Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Lancet Respir Med. 2024 Jan;12(1):34-44. doi: 10.1016/S2213-2600(23)00293-X. Epub 2023 Sep 10.
Evidence is low regarding the choice of calcineurin inhibitor for immunosuppression after lung transplantation. We aimed to compare the use of tacrolimus once per day with ciclosporin twice per day according to the current definition of chronic lung allograft dysfunction (CLAD) after lung transplantation.
ScanCLAD is an investigator-initiated, open-label, multicentre, randomised, controlled trial in Scandinavia evaluating whether an immunosuppressive protocol based on anti-thymocyte globulin induction followed by tacrolimus (once per day), mycophenolate mofetil, and corticosteroids reduces the incidence of CLAD after de novo lung transplantation compared with a protocol using ciclosporin (twice per day), mycophenolate mofetil, and corticosteroids. Patients aged 18-70 years who were scheduled to undergo double lung transplantation were randomly allocated (1:1) to receive either oral ciclosporin (2-3 mg/kg before transplantation and 3 mg/kg [twice per day] from postoperative day 1) or oral tacrolimus (0·05-0·1 mg/kg before transplantation and 0·1-0·2 mg/kg from postoperative day 1). The primary endpoint was CLAD at 36 months post transplantation, determined by repeated lung function tests and adjudicated by an independent committee, and was assessed with a competing-risks analysis with death and re-transplantation as competing events. The primary outcome was assessed in the modified intention-to-treat (mITT) population, defined as those who underwent transplantation and received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02936505) and EudraCT (2015-004137-27).
Between Oct 21, 2016, and July 10, 2019, 383 patients were screened for eligibility. 249 patients underwent double lung transplantation and received at least one dose of study drug, and were thus included in the mITT population: 125 (50%) in the ciclosporin group and 124 (50%) in the tacrolimus group. The mITT population consisted of 138 (55%) men and 111 (45%) women, with a mean age of 55·2 years (SD 10·2), and no patients were lost to follow-up. In the mITT population, CLAD occurred in 48 patients (cumulative incidence 39% [95% CI 31-48]) in the ciclosporin group and 16 patients (13% [8-21]) in the tacrolimus group at 36 months post transplantation (hazard ratio [HR] 0·28 [95% CI 0·15-0·52], log-rank p<0·0001). Overall survival did not differ between groups at 3 years in the mITT population (74% [65-81] for ciclosporin vs 79% [70-85] for tacrolimus; HR 0·72 [95% CI 0·41-1·27], log-rank p=0·25). However, in the per protocol CLAD population (those in the mITT population who also had at least one post-baseline lung function test allowing assessment of CLAD), allograft survival was significantly better in the tacrolimus group (HR 0·49 [95% CI 0·26-0·91], log-rank p=0·021). Adverse events totalled 1516 in the ciclosporin group and 1459 in the tacrolimus group. The most frequent adverse events were infection (453 events), acute rejection (165 events), and anaemia (129 events) in the ciclosporin group, and infection (568 events), anaemia (108 events), and acute rejection (98 events) in the tacrolimus group. 112 (90%) patients in the ciclosporin group and 108 (87%) in the tacrolimus group had at least one serious adverse event.
Immunosuppression based on use of tacrolimus once per day significantly reduced the incidence of CLAD compared with use of ciclosporin twice per day. These findings support the use of tacrolimus as the first choice of calcineurin inhibitor after lung transplantation.
Astellas, the ALF-agreement, Scandiatransplant Organization, and Heart Centre Research Committee, Rigshospitalet, Denmark.
肺移植后，选择钙调磷酸酶抑制剂进行免疫抑制的证据有限。我们的目的是根据当前慢性肺移植物功能障碍（CLAD）的定义，比较每天使用他克莫司与每天使用环孢素 2 次治疗肺移植后的患者。
ScanCLAD 是一项由研究者发起的、开放标签、多中心、随机对照试验，在斯堪的纳维亚进行，评估基于抗胸腺细胞球蛋白诱导的免疫抑制方案（每天使用他克莫司、霉酚酸酯和皮质类固醇）与基于环孢素（每天 2 次使用、霉酚酸酯和皮质类固醇）的方案相比，是否可以降低肺移植后新发 CLAD 的发生率。计划接受双肺移植的年龄在 18-70 岁的患者，按照 1:1 的比例随机分配，接受口服环孢素（移植前 2-3mg/kg，术后第 1 天起 3mg/kg[每天 2 次]）或口服他克莫司（移植前 0.05-0.1mg/kg，术后第 1 天起 0.1-0.2mg/kg）。主要终点是移植后 36 个月时的 CLAD，通过重复肺功能测试确定，并由独立委员会裁决，采用竞争风险分析，以死亡和再次移植为竞争事件。主要结局在改良意向治疗（mITT）人群中进行评估，定义为接受移植并至少接受一剂研究药物的人群。该研究在 ClinicalTrials.gov（NCT02936505）和 EudraCT（2015-004137-27）注册。
2016 年 10 月 21 日至 2019 年 7 月 10 日，对 383 名患者进行了筛选，以确定其是否符合条件。249 名患者接受了双肺移植，并至少接受了一剂研究药物，因此纳入 mITT 人群：环孢素组 125 例（50%），他克莫司组 124 例（50%）。mITT 人群中，138 例（55%）为男性，111 例（45%）为女性，平均年龄 55.2 岁（标准差 10.2），无患者失访。在 mITT 人群中，环孢素组 48 例（累积发生率 39%[95%CI 31-48]）和他克莫司组 16 例（13%[8-21]）在移植后 36 个月时发生 CLAD（风险比[HR]0.28[95%CI 0.15-0.52]，对数秩检验 p<0.0001）。在 mITT 人群中，3 年时总体生存率在两组之间没有差异（环孢素组为 74%[65-81]，他克莫司组为 79%[70-85]；HR 0.72[95%CI 0.41-1.27]，对数秩检验 p=0.25）。然而，在按方案 CLAD 人群（mITT 人群中至少有一次基线后肺功能测试可评估 CLAD）中，他克莫司组的移植物存活率显著提高（HR 0.49[95%CI 0.26-0.91]，对数秩检验 p=0.021）。环孢素组发生了 1516 次不良事件，他克莫司组发生了 1459 次不良事件。环孢素组最常见的不良事件是感染（453 例）、急性排斥反应（165 例）和贫血（129 例），他克莫司组是感染（568 例）、贫血（108 例）和急性排斥反应（98 例）。环孢素组有 112 例（90%）患者和他克莫司组有 108 例（87%）患者发生至少一次严重不良事件。
与每天使用环孢素 2 次相比，每天使用他克莫司显著降低了 CLAD 的发生率。这些发现支持将他克莫司作为肺移植后钙调磷酸酶抑制剂的首选。
Astellas、ALF 协议、Scandiatransplant Organization、丹麦 Rigshospitalet 心脏中心研究委员会。
