尼可地尔临床疗效的系统评价
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摘要
研究背景
心脏保护有两个含义,不但要“保护”(preservation),而且要“帮助并使其受益“(favouritism or patronage)。心脏保护(cardioprotection)具体是指通过某种方式,预防、延缓及减少心肌损伤,尤其是指在潜在的致命性缺血性应激后,通过心肌减慢能量需求,产生更少的有毒糖酵解产物,表现出心肌损伤减少。例如ACEI(angiotensin converting enzyme inhibitors)对受损的左室功能提供保护作用,是心脏保护的一种表现。目前心血管疾病中,以动脉(粥样)硬化病变为基础的心血管疾病占全部心血管疾病的绝大部分。除了一级预防控制危险因素外,需强调二级预防的心血管疾病有：1)稳定的冠心病患者,2)不稳定型心绞痛,3)有急性心肌梗塞病史,4)有冠脉搭桥术史,5)有经皮冠脉内介入治疗史。这五类可以归因为冠脉狭窄或阻塞引起的心肌缺血性疾病。
在过去的二三十年间,已经证实提供有力的心脏保护能够对抗心肌梗死及其并发的缺血再灌注损伤。2011年美国心脏病协会(American Heart Association,AHA)/美国心脏协会基金会(American College of Cardiology Foundation, ACCF)更新了心血管疾病二级预防指南,推荐了以阿司匹林(Aspirin)或氯吡格雷、p受体阻滞剂(β-Blocker)及肾素血管紧张素醛固酮系统阻断剂(ACEI, ARB和醛固酮拮抗剂)和降脂药为基础的二级预防方案(Ⅰ类证据),其目的是防复发,防猝死,防左室重构。但上述药物有各自的局限性,冠脉介入治疗和冠脉搭桥术仅解决狭窄,却未能使患者远期受益。因此临床上需要研发新的能提供心脏保护的药物。
2012年,基于上述不尽人意的现有治疗模式,有学者提出应当从“专注于阻塞性冠状动脉粥样硬化中心论”转为“心肌细胞缺血中心论”。如果将心肌细胞作为主要的保护目标,阻塞性冠脉粥样硬化则只是其中一个常见病理因素,学者们可以考虑更多潜在的致心肌细胞缺血因素,从而研发更多更新的保护心肌缺血性损伤的策略。三磷酸腺苷敏感的钾(KATP)通道开放剂的心脏保护作用由此受到关注。尼可地尔是目前临床上研究较为深入的KATP通道开放剂。
尼可地尔,烟酰胺衍生物,又名烟浪丁,具有硝酸根部分,类硝酸酯特性,同时还是ATP敏感的钾通道激动剂(ATP-sensitive potassium channel openers,KATP),因具有双重药理机制,所以与硝酸甘油或硝酸异山梨酯不同,该药对心率,血压等血流动力学影响很小,产生抗心绞痛作用的临床剂量对心脏收缩影响很小,并提供长期的心脏保护。现在临床上有口服制剂和静脉制剂。口服制剂常用于治疗高血压、稳定型心绞痛、心肌梗死(包括PCI后)、心律失常和慢性心力衰竭等心血管疾病：静脉制剂可以冠状动脉内注射或静脉内注射,常用于急性心肌梗死和急性心力衰竭。该药的作用机理特别强调其诱导缺血预适应。
随着临床研究的不断发展和循证医学的兴起,设计合理严密的系统综述(systematic review)和Meta分析(Meta-analysis)被视为评价和合成某一特定研究问题的最佳方式,同时被视为最高等级的临床证据。目前关于尼可地尔的临床应用评价,已有四篇Meta分析,分别是：尼可地尔对急性心肌梗死的治疗作用；系统评价尼可地尔与p受体阻滞剂、长效硝酸酯类药和钙离子拮抗剂对稳定型心绞痛有效性及安全性比较；尼可地尔预防冠脉内支架置入术后无再流效果的系统评价；尼可地尔对急性心肌梗死再灌注疗效的Meta分析。尚无关于尼可地尔对心血管事件和急性、慢性心力衰竭的系统评价报道。
研究目的
应用国际循证医学通用的系统评价方法,对目前临床应用尼可地尔的国内外临床研究分别进行系统评价,阐明以下问题：(1)评价在传统治疗方案基础上加用尼可地尔对心血管事件的影响；(2)评价在传统治疗方案基础上加用尼可地尔对慢性心力衰竭的临床疗效；(3)评价在传统治疗方案基础上加用尼可地尔对急性心力衰竭的临床疗效。通过系统回顾及Meta分析方法,旨在了解尼可地尔能否在现有标准治疗的基础上进一步使心血管疾病患者获益,起到心脏保护作用,改善心血管疾病患者预后。
研究方法
[尼可地尔对冠心病患者全因死亡率和心血管事件的影响]
按照循证医学的原则,系统检索由数据库建立初始至2013年1月的cochrane对照试验注册数据库、PubMed、MEDLINE、EMbase、OVID、CBM、 CNKI、万方数据资源。检索词包括：中文为“尼可地尔”AND“心脏”AND“终点”OR“死亡”OR“预后”；英文是"nicorandil"AND"heart"AND "death"OR"event" OR "end point" OR "mortality" OR "prognosis";随机对照的检索词为"randomized controlled"OR"clinical trial" OR"clinical study".初次检索得到的结果再按纳入和排除标准进行筛选。由2名评价者独立评价纳入研究的质量、提取资料并交叉核对,采用Stata11.0软件进行全因死亡率、再次血运重建和心血管事件的Meta分析。分类资料用计数和率来记录。生存分析资料的效应量指标为危险比HR,计数资料的二分类资料采用优势比OR和相对危险度RR作为效应量。各效应量均以95%可信区间(CI)表示。对各纳入研究结果间的异质性采用Q检验和I2检验。根据检验结果采用相应效应模型进行合并效应量。当各研究间有统计学同质性(P>0.1,I2<50%)时,采用固定效应模型；反之,若P≤0.1,I2≥50%采用随机效应模型。各研究间异质性较大时(I2≥50%),进一步进行敏感性分析、Meta回归和亚组分析,尽可能寻找异质性的来源,并分析异质性产生原因。两组异质性过大或无法找寻数据来源时,采用描述性分析。Meta回归进行协变量筛选时,显著性水平定义为P<0.1。用漏斗图和定量检验(Egger线性回归法)评估发表偏倚,如P>0.05则提示研究存在偏倚的可能性较小；如P<0.05,则提示研究存在偏倚的可能性较大。其中心血管事件定义为出现以下情况：心血管疾病死亡、猝死(sudden death)、急性冠脉综合征(包括致命或非致命的急性心肌梗死)、因胸痛或充血性心衰再入院。
[尼可地尔对慢性心力衰竭的系统评价]
按照循证医学的原则,系统检索由数据库建立初始至2012年3月的cochrane对照试验注册数据库、PubMed、MEDLINE、EMbase、CBM、CNKI、万方数据资源。检索词包括：中文为“尼可地尔”、“心功能”；英文是"nicorandil"AND"heart failure"OR"cardiomyopathy" OR "heart function"OR "ventricular function";随机对照的检索词为"randomized controlled"OR"clinical trial"。初次检索得到的结果再按纳入和排除标准进行筛选。由2名评价者独立评价纳入研究的质量、提取资料并交叉核对,主要观察指标：心率(HR)、平均动脉血压(MBP)、肺毛细血管楔压(PCWP)、RAP(right atrial pressure)、 SVR (systemic vascular resistance全身血管阻力)、CI (Cardiac index心脏指数)、左室射血分数(LVEF)、B型利钠肽(BNP)、6分钟步行测试(6MWT)。采用Stata11.0软件进行Meta分析。采用Stata11.0软件进行Meta分析。计量资料采用加权均数差(MD)作为效应量,各效应量均以95%CI表示。先对各纳入研究结果间的异质性采用Q检验和I2检验。当各研究间有统计学同质性(P>0.1,I2<50%)时,采用固定效应模型；反之,采用随机效应模型。各研究间异质性较大时(I2<50%),进一步进行敏感性分析和τ2(tau-squared)检验。两组异质性过大或无法找寻数据来源时,采用描述性分析。检验水准P<0.05为差异有显著性。
[尼可地尔对急性心力衰竭的系统评价]
按照循证医学的原则,系统检索由数据库建立初始至2013年1月的cochrane对照试验注册数据库、PubMed、MEDLINE、EMbase、CBM、CNKI、万方数据资源。检索词包括：检索词包括：中文为“尼可地尔”AND“急性"AND“心力衰竭"AND“患者”；英文是"nicorandil"AND"heart failure" AND"acute";研究设计类型选择“随机对照试验”、“随机”、“对照”,“观察研究”,“病例对照研究”,"randomized controlled"OR"clinical trial"OR "random" OR "control" OR "RCT"OR"observational study" OR "case-control".初次检索得到的结果再按纳入和排除标准进行筛选。检索时运用主题检索和分类检索两种方法避免漏检相关文献。由2名评价者独立评价纳入研究的质量、提取资料并交叉核对,主要观察指标应用尼可地尔注射液后的血流动力学及心功能指标变化。采用RevMan5.0软件进行数据分析。计量资料采用加权均数差(MD)作为效应量,各效应量均以95%CI表示。先对各纳入研究结果间的异质性采用Q检验和I2检验。当各研究间有统计学同质性(P>0.1,I2<50%)时,采用固定效应模型；反之,采用随机效应模型。两组异质性过大或无法找寻数据来源时,采用描述性分析。检验水准P<0.05为统计学差异有显著性。
结果
[尼可地尔对冠心病患者全因死亡率和心血管事件的影响]
本研究共检索到英文文献153篇,中文文献为72篇,共计225篇,按照纳入和排除标准,通过题目、摘要及进一步的全文阅读,最终纳入17个研究,纳入的心血管疾病患者主要是不同类型的冠心病患者,包含了急性冠脉综合征(急性心肌梗死和不稳定型心绞痛)以及稳定型心绞痛,有或无冠脉介入术及冠脉搭桥术的病史。治疗方式上干预组尼可地尔组在常规治疗基础上加用尼可地尔,对照组为空白对照或安慰剂对照或硝酸酯类对照,对照组无应用尼可地尔者。最短观察期为2天,最长观察期为5年。研究质量评价方面,17个研究均为随机对照研究,其中6个研究为A级,完整描述了随机分配的方法,双盲的具体操作,分配隐藏方法及失访和意向性分析；6个研究为B级,描述了随机分配的方法,双盲的具体操作和随访情况,但未提到分配隐藏；5个研究为C级,仅提到随机,未具体描述随机分配的方法,有无盲法及分配隐藏。
(1)尼可地尔对全因死亡率影响的Meta分析结果：
采用危险比HR为效应量,纳入3个研究,这3个研究均是随访严密的RCT研究,文献质量均为A级,平均随访时间超过一年半,meta分析结果显示Q检验χ2=3.97(d.f.=2,P=0.137>0.1),I2=49.7%,Z=2.27(P=0.023<0.05),合并效应量HR为0.77(0.61-0.96),提示长期应用尼可地尔能显著降低冠心病患者的全因死亡率。研究间异质性来源考虑与用药途径,纳入患者人群及给药方案不同有关。但仅纳入3个研究,Meta结果可能不稳定。
若采用死亡人数进行meta分析,可纳入14个研究,共纳入患者6993例,尼可地尔组3494例,死亡135例,死亡率3.86%；对照组3499例,死亡166例,死亡率4.74%。以优势比OR做合并效应量,Q检验χ2=3.42(d.f.=13),P:0.996,I2=0.0%,研究间无异质性。Z=1.77,合并OR值为0.818(0.655-1.022),P=0.077.若采用相对危险度RR做合并效应量,Q检验χ2=3.32(d.f=13),P=0.996,I2=0.0%,研究间无异质性。Z=1.77,合并RR值为0.826(0.6669-1.021),P=0.077。考虑到研究间无异质性,即综合考虑到纳入研究在给药途径、用药剂量、随访年限及文献质量方面的不同,均提示使用尼可地尔未能明显降低全因死亡率。
(2)尼可地尔对再次血运重建事件影响的Meta分析结果：
有5个研究报道了再次血运重建情况。纳入患者共1030例,尼可地尔组513例,再次血运重建的患者67例,事件率13.0%；对照组517例,再次血运重建的患者70例,事件率13.5%。采用优势比OR做合并效应量,Q检验x2=5.96,(d.f=4),P=0.202,I2=32.9%,研究间有中度异质性。Z=0.02,合并OR值为1.006(0.576-1.755),P=0.985。采用相对危险度RR做合并效应量,Q检验x2=5.82,(d.f.=4),P=0.213,I2=31.2%,研究间有中度异质性。Z=0.05,合并RR值为0.987(0.613-1.588),P=0.957。由于存在异质性,考虑到纳入研究在给药途径、随访年限及文献质量方面的不同,采用亚组分析,P值均大于0.05,提示使用尼可地尔未能显著降低再次血运重建的事件发生。
(3)尼可地尔对心血管事件影响的Meta分析结果：
纳入的11个研究均是不同类型的冠心病患者,包含了急性冠脉综合征(急性心肌梗死和不稳定型心绞痛)以及稳定型心绞痛,有或无冠脉介入术及冠脉搭桥术的病史。治疗方式上干预组尼可地尔组在常规治疗基础上加用尼可地尔,对照组为空白对照或安慰剂对照或硝酸酯类对照,对照组无应用尼可地尔者。最短观察期为2天,最长观察期为5年。研究质量评价方面,11个研究均为随机对照研究,其中6个研究为A级,完整描述了随机分配的方法,双盲的具体操作,分配隐藏方法及失访和意向性分析；3个研究为B级,描述了随机分配的方法,双盲的具体操作和随访情况,但未提到分配隐藏；2个研究为C级,仅提到随机,未具体描述随机分配的方法,有无盲法及分配隐藏。各组的男性比例及糖尿病患者比例不同。
纳入11个研究,患者共7705例,尼可地尔组3785例,发生心血管事件患者401例,事件率10.59%；对照组3920例,发生心血管事件患者539例,事件率13.75%。采用优势比OR做合并效应量,Q检验x2=21.11(d.f.=10),P=0.020,I2=52.6%,研究间异质性>50%,采用随机效应模型进行分析。Z=4.08,合并OR值为0.441(0.297-0.653),P=0.000<0.001。采用相对危险度RR做合并效应量,Q检验x2=18.81(d.f.=10),P=0.043, I2=46.8%<50%,研究间有中度异质性,但可以应用固定效应模型进行分析。Z=4.87,合并RR值为0.744(0.660-0.838),P=0.000<0.001。由于存在异质性,考虑到纳入研究在给药途径、随访年限及文献质量等方面的不同,进一步采用敏感性分析、meta回归及亚组分析、寻找异质性来源。
通过敏感性分析,提示IONA研究是异质性的主要来源,它与其他纳入的10个研究有显著不同的地方是大样本量的研究。
通过Meta回归结果,发现引起异质性的主要来源依次有样本量(Adj R2=100%, P=0.003)、国家(Adj R2=59.02%, P=0.071)、糖尿病患者在各研究中所占比例(Adj R2=80.25%, P=0.026),均具有显著的统计学意义(P值均大于0.1)。进一步用Mento Carlo置换法检验计算上述协变量的矫正P值,协变量“样本量“的P值为0.068,协变量“国家”的P值为0.439,协变量”糖尿病患者在各研究中所占比例”的P值为0.329。因此,糖尿病患者所占比例与尼可地尔减少心血管事件相对危险度RR值之间不呈显著的线性关系。Meta回归图显示了以下趋势：糖尿病患者在研究中所占比例越高,服用尼可地尔后发生心血管事件的相对危险度RR数值越低。
按样本量分层后的亚组分析,所有异质性完全消除(I2=0.0%)。大样本量(纳入患者数大于1000例)研究1个,即IONA研究,相对危险度RR值为0.845(0.739-0.967),P=0.014；中样本量(纳入患者数100例至1000例之间)的研究6个,合并相对危险度RR值为0.479(0.353-0.651),P=0.000<0.001；小样本量(纳入患者数小于100例)的研究4个,合并相对危险度RR值为0.387(0.223-0.671),P=0.001。因此,无论样本量大小,均提示应用尼可地尔之后可以显著降低心血管事件的发生风险。
按国家分层后的亚组分析,消除部分异质性。韩国2项研究,I2=0.0%,合并相对危险度RR值为0.559(0.106-2.956),P=0.494；日本6项研究,I2=0.0%,合并相对危险度RR值为0.375(0.260-0.542),P=0.000<0.001；英国2项研究,I2=55.0%,合并相对危险度RR值为0.823(0.724-0.936),P=0.003；中国1项研究,合并相对危险度RR值为0.600(0.234-1.539),P=0.288。日本与英国的研究在纳入的11项研究中占8项,提示应用尼可地尔降低心血管事件发生风险可能与人种及地区关系不大。
按文献质量分层后的亚组分析：按Jadad score评价研究质量等级为C的2项研究,I2=0.0%,合并相对危险度RR值为0.581(0.242-1.393),P=0.224；按Jadad score评价研究质量等级为B的3项研究,I2=0.0%,合并相对危险度RR值为0.381(0.216-0.670),P=0.001；按Jadad score评价研究质量等级为A的6项研究,I2=59.3%,合并相对危险度RR值为0.772(0.682-0.873),P=0.000<0.001。因此,质量为等级A和B的研究均显示应用尼可地尔能显著降低冠心病患者心血管事件的发生风险,提示该Meta分析结果可靠性较高。
按随访时间分层后的亚组分析结果,随访时间小于1个月的研究有4项,I2=0.0%,合并相对危险度RR值为0.527(0.372-0.745),P=0.000<0.001；随访时间为半年的研究有2项,I2=0.0%,合并相对危险度RR值为0.414(0.173-0.990),P=0.048；随访时间大于1年的研究有5项,I2=62.8%,合并相对危险度RR值为0.787(0.692-0.895),P=0.000<0.001。提示无论应用尼可地尔时间长短,均显著减少心血管事件的发生风险。
按给药途径分层后的亚组分析,有1项研究实施了冠脉内注射尼可地尔,相对危险度RR值为0.486(0.046-5.133),P=0.549；有4项研究为单纯口服尼可地尔,I2=51.9%,合并相对危险度RR值为0.800(0.706-0.907),P<0.001；有4项研究为单纯静脉应用尼可地尔,I2=0.0%,合并相对危险度RR值为0.384(0.233-0.629),P=0.000<0.001；有2项研究为先静脉注射再续以口服用药,I2=0.0%,合并相对危险度RR值为0.382(0.188-0.774),P=0.008。提示不同给药途径不影响尼可地尔较少心血管事件发生风险的作用。
发表偏倚检测：11个研究的漏斗图提示研究分布并不对称,Egger's test的检验结果P=0.002(-2.1755,-0.6881),提示存在发表性偏倚。经剪补法纠正后,meta分析结果一致：固定效应模型计算合并效应量RR值为0.749(0.664,0.845),Z=-4.718,P=0.000；随机效应模型计算合并效应量RR值为0.525(0.387,0.712),Z=-4.140,P=0.000。提示此次Meta分析结果稳定可靠。
[尼可地尔对慢性心力衰竭的系统评价]
共纳入9个研究,共计279例患者。Meta分析结果显示：①与静脉应用硝酸甘油相比较,静脉连续应用尼可地尔24小时,可引起心率轻度增快(MD=I.272,95%的CI值为0.385-2.160,P=0.005)；PCWP显著降低(MD=-2.255,95%的CI值为-4.236～-0.274,P=0.026)；SVR明显下降(MD=-0.832,95%的CI值为-1.304～-0.359,P=0.001)。但是,RAP、CI (Cardiac index心脏指数)、MBP的变化与硝酸甘油组相比无差异。②单次剂量口服40mg或者60mg尼可地尔片,有助于降低PCWP、SVR及MBP。③在传统治疗方案的基础上(包括洋地黄、利尿剂、ACEI(ARB)、BB,硝酸酯类)加用口服尼可地尔5mg,一天三次,短期效果及长期持续应用5至6个月,均可以明显改善LVEF (MD=1.712,95%的CI值为0.658～2.767,P=0.001)。结论：在传统治疗方案基础上,无论是否与其他血管扩张剂合用,经口服途径或静脉途径应用尼可地尔,均可对由缺血性心肌病(含PCI术后6个月的患者)、扩张性心肌病、瓣膜性心脏病、高血压性心脏病等引起的慢性充血性心力衰竭患者的LVEF、 PCWP及SVR方面,获得较好的疗效。
[尼可地尔对急性心力衰竭的系统评价]
共检索到32篇文献,通过题目、摘要进行初筛,并进一步阅读全文后,剔除29篇,纳入3篇关于尼可地尔治疗急性心力衰竭的研究,其中2篇为随机对照研究,1篇为观察性研究。共计纳入患者471例,其中尼可地尔组113例,对照组358例。纳入患者平均年龄大于65岁,血压不低于90mmHg,左室射血分数正常或下降,排除了急性冠脉综合征合并急性心力衰竭。纳入研究均为静脉途径间歇或持续应用尼可地尔,观察时间48小时至5天不等,均报道了通过静脉应用尼可地尔后的血流动力学及心功能改变情况。应用Meta分析了静脉应用尼可地尔后48小时到72小时的动脉收缩压情况,结果显示Z=0.54,P=0.59,提示在AHF早期阶段静脉应用尼可地尔后,动脉收缩压与对照组无显著差异。同时,3个纳入研究提示AHF的心衰指标得到改善,有1个研究提示在AHF早期阶段应用静脉尼可地尔可降低半年内的心血管事件发生率。
结论
[尼可地尔对冠心病患者全因死亡率和心血管事件的影响]
研究结果提示,在标准治疗的基础上加用尼可地尔能显著降低冠心病患者心血管事件的发生风险,包括心血管死亡、致命及非致命心肌梗塞及因胸痛和心衰发作非计划入院；可能降低全因死亡率的发生危险；未能显著降低再次血运重建事件。在降低冠心病患者心血管事件发生风险方面,应用尼可地尔的给药途径包括口服、静脉注射及冠脉内注射；应用时间短至2天,长至5年；应用人种和地区不限。尼可地尔能够在冠心病二级预防过程中使患者受益,可能与其保护心脏细胞的作用有关。应用尼可地尔可能使冠心病合并糖尿病、冠心病合并终末期肾病患者进一步获益的趋势,尚待大样本的随机对照研究进一步明确。
[尼可地尔对慢性心力衰竭的系统评价]
在传统治疗方案基础上,无论是否与其他血管扩张剂合用,经口服途径或静脉途径应用尼可地尔,均可对由缺血性心肌病(含PCI术后6个月的患者)、扩张性心肌病、瓣膜性心脏病、高血压性心脏病等引起的慢性充血性心力衰竭患者的LVEF、PCWP及SVR方面,获得较好的疗效。
[尼可地尔对急性心力衰竭的系统评价]
在急性心力衰竭早期阶段静脉应用尼可地尔可以改善血流动力学及心功能,且不会引起血压显著下降。
局限性及展望
[尼可地尔对冠心病患者全因死亡率和心血管事件的影响]
目前关于尼可地尔对冠心病患者预后方面的大样本研究主要是IONA、 JCAD及OACIS,其中IONA是随机对照研究,而JCAD和OACIS是非随机对照研究,因此未能纳入本次Meta分析。已纳入研究除IONA外,样本量均不大,降低了对全因死亡率的检验效能；另外,应关注冠心病合并糖尿病患者和冠心病合并终末期肾病患者能否在应用尼可地尔后进一步获益,且需要更多的大样本随机对照研究来证实其对上述人群的心脏保护作用。
[尼可地尔对慢性心力衰竭的系统评价]
该系统评价中纳入的临床研究样本量均较小,而且观察时间最长为6个月,未能得到与临床硬终点如死亡率方面的确切结论,而这些指标才是评价药物疗效的金标准。同时我们还看到,纳入研究的年限较早,可能与尼可地尔的主要应用范围是冠心病患者有关。随着目前对KATP在心脏保护作用的机制研究更为深入,有望逐步开展尼可地尔对各种病因引起的慢性心力衰竭的长期随访研究。
[尼可地尔对急性心力衰竭的系统评价]
本研究存在一定的局限性。目前关于尼可地尔用于AHF的临床试验研究较少,已有研究的样本量不大,随机对照研究不多,以观察性研究为主,可能与AHF是一种高危急症有关。纳入研究较少,混杂因素相对较多,对Meta分析结果的检验效能会产生影响。另外,各项研究的观察重点是血流动力学变化及心功能指标有无改善,而并非死亡率这种硬终点指标。因此未来仍需要设计严密的随机对照研究或高质量的观察性研究来证明其疗效。
Background
Heart protection means two implications, not only to "protect"(preservation), but also help to benefit for (favouritism or patronage). ACEI (angiotensin converting enzyme inhibitors) to provide a protective effect of impaired left ventricular function, is a manifestation of the heart protection. Heart Protection (cardioprotection) specifically refers to in some way, to prevent, delay and reduce myocardial injury, especially by means potentially fatal ischemic stress myocardial slow energy demand, and produce less toxic sugar leaven hydrolysates showed reduced myocardial injury. In the past two or three decades, it has been confirmed that provide strong heart protection against myocardial infarction complicated by ischemia-reperfusion injury.2011American Heart Association (American Heart Association, AHA)/American Heart Association Foundation (American College of Cardiology Foundation, ACCF) updated cardiovascular disease secondary prevention guidelines recommend aspirin (Aspirin) or clopidogrel p-blockers (β-Blocker) and the renin-angiotensin-aldosterone system blockers (ACEI, ARB, and aldosterone antagonists) and lipid-lowering drugs for secondary prevention program (class I evidence), the purpose relapse prevention, anti-sudden death, anti-left ventricular remodeling.
Control of the existing mode of treatment for cardiovascular disease is still unsatisfactory, these drugs also have their own limitations, only solve narrow coronary intervention and coronary artery bypass grafting, but did not make the long-term benefit of patients.[4] Clinical research and development of new drugs for heart protection. In2012, based on the clinical practice of the unsatisfactory results, scholars:ischemic heart disease awareness should focus on obstructive coronary atherosclerosis center theory "to" myocardial ischemia center theory ". If myocardial ischemia as the main protection targets, obstructive coronary atherosclerosis is a common pathological factors, scholars can consider more potential induced myocardial ischemia factors, which developed more updated protection myocardial ischemic injury in strategy. Cardioprotective effects of adenosine triphosphate-sensitive potassium (KATP) channel opener this attention. Nicorandil clinical study more deeply the KATP channel opener.
Nicorandil, a nicotinamide derivative, also known as smoke waves Ding has the nitrate part class nitrates characteristics, ATP-sensitive potassium channel agonist (ATP-sensitive potassium channel openers, KATP), a dual pharmacological mechanism with nitroglycerin or isosorbide esters, the drug has little effect on heart rate, blood pressure and other hemodynamic to produce clinical doses of antianginal little effect on cardiac contractility, and provide long-term protection of the heart. Now clinical oral formulations commonly used in the treatment of hypertension, stable angina pectoris, myocardial infarction (including PCI), cardiac arrhythmias, heart failure and other cardiovascular diseases, intravenous formulation for commonly used in intracoronary injection, with particular emphasis on its inducible ischemia preconditioning effect (transient ischemic preconditioning period caused ischemia reperfusion injury in a strong protective effect). Clinical application of nicorandil three Meta-analysis are:the role of nicorandil on the treatment of acute myocardial infarction (2009foreign language), system evaluation nicorandil beta blockers, long-acting nitrates drugs and calcium antagonists (Japanese)2010compared the efficacy and safety of stable angina, nicorandil prevention of coronary stenting no-reflow effect of systematic reviews (2010Chinese), nicorandil reperfusion in acute myocardial infarction efficacy Meta-analysis (2012, Chinese)
Nicorandil (nicorandil) is a unique, ATP-sensitive potassium (KATP) channel the excited and class nitrates features dual pharmacological mechanism of drugs, and provide long-term protection of the heart. Drug against acute or chronic ischemic heart disease, congestive heart failure in patients with heart damage, with particular emphasis (ischaemic postconditioning, IPoC, that for a short pre-ischemic period caused ischemia-reperfusion injury induced ischemic preconditioning strong protective effect) effect.
With the continuous development of the clinical research and the rise of evidence-based medicine, rational design rigorous systematic review (systematic review) and Meta-analysis (Meta-analysis) is regarded as the best way of evaluation and synthesis of a specific research question, while regarded as the highest level of clinical evidence. The Meta-analysis of a number of independent studies of the same problem is comprehensive quantitative statistical methods to increase statistical power and effect sizes estimated accuracy advantages. The Meta-analysis is not limited to synthesis of randomized controlled trials, more and more researchers began to quantitative combination of epidemiological studies, such as cohort studies and case-control studies, Meta-analysis.
Objectives
Application of evidence-based medicine generic system evaluation methods, systematic evaluation of clinical research at home and abroad on the clinical application of nicorandil, to clarify the following question:(1) evaluation of traditional treatment programs based on the addition of nicorandil onall-cause mortality;(2) evaluation of nicorandil plus traditional treatment programs based on the clinical efficacy of chronic heart failure. Through the system evaluation methods aimed at understanding the nicorandil, whether on the basis of the existing standard treatment in patients with cardiovascular disease further benefits play a role in heart protection and improve the prognosis of patients with cardiovascular disease.
Materials and methods
[All cause mortality and cardiovascular events of Nicorandil in patient with heart disease:systematic review and Meta-analysis]
In accordance with the principle of evidence-based medicine, the system retrieves from the database to establish the initial to January2013, the Cochrane Controlled Trials Register database, PubMed, MEDLINE, EMBASE, Ovid, CBM, CNKI, Data resources. Search term:Chinese nicorandil "AND" heart "AND" end point "OR" death "OR" prognosis "; English" nicorandil "AND" heart "AND" death "OR" event "OR" end point "OR" mortality "OR" prognosis "; randomized controlled search terms" randomized controlled "OR" Clinical trial "OR" clinical study ". Initial results and then retrieved inclusion and exclusion criteria to filter. By two reviewers independently evaluated the quality of the included studies, extracted data and cross-checking, using Stata11.0software for all-cause mortality, Meta-analysis of revascularization and cardiovascular events. Effect sizes are HR, odds ratio (OR) and relative risk RR.Q test and I2test were used for heterogeneity. According to the test results using the corresponding effects model for effect size. Statistical homogeneity (P>0.1,12<50%) between studies, the use of a fixed effects model; Conversely, if P≤0, I2≥50%using a random effects model. Greater heterogeneity between studies (I2≥50%), further sensitivity analysis, meta-regression and subgroup analyzes, as far as possible to find the source of heterogeneity, and analysis of heterogeneous causes. Heterogeneity of the two groups is too large or can not find the data source, using the descriptive analysis. Meta-regression covariates screening, the level of significance defined as P<0.1.(Egger linear regression method) to assess publication bias funnel plot and quantitative tests, P>0.05prompt research the existence of the possibility of bias; such as P<0.05, is likely to prompt biased. Cardiovascular events is defined as the following conditions:cardiovascular death, sudden death (Sudden Death), acute coronary syndrome (including fatal or nonfatal acute myocardial infarction), chest pain or congestive heart failure readmission.
[Nicorandil systematic reviews of chronic heart failure]
In accordance with the principles of evidence-based medicine, the system retrieves from a database to establish initial to March2012cochrane Controlled Trials Register database, PubMed, MEDLINE, EMBASE, CBM, CNKI. Data resources. Search terms include:Chinese as the the nicorandil "," heart function; English is "the nicorandil" AND "heart failure" OR "cardiomyopathy" OR "heart the function OR" ventricular function; randomized controlled search term " randomized controlled "OR" clinical trial ". Initial results retrieved press the inclusion and exclusion criteria for screening. By two reviewers independently evaluate the quality of the included studies, data extraction and cross-checking. Main outcome measures: heart rate (HR), mean arterial blood pressure (MBP), pulmonary capillary wedge pressure (PCWP), RAP (right atrial pressure) SVR (systemic vascular resistance systemic vascular resistance), CI (Cardiac index cardiac index), left ventricular ejection fraction (LVEF), the type B natriuretic peptide (BNP),6-minute walk test (6MWT). Meta-analysis using Stata11.0Software. Meta-analysis using Stata11.0Software. Measurement data using the weighted mean difference (MD) as the effect size, the effect of volume,95%CI. First Q-test and I2test for heterogeneity between each incorporate research results. When statistical homogeneity (P>0.1,I2<50%) across studies, using the fixed effects model; Conversely, using a random effects model. Heterogeneity across studies is large (I2<50%), further sensitivity analysis and τ2(tau-squared) test. Two sets of heterogeneity is too large or can not find the data sources, using descriptive analysis. Test level of P<0.05was considered significant.
[Nicorandil systematic reviews of acute heart failure]
We searched databases of Cochrane Controlled Trials Register, PubMed, Ovid, Chinese Biomedical Literature Database (CBM), China Academic Journal Full-text Database (CNKI), and VIP database from inception through January,2013. Randomized controlled trials or observational studies were included if they compared the nicorandil group with a control group without receiving nicorandil treatment. Search term:"nicorandil" AND "acute" AND "heart failure" AND "patient" in Chinese;"nicorandil" AND "heart failure" AND the "acute" in English;study design was "randomized controlled trials.","random","control","observation","case-control studies, randomized controlled" OR "Clinical trial" OR "random" OR "control" OR "RCT" OR "observational study" OR "case-control ". Two investigators independently extracted study characteristics. RevMan software was used to analyze the data.
Results
[All cause mortality and cardiovascular events of Nicorandil in patient with heart disease:systematic review and Meta-analysis]
The study retrieved a total of225papers, according to the inclusion and exclusion criteria, the title, abstract, further and full-text reading, finally included17studies included patients with cardiovascular disease different types of patients with coronary artery disease, acute coronary syndrome (acute myocardial infarction and unstable angina) and stable angina, with or without a history of coronary intervention surgery and coronary artery bypass grafting. Nicorandil group on the basis of conventional therapy plus nicorandil, the control group was a control or placebo-controlled or nitrates were the control group without application of nicorandil treatment intervention group. The shortest observation period of2days, the longest observation period of five years. Quality of research evaluation,17studies were randomized controlled study, Six studies (Class A) complete description of the method of random distribution, double-blind operation, the method of allocation concealment and lost to follow-and intentional analysis; six studies (Class B) describes the method of random allocation, double-blind operation and follow-up with no reference to allocation concealment;5studies as(Class C), refer only to random, not specifically described randomly assigned, with or without blind Act and allocation concealment.
(1) Meta-analysis of the effects on all-cause mortality results:
①The hazard ratio included3studies, which are rigorous RCT study follow-up, the quality of the literature are Class A, with an average follow-up time for more than a year and a half, a meta-analysis results show that the Q test x2=3.97(df=2, P=0.137>0.1), I2=49.7%, Z=2.27(P=0.023<0.05), the combined effect of HR0.77(0.61-0.96), suggesting that long-term use of nicorandil can significantly reduce in patients with coronary heart disease, all-cause mortality. Sources of heterogeneity between studies consider the route of administration, into the patient population related to the different dosing regimens. But included only three studies, Meta results may be unstable.
②If the number of deaths meta-analysis, can be included in the14studies included a total of6993cases of patients, the nicorandil group of3494cases,135cases of death, the mortality rate of3.86%;3499cases of the control group,166cases of death, the death rate4.74%. The odds ratio (OR) effect size, Q test x2=3.42(df=13), P=0.996,12=0.0%, no heterogeneity between studies. Z=1.77, to merge OR=0.818(0.655-1.022), P=0.077. Relative risk RR do effect size, Q test, x2=3.32(df=13), P=0.996, f=0.0%, no heterogeneity between studies. Z= 1.77, pooled RR value of0.826(0.6669-1.021),P=0.077. Taking into account the heterogeneity between studies, comprehensive consideration to be included in study different aspects of the route of administration, dosage, the follow-up period and the quality of the literature are prompted to use the nicorandil not significantly reduced all-cause mortality.
(2) Revascularization events affect Meta-analysis of results:
Five studies reported Revascularization. Into patients with a total of1030cases the nicorandil group of513cases,67cases of repeat revascularization in patients, the event rate was13.0%;517cases of the control group,70patients with repeat revascularization, the event rate was13.5%. Using the odds ratio (OR) effect size, Q test x2=5.96(df=4), P=0.202,12=32.9%, with moderate heterogeneity between studies. Z=0.02, to merge OR=1.006(0.576-1.755), P=0.985. Relative risk RR for the combined effect size, Q test x2=5.82,(df=4), P=0.213,11=31.2%, with moderate heterogeneity between studies. Z=0.05, the combined RR value of0.987(0.613-1.588), P=0.957. Due to the presence of heterogeneity, taking into account the different route of administration, the follow-up period and the quality of the literature included in the study, subgroup analysis, P values were greater than0.05, suggesting that use of nicorandil failed to significantly reduce repeat revascularization event occurs.
(3) Impact on cardiovascular events Meta-analysis of results:
①11studies included different types of patients with coronary heart disease, including acute coronary syndrome (acute myocardial infarction and unstable angina), and stable angina, with or without coronary intervention and coronary artery bypass grafting history. Nicorandil group on the basis of conventional therapy plus nicorandil, the control group was a control or placebo-controlled or nitrates were the control group without application of nicorandil treatment intervention group. The shortest observation period of2days, the longest observation period of five years. Quality of research evaluation,11studies were randomized controlled study, Six studies A complete description of a randomly assigned, double-blind operation, the method of allocation concealment and lost to follow-and intentional analysis;3studies as Class B, describes a method of randomly assigned, double-blind operation and follow-up with no reference to allocation concealment;2study as Class C, refer only to random, not specifically described randomly assigned, with or without blind Act and assigned hide. The proportion of males of each group and the proportion of patients with diabetes.
②included in the11study patients with a total of7705cases the nicorandil group of3785cases,401cases of patients with cardiovascular events, the event rate of10.59%;3920cases of the control group, the occurrence of cardiovascular events in patients with539cases, the event rate was13.75%. The odds ratio (OR) effect size, Q test, x2=21.11(df=10), P=0.020, I2=52.6%, heterogeneity between studies>50%, using a random effects model analysis. Z=4.08, combined OR=0.441(0.297-0.653), P=0.000<0.001. The relative risk RR effect size, the Q test x2=18.81(df=10), P=0.043,I2=46.8%<50%, with moderate heterogeneity between studies, but can be applied to the fixed effect model analysis. Z=4.87, the combined RR value of0.744(0.660-0.838), P=0.000<0.001. Due to the presence of heterogeneity, taking into account included in the study in the different route of administration, the follow-up period, and the quality of the literature, and further sensitivity analysis, meta-regression and subgroup analysis, looking for sources of heterogeneity.
(③by the sensitivity analysis, prompted the the IONA study is the main source of heterogeneity, it included10studies with other significantly different is the study of the large sample size.
④through the meta-regression results found that caused the main source of heterogeneity sample size (Adj R2=100%, P=0.003), countries (Adj R2=59.02%, P=0.071), diabetes patients in each study proportionate share (Adj R2=80.25%, P=0.026) were significant statistical significance (P values were greater than0.1). Mento Carlo replacement method test further the covariates corrected P value, the covariate "sample size" P=0.068, covariate "national" P value of0.439, covariate diabetes share of patients in each study Scale P value of0.329. Therefore, the proportion of patients with diabetes and nicorandil reduces cardiovascular events was a significant linear relationship between the relative risk RR value. Meta-regression diagram shows the following trend:the higher proportion of diabetic patients in the study, the lower the value of taking nicorandil and later cardiovascular events relative risk RR.
⑤by a subgroup analysis stratified sample size, completely eliminate all heterogeneity (I2=0.0%). Greater than1000cases) large sample size (number of patients included in study1, the IONA study, the relative risk RR=0.845(0.739-0.967), P=0.014; Sample Size (included in the number of patients between100-1000cases) study6, the combined relative risk RR=0.479(0.353-0.651), P=0.000<0.001;4small sample sizes (included in the number of patients with less than100cases), combined relative risk RR value of0.387(0.223-0.671), P=0.001. Therefore, regardless of the sample size, prompt application of nicorandil can significantly reduce the risk of cardiovascular events.
⑥Press the national stratified subgroup analysis, the elimination of part of the heterogeneity. South Korea2studies,I2=0.0%combined relative risk RR value of0.559(0.106-2.956), P=0.494; six studies in Japan, I2=0.0%, the merger relative risk RR=0.375(0.260-0.542), P=0.000<0.001;2study in the UK, I2=55.0%, the combined relative risk RR value of0.823(0.724-0.936), P=0.003; China one study, the combined relative risk RR=0.600(0.234-1.539), P=0.288. Research in Japan and the United Kingdom accounted for8of the11studies included, suggesting that application of nicorandil reducing the risk of cardiovascular events may be related to ethnic and regional relations.
⑦subgroups stratified by the quality of the literature:the Jadad score assessed2studies quality level for the Class C,I2=0.0%, the combined relative risk RR value of0.581(0.242-1.393), P=0.224; Jadad score assessed3studies quality class B, I2=0.0%, the merger relative risk RR=0.381(0.216-0.670), P=0.001; the Jadad score evaluation of quality grade A six studies,I2=59.3%, the combined relative risk RR value of0.772(0.682-0.873), P=0.000<0.001. Therefore, the quality of class A and B show the application of nicorandil can significantly reduce the risk of cardiovascular events in patients with coronary heart disease, suggesting that the results of the Meta-analysis of high reliability.
⑧according to the follow-up time stratified subgroup analysis,4studies of follow-up time were less than a month, I2=0.0%, the combined relative risk RR value of0.527(0.372-0.745), P=0.000<0.001;2studies of follow-up were six months, I2=0.0%, the merger relative risk RR was0.414(0.173-0.990), P=0.048;5studies with a minimum1-year study, I2=62.8%, combined relative risk RR=0.787(0.692-0.895), P=0.000<0.001. Prompt the length of time regardless of the application of nicorandil, were significantly reduced risk of cardiovascular events.
⑨subgroup analysis stratified by administration nicorandil, a study implemented intracoronary injection of nicorandil, relative risk RR value of0.486(0.046-5.133), P=0.549;4researches simple oral nicorandil, I2=51.9%, the merger relative risk RR=0.800(0.706-0.907), P<0.001; four studies of simple intravenous application of nicorandil, I2=0.0%, combined relative risk RR value of0.384(0.233-0.629), P=0.000<0.001;2study adjourned to the first intravenous to oral medication, I2=0.0%, the combined relative risk RR was0.382(0.188-0.774), P=0.008. Tip different route of administration does not affect the nicorandil less the risk of cardiovascular events.
⑩publication bias detection:distribution and asymmetry of the funnel plot of the11studies prompted research, the test of the Egger's test P=0.002(-2.1755,-0.6881), suggests the presence of publication bias. Corrected by the trim and fill method, a meta-analysis results are consistent:the fixed effects model to calculate the combined effect of the amount of RR was0.749(0.664,0.845), Z=-4.718, P=0.000; random effects model to calculate the combined effect of the amount of RR value of0.525(0.387,0.712), Z=-4.140, P=0.000. Prompted the meta-analysis results are stable and reliable.
[The Clinical Efficacy of Nicorandil in Chronic Heart Failure:Meta-analysis]
Nine studies were included, a total of279patients. Meta-analysis results showed that:①and intravenous nitroglycerin, intravenous nicorandil24hours continuous application, which can cause the heart rate mildly increased faster (MD=1.272,95%of the CI value from0.385to2.160, P=0.005); PCWP significantly reduce (MD=-2.255,95the CI value of-4.236to-0.274, P=0.026); the SVR was significantly decreased (MD=-0.832,95the CI value of-1.304to-0.359, P=0.001). However, RAP, CI (Cardiac index cardiac index), compared to the MBP changes in the nitroglycerin group no difference.②single oral dose of40mg or60mg nicorandil tablets help reduce PCWP, SVR, and MBP.③on the basis of traditional treatment programs (including digitalis, diuretics, ACEI (ARB), BB, nitrates) plus oral nicorandil5mg, three times a day, short-term results and long-term sustained application of5-6months can be significantly improved LVEF (MD=1.712,95%of the CI value of0.658to2.767, P=0.001). Conclusion:The traditional treatment programs based on whether or not in combination with other vasodilators, nicorandil application by the oral route or intravenous routes, available in patients with ischemic cardiomyopathy (including6months after PCI) LVEF, PCWP, and SVR, dilated cardiomyopathy, valvular heart disease, hypertensive heart disease, such as congestive heart failure caused by chronic patients, access to good effect.
[Nicorandil systematic reviews of acute heart failure]
We identified32studies reporting nicorandil treatment in AHF,but only3of these studies met our criteria by reporting clinical efficacy of nicorandil in AHF.Two randomized controlled studies and one observational study were included with total of471cases enrolled.Nicorandil groups (n=113) were compared directly with controls (n=358) in3studies. Mean age of these patients were greater than65years, with blood pressure not less than90mmHg.Whether left ventricular ejection fraction was normal or reduced was ignorable. Those who have acute coronary syndrome with acute heart failure were exculed. nicorandil was continuous injection within30minutes for5days or continuously injected for48to72hours in3studies included. Changes of hemodynamics and cardiac function were reported. Result of meta-analysis showed that no significant difference was observed in the systolic blood pressure between nicorandil group and controls after intravenous nicorandil treatment48h to72h(Z=0.54,P=0.59). And it was indicated that indicators of AHF were improved after intravenous nicorandil treatment48h to72h in3included studies.One study showed that intravenous nicorandil treatment from the urgent phase of AHF may improve the prognosis.
Conclusion
[All cause mortality and cardiovascular events of Nicorandil in patient with heart disease:systematic review and Meta-analysis]
On the basis of the standard treatment plus nicorandil can significantly reduce the risk of cardiovascular events in patients with coronary heart disease, including cardiovascular death, fatal and non-fatal myocardial infarction admitted to hospital because of chest pain and heart failure attacks unplanned; may reduce the fulldue to the risk of mortality; did not significantly reduce repeat revascularization events. In reducing cardiovascular events in patients with coronary heart disease risk aspects, route of administration including oral, intravenous and intracoronary application of nicorandil; the application short time up to2days, as long as five years; application race and region are not limited.
[Nicorandil systematic reviews of chronic heart failure]
Traditional treatment programs based on whether or not in combination with other vasodilators, nicorandil application by the oral route or intravenous routes are available in patients with ischemic cardiomyopathy (including6months after PCI), expansion cardiomyopathy, valvular heart disease, hypertensive heart disease caused by chronic congestive heart failure in patients with LVEF, PCWP and SVR, to obtain a good effect.
[Nicorandil systematic reviews of acute heart failure]
Although limitations, the Meta-analysis results of this study suggested that blood pressure did not decreased significantly after intravenous nicorandil injection in the AHF the early stages.At the same time, the LVEF, LVD, CO, BNP and NT-pro-BNP were improved in patients with AHF, and possibly the event rate within six months could be reduced.
Limitation
[All cause mortality and cardiovascular events of Nicorandil in patient with heart disease:systematic review and Meta-analysis]
Nicorandil on large sample study of the prognosis of patients with coronary heart disease mainly the IONA, JCAD and Trend of OACIS of, which IONA randomized controlled trials, the JCAD and OACIS of non-randomized controlled study therefore not included in the meta-analysis. Has been included in the study except IONA, small sample volume, reducing the test performance of all-cause mortality; patients with coronary heart disease and diabetes should be concerned about the possibility of the application of nicorandil thereafter further benefit, and need more large, randomized, controlled study to prove its cardioprotective effects.
[Nicorandil systematic reviews of chronic heart failure]
Smaller study sample included in the clinical evaluation of the system volume, and the observation time of up to six months, unable to get a definitive conclusion with hard clinical endpoints such as mortality, these indicators is the evaluation of drug efficacy gold standard. Meanwhile, we also see that included in the study years earlier may nicorandil range of applications in patients with coronary heart disease. With the protective mechanism in the heart of the KATP research is expected to gradually carry out more in-depth, nicorandil various causes long-term follow-up study of chronic heart failure.
[Nicorandil systematic reviews of acute heart failure]
Our study has some limitations. Nicorandil for AHF clinical trials few existing research sample size, few randomized controlled trials, observational studies, may be related to the AHF is a high-risk acute. Less included in the study, relatively more confounding factors will have an impact on the test performance of the meta-analysis results. In addition, observation of the various studies focused on hemodynamic changes and cardiac function without improvement, rather than mortality hard endpoint. So the future still need to design rigorous randomized controlled studies or high-quality observational studies to prove its efficacy.
心脏保护有两个含义,不但要“保护”(preservation),而且要“帮助并使其受益“(favouritism or patronage)。心脏保护(cardioprotection)具体是指通过某种方式,预防、延缓及减少心肌损伤,尤其是指在潜在的致命性缺血性应激后,通过心肌减慢能量需求,产生更少的有毒糖酵解产物,表现出心肌损伤减少。例如ACEI(angiotensin converting enzyme inhibitors)对受损的左室功能提供保护作用,是心脏保护的一种表现。目前心血管疾病中,以动脉(粥样)硬化病变为基础的心血管疾病占全部心血管疾病的绝大部分。除了一级预防控制危险因素外,需强调二级预防的心血管疾病有：1)稳定的冠心病患者,2)不稳定型心绞痛,3)有急性心肌梗塞病史,4)有冠脉搭桥术史,5)有经皮冠脉内介入治疗史。这五类可以归因为冠脉狭窄或阻塞引起的心肌缺血性疾病。
在过去的二三十年间,已经证实提供有力的心脏保护能够对抗心肌梗死及其并发的缺血再灌注损伤。2011年美国心脏病协会(American Heart Association,AHA)/美国心脏协会基金会(American College of Cardiology Foundation, ACCF)更新了心血管疾病二级预防指南,推荐了以阿司匹林(Aspirin)或氯吡格雷、p受体阻滞剂(β-Blocker)及肾素血管紧张素醛固酮系统阻断剂(ACEI, ARB和醛固酮拮抗剂)和降脂药为基础的二级预防方案(Ⅰ类证据),其目的是防复发,防猝死,防左室重构。但上述药物有各自的局限性,冠脉介入治疗和冠脉搭桥术仅解决狭窄,却未能使患者远期受益。因此临床上需要研发新的能提供心脏保护的药物。
2012年,基于上述不尽人意的现有治疗模式,有学者提出应当从“专注于阻塞性冠状动脉粥样硬化中心论”转为“心肌细胞缺血中心论”。如果将心肌细胞作为主要的保护目标,阻塞性冠脉粥样硬化则只是其中一个常见病理因素,学者们可以考虑更多潜在的致心肌细胞缺血因素,从而研发更多更新的保护心肌缺血性损伤的策略。三磷酸腺苷敏感的钾(KATP)通道开放剂的心脏保护作用由此受到关注。尼可地尔是目前临床上研究较为深入的KATP通道开放剂。
尼可地尔,烟酰胺衍生物,又名烟浪丁,具有硝酸根部分,类硝酸酯特性,同时还是ATP敏感的钾通道激动剂(ATP-sensitive potassium channel openers,KATP),因具有双重药理机制,所以与硝酸甘油或硝酸异山梨酯不同,该药对心率,血压等血流动力学影响很小,产生抗心绞痛作用的临床剂量对心脏收缩影响很小,并提供长期的心脏保护。现在临床上有口服制剂和静脉制剂。口服制剂常用于治疗高血压、稳定型心绞痛、心肌梗死(包括PCI后)、心律失常和慢性心力衰竭等心血管疾病：静脉制剂可以冠状动脉内注射或静脉内注射,常用于急性心肌梗死和急性心力衰竭。该药的作用机理特别强调其诱导缺血预适应。
随着临床研究的不断发展和循证医学的兴起,设计合理严密的系统综述(systematic review)和Meta分析(Meta-analysis)被视为评价和合成某一特定研究问题的最佳方式,同时被视为最高等级的临床证据。目前关于尼可地尔的临床应用评价,已有四篇Meta分析,分别是：尼可地尔对急性心肌梗死的治疗作用；系统评价尼可地尔与p受体阻滞剂、长效硝酸酯类药和钙离子拮抗剂对稳定型心绞痛有效性及安全性比较；尼可地尔预防冠脉内支架置入术后无再流效果的系统评价；尼可地尔对急性心肌梗死再灌注疗效的Meta分析。尚无关于尼可地尔对心血管事件和急性、慢性心力衰竭的系统评价报道。
研究目的
应用国际循证医学通用的系统评价方法,对目前临床应用尼可地尔的国内外临床研究分别进行系统评价,阐明以下问题：(1)评价在传统治疗方案基础上加用尼可地尔对心血管事件的影响；(2)评价在传统治疗方案基础上加用尼可地尔对慢性心力衰竭的临床疗效；(3)评价在传统治疗方案基础上加用尼可地尔对急性心力衰竭的临床疗效。通过系统回顾及Meta分析方法,旨在了解尼可地尔能否在现有标准治疗的基础上进一步使心血管疾病患者获益,起到心脏保护作用,改善心血管疾病患者预后。
研究方法
[尼可地尔对冠心病患者全因死亡率和心血管事件的影响]
按照循证医学的原则,系统检索由数据库建立初始至2013年1月的cochrane对照试验注册数据库、PubMed、MEDLINE、EMbase、OVID、CBM、 CNKI、万方数据资源。检索词包括：中文为“尼可地尔”AND“心脏”AND“终点”OR“死亡”OR“预后”；英文是"nicorandil"AND"heart"AND "death"OR"event" OR "end point" OR "mortality" OR "prognosis";随机对照的检索词为"randomized controlled"OR"clinical trial" OR"clinical study".初次检索得到的结果再按纳入和排除标准进行筛选。由2名评价者独立评价纳入研究的质量、提取资料并交叉核对,采用Stata11.0软件进行全因死亡率、再次血运重建和心血管事件的Meta分析。分类资料用计数和率来记录。生存分析资料的效应量指标为危险比HR,计数资料的二分类资料采用优势比OR和相对危险度RR作为效应量。各效应量均以95%可信区间(CI)表示。对各纳入研究结果间的异质性采用Q检验和I2检验。根据检验结果采用相应效应模型进行合并效应量。当各研究间有统计学同质性(P>0.1,I2<50%)时,采用固定效应模型；反之,若P≤0.1,I2≥50%采用随机效应模型。各研究间异质性较大时(I2≥50%),进一步进行敏感性分析、Meta回归和亚组分析,尽可能寻找异质性的来源,并分析异质性产生原因。两组异质性过大或无法找寻数据来源时,采用描述性分析。Meta回归进行协变量筛选时,显著性水平定义为P<0.1。用漏斗图和定量检验(Egger线性回归法)评估发表偏倚,如P>0.05则提示研究存在偏倚的可能性较小；如P<0.05,则提示研究存在偏倚的可能性较大。其中心血管事件定义为出现以下情况：心血管疾病死亡、猝死(sudden death)、急性冠脉综合征(包括致命或非致命的急性心肌梗死)、因胸痛或充血性心衰再入院。
[尼可地尔对慢性心力衰竭的系统评价]
按照循证医学的原则,系统检索由数据库建立初始至2012年3月的cochrane对照试验注册数据库、PubMed、MEDLINE、EMbase、CBM、CNKI、万方数据资源。检索词包括：中文为“尼可地尔”、“心功能”；英文是"nicorandil"AND"heart failure"OR"cardiomyopathy" OR "heart function"OR "ventricular function";随机对照的检索词为"randomized controlled"OR"clinical trial"。初次检索得到的结果再按纳入和排除标准进行筛选。由2名评价者独立评价纳入研究的质量、提取资料并交叉核对,主要观察指标：心率(HR)、平均动脉血压(MBP)、肺毛细血管楔压(PCWP)、RAP(right atrial pressure)、 SVR (systemic vascular resistance全身血管阻力)、CI (Cardiac index心脏指数)、左室射血分数(LVEF)、B型利钠肽(BNP)、6分钟步行测试(6MWT)。采用Stata11.0软件进行Meta分析。采用Stata11.0软件进行Meta分析。计量资料采用加权均数差(MD)作为效应量,各效应量均以95%CI表示。先对各纳入研究结果间的异质性采用Q检验和I2检验。当各研究间有统计学同质性(P>0.1,I2<50%)时,采用固定效应模型；反之,采用随机效应模型。各研究间异质性较大时(I2<50%),进一步进行敏感性分析和τ2(tau-squared)检验。两组异质性过大或无法找寻数据来源时,采用描述性分析。检验水准P<0.05为差异有显著性。
[尼可地尔对急性心力衰竭的系统评价]
按照循证医学的原则,系统检索由数据库建立初始至2013年1月的cochrane对照试验注册数据库、PubMed、MEDLINE、EMbase、CBM、CNKI、万方数据资源。检索词包括：检索词包括：中文为“尼可地尔”AND“急性"AND“心力衰竭"AND“患者”；英文是"nicorandil"AND"heart failure" AND"acute";研究设计类型选择“随机对照试验”、“随机”、“对照”,“观察研究”,“病例对照研究”,"randomized controlled"OR"clinical trial"OR "random" OR "control" OR "RCT"OR"observational study" OR "case-control".初次检索得到的结果再按纳入和排除标准进行筛选。检索时运用主题检索和分类检索两种方法避免漏检相关文献。由2名评价者独立评价纳入研究的质量、提取资料并交叉核对,主要观察指标应用尼可地尔注射液后的血流动力学及心功能指标变化。采用RevMan5.0软件进行数据分析。计量资料采用加权均数差(MD)作为效应量,各效应量均以95%CI表示。先对各纳入研究结果间的异质性采用Q检验和I2检验。当各研究间有统计学同质性(P>0.1,I2<50%)时,采用固定效应模型；反之,采用随机效应模型。两组异质性过大或无法找寻数据来源时,采用描述性分析。检验水准P<0.05为统计学差异有显著性。
结果
[尼可地尔对冠心病患者全因死亡率和心血管事件的影响]
本研究共检索到英文文献153篇,中文文献为72篇,共计225篇,按照纳入和排除标准,通过题目、摘要及进一步的全文阅读,最终纳入17个研究,纳入的心血管疾病患者主要是不同类型的冠心病患者,包含了急性冠脉综合征(急性心肌梗死和不稳定型心绞痛)以及稳定型心绞痛,有或无冠脉介入术及冠脉搭桥术的病史。治疗方式上干预组尼可地尔组在常规治疗基础上加用尼可地尔,对照组为空白对照或安慰剂对照或硝酸酯类对照,对照组无应用尼可地尔者。最短观察期为2天,最长观察期为5年。研究质量评价方面,17个研究均为随机对照研究,其中6个研究为A级,完整描述了随机分配的方法,双盲的具体操作,分配隐藏方法及失访和意向性分析；6个研究为B级,描述了随机分配的方法,双盲的具体操作和随访情况,但未提到分配隐藏；5个研究为C级,仅提到随机,未具体描述随机分配的方法,有无盲法及分配隐藏。
(1)尼可地尔对全因死亡率影响的Meta分析结果：
采用危险比HR为效应量,纳入3个研究,这3个研究均是随访严密的RCT研究,文献质量均为A级,平均随访时间超过一年半,meta分析结果显示Q检验χ2=3.97(d.f.=2,P=0.137>0.1),I2=49.7%,Z=2.27(P=0.023<0.05),合并效应量HR为0.77(0.61-0.96),提示长期应用尼可地尔能显著降低冠心病患者的全因死亡率。研究间异质性来源考虑与用药途径,纳入患者人群及给药方案不同有关。但仅纳入3个研究,Meta结果可能不稳定。
若采用死亡人数进行meta分析,可纳入14个研究,共纳入患者6993例,尼可地尔组3494例,死亡135例,死亡率3.86%；对照组3499例,死亡166例,死亡率4.74%。以优势比OR做合并效应量,Q检验χ2=3.42(d.f.=13),P:0.996,I2=0.0%,研究间无异质性。Z=1.77,合并OR值为0.818(0.655-1.022),P=0.077.若采用相对危险度RR做合并效应量,Q检验χ2=3.32(d.f=13),P=0.996,I2=0.0%,研究间无异质性。Z=1.77,合并RR值为0.826(0.6669-1.021),P=0.077。考虑到研究间无异质性,即综合考虑到纳入研究在给药途径、用药剂量、随访年限及文献质量方面的不同,均提示使用尼可地尔未能明显降低全因死亡率。
(2)尼可地尔对再次血运重建事件影响的Meta分析结果：
有5个研究报道了再次血运重建情况。纳入患者共1030例,尼可地尔组513例,再次血运重建的患者67例,事件率13.0%；对照组517例,再次血运重建的患者70例,事件率13.5%。采用优势比OR做合并效应量,Q检验x2=5.96,(d.f=4),P=0.202,I2=32.9%,研究间有中度异质性。Z=0.02,合并OR值为1.006(0.576-1.755),P=0.985。采用相对危险度RR做合并效应量,Q检验x2=5.82,(d.f.=4),P=0.213,I2=31.2%,研究间有中度异质性。Z=0.05,合并RR值为0.987(0.613-1.588),P=0.957。由于存在异质性,考虑到纳入研究在给药途径、随访年限及文献质量方面的不同,采用亚组分析,P值均大于0.05,提示使用尼可地尔未能显著降低再次血运重建的事件发生。
(3)尼可地尔对心血管事件影响的Meta分析结果：
纳入的11个研究均是不同类型的冠心病患者,包含了急性冠脉综合征(急性心肌梗死和不稳定型心绞痛)以及稳定型心绞痛,有或无冠脉介入术及冠脉搭桥术的病史。治疗方式上干预组尼可地尔组在常规治疗基础上加用尼可地尔,对照组为空白对照或安慰剂对照或硝酸酯类对照,对照组无应用尼可地尔者。最短观察期为2天,最长观察期为5年。研究质量评价方面,11个研究均为随机对照研究,其中6个研究为A级,完整描述了随机分配的方法,双盲的具体操作,分配隐藏方法及失访和意向性分析；3个研究为B级,描述了随机分配的方法,双盲的具体操作和随访情况,但未提到分配隐藏；2个研究为C级,仅提到随机,未具体描述随机分配的方法,有无盲法及分配隐藏。各组的男性比例及糖尿病患者比例不同。
纳入11个研究,患者共7705例,尼可地尔组3785例,发生心血管事件患者401例,事件率10.59%；对照组3920例,发生心血管事件患者539例,事件率13.75%。采用优势比OR做合并效应量,Q检验x2=21.11(d.f.=10),P=0.020,I2=52.6%,研究间异质性>50%,采用随机效应模型进行分析。Z=4.08,合并OR值为0.441(0.297-0.653),P=0.000<0.001。采用相对危险度RR做合并效应量,Q检验x2=18.81(d.f.=10),P=0.043, I2=46.8%<50%,研究间有中度异质性,但可以应用固定效应模型进行分析。Z=4.87,合并RR值为0.744(0.660-0.838),P=0.000<0.001。由于存在异质性,考虑到纳入研究在给药途径、随访年限及文献质量等方面的不同,进一步采用敏感性分析、meta回归及亚组分析、寻找异质性来源。
通过敏感性分析,提示IONA研究是异质性的主要来源,它与其他纳入的10个研究有显著不同的地方是大样本量的研究。
通过Meta回归结果,发现引起异质性的主要来源依次有样本量(Adj R2=100%, P=0.003)、国家(Adj R2=59.02%, P=0.071)、糖尿病患者在各研究中所占比例(Adj R2=80.25%, P=0.026),均具有显著的统计学意义(P值均大于0.1)。进一步用Mento Carlo置换法检验计算上述协变量的矫正P值,协变量“样本量“的P值为0.068,协变量“国家”的P值为0.439,协变量”糖尿病患者在各研究中所占比例”的P值为0.329。因此,糖尿病患者所占比例与尼可地尔减少心血管事件相对危险度RR值之间不呈显著的线性关系。Meta回归图显示了以下趋势：糖尿病患者在研究中所占比例越高,服用尼可地尔后发生心血管事件的相对危险度RR数值越低。
按样本量分层后的亚组分析,所有异质性完全消除(I2=0.0%)。大样本量(纳入患者数大于1000例)研究1个,即IONA研究,相对危险度RR值为0.845(0.739-0.967),P=0.014；中样本量(纳入患者数100例至1000例之间)的研究6个,合并相对危险度RR值为0.479(0.353-0.651),P=0.000<0.001；小样本量(纳入患者数小于100例)的研究4个,合并相对危险度RR值为0.387(0.223-0.671),P=0.001。因此,无论样本量大小,均提示应用尼可地尔之后可以显著降低心血管事件的发生风险。
按国家分层后的亚组分析,消除部分异质性。韩国2项研究,I2=0.0%,合并相对危险度RR值为0.559(0.106-2.956),P=0.494；日本6项研究,I2=0.0%,合并相对危险度RR值为0.375(0.260-0.542),P=0.000<0.001；英国2项研究,I2=55.0%,合并相对危险度RR值为0.823(0.724-0.936),P=0.003；中国1项研究,合并相对危险度RR值为0.600(0.234-1.539),P=0.288。日本与英国的研究在纳入的11项研究中占8项,提示应用尼可地尔降低心血管事件发生风险可能与人种及地区关系不大。
按文献质量分层后的亚组分析：按Jadad score评价研究质量等级为C的2项研究,I2=0.0%,合并相对危险度RR值为0.581(0.242-1.393),P=0.224；按Jadad score评价研究质量等级为B的3项研究,I2=0.0%,合并相对危险度RR值为0.381(0.216-0.670),P=0.001；按Jadad score评价研究质量等级为A的6项研究,I2=59.3%,合并相对危险度RR值为0.772(0.682-0.873),P=0.000<0.001。因此,质量为等级A和B的研究均显示应用尼可地尔能显著降低冠心病患者心血管事件的发生风险,提示该Meta分析结果可靠性较高。
按随访时间分层后的亚组分析结果,随访时间小于1个月的研究有4项,I2=0.0%,合并相对危险度RR值为0.527(0.372-0.745),P=0.000<0.001；随访时间为半年的研究有2项,I2=0.0%,合并相对危险度RR值为0.414(0.173-0.990),P=0.048；随访时间大于1年的研究有5项,I2=62.8%,合并相对危险度RR值为0.787(0.692-0.895),P=0.000<0.001。提示无论应用尼可地尔时间长短,均显著减少心血管事件的发生风险。
按给药途径分层后的亚组分析,有1项研究实施了冠脉内注射尼可地尔,相对危险度RR值为0.486(0.046-5.133),P=0.549；有4项研究为单纯口服尼可地尔,I2=51.9%,合并相对危险度RR值为0.800(0.706-0.907),P<0.001；有4项研究为单纯静脉应用尼可地尔,I2=0.0%,合并相对危险度RR值为0.384(0.233-0.629),P=0.000<0.001；有2项研究为先静脉注射再续以口服用药,I2=0.0%,合并相对危险度RR值为0.382(0.188-0.774),P=0.008。提示不同给药途径不影响尼可地尔较少心血管事件发生风险的作用。
发表偏倚检测：11个研究的漏斗图提示研究分布并不对称,Egger's test的检验结果P=0.002(-2.1755,-0.6881),提示存在发表性偏倚。经剪补法纠正后,meta分析结果一致：固定效应模型计算合并效应量RR值为0.749(0.664,0.845),Z=-4.718,P=0.000；随机效应模型计算合并效应量RR值为0.525(0.387,0.712),Z=-4.140,P=0.000。提示此次Meta分析结果稳定可靠。
[尼可地尔对慢性心力衰竭的系统评价]
共纳入9个研究,共计279例患者。Meta分析结果显示：①与静脉应用硝酸甘油相比较,静脉连续应用尼可地尔24小时,可引起心率轻度增快(MD=I.272,95%的CI值为0.385-2.160,P=0.005)；PCWP显著降低(MD=-2.255,95%的CI值为-4.236～-0.274,P=0.026)；SVR明显下降(MD=-0.832,95%的CI值为-1.304～-0.359,P=0.001)。但是,RAP、CI (Cardiac index心脏指数)、MBP的变化与硝酸甘油组相比无差异。②单次剂量口服40mg或者60mg尼可地尔片,有助于降低PCWP、SVR及MBP。③在传统治疗方案的基础上(包括洋地黄、利尿剂、ACEI(ARB)、BB,硝酸酯类)加用口服尼可地尔5mg,一天三次,短期效果及长期持续应用5至6个月,均可以明显改善LVEF (MD=1.712,95%的CI值为0.658～2.767,P=0.001)。结论：在传统治疗方案基础上,无论是否与其他血管扩张剂合用,经口服途径或静脉途径应用尼可地尔,均可对由缺血性心肌病(含PCI术后6个月的患者)、扩张性心肌病、瓣膜性心脏病、高血压性心脏病等引起的慢性充血性心力衰竭患者的LVEF、 PCWP及SVR方面,获得较好的疗效。
[尼可地尔对急性心力衰竭的系统评价]
共检索到32篇文献,通过题目、摘要进行初筛,并进一步阅读全文后,剔除29篇,纳入3篇关于尼可地尔治疗急性心力衰竭的研究,其中2篇为随机对照研究,1篇为观察性研究。共计纳入患者471例,其中尼可地尔组113例,对照组358例。纳入患者平均年龄大于65岁,血压不低于90mmHg,左室射血分数正常或下降,排除了急性冠脉综合征合并急性心力衰竭。纳入研究均为静脉途径间歇或持续应用尼可地尔,观察时间48小时至5天不等,均报道了通过静脉应用尼可地尔后的血流动力学及心功能改变情况。应用Meta分析了静脉应用尼可地尔后48小时到72小时的动脉收缩压情况,结果显示Z=0.54,P=0.59,提示在AHF早期阶段静脉应用尼可地尔后,动脉收缩压与对照组无显著差异。同时,3个纳入研究提示AHF的心衰指标得到改善,有1个研究提示在AHF早期阶段应用静脉尼可地尔可降低半年内的心血管事件发生率。
结论
[尼可地尔对冠心病患者全因死亡率和心血管事件的影响]
研究结果提示,在标准治疗的基础上加用尼可地尔能显著降低冠心病患者心血管事件的发生风险,包括心血管死亡、致命及非致命心肌梗塞及因胸痛和心衰发作非计划入院；可能降低全因死亡率的发生危险；未能显著降低再次血运重建事件。在降低冠心病患者心血管事件发生风险方面,应用尼可地尔的给药途径包括口服、静脉注射及冠脉内注射；应用时间短至2天,长至5年；应用人种和地区不限。尼可地尔能够在冠心病二级预防过程中使患者受益,可能与其保护心脏细胞的作用有关。应用尼可地尔可能使冠心病合并糖尿病、冠心病合并终末期肾病患者进一步获益的趋势,尚待大样本的随机对照研究进一步明确。
[尼可地尔对慢性心力衰竭的系统评价]
在传统治疗方案基础上,无论是否与其他血管扩张剂合用,经口服途径或静脉途径应用尼可地尔,均可对由缺血性心肌病(含PCI术后6个月的患者)、扩张性心肌病、瓣膜性心脏病、高血压性心脏病等引起的慢性充血性心力衰竭患者的LVEF、PCWP及SVR方面,获得较好的疗效。
[尼可地尔对急性心力衰竭的系统评价]
在急性心力衰竭早期阶段静脉应用尼可地尔可以改善血流动力学及心功能,且不会引起血压显著下降。
局限性及展望
[尼可地尔对冠心病患者全因死亡率和心血管事件的影响]
目前关于尼可地尔对冠心病患者预后方面的大样本研究主要是IONA、 JCAD及OACIS,其中IONA是随机对照研究,而JCAD和OACIS是非随机对照研究,因此未能纳入本次Meta分析。已纳入研究除IONA外,样本量均不大,降低了对全因死亡率的检验效能；另外,应关注冠心病合并糖尿病患者和冠心病合并终末期肾病患者能否在应用尼可地尔后进一步获益,且需要更多的大样本随机对照研究来证实其对上述人群的心脏保护作用。
[尼可地尔对慢性心力衰竭的系统评价]
该系统评价中纳入的临床研究样本量均较小,而且观察时间最长为6个月,未能得到与临床硬终点如死亡率方面的确切结论,而这些指标才是评价药物疗效的金标准。同时我们还看到,纳入研究的年限较早,可能与尼可地尔的主要应用范围是冠心病患者有关。随着目前对KATP在心脏保护作用的机制研究更为深入,有望逐步开展尼可地尔对各种病因引起的慢性心力衰竭的长期随访研究。
[尼可地尔对急性心力衰竭的系统评价]
本研究存在一定的局限性。目前关于尼可地尔用于AHF的临床试验研究较少,已有研究的样本量不大,随机对照研究不多,以观察性研究为主,可能与AHF是一种高危急症有关。纳入研究较少,混杂因素相对较多,对Meta分析结果的检验效能会产生影响。另外,各项研究的观察重点是血流动力学变化及心功能指标有无改善,而并非死亡率这种硬终点指标。因此未来仍需要设计严密的随机对照研究或高质量的观察性研究来证明其疗效。
Background
Heart protection means two implications, not only to "protect"(preservation), but also help to benefit for (favouritism or patronage). ACEI (angiotensin converting enzyme inhibitors) to provide a protective effect of impaired left ventricular function, is a manifestation of the heart protection. Heart Protection (cardioprotection) specifically refers to in some way, to prevent, delay and reduce myocardial injury, especially by means potentially fatal ischemic stress myocardial slow energy demand, and produce less toxic sugar leaven hydrolysates showed reduced myocardial injury. In the past two or three decades, it has been confirmed that provide strong heart protection against myocardial infarction complicated by ischemia-reperfusion injury.2011American Heart Association (American Heart Association, AHA)/American Heart Association Foundation (American College of Cardiology Foundation, ACCF) updated cardiovascular disease secondary prevention guidelines recommend aspirin (Aspirin) or clopidogrel p-blockers (β-Blocker) and the renin-angiotensin-aldosterone system blockers (ACEI, ARB, and aldosterone antagonists) and lipid-lowering drugs for secondary prevention program (class I evidence), the purpose relapse prevention, anti-sudden death, anti-left ventricular remodeling.
Control of the existing mode of treatment for cardiovascular disease is still unsatisfactory, these drugs also have their own limitations, only solve narrow coronary intervention and coronary artery bypass grafting, but did not make the long-term benefit of patients.[4] Clinical research and development of new drugs for heart protection. In2012, based on the clinical practice of the unsatisfactory results, scholars:ischemic heart disease awareness should focus on obstructive coronary atherosclerosis center theory "to" myocardial ischemia center theory ". If myocardial ischemia as the main protection targets, obstructive coronary atherosclerosis is a common pathological factors, scholars can consider more potential induced myocardial ischemia factors, which developed more updated protection myocardial ischemic injury in strategy. Cardioprotective effects of adenosine triphosphate-sensitive potassium (KATP) channel opener this attention. Nicorandil clinical study more deeply the KATP channel opener.
Nicorandil, a nicotinamide derivative, also known as smoke waves Ding has the nitrate part class nitrates characteristics, ATP-sensitive potassium channel agonist (ATP-sensitive potassium channel openers, KATP), a dual pharmacological mechanism with nitroglycerin or isosorbide esters, the drug has little effect on heart rate, blood pressure and other hemodynamic to produce clinical doses of antianginal little effect on cardiac contractility, and provide long-term protection of the heart. Now clinical oral formulations commonly used in the treatment of hypertension, stable angina pectoris, myocardial infarction (including PCI), cardiac arrhythmias, heart failure and other cardiovascular diseases, intravenous formulation for commonly used in intracoronary injection, with particular emphasis on its inducible ischemia preconditioning effect (transient ischemic preconditioning period caused ischemia reperfusion injury in a strong protective effect). Clinical application of nicorandil three Meta-analysis are:the role of nicorandil on the treatment of acute myocardial infarction (2009foreign language), system evaluation nicorandil beta blockers, long-acting nitrates drugs and calcium antagonists (Japanese)2010compared the efficacy and safety of stable angina, nicorandil prevention of coronary stenting no-reflow effect of systematic reviews (2010Chinese), nicorandil reperfusion in acute myocardial infarction efficacy Meta-analysis (2012, Chinese)
Nicorandil (nicorandil) is a unique, ATP-sensitive potassium (KATP) channel the excited and class nitrates features dual pharmacological mechanism of drugs, and provide long-term protection of the heart. Drug against acute or chronic ischemic heart disease, congestive heart failure in patients with heart damage, with particular emphasis (ischaemic postconditioning, IPoC, that for a short pre-ischemic period caused ischemia-reperfusion injury induced ischemic preconditioning strong protective effect) effect.
With the continuous development of the clinical research and the rise of evidence-based medicine, rational design rigorous systematic review (systematic review) and Meta-analysis (Meta-analysis) is regarded as the best way of evaluation and synthesis of a specific research question, while regarded as the highest level of clinical evidence. The Meta-analysis of a number of independent studies of the same problem is comprehensive quantitative statistical methods to increase statistical power and effect sizes estimated accuracy advantages. The Meta-analysis is not limited to synthesis of randomized controlled trials, more and more researchers began to quantitative combination of epidemiological studies, such as cohort studies and case-control studies, Meta-analysis.
Objectives
Application of evidence-based medicine generic system evaluation methods, systematic evaluation of clinical research at home and abroad on the clinical application of nicorandil, to clarify the following question:(1) evaluation of traditional treatment programs based on the addition of nicorandil onall-cause mortality;(2) evaluation of nicorandil plus traditional treatment programs based on the clinical efficacy of chronic heart failure. Through the system evaluation methods aimed at understanding the nicorandil, whether on the basis of the existing standard treatment in patients with cardiovascular disease further benefits play a role in heart protection and improve the prognosis of patients with cardiovascular disease.
Materials and methods
[All cause mortality and cardiovascular events of Nicorandil in patient with heart disease:systematic review and Meta-analysis]
In accordance with the principle of evidence-based medicine, the system retrieves from the database to establish the initial to January2013, the Cochrane Controlled Trials Register database, PubMed, MEDLINE, EMBASE, Ovid, CBM, CNKI, Data resources. Search term:Chinese nicorandil "AND" heart "AND" end point "OR" death "OR" prognosis "; English" nicorandil "AND" heart "AND" death "OR" event "OR" end point "OR" mortality "OR" prognosis "; randomized controlled search terms" randomized controlled "OR" Clinical trial "OR" clinical study ". Initial results and then retrieved inclusion and exclusion criteria to filter. By two reviewers independently evaluated the quality of the included studies, extracted data and cross-checking, using Stata11.0software for all-cause mortality, Meta-analysis of revascularization and cardiovascular events. Effect sizes are HR, odds ratio (OR) and relative risk RR.Q test and I2test were used for heterogeneity. According to the test results using the corresponding effects model for effect size. Statistical homogeneity (P>0.1,12<50%) between studies, the use of a fixed effects model; Conversely, if P≤0, I2≥50%using a random effects model. Greater heterogeneity between studies (I2≥50%), further sensitivity analysis, meta-regression and subgroup analyzes, as far as possible to find the source of heterogeneity, and analysis of heterogeneous causes. Heterogeneity of the two groups is too large or can not find the data source, using the descriptive analysis. Meta-regression covariates screening, the level of significance defined as P<0.1.(Egger linear regression method) to assess publication bias funnel plot and quantitative tests, P>0.05prompt research the existence of the possibility of bias; such as P<0.05, is likely to prompt biased. Cardiovascular events is defined as the following conditions:cardiovascular death, sudden death (Sudden Death), acute coronary syndrome (including fatal or nonfatal acute myocardial infarction), chest pain or congestive heart failure readmission.
[Nicorandil systematic reviews of chronic heart failure]
In accordance with the principles of evidence-based medicine, the system retrieves from a database to establish initial to March2012cochrane Controlled Trials Register database, PubMed, MEDLINE, EMBASE, CBM, CNKI. Data resources. Search terms include:Chinese as the the nicorandil "," heart function; English is "the nicorandil" AND "heart failure" OR "cardiomyopathy" OR "heart the function OR" ventricular function; randomized controlled search term " randomized controlled "OR" clinical trial ". Initial results retrieved press the inclusion and exclusion criteria for screening. By two reviewers independently evaluate the quality of the included studies, data extraction and cross-checking. Main outcome measures: heart rate (HR), mean arterial blood pressure (MBP), pulmonary capillary wedge pressure (PCWP), RAP (right atrial pressure) SVR (systemic vascular resistance systemic vascular resistance), CI (Cardiac index cardiac index), left ventricular ejection fraction (LVEF), the type B natriuretic peptide (BNP),6-minute walk test (6MWT). Meta-analysis using Stata11.0Software. Meta-analysis using Stata11.0Software. Measurement data using the weighted mean difference (MD) as the effect size, the effect of volume,95%CI. First Q-test and I2test for heterogeneity between each incorporate research results. When statistical homogeneity (P>0.1,I2<50%) across studies, using the fixed effects model; Conversely, using a random effects model. Heterogeneity across studies is large (I2<50%), further sensitivity analysis and τ2(tau-squared) test. Two sets of heterogeneity is too large or can not find the data sources, using descriptive analysis. Test level of P<0.05was considered significant.
[Nicorandil systematic reviews of acute heart failure]
We searched databases of Cochrane Controlled Trials Register, PubMed, Ovid, Chinese Biomedical Literature Database (CBM), China Academic Journal Full-text Database (CNKI), and VIP database from inception through January,2013. Randomized controlled trials or observational studies were included if they compared the nicorandil group with a control group without receiving nicorandil treatment. Search term:"nicorandil" AND "acute" AND "heart failure" AND "patient" in Chinese;"nicorandil" AND "heart failure" AND the "acute" in English;study design was "randomized controlled trials.","random","control","observation","case-control studies, randomized controlled" OR "Clinical trial" OR "random" OR "control" OR "RCT" OR "observational study" OR "case-control ". Two investigators independently extracted study characteristics. RevMan software was used to analyze the data.
Results
[All cause mortality and cardiovascular events of Nicorandil in patient with heart disease:systematic review and Meta-analysis]
The study retrieved a total of225papers, according to the inclusion and exclusion criteria, the title, abstract, further and full-text reading, finally included17studies included patients with cardiovascular disease different types of patients with coronary artery disease, acute coronary syndrome (acute myocardial infarction and unstable angina) and stable angina, with or without a history of coronary intervention surgery and coronary artery bypass grafting. Nicorandil group on the basis of conventional therapy plus nicorandil, the control group was a control or placebo-controlled or nitrates were the control group without application of nicorandil treatment intervention group. The shortest observation period of2days, the longest observation period of five years. Quality of research evaluation,17studies were randomized controlled study, Six studies (Class A) complete description of the method of random distribution, double-blind operation, the method of allocation concealment and lost to follow-and intentional analysis; six studies (Class B) describes the method of random allocation, double-blind operation and follow-up with no reference to allocation concealment;5studies as(Class C), refer only to random, not specifically described randomly assigned, with or without blind Act and allocation concealment.
(1) Meta-analysis of the effects on all-cause mortality results:
①The hazard ratio included3studies, which are rigorous RCT study follow-up, the quality of the literature are Class A, with an average follow-up time for more than a year and a half, a meta-analysis results show that the Q test x2=3.97(df=2, P=0.137>0.1), I2=49.7%, Z=2.27(P=0.023<0.05), the combined effect of HR0.77(0.61-0.96), suggesting that long-term use of nicorandil can significantly reduce in patients with coronary heart disease, all-cause mortality. Sources of heterogeneity between studies consider the route of administration, into the patient population related to the different dosing regimens. But included only three studies, Meta results may be unstable.
②If the number of deaths meta-analysis, can be included in the14studies included a total of6993cases of patients, the nicorandil group of3494cases,135cases of death, the mortality rate of3.86%;3499cases of the control group,166cases of death, the death rate4.74%. The odds ratio (OR) effect size, Q test x2=3.42(df=13), P=0.996,12=0.0%, no heterogeneity between studies. Z=1.77, to merge OR=0.818(0.655-1.022), P=0.077. Relative risk RR do effect size, Q test, x2=3.32(df=13), P=0.996, f=0.0%, no heterogeneity between studies. Z= 1.77, pooled RR value of0.826(0.6669-1.021),P=0.077. Taking into account the heterogeneity between studies, comprehensive consideration to be included in study different aspects of the route of administration, dosage, the follow-up period and the quality of the literature are prompted to use the nicorandil not significantly reduced all-cause mortality.
(2) Revascularization events affect Meta-analysis of results:
Five studies reported Revascularization. Into patients with a total of1030cases the nicorandil group of513cases,67cases of repeat revascularization in patients, the event rate was13.0%;517cases of the control group,70patients with repeat revascularization, the event rate was13.5%. Using the odds ratio (OR) effect size, Q test x2=5.96(df=4), P=0.202,12=32.9%, with moderate heterogeneity between studies. Z=0.02, to merge OR=1.006(0.576-1.755), P=0.985. Relative risk RR for the combined effect size, Q test x2=5.82,(df=4), P=0.213,11=31.2%, with moderate heterogeneity between studies. Z=0.05, the combined RR value of0.987(0.613-1.588), P=0.957. Due to the presence of heterogeneity, taking into account the different route of administration, the follow-up period and the quality of the literature included in the study, subgroup analysis, P values were greater than0.05, suggesting that use of nicorandil failed to significantly reduce repeat revascularization event occurs.
(3) Impact on cardiovascular events Meta-analysis of results:
①11studies included different types of patients with coronary heart disease, including acute coronary syndrome (acute myocardial infarction and unstable angina), and stable angina, with or without coronary intervention and coronary artery bypass grafting history. Nicorandil group on the basis of conventional therapy plus nicorandil, the control group was a control or placebo-controlled or nitrates were the control group without application of nicorandil treatment intervention group. The shortest observation period of2days, the longest observation period of five years. Quality of research evaluation,11studies were randomized controlled study, Six studies A complete description of a randomly assigned, double-blind operation, the method of allocation concealment and lost to follow-and intentional analysis;3studies as Class B, describes a method of randomly assigned, double-blind operation and follow-up with no reference to allocation concealment;2study as Class C, refer only to random, not specifically described randomly assigned, with or without blind Act and assigned hide. The proportion of males of each group and the proportion of patients with diabetes.
②included in the11study patients with a total of7705cases the nicorandil group of3785cases,401cases of patients with cardiovascular events, the event rate of10.59%;3920cases of the control group, the occurrence of cardiovascular events in patients with539cases, the event rate was13.75%. The odds ratio (OR) effect size, Q test, x2=21.11(df=10), P=0.020, I2=52.6%, heterogeneity between studies>50%, using a random effects model analysis. Z=4.08, combined OR=0.441(0.297-0.653), P=0.000<0.001. The relative risk RR effect size, the Q test x2=18.81(df=10), P=0.043,I2=46.8%<50%, with moderate heterogeneity between studies, but can be applied to the fixed effect model analysis. Z=4.87, the combined RR value of0.744(0.660-0.838), P=0.000<0.001. Due to the presence of heterogeneity, taking into account included in the study in the different route of administration, the follow-up period, and the quality of the literature, and further sensitivity analysis, meta-regression and subgroup analysis, looking for sources of heterogeneity.
(③by the sensitivity analysis, prompted the the IONA study is the main source of heterogeneity, it included10studies with other significantly different is the study of the large sample size.
④through the meta-regression results found that caused the main source of heterogeneity sample size (Adj R2=100%, P=0.003), countries (Adj R2=59.02%, P=0.071), diabetes patients in each study proportionate share (Adj R2=80.25%, P=0.026) were significant statistical significance (P values were greater than0.1). Mento Carlo replacement method test further the covariates corrected P value, the covariate "sample size" P=0.068, covariate "national" P value of0.439, covariate diabetes share of patients in each study Scale P value of0.329. Therefore, the proportion of patients with diabetes and nicorandil reduces cardiovascular events was a significant linear relationship between the relative risk RR value. Meta-regression diagram shows the following trend:the higher proportion of diabetic patients in the study, the lower the value of taking nicorandil and later cardiovascular events relative risk RR.
⑤by a subgroup analysis stratified sample size, completely eliminate all heterogeneity (I2=0.0%). Greater than1000cases) large sample size (number of patients included in study1, the IONA study, the relative risk RR=0.845(0.739-0.967), P=0.014; Sample Size (included in the number of patients between100-1000cases) study6, the combined relative risk RR=0.479(0.353-0.651), P=0.000<0.001;4small sample sizes (included in the number of patients with less than100cases), combined relative risk RR value of0.387(0.223-0.671), P=0.001. Therefore, regardless of the sample size, prompt application of nicorandil can significantly reduce the risk of cardiovascular events.
⑥Press the national stratified subgroup analysis, the elimination of part of the heterogeneity. South Korea2studies,I2=0.0%combined relative risk RR value of0.559(0.106-2.956), P=0.494; six studies in Japan, I2=0.0%, the merger relative risk RR=0.375(0.260-0.542), P=0.000<0.001;2study in the UK, I2=55.0%, the combined relative risk RR value of0.823(0.724-0.936), P=0.003; China one study, the combined relative risk RR=0.600(0.234-1.539), P=0.288. Research in Japan and the United Kingdom accounted for8of the11studies included, suggesting that application of nicorandil reducing the risk of cardiovascular events may be related to ethnic and regional relations.
⑦subgroups stratified by the quality of the literature:the Jadad score assessed2studies quality level for the Class C,I2=0.0%, the combined relative risk RR value of0.581(0.242-1.393), P=0.224; Jadad score assessed3studies quality class B, I2=0.0%, the merger relative risk RR=0.381(0.216-0.670), P=0.001; the Jadad score evaluation of quality grade A six studies,I2=59.3%, the combined relative risk RR value of0.772(0.682-0.873), P=0.000<0.001. Therefore, the quality of class A and B show the application of nicorandil can significantly reduce the risk of cardiovascular events in patients with coronary heart disease, suggesting that the results of the Meta-analysis of high reliability.
⑧according to the follow-up time stratified subgroup analysis,4studies of follow-up time were less than a month, I2=0.0%, the combined relative risk RR value of0.527(0.372-0.745), P=0.000<0.001;2studies of follow-up were six months, I2=0.0%, the merger relative risk RR was0.414(0.173-0.990), P=0.048;5studies with a minimum1-year study, I2=62.8%, combined relative risk RR=0.787(0.692-0.895), P=0.000<0.001. Prompt the length of time regardless of the application of nicorandil, were significantly reduced risk of cardiovascular events.
⑨subgroup analysis stratified by administration nicorandil, a study implemented intracoronary injection of nicorandil, relative risk RR value of0.486(0.046-5.133), P=0.549;4researches simple oral nicorandil, I2=51.9%, the merger relative risk RR=0.800(0.706-0.907), P<0.001; four studies of simple intravenous application of nicorandil, I2=0.0%, combined relative risk RR value of0.384(0.233-0.629), P=0.000<0.001;2study adjourned to the first intravenous to oral medication, I2=0.0%, the combined relative risk RR was0.382(0.188-0.774), P=0.008. Tip different route of administration does not affect the nicorandil less the risk of cardiovascular events.
⑩publication bias detection:distribution and asymmetry of the funnel plot of the11studies prompted research, the test of the Egger's test P=0.002(-2.1755,-0.6881), suggests the presence of publication bias. Corrected by the trim and fill method, a meta-analysis results are consistent:the fixed effects model to calculate the combined effect of the amount of RR was0.749(0.664,0.845), Z=-4.718, P=0.000; random effects model to calculate the combined effect of the amount of RR value of0.525(0.387,0.712), Z=-4.140, P=0.000. Prompted the meta-analysis results are stable and reliable.
[The Clinical Efficacy of Nicorandil in Chronic Heart Failure:Meta-analysis]
Nine studies were included, a total of279patients. Meta-analysis results showed that:①and intravenous nitroglycerin, intravenous nicorandil24hours continuous application, which can cause the heart rate mildly increased faster (MD=1.272,95%of the CI value from0.385to2.160, P=0.005); PCWP significantly reduce (MD=-2.255,95the CI value of-4.236to-0.274, P=0.026); the SVR was significantly decreased (MD=-0.832,95the CI value of-1.304to-0.359, P=0.001). However, RAP, CI (Cardiac index cardiac index), compared to the MBP changes in the nitroglycerin group no difference.②single oral dose of40mg or60mg nicorandil tablets help reduce PCWP, SVR, and MBP.③on the basis of traditional treatment programs (including digitalis, diuretics, ACEI (ARB), BB, nitrates) plus oral nicorandil5mg, three times a day, short-term results and long-term sustained application of5-6months can be significantly improved LVEF (MD=1.712,95%of the CI value of0.658to2.767, P=0.001). Conclusion:The traditional treatment programs based on whether or not in combination with other vasodilators, nicorandil application by the oral route or intravenous routes, available in patients with ischemic cardiomyopathy (including6months after PCI) LVEF, PCWP, and SVR, dilated cardiomyopathy, valvular heart disease, hypertensive heart disease, such as congestive heart failure caused by chronic patients, access to good effect.
[Nicorandil systematic reviews of acute heart failure]
We identified32studies reporting nicorandil treatment in AHF,but only3of these studies met our criteria by reporting clinical efficacy of nicorandil in AHF.Two randomized controlled studies and one observational study were included with total of471cases enrolled.Nicorandil groups (n=113) were compared directly with controls (n=358) in3studies. Mean age of these patients were greater than65years, with blood pressure not less than90mmHg.Whether left ventricular ejection fraction was normal or reduced was ignorable. Those who have acute coronary syndrome with acute heart failure were exculed. nicorandil was continuous injection within30minutes for5days or continuously injected for48to72hours in3studies included. Changes of hemodynamics and cardiac function were reported. Result of meta-analysis showed that no significant difference was observed in the systolic blood pressure between nicorandil group and controls after intravenous nicorandil treatment48h to72h(Z=0.54,P=0.59). And it was indicated that indicators of AHF were improved after intravenous nicorandil treatment48h to72h in3included studies.One study showed that intravenous nicorandil treatment from the urgent phase of AHF may improve the prognosis.
Conclusion
[All cause mortality and cardiovascular events of Nicorandil in patient with heart disease:systematic review and Meta-analysis]
On the basis of the standard treatment plus nicorandil can significantly reduce the risk of cardiovascular events in patients with coronary heart disease, including cardiovascular death, fatal and non-fatal myocardial infarction admitted to hospital because of chest pain and heart failure attacks unplanned; may reduce the fulldue to the risk of mortality; did not significantly reduce repeat revascularization events. In reducing cardiovascular events in patients with coronary heart disease risk aspects, route of administration including oral, intravenous and intracoronary application of nicorandil; the application short time up to2days, as long as five years; application race and region are not limited.
[Nicorandil systematic reviews of chronic heart failure]
Traditional treatment programs based on whether or not in combination with other vasodilators, nicorandil application by the oral route or intravenous routes are available in patients with ischemic cardiomyopathy (including6months after PCI), expansion cardiomyopathy, valvular heart disease, hypertensive heart disease caused by chronic congestive heart failure in patients with LVEF, PCWP and SVR, to obtain a good effect.
[Nicorandil systematic reviews of acute heart failure]
Although limitations, the Meta-analysis results of this study suggested that blood pressure did not decreased significantly after intravenous nicorandil injection in the AHF the early stages.At the same time, the LVEF, LVD, CO, BNP and NT-pro-BNP were improved in patients with AHF, and possibly the event rate within six months could be reduced.
Limitation
[All cause mortality and cardiovascular events of Nicorandil in patient with heart disease:systematic review and Meta-analysis]
Nicorandil on large sample study of the prognosis of patients with coronary heart disease mainly the IONA, JCAD and Trend of OACIS of, which IONA randomized controlled trials, the JCAD and OACIS of non-randomized controlled study therefore not included in the meta-analysis. Has been included in the study except IONA, small sample volume, reducing the test performance of all-cause mortality; patients with coronary heart disease and diabetes should be concerned about the possibility of the application of nicorandil thereafter further benefit, and need more large, randomized, controlled study to prove its cardioprotective effects.
[Nicorandil systematic reviews of chronic heart failure]
Smaller study sample included in the clinical evaluation of the system volume, and the observation time of up to six months, unable to get a definitive conclusion with hard clinical endpoints such as mortality, these indicators is the evaluation of drug efficacy gold standard. Meanwhile, we also see that included in the study years earlier may nicorandil range of applications in patients with coronary heart disease. With the protective mechanism in the heart of the KATP research is expected to gradually carry out more in-depth, nicorandil various causes long-term follow-up study of chronic heart failure.
[Nicorandil systematic reviews of acute heart failure]
Our study has some limitations. Nicorandil for AHF clinical trials few existing research sample size, few randomized controlled trials, observational studies, may be related to the AHF is a high-risk acute. Less included in the study, relatively more confounding factors will have an impact on the test performance of the meta-analysis results. In addition, observation of the various studies focused on hemodynamic changes and cardiac function without improvement, rather than mortality hard endpoint. So the future still need to design rigorous randomized controlled studies or high-quality observational studies to prove its efficacy.
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