BackgroundCardiac allograft vasculopathy (CAV) limits survival after heart transplantation, and the effect of different immunosuppressive regimens on CAV is not fully understood. The randomized SCHEDULE trial (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) evaluated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine elimination can reduce CAV development.Methods and ResultsThe SCHEDULE trial was a multicenter Scandinavian trial, where 115 de novo heart transplantation recipients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Seventy-six (66%) patients had matched intravascular ultrasound examinations at baseline and 12 and 36 months. Intravascular ultrasound analysis evaluated maximal intimal thickness, percent atheroma volume, and total atheroma volume. Qualitative plaque analysis using virtual histology assessed fibrous, fibrofatty, and calcified tissue as well as necrotic core. Serum inflammatory markers were measured in parallel. The everolimus group (n=37) demonstrated significantly reduced CAV progression as compared with the cyclosporine group (n=39) at 36 months (Δ maximal intimal thickness, 0.09±0.05 versus 0.15±0.16 mm [P=0.03]; Δ percent atheroma volume, 5.3±2.8% versus 7.6±5.9% [P=0.03]; and Δ total atheroma volume, 33.9±71.2 versus 54.2±96.0 mm³ [P=0.34], respectively]. At 36 months the number of everolimus patients with rejection graded ≥2R was 15 (41%) as compared with 5 (13%) in the cyclosporine group (P=0.01). Everolimus did not affect CAV morphology or immune marker activity during the follow-up period.ConclusionsThe SCHEDULE trial demonstrates that everolimus initiation and early cyclosporine elimination significantly reduces CAV progression at 12 months, and this beneficial effect is clearly sustained at 36 months.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01266148.

中文翻译：

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依维莫司引发和钙调神经磷酸酶抑制剂的消除对从头心脏移植受者心脏同种异体移植血管病变的影响

背景心脏同种异体移植血管病（CAV）限制了心脏移植后的生存，并且尚未完全了解不同免疫抑制方案对CAV的影响。随机的SCHEDULE试验（斯堪的纳维亚心脏移植Everolimus De Novo研究与早期钙调神经磷酸酶抑制剂的避免）评估了启动增殖信号抑制剂依维莫司和早期环孢霉素的消除是否可以减少CAV的发展。心脏移植或标准的基于环孢素的免疫抑制后7至11周，将新接受心脏移植的患者随机分配至依维莫司，并完全停用环孢素。七十六名（66％）患者在基线以及12和36个月时进行了匹配的血管内超声检查。血管内超声分析评估了最大内膜厚度，动脉粥样硬化体积百分比和总动脉粥样硬化体积。使用虚拟组织学对斑块进行定性分析，评估了纤维，纤维脂肪和钙化组织以及坏死核心。平行测量血清炎症标志物。与环孢素组（n = 39）相比，依维莫司组（n = 37）在36个月时CAV进程显着降低（最大内膜厚度Δ为0.09±0.05，而0.15±0.16 mm [P = 0.03]；动脉粥样硬化体积的百分比百分比为5.3±2.8％和7.6±5.9％[ P = 0.03]；和动脉粥样硬化总体积分别为33.9±71.2和54.2±96.0 mm ³ [ P = 0.34]。在36个月时，排斥反应≥2R的依维莫司患者为15（41％），而环孢素组为5（13％）（P = 0.01）。结论：依维莫司在随访期间未影响CAV形态或免疫标记活性。结论SCHEDULE试验表明依维莫司的启动和早期环孢菌素的消除在12个月时显着降低了CAV的进展，并且这种有益效果在36个月时明显得以维持。 ：https：//www.clinicaltrials.gov。唯一标识符：NCT01266148。