阿加曲班治疗急性缺血性卒中中国专家共识指南2021

2021-12-15 中国卒中杂志 网络

目前针对AIS发病早期抗凝治疗的随机对照研究显示,多数抗凝药物虽在一定程度上可降低卒中复发率或减少深静脉血栓形成的风险,但同时会增加出血事件的风险。

卒中是严重危害人类健康的疾病之一,具有高发病率、高残疾率、高死亡率和高复发率的特点,现已成为我国居民(尤其是农村人群)死亡的首要病因,其中急性缺血性卒中(acute ischemic stroke,AIS)约占70%。目前AIS的治疗原则是在治疗时间窗内进行静脉溶栓和(或)血管内治疗(endovascular therapy,EVT),并针对不同病因采取相应的治疗措施,包括抗血小板聚集、抗凝、降血压、降脂和康复治疗等,以减少神经功能残疾和改善疾病预后。
 
目前针对AIS发病早期抗凝治疗的随机对照研究显示,多数抗凝药物虽在一定程度上可降低卒中复发率或减少深静脉血栓形成的风险,但同时会增加出血事件的风险。在抗凝药物中,阿加曲班报道的出血事件较少,且未见肝素诱导性血小板减少(heparin-induced thrombocytopenia,HIT)的报道。鉴于此,阿加曲班已陆续在我国、日本、韩国等国家被批准用于AIS治疗。
 
阿加曲班由日本科学家在1970年研发,是一种经静脉注射的直接凝血酶抑制剂,具有起效快、作用时间短、出血倾向小、无免疫原性等优点。20世纪80年代初在日本首次用于治疗外周动脉闭塞性疾病,后来被批准用于动脉血栓形成、AIS和抗凝血酶缺乏的血液透析患者的抗凝治疗。2000年,阿加曲班被美国食品和药品管理局(Food and Drug Administration,FDA)批准用于预防和治疗成人HIT,包括需要接受经皮冠状动脉介入治疗者。2005年,阿加曲班获得中国国家药品监督管理局批准用于治疗AIS,并且作为二类新药列入“十一五”国家高技术研究发展计划(863计划)。
 
尽管如此,目前对阿加曲班在AIS临床治疗中的应用仍存在着分歧,且在临床实际中的使用经验相对不足。为促进临床医师更加合理、规范地使用阿加曲班,北京神经科学学会组织国内脑血管领域的专家参考国内外抗凝治疗相关指南与专家共识,全面复习阿加曲班相关文献,并结合国内该药的实际应用情况,编写阿加曲班治疗AIS的中国专家共识。治疗方案的推荐等级和证据水平根据表1所列的标准加以衡量和分级,由阿加曲班治疗急性缺血性卒中中国专家共识组的撰写组起草、表决和修订了分级建议和无等级基于共识的声明,直至达成共识。
 

1 阿加曲班的作用机制和药理学特性
1.1 作用机制
阿加曲班是一种直接的凝血酶抑制剂,对游离的或与血块结合的凝血酶活性均可抑制。该药不依赖于抗凝血酶且不被丝氨酸蛋白酶所降解,可高度选择性地与凝血酶完全可逆性结合(抑制指数Ki值约39 nm)并灭活其酶活性,进而抑制由凝血酶催化或诱导的反应,包括纤维蛋白形成、凝血因子(Ⅴ因子、Ⅷ因子和ⅩⅢ 因子)活化、蛋白酶C的活化以及血小板聚集,从而发挥其抗凝作用(图1)。此外,阿加曲班还有抗炎和抗病毒等抗凝以外的药理作用。
 
1.2 药理学特性
 
阿加曲班是人工合成的左旋精氨酸衍生物,分子质量527 Da,是一种低分子抑制物。该药起效快,作用时间短,在具有正常清除率的个体中达到稳态血药浓度的时间仅为1~3 h,且其浓度高低呈药物剂量依赖性关系(输注速率≥40µg·kg-1·min-1),药物清除半衰期为39~51 min,停药后部分活化凝血酶时间(activated partial thromboplastin time,APTT)在2~4 h内即可恢复正常,故临床上可通过APTT监测调控药物的输注速率]。阿加曲班的代谢不受肾功能影响,而是由肝脏的CYP3A4/5氧化酶代谢,代谢物为3-甲基-1,2,3,4-四氢喹啉环,主要通过胆道系统经粪便排出,故在患者肝功能不全时应加强监测。
2  阿加曲班用药途径和剂量、不良反应及预防
 
2.1 用药途径和剂量
治疗发病<48 h的AIS时,阿加曲班推荐的用药剂量和方式为:初始每4 h给药10 mg,持续静脉内泵入,以适当的液体(推荐生理盐水)稀释,连续用药48 h;48 h后改为每12 h一次,每次10 mg,以适当的液体稀释(推荐生理盐水),静脉滴注持续时间≥3 h,连续5 d,总治疗时间为7 d。
2.2  不良反应
阿加曲班的不良反应主要是不同部位的出血,其中出血性脑梗死的发生率为1.2%,消化道出血发生率为0.2%,脑出血发生率为0.1%,另外,偶见过敏和过敏性休克(包括荨麻疹、呼吸困难、血压降低等)。
 
2.3 不良反应的预防
 
(1)AIS患者合并糖尿病高血压[血压≤180/110 mm Hg(1 mm Hg=0.133 kPa)]、冠心病、HIT、肾功能不全时可应用阿加曲班,合并严重的肝脏疾病或肝功能异常患者不建议应用,以防止增加出血风险。
 
(2)阿加曲班应谨慎与溶栓、抗凝、抗血小板聚集或降纤药物联合应用,因与上述药物合用可造成出血风险增加,如必须应用时应注意减量,并进行严密的临床(出血症状)和实验室监测(如APTT)。
 
(3)建议用药最初2 h内监测APTT,应确定APTT在基线值1.5~3.0倍且<100 s,以降低出血风险。APTT监测应每日进行,剂量药物调整时应随时进行。
 
3  阿加曲班在急性缺血性卒中临床治疗中的应用
3.1阿加曲班单药治疗
1997年日本进行的一项多中心、随机、双盲、安慰剂对照研究共纳入了1 1 9 例发病5 d内的大动脉粥样硬化性(large artery atherothrombotic,LAA)缺血性卒中患者,阿加曲班组给予静脉输注阿加曲班60 mg/d,持续48 h,然后静脉输注20 mg,每日2次,持续5 d;安慰剂对照组则静脉输注山梨醇。研究结果显示,与安慰剂对照组相比,阿加曲班组28 d时的整体病况改善(日本昏迷量表、主观症状量表和日常生活能力量表)更为显著(54.2% vs 23.7%);亚组分析显示发病48 h内接受阿加曲班治疗者的整体病况改善率高于发病48 h后接受治疗者(66.7% vs 41.4%);出血不良事件在治疗组和安慰剂对照组中的发生率均较低(1/60和2/59)。该研究首次证实了阿加曲班治疗LAA所致AIS的疗效和安全性。随后韩国、中国的回顾性观察研究也得出了类似结果。近期一项日本全国的回顾性观察研究报道,经倾向性评分匹配(propensity score matching,PSM)后,将发病1 d内的动脉粥样硬化性AIS患者分为阿加曲班治疗组(2289例)和对照组(2289例),并进行了分析,结果发现阿加曲班组与对照组出院时mRS评分无显著差异(OR 1.01,95%CI 0.88~1.16),出血并发症的发生率亦无显著差异(3.5% vs 3.8%,P =0.58),提示阿加曲班尽管使用安全,但对动脉粥样硬化性AIS的早期预后并无额外获益。
 
一项日本标准卒中登记研究回顾性评价了阿加曲班治疗心源性卒中的有效性和安全性,研究共纳入2529例患者,分别使用阿加曲班、肝素和无抗凝治疗。结果显示,与无抗凝治疗组相比,阿加曲班组有降低中型卒中(NIHSS 11~22分)患者的临床严重程度和死亡率的趋势,提示阿加曲班对中型心源性卒中可能有效。
 
另外,还有一些研究也证明了阿加曲班的安全性和有效性,但因其并非专门针对心源性卒中患者,样本量较小,且不是标准的随机对照研究,故证据质量不高。
 
迄今为止,阿加曲班在腔隙性卒中(小动脉闭塞性)方面的研究不多,一项针对非心源性卒中的回顾性研究的亚组分析结果提示,阿加曲班可在一定程度上促进腔隙性卒中患者的神经功能恢复,与LAA亚型患者相比疗效略优,出院时腔隙性卒中患者mRS评分按其分值大小分布的比例是0分(14.5%)、1分(29.7%)、2分(19.6%)、3分(22.5%)、4分(12.3%)、5分(1.4%),而LAA亚型患者则是0分(10.2%)、1分(17.2%)、2分(20.5%)、3分(16.7%)、4分(21.9%)、5分(11.2%)、6分(2.3%)。不过上述研究样本量小、观察时间短,其结论有待更高质量的研究进一步验证。
 
鉴于缺血性卒中是HIT的常见神经系统并发症之一,有研究者对两项阿加曲班治疗HIT所致AIS的前瞻性研究进行了事后分析(960例),将纳入患者分为阿加曲班治疗组(767例)和对照组(193例),其中治疗组接受静脉输注阿加曲班(2 µg·kg-1·min-1),并调整APTT达到基线值的1.5~3倍。结果显示,与对照组相比,阿加曲班治疗组新发缺血性卒中的发生率(OR 0.31,95%CI 0.10~0.96,P =0.041)和卒中相关死亡率(OR 0.18,95%CI 0.03~0.92,P =0.039)均显著降低,且在治疗期间未发生出血事件。目前尚缺乏阿加曲班治疗其他原因或不明原因所致缺血性卒中的研究数据[29]。
 
推荐意见
 
①对于动脉粥样硬化性急性缺血性卒中患者,建议在其发病48 h内启动阿加曲班治疗(强推荐,中等质量证据)。
 
②对于肝素诱导性血小板减少症所致急性缺血性卒中,建议可选择阿加曲班作为抗凝治疗药物(非肝素类)之一(强推荐,中等质量证据)。
 
③对于轻-中型心源性急性缺血性卒中患者,可考虑给予阿加曲班治疗[弱(限定条件)推荐,低质量证据]。
 
④对于小动脉闭塞性急性缺血性卒中患者,可视情形(如为了改善长期预后)使用阿加曲班治疗[弱(限定条件)推荐,低质量证据]。
 
⑤对于其他原因或不明原因所致急性缺血性卒中患者,不建议常规使用阿加曲班治疗(无等级基于共识的声明)。
3.2 阿加曲班联合用药
3.2.1 抗血小板药物
 
一项国内单中心回顾性研究比较了阿加曲班与阿司匹林联用是否比单用阿司匹林更有益于A I S患者的早期结局,其中单用阿司匹林组10 51例,阿加曲班+阿司匹林联合治疗组434例。单用阿司匹林组的治疗方案为阿司匹林300 mg/d,联合治疗组的方案为在阿司匹林100 mg/d的基础上加用①阿加曲班60 mg/d,连续2 d,然后改为20 mg/d,总治疗时间≤4周,或②持续阿加曲班20 mg/d,治疗时间≤4周。研究结果显示,单用阿司匹林组和联合治疗组均未观察到症状性脑出血;两组患者出院时NIHSS评分均较本组治疗前显著降低;两组间出院时的NIHSS评分变化(较治疗前)无显著性差异(P =0.059)。在轻型卒中(NIHSS≤4分)亚组中,阿加曲班组出院时的NIHSS评分较本组治疗前更高(P =0.002),而阿司匹林组NIHSS评分则较治疗前明显下降(P <0.0 01)。在中型卒中(NIHS S 5~15分)亚组中,两组患者出院时NIHSS评分均较治疗前均显著降低(均P <0.001),两组间出院时的NIHS S评分变化(较治疗前)无显著性差异(P =0.059)。上述结果提示,阿加曲班与阿司匹林联合治疗中型AIS有效且安全,且与高剂量阿司匹林单药治疗效果相当,但对轻型AIS的治疗效果可能劣于后者。近来国内另一项回顾性研究(502例)则报道了阿加曲班与双重抗血小板治疗(dual antiplatelet therapy,DAPT)对NIHSS≤10分的轻型后循环缺血性卒中患者早期神经功能恶化(earlyneurological deterioration,END)的疗效。
 
其中阿加曲班的方案为6 0 mg/d,连续输注2 d,随后每天输注20 mg或30 mg,持续2~5 d;DAPT方案为氯吡格雷单次负荷量300 mg,随后75 mg/d+阿司匹林100 mg/d,持续7 d。研究结果显示,与单用DAPT治疗组(467例)比较,阿加曲班联合DAPT组(35例)未发生END(PSM前:0 vs 6.2%,P =0.250;PSM后:0 vs 5.9%,P =0.298);从基线检查到住院7 d后的NIHSS评分亦显著降低(P =0.032),但该差异在PSM后未达统计学意义(P =0.369);所有患者均未出现症状性颅内出血,表明阿加曲班与DAPT短期联合应用对急性轻型后循环缺血性卒中安全且有效。与之类似,日本的一项回顾性研究也报道了阿加曲班与DAPT联合应用治疗急性(发病≤48 h)穿支动脉梗死的疗效。在该研究中,患者被分为阿加曲班+阿司匹林+氯吡格雷(argatroban,aspirin and clopidogrel,AAC)组和阿加曲班+阿司匹林(argatroban and aspirin,AA)两组,阿加曲班的用法为60 mg/d连续使用2 d,随后20 mg/d连用5 d;阿司匹林单次负荷量200 mg,随后100 mg/d治疗;氯吡格雷单次负荷量300 mg,随后75 mg/d治疗,以上三种药物总疗程均为7 d。结果显示AAC组卒中进展(入院7 d的NIHSS评分较入院时升高≥2分)发生率显著低于AA组。另一项日本的研究则回顾分析了阿加曲班联合抗血小板药物治疗AIS和TIA的安全性,所有入组患者(341例)均接受阿加曲班60 mg/d+西洛他唑200 mg/d+氯吡格雷75 mg/d(75%入组者氯吡格雷单次负荷量300 mg,其余25%则初始剂量为75 mg/d),66%的入组者在阿加曲班治疗后开始连续静脉注射肝素[中位时间5 d(1~26 d)],西洛他唑和氯吡格雷这两种抗血小板药物的中位持续时间为12 d(2~30 d)。结果显示,入组患者中重度、中度和轻度颅外出血分别发生了1例(0.3%)、3例(0.9%)和4例(1.2%),无症状性颅内出血发生,研究再次证实了阿加曲班与抗血小板药物联合应用的安全性。
 
推荐意见
 
①对于中型缺血性卒中(NIHSS 5~15分)且低出血风险的患者,建议给予阿加曲班联合阿司匹林治疗[弱(限定条件)推荐,中等质量证据]。
 
②对于急性穿支动脉梗死或后循环梗死患者,建议可谨慎选用阿加曲班联合双重抗血小板治疗(阿司匹林联合氯吡格雷)进行治疗,但须注意出血风险[弱(限定条件)推荐,低质量证据]。
 
3.2.2 静脉溶栓和血管内治疗
 
为了探究阿加曲班与rt-PA联合应用的安全性和有效性,欧美国家开展了一系列阿加曲班联合r t-PA治疗急性卒中(argatroban with recombinant tissue plasminogen activator for acute stroke,ARTSS)的多中心研究。ARTSS-1是一项开放标签的探索性研究,旨在分析阿加曲班联合静脉注射rt-PA的安全性。该试验纳入了6 5 例A I S患者,责任血管为大脑中动脉M1或M2段、颈内动脉终末端、大脑后动脉P1或P2段近端、椎动脉远端或基底动脉,NIHSS中位数为13分,58例患者(89%)在rt-PA注射1 h内给予阿加曲班静脉团注3~5 min(100 μg / k g),随后静脉滴注(1µg·kg-1·min-1)48 h,并调整APTT至其基线值的1.75倍左右(±10%),在发病2~2 4 h内利用TCD或CTA评估是否血管再通。该研究中4例患者发生脑出血(6.2%,95%CI 1.7%~15.0%),其中3例为症状性出血(4.6%,95%CI 0.9%~12.9%);7例患者(10%)在发病7 d内死亡;在2 h监测期内,TCD检查显示29例(61%)患者血管再通,其中19例(40%)为完全再通,10例(21%)为部分再通。该研究结果表明,对颅内动脉近端血管闭塞所致中型AIS,阿加曲班联合静脉rt-PA溶栓治疗安全,且可能较单纯静脉溶栓治疗血管再通率更高。
 
ARTSS-2作为一项随机探索性研究,旨在检验阿加曲班联合静脉rt-PA溶栓治疗AIS的有效性和安全性。90例患者被随机分为单纯rt-PA组(29例)、rt-PA+低剂量阿加曲班组(30例)和rt-PA+高剂量阿加曲班组(31例)。低剂量阿加曲班治疗方案为100 μg/kg静脉团注3~5 min,随后静脉滴注1 µg·kg-1·min-1,持续48 h,调整APTT至其基线值的1.75倍;高剂量阿加曲班治疗方案为100 μg/kg静脉团注3~5 min,随后静脉滴注3 µg·kg-1·min-1,持续48 h,调整APTT至其基线值的2.25倍。结果显示,对照组、低剂量组和高剂量组的症状性脑出血发生率分别为3/29(10%)、4/30(13%)和2/31(7%);低剂量、高剂量、低剂量+高剂量阿加曲班组mRS 0~1分的OR(95%CI)分别为1.17(0.57~2.37)、1.27(0.63~2.53)和1.34(0.68~2.76),以上三组阿加曲班辅助治疗优于单用r t-PA的概率分别为67%、74%和80%。该研究结果表明阿加曲班与rt-PA联合应用安全,并提示rt-PA与阿加曲班联合用药较单用rt-PA有潜在优势。
 
美国一项临床Ⅱ期、单臂、可行性和安全性ARTSS-动脉治疗(ARTSS-arterial therapy in stroke,ARTSS-IA)研究中,对10例由颅内前后循环大血管闭塞所致AIS患者进行了标准剂量rt-PA静脉溶栓,且在发病6 h内桥接EVT,静脉溶栓期间 阿加曲班静脉团注3~5 min(100 μg/kg),随后静脉滴注(3 µg·kg-1·min-1)12 h,并调整APTT至其基线值的2.25倍左右(±10%)。研究结果显示,9例(90%)患者血管造影示血管再通(TICI≥2b级),其中7例为完全再通(TICI 3级);所有患者无症状性颅内出血、全身出血或EVT并发症;发病90 d时,6例(60%)患者的mRS为0~2分,无患者死亡。该研究结果提示,对于接受rt-PA静脉溶栓和EVT的AIS患者,静脉溶栓期间联合阿加曲班可行,血管再通率较高且较安全。
 
在韩国一项研究中,Kim等共纳入302例大血管闭塞8 h内行EVT的患者,其中182例接受机械取栓(mechanical thrombectomy,MT)+阿加曲班治疗,治疗方案为在MT后迅速给予阿加曲班静脉团注3~5 min(100 μg/kg),随后静脉滴注(3 µg·kg-1·min-1)24 h,并调整APTT值达到其基线值的1.75~2.25倍(±10%),120例仅接受MT治疗。结果显示,与MT组相比,MT+阿加曲班组在24 h和7 d内血管再闭塞的发生率均显著降低(2.5% vs 6.0%,P =0.018;4.2% vs 8.2%,P =0.020),而两组之间的并发症(如脑出血)发生率则无显著差异,表明MT术后应用阿加曲班可防止靶动脉再闭塞,且不增加出血风险。
 
推荐意见
 
①对于需要静脉溶栓的急性缺血性卒中患者,应视其病情严重程度和出血风险等情况,在充分权衡治疗所带来的获益和风险后,于rt-PA注射1 h内给予阿加曲班治疗,首先静脉团注3~5 min(100 μg/kg),随后静脉滴注(1 µg·kg-1·min-1),并调整APTT至其基线值的1.75倍左右(±10%)[弱(限定条件)推荐,中等质量证据]。
 
②对于由颅内大血管闭塞所致急性缺血性卒中患者,在接受机械取栓或桥接治疗(静脉溶栓+机械取栓)时,建议视同①情况,在充分权衡治疗所带来的获益和风险后,于取栓后或静脉溶栓后给予阿加曲班治疗,并调整APTT至其基线值的1.75~2.25倍(±10%)[弱(限定条件)推荐,低质量证据]。

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    2022-05-22 yahu
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    2021-12-16 ms3000001643437590

    棒棒哒

    0

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    2021-12-16 wangaihe2008

    学习

    0

  8. [GetPortalCommentsPageByObjectIdResponse(id=1747867, encodeId=28a71e47867e9, content=<a href='/topic/show?id=be239e730a8' target=_blank style='color:#2F92EE;'>#阿加曲班#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=48, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97730, encryptionId=be239e730a8, topicName=阿加曲班)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e32535969012, createdName=yahu, createdTime=Sun May 22 11:23:54 CST 2022, time=2022-05-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1741678, encodeId=90821e4167852, content=<a href='/topic/show?id=c2c621665c4' target=_blank style='color:#2F92EE;'>#中国专家共识#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=65, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=21665, encryptionId=c2c621665c4, topicName=中国专家共识)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=218a34934063, createdName=12498f1em19(暂无昵称), createdTime=Tue Nov 08 16:23:54 CST 2022, time=2022-11-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1893456, encodeId=31f1189345683, content=<a href='/topic/show?id=c738e93521f' target=_blank style='color:#2F92EE;'>#缺血性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=79352, encryptionId=c738e93521f, topicName=缺血性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=66ec123, createdName=guihongzh, createdTime=Sun Feb 27 02:23:54 CST 2022, time=2022-02-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1806485, encodeId=d5301806485ab, content=<a href='/topic/show?id=b649e9358fa' target=_blank style='color:#2F92EE;'>#缺血性卒#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=79358, encryptionId=b649e9358fa, topicName=缺血性卒)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Tue May 31 16:23:54 CST 2022, time=2022-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1845885, encodeId=40d118458855a, content=<a href='/topic/show?id=5d2f206482e' target=_blank style='color:#2F92EE;'>#专家共识#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=20648, encryptionId=5d2f206482e, topicName=专家共识)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=568152, createdName=snowpeakxu, createdTime=Thu May 05 17:23:54 CST 2022, time=2022-05-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1080737, encodeId=a6c01080e37cb, content=棒棒哒, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=af2c5726846, createdName=ms3000001643437590, createdTime=Thu Dec 16 13:36:30 CST 2021, time=2021-12-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1080682, encodeId=37a210806825a, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=9cf01367543, createdName=wangaihe2008, createdTime=Thu Dec 16 10:42:47 CST 2021, time=2021-12-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1080474, encodeId=b60a10804e46b, content=挺好学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=92c21342778, createdName=478731624qq, createdTime=Wed Dec 15 23:35:07 CST 2021, time=2021-12-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1080362, encodeId=11da108036215, content=不错,学习了。, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210606/e8b96fdba070433da10cd357c0646807/28bf16f46e314caaad8396c0c7df7a04.jpg, createdBy=adb15496357, createdName=仁术2021, createdTime=Wed Dec 15 17:56:57 CST 2021, time=2021-12-15, status=1, ipAttribution=)]
    2021-12-15 478731624qq

    挺好学习了

    0

  9. [GetPortalCommentsPageByObjectIdResponse(id=1747867, encodeId=28a71e47867e9, content=<a href='/topic/show?id=be239e730a8' target=_blank style='color:#2F92EE;'>#阿加曲班#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=48, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97730, encryptionId=be239e730a8, topicName=阿加曲班)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e32535969012, createdName=yahu, createdTime=Sun May 22 11:23:54 CST 2022, time=2022-05-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1741678, encodeId=90821e4167852, content=<a href='/topic/show?id=c2c621665c4' target=_blank style='color:#2F92EE;'>#中国专家共识#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=65, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=21665, encryptionId=c2c621665c4, topicName=中国专家共识)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=218a34934063, createdName=12498f1em19(暂无昵称), createdTime=Tue Nov 08 16:23:54 CST 2022, time=2022-11-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1893456, encodeId=31f1189345683, content=<a href='/topic/show?id=c738e93521f' target=_blank style='color:#2F92EE;'>#缺血性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=79352, encryptionId=c738e93521f, topicName=缺血性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=66ec123, createdName=guihongzh, createdTime=Sun Feb 27 02:23:54 CST 2022, time=2022-02-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1806485, encodeId=d5301806485ab, content=<a href='/topic/show?id=b649e9358fa' target=_blank style='color:#2F92EE;'>#缺血性卒#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=79358, encryptionId=b649e9358fa, topicName=缺血性卒)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Tue May 31 16:23:54 CST 2022, time=2022-05-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1845885, encodeId=40d118458855a, content=<a href='/topic/show?id=5d2f206482e' target=_blank style='color:#2F92EE;'>#专家共识#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=20648, encryptionId=5d2f206482e, topicName=专家共识)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=568152, createdName=snowpeakxu, createdTime=Thu May 05 17:23:54 CST 2022, time=2022-05-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1080737, encodeId=a6c01080e37cb, content=棒棒哒, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=af2c5726846, createdName=ms3000001643437590, createdTime=Thu Dec 16 13:36:30 CST 2021, time=2021-12-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1080682, encodeId=37a210806825a, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=9cf01367543, createdName=wangaihe2008, createdTime=Thu Dec 16 10:42:47 CST 2021, time=2021-12-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1080474, encodeId=b60a10804e46b, content=挺好学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=92c21342778, createdName=478731624qq, createdTime=Wed Dec 15 23:35:07 CST 2021, time=2021-12-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1080362, encodeId=11da108036215, content=不错,学习了。, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210606/e8b96fdba070433da10cd357c0646807/28bf16f46e314caaad8396c0c7df7a04.jpg, createdBy=adb15496357, createdName=仁术2021, createdTime=Wed Dec 15 17:56:57 CST 2021, time=2021-12-15, status=1, ipAttribution=)]
    2021-12-15 仁术2021

    不错,学习了。

    0

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