Intracranial Hemorrhage in Patients With Stroke After Endovascular Treatment With or Without IV AlteplaseAn Individual Participant Data Meta-Analysis

Yu Zhou, MD1,2; Lei Zhang, MD1; Fabiano Cavalcante, MD, MSc3; et al

2025년 8월 11일

JAMA Neurol . August 11, 2025

DOI: 10.1001/jamaneurol.2025.2610

Abstract

Importance  For patients with acute ischemic stroke due to anterior circulation large vessel occlusion and presenting directly to endovascular treatment (EVT)–capable centers, intravenous thrombolysis (IVT) before EVT raises concerns about intracranial hemorrhage (ICH), but details are not well understood.

Objective  To determine the frequency and subtypes of ICH in patients treated with IVT plus EVT vs EVT alone and to determine the association between various ICH subtypes and patient functional outcomes.

Data Sources  PubMed and MEDLINE were searched from database inception through March 9, 2023.

Study Selection  Randomized clinical trials comparing EVT alone with IVT plus EVT for anterior circulation large vessel occlusion stroke were included.

Data Extraction and Synthesis  Individual participant data were extracted following the Preferred Reporting Items for Systematic Review and Meta-Analyses of independent participant data (PRISMA-IPD) reporting guidelines. Data were pooled using a random-effects model. Data were analyzed between April 2024 and February 2025.

Main Outcomes and Measures  The primary outcomes were ICH and its subtypes according to the Heidelberg Bleeding Classification (hemorrhagic infarction type 1 [HI1], hemorrhagic infarction type 2 [HI2], parenchymal hematoma type 1 [PH1], parenchymal hematoma type 2 [PH2], and others; symptomatic or asymptomatic ICH), which were evaluated using a mixed-model approach with multinomial or binary regression.

Results  The analysis involved 2313 participants (1160 allocated to the IVT plus EVT group vs 1153 to EVT alone; median [IQR] age, 71 [62-78] years; 1025 female participants [44%]) from 6 studies. Any ICH occurred in 768 of 2261 participants (34%). IVT was associated with an increased rate of any ICH (411 of 1133 [36%] vs 357 of 1128 [32%]; adjusted odds ratio [OR], 1.23; 95% CI, 1.02-1.49; P = .03) and a higher rate of any parenchymal hematoma (PH1 or PH2) (82 of 1133 [7%] vs 61 of 1128 [5%]; adjusted OR, 1.54; 95% CI, 1.02-2.34; P = .04). Compared with participants without ICH, asymptomatic ICH (adjusted common OR, 0.55; 95% CI, 0.46-0.65) and symptomatic ICH (adjusted common OR, 0.08; 95% CI, 0.05-0.13) were both associated with worse functional outcomes, and there was a graded association of ICH radiologic patterns and patient outcomes.

Conclusions and Relevance  In this individual participant data meta-analysis, compared with EVT alone, IVT plus EVT modestly increased the risk of ICH, notably any parenchymal hematoma. Although ICH was associated with worse functional outcomes, this effect may be offset by IVT’s benefit in final successful reperfusion and early reperfusion.

 Key Points

Question  What is the profile of intracranial hemorrhage (ICH) in patients with stroke after endovascular treatment with or without intravenous alteplase, and what is the association with patient outcomes?

Findings  In this individual participant data meta-analysis (n = 2313 participants) of 6 randomized clinical trials, intravenous thrombolysis before thrombectomy was associated with a significant increase of any ICH (36% vs 32%) and parenchymal hematoma (7% vs 5%) vs thrombectomy alone. Asymptomatic and symptomatic ICH were both associated with worse functional outcomes.

Meaning  Intravenous thrombolysis before thrombectomy may modestly increase the risk of ICH (notably, any parenchymal hematoma), but this effect may be offset by its benefit in reperfusion.

Table 2.  Hemorrhage Distribution Across the Treatment Groups in the Intention-to-Treat Population

Table 3.  Association Between Intracranial Hemorrhage (ICH) and Patient Functional Outcome at 90-Day Follow-Up

요약

·         중요성  전순환(anterior circulation) 대혈관 폐색으로 인한 급성 허혈성 뇌졸중 환자 중, 혈관 내 치료(EVT) 가능 센터에 직접 내원한 경우, EVT 전에 시행하는 정맥 내 혈전용해(IVT)는 두개내 출혈(ICH) 위험 증가 우려가 있으나, 구체적인 세부 양상은 잘 알려져 있지 않다.

·         목적   IVT + EVT군과 EVT 단독군에서 ICH 발생 빈도와 아형(subtype)을 비교하고, ICH 아형별로 환자의 기능적 예후와의 연관성을 규명하는 것.

·         자료원  PubMed와 MEDLINE에서 데이터베이스 시작 시점부터 2023년 3월 9일까지 검색.

·         연구선택기준  전순환 대혈관 폐색 뇌졸중에서 EVT 단독과 IVT + EVT를 비교한 무작위 임상시험(RCT).

·         자료 추출 및 분석  PRISMA-IPD(개별 참가자 데이터 체계적 문헌고찰 보고 지침)에 따라 자료를 추출하였으며, 랜덤효과모델(random-effects model)로 통합 분석. 분석 기간: 2024년 4월~2025년 2월.

·         주요 평가변수 

주요 결과는 하이델베르크 출혈 분류(Heidelberg Bleeding Classification)에 따른 ICH 및 아형:

-출혈성 경색 1형(HI1), 2형(HI2)

-실질내 혈종 1형(PH1), 2형(PH2)

-기타(others)

-증상성(symptomatic) 또는 무증상성(asymptomatic) ICH

이를 다항 혹은 이분 회귀분석을 포함한 혼합모형(mixed-model approach)으로 평가.

·         결과

총 6개 연구, 2313명(IVT+EVT군 1160명, EVT 단독군 1153명; 중앙값 연령 71세[IQR 62–78], 여성 44%)이 분석에 포함됨.

-전체 ICH 발생: 2261명 중 768명(34%)

-IVT+EVT군 vs EVT 단독군:

• 모든 ICH: 36%(411/1133) vs 32%(357/1128)

보정된 OR 1.23 (95% CI, 1.02–1.49; P=0.03)

• 모든 실질내 혈종(PH1 또는 PH2): 7%(82/1133) vs 5%(61/1128)

보정된 OR 1.54 (95% CI, 1.02–2.34; P=0.04)

ICH가 없는 환자 대비,

-무증상 ICH: 공통 OR 0.55 (95% CI, 0.46–0.65)

-증상성 ICH: 공통 OR 0.08 (95% CI, 0.05–0.13)모두 기능적 예후 불량과 연관. ICH 영상 아형과 환자 예후 사이에는 단계적(graded) 연관이 관찰됨.

·         결론 및 의의  EVT 단독에 비해 IVT+EVT는 ICH, 특히 실질내 혈종 위험을 다소 증가시켰다.

그러나 ICH는 예후 불량과 연관되더라도, IVT의 최종 재관류 성공 및 조기 재관류 혜택이 이 위험을 상쇄할 가능성이 있다.