OBJECTIVES: This study sought to evaluate the effect of macitentan on hospitalization of patients with symptomatic pulmonary arterial hypertension (PAH). BACKGROUND: PAH is a progressive, life-threatening disease often requiring hospitalization. METHODS: In the multicenter, double-blind, randomized, event-driven, phase III SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) trial, patients with symptomatic PAH were randomized (1:1:1) to receive placebo or 3 mg or 10 mg of macitentan. Effects of macitentan on the risk, rate, and number of hospital days for all-cause and PAH-related hospitalizations were compared with those for placebo. Risk and causes of hospitalizations unrelated to PAH were investigated. RESULTS: Of 742 randomized patients, 250 received placebo, 250 received 3 mg of macitentan, and 242 received 10 mg of macitentan; the overall median duration of treatment was 115 weeks. Risk of all-cause hospitalization was reduced by 18.9% (p = 0.1208) and 32.3% (p = 0.0051) in the macitentan 3-mg and 10-mg arm, respectively. Rates of all-cause hospitalizations and numbers of hospital days were reduced by 20.5% (p = 0.0378) and 30.6% (p = 0.0278), respectively, with 3 mg of macitentan and by 33.1% (p = 0.0005) and 31.0% (p = 0.0336), respectively, with 10 mg of macitentan. Risk of PAH-related hospitalizations were reduced by 42.7% (p = 0.0015) and 51.6% (p < 0.0001) in the macitentan 3-mg and 10-mg arms, respectively. Rate of PAH-related hospitalizations and numbers of hospital days were reduced by 44.5% (p = 0.0004) and 53.3% (p = 0.0001), respectively, with 3 mg of macitentan, and reduced by 49.8% (p < 0.0001) and 52.3% (p = 0.0003), respectively, with 10 mg of macitentan. Risk of non-PAH-related hospitalization was similar between treatment arms. CONCLUSIONS: Macitentan 10 mg significantly reduced the risk and rate of all-cause hospitalization, which was driven by reductions in the risk and rate of PAH-related hospitalization. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension; NCT00660179).

• Klíčová slova
• hospitalization, macitentan, pulmonary arterial hypertension,
• MeSH
• antagonisté endotelinového receptoru A aplikace a dávkování   MeSH
• aplikace orální MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• familiární plicní arteriální hypertenze farmakoterapie   patofyziologie   MeSH
• hospitalizace trendy   MeSH
• lidé středního věku MeSH
• lidé MeSH
• plicní tlak v zaklínění účinky léků   MeSH
• progrese nemoci MeSH
• pyrimidiny aplikace a dávkování   MeSH
• senioři MeSH
• sulfonamidy aplikace a dávkování   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté endotelinového receptoru A MeSH
• macitentan MeSH Prohlížeč
• pyrimidiny MeSH
• sulfonamidy MeSH

AIMS: To demonstrate the bioequivalence of macitentan/tadalafil fixed-dose combination (FDC) tablets with single-component tablets of macitentan and tadalafil in healthy subjects. METHODS: Studies AC-077-101 and AC-077-103 were single-centre, open-label, single-dose, 2-period, randomized, crossover Phase 1 studies conducted in healthy subjects. Two FDCs were investigated: FDC-1 and FDC-2 in Study AC-077-101 and FDC-2 in Study AC-077-103. Both FDCs contained 10 mg/40 mg of macitentan/tadalafil and differed in excipients and coating materials used. In both studies, pharmacokinetic sampling over 216 hours was conducted, and pharmacokinetic parameters were derived using noncompartmental methods. RESULTS: Bioequivalence of macitentan, its active metabolite ACT-132577, and tadalafil was established for FDC-2 in both studies AC-077-101 and AC-077-103 in which tadalafil as a single component was sourced from the USA and EU, respectively, to fulfil regional regulatory requirements. The area under the plasma concentration-time curve and maximum plasma concentration with 90% confidence intervals of all components were entirely within the bioequivalence limits (0.8000-1.2500). No subject died and no serious adverse events were reported in either studies. CONCLUSION: The FDC-2 tablet containing 10 mg/40 mg of macitentan/tadalafil was bioequivalent to the free combination of 10 mg macitentan and 40 mg tadalafil (both US and EU sourced). Macitentan and tadalafil were well tolerated when administered as FDC or as a free combination.

• Klíčová slova
• bioequivalence, fixed-dose combination, macitentan, pulmonary arterial hypertension, tadalafil,
• MeSH
• dospělí MeSH
• fixní kombinace léků MeSH
• hypoglykemika * farmakologie   MeSH
• klinické křížové studie MeSH
• léky s prodlouženým účinkem MeSH
• lidé středního věku MeSH
• lidé MeSH
• metformin * MeSH
• mladiství MeSH
• mladý dospělý MeSH
• plocha pod křivkou MeSH
• pyrimidiny * farmakologie   MeSH
• sulfonamidy * farmakologie   MeSH
• tablety MeSH
• tadalafil * farmakologie   MeSH
• terapeutická ekvivalence MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fixní kombinace léků MeSH
• hypoglykemika * MeSH
• léky s prodlouženým účinkem MeSH
• macitentan MeSH Prohlížeč
• metformin * MeSH
• pyrimidiny * MeSH
• sulfonamidy * MeSH
• tablety MeSH
• tadalafil * MeSH

BACKGROUND: Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial hypertension (PAH) patients. A fixed-dose combination of the ERA macitentan and PDE5i tadalafil (M/T FDC) in a once-daily, single tablet would simplify treatment. OBJECTIVES: The multicenter, double-blind, adaptive phase 3 A DUE study investigated the efficacy and safety of M/T FDC vs macitentan 10 mg and vs tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients. METHODS: World Health Organization functional class II-III patients were randomized to M/T FDC, macitentan, or tadalafil depending on their PAH treatment (treatment-naïve, ERA, or PDE5i monotherapy) at baseline. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16. RESULTS: In total, 187 patients were randomized to single-tablet M/T FDC (n = 108), macitentan (n = 35), or tadalafil (n = 44). PVR reduction with M/T FDC was significantly greater vs macitentan (29%; geometric mean ratio 0.71; 95% CL: 0.61-0.82; P < 0.0001) and vs tadalafil (28%; geometric mean ratio 0.72; 95% CL: 0.64-0.80; P < 0.0001). Three patients died in the M/T FDC arm (judged unrelated to treatment). Adverse events (AEs) leading to discontinuation, serious AEs, and those of special interest (anemia, hypotension, and edema) were more frequent with M/T FDC. CONCLUSIONS: Macitentan and tadalafil FDC significantly improved PVR vs monotherapies in PAH patients, with a safety and tolerability profile consistent with the individual components. The A DUE study supports M/T FDC as a once-daily, single-tablet combination for initial therapy and escalation to double combination therapy in patients with PAH. (Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension [PAH]) [A DUE]; NCT03904693).

• Klíčová slova
• macitentan, pulmonary arterial hypertension, randomized controlled trial, single-tablet (fixed-dose) combination therapy, tadalafil,
• MeSH
• antagonisté endotelinového receptoru MeSH
• inhibitory fosfodiesterasy 5 MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• plicní arteriální hypertenze * MeSH
• pyrimidiny * MeSH
• sulfonamidy * MeSH
• tablety MeSH
• tadalafil MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté endotelinového receptoru MeSH
• inhibitory fosfodiesterasy 5 MeSH
• macitentan MeSH Prohlížeč
• pyrimidiny * MeSH
• sulfonamidy * MeSH
• tablety MeSH
• tadalafil MeSH

The MELODY-1 study evaluated macitentan for pulmonary hypertension because of left heart disease (PH-LHD) in patients with combined post- and pre-capillary PH.63 patients with PH-LHD and diastolic pressure gradient ≥7 mmHg and pulmonary vascular resistance (PVR) >3WU were randomised to macitentan 10 mg (n=31) or placebo (n=32) for 12 weeks. The main end-point assessed a composite of significant fluid retention (weight gain ≥5% or ≥5 kg because of fluid overload or parenteral diuretic administration) or worsening in New York Heart Association functional class from baseline to end of treatment. Exploratory end-points included changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) and haemodynamics at week 12.Seven macitentan-treated and four placebo-treated patients experienced significant fluid retention/worsening functional class; treatment difference, 10.08% (95% CI -15.07-33.26; p=0.34). The difference, driven by the fluid retention component, was apparent within the first month. At week 12, versus placebo, the macitentan group showed no change in PVR, mean right atrial pressure or pulmonary arterial wedge pressure; a non-significant increase in cardiac index (treatment effect 0.4 (95% CI 0.1-0.7) L·min-1·m-2) and decrease in NT-proBNP (0.77 (0.55-1.08)) was observed. Adverse events and serious adverse events were numerically more frequent with macitentan versus placebo.Macitentan-treated patients were quantitatively more likely to experience significant fluid retention versus placebo. Macitentan resulted in no significant changes in any exploratory end-points.

• MeSH
• cévní rezistence účinky léků   MeSH
• dvojitá slepá metoda MeSH
• dysfunkce levé srdeční komory komplikace   MeSH
• internacionalita MeSH
• krevní tlak účinky léků   MeSH
• lidé MeSH
• natriuretický peptid typu B účinky léků   metabolismus   MeSH
• peptidové fragmenty účinky léků   metabolismus   MeSH
• plicní hypertenze farmakoterapie   patofyziologie   MeSH
• plicní tlak v zaklínění účinky léků   MeSH
• pyrimidiny aplikace a dávkování   MeSH
• senioři MeSH
• sulfonamidy aplikace a dávkování   MeSH
• test chůzí MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• macitentan MeSH Prohlížeč
• natriuretický peptid typu B MeSH
• peptidové fragmenty MeSH
• pro-brain natriuretic peptide (1-76) MeSH Prohlížeč
• pyrimidiny MeSH
• sulfonamidy 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

INTRODUCTION: In SERAPHIN, a long-term, event-driven, double-blind randomised controlled trial in pulmonary arterial hypertension (PAH), macitentan 10 mg significantly reduced the risk of morbidity/mortality compared with placebo. Its open-label extension study (SERAPHIN OL) further assessed long-term safety and tolerability of macitentan 10 mg in PAH patients. METHODS: Patients in SERAPHIN who completed the double-blind treatment period or experienced a morbidity event during the study could enter SERAPHIN OL. Patients received macitentan 10 mg once daily, and safety and survival were assessed until end of treatment (+ 28 days). Two overlapping sets were analysed for safety: (1) all patients in SERAPHIN OL (OL safety set); (2) patients randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Survival was evaluated as an exploratory endpoint in the latter set. RESULTS: Of 742 patients randomised in SERAPHIN, 550 (74.1%) entered SERAPHIN OL (OL safety set); 242 patients were randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Median (min, max) exposure to macitentan 10 mg was 40.1 (0.1, 130.5) months (2074.7 patient-years; OL safety set) and 54.7 (0.1, 141.3) months (1151.0 patient-years; long-term safety/survival set). Safety in both analysis sets was comparable to the known safety profile of macitentan. Kaplan-Meier survival estimates (95% CI) at 1, 5, 7 and 9 years were 95.0% (91.3, 97.1), 73.3% (66.6, 78.9), 62.6% (54.6, 69.6) and 52.7% (43.6, 61.0), respectively (long-term safety/survival set; median follow-up: 5.9 years). CONCLUSIONS: This analysis provides the longest follow-up for safety and survival published to date for any PAH therapy. The safety profile of macitentan 10 mg over this extensive treatment period was in line with that observed in SERAPHIN. As the majority of patients were receiving other PAH therapy at macitentan initiation, our study provides additional insight into the long-term safety of macitentan, including as part of combination therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00660179 and NCT00667823.

• Klíčová slova
• Combination therapy, Endothelin receptor antagonist (ERA), Long-term outcomes, Macitentan, Open-label extension, Pulmonary arterial hypertension (PAH), SERAPHIN, Safety, Survival, Tolerability,
• MeSH
• familiární plicní arteriální hypertenze farmakoterapie   MeSH
• lidé MeSH
• plicní arteriální hypertenze * farmakoterapie   MeSH
• pyrimidiny škodlivé účinky   MeSH
• sulfonamidy škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• macitentan MeSH Prohlížeč
• pyrimidiny MeSH
• sulfonamidy MeSH

BACKGROUND: Macitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug-drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH. OBJECTIVE: Two Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan. METHODS: Healthy male subjects received a single oral dose of rosuvastatin 10 mg (n = 20) or riociguat 1 mg (n = 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0-t), the AUC from zero to infinity (AUC0-∞) and the terminal elimination half-life (t½) of rosuvastatin, riociguat and riociguat's metabolite, M1. The difference in the time to reach maximum plasma concentration (tmax) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout. RESULTS: Ninety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80-1.25. There was no significant difference between test and reference tmax. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs. CONCLUSIONS: Macitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects. EudraCT numbers: 2017-003095-31 and 2017-003502-41.

• MeSH
• ABC transportér z rodiny G, člen 2 metabolismus   MeSH
• dospělí MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové proteiny metabolismus   MeSH
• pyrazoly farmakokinetika   MeSH
• pyrimidiny farmakokinetika   farmakologie   MeSH
• rosuvastatin kalcium farmakokinetika   MeSH
• sulfonamidy farmakologie   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABCG2 protein, human MeSH Prohlížeč
• macitentan MeSH Prohlížeč
• nádorové proteiny MeSH
• pyrazoly MeSH
• pyrimidiny MeSH
• riociguat MeSH Prohlížeč
• rosuvastatin kalcium MeSH
• sulfonamidy MeSH

To compare the pharmacokinetic (PK) properties of the pediatric dispersible tablet formulation of macitentan and the adult film-coated tablet formulation of macitentan in healthy subjects. A randomized, open-label, single-dose, two-sequence, two-period, crossover, Phase 1 study was conducted in 12 healthy adults. Subjects were randomized to one of the two possible treatment sequences A/B or B/A on Day 1 under fasted conditions. Treatment A was a single 10 mg dose of macitentan (film-coated adult formulation) and Treatment B was a single 10 mg dose of macitentan, consisting of two 5 mg dispersible tablets (pediatric formulation). PK sampling over 216 hours was conducted, and PK parameters were derived using non-compartmental methods. For macitentan, geometric means ratio of peak plasma concentrations (Cmax ), plasma concentration-time curve from zero to the time of the last quantifiable concentration (AUC0-t ), and plasma concentration-time curve from zero to infinity (AUC0-∞ ) were 1.140, 0.974, and 0.974, respectively. The corresponding 90% confidence intervals fell entirely within the referenced range of 0.8000 to 1.2500, which is used for evaluation of bioequivalence. These results indicate no significant differences between the pediatric dispersible tablet and the adult film-coated tablet. Both formulations were well tolerated. The pediatric dispersible tablet is biocomparable to the adult film-coated tablet formulation.

• Klíčová slova
• bioavailability, clinical trials, pediatrics, respiratory medicine,
• MeSH
• biologická dostupnost MeSH
• dítě MeSH
• dospělí MeSH
• klinické křížové studie MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• omezení příjmu potravy metabolismus   MeSH
• plocha pod křivkou MeSH
• pyrimidiny aplikace a dávkování   krev   farmakokinetika   MeSH
• sulfonamidy aplikace a dávkování   krev   farmakokinetika   MeSH
• tablety MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• macitentan MeSH Prohlížeč
• pyrimidiny MeSH
• sulfonamidy MeSH
• tablety MeSH

AIMS: The effect of macitentan on haemodynamic parameters and NT-proBNP levels was evaluated in pulmonary arterial hypertension (PAH) patients in the SERAPHIN study. Association between these parameters and disease progression, assessed by the primary endpoint (time to first morbidity/mortality event), was explored. METHODS AND RESULTS: Of the 742 randomized patients, 187 with right heart catheterization at baseline and month 6 participated in a haemodynamic sub-study. Prespecified endpoints included change from baseline to month 6 in cardiac index (CI), right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), mixed-venous oxygen saturation, and NT-proBNP. Exploratory analyses examined associations between CI, RAP, and NT-proBNP and disease progression using the Kaplan-Meier method and Cox regression models. Macitentan improved CI, RAP, mPAP, PVR and NT-proBNP vs. placebo at month 6. Absolute levels of CI, RAP and NT-proBNP at baseline and month 6, but not their changes, were associated with morbidity/mortality events. Patients with CI > 2.5 L/min/m2, RAP < 8 mmHg, or NT-proBNP < 750 fmol/ml at month 6 had a lower risk of morbidity/mortality than those not meeting these thresholds (HR 0.49, 95% CL 0.28-0.86; HR 0.72, 95% CL 0.42-1.22; and HR 0.22, 95% CL 0.15-0.33, respectively). CONCLUSIONS: For all treatment groups, baseline and month 6 values of CI, RAP, and NT-proBNP, but not their changes, were associated with morbidity/mortality events, confirming their relevance in predicting disease progression in patients with PAH. By improving those parameters, macitentan increased the likelihood of reaching threshold values associated with lower risk of morbidity/mortality.

• Klíčová slova
• Haemodynamics, Macitentan, Prognosis, Pulmonary hypertension, Right ventricular function,
• MeSH
• antagonisté endotelinového receptoru aplikace a dávkování   škodlivé účinky   MeSH
• dysfunkce pravé srdeční komory mortalita   patofyziologie   MeSH
• hemodynamika účinky léků   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• natriuretický peptid typu B metabolismus   MeSH
• peptidové fragmenty metabolismus   MeSH
• plicní hypertenze farmakoterapie   mortalita   patofyziologie   MeSH
• progrese nemoci MeSH
• pyrimidiny aplikace a dávkování   škodlivé účinky   MeSH
• rizikové faktory MeSH
• srdeční katetrizace MeSH
• sulfonamidy aplikace a dávkování   škodlivé účinky   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté endotelinového receptoru MeSH
• macitentan MeSH Prohlížeč
• natriuretický peptid typu B MeSH
• peptidové fragmenty MeSH
• pro-brain natriuretic peptide (1-76) MeSH Prohlížeč
• pyrimidiny MeSH
• sulfonamidy MeSH

BACKGROUND: Pulmonary arterial hypertension (PAH) leads to reduced health-related quality of life (HRQoL). The objectives of this analysis were to evaluate the effect of macitentan on HRQoL in patients with PAH in the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) study. The association between baseline HRQoL and long-term outcomes was also investigated. METHODS: Patients were randomized to placebo, macitentan 3 mg, or macitentan 10 mg once daily. Patients aged 14 years or older completed the 36-Item Short Form Survey (SF-36) at baseline, at month 6 and month 12, and at the end of treatment (EOT). The absolute change from baseline to month 6 in SF-36 scores was calculated. The time to a clinically meaningful deterioration in the SF-36 physical component summary and mental component summary (PCS and MCS) scores and associations between baseline PCS/MCS scores and time to morbidity/mortality events were also assessed. RESULTS: At month 6, macitentan 10 mg significantly improved seven of eight SF-36 domains and the PCS and MCS scores vs placebo. Macitentan 10 mg significantly reduced the risk of a three-point or greater deterioration in PCS (hazard ratio [HR], 0.60; 95% CI, 0.47-0.76; P < .0001) and MCS scores (HR, 0.76; 95% CI, 0.61-0.95; P = .0173) until EOT vs placebo. Patients with a baseline PCS score greater than the median baseline value had a significantly reduced risk of morbidity/mortality compared with patients with a PCS score less than the median; a similar result was observed for the MCS score. CONCLUSIONS: Macitentan significantly improved HRQoL in patients with PAH compared with placebo and significantly reduced the risk of a clinically meaningful HRQoL deterioration. An association between better baseline HRQoL and improved long-term outcomes was shown. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00660179; URL: clinicaltrials.gov.

• Klíčová slova
• health-related quality of life, pharmacotherapy, pulmonary arterial hypertension,
• MeSH
• antagonisté endotelinového receptoru B aplikace a dávkování   škodlivé účinky   MeSH
• dospělí MeSH
• kvalita života * MeSH
• lidé středního věku MeSH
• lidé MeSH
• monitorování léčiv metody   MeSH
• plicní hypertenze * diagnóza   farmakoterapie   patofyziologie   psychologie   MeSH
• posouzení stavu pacienta MeSH
• pyrimidiny * aplikace a dávkování   škodlivé účinky   MeSH
• sulfonamidy * aplikace a dávkování   škodlivé účinky   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté endotelinového receptoru B MeSH
• macitentan MeSH Prohlížeč
• pyrimidiny * MeSH
• sulfonamidy * MeSH