Residual Risk of Recurrent Stroke Despite Anticoagulation in Patients With Atrial FibrillationA Systematic Review and Meta-Analysis

John J. McCabe, PhD1,2,3; Yuen Cheung, MB1,2,3; Marianne Foley, MB1,2,3; et al

2025년 5월 21일

JAMA Neurol. Published online May 21, 2025.

DOI: 10.1001/jamaneurol.2025.1337

Abstract

Importance   Atrial fibrillation (AF) is a leading cause of stroke, and oral anticoagulants (OAC) reduce this risk. However, there are limited data on the residual risk of recurrent stroke in patients with AF.

Objective   To determine the recurrent stroke risk in patients with AF by performing a systematic review and meta-analysis.

Data Sources   Eligible studies were identified by searching Ovid MEDLINE and Embase from inception (Ovid: January 1946; Embase: January 1970) until January 2025.

Study Selection   Eligible studies enrolled patients with prior ischemic stroke and AF, reported information on incidence of recurrent stroke, and had follow-up data for 1 or more years. Three reviewers independently screened abstracts and performed full-text reviews.

Data Extraction and Synthesis   Data extraction was performed by 2 reviewers and independently verified by a third. Incidence rates were pooled using random-effects meta-analysis. Analysis was repeated in patients whose qualifying event occurred despite OAC. Study quality was assessed using the Quality In Prognosis Studies tool.

Main Outcomes and Measures   The primary outcome was recurrent ischemic stroke. The secondary outcomes were any recurrent stroke (ischemic stroke or intra-cerebral hemorrhage [ICH]) and ICH during follow-up.

Results   A total of 23 studies were identified, which included 78 733 patients and 140 307 years of follow-up. The median proportion of OAC use across studies was 92%. The pooled incidence of recurrent ischemic stroke was 3.75% per year (95% CI, 3.17%-4.33%). The risk was higher in noninterventional observational cohorts (4.20% per year; 95% CI, 3.41%-4.99%) compared with randomized clinical trials (2.26% per year; 95% CI, 1.96%-2.57%) (P value for interaction <.001). The risk of any recurrent stroke was 4.88% per year (95% CI, 3.87%-5.90%), and the risk of ICH was 0.58% per year (95% CI, 0.43%-0.73%). In patients with stroke despite OAC, the risk was 7.20% per year (95% CI, 5.05%-9.34%) for ischemic stroke, 8.96% per year (95% CI, 8.25%-9.67%) for any stroke, and 1.40% per year (95% CI, 0.40%-2.40%) for ICH.

Conclusions and Relevance   In this systematic review and meta-analysis, even with modern prevention therapy, the residual recurrence risk after AF-related stroke is high, with an estimated 1 in 6 patients experiencing a recurrent ischemic stroke at 5 years. These data demonstrate an urgent need to improve our understanding of the biological processes responsible for recurrence, improve risk stratification, and develop new secondary prevention strategies after AF-related stroke

Figure 1.  Annualized Risk of Recurrent Stroke

Figure 2.  Meta-Regression Analysis

Figure 3.  Annualized Risk of Recurrence After Stroke Despite Anticoagulation

Key Points

Question  What is the residual risk of recurrent stroke in patients with atrial fibrillation (AF)?

Findings  In this systematic review and meta-analysis, the incidence of recurrence after AF-related stroke was 3.75% per year, but this risk was twice as high in noninterventional observational studies compared to cohorts derived from randomized clinical trials (RCTs). The pooled recurrence risk was 7.20% per year after stroke despite anticoagulation.

Meaning  The residual recurrence risk after AF-related stroke remains unacceptably high despite modern secondary prevention, emphasizing the urgent need for new therapeutic strategies and RCTs in this patient population.

요약

·         중요성  심방세동(AF)은 뇌졸중의 주요 원인 중 하나이며, 경구용 항응고제(OAC)는 이러한 위험을 줄여준다. 그러나 심방세동 환자에서 뇌졸중 재발에 대한 잔존 위험도에 대한 자료는 제한적이다.

·         목적  심방세동(AF) 환자에서 뇌졸중 재발 위험을 파악하기 위해 체계적 문헌고찰 및 메타분석을 수행하였다.

·         자료원 Ovid MEDLINE(시작: 1946년 1월) 및 Embase(시작: 1970년 1월)에서 2025년 1월까지 검색하여 적격한 연구들을 선정하였다.

·         연구 선택기준

▫ 이전에 허혈성 뇌졸중을 진단받고 AF가 있는 환자를 대상으로 한 연구

▫ 뇌졸중 재발률을 보고

▫ 최소 1년 이상의 추적 관찰 자료를 포함한 연구

▫ 3명의 리뷰어가 초록을 독립적으로 검토하고, 전문(full-text)을 평가

·         자료 추출 및 분석

▫ 2명의 리뷰어가 데이터를 추출하고, 제3의 리뷰어가 독립적으로 검증

▫ 무작위 효과 메타분석(random-effects meta-analysis)을 통해 발생률을 통합

▫ 항응고제를 복용 중에도 뇌졸중이 발생한 환자에 대해 별도로 분석

▫ 연구의 질은 Quality In Prognosis Studies(QIPS) 도구를 통해 평가

·         주요 결과 및 측정지표

▫ 1차 결과: 재발성 허혈성 뇌졸중

▫ 2차 결과: 모든 재발성 뇌졸중(허혈성 또는 뇌내출혈), 추적 기간 중 발생한 뇌내출혈(ICH)

·         결과

▫ 총 23개 연구, 78,733명 환자, 140,307인년(person-years) 추적 관찰 포함

▫ OAC 사용률의 중앙값: 92%

▫ 재발 허혈성 뇌졸중의 통합 발생률: 연간 3.75% (95% CI, 3.17%-4.33%)

▫ 비중재 관찰 연구군: 연간 4.20% (95% CI, 3.41%-4.99%)

▫ 무작위 임상시험(RCT): 연간 2.26% (95% CI, 1.96%-2.57%)

- 두 그룹 간 차이는 유의미 (P < .001)

▫ 모든 뇌졸중(허혈성 또는 출혈성 포함) 재발률: 연간 4.88% (95% CI, 3.87%-5.90%)

▫ ICH 발생률: 연간 0.58% (95% CI, 0.43%-0.73%)

OAC 복용 중에도 뇌졸중이 발생한 환자군에서는

▫ 허혈성 뇌졸중 재발률: 7.20%/년 (95% CI, 5.05%-9.34%)

▫ 모든 뇌졸중 재발률: 8.96%/년 (95% CI, 8.25%-9.67%)

▫ ICH 발생률: 1.40%/년 (95% CI, 0.40%-2.40%)

·         결론 및 의의 

이 체계적 문헌고찰 및 메타분석에 따르면, 현대적인 예방 치료(항응고 치료 포함)에도 불구하고 심방세동 환자에게서 뇌졸중 재발의 잔존 위험은 여전히 높다. 5 년 이내에 환자 6명 중 1명 꼴로 재발성 허혈성 뇌졸중을 경험하게 된다. 이러한 데이터는 다음과 같은 점에서 시급한 필요성을 보여준다.

▫재발에 영향을 미치는 생물학적 기전에 대한 이해가 필요

▫ 위험도 분류 체계의 개선

▫ 새로운 2차 예방전략의 개발