心肌梗塞和脑梗塞溶栓治疗的证据比较
心肌梗塞和脑梗塞溶栓治疗的证据比较
摘要:
关键词:
心肌梗塞和脑梗塞是对人们健康危害极大的一种疾病,死亡率高。它们都是由于血管被血栓阻塞
引起的心、脑细胞供血不足所致的缺血性坏死。溶栓药物可以通过溶解血栓、恢复血供来减少心、
脑细胞的损伤。溶栓治疗在心肌梗塞已经成为经典的治疗方法之一,大量的随机对照试验
(randomized control trial, RCT)已证实,溶栓治疗能够降低死亡率。但心肌梗塞患者是否
溶栓治疗是最佳选择?PTCA 相对于溶栓治疗优势何在?由于相同的病理生理机制,脑梗塞患者
溶栓治疗情况如何?是最佳选择吗?等等,都是临床医生关心的问题。本文通过复习近年来所发
表的,能提供临床证据的RCT 和系统评价,对上述问题进行阐述说明。
一.检索资源和内容
我们检索了最新Cochrane 图书馆(2001年第2期)、MEDLINE (1980-2001.6),收集有关心
肌梗塞和脑梗塞溶栓治疗的系统评价和Meta 分析以及大型的RCT 。
二. 研究结果
1.脑梗塞溶栓治疗已完成2个系统评价(systematic review,SR )。一个SR 是评价溶栓治疗
对脑梗塞的有效性和安全性,共纳入17个RCT ,5216名患者,以死亡率、致残率为试验终点,
15个RCT 为双盲设计,溶栓药物包括尿激酶、链激酶、重组组织纤维蛋白溶酶原激活物
( recombinant tissue plasminogen activator,tPA )或重组尿激酶原( recombinant
pro-urokinase ), 2个试验采取动脉内给药,余均是静脉途径用药。一半的试验资料是静脉用
tPA 。
trials testing intravenous tissue Plasminogen Activator. Thrombolytic therapy
significantly increased the odds of death within the first ten days (odds ratio [OR]
1.85, 95% confidence interval [CI] 1.48 to 2.32). The main cause of the increase in deaths
was fatal intracranial haemorrhage following thrombolysis (OR 4.15, 95% CI 2.96 to 5.84).
Symptomatic intracranial haemorrhage is also increased following thrombolysis (OR 3.53,
95% CI 2.79 to 4.45). Thrombolytic therapy also increased the odds of death at the end
of follow-up (OR 1.31, 95% CI 1.13 to 1.52). Despite this, thrombolytic therapy,
administered up to six hours after ischaemic stroke, significantly reduced the
proportion of patients who were dead or dependent (modified Rankin 3 to 6) at the end
of follow-up (OR 0.83, 95% CI 0.73 to 0.94). For patients treated within three hours
of stroke, thrombolytic therapy appeared more effective in reducing death or dependency
(OR 0.58, 95% CI 0.46 to 0.74) with less adverse effect on death (OR 1.11, 95% CI 0.84
to 1.47). There was heterogeneity between the trials that could have been due to :
thrombolytic drug used, variation in the concomitant use of aspirin and heparin, severity
of the stroke, and time to treatment. Trials testing intravenous recombinant tissue
Plasminogen Activator suggest that it may be associated with slightly less hazard and
more benefit when given up to six hours after stroke - death within the first ten days
OR 1.24, 95% CI 0.85 to 1.81, death at the end of follow-up OR 1.16, 95% CI 0.94 to 1.44,
dead or
dependent at the end of follow-up OR 0.79, 95% CI 0.68 to 0.92. One trial that tested
thrombolysis plus aspirin showed an increase in deaths of patients given both drugs in
combination compared with thrombolysis alone. Reviewers' conclusions: Thrombolytic
therapy increases deaths within the first seven to ten days, and deaths at final follow-up.
Thrombolytic therapy also significantly increases symptomatic and fatal intracranial
haemorrhage. These risks are offset by a reduction in disability in survivors, so that
there is, overall, a significant net reduction in the proportion of patients dead or
dependent in activities of daily living. The data from trials using intravenous
recombinant tissue Plasminogen Activator, from which there is the most evidence on
thrombolytic therapy so far, suggest that it may be associated with less hazard and more
benefit. There was heterogeneity between the trials and the optimum criteria to identify
the patients most likely to benefit and least likely to be harmed, the agent, dose, and
route of administration, are not clear. The data are promising and may justify the use
of thrombolytic therapy with intravenous recombinant tissue Plasminogen Activator in
experienced centres in selected patients. However, the widespread use of thrombolytic
therapy in routine clinical practice at this time cannot be supported. Further trials
will be needed to identify which patients are most likely to benefit from treatment and
the environment in which it may best be given, before thrombolytic therapy should be
adopted on a
wider scale.
结果显示,溶栓治疗可以降低随访终点时的死亡率和残废率(OR=0.83,95%CI 0.73-0.94),相
当于每治疗1000人可以减少44人的死亡或残废。r-tPA 在6个试验共有2764人使用,结果显
示r-tPA 效果更好,(OR=0.79,95%CI 0.68-0.92),相当于每治疗1000人减少57人的死亡或
残废。
1. 1短期的死亡率(10天内)
溶栓治疗增加短期的死亡率(OR=1.85,95%CI 1.48-2.32),等于说每治疗1000人增加了68
人的短期死亡;
1. 2随访终点的死亡率
溶栓治疗增加了随访终点时的死亡率(OR=1.31,95%CI 1.13-1.52),等于每治疗1000人引起
随访终点时的死亡增加了36人;如果使用r-tPA ,死亡率增加不明显(OR=1.16,95%CI
0.94-1.44),相当于每治疗1000人随访终点时的死亡增加了18人。
1. 3致死性的颅内出血
致死性的颅内出血是引起死亡的主要原因,溶栓组中致死性颅内出血的发生率比对照组几乎高出
5倍(OR=4.15,95%CI 2.96-5.84);使用r-tPA 比使用链激酶引起颅内出血的发生率低:每治
疗1000人,r-tPA 增加了29例致死性颅内出血(OR=3.2,95%CI 2.0-5.2)而链激酶则增加92
例致死性颅内出血(OR=6.03,95%CI 3.47-10.47)。
1. 4非致死性但有临床症状的颅内出血
溶栓治疗会明显增加非致死性但有临床症状的颅内出血(OR=3.5,95%CI 2.8-4.5),相当于每
治疗1000人增加了70人颅内出血。
另一SR 是评价不同溶栓制剂、给药途径和剂量对脑梗塞的效果。纳入8个RCT ,1334个病人,
分配方案进行了隐藏,所有试验均在日本进行,adequate. All the trials were conducted in
Japan. Different doses (of tissue plasminogen activator or urokinase) were compared in
seven trials. Different agents (tissue plasminogen activator versus urokinase, or
tissue-cultured urokinase versus conventional urokinase) were compared in three trials.
Few data were available for functional outcomes. A higher dose of thrombolytic therapy
was associated with a five-fold increase in fatal intracranial haemorrhages (odds ratio
5.02, 95% confidence interval 1.56 to 16.18). This was based on 11 events among 369
higher-dose patients and one event among 356 lower-dose patients in six trials. There
was a non-significant trend towards more early deaths or clinically significant
intracranial haemorrhages. No difference in late deaths or extra-cranial haemorrhages
was shown between low and higher doses. However, very few of these events occurred. No
difference was shown between the different thrombolytic agents tested. Reviewers'
conclusions: There is not enough evidence to conclude whether lower doses of thrombolytic
agents might be safer or more effective than higher doses in acute ischaemic stroke.
It is not possible to conclude whether one agent might be better than another, or which
route of administration might be best. No comparative
心肌梗塞:到目前为止,仅完成1篇关于溶栓治疗与PTCA 疗效比较的SR ,但从MEDLINE 检索到
相关的一些大型临床RCT 。
2.1病死率
溶栓治疗可以降低病死率:GISSI (意大利治疗心肌梗死生存试验)证实SK 使病死率减少20%-25%。
ASSET (北欧早期溶栓治疗)证实t-PA 降低病死率26%,AIMS (英国APSAC 治疗心肌梗死研究)
由于降低病死率约50%而提前终止试验。国际上最大的溶栓试验(ISIS-Ⅲ国际心肌梗死生存试
验-Ⅲ)比较了SK ,t-PA 、APSAC 疗效,5周病死率分别为10.5%、10.3%、10.6%,均使病死率明
显降低。最近溶栓治疗试验汇总资料表明,溶栓组0-35天AMI 病死率为9.4%显著低于对照组
11.3%,但36-182天病死率(3.8%比4.0%)及>183天(8.3%比8.3%)却无明显差异。
2.2治疗时间窗:
从胸痛发作到溶栓的时间间隔,一般来讲越短越好,0~6小时入选的溶栓治疗可使病死率(8.7%)
较对照组(11.1%)减少24%±3%;如果7~12小时入选 (11.0%)较对照组(12.6%)减少15%±
5%;13~24小时入选(10%)较对照组(10.5%)减少4%±7%。说明溶栓的时间延迟越长,效果
越差。
LATE 试验(1993年)证实了6-24小时晚期溶栓仍有益,该试验评价了急性心肌梗塞后6~24
小时开始应用rt-PA 的效果与安慰剂对照。rt-PA 组和对照组35天死亡率分别为8.86%和10.31%,
相对降低14.1%。但12小时内进行溶栓治疗的分析表明rt-PA 组死亡率显著降低:两组35天死
亡率分别为8.9%和11.97%,相对降低25.6%(95%CI为6.3% ~45.0%,P=0.023)。
2.3安全性:
t-PA 0-35天脑出血发生率为0.5%(134/24387),显著高于SK0.3%(64/24457),2P
年龄越大,t-PA 组脑出血发生率越高。APSAC 组脑出血发生率为0.5%(76/13849)也显著高于
SK0.2%(33/13858),2P
2.4溶栓药物的比较
GISSI-2,ISIS-3,ISSIS-2等试验提示:各种溶栓药物均明显降低死亡率,效果无明显差异。
t-PA 与SK 合用,与单独使用t-PA 、SK 并无明显差异。
2.5溶栓治疗与PTCA 疗效比较
被评价的转归结局包括:研究终点时的总死亡率、再梗塞、任何形式的中风、死亡与再梗塞的复
合终点、反复心肌缺血、严重出血和冠脉旁路手术。主要结果是:收集了10个临床试验,包括
2573例病人。与溶栓治疗相比,直接PTCA 疗效更好。短期死亡率显著降低(Relative reduction
risk 相对危险降低RRR=32%, 95%CI=5%-50%)。观察到再梗塞有同样降低(RRR=52%, 95%
CI=30%-67%),反复心肌缺血(RRR=54%,95%CI=39%-66%),死亡与再梗塞的复合终点(RRR=46%,
95%CI=30-58%),中风明显降低66%(95% CI=28%-84%)。大出血的发生无显著差异(RR=1.18,95%
CI=0.73-1.90,但这个可信区间较大)。考虑死亡及再梗塞作为联合终点,直接PTCA 的优越性
优于溶栓,但与加速性t-PA 相比优越性较低(RR=0.70,95%CI=0.51-0.97),与链激酶相比较高
(RR=0.30,95%CI=0.17-0.53)。
三. 讨论
在脑梗塞的治疗中,尽管溶栓治疗会增高10天内的死亡率以及随访终点时的死亡率,并增加了
颅内出血的发生率,但总的说来,溶栓治疗是利大于弊,使幸存的患者病残率减少。在MAST-I
试验中,研究了联合使用阿司匹林和溶栓治疗的安全性,结果提示联合使用阿司匹林和链激酶会
明显增高各阶段的脑血管性死亡(OR=2.0,95%CI 1.1-3.7)和致死性的颅内出血(OR=2.2,95%CI
1.0-5.0)。根据所得的资料,溶栓治疗引起的死亡主要是由于24小时内联合使用抗凝剂或抗血
小板药物,并且接受溶栓治疗的病人病情重,脑梗塞面积较大。目前尚无充足的证据回答关于溶
栓治疗的时间窗是多少,但是NINDS 试验中,使用r-tPA 在3小时内进行溶栓治疗可以降低随访
期内病人的死亡率及病残率。由于病例数少,需要更大型的随机临床试验来证实。美国FDA 及加
拿大的溶栓治疗指南中指出:r-tPA 治疗急性缺血性中风的时间窗为3小时内。关于溶栓治疗的
不同药物和同一药物的不同剂量,仅有一篇系统评价进行了研究,结果是:8个试验共1334名
病人。大剂量比小剂量要增加致死性的颅内出血5倍(OR=5.02,95%CI 1.56-16.18),无统计
学差异;不同的溶栓药物之间无明显差别。尽管一些试验提示r-tPA 出血风险较小,病人的获益
较大。但目前尚无充足证据说明哪一种剂量、药物及给药方法更好一些,需要更大型的随机临床
试验来证实。总之,溶栓治疗在有经验的研究中心并且严格选择病人使用时会得到有益的结果,
但在常规临床实践中溶栓治疗不能被广泛的应用。
a) 关于心肌梗塞的治疗,许多大型临床随机试验都一致证明了溶栓可以降低病人的死亡率。一
般在6个小时内进行治疗。r-tPA 颅内出血的发生率较SK 高,高龄(>65岁)、低体重(
高血压(SBP≥170mmmHg ,DBP ≥95mmmHg) 、应用t-PA 是颅内出血的四个危险因素。当出血危险高
的病人溶栓时,需要权衡利弊,为减少颅内出血,应使用SK 。
目前的证据支持PTCA 比溶栓治疗更有益,但目前最大最多中心参加的试验GUSTO2B 试验得出的
结论是:PTCA 比溶栓治疗的优越性不明显。这一倾向提示,当采用最理想的溶栓治疗时,PTCA
的优越性降低。相信随着医学的发展,更好的溶栓药物出现,PTCA 的优越性将逐步降低。直接
PTCA 能直接判断冠脉通畅的级别,冠脉开通率更高,(一般能达到TIMI 3级),冠脉造影结果
提示左主干闭塞者可立即转送做CABG ,再闭塞率低,卒中危险性小,适用于老年、心源性休克
等高危患者。在富有经验的医疗中心,能及时行PTCA 时,直接PTCA 可作为AMI 再灌注的首选策
略。绝大多数情况下,适宜的溶栓治疗仍将被认为是很好的再灌注策略。