INTRODUCTION: Ralinepag is a potent, titratable, orally administered prostacyclin (IP) receptor agonist to treat pulmonary arterial hypertension. A phase II randomized, double-blind, parallel-group, placebo-controlled, 22-week study of immediate-release (IR) ralinepag safety and efficacy met its primary endpoint, significantly reducing pulmonary vascular resistance (PVR) compared with placebo. This phase II open-label extension (OLE) study assessed long-term safety and tolerability of ralinepag. METHODS: Participants were eligible for the OLE if they completed the parent study or experienced a clinical worsening event while receiving placebo. Those previously receiving IR ralinepag remained on their current dose, and participants formerly administered placebo were titrated to the highest tolerated dose. Participants were transitioned to an extended-release ralinepag formulation toward the end of the OLE. The primary objective evaluated long-term safety and tolerability; secondary endpoints included changes in 6-min walk distance (6MWD), World Health Organization/New York Heart Association functional class, clinical worsening, and hemodynamic measures. RESULTS: In total, 45/61 participants enrolled in the OLE study, 30 from the IR ralinepag group and 15 from the placebo group. The most common adverse events (AEs) were known prostacyclin-related effects (e.g., headache, 64.4%; diarrhea, 37.8%; jaw pain, 33.3%). There was a notable decline in AEs after reaching and maintaining a stable dose. At month 24 after entering the OLE, 6MWD significantly increased by a mean of 36.3 m (P = 0.004) from OLE baseline, and most participants remained stable in their functional class (84.8%). Post-baseline PVR in 1 or 2 years decreased by a median of 52.2 dyn.s/cm5 and mean pulmonary arterial pressure decreased by a median of 2.0 mmHg (P = 0.05). CONCLUSION: Ralinepag produced sustained, durable improvements in 6MWD along with durable reductions in PVR and a manageable AE profile. Most participants continuing treatment with ralinepag maintained functional measures throughout the OLE and those switching from placebo to ralinepag often experienced functional improvements.

Pulmonary arterial hypertension is a rare disease caused by elevated pressure in the blood vessels connecting the heart to the lungs. A previous phase 2 study found that ralinepag significanlty reduced pulmonary vascular resistance (the force or resistance that blood encounters as it flows through the blood vessels in the lungs) compared with placebo. This clinical study of 45 patients investigated whether ralinepag was safe and effective for long-term use to treat people with pulmonary arterial hypertension. All participants received ralinepag twice daily until a new once daily pill was available later in the study. The primary endpoints were long-term safety and tolerability, and secondary endpoints included exercise capacity, impact on daily life (functional class), clinical worsening, and hemodynamic measures (metrics to measure how well the heart is working). The study found that ralinepag had a manageable side effect profile, with a decrease in side effects for patients who continued taking ralinepag over time. Moreover, the study showed that ralinepag improved the ability to exercise, maintained functional measures, and helped to reduce pressure in the blood vessels connecting the heart to the lungs over a 24-month period for participants with pulmonary arterial hypertension.

• Klíčová slova
• ADVANCE, Combination therapy, Long-term outcomes, Open-label extension, PAH, Ralinepag, Safety, Tolerability,
• MeSH
• acetáty * škodlivé účinky   MeSH
• dvojitá slepá metoda MeSH
• karbamáty * MeSH
• lidé MeSH
• plicní arteriální hypertenze * farmakoterapie   MeSH
• prostaglandiny I škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• acetáty * MeSH
• karbamáty * MeSH
• prostaglandiny I MeSH
• ralinepag MeSH Prohlížeč

Many patients with pulmonary arterial hypertension do not achieve treatment goals with monotherapy, and therefore combination therapy is becoming the standard of care. The soluble guanylate cyclase stimulator riociguat is licensed for the treatment of pulmonary arterial hypertension; here we present findings from patients who were receiving combined riociguat plus endothelin receptor antagonists or non-intravenous prostanoids in the randomized, placebo-controlled PATENT-1 study and its open-label extension (PATENT-2). Moreover, we include new data from patients receiving early sequential combination therapy (three to six months of endothelin receptor antagonist treatment) or long-term background endothelin receptor antagonist therapy (>6 months). Patients were randomized to riociguat 2.5 mg-maximum (N = 131 pretreated patients) and placebo (N = 60 pretreated patients). Riociguat improved 6-min walking distance (PATENT-1 primary endpoint), functional capacity, and hemodynamics after 12 weeks in pretreated patients. The placebo-corrected changes in 6-min walking distance were +24 m in endothelin receptor antagonist-pretreated patients and +106 m in the small group of prostanoid-pretreated patients. In the early sequential combination and long-term background endothelin receptor antagonist groups, the placebo-corrected changes in 6-min walking distance were +65 m (95% CI: 17 to 113 m) and +13 m (95% CI: -8 to 33 m), respectively. In conclusion, these data suggest that early sequential combination of an endothelin receptor antagonist plus riociguat is a feasible treatment option. Both early sequential therapy and long-term background endothelin receptor antagonist plus riociguat were well tolerated in the PATENT studies.

• Klíčová slova
• endothelin receptor antagonists, hemodynamics, hypertension, prostaglandins, pulmonary, soluble guanylyl cyclase,
• Publikační typ
• časopisecké články MeSH

Background Conducting randomized controlled trials to investigate survival in a rare disease like pulmonary arterial hypertension has considerable ethical and logistical constraints. In many studies, such as the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) randomized controlled trial, evaluating survival is further complicated by bias introduced by allowing active therapy among placebo-treated patients who clinically deteriorate. Methods and Results SERAPHIN enrolled and followed patients in the same time frame as the US Registry to Evaluate Early And Long-term PAH Disease Management, providing an opportunity to compare observed survival for SERAPHIN patients with predicted survival had they received real-world treatment as in the Registry to Evaluate Early And Long-term PAH Disease Management. From the Registry to Evaluate Early And Long-term PAH Disease Management (N=3515), 734 patients who met SERAPHIN eligibility criteria were selected and their data used to build a prediction model for time to death up to 3 years based on 10 baseline prognostic variables. The model was used to predict a survival curve for each of the 742 SERAPHIN patients via their baseline variables. The average of these predicted survival curves was compared with observed survival of the placebo (n=250) and macitentan 10 mg (n=242) groups using a log-rank test and Cox proportional hazard model. Observed mortality risk for patients randomized to placebo, 62% of whom were taking background pulmonary arterial hypertension therapy, tended to be lower than that predicted for all SERAPHIN patients (16% lower; P=0.259). The observed placebo survival curve closely approximated the predicted survival curve for the first 15 months. Beyond that time, observed risk of mortality decreased compared with predicted mortality, potentially reflecting the impact of crossover of patients in the placebo group to active therapy. Over 3 years, risk of mortality observed with macitentan 10 mg was 35% lower than predicted mortality ( P=0.010). Conclusions These analyses show that, in a rare disease, real-world observational data can complement randomized controlled trial data to overcome some challenges associated with assessing survival in the setting of a randomized controlled trial. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifiers: NCT00660179 and NCT00370214.

• Klíčová slova
• hypertension, pulmonary, macitentan, prognosis, rare diseases, survival,
• MeSH
• antagonisté endotelinového receptoru škodlivé účinky   terapeutické užití   MeSH
• antihypertenziva škodlivé účinky   terapeutické užití   MeSH
• časové faktory MeSH
• dospělí MeSH
• hodnocení rizik MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• medicína založená na důkazech MeSH
• multicentrické studie jako téma MeSH
• plicní arteriální hypertenze diagnóza   farmakoterapie   mortalita   MeSH
• pozorovací studie jako téma MeSH
• příčina smrti MeSH
• progrese nemoci MeSH
• randomizované kontrolované studie jako téma MeSH
• rizikové faktory MeSH
• senioři MeSH
• výsledek terapie MeSH
• vzácné nemoci diagnóza   farmakoterapie   mortalita   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antagonisté endotelinového receptoru MeSH
• antihypertenziva MeSH

UNLABELLED: SERAPHIN was a double-blind, placebo-controlled, event-driven phase III trial that evaluated the effects of long-term treatment with macitentan, an oral endothelin receptor antagonist, in patients with pulmonary arterial hypertension (PAH). The majority of patients were receiving PAH therapy at enrollment, providing the opportunity to evaluate the efficacy and safety of macitentan in combination with other PAH therapies (predominantly phosphodiesterase type 5 inhibitors [PDE-5i]). In patients receiving background therapy, macitentan reduced the risk of morbidity/mortality by 38% compared with placebo (hazard ratio [HR] 0.62; 95% confidence level [CL] 0.43-0.89; p = 0.009). Furthermore, patients receiving macitentan and background therapy had a 37% reduction in the risk of being hospitalized for PAH (HR 0.63; 95% CL 0.41-0.96) compared with patients receiving background therapy only (placebo arm). Macitentan treatment in combination with background therapy was also associated with improvements in exercise capacity, functional class, cardiopulmonary hemodynamics, and health-related quality of life compared with background therapy alone. The safety profile of macitentan as part of a combination therapy regimen was consistent with that of macitentan in the overall SERAPHIN population. The SERAPHIN study has provided evidence that combination therapy with macitentan and a PDE-5i is effective and well tolerated in the management of PAH. Based on these data, and those from subsequent long-term trials, combination therapy is increasingly recognized as an important treatment option for improving long-term outcomes in PAH. CLINICAL TRIAL REGISTRATION NUMBER: NCT00660179.

• MeSH
• antagonisté endotelinového receptoru aplikace a dávkování   MeSH
• dvojitá slepá metoda MeSH
• inhibitory fosfodiesterasy 5 aplikace a dávkování   MeSH
• klinické zkoušky, fáze III jako téma metody   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• plicní hypertenze diagnóza   farmakoterapie   MeSH
• pyrimidiny aplikace a dávkování   MeSH
• sulfonamidy aplikace a dávkování   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antagonisté endotelinového receptoru MeSH
• inhibitory fosfodiesterasy 5 MeSH
• macitentan MeSH Prohlížeč
• pyrimidiny MeSH
• sulfonamidy MeSH

BACKGROUND: Few controlled clinical trials exist to support oral combination therapy in pulmonary arterial hypertension (PAH). METHODS: Patients with PAH (idiopathic [IPAH] or associated with connective tissue disease [APAH-CTD]) taking bosentan (62.5 or 125 mg twice daily at a stable dose for ≥3 months) were randomized (1:1) to sildenafil (20 mg, 3 times daily; n = 50) or placebo (n = 53). The primary endpoint was change from baseline in 6-min walk distance (6MWD) at week 12, assessed using analysis of covariance. Patients could continue in a 52-week extension study. An analysis of covariance main-effects model was used, which included categorical terms for treatment, baseline 6MWD (<325 m; ≥325 m), and baseline aetiology; sensitivity analyses were subsequently performed. RESULTS: In sildenafil versus placebo arms, week-12 6MWD increases were similar (least squares mean difference [sildenafil-placebo], -2.4 m [90% CI: -21.8 to 17.1 m]; P = 0.6); mean ± SD changes from baseline were 26.4 ± 45.7 versus 11.8 ± 57.4 m, respectively, in IPAH (65% of population) and -18.3 ± 82.0 versus 17.5 ± 59.1 m in APAH-CTD (35% of population). One-year survival was 96%; patients maintained modest 6MWD improvements. Changes in WHO functional class and Borg dyspnoea score and incidence of clinical worsening did not differ. Headache, diarrhoea, and flushing were more common with sildenafil. CONCLUSIONS: Sildenafil, in addition to stable (≥3 months) bosentan therapy, had no benefit over placebo for 12-week change from baseline in 6MWD. The influence of PAH aetiology warrants future study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00323297 (registration date: May 5, 2006).

• Klíčová slova
• Combination therapy, Sildenafil - Bosentan - pulmonary hypertension - randomized controlled trial -exercise test,
• MeSH
• antagonisté endotelinového receptoru aplikace a dávkování   škodlivé účinky   MeSH
• antihypertenziva aplikace a dávkování   škodlivé účinky   MeSH
• arteria pulmonalis účinky léků   patofyziologie   MeSH
• arteriální tlak účinky léků   MeSH
• bosentan MeSH
• časové faktory MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• inhibitory fosfodiesterasy 5 aplikace a dávkování   škodlivé účinky   MeSH
• kombinovaná farmakoterapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• metoda nejmenších čtverců MeSH
• obnova funkce MeSH
• plicní hypertenze diagnóza   farmakoterapie   patofyziologie   MeSH
• senioři MeSH
• sildenafil citrát aplikace a dávkování   škodlivé účinky   MeSH
• sulfonamidy aplikace a dávkování   škodlivé účinky   MeSH
• test chůzí MeSH
• tolerance zátěže účinky léků   MeSH
• vazodilatancia aplikace a dávkování   škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté endotelinového receptoru MeSH
• antihypertenziva MeSH
• bosentan MeSH
• inhibitory fosfodiesterasy 5 MeSH
• sildenafil citrát MeSH
• sulfonamidy MeSH
• vazodilatancia MeSH

A proportion of pulmonary arterial hypertension (PAH) patients do not reach treatment goals with phosphodiesterase-5 inhibitors (PDE5i). RESPITE investigated the safety, feasibility and benefit of switching from PDE5i to riociguat in these patients.RESPITE was a 24-week, open-label, multicentre, uncontrolled study. Patients in World Health Organization (WHO) functional class (FC) III, with 6-min walking distance (6MWD) 165-440 m, cardiac index <3.0 L·min-1·m-2 and pulmonary vascular resistance >400 dyn·s·cm-5 underwent a 1-3 day PDE5i treatment-free period before receiving riociguat adjusted up to 2.5 mg maximum t.i.d Exploratory end-points included change in 6MWD, WHO FC, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and safety.Of 61 patients enrolled, 51 (84%) completed RESPITE. 50 (82%) were receiving concomitant endothelin receptor antagonists. At week 24, mean±sd 6MWD had increased by 31±63 m, NT-proBNP decreased by 347±1235 pg·mL-1 and WHO FC improved in 28 patients (54%). 32 patients (52%) experienced study drug-related adverse events and 10 (16%) experienced serious adverse events (2 (3%) study drug-related, none during the PDE5i treatment-free period). Six patients (10%) experienced clinical worsening, including death in two (not study drug-related).In conclusion, selected patients with PAH may benefit from switching from PDE5i to riociguat, but this strategy needs to be further studied.

• MeSH
• antagonisté endotelinového receptoru terapeutické užití   MeSH
• antihypertenziva škodlivé účinky   terapeutické užití   MeSH
• cévní rezistence účinky léků   MeSH
• dospělí MeSH
• inhibitory fosfodiesterasy 5 terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• natriuretický peptid typu B krev   MeSH
• peptidové fragmenty krev   MeSH
• plicní hypertenze farmakoterapie   mortalita   patofyziologie   MeSH
• prospektivní studie MeSH
• pyrazoly škodlivé účinky   terapeutické užití   MeSH
• pyrimidiny škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• Světová zdravotnická organizace MeSH
• test chůzí MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH
• Severní Amerika MeSH
• Názvy látek
• antagonisté endotelinového receptoru MeSH
• antihypertenziva MeSH
• inhibitory fosfodiesterasy 5 MeSH
• natriuretický peptid typu B MeSH
• peptidové fragmenty MeSH
• pro-brain natriuretic peptide (1-76) MeSH Prohlížeč
• pyrazoly MeSH
• pyrimidiny MeSH
• riociguat MeSH Prohlížeč