Transplantation Center Munich, Ludwig-Maximilians-University, Munich, Germany.
J Heart Lung Transplant. 2013 Mar;32(3):277-84. doi: 10.1016/j.healun.2012.11.028.
Despite improvements in immunosuppressive therapy, the most advantageous combination for cardiac transplant recipients has not been established. This randomized controlled trial was performed to evaluate the efficacy and safety of 3 immunosuppressive protocols.
Between 2003 and 2005, 78 de novo cardiac transplant recipients were randomized 2:2:1 to receive steroids and tacrolimus plus mycophenolate mofetil (TAC/MMF; n = 34), TAC and sirolimus (TAC/SRL; n = 29), or SRL and MMF (SRL/MMF) plus anti-thymocyte globulin (ATG; n = 15). Steroids were withdrawn after 6 months.
The 5-year survival was 85.3% for TAC/MMF, 93.1% for TAC/SRL, and 86.7% for SRL/MMF (p = 0.31 for TAC/MMF vs TAC/SIR; p = 0.47 for TAC/MMF vs SIR/MMF and p = 0.86 for TAC/SIR vs SIR/MMF). Despite the use of ATG, patients in the SRL/MMF group revealed numerically fewer freedom from acute rejection episodes: TAC/MMF, 82.4%; TAC/SRL, 85.2%; SRL/MMF, 73.3% (p = 0.33). Mean creatinine at 5 years revealed preservation of renal function in the SRL/MMF vs the TAC/MMF group (p = 0.045): TAC/MMF, 1.70±0.91 mg/dl; TAC/SRL, 1.44±0.65 mg/dl; and SRL/MMF, 1.25±0.46 mg/dl. Freedom from cardiac allograft vasculopathy was improved in the SRL/MMF group (93.3%) compared with TAC/MMF (73.5%) and TAC/SRL (80.8%) groups, reaching no statistical significance. Freedom from cytomegalovirus infection was TAC/MMF, 72.2%; TAC/SRL, 89.7%; and SRL/MMF, 86.7%. There was a trend toward improved freedom from cytomegalovirus infection with TAC/SRL vs TAC/MMF (p = 0.076). More frequent discontinuations of study medication occurred in SRL-based immunosuppression protocols (TAC/SRL vs TAC/MMF, p = 0.034; SRL/MMF vs TAC/MMF, p = 0.003).
The 3 strategies yield no survival advantage at 5 years, with higher numeric rates of rejection and adverse effects in the calcineurin inhibitor-free arm. A trend was observed in favor of freedom from cardiac allograft vasculopathy and preservation of renal function in the calcineurin inhibitor-free arm. However, the clinical relevance on outcomes is unclear because only few patients were receiving the assigned treatment protocols.
尽管免疫抑制治疗有所改善，但尚未确定心脏移植受者最有利的联合用药方案。本随机对照试验旨在评估 3 种免疫抑制方案的疗效和安全性。
2003 年至 2005 年，78 例初发心脏移植受者随机分为 2:2:1 组，分别接受类固醇和他克莫司加霉酚酸酯（TAC/MMF；n = 34）、他克莫司和西罗莫司（TAC/SRL；n = 29）或西罗莫司和霉酚酸酯（SRL/MMF）加抗胸腺细胞球蛋白（ATG；n = 15）。类固醇在 6 个月后停用。
TAC/MMF、TAC/SRL 和 SRL/MMF 组的 5 年生存率分别为 85.3%、93.1%和 86.7%（TAC/MMF 与 TAC/SRL 相比，p = 0.31；TAC/MMF 与 SRL/MMF 相比，p = 0.47；TAC/SRL 与 SRL/MMF 相比，p = 0.86）。尽管使用了 ATG，但 SRL/MMF 组急性排斥反应发作的无事件率较低：TAC/MMF 组为 82.4%，TAC/SRL 组为 85.2%，SRL/MMF 组为 73.3%（p = 0.33）。5 年时的平均肌酐值显示 SRL/MMF 组肾功能保存优于 TAC/MMF 组（p = 0.045）：TAC/MMF 组为 1.70±0.91mg/dl，TAC/SRL 组为 1.44±0.65mg/dl，SRL/MMF 组为 1.25±0.46mg/dl。SRL/MMF 组的心脏移植血管病无事件率（93.3%）优于 TAC/MMF 组（73.5%）和 TAC/SRL 组（80.8%），但无统计学意义。TAC/MMF 组、TAC/SRL 组和 SRL/MMF 组的巨细胞病毒感染无事件率分别为 72.2%、89.7%和 86.7%。TAC/SRL 组较 TAC/MMF 组巨细胞病毒感染无事件率有升高趋势（p = 0.076）。SRL 为基础的免疫抑制方案中更频繁地停用研究药物（TAC/SRL 与 TAC/MMF 相比，p = 0.034；SRL/MMF 与 TAC/MMF 相比，p = 0.003）。
3 种策略在 5 年内均未显示生存优势，无钙调神经磷酸酶抑制剂组排斥反应和不良反应的发生率更高。无钙调神经磷酸酶抑制剂组的心脏移植血管病无事件率和肾功能保存有升高趋势。然而，由于只有少数患者接受了指定的治疗方案，因此其对结果的临床相关性尚不清楚。
