muscarinic acetylcholine type 2 receptor ) receptors , and acetylcholinesterase activity were evaluated in RV ( n=11 ) and lungs ( n=7 ) from patients with PAH undergoing heart/lung transplantation and compared with tissue obtained from controls . In addition , we investigated the effects of PYR ( 40 mg/kg per day ) in experimental PH . PH was induced in male rats by SU5416 ( 25 mg/kg subcutaneously ) injection followed by 4 weeks of hypoxia . In a subgroup , sympathetic/parasympathetic modulation was assessed by power spectral analysis . At week 6 , PH status was confirmed by echocardiography , and rats were r and omly assigned to vehicle or treatment ( both n=12 ) . At the end of the study , echocardiography was repeated , with additional RV pressure-volume measurements , along with lung , RV histological , and protein analyses . Results : Patients with PAH with lower RV ejection fraction ( < 41 % ) had a significantly reduced heart rate recovery in comparison with patients with higher RV ejection fraction . In PAH RV sample s , & agr;-7 nicotinic acetylcholine receptor was increased and acetylcholinesterase activity was reduced versus controls . No difference in muscarinic acetylcholine type 2 receptor expression was observed . Chronic PYR treatment in PH rats normalized the cardiovascular autonomic function , demonstrated by an increase in parasympathetic activity and baroreflex sensitivity . PYR improved survival , increased RV contractility , and reduced RV stiffness , RV hypertrophy , RV fibrosis , RV inflammation , and RV & agr;-7 nicotinic acetylcholine receptor and muscarinic acetylcholine type 2 receptor expression , as well . Furthermore , PYR reduced pulmonary vascular resistance , RV afterload , and pulmonary vascular remodeling , which was associated with reduced local and systemic inflammation . Conclusions : RV dysfunction is associated with reduced systemic parasympathetic activity in patients with PAH , with an inadequate adaptive response of the cholinergic system in the RV . Enhancing parasympathetic activity by PYR improved survival , RV function , and pulmonary vascular remodeling in experimental PH BACKGROUND Detailed hemodynamic data from the phase III PATENT-1 study of riociguat in patients with pulmonary arterial hypertension ( PAH ) were investigated . METHODS Patients with PAH who were treatment naïve or pre-treated with endothelin receptor antagonists or non-intravenous prostanoids  were r and omly assigned to riociguat up to 2.5 mg 3 times a day or placebo . Hemodynamic parameters were assessed at baseline and week 12 . RESULTS Riociguat significantly decreased pulmonary vascular resistance in treatment-naïve ( n = 221 ; least squares [ LS ] mean difference -266 dyne∙sec∙cm-5 [ 95 % confidence interval ( CI ) -357 to -175 ; p < 0.0001 ] ) and pre-treated ( n = 222 ; LS mean difference -186 dyne∙sec ∙cm-5 [ 95 % CI -252 to -120 ; p < 0.0001 ] ) patients and significantly increased cardiac index ( LS mean difference + 0.7 [ 95 % CI 0.5 to 0.8 ] and + 0.5 [ 95 % CI 0.3 to 0.7 ] , respectively [ both p < 0.0001 ] ) . Mean pulmonary artery pressure ( p = 0.0056 and p = 0.0019 for treatment-naïve and pre-treated patients , respectively ) , mean arterial pressure ( both p < 0.0001 ) , and systemic vascular resistance ( both p < 0.0001 ) were significantly reduced , and there was an increase in mixed venous oxygen saturation ( p < 0.0001 and p = 0.0004 , respectively ) . Results were similar in patients pre-treated with endothelin receptor antagonists and patients pre-treated with non-intravenous prostanoids . Improvements in 6-minute walking distance correlated very weakly with improvements in pulmonary vascular resistance ( r = -0.21 [ 95 % CI -0.30 to -0.11 ; p < 0.0001 ] ) and cardiac index ( r = 0.16 [ 95 % CI 0.06 to 0.25 ; p < 0.0016 ] ) . CONCLUSIONS Riociguat significantly improved hemodynamic parameters in pre-treated and treatment-naïve patients with PAH Background — Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality ; however , no treatment is approved for this indication . We hypothesized that riociguat , a novel soluble guanylate cyclase stimulator , would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction . Methods and Results — Overall , 201 patients with heart failure result ing from pulmonary hypertension caused by systolic left ventricular dysfunction were r and omized to double-blind treatment with oral placebo or riociguat ( 0.5 , 1 , or 2 mg 3 times daily ) for 16 weeks in 4 parallel arms . The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure . Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group ( −6.1±1.3 mm Hg ; P<0.0001 versus baseline ) was not significantly different from placebo ( P=0.10 ) , cardiac index ( 0.4 L·min−1·m−2 ; 95 % confidence interval , 0.2–0.5 ; P=0.0001 ) and stroke volume index ( 5.2 mL·m−2 ; 95 % confidence interval , 2.0–8.4 ; P=0.0018 ) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo . Both pulmonary ( −46.6 dynes·s−1·cm−5 ; 95 % confidence interval , –89.4 to –3.8 ; P=0.03 ) and systemic vascular resistance ( −239.3 dynes·s−1·cm−5 ; 95 % confidence interval , –363.4 to –115.3 ; P=0.0002 ) were significantly reduced with riociguat 2 mg . Riociguat  reduced the Minnesota Living With Heart Failure score ( P=0.0002 ) . Discontinuation of treatment was similar between treatment groups . Conclusions — Although the primary end point of the study was not met , riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01065454 We assessed the therapeutic potential of riociguat , a novel soluble guanylate cyclase stimulator , in adults with chronic thromboembolic pulmonary hypertension ( CTEPH ; n = 42 ) or pulmonary arterial hypertension ( PAH ; n = 33 ) in World Health Organization ( WHO ) functional class II/III . In this 12-week , multicentre , open-label , uncontrolled phase II study , patients received oral riociguat 1.0–2.5 mg t.i.d . titrated according to systemic systolic blood pressure ( SBP ) . Primary end-points were safety and tolerability ; pharmacodynamic changes were secondary end-points . Riociguat was generally well tolerated . Asymptomatic hypotension ( SBP < 90 mmHg ) occurred in 11 patients , but blood pressure normalised without dose alteration in nine and after dose reduction in two . Median 6-min walking distance increased in patients with CTEPH ( 55.0 m from baseline ( 390 m ) ; p<0.0001 ) and PAH ( 57.0 m from baseline ( 337 m ) ; p<0.0001 ) ; patients in functional class II or III and bosentan pre-treated patients showed similar improvements . Pulmonary vascular resistance was significantly reduced by 215 dyn·s·cm−5 from baseline ( 709 dyn·s·cm−5 ; p<0.0001 ) . 42 ( 56 % ) patients were considered to have experienced drug-related adverse events ( AEs ; 96 % mild or moderate ) . Dyspepsia , headache and hypotension were the most frequent AEs . Study discontinuation because of AEs was 4 % . These preliminary data show that riociguat has a favourable safety profile and improves exercise capacity , symptoms and pulmonary haemodynamics in CTEPH and PAH . R and omised controlled trials are underway Background Following positive results from the Phase III CHEST-1 study in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension ( CTEPH ) , the Phase IIIb CTEPH early access study ( EAS ) was design ed to assess the safety and tolerability of riociguat in real-world clinical practice , as well as to provide patients with early access to riociguat before launch . Riociguat is approved for the treatment of inoperable and persistent/recurrent CTEPH . Methods We performed an open-label , uncontrolled , single-arm , early access study in which 300 adult patients with inoperable or persistent/recurrent CTEPH received riociguat adjusted from 1 mg three times daily ( tid ) to a maximum of 2.5 mg tid . Patients switching from unsatisfactory prior pulmonary arterial hypertension (PAH)-targeted therapy ( n = 84 ) underwent a washout period of at least 3 days before initiating riociguat . The primary aim was to assess the safety and tolerability of riociguat , with World Health Organization functional class and 6-min walking distance ( 6MWD ) as explor 
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Es gab keine Zunahme unerwünschter Ereignisse unter Riociguattherapie i m Vergleich zur Kontrollintervention ( RR = 1,04 ; 95%-KI = 0,98–1,09 ; p = 0,19).SchlussfolgerungDie Beh and lung einer pulmonalarteriellen Hypertonie  mit Riociguat führte zu einer signifikanten Steigerung beim 6‑MWD , EQ-5D-Score und Herzindex sowie zu einer Abnahme des LPH-Scores und des PVR