Clift Paul, Berger Felix, Sondergaard Lars, Antonova Petra, Disney Patrick, Nicolarsen Jeremy, Thambo Jean-Benoît, Tomkiewicz Pajak Lidia, Wang Jou-Kou, Schophuus Jensen Annette, Efficace Michela, Friberg Michael, Haberle Diana, Walter Verena, d'Udekem Yves
Adult Congenital Heart Disease Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.
Department of Congenital Heart Disease/Pediatric Cardiology, Deutsches Herzzentrum der Charité, Charité - Universitaetsmedizin Berlin, Berlin, Germany.
J Thorac Cardiovasc Surg. 2025 Feb;169(2):385-394.e5. doi: 10.1016/j.jtcvs.2024.08.039. Epub 2024 Aug 29.
The efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in a 52-week, prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in Fontan-palliated adult and adolescent patients (RUBATO-DB) and an open-label extension trial (RUBATO-OL).
Patients aged 12 years and older with New York Heart Association functional class II or III underwent total cavopulmonary connection more than 1 year before screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, the primary efficacy end point was change in peak oxygen consumption from baseline to week 16; secondary end points were change from baseline over 52 weeks in peak oxygen consumption and change in mean count/minute of daily physical activity via accelerometer from baseline to week 16. Safety was assessed throughout both studies.
In RUBATO-DB, 137 patients were randomized to macitentan 10 mg (n = 68) or placebo (n = 69); 92.7% completed 52-week double-blind treatment. At week 16, mean ± SD change in peak oxygen consumption was -0.16 ± 2.86 versus -0.67 ± 2.66 mL/kg/minute with macitentan versus placebo (median unbiased treatment difference estimate, 0.62 mL/kg/minute [99% repeated CI, -0.62 to 1.85]; P = .19). No treatment effect was observed in either of the secondary end points. During RUBATO-DB, most common adverse events with macitentan were headache, nasopharyngitis, and pyrexia. Across RUBATO-DB and RUBATO-OL, most common adverse events were COVID-19, headache, and fatigue. RUBATO-OL was prematurely discontinued because RUBATO-DB did not meet its primary or secondary end point.
The primary end point of RUBATO-DB was not met; macitentan did not improve exercise capacity versus placebo in patients with Fontan palliation. Macitentan was generally well tolerated over long-term treatment.
在一项为期52周的前瞻性、多中心、双盲、随机、安慰剂对照、平行组研究（RUBATO-DB）中评估内皮素受体拮抗剂马昔腾坦的疗效和安全性，该研究评估马昔腾坦在接受Fontan姑息手术的成年和青少年患者中的疗效和安全性，同时进行一项开放标签扩展试验（RUBATO-OL）。
年龄在12岁及以上、纽约心脏协会心功能分级为II或III级的患者在筛查前1年多接受了全腔静脉肺动脉连接术，且未出现Fontan衰竭/临床恶化的迹象。在RUBATO-DB中，主要疗效终点是从基线到第16周峰值耗氧量的变化；次要终点是52周内峰值耗氧量相对于基线的变化，以及通过加速度计测量从基线到第16周每日体力活动平均次数/分钟的变化。在两项研究中均对安全性进行了评估。
在RUBATO-DB中，137例患者被随机分为马昔腾坦10 mg组（n = 68）或安慰剂组（n = 69）；92.7%的患者完成了52周的双盲治疗。在第16周时，马昔腾坦组与安慰剂组相比，峰值耗氧量的平均±标准差变化为-0.16±2.86与-0.67±2.66 mL/kg/分钟（中位无偏治疗差异估计值，0.62 mL/kg/分钟[99%重复置信区间，-0.62至1.85]；P = 0.19）。在任何一个次要终点均未观察到治疗效果。在RUBATO-DB期间，马昔腾坦最常见的不良事件是头痛、鼻咽炎和发热。在RUBATO-DB和RUBATO-OL中，最常见的不良事件是新型冠状病毒肺炎、头痛和疲劳。RUBATO-OL提前终止，因为RUBATO-DB未达到其主要或次要终点。
RUBATO-DB的主要终点未达到；在Fontan姑息治疗患者中，与安慰剂相比，马昔腾坦并未改善运动能力。马昔腾坦在长期治疗中总体耐受性良好。
