ST段抬高心肌梗死溶栓后早期冠脉介入治疗对心肌灌注的影响及山莨菪碱的心肾保护作用
摘要
ST段抬高心肌梗死(ST-segment elevation myocardial infarction,STEMI)是在冠状动脉病变的基础上,发生冠状动脉血供急剧减少或中断,使相应的心肌严重而持久地急性缺血而导致的心肌坏死。目前,全球每年约有1700万人死于心血管疾病,其中近半数死于STEMI。近年来,我国STEMI的发病率一直呈上升趋势,急性期病死率高,并且发病人群有年轻化趋势,形势日趋严峻。及早、有效的实施再灌注治疗是STEMI治疗的关键。然而根据卫生部的资料,我国每年发病12小时内进行的急诊直接经皮冠状动脉介入治疗(percutenous coronary intervention, PCI)的患者仅占STEMI患者的3%,仍有相当多的患者未能在STEMI发病早期接受有效的再灌注治疗,进而导致患者预后不良。为缩短再灌注治疗延迟时间、提高再灌注治疗的成功率、改善患者预后,将药物治疗与介入干预相结合的药物介入联合干预策略(pharmacoinvasive strategy)是未来STEMI救冶的主要方向之一,这也是近年来欧美相关指南所传递的重要信息。但是目前在对溶栓后早期PCI的心肌灌注效果、出血并发症以及远期预后方面仍有待深入研究。
再灌注治疗的目标是恢复冠脉血流,保证心肌灌注。但是部分患者在心外膜冠脉开通后无法实现心肌水平的完全灌注,造成心肌持续损伤。近年来,人们尝试采用药物治疗和血栓抽吸等多种方式改善PCI后心肌灌注,然而其治疗策略仍有待进一步探索。山莨菪碱(anisodamine)为我国从茄科植物唐古特莨菪中分离出的一种生物碱,具有提高冠脉灌注压、改善微循环、降低血小板聚集、抑制血栓形成、保护心肌的作用。血小板GPIIb
Ⅲa受体拮抗剂替罗非班可以作用于血小板聚集的最终共同通路,抑制血小板的活化、黏附和聚集,从而阻止动脉血栓形成,不仅可以改善心外膜血流,也可减少无复流现象,在心肌微循环水平实现更好的血流灌注。我中心前期研究发现,冠脉内注射山莨菪碱和替罗非班对STEMI患者直接PCI术中的无复流现象具有逆转作用。但是上述两种药物对溶栓后早期PCI心肌灌注的影响尚缺乏研究,两种药物联用时是否存在协同效应尚不明确。
本研究以前期研究为基础,着重探讨对首诊于无直接PCI条件医院的STEMI患者溶栓后早期(12小时内)经前臂桡动脉入径行PCI的安全性和可行性,并观察早期PCI前预防性冠脉应用山莨菪碱和替罗非班对溶栓早期PCI后心肌灌注的改善作用,分析山莨菪碱的血流动力学效应以及两种药物的相互作用关系,同时观察研究山莨菪碱对直接PCI术后对比剂肾病(contrast induced nephropathy, CIN)的防治作用,以期为优化STEMI早期再灌注治疗提供参考。
本研究共分为四个部分：
第一部分
ST段抬高心肌梗死患者溶栓后早期经桡动脉入径行经皮冠状动脉介入治疗的安全性和有效性
目的：观察比较溶栓后早期经桡动脉入径行经皮冠状动脉介入治疗(PCI)与直接PCI对冠脉血流、心肌灌注水平、心功能以及主要心脏不良事件((?)major adverse cardiac events, MACE)的影响,探讨ST段抬高心肌梗死(STEMI)患者经桡动脉入径行溶栓后早期PCI的安全性和有效性。
方法：入选2009年9月至2010年3月就诊于河北医科大学第二医院的发病12小时内STEMI连续病例以及同期就诊的溶栓后12小时内拟行早期PCI的STEMI连续病例。根据患者先前是否接受静脉溶栓治疗将符合条件的患者分为：早期PCI组(early PCI group, E-PCI组,患者在无PCI条件医院接受溶栓治疗后立即转运行早期PCI)和直接PCI组(primary PCI group, P-PCI组,患者接受直接PCI治疗)。E-PCI组患者在外院应用阿替普酶或瑞替普酶进行静脉溶栓治疗后转运至我院行早期PCI。冠脉造影检查(coronary angiography, CAG)和PCI均经桡动脉入径进行。根据患者CAG结果,对梗死相关动脉(infarction related artery, IRA)血流未达到TIMI3级或IRA血流达到TIMI3级但狭窄超过75%的患者行PCI治疗。药物治疗(阿司匹林、氯吡格雷、静脉血管扩张剂、他汀类药物、beta受体阻滞剂以及ACEI等)根据现行指南推荐的最佳治疗方案给予患者。比较两组患者冠脉造影结果、心肌灌注水平、PCI术后出血并发症的发生情况以及住院时程。PCI术后进行6个月随访记录,比较两组患者心功能变化和MACE事件发生情况。主要终点事件为PCI术后心肌灌注水平,采用TIMI血流分级(TFG)、校正的TIMI记帧(CTFC)和TIMI心肌灌注分级(TMPG)评价；次要终点事件为住院期间出血并发症和6个月MACE的发生情况。所有统计学分析使用SPSS17.0软件(SPSS Inc., Chicago, Illinois)进行。双侧P<0.05认为存在统计学差异。
结果：本研究共计入选病例161例,其中E-PCI组53例,P-PCI组108例。与P-PCI组患者相比,E-PCI组患者较年轻(51.36±12.24岁vs.57.31±9.87岁,P=0.003)。两组其他基线临床资料如性别、killip分级、梗死部位、基线BNP水平、血肌酐和血红蛋白浓度,以及基础药物的使用情况均无显著差异(all P>0.05)。E-PCI组患者发病至接受溶栓治疗的平均时间为3.62±1.85小时,溶栓至PCI的平均时间为5.13±3.03小时。P-PCI组患者发病至接受直接PCI的时间为6.03±3.19h。PCI术前E-PCI组IRA血栓积分较低,TIMI血流3级的比例较高(both P<0.05)。PCI术后TIMI血流3级比例相似(P=0.076),两组患者使用对比剂剂量无明显差异(167.92±58.49ml vs.174.40±48.04ml, P=0.456)。然而,PCI术后E-PCI组CTFC明显低于P-PCI组(28.12±5.06vs.30.89±8.74, P=0.034), TMPG3级的比例高于P-PCI组(82.8%vs.68.0%,P=0.042)。两组患者均使用药物洗脱支架,人均植入支架数、植入支架的平均长度以及支架植入后病变最小内径(MLD)相似(all P>0.05)。与P-PCI组相比,E-PCI组患者CK-MB峰值存在减低趋势(229.08±189.53U/L vs.275.35±129.67U/L, P=0.071)。两组患者住院期间出血并发症发生率和住院时间无统计学差异(both P>0.05)。E-PCI组患者PCI术后7天心功能与P-PCI组患者具有改善趋势。随访6个月对两组患者进行超声心动图复查,结果发现,两组患者心功能均较PCI术后7天时明显改善,左室舒张末期容积指数(LVEDVI)和左室收缩末期容积指数(LVESVI)明显降低(both P<0.01),左室射血分数(LVEF)显著升高(56.84%±6.02%vs.53.88%±5.29%in E-PCI group,55.13%±5.28%vs.52.19±7.00%in P-PCI group, both P<0.01), E-PCI组心功能仍较P-PCI组具有改善趋势。随访6个月两组患者MACE发生率相似(P=0.977)。
结论：
1.与直接PCI相比,溶栓后早期PCI可获得更佳的心肌灌注。
2.溶栓后早期PCI患者术后7天和6个月时心功能较接受直接PCI的患者具有改善趋势。
3.溶栓后早期经桡动脉行PCI并未增加出血风险和MACE发生率,对于首诊于无PCI条件医院的STEMI患者溶栓后早期经桡动脉行PCI安全有效。
第二部分
血流动力学参数对溶栓后早期经皮冠状动脉介入治疗心肌灌注水平的预测价值及山莨菪碱的心肌保护作用
目的：本研究旨在对PCI前血流动力学状态与溶栓后早期PCI治疗后心肌灌注水平的关系进行探讨,并观察PCI前预防性冠脉内应用山莨菪碱对血流动力学和心肌灌注的影响。
方法：本研究分为2个阶段。第一阶段回顾收集2007年1月至2009年6月于我中心接受溶栓后早期PCI的STEMI患者的病历资料。根据患者PCI术后TIMI心肌灌注分级(TMPG)将患者分为心肌灌注不良组(TMPG≤2级)和心肌灌注正常组(TMPG=3级)。记录患者溶栓后PCI前主动脉收缩压(SBP)、主动脉舒张压(DBP)和心率。比较两组患者PCI后TIMI血流分级、校正的TIMI血流计帧数、TIMI(?)心肌灌注分级以及血栓负荷积分。分析入院后CK-MB峰值作为心肌梗死面积的估测指标以及住院期间肝肾功能和血红蛋白浓度的变化。记录所有入选病例PCI后7天的左室射血分数(LVEF)。比较两组患者基线资料,对两组存在差异的基线资料、造影检查参数以及血流动力学参数进行单因素Logistic回归分析,筛选确定自变量。以TMPG分级为因变量(TMPG≤2级记为1,TMPG3级记为0),以单因素Logistic回归分析筛选的参数为自变量,进行多因素Logistic回归分析。各自变量的相对危险度以比数比(OR)表示,记录95%可信区间(95%CI)及P值。以多因素分析结果得出的独立预测因子构建预测TMPG<2级发生风险的Logistic回归方程。将预测因子代入回归方程,计算每例STEMI患者溶栓早期PCI治疗后TMPG<2级的发生概率。以Logistic回归方程计算出的每例STEMI患者溶栓早期PCI治疗后TMPG<2级的发生概率值构建以TMPG确定的心肌灌注水平为金标准的ROC曲线,分析ROC曲线下面积及最佳截点诊断STEMI患者溶栓早期PCI治疗后TMPG<2级发生的特异性及敏感性。
第二阶段前瞻性研究2010年3月至2010年12月溶栓后12小时内就诊于我中心接受溶栓后早期PCI的STEMI患者。入选患者随机分为山莨菪碱治疗组(ANI group)和对照组(CON group)。ANI组患者在导管室内PCI术前根据患者心率、血压等血流动力学参数以200μg/1ml的浓度分次冠脉内注射山莨菪碱,首次2000μg,间隔2min后再次注射2000gg。CON组以同样方式予以等容积生理盐水。其他治疗方法和实验室检查同第一阶段。主要终点事件定义为PCI后TMPG水平。次要重点事件定义为血流动力学参数变化、ST完全回落(STR)、CK-MB峰值、TIMI血流分级以及住院期间主要不良心脏事件(MACE,包括死亡、再梗死、靶血管再次血运重建)。所有统计学分析使用SPSS17.0软件(SPSS Inc., Chicago, Illinois)进行。双侧P<0.05认为存在统计学差异。
结果：第一阶段累计入选患者159例,其中灌注不良组31例,灌注正常组128例,溶栓后早期PCI术后心肌灌注不良的发生率19.50%。灌注不良组患者PCI前SBP和DBP均低于灌注正常组(both P<0.001)。与灌注正常组患者相比,灌注不良组患者PCI前心率有增加趋势(P=0.098)。PCI后7天灌注正常组患者的心功能较好(P=0.005),梗死面积有降低趋势(P=0.054)。两组患者的其他基线资料无统计学意义(all P>0.05)。两组患者PCI前心功能Killip分级、IRA分布、基线TIMI血流分级以及血栓积分水平相似(all P>0.05)。PCI后灌注正常组TIMI血流3级比例高于灌注不良组(P=0.039), CTFC水平低于灌注不良组(24.59±1.444Vs.28.00±3.642,P<0.001)。与灌注正常组患者相比,灌注不良组患者应用替罗非班比例较高(P<0.001)。将上述因素进行Logistic回归分析。单因素分析结果显示,PCI前TIMI血流分级较低、PCI前SBP和DBP水平较低是PCI后心肌灌注不良的预测因素。多因素Logistic回归分析发现,PCI前舒张压过低以及糖尿病病史是PCI后心肌灌注不良的独立预测因素。建立心肌灌注预报概率模型,hemodynamic parameter=1+exp(-(-4.091+0.085×DBP+O.016×SBP-0.037×HR)),求出各个样本TMPG水平的综合预报概率,以此作为绘制ROC曲线的检验变量。计算ROC曲线下面积0.775(95％CI0.683-0.868,P<0.001),当截点值为0.789时,敏感性和特异性分别为78.1%和71.0%。
第二阶段前瞻性入选病例76例,其中ANI组39例,CON组37例。两组患者年龄、性别、病史、梗死部位、心功能分级以及基线实验室检查结果均未见明显异常(all P>0.05).两组患者发病至溶栓时间、发病至球囊扩张时间以及IRA分布相似。PCI前两组患者TIMI血流状态和血栓积分相似。PCI后ANI组与对照组相比,TMPG3级比例较高(P=0.044),CTFC较低(P=0.0098).PCI前两组患者血流动力学参数相似(all P>0.05),冠脉内注射山莨菪碱2000μg后5分钟,ANI组患者心率、收缩压和舒张压均较给药前明显升高(all P<0.05),按第一阶段预测模型计算所得血流动力学综合参数明显降低(P=0.013)。与对照组相比,ANI组患者峰值CK-MB水平较低(234.10±76.96U/L vs.277.83±84.21U/L,P=0.021), LVEF较高(56.59%±7.82%vs.52.28%±6.13%,P=O.010),ST段完全回落比例较高(P=0.040)。两组患者住院期间MACE发生率相似(P=0.643)。
结论：
1.低DBP水平是接受溶栓后早期PCI的心肌梗死患者心肌灌注不良的危险因素。以综合预测模型0.789为截点具有良好的敏感性和阴性预测价值。也就是说,对于接受溶栓后早期PCI的STEMI患者,PCI前不必将DBP降得过低。
2.预防性应用山莨菪碱可以改善冠脉血流和PCI术后的心肌灌注水平,其作用机制可能与血流动力学改善效应有关。
第三部分
冠脉内联合注射替罗非班和山莨菪碱对ST段抬高心肌梗死患者溶栓早期PCI心肌灌注改善作用的评价
目的：探讨在溶栓后行早期经皮冠状动脉介入治疗(PCI)中预防性应用山莨菪碱和替罗非班对ST-段抬高型心肌梗死(ST-segment elevation myocardial infarction, STEMI)患者心肌灌注的改善效应,及两者的相互作用。
方法：入选2010年12月至2011年12月首诊于河北医科大学第二医院的溶栓后12小时内拟行早期PCI的STEMI连续病例。入选患者被随机分为4组：早期PCI组(PCI),山莨菪碱组(ANI),替罗非班组(TIR)和联合治疗组(ANI+TIR)。患者在接受溶栓治疗同时进行规范的抗血小板、抗凝治疗。冠脉造影检查(CAG)和PCI均经桡动脉入径进行。根据患者CAG结果,对IRA血流未达到TIMI3级或IRA血流达到TIMI3级但狭窄超过75%的患者行PCI治疗。TIR组和TIR+ANI组患者在PCI术前接受替罗非班,用法为负荷剂量10μg/kg冠脉内注射3分钟,继之以0.075μg/kg/min持续静点12小时。PCI组和ANI组患者以同样方式予以等剂量生理盐水。ANI组和ANI+TIR组患者按试验设计于PCI前预防性冠脉内应用山莨菪碱,山莨菪碱的用法为根据患者心率、血压等血流动力学参数以200μg/ml的浓度分次冠脉内注射,首次2000μg,间隔2min后再次注射2000μg。PCI组和TIR组以同样方式予以等剂量生理盐水。接受的替罗非班治疗的患者PCI术中继续给予肝素维持ACT250s左右,未接受替罗非班治疗的患者ACT时间保持在300s左右。入院后详细记录两组患者基本临床资料包括年龄、性别、体重指数、冠心病危险因素(高血压,糖尿病,血脂异常,吸烟史)、心肌梗死部位、心功能分级及基本药物使用情况。比较各组患者TIMI血流分级、校正的TIMI血流计帧数(CTFC)、TIMI(?)心肌灌注分级评价标准(TMPG)以及血栓负荷积分对所有入选病例出院前进行二维超声心动图检查,评价心室功能和室壁运动情况。监测心肌酶学变化,以CK-MB峰值作为心肌梗死面积的估测指标。同时监测患者住院期间肝肾功能、血红蛋白浓度的变化。记录入院时、PCI术后即刻、PCI后24小时内每6小时的标准12导联心电图数据。ST段回落(ST-segment resolution, STR)定义为PCI术前后ST计分的变化,PCI后ST计分较术前降低70%以上记为完全回落。记录患者住院期间的MACE事件发生情况,定义为反复发作的缺血症状、原有梗死相关动脉(infarction related artery, IRA)导致的再发心肌梗死、靶血管再次血运重建和死亡。所有数据统计应用SPSS17.0完成。双侧P<0.05认为有统计学意义。
结果：总共入选了96例患者,每组各24例。各组患者基线资料,包括年龄、性别、既往病史、梗死部位、心功能状态以及基线实验室检查结果,均无显著差异(all P>0.05)。各组CAG检查和PCI操作时间相似(all P>0.05)。各组患者IRA分布、PCI前TIMI血流以及血栓计分相似(all P>0.05)。PCI后ANI、TIR和ANI+TIR组患者CTFC水平较低,TMPG3级以及TIMI3级比例较高(all P<0.05)。ANI、TIR和ANI+TIR组患者CK-MB峰值水平有降低趋势(P=0.245),且LVEF和ST段完全回落比例较高(both P<0.05)。住院期间各组患者出血事件和MACE发生率相似(all P>0.05)。ANI组和ANI+TIR组患者应用山莨菪碱后患者心率轻度增加10-15次/min,停药后10分钟患者心率恢复至基线水平；12例患者感觉轻度口渴,可耐受；无严重高血压及尿潴留等不良反应发生。所有患者均未发生恶性心律失常。Logostic回归分析显示,山莨菪碱和替罗非班对改善心肌灌注具有协同作用趋势,在减少梗死面积,改善心功能等方面存在协同作用趋势。
结论：
1.PCI前预防性冠脉内应用山莨菪碱或减量替罗非班均可改善冠脉微循环和心肌灌注。
2.对于溶栓后行早期PCI的STEMI患者,山莨菪碱在改善心肌灌注方面与替罗非班具有协同作用趋势,并可以在一定程度上减少心肌梗死面积,改善心功能。
第四部分
山莨菪碱对ST段抬高心肌梗死患者直接经皮冠状动脉介入治疗术后肾功能的保护作用
目的：本研究通过单盲、安慰剂随机对照的方法评价山莨菪碱对ST-段抬高型心肌梗死(STEMI)患者直接经皮冠状动脉介入治疗(PCI)术后对比剂肾病(CIN)的防治作用。
方法：入选2010年3月至2011年12月首诊于河北医科大学第二医院的发病12小时内的STEMI连续病例。将入选患者随机分为山莨菪碱组(ANI)和对照组(CON)。AM组患者首先静脉弹丸式注射山莨菪碱50μg/kg,继之以0.1-0.2μg/kg/min持续静脉滴注24小时。CON组患者按同样方法给予等剂量生理盐水(0.9%氯化钠注射液)。其他药物(如阿司匹林、氯吡格雷、利尿剂、正性肌力药物、血管扩张剂、他汀类药物、p受体阻滞剂、ACEI/ARB以及抗凝药物)均按照现行指南规范使用。所有患者在入院后即刻采用标准技术进行直接PCI。对比剂使用非离子型低渗对比剂(优维显370,碘含量370mg/ml, Schering Pharmaceutical Ltd., China)。详细记录两组患者入院后基本临床资料包括年龄、性别、体重指数、冠心病危险因素(高血压,糖尿病,血脂异常,吸烟史)、心肌梗死部位、心功能分级及基本药物使用情况。并于患者入院后24小时内进行二维超声心动图检查,由超声科医生盲法评价左心室功能,记录左室射血分数(LVEF)。采集患者入院时及PCI后24、48、72小时肘静脉血检测血肌酐水平(SCr)。计算估测的肾小球滤过率(estimated glomerular filtration rate, eGFR)。主要终点事件定义为患者直接PCI术后72小时内CIN的发生率。CIN定义为PCI术后48-72小时SCr水平升高超过0.5mg/dl (>44.2μmol/L)或SCr水平较极限值上升25%。应用SPSS17.0软件进行统计学处理。P<0.05(双侧)认为有统计学差异。
结果：累计入选2010年3月至2011年12月首诊于河北医科大学第二医院、发病12小时内的STEMI连续病例177例,其中ANI组88例(男性79例,平均年龄55.01±13.2岁),CON组89例(男性79例,平均年龄54.56±12.73岁)。所有患者均按试验设计完成试验。两组患者包括平均年龄、性别、危险因素以及临床表现方面没有明显差异。患者入院时实验室检查和药物应用方面亦无明显差异。两组患者CAG和PCI操作、对比剂用量以及水化剂量等方面没有明显差异。两组患者入院时SCr水平相似。PCI术后48和72小时ANI组SCr水平明显低于CON组(99.5±26.2μmol/L vs.109.6±37.3μmol/L,82.9±15.6μmol/L vs.94.1±25.8μmol/L,both P<0.01)。两组患者PCI术后SCr水平均较基线值明显升高,峰值水平出现在术后48小时,然后SCr水平逐渐下降。术后72小时ANI组患者SCr水平恢复至基线水平(82.9±15.6μmol/L vs.88.1±22.7μmol/L,P>0.05),而CON组患者SCr水平仍高于基线水平(94.1±25.8μmol/L vs.85.1±18.6μmol/L,P<0.01)。两组患者基线eGFR水平相似。与CON组相比,ANI组患者PCI后24、48、72小时eGFR水平均较高(91.5±22.1ml·min-1·1.73m-2vs.83.2±21.3ml·min-1·1.73m-2,80.2±17.6ml·min-1·1.73m-2vs.73.4±18.5ml·min-1·1.73m-2.93.2±18.4ml·min-1·1.73m-2vs.86.3±21.7ml·min-1·1.73m-2,all P<0.05)。ANI组患者PCI术后72小时eGFR水平明显高于术后48小时(93.2±18.4ml·min-1·1.73m-2vs.80.2±17.6ml·min-1·1.73m-2,P<0.01),并恢复至基线水平(93.2±18.4ml·min-1·1.73m-2vs.92.1±21.3ml·min-1·1.73m-2,P>0.05):CON组患者术后72小时eGFR水平虽有所增加(86.3±21.7ml·min-1·1.73m-2vs.73.4±18.5ml·min-1·1.73m-2,P<0.01),但是仍低于基线水平(86.3±21.7ml·min-1·1.73m-2vs.92.5±22.5ml·min-1·1.73m-2,P<0.05)。多因素回归分析结果显示,糖尿病病史和心功能不全(LVEF<55%)是CIN发生的危险因素,而应用山莨菪碱进行防治是CIN发生的独立保护因素(OR,0.369;95%CI,0.171to0.794;P=0.011)ANI组和CON组CIN的发生率分别为20.5%(18/88)和33.7%(30/89)。ANI组患者CIN发生率明显低于CON组(P<0.05)。两组患者均无因C1N接受透析治疗的病例发生。应用山莨菪碱后患者心率轻度增加(73.0±12.3beats/min vs.76.4±9.1beats/min,P<0.05),峰值水平出现弹丸式注射山莨菪碱后(73.0±12.3beats/min vs.87.0±16.1beats/min,P<0.05),停药后6小时患者心率恢复至基线水平。ANI组患者在应用山莨菪碱治疗期间有17例出现心悸,21例感觉口渴,均可耐受。所有患者均未发生恶性心律失常。
结论：
1.糖尿病和心功能不全是CIN发生的独立预测因素。
2.直接PCI术前和术后应用山莨菪碱可以有效降低STEMI患者CIN发生率,且无明显副作用。
ST-segment elevation myocardial infarction (STEMI) is one of the most severe types of heart attack which usually occurs when thrombus forms on a ruptured atheromatous plaque and occludes an epicardial coronary artery. Approximately17million deaths related to the coronary artery occur each year in the world, and half of them due to STEMI. In recent years, the prevalence of STEMI is growing rapidly in China, with the high mortality in the early stage.
Early and effective reperfusion therapy is the most important treatment for STEMI patients. However, only3%of STEMI patients received primary percutaneous coronary intervention (PCI) within12hours of symptom onset, which indicated that effective reperfusion was not achieved in the majority of STEMI patients in China. In order to reduce the time delay and improve the success of reperfution, an advanced pharmacoinvasive therapy which combined medical treatment with PCI may be the direction of treatment for STEMI in the future. However, the effects of myocardial perfusion, bleeding complications and outcoms of early PCI following thrombolysis should be further studied.
Anisodamine (6-[s]hydroxyhyoscyamine), a belladonna alkaloid derived from the Chinese medicinal herb Scopalia tangutica Maxim of the Solanaceae family that is indigenous to Tibet, is a blocker of M-choline receptors and has the effect of improving the microcirculation and increasing tolerance to ischemia in patients with microcirculatory disorders. Several latest large clinical trials suggested that platelet GP Ⅱb/Ⅲa inhibitor tirofiban could significantly improve reperfusion of infarct area and clinical outcomes of STEMI patients. Our precious studies have shown that intracoronary administration of anisodamine and tiroftban can further improve the coronary flow in STEMI patients underwent primary PCI. So far, the effect of intracoronary administration of anisodamine and tirofiban on myocardial perfusion in STEMI patients undergoing early PCI following thrombolysis and the interaction between them have not been carried out.
Based on our previous work, this study was designed to evaluate the effect of early PCI following thrombolysis via transradial artery approach on myocardial perfusion, and the preventive effect of anisadamine on contrast induced nephropathy. The possible mechanisms were also probed.
The detailed methods and results of our study are as follows:
Part Ⅰ
Safety and Efficacy of Thrombolysis followed by Early Percutaneous Coronary Intervention via Transradial Artery Approach in Patients with ST-segment Elevation Myocardial Infarction
Objective:This study was to compare coronary flow, myocardial perfusion, left ventricular function and major adverse cardiac events (MACE) between thrombolysis followed by early percutaneous coronary intervention (PCI) via transradial artery approach and primary PCI, and to investigate the safety and efficacy of thrombolysis followed by early PCI via transradial artery approach in patients with ST-segment elevation myocardial infarction (STEMI).
Methods:From September2009to March2010, all consecutive STEMI patients within12hours from symptom onset or thrombolysis in the Department of Cardiology of the Second Hospital of Hebei Medical University were enrolled. All eligible STEMI patients were divided into two groups according to patients received thrombolysis or not:early PCI group (E-PCI group, patients received thrombolytic agents in non-PCI capable hospital and immediately transferred to receive early PCI) and primary PCI group (P-PCI group, patients received primary PCI). Coronary angiography (CAG) and PCI were performed immediately after admission via transradial artery approach for patients in both groups with standard technique. According to the results of angiography, PCI was performed unless the blood flow of IRA achieved TIMI flow grade3without significant stenosis. The other medications were administered to the patients (including aspirin, clopidogrel, diuretics, isotropic agents, intravenous vasodilator, lipid-lowering, beta-blockade, and angiotensin of converting enzyme inhibitors) according to current best practice. Thrombus score, TIMI flow grade (TFG) of IRA before and after PCI, corrected TIMI frame count (CTFC), TIMI myocardial perfusion grade (TMPG) post PCI were analyzed. Bleeding complications was also observed and evaluated. All patients were followed up for6months to assess major adverse cardiac events (MACE). The primary end point was myocardial perfusion post PCI assessed by TFG, CTFC and TMPG, and the second end points were bleeding complications during hospital and30-day MACE. SPSS17.0for Windows (SPSS Inc., Chicago, Illinois) was used for statistical analysis. Values of P<0.05were considered statistically significant.
Results:A total of161cases were enrolled, with53cases in E-PCI group and108cases in P-PCI group. The patients in E-PCI group were younger than those in P-PCI group (51.36±12.24vs.57.31±9.87, P=0.003). The other baseline clinical characteristics such as gender distribution, baseline levels of serum BNP, SCr and Hb, and the medication therapies were similar between the two groups (all P>0.05). The mean time from symptom onset to thrombolysis was3.62±1.85h in E-PCI group, and the time from thrombolysis to PCI was5.13±3.03h. Compared to P-PCI group, the mean time from onset to PCI was longer in E-PCI group (8.75±2.86vs.6.03±3.19h, P<0.001). There were no differences in door to balloon time and IRA distribution between the two groups. Of the53patients treated with thrombolysis,51patients underwent early PCI when transferred to our hospital except2patients who only underwent CAG. In the P-PCI group,106patients underwent primary PCI, while2patients underwent CAG. Before PCI procedure, the thrombus score of IRA in E-PCI group was lower, and the percentage of TIMI3flow was higher (both P<0.05) compared to those in P-PCI group. TFG of IRA after PCI was similar, and there was no significant difference in the volume of contrast medium (P>0.05). However, CTFC of IRA post PCI in E-PCI group was lower than that in P-PCI group (28.12±5.06vs.30.89±8.74, P<0.05), and rate of TMPG3in E-PCI group was higher than that in P-PCI group (82.8%vs.68.0%, P<0.05). All of the implanted stents were drug-eluting stents. No differences were found in the stent implantations between the two groups (all P>0.05). There was a trend toward lower in the peak value of serum CK-MB in E-PCI group. No significant differences were found in the incidence of bleeding complications and hospital stay between the two groups. There was a trend of better left ventricular function7days after PCI in E-PCI group than that in P-PCI group. After6-month follow-up, the left ventricular function was improved in both the two groups (all P<0.05), and there was still a better trend in E-PCI group. Overall, there was no significant difference in6-month MACE between the two groups (P=0.977).
Conclusion:
1. The myocardial perfusion was better in patients undergoing thrombolysis followed by early PCI, and there was a trend of improving left ventricular function in patients underwent thrombolysis followed by early PCI, without increases of bleeding complications and incidence of MACE.
2. It is safe and efficacious for STEMI patients to receive thrombolysis followed by early PCI via transradial artery approach.
Part II
Prediction of hemodynamic parameters on myocardial perfusion in patients undergoing early percutaneous coronary intervention following thrombolysis and the myocardial protective effects of anisodamine
Objectives:This study was designed to investigate the relation between hemodynamic states before PCI and myocardial perfusion after early percutaneous coronary intervention (PCI) following thrombolysis, and to observe the predictive effects of anisodamine on myocardial perfusion in patients with ST-segment elevation myocardial infarction (STEMI) undergoing early PCI following thrombolysis.
Methods:This study was performed as a two-phase study.
Phase1represented a retrospective analysis of the consecutive STEMI patients undergoing early PCI following thrombolysis who were admitted to the second hospital of Hebei medical university from June2007to June2009. According to the TIMI myocardial perfusion grading (TMPG) after PCI, all the eligible patients were divided into poor perfusion group (TMPG≤2) and normal perfusion group (TMPG=3). The systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate before PCI were recorded. The TIMI flow grade (TFG), corrected TIMI frame (CTFC) and TMPG, as well as thrombosis score were compared between the two groups. The peak value of CK-MB was monitored and evaluated as infarction area. Echocardiographic examination was performed at discharge by a cardiologist blinded to the randomization results. Left ventricular ejection fraction (LVEF) was determined from apical2and4chambers views by Simpson's biplane formula. Medications were also recorded in a database. Univariate logistic regression was used to analyze the baseline characteristics, angiograph characteristics and hemodynamic states before PCI. The TMPG was used as dependent factor, and multivariate logistic was performed to analyze the independent variants which were selected by univariate logistic regressions. The odds ratios (ORs) and their corresponding95%confidence intervals (CIs) were provided. The logistic regression equation was established according to the result of multivariate logistic regression to predict the risk of incomplete perfusion (TMPG≤2) after PCI. The receiver operating characteristic (ROC) curve was applied to evaluate the sensitivity and specificity of the cutoff value.
Phase2prospectively observed the hemodynamic effects of anisodemine in STEMI patients undergoing early PCI following thrombolysis. From March2010to December2010, concecutive STEMI patients within12hours after thrombolysis were enrolled. All eligible patients were randomly assigned to anisodamine group (ANI) and control group (CON). Patients in ANI group received intracoronary bolus injection of anisodamine (2000μg,10ml) over2minutes according to the heart rate and blood pressure, and the same vulome of0.9%sodium chloride in the CON group. The other medications and laboratory examinations were the same as phase1. The primary end point was the level of TMPG after PCI, and the second end points were including the hemodymanic parameters, STR, peak level of CK-MB, TIMI flow grade and major adverse cardiac events after PCI. The software of SPSS17.0(SPSS Inc. Chicago, Illinois) was used in the statistic analysis, and P<0.05was consided statistically significant.
Result:A total of159patients were enrolled in phase1, with31in poor perfusion group and128in normal perfusion group. Both SBP and DBP before PCI were lower in poor perfusion group than those in normal perfusion group (P<0.001). There was a trend of faster heart rates in the poor perfusion (P=0.098). The LVEF in the normal perfusion group was better than that in the poor group (P=0.005). The other baseline clinical data were similar between the two groups (all.P>0.05). The Killip classification, IRA distribution, baseline TIMI flow grade and thrombosis score were all similar (all P>0.05). There were significant differences in Grade3TIMI flow and CTFC between the two groups. Univariate logistic analysis found that low level of TIMI flow grade, SBP and DBP before PCI were predictors for poor myocardial perfusion, while multivariate logistic regression showed that low level of SBP before PCI and the history of diabetes were predictive factors for poor myocardial perfusion. The predictive model established according to hemodynamic parameters before PCI was as follows:hemodynamic parameter=1+exp (-(-4.091+0.085×DBP+0.016×SBP-0.037×HR)). ROC analyses were performed to determine the best cut-off value of ratio for predicting poor perfusion. The area under the ROC curve for ratio was0.775(95%CI0.683-0.868, P<0.0001). The ratio of0.789was determined to be the best discriminating value for predicting poor perfusion, with a sensitivity of78.1%and a specificity of71.0%.
Seventy-six patients were prospectively enrolled in Phase2, with39in ANI group and37in CON group. No significant differences in baseline clinical data and baseline angiography data were found (all P>0.05). Compared to CON group, the rate of TMPG3was higher in ANI group, while the CTFC was lower (both P<0.05). There was a mild increase of heart rate, SBP and DBP after administration of anisodamine (all P<0.05). The hemodynamic parameter decreased according to the predictive model in phase1. There were sinificant differences in the peak level of CK-MB, LVEF, and STR in the ANI group. The incidences of MACE were similar between the two groups.
Conclusion:
1. Low level of DBP before PCI was one of independent predict facter for imcomplete perfusion.
2. Intracoronary administration of anisodamine before PCI could improve the myocardil perfusion which may be result in the hemodynamic effects of anisodamine.
Part Ⅲ
Additive benefit of glycoprotein Ⅲb/Ⅲa inhibition and adjunctive
Objectives:The aim of the study was to evaluate the additional benefit of preventive administration of anisodamine to tirofiban during primary PCI on myocardial reperfusion.
Methods:This study was a prospective, randomized, single blinded study with2×2factorial design. Consecutive STEMI patients undergoing early PCI within12h of thrombolysis and admitted from December2010to December2011were randomly assigned to1of the4intervention groups: primary PCI (PCI), anisodsamine infusion (ANI), tirofiban infusion (TIR) and PCI with both treatments (ANI+TIR). All patients received aspirin (300mg loading followed by100mg daily) and clopidogrel (600mg loading followed by75mg daily). Heparin boluses were administered to maintain an activated clotting time of250s in patients treated with tirofiban, and>300s in the remaining patients. According to the result of angiography, PCI was performed unless the blood flow of infarct-related artery (IRA) achieved TIMI grade3and the residual stenosis of IRA was less than75%. After coronary angiography, but before the first balloon inflation, patients in the ANI group and TIR+ANI group received intracoronary bolus injection of anisodamine (1000μg,5ml) over3minutes, and the same vulome of0.9%sodium chloride in the other two groups. Tirofiban was administered with a10μg/kg bolus intracoronary injection for over3minutes followed by0.075μg·kg-1·min-1infusion for12hours in TIR group and ANI+TIR group and the same vulome of0.9%sodium chloride in the remaining patients. The blood pressure and electrocardiogram were monitored and recorded during PCI. The other medications were administered to the patients (including aspirin, clopidogrel, diuretics, isotropic agents, intravenous vasodilator, lipid-lowering, beta-blockade, and angiotensin of converting enzyme inhibitors) according to current best practice. Serum creatine kinase (CK), MB fraction (CK-MB), and standard12-lead ECGs were recorded at admission, after the procedure, and then every6h for24h. Echocardiographic examination was performed at discharge by a cardiologist blinded to the randomization results. Left ventricular ejection fraction (LVEF) was determined from apical2and4chambers views by Simpson's biplane formula. The angiographic results before and after PCI by two independent cardiologists who were blinded to the procedures. Thrombosis score, TIMI flow grade (TFG) of IRA before and after PCI, corrected TIMI frame count (CTFC), TIMI myocardial perfusion grade (TMPG) after PCI were recorded. All ECGs were read at the core laboratory by2cardiologists blinded to the randomization. ST-segment resolution (STR) was determined by comparing the ST scores before and after the procedure,>70%decrease of the initial ST elevation was categorized as complete STR. Analyses were done using SPSS for Windows17.0(SPSS Inc., Chicago, Illinois). A two-sided of P-value <0.05was defined as statistically significant.
Results:A total of96patients were enrolled (24cases in each group), and all patients received the assigned treatment. No significant difference in baseline clinical characteristics was found among groups, including mean age, gender distribution, risk factors, and clinical presentations (all P>0.05). No different baseline angiographic characteristics were found among groups (all P>0.05). There was a trend of more patients achieving post-procedural TIMI3flow in the ANI+TIR group, compared to the primary PCI group (95.8%vs.75.0%, P=0.084). The post-procedural CTFC in ANI+TIR group was less than the other three groups (P=0.002), while the post-procedural CTFC in both ANI group and TIR group were improved. There was also a possible interaction regarding CTFC with the P=0.165of anisodamine×tirofiban. There was a trend of more complete STR in both ANI group and TIR group than that in primary PCI group, and a significant difference of more complete STR in ANI+TIR group was found than that in primary PCI group (91.7%vs.58.3%, P=0.039). There was a trend of high level of peak CK-MB in primary PCI group (P=0.245). No significant difference of bleeding complications was found among groups. There was a trend of higher LVEF at discharge in the TIR+ANI group, compared to the primary PCI group (56.19%±4.05%vs.50.70%±7.35%, P=0.005). No palpitation, thirst, blurred vision or retention of urine were found in the patients who were administered anisodamine. No malignant arrhythmia (defined as ventricular fibrillation or ventricular tachycardia with hemodynamic compromise requiring defibrillation) occurred in patients treated with anisodamine. No significant difference of occurrence of MACE was found among groups (P=0.686).
Conclusions:
1. Both anisodamine and tirofiban addministered before PCI may improve the myocardial reperfusion in STEMI patients undergoing early PCI following thrombolysis.
2. There are possible interactions of anisodamine and tirofiban on myocardial reperfusion.
Part Ⅳ
Protective Effects of Anisodamine on Renal Function in Patients with ST-Segment Elevation Myocardial Infarction undergoing Primary Percutaneous Coronary Intervention
Objective:This single blinded, placebo-controlled and randomized trial was to evaluate the effect of anisodamine on renal function in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI).
Methods:From March2010to December2011, all consecutive STEMI patients within12hours from onset of symptoms undergoing primary PCI in the Cardiology Department of the Second Hospital of Hebei Medical University were enrolled. Eligible patients were randomly assigned to receive anisodamine (anisodamine group, ANI) or placebo (control group, CON) by means of random number table. Patients in the ANI group received anisodamine50μg/kg bolus injection after randomization followed by an adjusted-dose (0.1-0.2μg/kg/min) to24h after PCI, while patients in CON received infusion of placebo (0.9%sodium chloride) with the same volume of ANI group. Other medications were administered to all the patients (including aspirin, clopidogrel, diuretics, isotropic agents, intravenous vasodilator, statins, beta-blockade, angiotensin converting enzyme inhibitors, and anticoagulation agents) according to current best practice. Primary PCI was performed with standard technique as soon as possible. PCI success was defined as grade3flow of post procedural thrombolysis in myocardial infarction (TIMI) and a decrease of residual stenosis to<20%by quantitative coronary analysis. The nonionic contrast (Ultravist370, iodine370mg/ml, Schering Pharmaceutical Ltd., China) was used in all patients. Intravenous hydration was given to all patients with intravenous isotonic saline (0.9%) at a rate of1ml/kg/hour or0.5ml/kg/hour in case of overt heart failure before the procedure and for12hours after the procedure. Left ventricular function was evaluated by echocardiography in all patients within24hours after admission. Investigators involved in the procedures and those reading echocardiograms were all blind to the randomized treatment. Serum creatinine (SCr) concentrations were measured at admission,24hours,48hours and72hours after PCI. Estimated glomerular filtration rate (eGFR) was calculated by the simplified modification of diet in renal disease study equation (MDRD):eGFR=186×Serum creatinine-1.154×age-0.203(female×0.742). All calculations were computed with the aid of SPSS17.0statistical software. A P Value of less than0.05(2-tailed) was considered statistically significant.
Results:Of the177patients enrolled,88were randomly assigned to anisodamine and89to placebo. There were no significant differences in baseline characteristics, including mean age, gender distribution, risk factors, and clinical presentations between the two groups. The laboratory results and medications used during the procedure were not significantly different. The SCr concentration on admission and eGFR were also similar between the two groups. The preexisting chronic kidney disease (defined as eGFR<60ml/min/1.73m2) was not different between the two groups. The average time of onset to balloon was similar between the two groups. There were no significant differences regarding the distribution of infarction related artery, interventions procedure, stent implantations, use of intravenous GP Ⅱb/Ⅲa receptor antagonist, total contrast volume consumption and the hydration volume. The SCr concentration at admission was not significantly different between the two groups. However, it was lower in ANI group than that in CON group at hour48and72after administration of contrast medium (99.5±26.2μmol/L vs.109.6±37.3μmol/L,82.9±15.6μmol/L vs.94.1±25.8μmol/L, both P<0.01). For both groups, SCr concentrations significantly increased after PCI (P<0.0001), with the peak value occurring at hour48, and then began to decrease. To be specific, in ANI group, SCr concentration decreased significantly at hour72, and returned to baseline level (82.9±15.6μmol/L vs.88.1±22.7μmol/L, P>0.05), while in CON group, SCr concentration also decreased significantly at hour72, but the result was still higher than baseline (94.1±25.8μmol/L vs.85.1±18.6μmol/L, P<0.01). The eGFR at admission was also similar between the two groups. The eGFR at hour24,48and72after primary PCI were higher in ANI group than those in control group (91.5±22.1ml·min-1·1.73m-2vs.83.2±21.3ml·min-11.73m-2,80.2±17.6ml·min-1·1.73m-2vs.73.4±18.5ml·min-1·1.73m-2,93.2±18.4ml·min-1·1.73m-2vs.86.3±21.7ml·min-1·1.73m-2, all P0.05). In ANI group, eGFR increased significantly at hour72compared with that at hour48(93.2±18.4ml·min-1±1.73m-2vs.80.2±17.6ml·min-1·1.73m-2, P<0.01), and the result was similar to the baseline level (93.2±18.4ml·min-1·1.73m-2vs.92.1±21.3ml·min-1·1.73m-2, P>0.05). In CON group, eGFR increased significantly (86.3±21.7ml·min-1·1.73m-2vs.73.4±18.5ml·min-1·1.73m-2, P<0.01) at hour72, but was still lower than baseline level (86.3±21.7ml·min-1·1.73m-2vs.92.5±22.5ml·min-1 1.73m-2, P<0.05). The results of multiple logistic regression showed that the history of diabetes and low LVEF before PCI were independent predictors of CIN, and treatment with anisodamine was an independent preventive factor of CIN (OR,0.369;95%CI,0.171to0.794; P=0.011). The incidences of CIN was20.5%(18/88) and33.7%(30/89) in ANI and CON group respectively, and the incidence of CIN in ANI group was lower than that in CON group within72hours after the procedure (P<0.05). Dialysis was not used in both groups. There was a mild increase of heart rate after administration of anisodamine (73.0±12.3beats/min vs.76.4±9.1beats/min, P<0.05), and the peak value occurred after bolus of anisodamine (73.0±12.3beats/min vs.87.0±16.1beats/min, P<0.05), and recovered6hours later after withdrawal of anisodamine. No malignant arrhythmia occurred in all patients.
Conclusion:
1. Both diabetes and low LVEF are indipendent predictors for CIN.
2. Intravenous infusion of anisodamine before and after primary PCI may reduce the occurrence of CIN in STEMI patients undergoing primary PCI safely.
再灌注治疗的目标是恢复冠脉血流,保证心肌灌注。但是部分患者在心外膜冠脉开通后无法实现心肌水平的完全灌注,造成心肌持续损伤。近年来,人们尝试采用药物治疗和血栓抽吸等多种方式改善PCI后心肌灌注,然而其治疗策略仍有待进一步探索。山莨菪碱(anisodamine)为我国从茄科植物唐古特莨菪中分离出的一种生物碱,具有提高冠脉灌注压、改善微循环、降低血小板聚集、抑制血栓形成、保护心肌的作用。血小板GPIIb
Ⅲa受体拮抗剂替罗非班可以作用于血小板聚集的最终共同通路,抑制血小板的活化、黏附和聚集,从而阻止动脉血栓形成,不仅可以改善心外膜血流,也可减少无复流现象,在心肌微循环水平实现更好的血流灌注。我中心前期研究发现,冠脉内注射山莨菪碱和替罗非班对STEMI患者直接PCI术中的无复流现象具有逆转作用。但是上述两种药物对溶栓后早期PCI心肌灌注的影响尚缺乏研究,两种药物联用时是否存在协同效应尚不明确。
本研究以前期研究为基础,着重探讨对首诊于无直接PCI条件医院的STEMI患者溶栓后早期(12小时内)经前臂桡动脉入径行PCI的安全性和可行性,并观察早期PCI前预防性冠脉应用山莨菪碱和替罗非班对溶栓早期PCI后心肌灌注的改善作用,分析山莨菪碱的血流动力学效应以及两种药物的相互作用关系,同时观察研究山莨菪碱对直接PCI术后对比剂肾病(contrast induced nephropathy, CIN)的防治作用,以期为优化STEMI早期再灌注治疗提供参考。
本研究共分为四个部分：
第一部分
ST段抬高心肌梗死患者溶栓后早期经桡动脉入径行经皮冠状动脉介入治疗的安全性和有效性
目的：观察比较溶栓后早期经桡动脉入径行经皮冠状动脉介入治疗(PCI)与直接PCI对冠脉血流、心肌灌注水平、心功能以及主要心脏不良事件((?)major adverse cardiac events, MACE)的影响,探讨ST段抬高心肌梗死(STEMI)患者经桡动脉入径行溶栓后早期PCI的安全性和有效性。
方法：入选2009年9月至2010年3月就诊于河北医科大学第二医院的发病12小时内STEMI连续病例以及同期就诊的溶栓后12小时内拟行早期PCI的STEMI连续病例。根据患者先前是否接受静脉溶栓治疗将符合条件的患者分为：早期PCI组(early PCI group, E-PCI组,患者在无PCI条件医院接受溶栓治疗后立即转运行早期PCI)和直接PCI组(primary PCI group, P-PCI组,患者接受直接PCI治疗)。E-PCI组患者在外院应用阿替普酶或瑞替普酶进行静脉溶栓治疗后转运至我院行早期PCI。冠脉造影检查(coronary angiography, CAG)和PCI均经桡动脉入径进行。根据患者CAG结果,对梗死相关动脉(infarction related artery, IRA)血流未达到TIMI3级或IRA血流达到TIMI3级但狭窄超过75%的患者行PCI治疗。药物治疗(阿司匹林、氯吡格雷、静脉血管扩张剂、他汀类药物、beta受体阻滞剂以及ACEI等)根据现行指南推荐的最佳治疗方案给予患者。比较两组患者冠脉造影结果、心肌灌注水平、PCI术后出血并发症的发生情况以及住院时程。PCI术后进行6个月随访记录,比较两组患者心功能变化和MACE事件发生情况。主要终点事件为PCI术后心肌灌注水平,采用TIMI血流分级(TFG)、校正的TIMI记帧(CTFC)和TIMI心肌灌注分级(TMPG)评价；次要终点事件为住院期间出血并发症和6个月MACE的发生情况。所有统计学分析使用SPSS17.0软件(SPSS Inc., Chicago, Illinois)进行。双侧P<0.05认为存在统计学差异。
结果：本研究共计入选病例161例,其中E-PCI组53例,P-PCI组108例。与P-PCI组患者相比,E-PCI组患者较年轻(51.36±12.24岁vs.57.31±9.87岁,P=0.003)。两组其他基线临床资料如性别、killip分级、梗死部位、基线BNP水平、血肌酐和血红蛋白浓度,以及基础药物的使用情况均无显著差异(all P>0.05)。E-PCI组患者发病至接受溶栓治疗的平均时间为3.62±1.85小时,溶栓至PCI的平均时间为5.13±3.03小时。P-PCI组患者发病至接受直接PCI的时间为6.03±3.19h。PCI术前E-PCI组IRA血栓积分较低,TIMI血流3级的比例较高(both P<0.05)。PCI术后TIMI血流3级比例相似(P=0.076),两组患者使用对比剂剂量无明显差异(167.92±58.49ml vs.174.40±48.04ml, P=0.456)。然而,PCI术后E-PCI组CTFC明显低于P-PCI组(28.12±5.06vs.30.89±8.74, P=0.034), TMPG3级的比例高于P-PCI组(82.8%vs.68.0%,P=0.042)。两组患者均使用药物洗脱支架,人均植入支架数、植入支架的平均长度以及支架植入后病变最小内径(MLD)相似(all P>0.05)。与P-PCI组相比,E-PCI组患者CK-MB峰值存在减低趋势(229.08±189.53U/L vs.275.35±129.67U/L, P=0.071)。两组患者住院期间出血并发症发生率和住院时间无统计学差异(both P>0.05)。E-PCI组患者PCI术后7天心功能与P-PCI组患者具有改善趋势。随访6个月对两组患者进行超声心动图复查,结果发现,两组患者心功能均较PCI术后7天时明显改善,左室舒张末期容积指数(LVEDVI)和左室收缩末期容积指数(LVESVI)明显降低(both P<0.01),左室射血分数(LVEF)显著升高(56.84%±6.02%vs.53.88%±5.29%in E-PCI group,55.13%±5.28%vs.52.19±7.00%in P-PCI group, both P<0.01), E-PCI组心功能仍较P-PCI组具有改善趋势。随访6个月两组患者MACE发生率相似(P=0.977)。
结论：
1.与直接PCI相比,溶栓后早期PCI可获得更佳的心肌灌注。
2.溶栓后早期PCI患者术后7天和6个月时心功能较接受直接PCI的患者具有改善趋势。
3.溶栓后早期经桡动脉行PCI并未增加出血风险和MACE发生率,对于首诊于无PCI条件医院的STEMI患者溶栓后早期经桡动脉行PCI安全有效。
第二部分
血流动力学参数对溶栓后早期经皮冠状动脉介入治疗心肌灌注水平的预测价值及山莨菪碱的心肌保护作用
目的：本研究旨在对PCI前血流动力学状态与溶栓后早期PCI治疗后心肌灌注水平的关系进行探讨,并观察PCI前预防性冠脉内应用山莨菪碱对血流动力学和心肌灌注的影响。
方法：本研究分为2个阶段。第一阶段回顾收集2007年1月至2009年6月于我中心接受溶栓后早期PCI的STEMI患者的病历资料。根据患者PCI术后TIMI心肌灌注分级(TMPG)将患者分为心肌灌注不良组(TMPG≤2级)和心肌灌注正常组(TMPG=3级)。记录患者溶栓后PCI前主动脉收缩压(SBP)、主动脉舒张压(DBP)和心率。比较两组患者PCI后TIMI血流分级、校正的TIMI血流计帧数、TIMI(?)心肌灌注分级以及血栓负荷积分。分析入院后CK-MB峰值作为心肌梗死面积的估测指标以及住院期间肝肾功能和血红蛋白浓度的变化。记录所有入选病例PCI后7天的左室射血分数(LVEF)。比较两组患者基线资料,对两组存在差异的基线资料、造影检查参数以及血流动力学参数进行单因素Logistic回归分析,筛选确定自变量。以TMPG分级为因变量(TMPG≤2级记为1,TMPG3级记为0),以单因素Logistic回归分析筛选的参数为自变量,进行多因素Logistic回归分析。各自变量的相对危险度以比数比(OR)表示,记录95%可信区间(95%CI)及P值。以多因素分析结果得出的独立预测因子构建预测TMPG<2级发生风险的Logistic回归方程。将预测因子代入回归方程,计算每例STEMI患者溶栓早期PCI治疗后TMPG<2级的发生概率。以Logistic回归方程计算出的每例STEMI患者溶栓早期PCI治疗后TMPG<2级的发生概率值构建以TMPG确定的心肌灌注水平为金标准的ROC曲线,分析ROC曲线下面积及最佳截点诊断STEMI患者溶栓早期PCI治疗后TMPG<2级发生的特异性及敏感性。
第二阶段前瞻性研究2010年3月至2010年12月溶栓后12小时内就诊于我中心接受溶栓后早期PCI的STEMI患者。入选患者随机分为山莨菪碱治疗组(ANI group)和对照组(CON group)。ANI组患者在导管室内PCI术前根据患者心率、血压等血流动力学参数以200μg/1ml的浓度分次冠脉内注射山莨菪碱,首次2000μg,间隔2min后再次注射2000gg。CON组以同样方式予以等容积生理盐水。其他治疗方法和实验室检查同第一阶段。主要终点事件定义为PCI后TMPG水平。次要重点事件定义为血流动力学参数变化、ST完全回落(STR)、CK-MB峰值、TIMI血流分级以及住院期间主要不良心脏事件(MACE,包括死亡、再梗死、靶血管再次血运重建)。所有统计学分析使用SPSS17.0软件(SPSS Inc., Chicago, Illinois)进行。双侧P<0.05认为存在统计学差异。
结果：第一阶段累计入选患者159例,其中灌注不良组31例,灌注正常组128例,溶栓后早期PCI术后心肌灌注不良的发生率19.50%。灌注不良组患者PCI前SBP和DBP均低于灌注正常组(both P<0.001)。与灌注正常组患者相比,灌注不良组患者PCI前心率有增加趋势(P=0.098)。PCI后7天灌注正常组患者的心功能较好(P=0.005),梗死面积有降低趋势(P=0.054)。两组患者的其他基线资料无统计学意义(all P>0.05)。两组患者PCI前心功能Killip分级、IRA分布、基线TIMI血流分级以及血栓积分水平相似(all P>0.05)。PCI后灌注正常组TIMI血流3级比例高于灌注不良组(P=0.039), CTFC水平低于灌注不良组(24.59±1.444Vs.28.00±3.642,P<0.001)。与灌注正常组患者相比,灌注不良组患者应用替罗非班比例较高(P<0.001)。将上述因素进行Logistic回归分析。单因素分析结果显示,PCI前TIMI血流分级较低、PCI前SBP和DBP水平较低是PCI后心肌灌注不良的预测因素。多因素Logistic回归分析发现,PCI前舒张压过低以及糖尿病病史是PCI后心肌灌注不良的独立预测因素。建立心肌灌注预报概率模型,hemodynamic parameter=1+exp(-(-4.091+0.085×DBP+O.016×SBP-0.037×HR)),求出各个样本TMPG水平的综合预报概率,以此作为绘制ROC曲线的检验变量。计算ROC曲线下面积0.775(95％CI0.683-0.868,P<0.001),当截点值为0.789时,敏感性和特异性分别为78.1%和71.0%。
第二阶段前瞻性入选病例76例,其中ANI组39例,CON组37例。两组患者年龄、性别、病史、梗死部位、心功能分级以及基线实验室检查结果均未见明显异常(all P>0.05).两组患者发病至溶栓时间、发病至球囊扩张时间以及IRA分布相似。PCI前两组患者TIMI血流状态和血栓积分相似。PCI后ANI组与对照组相比,TMPG3级比例较高(P=0.044),CTFC较低(P=0.0098).PCI前两组患者血流动力学参数相似(all P>0.05),冠脉内注射山莨菪碱2000μg后5分钟,ANI组患者心率、收缩压和舒张压均较给药前明显升高(all P<0.05),按第一阶段预测模型计算所得血流动力学综合参数明显降低(P=0.013)。与对照组相比,ANI组患者峰值CK-MB水平较低(234.10±76.96U/L vs.277.83±84.21U/L,P=0.021), LVEF较高(56.59%±7.82%vs.52.28%±6.13%,P=O.010),ST段完全回落比例较高(P=0.040)。两组患者住院期间MACE发生率相似(P=0.643)。
结论：
1.低DBP水平是接受溶栓后早期PCI的心肌梗死患者心肌灌注不良的危险因素。以综合预测模型0.789为截点具有良好的敏感性和阴性预测价值。也就是说,对于接受溶栓后早期PCI的STEMI患者,PCI前不必将DBP降得过低。
2.预防性应用山莨菪碱可以改善冠脉血流和PCI术后的心肌灌注水平,其作用机制可能与血流动力学改善效应有关。
第三部分
冠脉内联合注射替罗非班和山莨菪碱对ST段抬高心肌梗死患者溶栓早期PCI心肌灌注改善作用的评价
目的：探讨在溶栓后行早期经皮冠状动脉介入治疗(PCI)中预防性应用山莨菪碱和替罗非班对ST-段抬高型心肌梗死(ST-segment elevation myocardial infarction, STEMI)患者心肌灌注的改善效应,及两者的相互作用。
方法：入选2010年12月至2011年12月首诊于河北医科大学第二医院的溶栓后12小时内拟行早期PCI的STEMI连续病例。入选患者被随机分为4组：早期PCI组(PCI),山莨菪碱组(ANI),替罗非班组(TIR)和联合治疗组(ANI+TIR)。患者在接受溶栓治疗同时进行规范的抗血小板、抗凝治疗。冠脉造影检查(CAG)和PCI均经桡动脉入径进行。根据患者CAG结果,对IRA血流未达到TIMI3级或IRA血流达到TIMI3级但狭窄超过75%的患者行PCI治疗。TIR组和TIR+ANI组患者在PCI术前接受替罗非班,用法为负荷剂量10μg/kg冠脉内注射3分钟,继之以0.075μg/kg/min持续静点12小时。PCI组和ANI组患者以同样方式予以等剂量生理盐水。ANI组和ANI+TIR组患者按试验设计于PCI前预防性冠脉内应用山莨菪碱,山莨菪碱的用法为根据患者心率、血压等血流动力学参数以200μg/ml的浓度分次冠脉内注射,首次2000μg,间隔2min后再次注射2000μg。PCI组和TIR组以同样方式予以等剂量生理盐水。接受的替罗非班治疗的患者PCI术中继续给予肝素维持ACT250s左右,未接受替罗非班治疗的患者ACT时间保持在300s左右。入院后详细记录两组患者基本临床资料包括年龄、性别、体重指数、冠心病危险因素(高血压,糖尿病,血脂异常,吸烟史)、心肌梗死部位、心功能分级及基本药物使用情况。比较各组患者TIMI血流分级、校正的TIMI血流计帧数(CTFC)、TIMI(?)心肌灌注分级评价标准(TMPG)以及血栓负荷积分对所有入选病例出院前进行二维超声心动图检查,评价心室功能和室壁运动情况。监测心肌酶学变化,以CK-MB峰值作为心肌梗死面积的估测指标。同时监测患者住院期间肝肾功能、血红蛋白浓度的变化。记录入院时、PCI术后即刻、PCI后24小时内每6小时的标准12导联心电图数据。ST段回落(ST-segment resolution, STR)定义为PCI术前后ST计分的变化,PCI后ST计分较术前降低70%以上记为完全回落。记录患者住院期间的MACE事件发生情况,定义为反复发作的缺血症状、原有梗死相关动脉(infarction related artery, IRA)导致的再发心肌梗死、靶血管再次血运重建和死亡。所有数据统计应用SPSS17.0完成。双侧P<0.05认为有统计学意义。
结果：总共入选了96例患者,每组各24例。各组患者基线资料,包括年龄、性别、既往病史、梗死部位、心功能状态以及基线实验室检查结果,均无显著差异(all P>0.05)。各组CAG检查和PCI操作时间相似(all P>0.05)。各组患者IRA分布、PCI前TIMI血流以及血栓计分相似(all P>0.05)。PCI后ANI、TIR和ANI+TIR组患者CTFC水平较低,TMPG3级以及TIMI3级比例较高(all P<0.05)。ANI、TIR和ANI+TIR组患者CK-MB峰值水平有降低趋势(P=0.245),且LVEF和ST段完全回落比例较高(both P<0.05)。住院期间各组患者出血事件和MACE发生率相似(all P>0.05)。ANI组和ANI+TIR组患者应用山莨菪碱后患者心率轻度增加10-15次/min,停药后10分钟患者心率恢复至基线水平；12例患者感觉轻度口渴,可耐受；无严重高血压及尿潴留等不良反应发生。所有患者均未发生恶性心律失常。Logostic回归分析显示,山莨菪碱和替罗非班对改善心肌灌注具有协同作用趋势,在减少梗死面积,改善心功能等方面存在协同作用趋势。
结论：
1.PCI前预防性冠脉内应用山莨菪碱或减量替罗非班均可改善冠脉微循环和心肌灌注。
2.对于溶栓后行早期PCI的STEMI患者,山莨菪碱在改善心肌灌注方面与替罗非班具有协同作用趋势,并可以在一定程度上减少心肌梗死面积,改善心功能。
第四部分
山莨菪碱对ST段抬高心肌梗死患者直接经皮冠状动脉介入治疗术后肾功能的保护作用
目的：本研究通过单盲、安慰剂随机对照的方法评价山莨菪碱对ST-段抬高型心肌梗死(STEMI)患者直接经皮冠状动脉介入治疗(PCI)术后对比剂肾病(CIN)的防治作用。
方法：入选2010年3月至2011年12月首诊于河北医科大学第二医院的发病12小时内的STEMI连续病例。将入选患者随机分为山莨菪碱组(ANI)和对照组(CON)。AM组患者首先静脉弹丸式注射山莨菪碱50μg/kg,继之以0.1-0.2μg/kg/min持续静脉滴注24小时。CON组患者按同样方法给予等剂量生理盐水(0.9%氯化钠注射液)。其他药物(如阿司匹林、氯吡格雷、利尿剂、正性肌力药物、血管扩张剂、他汀类药物、p受体阻滞剂、ACEI/ARB以及抗凝药物)均按照现行指南规范使用。所有患者在入院后即刻采用标准技术进行直接PCI。对比剂使用非离子型低渗对比剂(优维显370,碘含量370mg/ml, Schering Pharmaceutical Ltd., China)。详细记录两组患者入院后基本临床资料包括年龄、性别、体重指数、冠心病危险因素(高血压,糖尿病,血脂异常,吸烟史)、心肌梗死部位、心功能分级及基本药物使用情况。并于患者入院后24小时内进行二维超声心动图检查,由超声科医生盲法评价左心室功能,记录左室射血分数(LVEF)。采集患者入院时及PCI后24、48、72小时肘静脉血检测血肌酐水平(SCr)。计算估测的肾小球滤过率(estimated glomerular filtration rate, eGFR)。主要终点事件定义为患者直接PCI术后72小时内CIN的发生率。CIN定义为PCI术后48-72小时SCr水平升高超过0.5mg/dl (>44.2μmol/L)或SCr水平较极限值上升25%。应用SPSS17.0软件进行统计学处理。P<0.05(双侧)认为有统计学差异。
结果：累计入选2010年3月至2011年12月首诊于河北医科大学第二医院、发病12小时内的STEMI连续病例177例,其中ANI组88例(男性79例,平均年龄55.01±13.2岁),CON组89例(男性79例,平均年龄54.56±12.73岁)。所有患者均按试验设计完成试验。两组患者包括平均年龄、性别、危险因素以及临床表现方面没有明显差异。患者入院时实验室检查和药物应用方面亦无明显差异。两组患者CAG和PCI操作、对比剂用量以及水化剂量等方面没有明显差异。两组患者入院时SCr水平相似。PCI术后48和72小时ANI组SCr水平明显低于CON组(99.5±26.2μmol/L vs.109.6±37.3μmol/L,82.9±15.6μmol/L vs.94.1±25.8μmol/L,both P<0.01)。两组患者PCI术后SCr水平均较基线值明显升高,峰值水平出现在术后48小时,然后SCr水平逐渐下降。术后72小时ANI组患者SCr水平恢复至基线水平(82.9±15.6μmol/L vs.88.1±22.7μmol/L,P>0.05),而CON组患者SCr水平仍高于基线水平(94.1±25.8μmol/L vs.85.1±18.6μmol/L,P<0.01)。两组患者基线eGFR水平相似。与CON组相比,ANI组患者PCI后24、48、72小时eGFR水平均较高(91.5±22.1ml·min-1·1.73m-2vs.83.2±21.3ml·min-1·1.73m-2,80.2±17.6ml·min-1·1.73m-2vs.73.4±18.5ml·min-1·1.73m-2.93.2±18.4ml·min-1·1.73m-2vs.86.3±21.7ml·min-1·1.73m-2,all P<0.05)。ANI组患者PCI术后72小时eGFR水平明显高于术后48小时(93.2±18.4ml·min-1·1.73m-2vs.80.2±17.6ml·min-1·1.73m-2,P<0.01),并恢复至基线水平(93.2±18.4ml·min-1·1.73m-2vs.92.1±21.3ml·min-1·1.73m-2,P>0.05):CON组患者术后72小时eGFR水平虽有所增加(86.3±21.7ml·min-1·1.73m-2vs.73.4±18.5ml·min-1·1.73m-2,P<0.01),但是仍低于基线水平(86.3±21.7ml·min-1·1.73m-2vs.92.5±22.5ml·min-1·1.73m-2,P<0.05)。多因素回归分析结果显示,糖尿病病史和心功能不全(LVEF<55%)是CIN发生的危险因素,而应用山莨菪碱进行防治是CIN发生的独立保护因素(OR,0.369;95%CI,0.171to0.794;P=0.011)ANI组和CON组CIN的发生率分别为20.5%(18/88)和33.7%(30/89)。ANI组患者CIN发生率明显低于CON组(P<0.05)。两组患者均无因C1N接受透析治疗的病例发生。应用山莨菪碱后患者心率轻度增加(73.0±12.3beats/min vs.76.4±9.1beats/min,P<0.05),峰值水平出现弹丸式注射山莨菪碱后(73.0±12.3beats/min vs.87.0±16.1beats/min,P<0.05),停药后6小时患者心率恢复至基线水平。ANI组患者在应用山莨菪碱治疗期间有17例出现心悸,21例感觉口渴,均可耐受。所有患者均未发生恶性心律失常。
结论：
1.糖尿病和心功能不全是CIN发生的独立预测因素。
2.直接PCI术前和术后应用山莨菪碱可以有效降低STEMI患者CIN发生率,且无明显副作用。
ST-segment elevation myocardial infarction (STEMI) is one of the most severe types of heart attack which usually occurs when thrombus forms on a ruptured atheromatous plaque and occludes an epicardial coronary artery. Approximately17million deaths related to the coronary artery occur each year in the world, and half of them due to STEMI. In recent years, the prevalence of STEMI is growing rapidly in China, with the high mortality in the early stage.
Early and effective reperfusion therapy is the most important treatment for STEMI patients. However, only3%of STEMI patients received primary percutaneous coronary intervention (PCI) within12hours of symptom onset, which indicated that effective reperfusion was not achieved in the majority of STEMI patients in China. In order to reduce the time delay and improve the success of reperfution, an advanced pharmacoinvasive therapy which combined medical treatment with PCI may be the direction of treatment for STEMI in the future. However, the effects of myocardial perfusion, bleeding complications and outcoms of early PCI following thrombolysis should be further studied.
Anisodamine (6-[s]hydroxyhyoscyamine), a belladonna alkaloid derived from the Chinese medicinal herb Scopalia tangutica Maxim of the Solanaceae family that is indigenous to Tibet, is a blocker of M-choline receptors and has the effect of improving the microcirculation and increasing tolerance to ischemia in patients with microcirculatory disorders. Several latest large clinical trials suggested that platelet GP Ⅱb/Ⅲa inhibitor tirofiban could significantly improve reperfusion of infarct area and clinical outcomes of STEMI patients. Our precious studies have shown that intracoronary administration of anisodamine and tiroftban can further improve the coronary flow in STEMI patients underwent primary PCI. So far, the effect of intracoronary administration of anisodamine and tirofiban on myocardial perfusion in STEMI patients undergoing early PCI following thrombolysis and the interaction between them have not been carried out.
Based on our previous work, this study was designed to evaluate the effect of early PCI following thrombolysis via transradial artery approach on myocardial perfusion, and the preventive effect of anisadamine on contrast induced nephropathy. The possible mechanisms were also probed.
The detailed methods and results of our study are as follows:
Part Ⅰ
Safety and Efficacy of Thrombolysis followed by Early Percutaneous Coronary Intervention via Transradial Artery Approach in Patients with ST-segment Elevation Myocardial Infarction
Objective:This study was to compare coronary flow, myocardial perfusion, left ventricular function and major adverse cardiac events (MACE) between thrombolysis followed by early percutaneous coronary intervention (PCI) via transradial artery approach and primary PCI, and to investigate the safety and efficacy of thrombolysis followed by early PCI via transradial artery approach in patients with ST-segment elevation myocardial infarction (STEMI).
Methods:From September2009to March2010, all consecutive STEMI patients within12hours from symptom onset or thrombolysis in the Department of Cardiology of the Second Hospital of Hebei Medical University were enrolled. All eligible STEMI patients were divided into two groups according to patients received thrombolysis or not:early PCI group (E-PCI group, patients received thrombolytic agents in non-PCI capable hospital and immediately transferred to receive early PCI) and primary PCI group (P-PCI group, patients received primary PCI). Coronary angiography (CAG) and PCI were performed immediately after admission via transradial artery approach for patients in both groups with standard technique. According to the results of angiography, PCI was performed unless the blood flow of IRA achieved TIMI flow grade3without significant stenosis. The other medications were administered to the patients (including aspirin, clopidogrel, diuretics, isotropic agents, intravenous vasodilator, lipid-lowering, beta-blockade, and angiotensin of converting enzyme inhibitors) according to current best practice. Thrombus score, TIMI flow grade (TFG) of IRA before and after PCI, corrected TIMI frame count (CTFC), TIMI myocardial perfusion grade (TMPG) post PCI were analyzed. Bleeding complications was also observed and evaluated. All patients were followed up for6months to assess major adverse cardiac events (MACE). The primary end point was myocardial perfusion post PCI assessed by TFG, CTFC and TMPG, and the second end points were bleeding complications during hospital and30-day MACE. SPSS17.0for Windows (SPSS Inc., Chicago, Illinois) was used for statistical analysis. Values of P<0.05were considered statistically significant.
Results:A total of161cases were enrolled, with53cases in E-PCI group and108cases in P-PCI group. The patients in E-PCI group were younger than those in P-PCI group (51.36±12.24vs.57.31±9.87, P=0.003). The other baseline clinical characteristics such as gender distribution, baseline levels of serum BNP, SCr and Hb, and the medication therapies were similar between the two groups (all P>0.05). The mean time from symptom onset to thrombolysis was3.62±1.85h in E-PCI group, and the time from thrombolysis to PCI was5.13±3.03h. Compared to P-PCI group, the mean time from onset to PCI was longer in E-PCI group (8.75±2.86vs.6.03±3.19h, P<0.001). There were no differences in door to balloon time and IRA distribution between the two groups. Of the53patients treated with thrombolysis,51patients underwent early PCI when transferred to our hospital except2patients who only underwent CAG. In the P-PCI group,106patients underwent primary PCI, while2patients underwent CAG. Before PCI procedure, the thrombus score of IRA in E-PCI group was lower, and the percentage of TIMI3flow was higher (both P<0.05) compared to those in P-PCI group. TFG of IRA after PCI was similar, and there was no significant difference in the volume of contrast medium (P>0.05). However, CTFC of IRA post PCI in E-PCI group was lower than that in P-PCI group (28.12±5.06vs.30.89±8.74, P<0.05), and rate of TMPG3in E-PCI group was higher than that in P-PCI group (82.8%vs.68.0%, P<0.05). All of the implanted stents were drug-eluting stents. No differences were found in the stent implantations between the two groups (all P>0.05). There was a trend toward lower in the peak value of serum CK-MB in E-PCI group. No significant differences were found in the incidence of bleeding complications and hospital stay between the two groups. There was a trend of better left ventricular function7days after PCI in E-PCI group than that in P-PCI group. After6-month follow-up, the left ventricular function was improved in both the two groups (all P<0.05), and there was still a better trend in E-PCI group. Overall, there was no significant difference in6-month MACE between the two groups (P=0.977).
Conclusion:
1. The myocardial perfusion was better in patients undergoing thrombolysis followed by early PCI, and there was a trend of improving left ventricular function in patients underwent thrombolysis followed by early PCI, without increases of bleeding complications and incidence of MACE.
2. It is safe and efficacious for STEMI patients to receive thrombolysis followed by early PCI via transradial artery approach.
Part II
Prediction of hemodynamic parameters on myocardial perfusion in patients undergoing early percutaneous coronary intervention following thrombolysis and the myocardial protective effects of anisodamine
Objectives:This study was designed to investigate the relation between hemodynamic states before PCI and myocardial perfusion after early percutaneous coronary intervention (PCI) following thrombolysis, and to observe the predictive effects of anisodamine on myocardial perfusion in patients with ST-segment elevation myocardial infarction (STEMI) undergoing early PCI following thrombolysis.
Methods:This study was performed as a two-phase study.
Phase1represented a retrospective analysis of the consecutive STEMI patients undergoing early PCI following thrombolysis who were admitted to the second hospital of Hebei medical university from June2007to June2009. According to the TIMI myocardial perfusion grading (TMPG) after PCI, all the eligible patients were divided into poor perfusion group (TMPG≤2) and normal perfusion group (TMPG=3). The systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate before PCI were recorded. The TIMI flow grade (TFG), corrected TIMI frame (CTFC) and TMPG, as well as thrombosis score were compared between the two groups. The peak value of CK-MB was monitored and evaluated as infarction area. Echocardiographic examination was performed at discharge by a cardiologist blinded to the randomization results. Left ventricular ejection fraction (LVEF) was determined from apical2and4chambers views by Simpson's biplane formula. Medications were also recorded in a database. Univariate logistic regression was used to analyze the baseline characteristics, angiograph characteristics and hemodynamic states before PCI. The TMPG was used as dependent factor, and multivariate logistic was performed to analyze the independent variants which were selected by univariate logistic regressions. The odds ratios (ORs) and their corresponding95%confidence intervals (CIs) were provided. The logistic regression equation was established according to the result of multivariate logistic regression to predict the risk of incomplete perfusion (TMPG≤2) after PCI. The receiver operating characteristic (ROC) curve was applied to evaluate the sensitivity and specificity of the cutoff value.
Phase2prospectively observed the hemodynamic effects of anisodemine in STEMI patients undergoing early PCI following thrombolysis. From March2010to December2010, concecutive STEMI patients within12hours after thrombolysis were enrolled. All eligible patients were randomly assigned to anisodamine group (ANI) and control group (CON). Patients in ANI group received intracoronary bolus injection of anisodamine (2000μg,10ml) over2minutes according to the heart rate and blood pressure, and the same vulome of0.9%sodium chloride in the CON group. The other medications and laboratory examinations were the same as phase1. The primary end point was the level of TMPG after PCI, and the second end points were including the hemodymanic parameters, STR, peak level of CK-MB, TIMI flow grade and major adverse cardiac events after PCI. The software of SPSS17.0(SPSS Inc. Chicago, Illinois) was used in the statistic analysis, and P<0.05was consided statistically significant.
Result:A total of159patients were enrolled in phase1, with31in poor perfusion group and128in normal perfusion group. Both SBP and DBP before PCI were lower in poor perfusion group than those in normal perfusion group (P<0.001). There was a trend of faster heart rates in the poor perfusion (P=0.098). The LVEF in the normal perfusion group was better than that in the poor group (P=0.005). The other baseline clinical data were similar between the two groups (all.P>0.05). The Killip classification, IRA distribution, baseline TIMI flow grade and thrombosis score were all similar (all P>0.05). There were significant differences in Grade3TIMI flow and CTFC between the two groups. Univariate logistic analysis found that low level of TIMI flow grade, SBP and DBP before PCI were predictors for poor myocardial perfusion, while multivariate logistic regression showed that low level of SBP before PCI and the history of diabetes were predictive factors for poor myocardial perfusion. The predictive model established according to hemodynamic parameters before PCI was as follows:hemodynamic parameter=1+exp (-(-4.091+0.085×DBP+0.016×SBP-0.037×HR)). ROC analyses were performed to determine the best cut-off value of ratio for predicting poor perfusion. The area under the ROC curve for ratio was0.775(95%CI0.683-0.868, P<0.0001). The ratio of0.789was determined to be the best discriminating value for predicting poor perfusion, with a sensitivity of78.1%and a specificity of71.0%.
Seventy-six patients were prospectively enrolled in Phase2, with39in ANI group and37in CON group. No significant differences in baseline clinical data and baseline angiography data were found (all P>0.05). Compared to CON group, the rate of TMPG3was higher in ANI group, while the CTFC was lower (both P<0.05). There was a mild increase of heart rate, SBP and DBP after administration of anisodamine (all P<0.05). The hemodynamic parameter decreased according to the predictive model in phase1. There were sinificant differences in the peak level of CK-MB, LVEF, and STR in the ANI group. The incidences of MACE were similar between the two groups.
Conclusion:
1. Low level of DBP before PCI was one of independent predict facter for imcomplete perfusion.
2. Intracoronary administration of anisodamine before PCI could improve the myocardil perfusion which may be result in the hemodynamic effects of anisodamine.
Part Ⅲ
Additive benefit of glycoprotein Ⅲb/Ⅲa inhibition and adjunctive
Objectives:The aim of the study was to evaluate the additional benefit of preventive administration of anisodamine to tirofiban during primary PCI on myocardial reperfusion.
Methods:This study was a prospective, randomized, single blinded study with2×2factorial design. Consecutive STEMI patients undergoing early PCI within12h of thrombolysis and admitted from December2010to December2011were randomly assigned to1of the4intervention groups: primary PCI (PCI), anisodsamine infusion (ANI), tirofiban infusion (TIR) and PCI with both treatments (ANI+TIR). All patients received aspirin (300mg loading followed by100mg daily) and clopidogrel (600mg loading followed by75mg daily). Heparin boluses were administered to maintain an activated clotting time of250s in patients treated with tirofiban, and>300s in the remaining patients. According to the result of angiography, PCI was performed unless the blood flow of infarct-related artery (IRA) achieved TIMI grade3and the residual stenosis of IRA was less than75%. After coronary angiography, but before the first balloon inflation, patients in the ANI group and TIR+ANI group received intracoronary bolus injection of anisodamine (1000μg,5ml) over3minutes, and the same vulome of0.9%sodium chloride in the other two groups. Tirofiban was administered with a10μg/kg bolus intracoronary injection for over3minutes followed by0.075μg·kg-1·min-1infusion for12hours in TIR group and ANI+TIR group and the same vulome of0.9%sodium chloride in the remaining patients. The blood pressure and electrocardiogram were monitored and recorded during PCI. The other medications were administered to the patients (including aspirin, clopidogrel, diuretics, isotropic agents, intravenous vasodilator, lipid-lowering, beta-blockade, and angiotensin of converting enzyme inhibitors) according to current best practice. Serum creatine kinase (CK), MB fraction (CK-MB), and standard12-lead ECGs were recorded at admission, after the procedure, and then every6h for24h. Echocardiographic examination was performed at discharge by a cardiologist blinded to the randomization results. Left ventricular ejection fraction (LVEF) was determined from apical2and4chambers views by Simpson's biplane formula. The angiographic results before and after PCI by two independent cardiologists who were blinded to the procedures. Thrombosis score, TIMI flow grade (TFG) of IRA before and after PCI, corrected TIMI frame count (CTFC), TIMI myocardial perfusion grade (TMPG) after PCI were recorded. All ECGs were read at the core laboratory by2cardiologists blinded to the randomization. ST-segment resolution (STR) was determined by comparing the ST scores before and after the procedure,>70%decrease of the initial ST elevation was categorized as complete STR. Analyses were done using SPSS for Windows17.0(SPSS Inc., Chicago, Illinois). A two-sided of P-value <0.05was defined as statistically significant.
Results:A total of96patients were enrolled (24cases in each group), and all patients received the assigned treatment. No significant difference in baseline clinical characteristics was found among groups, including mean age, gender distribution, risk factors, and clinical presentations (all P>0.05). No different baseline angiographic characteristics were found among groups (all P>0.05). There was a trend of more patients achieving post-procedural TIMI3flow in the ANI+TIR group, compared to the primary PCI group (95.8%vs.75.0%, P=0.084). The post-procedural CTFC in ANI+TIR group was less than the other three groups (P=0.002), while the post-procedural CTFC in both ANI group and TIR group were improved. There was also a possible interaction regarding CTFC with the P=0.165of anisodamine×tirofiban. There was a trend of more complete STR in both ANI group and TIR group than that in primary PCI group, and a significant difference of more complete STR in ANI+TIR group was found than that in primary PCI group (91.7%vs.58.3%, P=0.039). There was a trend of high level of peak CK-MB in primary PCI group (P=0.245). No significant difference of bleeding complications was found among groups. There was a trend of higher LVEF at discharge in the TIR+ANI group, compared to the primary PCI group (56.19%±4.05%vs.50.70%±7.35%, P=0.005). No palpitation, thirst, blurred vision or retention of urine were found in the patients who were administered anisodamine. No malignant arrhythmia (defined as ventricular fibrillation or ventricular tachycardia with hemodynamic compromise requiring defibrillation) occurred in patients treated with anisodamine. No significant difference of occurrence of MACE was found among groups (P=0.686).
Conclusions:
1. Both anisodamine and tirofiban addministered before PCI may improve the myocardial reperfusion in STEMI patients undergoing early PCI following thrombolysis.
2. There are possible interactions of anisodamine and tirofiban on myocardial reperfusion.
Part Ⅳ
Protective Effects of Anisodamine on Renal Function in Patients with ST-Segment Elevation Myocardial Infarction undergoing Primary Percutaneous Coronary Intervention
Objective:This single blinded, placebo-controlled and randomized trial was to evaluate the effect of anisodamine on renal function in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI).
Methods:From March2010to December2011, all consecutive STEMI patients within12hours from onset of symptoms undergoing primary PCI in the Cardiology Department of the Second Hospital of Hebei Medical University were enrolled. Eligible patients were randomly assigned to receive anisodamine (anisodamine group, ANI) or placebo (control group, CON) by means of random number table. Patients in the ANI group received anisodamine50μg/kg bolus injection after randomization followed by an adjusted-dose (0.1-0.2μg/kg/min) to24h after PCI, while patients in CON received infusion of placebo (0.9%sodium chloride) with the same volume of ANI group. Other medications were administered to all the patients (including aspirin, clopidogrel, diuretics, isotropic agents, intravenous vasodilator, statins, beta-blockade, angiotensin converting enzyme inhibitors, and anticoagulation agents) according to current best practice. Primary PCI was performed with standard technique as soon as possible. PCI success was defined as grade3flow of post procedural thrombolysis in myocardial infarction (TIMI) and a decrease of residual stenosis to<20%by quantitative coronary analysis. The nonionic contrast (Ultravist370, iodine370mg/ml, Schering Pharmaceutical Ltd., China) was used in all patients. Intravenous hydration was given to all patients with intravenous isotonic saline (0.9%) at a rate of1ml/kg/hour or0.5ml/kg/hour in case of overt heart failure before the procedure and for12hours after the procedure. Left ventricular function was evaluated by echocardiography in all patients within24hours after admission. Investigators involved in the procedures and those reading echocardiograms were all blind to the randomized treatment. Serum creatinine (SCr) concentrations were measured at admission,24hours,48hours and72hours after PCI. Estimated glomerular filtration rate (eGFR) was calculated by the simplified modification of diet in renal disease study equation (MDRD):eGFR=186×Serum creatinine-1.154×age-0.203(female×0.742). All calculations were computed with the aid of SPSS17.0statistical software. A P Value of less than0.05(2-tailed) was considered statistically significant.
Results:Of the177patients enrolled,88were randomly assigned to anisodamine and89to placebo. There were no significant differences in baseline characteristics, including mean age, gender distribution, risk factors, and clinical presentations between the two groups. The laboratory results and medications used during the procedure were not significantly different. The SCr concentration on admission and eGFR were also similar between the two groups. The preexisting chronic kidney disease (defined as eGFR<60ml/min/1.73m2) was not different between the two groups. The average time of onset to balloon was similar between the two groups. There were no significant differences regarding the distribution of infarction related artery, interventions procedure, stent implantations, use of intravenous GP Ⅱb/Ⅲa receptor antagonist, total contrast volume consumption and the hydration volume. The SCr concentration at admission was not significantly different between the two groups. However, it was lower in ANI group than that in CON group at hour48and72after administration of contrast medium (99.5±26.2μmol/L vs.109.6±37.3μmol/L,82.9±15.6μmol/L vs.94.1±25.8μmol/L, both P<0.01). For both groups, SCr concentrations significantly increased after PCI (P<0.0001), with the peak value occurring at hour48, and then began to decrease. To be specific, in ANI group, SCr concentration decreased significantly at hour72, and returned to baseline level (82.9±15.6μmol/L vs.88.1±22.7μmol/L, P>0.05), while in CON group, SCr concentration also decreased significantly at hour72, but the result was still higher than baseline (94.1±25.8μmol/L vs.85.1±18.6μmol/L, P<0.01). The eGFR at admission was also similar between the two groups. The eGFR at hour24,48and72after primary PCI were higher in ANI group than those in control group (91.5±22.1ml·min-1·1.73m-2vs.83.2±21.3ml·min-11.73m-2,80.2±17.6ml·min-1·1.73m-2vs.73.4±18.5ml·min-1·1.73m-2,93.2±18.4ml·min-1·1.73m-2vs.86.3±21.7ml·min-1·1.73m-2, all P0.05). In ANI group, eGFR increased significantly at hour72compared with that at hour48(93.2±18.4ml·min-1±1.73m-2vs.80.2±17.6ml·min-1·1.73m-2, P<0.01), and the result was similar to the baseline level (93.2±18.4ml·min-1·1.73m-2vs.92.1±21.3ml·min-1·1.73m-2, P>0.05). In CON group, eGFR increased significantly (86.3±21.7ml·min-1·1.73m-2vs.73.4±18.5ml·min-1·1.73m-2, P<0.01) at hour72, but was still lower than baseline level (86.3±21.7ml·min-1·1.73m-2vs.92.5±22.5ml·min-1 1.73m-2, P<0.05). The results of multiple logistic regression showed that the history of diabetes and low LVEF before PCI were independent predictors of CIN, and treatment with anisodamine was an independent preventive factor of CIN (OR,0.369;95%CI,0.171to0.794; P=0.011). The incidences of CIN was20.5%(18/88) and33.7%(30/89) in ANI and CON group respectively, and the incidence of CIN in ANI group was lower than that in CON group within72hours after the procedure (P<0.05). Dialysis was not used in both groups. There was a mild increase of heart rate after administration of anisodamine (73.0±12.3beats/min vs.76.4±9.1beats/min, P<0.05), and the peak value occurred after bolus of anisodamine (73.0±12.3beats/min vs.87.0±16.1beats/min, P<0.05), and recovered6hours later after withdrawal of anisodamine. No malignant arrhythmia occurred in all patients.
Conclusion:
1. Both diabetes and low LVEF are indipendent predictors for CIN.
2. Intravenous infusion of anisodamine before and after primary PCI may reduce the occurrence of CIN in STEMI patients undergoing primary PCI safely.
引文
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