慢性血栓栓塞性肺高壓藥物之療效：系統性文獻回顧、統合分析以及臨床試驗計畫書

Abstract

背景 慢性血栓栓塞性肺動脈高壓（CTEPH）是一種罕見疾病，造成此疾病的原因是肺動脈中存在血栓，栓塞後纖維化的阻塞，導致肺內血壓升高以致可能出現嚴重併發症。對於CTEPH的治療，治療策略是綜合性的，可能包括手術、球囊肺血管成形術（BPA）和針對微血管端的藥物治療；此外，通常建議終身抗凝血劑治療，以幫助預防CTEPH患者復發血栓。在本研究中，主要目的是透過現有文獻的系統性回顧和統合分析，評估用於無法進行手術CTEPH病患的藥物治療，以現有證據並針對統合分析結果得出的結論來架構具有潛力的臨床試驗。 方法 本研究依據PRISMA指南進行系統性回顧，於EMBASE、PubMed和Cochrane等資料庫，搜尋2000年1月至2023年12月發表的隨機對照試驗（RCT），並篩選納入無法手術的CTEPH病人以藥物進行治療的試驗。進而對重要的測量結果進行統合分析，包含6分鐘步行距離（6MWD）、肺血管阻力（PVR）、平均肺動脈壓（mPAP）和氮端原生B型利鈉蛋白鏈（NT-proBNP）。 結果 在系統性回顧中，從資料庫中初步篩選1075篇研究以及從登記資料庫中初步篩選出276篇登記研究。篩選重複和不相關的記錄後，最終納入10篇研究。於這些研究中總共招募了815名無法進行手術的CTEPH患者。RCT結果分析中，6MWD有顯著改善，總效果量為18.22公尺（95% CI：[3.09，33.34]，p = 0.02）。PVR的整體治療效果為-174.85 dyn·s·cm–5（95% CI: [-212.02, -137.68]，p < 0.00001），顯示有顯著療效。mPAP的治療效果估計為-4.36 mmHg（95% CI: [-7.38, -1.35]，p = 0.005）。分析結果顯示，治療對於NT-proBNP的改善沒有達到統計意義有改善，整體治療效果估計為-55.26 pg/mL（95% CI：[-155.29，44.77]，p = 0.28）。 結論 從統合分析的結果來看riociguat、macitentan以及treprostinil對於CTEPH是有效的，其中，riociguat以及treprostinil已經拿到CTEPH適應症的核准。 在Ghofrani（2018）的臨床2期研究提供了數據支持macitentan顯著改善6MWD和PVR，並具有改善CTEPH病患右心功能以及活動功能的潛力。隨後在2020年又發起評估更高劑量的MACiTEPH研究（NCT04271475），該試驗卻在2023年宣布因無效而終止。 然而，在納入分析的研究中，2019年後允許使用其他肺動脈高壓(PH)藥物。selexipag研究中的亞組分析顯示，排除使用肺血管擴張劑的患者後，治療效果有顯著差異，顯示合併PH藥物可能會混淆治療效果。另外，在一項macitentan多劑量藥物效應動力學研究中，與10 mg的macitentan相比，30 mg的內皮素-1濃度沒有顯著增加，顯示已達到最大值。因此，增加劑量無法確認是否對於試驗的結果會有助益。 因此，透過總結統合分析和討論的結果，將提出一個10 mg macitentan不併用其他肺高壓藥物的臨床研究。考慮到CTEPH患者可以供選擇的藥物非常受限，為了增進該病患族群的福祉，透過提出的試驗評估macitentan在改善CTEPH患者預後方面的潛在益處和風險，解決目前的證據差距，並加深對其在治療這種具有挑戰性的疾病中的作用的理解。

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare condition characterized by the presence of persistent blood clots in the pulmonary arteries, resulting in increased pressure within the lungs and potential severe complications. For managing CTEPH, treatment strategies are comprehensive and may include surgery, balloon pulmonary angioplasty (BPA), and pharmacological therapies targeting the microvascular component of the disease. Additionally, lifelong anticoagulation is often recommended to help prevent recurrent blood clots in patients with CTEPH. In the context of this study, the primary objective was to evaluate the available evidence regarding medical treatments for inoperable CTEPH through a systematic review and meta-analysis of existing literature. Furthermore, the study aimed to explore the potential for a clinical trial based on the insights and conclusions derived from the meta-analysis findings. Methods A systematic review and meta-analysis following PRISMA guidelines, searching EMBASE, PubMed, and Cochrane Library for randomized controlled trials (RCTs) published from January 2000 to December 2023. Studies with inoperable CTEPH and medication therapies were included. Key outcome measurements such as the 6-minute walk distance (6MWD), pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were analyzed across the studies Results In the systematic review, 1,075 database studies and 276 register studies were initially identified. After filtering out duplicates and irrelevant records, 10 studies were included in the final analysis. In total, 815 inoperable CTEPH patients were enrolled across these studies. The analysis of outcomes from RCTs revealed significant improvements in 6MWD with total effect size of 18.22 meters (95% CI: [3.09, 33.34], p = 0.02). The overall treatment effect on PVR is -174.85 dyn·s·cm–5 (95% CI: [-212.02, -137.68], p < 0.00001), indicating a significant improvement. For the treatment effect on mPAP is estimated to be -4.36 mmHg (95% CI: [-7.38, -1.35], p = 0.005). The analysis indicates that there is no statistical significance in the treatment effect on NT-proBNP, with an overall treatment effect estimated at -55.26 pg/mL (95% CI: [-155.29, 44.77], p = 0.28). Conclusions From the results of the meta-analysis, the efficacy was observed in the studies of riociguat, macitentan and treprostinil. Among these medications, riociguat and treprostinil have been approved for CTEPH indications. The clinical phase 2 study in Ghofrani, 2018 provided data to support that macitentan significantly improved 6MWD and PVR, and had the potential to improve right ventricular function and activity function in patients with CTEPH. Subsequently, a study (MACiTEPH , NCT04271475) to evaluate higher doses was initiated in 2020, but the trial was announced to be terminated due to futility in 2023. However, in the studies included in the analysis, the use of other pulmonary hypertension (PH) medications was allowed after 2019. Subgroup analysis in the selexipag studies showed significant differences in treatment effects after excluding patients with the use of pulmonary vasodilators, suggesting that concomitant PH medications may confound treatment effects. Additionally, in a multiple-dose pharmacodynamic study of macitentan, endothelin-1 concentrations at 30 mg did not significantly increase compared with 10 mg of macitentan, indicating that the maximum value had been reached. Therefore, higher dose may not necessarily benefit the results of the trial. Therefore, by summarizing the results of the meta-analysis and discussion, a clinical study of 10 mg macitentan without other pulmonary hypertension drugs will be proposed. Considering that the drug choices available to CTEPH patients are very limited, in order to improve the welfare of this patient group, the proposed trial will evaluate the potential benefits and risks of macitentan in improving the prognosis of CTEPH patients, address the current evidence gap, and deepen the understanding of and understanding of its role in the treatment of this challenging disease.