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视网膜静脉阻塞继发黄斑水肿的抗VEGF治疗方案的研究进展

Research progress in anti-vascular endothelial growth factor treatment regimens for macular edema secondary to retinal vein occlusion

来源期刊: 眼科学报 | 2021年5月 第36卷 第5期 371-379 发布时间: 收稿时间:2023/5/19 15:45:48 阅读量:3761
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视网膜静脉阻塞黄斑水肿抗血管内皮生长因子治疗方案
retinal vein occlusion macular edema anti-vascular endothelial growth factor treatment regimens
DOI:
10.3978/j.issn.1000-4432.2021.04.08
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抗血管内皮生长因子(vascular endothelial growth factor,VEGF)治疗视网膜静脉阻塞(retinal vein occlusion,RVO)继发黄斑水肿(macular edema,ME)的有效性及安全性已得到广泛证实。但抗VEGF治疗方案尚无统一标准。现行的治疗方案主要包括固定治疗方案、按需(pro re nata,PRN)治疗方案、稳定性标准驱使的按需(stabilization criteria-driven PRN)治疗方案、治疗与延长(treat and extend,T&E)方案。近年来不少研究综合比较了各个治疗方案在改善视功能、量化评估疾病活动性、调整随访频率等多个维度的表现,为临床医生提供选择抗VEGF治疗方案的参考依据。本文旨在回顾并总结近年来对抗VEGF药物治疗RVO继发ME的研究,阐述抗VEGF治疗方案的研究进展。
The efficacy and safety of anti-vascular endothelial growth factor (VEGF) in the treatment of macular edema (ME) secondary to retinal vein occlusion (RVO) have been widely confirmed. However, there is no unified standard for anti-VEGF treatment regimens. Current treatment regimens mainly include fixed treatment regimen, pro re nata (PRN) treatment regimen, stabilization criteria-driven PRN treatment regimen, and treat and extend (T&E) regimen. In recent years, many studies have compared different treatment regimens in composite dimensions,including improving visual function, assessing disease activity quantitatively and adjusting the follow-up frequency,to provide clinicians with a reference of choosing anti-VEGF treatment regimens. The purpose of this article is to review and summarize recent researches on anti-VEGF drugs in the treatment of ME secondary to RVO, and to clarify the research progress in the anti-VEGF treatment regimens.
视网膜静脉阻塞(retinal vein occlusion,RVO)是常见的视网膜血管疾病及主要的全球性致盲疾病之一[1-2]。黄斑水肿(macular edema,ME)是导致RVO患者视力下降的重要原因,发生机制为静脉阻塞引起视网膜静水压增加,血管内皮功能损害,导致血-视网膜屏障破坏,引发眼内包括血管内皮生长因子(vascular endothelial growth factor,VEGF)在内的多种细胞因子上调,从而导致视网膜内毛细血管渗漏,液体积聚形成ME[3]。基于这一病理生理机制,玻璃体腔内注射抗VEGF药物被推荐为治疗RVO继发M E的一线方案,目前获批或超说明书适应证(off-label)的抗VEGF药物主要包括贝伐单抗、雷珠单抗、阿柏西普、康柏西普等[4-8]。在实际的临床应用中,除药物种类外,治疗及随访频率、再治疗标准等问题,也是临床医生在制定治疗方案时应考虑的要点。由此衍生出了诸多抗VEGF治疗方案,如固定治疗方案、按需治疗(pro re nata,PRN)方案、稳定性标准驱使的按需(stability criteria-driven,PRN)治疗方案、治疗与延长(treat and extend,T&E)方案,现将这些抗VEGF治疗方案的研究进展如下。

1 固定治疗方案

在抗VEGF临床试验中,RVO继发ME患者的治疗方案一般采取固定的注射周期。大型随机对照试验一般多以每月注射1次(quaque 1 month,Q1M)的频率进行抗VEGF治疗[9-14],少数研究采用每2个月进行1次注射(quaque 2 month,Q2M)的方案[15]
CRUISE研究[9]、BRAVO研究[10]、COPERNICUS研究[11]、GALILEO研究[13]均证实抗VEGF的Q1M方案与假注射相比,显著改善了RVO患者的视力,降低了黄斑中心凹厚度(central macular thickness,CMT);VIBRANT研究[12]发现阿柏西普的Q1M方案在改善视网膜分支静脉阻塞(branch retinal vein occlusion,BRVO)患者视力及消退M E方面,疗效优于视网膜激光光凝;SCORE2研究[14]表明:阿柏西普和贝伐单抗的Q1M方案均可显著提高视网膜中央静脉阻塞(central retinal vein occlusion,CRVO)患者的视力。结果见表1。
固定治疗方案虽为RVO患者带来了显著的视功能获益及视网膜结构改善,但Thach等[16]回顾BR AVO和CRUISE实验数据后发现:在接受持续6个月的Q1M方案后,超过一半的RVO患者后续仅依赖PRN治疗便足以保持已获得的视力收益,这提示固定治疗方案可能存在一定程度的“过度”治疗。由于频繁的抗VEGF治疗对患者造成的负担较大,临床实践中长时间的固定治疗方案往往很难被严格执行,因此提出更优化的治疗方案势在必行。

表1 固定治疗方案的研究结果
Table 1 Research results of fixed treatment regimen

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2 按需治疗方案

按需治疗方案的提出标志着对“个性化”治疗的探索与尝试,期待在保证患者视力获益的前提下,尽可能减少注射次数。
单纯的PRN方案从治疗初始便完全按照医生对患者病情的判断来决定注射的时机,再治疗的标准大同小异,一般依赖于视力和光学相干断层成像(optical coherence tomography,OCT)检查,若患者满足以下条件中的一项或多项,则行抗VEGF治疗:1)最佳矫正视力(best corrected visual acuity,BCVA)<0.5;2)BCVA较随访期内最佳测量结果降低≥5个字母(提示ME复发或恶化);3 )BCVA较上次随访提升≥5个字母(提示患者BCVA仍有提升空间);4)CMT>300 μm或CMT较随访期内最低值升高>50 μm。
Ahn等[17]比较了贝伐单抗连续3次Q1M的固定治疗方案与PRN方案,发现两种方案中BRVO患者的BCVA或CMT改变在6个月的随访期内无差异,但PRN组平均注射次数[(1.8±0.8)次]显著低于固定治疗方案组[(3.4±0.5)次],提示PRN方案在短期内能以更少的注射次数为BRVO患者争取到与固定治疗方案相似的治疗效果。
PRN治疗方案继续发展,结合了固定治疗方案与单纯PRN方案两者的特点,包含初始的“负荷期”与后续的“维持期”。SHORE研究[18]表明:经过7次连续抗VEGF治疗后BCVA达到稳定者,在第8~15个月无论继续Q1M治疗还是转而接受PRN治疗,其BCVA时间变化率、BCVA的提升及CMT的降低均无显著差异,这提示病情得到一定控制后的M E复发不会对最终视力结局产生不利影响,PRN方案的疗效值得肯定。MARVEL研究[19]发现:1+PRN治疗方案(负荷期予以1次注射,维持期每月随访并决定是否需要再次注射)能显著改善BRVO患者的视力、降低CMT,且通常不需要补救性视网膜光凝治疗。ROCC研究[20]显示:接受雷珠单抗3+PRN治疗方案(负荷期内行连续3次Q1M方案,维持期内每月随访并决定是否需要再次注射)的CRVO患者中,80%(12只眼)在6个月内需要3次以上抗VEGF治疗,因此他们认为即便是负荷期已行3次抗VEGF治疗,维持期的PRN治疗对于保持患者的视力获益依然是必要的。近年来越来越多的临床研究[21-23]证实了3+PRN方案治疗RVO继发ME的有效性及安全性。结果见表2。

表2 PRN治疗方案的研究结果
Table 2 Research results of PRN treatment regimen

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续表2

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为比较1+PRN和3+PRN方案的差异,探讨进一步减少注射次数的可能性,有研究对比了这两种方案的疗效和总注射次数。Ito等[24]认为贝伐单抗治疗BRVO无论是采用1+PRN还是3+PRN方案,均能显著提高BCVA和降低CMT,且1+PRN方案的总注射次数更少。蔡骐等[25]对BRVO患者为期12个月、Osaka等[26]对CRVO患者为期12个月、富莉莉等[27]对RVO患者6个月的研究也报道了1+PRN方案的总注射次数少于3+PRN方案。然而,Miwa等[28]开展的一项前瞻性研究虽再一次证实了雷珠单抗1+PRN和3+PRN方案治疗CRVO在12个月时的疗效及安全性无明显差异,但两组间的总注射次数差异无统计学意义。赵宏锟等[29]对康柏西普治疗BRVO的6个月研究也提示,1+PRN方案对减少总注射次数的作用似乎并不大。LUMINOUS研究[30]是一项为期5年的全球、前瞻性、多中心、开放标签的研究,它观察了真实世界中眼底病患者使用雷珠单抗的实际情况,其中对BRVO的报道显示:接受3+PRN方案治疗者总注射次数虽多于负荷期未接受3针治疗者,但前者在治疗12个月后有更高的视力获益。结果见表2。
使用的抗VEGF药物种类不相同,可能是各个实验比较PRN方案总注射次数结论不一致的原因之一。BRVO患者的预后通常优于CRVO患者[31-32],各个研究纳入的RVO亚型不尽相同可能也是结论不一致的原因。此外可能的原因还有样本量、随访时间、患者基线BCVA、再治疗标准等。
虽然不同的PRN方案总注射次数是否有差异仍有争议,但上述研究展示了PRN方案在临床应用中的实际情况,为临床医生提供了切实的抗VEGF治疗方案参考。

3 稳定性标准驱使的PRN治疗方案

严格来说,稳定性标准驱使的PRN治疗方案依然属于PRN治疗方案的一种,但该方案强调暂停或重启抗VEGF治疗应以BCVA的连续稳定性为参考标准,主要包含3个连续的阶段——治疗启动、暂停、重启。1)初始的抗VEGF治疗为Q1M固定治疗方案,直至BCVA达到稳定标准。2)满足连续3次随访BCVA稳定的条件后,即可暂停抗VEGF治疗,而保持每月1次的随访频率。3)随访时若出现由疾病活动导致的视力下降,则重启治疗,直到视力重新恢复连续3次随访稳定的状态[33]
BRIGHTER研究[33-34]表明:BRVO患者接受雷珠单抗的稳定性标准驱使的PRN治疗方案后,无论是否联合激光治疗,均可快速提升视力,且视力获益至少可以维持24个月。BLOSSOM研究[35]在亚洲的BRVO患者中也得出了相似的结论,尽早开始抗VEGF治疗有利于视力提升,稳定性标准驱使的PRN治疗方案对视力的改善效果可持续至少1 2个月。结果见表3。
稳定性标准驱使的PRN治疗方案较之传统PRN方案,强调了BCVA连续稳定的重要性,但缺憾是仍需要患者每月随访,这种高频率的随访要求在临床实践中存在长期依从性不佳的可能,并且判断病情复发的标准仅有视力这一单一维度,对患者病情的评估略显片面。

表3 稳定性标准驱使的PRN治疗方案的研究结果
Table 3 Research results of stabilization criteria-driven PRN treatment regimen

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4 治疗与延长方案

T&E方案是一种基于某些指征来延长、维持或缩短治疗间隔的治疗方法,分为负荷期和T&E阶段。患者在负荷期接受至少连续3次的Q1M固定治疗,直至在连续3次随访中达到BCVA的稳定,进入T&E阶段。在T&E阶段,每次随访时需进行1次抗VEGF治疗。若随访时没有发现活动性病灶,则下次随访时间每次延长2周,至多可延长至间隔3个月进行一次抗VEGF治疗;若发现任意一项疾病活动性指征,则下次随访间隔缩短2周,直至重新回到Q1M固定治疗。疾病的活动性指征一般包括BCVA下降> 5个字母、眼底出血、OCT上出现视网膜层间积液或视网膜下积液等[36-37]
Hosogi等[38]报道了雷珠单抗T&E方案的有效性,认为T&E方案尤其对视力较差、年龄较大以及主(major)视网膜静脉发生了阻塞的BRVO患者有效。Dirani等[39]认为雷珠单抗的T&E方案稳定地延长了CRVO患者随访与治疗的时间间隔。Guichard等[40]的研究显示:雷珠单抗T&E组的注射次数虽显著多于PRN组,但T&E组患者获得了更好的视网膜形态学结果。SCORE2的延长研究[41]表明:在对抗VEGF药物反应性良好的RVO患者中,T&E方案较Q1M固定治疗方案显著减少了总注射次数,且两种方案疗效一致。结果见表4。
对于不易复发ME的患者,每月1次注射的固定治疗方案可能属过度治疗,但对于频繁复发ME的患者,PRN方案则可能治疗不足[42-43]。T&E方案最突出的特点是根据个体的病情变化来确定合适的随访及治疗时间间隔,并且评估标准综合考量了BCVA、视网膜厚度、OCT特征等多个维度。T&E方案可以说是一种以最小化疾病复发、最大化视力改善为目的的定制化治疗方案。

表4 T&E治疗方案的研究结果
Table 4 Research results of T&E treatment regimen

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5 结语

拥有大量高级别循证医学证据支持的固定治疗方案显然在改善并维持视力上具备突出优势,但该方案在实际临床工作中的治疗及随访成本较高,且玻璃体腔内注射属于有创操作,反复注射抗VEGF药物增加了患者的经济和心理负担,患者依从性可能不佳;PRN方案较固定治疗方案减少了注射次数,但对频繁复发M E的患者可能存在治疗不足的风险,并且1+PRN与3+PRN方案总注射次数的比较仍存在争议;稳定性标准驱使的PRN治疗方案较传统PRN方案强调了视力连续稳定的重要性,但仍需要患者进行每月一次的频繁随访;T&E治疗方案判断病情变化的标准更多元化,同时由于制定了“个性化”的随访及治疗间隔,在保证疗效的同时降低了治疗和随访成本,但对患者管理的要求较高,实际临床应用中较为复杂。虽然现行的抗VEGF治疗方案仍不完美或存在争议,但综合而言T&E方案可能是治疗多种视网膜血管性疾病中更为通用且合适的一种治疗策略[37]
抗VEGF药物在治疗RVO等视网膜血管病变中起到了重要作用,未来的研究除了注重探讨各个方案的疗效、注射次数、随访频率外,还可着眼于探索顽固性或复发性ME患者的预测因素、对抗VEGF药物无(低)应答患者的特征、其他剂量或联合激素的抗VEGF方案、结束抗VEGF治疗的时机及判断标准等,以针对不同的疾病特点设计出更完善的抗VEGF治疗方案。
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1、国家自然科学基金 (81974136);湖北省卫生健康委科研项目 (WJ2019M139)。
This work was supported by the National Natural Science Foundation of China (81974136) and the Scientific Research Project of Hubei Provincial Health Commission (Grant No. WJ2019M139), China.()
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