Purpose

To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab.

Design

Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm.

Participants

Participants with available plasma samples (N = 436).

Methods

Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects.

Main Outcome Measures

Changes in the natural log (ln) of plasma VEGF levels.

Results

Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61 pg/ml, −0.31±0.54 pg/ml, and −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were −0.01 (−0.12 to +0.10; P = 0.89), −0.31 (−0.44 to −0.18; P < 0.001), and −0.30 (−0.43 to −0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (−0.23 [−0.38 to −0.09]; P < 0.001); the difference between aflibercept and ranibizumab was −0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar.

Conclusions

These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.

中文翻译：

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玻璃体腔注射抗血管内皮生长因子治疗糖尿病性黄斑水肿后血浆血管内皮生长因子的浓度

目的

评估玻璃体内阿柏西普，贝伐单抗或兰尼单抗治疗后的全身血管内皮生长因子（VEGF）-A水平。

设计

进行比较治疗后，将参与者随机分配至2毫克abribercept，1.25毫克贝伐单抗或0.3毫克兰尼单抗的比较疗效试验。

参加者

有血浆样品的参与者（N = 436）。

方法

在基线，第4周，第52周和第104周的访问中，在注射前收集血浆样品。在预先计划的二次分析中，比较了抗VEGF药物与酶联免疫吸附法测定的无全身VEGF水平，并将其与全身副作用相关联。

主要观察指标

血浆VEGF水平的自然对数（ln）变化。

结果

所有三组的基线游离VEGF水平均相似。在第4周时，阿柏西单，贝伐单抗和兰尼单抗组的平均ln（VEGF）变化分别为-0.30±0.61 pg / ml，-0.31±0.54 pg / ml和-0.02±0.44 pg / ml。治疗组之间的调整差异（调整后的置信区间[CI]；P值）为-0.01（-0.12至+0.10；P  = 0.89），-0.31（-0.44至-0.18；P <0.001）和-0.30（分别为aflibercept-bevacizumab，aflibercept-ranibizumab和bevacizumab-ranibizumab为-0.43至-0.18；P <0.001）。在第52周时，贝伐单抗和兰尼单抗之间的平均VEGF变化差异持续存在（-0.23 [-0.38至-0.09]；P<0.001）; 阿柏西普和兰尼单抗之间的差异为-0.12（P  = 0.07），阿柏西普和贝伐单抗之间的差异为+0.11（P  = 0.07）。治疗组在2年时的差异与1年相似。在收集血浆前1或2个月内未接受注射的参与者队列中，在52或104周未发现明显的治疗差异。有（N = 9）和没有（N = 251）心脏病发作或中风的参与者的VEGF水平似乎相似。

结论

这些数据表明，与兰尼单抗相比，在第4周，用阿柏西单抗或贝伐单抗治疗后血浆游离VEGF水平的降低更大。在52周和104周时，观察到贝伐单抗相对于兰尼单抗的下降更大。来自在收集前至少1个月和2个月内未接受注射的参与者的2个亚组的结果表明，停止注射后VEGF水平发生了类似的变化。尚不清楚当药物从系统中清除后，VEGF水平是否恢复正常，或者药物的存在是否影响测定法准确测量游离VEGF的能力。没有观察到VEGF浓度与全身性因素之间的显着关联。