高危及中高危肺血栓栓塞症的溶栓治疗研究进展
高危及中高危肺血栓栓塞症的溶栓治疗研究进展
肺血栓栓塞症(PTE)是高致死率疾病,在全球范围内有很高的发病率[1]。PTE的死因主要是进行性右心功能衰竭,常见于血流动力学不稳定的高危患者或伴右心功能不全(right ventricular dysfunction,RVD)的中危患者[2]。溶栓治疗具有快速降低血栓负荷、缓解RVD的优点,可以更早地改善血流动力学,但同时增加了出血风险[3],对PTE长期预后的影响仍不明确。目前寻找有效的策略提高PTE溶栓的有效性及安全性至关重要,本文拟就近几年来相关方面的研究进展做一综述。
间歇充气加压用于静脉血栓栓塞症预防的中国专家共识(2022年版)
一、高危及中高危PTE的概念界定及溶栓治疗
是危险分层中的一部分,危险分层策略是急性PTE管理的基石之一,这一步决定了诊断和治疗策略的选择。2019年欧洲心脏病学会急性肺栓塞诊治指南(简称2019ESC指南)中对急性PTE患者进行三步危险分层策略,第一步基于血流动力学状态分为高危和非高危,第二步根据肺栓塞严重指数(pulmonary embolism severity index,PESI)或简化PESI(simplified PESI,sPESI)将患者分为中危和低危,第三步对中危患者,根据RVD和两个生物标志物分为中高危和中低危[4]。界定高危PTE的血流动力学不稳定状态指的是需心肺复苏的心脏骤停;持续性低血压,或即使使用升压药物,仍存在组织低灌注。中高危PTE 的定义是血流动力学稳定,sPESI≥1分,影像学出现RVD征象伴心脏生物标志物异常[4]。
高危PTE的患病率约为3.9%~4.2%,短期病死率高达15.8%~52.2%,病死率明显高于非高危PTE[5, 6, 7, 8]。与单纯肝素抗凝相比,溶栓治疗可更快改善PTE患者的肺梗阻、肺动脉压(PAP)和肺血管阻力(pulmonary vascular resistance,PVR),因此指南建议这部分患者在无禁忌证的情况下给予溶栓治疗。Keller等[9]的一项急性PTE溶栓治疗及预后研究结果显示,高危PTE[不含心肺复苏和(或)机械通气的患者],接受溶栓治疗的病死率明显低于未接受的患者(28.6%比49.9%,P<0.001);在需要心肺复苏的患者中,溶栓和生存之间也存在一定的相关性,其他真实世界研究的结果也体现出类似趋势[10, 11]。尽管如此,高危PTE接受溶栓治疗的比例并不高,对于高龄、存在近期手术史、肿瘤、冠心病及慢阻肺等共病的患者,溶栓比例更低[9, 10],医生的决策和患者的因素均有影响。无禁忌证者应尽早溶栓,存在出血高风险的非猝死患者可在维持血压平稳的条件下行介入治疗。
(2)中高危PTE溶栓争议的解决策略:对于中高危PTE,需要进一步的风险评估、细化分层来识别血流动力学恶化风险较高的患者,通过建立有效的预后评估模型可以帮助筛选适合溶栓的患者。Barco等[18]发现,存在以下两种或多种情况时(SPB≤110 mmHg、呼吸频率>20次/min、心力衰竭史和活动期肿瘤),全因死亡、血流动力学衰竭或复发性PTE风险增加20%。此外Zimmermann等[19]的研究结果也显示具有较低的SBP、更高的心率和呼吸频率的年轻中高危PTE患者可能从溶栓中获益。这些临床特征的早期识别有助于判定溶栓的目标人群。
心肌损伤标志物(心脏肌钙蛋白)和心衰标志物(BNP或NT-proBNP)是早期评估急性PTE预后的经典生物标志物。近期研究发现,血乳酸(lactate,lac)作为组织氧供需失衡的标志,是一项具有潜在价值的生物标志物,它可作为严重PTE伴明显或即将出现血流动力学损害的标志[4]。Vanni等[20]发现动脉血Lac≥2 mmol/L与30 d病死率之间存在显著相关性[HR值为11.67(95%CI:3.32~41.03)],而且这种关联与患者是否存在休克状态、低血压、RVD 或肌钙蛋白升高无关。Ebner等[21]的研究结果显示中高危PTE患者中,静脉血Lac≥3.3 mmol/L对院内不良事件有较好的预测价值[OR 5.2(95%CI 1.8~15.0)]。Lac可以快速检测并且状态稳定,有助于发现中高危PTE中有恶化风险的患者早期启动溶栓,其临界值的预测效能有待更多的前瞻性研究验证。
将临床特征、生化参数和RVD影像特征组合起来建立预后评估模型具有更好的预测性能[4]。Bova评分包括:SBP 90~100 mmHg(2分)、肌钙蛋白升高(2分)、RVD(2分)、心率≥110次/分(1分),分为Ⅰ级(0~2分)、Ⅱ级(3~4分)、Ⅲ级(>4分),Ⅲ级的PE相关30 d不良结局的风险增加了7倍[22],能较好地预测中危PTE的早期不良预后,但该评估纳入的研究对象不包括溶栓患者。TELOS评分包括:心脏彩超RVD征象和肌钙蛋白阳性、动脉Lac≥2 mmol/L,对血压正常的急性PTE诊断后7 d内不良结局有较好的预测效能[23]。SHIeLD评分包含四项指标:休克指数≥1、低氧血症(氧合指数绝对值)、动脉Lac(绝对值)和出现RVD征象(即肌钙蛋白和NT proBNP升高、CTPA上RV/LV比值>1),该模型以web应用程序的形式呈现,可用于PTE诊断后30天内死亡或挽救性溶栓风险的预测[24]。此外在2019ESC预后评估及Bova评分两种方案基础上纳入Lac升高这一因素,可大大提高原评分的阳性预测效能[21,25, 26]。目前我国尚无基于国内队列开发的预测模型,上述预测模型的效能也有待在我国PTE人群中进行验证。
二、PTE溶栓治疗中出血风险的评估与处理策略
溶栓治疗患者的大出血和颅内出血发生率明显高于抗凝治疗的患者[3],对有溶栓适应证的患者均应进行大出血风险评估,这也是其他降低大出血策略的基础。过去的PTE出血风险评估策略多针对院外长期抗凝的患者,以此来预测溶栓相关的早期大出血缺少针对性。近期开发的溶栓大出血风险评估模型对出血低危与高危患者显示出了较好的预测能力(见表1),为PTE治疗方案的选择提供了基础,提高了溶栓的安全性[27, 28, 29]。当然这些评估模型有待更多的验证,特别是在中国人群中的预测效能尚不清楚。
与系统溶栓相比,导管定向治疗(catheter-directed therapy,CDT)是一种局部溶栓措施,包括导管介导溶栓(catheter-directed fibrinolysis)、药物机械疗法(pharmaco-mechanical therapy)和机械取栓术(mechanical embolectomy)[38],导管介导溶栓是将低剂量纤溶剂经导管直接缓慢注入肺动脉溶解血栓,而近些年出现的超声辅助导管溶栓(ultrasound-assisted catheter-directed thrombolysis,USCDT)结合了超声对血栓的机械破坏作用,较传统导管溶栓更具优势[39]。SEATTLE-Ⅱ(EkoSonic® 血管内系统和激活酶治疗急性肺栓塞)研究[40] 和OPTALYSE PTE试验[41]的结果均显示USCDT在降低肺动脉压减轻 RV负荷方面有不错的疗效,且未发现严重出血并发症。
CDT技术对于有再灌注治疗指征和高出血风险的PTE患者来说是一种很有前景的选择,但目前缺乏与系统溶栓头对头比较的研究。来自真实世界研究的结果显示,CDT组1年的全因病死率明显低于系统溶栓组[12.2%比13.2%;HR 0.73(95%CI 0.56~0.94)],而两组的出血率相似[42]。另一项回顾性研究结果显示USCDT与系统溶栓相比疗效与安全性相当,但住院时间长、费用增加[43]。而针对中高危人群,CDT能否成为系统溶栓的替代方案有待进一步研究明确。
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三、PTE溶栓治疗对长期预后的影响
PTE溶栓治疗在长期生存获益上是否优于抗凝治疗,受研究对象的危险分层、共病、随访时间等多种因素影响,因此研究结果各不相同。一些研究显示中危PTE患者在接受溶栓治疗与单纯抗凝治疗后的长期随访期间(时间在3~37.8个月),两种治疗方案对病死率影响未见差异[14,32,33,35]。但Chatterjee等[3]的Meta分析结果与此不同,该研究中平均随访时间81.7 d,溶栓治疗的全因病死率低于单纯抗凝,无论是高危加中危组患者[OR 0.53(95%CI 0.32~0.88)]还是仅中危组患者[OR 0.48(95%CI 0.25~0.92)],但是在>65岁的亚组中,这种病死率优势并不显著。Zuo等[44] 的Meta分析结果也显示与单纯应用肝素或安慰剂加肝素相比,溶栓剂加肝素可能会降低病死率[OR 0.58(95%CI 0.38~0.88)]。但Meta分析中各研究之间存在很大的异质性,因此溶栓治疗在长期病死率上的优势需要谨慎解读。
PE后综合征的概念。急性PTE后规范治疗3~6个月,仍有多达一半的患者存在持续呼吸困难、运动不耐受和(或)功能受限,这些患者可能存在PPES。PPES被定义为慢性血栓栓塞性肺病(chronic thromboembolic pulmonary disease,CTEPD)伴或不伴肺动脉高压(PH)[45]。慢性血栓栓塞性肺动脉高压(chronic thromboembolic pulmonary hypertension,CTEPH)是指诊断PTE后,经过至少3个月的抗凝治疗仍未解除的持续肺动脉阻塞,导致平均肺动脉压升高(静息时>25 mmHg)[46]。一项针对PTE远期预后的多中心前瞻性研究—慢性血栓栓塞性肺动脉高压与肺栓塞后损害的研究(follow-up after acute pulmonary embolism study,FOCUS),系统评估了急性PTE的晚期预后,结果显示CTEPH的2年累积发病率为2.3%(95%CI:1.2%~4.4%)[47]。
我们希望早期溶栓治疗能够对预防PPES的发生起到有利的长期效果,但相关研究受样本量、随访时间及观察指标等影响,结果存在很大差异。
PEITHO研究的长期(中位时间37.8个月)随访结果显示,溶栓组和单纯肝素抗凝组在持续的临床症状或功能受限方面没有显著差异[14]。TOPCOAT研究结果显示,随访90天后溶栓组PTE患者的整体健康状况优于LMWH抗凝组,但一些临床和功能参数如:纽约心脏协会(NYHA)功能分级、6 min步行距离和生活质量评分,两种治疗组之间没有显著差异[15]。目前相关研究数量较少,尚无证据显示PTE溶栓治疗对减少症状和功能限制的发生优于抗凝治疗。
PTE治疗后的长期随访中,超声心动图出现肺动脉高压征象,提示可能发生CTEPH。MPOPETT研究结果显示,28个月随访结束时,溶栓组患者中出现肺动脉高压的比例明显低于抗凝组(16%比57%,P<0.001),与抗凝相比溶栓治疗可迅速降低肺动脉压并维持较长时间[32]。Fasullo等[48]和Mi等[33]的研究中也显示出类似优势。但Konstantinides等[14]及Yilmaz等[34]的研究结果却并未显示出溶栓治疗在降低肺动脉高压上的优势。因此溶栓治疗在减少CTEPH的发生上是否优于抗凝治疗尚不确定,随着对CTEPH认识和诊治水平的提高,右心导管检查和肺通气灌注扫描的完善,未来对长期随访数据研究的分析有望回答这一问题。
四、小结与展望
对于高危PTE,毋庸置疑溶栓治疗可以挽救生命,但实际接受溶栓的患者比例并不高,这多与患者自身基础状况有关。而中高危PTE虽然有潜在恶化风险,但如果选择不当,溶栓治疗会带来更大的出血风险,因此继续优化风险分层策略确定溶栓治疗的目标人群非常重要。此外PTE早期出血风险评估、降低溶栓药物剂量和利用CDT技术局部溶栓等方面的研究都是对溶栓治疗有效性和安全性的进一步探索,期待未来的前瞻性队列研究及大规模随机对照试验为肺栓塞溶栓提供更多的客观依据。
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引用:杨晶晶, 张宇, 翟振国, 等. 高危及中高危肺血栓栓塞症的溶栓治疗研究进展[J]. 中华结核和呼吸杂志, 2023, 46(7): 720-725. DOI: 10.3760/cma.j.cn112147-20221102-00866.
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