The management of pulmonary arterial hypertension (PAH) has evolved significantly in the last three decades based on the development of drugs which target three biochemical pathways involved in pulmonary vascular homeostasis: the nitric oxide (NO) pathway, the endothelin pathway and the prostacyclin pathway [1]. Initially employed as monotherapies, these new drugs changed PAH outcomes and had a direct impact on survival [2]. However, monotherapy proved over time to be insufficient for the vast majority of PAH patients and the next natural step in decreasing the still unacceptable lethality of PAH was the association of two or more drugs targeting distinct pathways. Results from two large randomised controlled trials demonstrated that the addition of a second or third drug in combination with an already established background therapy could significantly slow disease progression [3, 4], reinforcing the concept that more drugs can lead to greater benefit. This concept was further stressed by studying the upfront use of combination therapy. In the ambrisentan and tadalafil in patients with pulmonary arterial hypertension (AMBITION) trial [5], the combined use of an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 inhibitor (PDE5i) proved to be better than the use of either compound alone in decreasing the risk of clinical failure events. Successful use of initial double or triple combination therapies was also reported in multi-centre registry studies [6, 7]. These large trials and registries provided the basis for the current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines in which the use of combination therapy should be considered early, according to the stratification of the risk of death [8] (figure 1). A “switch” strategy might represent an alternative for well-selected patients in PAH http://ow.ly/ppEt30enWo0

中文翻译：

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挑战在肺动脉高压中添加更多药物的概念

肺动脉高压 (PAH) 的管理在过去 30 年中取得了重大进展，基于药物的开发，这些药物针对参与肺血管稳态的三种生化途径：一氧化氮 (NO) 途径、内皮素途径和前列环素途径 [1]。 1]。这些新药最初用作单一疗法，但改变了 PAH 的结局并对生存率产生了直接影响 [2]。然而，随着时间的推移，单药疗法对绝大多数 PAH 患者来说是不够的，而降低 PAH 仍然不可接受的致死率的下一个自然步骤是联合使用两种或两种以上针对不同途径的药物。两项大型随机对照试验的结果表明，将第二种或第三种药物与已经建立的背景疗法相结合可以显着减缓疾病进展 [3, 4]，强化了更多药物可以带来更大益处的概念。通过研究联合治疗的前期使用，进一步强调了这一概念。在肺动脉高压患者的安立生坦和他达拉非 (AMBITION) 试验 [5] 中，联合使用内皮素受体拮抗剂 (ERA) 和磷酸二酯酶-5 抑制剂 (PDE5i) 被证明比单独使用任何一种化合物更好降低临床失败事件的风险。多中心注册研究中也报告了初始双重或三重联合疗法的成功使用 [6, 7]。这些大型试验和注册为当前的欧洲心脏病学会 (ESC)/欧洲呼吸学会 (ERS) 指南提供了基础，其中应根据死亡风险分层尽早考虑使用联合治疗 [8] （图1）。“转换”策略可能代表 PAH 中精心挑选的患者的替代方案 http://ow.ly/ppEt30enWo0