UT Southwestern Medical Center, Professional Office Building II Dallas 5939 Harry Hines Blvd, Ste HQ 1.200, Dallas, TX, 75390, USA.
University of California Los Angeles, Los Angeles, CA, USA.
Adv Ther. 2024 Nov;41(11):4205-4227. doi: 10.1007/s12325-024-02964-0. Epub 2024 Sep 24.
Historically, patients recently (≤ 6 months) diagnosed with pulmonary arterial hypertension (PAH; incident) have had poorer survival than those with a longer (> 6 months) time from PAH diagnosis (prevalent). Despite guideline recommendations for initial combination therapy for most patients with PAH, many are initiated and maintained on monotherapy. Real-world evidence to evaluate the benefit of early combination treatment in newly-diagnosed patients is lacking.
Patients with PAH initiating combination therapy with the endothelin receptor antagonist macitentan and the phosphodiesterase-5 inhibitor tadalafil (M+T) were identified from the combined dataset of the US, multicenter OPUS (prospective, observational drug registry; NCT02126943) and OrPHeUS (retrospective, medical chart review; NCT03197688) studies (2013-2020). Descriptive analyses were performed for the incident and prevalent cohorts, as well as the subcohort of incident patients who received M+T as first-line combination therapy (incident initial combination).
In OPUS/OrPHeUS, 1336 patients with PAH received M+T during the observation period. For the incident [n = 453 (33.9%)], incident initial combination [n = 272 (20.4%)], and prevalent [n = 837 (62.6%)] cohorts: median (Q1, Q3) M+T exposure was 14.2 (4.2, 27.5), 12.2 (3.2, 25.5), and 14.7 (4.5, 28.0) months. 12-month Kaplan-Meier estimates (95% confidence limits) for survival were 91.2% (87.7, 93.7), 88.5% (83.2, 92.2), and 92.9% (90.6, 94.6), for patients free from hospitalization were 59.4% (54.1, 64.4), 56.3% (49.1, 62.9), and 62.3% (58.5, 65.9), and for patients persisting on combination therapy were 68.6% (63.9, 72.8), 65.0% (58.8, 70.6) and 66.9% (63.5, 70.0). Adverse events (OPUS only) were reported in 77.8%, 80.2%, and 80.3% of patients, respectively, with no unexpected adverse events observed.
Despite a historically worse prognosis, incident patients receiving M+T, including as initial combination therapy, had similar survival and hospitalization as prevalent patients. Safety profiles were similar across cohorts. Together, these data support the use of early combination therapy with macitentan and tadalafil.
从历史上看，最近（≤6 个月）被诊断为肺动脉高压（PAH；新发）的患者的生存率低于 PAH 诊断时间较长（>6 个月；既往）的患者。尽管指南建议大多数 PAH 患者初始采用联合治疗，但许多患者仍采用单药治疗。缺乏新诊断患者早期联合治疗获益的真实世界证据。
从美国多中心 OPUS（前瞻性、观察性药物登记研究；NCT02126943）和 OrPHeUS（回顾性、病历审查研究；NCT03197688）研究的合并数据集（2013-2020 年）中确定了新诊断为肺动脉高压并开始联合使用内皮素受体拮抗剂马昔腾坦和磷酸二酯酶-5 抑制剂他达拉非（M+T）治疗的患者。对新发和既往队列以及接受 M+T 作为一线联合治疗的新发患者亚组（新发初始联合）进行描述性分析。
在 OPUS/OrPHeUS 中，有 1336 例 PAH 患者在观察期间接受了 M+T 治疗。对于新发患者（n=453[33.9%]）、新发初始联合患者（n=272[20.4%]）和既往患者（n=837[62.6%]）：M+T 暴露的中位数（Q1，Q3）分别为 14.2（4.2，27.5）、12.2（3.2，25.5）和 14.7（4.5，28.0）个月。12 个月时的生存 Kaplan-Meier 估计值（95%置信区间）分别为无住院患者的 91.2%（87.7，93.7）、88.5%（83.2，92.2）和 92.9%（90.6，94.6），无住院患者的 59.4%（54.1，64.4）、56.3%（49.1，62.9）和 62.3%（58.5，65.9），持续联合治疗患者的 68.6%（63.9，72.8）、65.0%（58.8，70.6）和 66.9%（63.5，70.0）。分别有 77.8%、80.2%和 80.3%的患者报告了不良事件（仅 OPUS），未观察到意外不良事件。
尽管从历史上看预后较差，但接受 M+T 治疗的新发患者，包括作为初始联合治疗，其生存率和住院率与既往患者相似。各队列的安全性特征相似。这些数据共同支持马昔腾坦和他达拉非的早期联合治疗。
