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Original Investigation
May 3, 2021

Association Between Intracerebral Hemorrhage and Subsequent Arterial Ischemic Events in Participants From 4 Population-Based Cohort Studies

Author Affiliations
  • 1Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medicine, New York, New York
  • 2Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, New York
  • 3Department of Epidemiology, University of Alabama at Birmingham, Birmingham
  • 4School of Public Health, Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland
  • 5The Stanley Steyer School of Health Professions, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  • 6Department of Biostatistics, University of Washington, Seattle
  • 7Vagelos College of Physicians and Surgeons, Department of Neurology, Columbia University, New York, New York
  • 8Mailman School of Public Health, Department of Epidemiology, Columbia University, New York, New York
  • 9Department of Medicine, Weill Cornell Medicine, New York, New York
  • 10Department of Neurology, University of Washington, Seattle
  • 11Department of Epidemiology, University of Washington, Seattle
  • 12Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 13Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida
  • 14Department of Biostatistics, University of Alabama at Birmingham, Birmingham
  • 15Deputy Editor, JAMA Neurology
JAMA Neurol. 2021;78(7):809-816. doi:10.1001/jamaneurol.2021.0925
Key Points

Question  Is there an association between intracerebral hemorrhage and an increased risk of arterial ischemic events?

Findings  In this individual pooled study of longitudinal data on nearly 50 000 participants from 4 population-based cohort studies, intracerebral hemorrhage was associated with an approximately 2-fold increased risk of ischemic stroke and myocardial infarction, independent of vascular risk factors and antithrombotic medication use.

Meaning  This study suggests that intracerebral hemorrhage may be a novel marker of risk for subsequent arterial ischemic disease.

Abstract

Importance  Intracerebral hemorrhage and arterial ischemic disease share risk factors, to our knowledge, but the association between the 2 conditions remains unknown.

Objective  To evaluate whether intracerebral hemorrhage was associated with an increased risk of incident ischemic stroke and myocardial infarction.

Design, Setting, and Participants  An analysis was conducted of pooled longitudinal participant-level data from 4 population-based cohort studies in the United States: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Northern Manhattan Study (NOMAS), and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Patients were enrolled from 1987 to 2007, and the last available follow-up was December 31, 2018. Data were analyzed from September 1, 2019, to March 31, 2020.

Exposure  Intracerebral hemorrhage, as assessed by an adjudication committee based on predefined clinical and radiologic criteria.

Main Outcomes and Measures  The primary outcome was an arterial ischemic event, defined as a composite of ischemic stroke or myocardial infarction, centrally adjudicated within each study. Secondary outcomes were ischemic stroke and myocardial infarction. Participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction at their baseline study visit were excluded. Cox proportional hazards regression was used to examine the association between intracerebral hemorrhage and subsequent arterial ischemic events after adjustment for baseline age, sex, race/ethnicity, vascular comorbidities, and antithrombotic medications.

Results  Of 55 131 participants, 47 866 (27 639 women [57.7%]; mean [SD] age, 62.2 [10.2] years) were eligible for analysis. During a median follow-up of 12.7 years (interquartile range, 7.7-19.5 years), there were 318 intracerebral hemorrhages and 7648 arterial ischemic events. The incidence of an arterial ischemic event was 3.6 events per 100 person-years (95% CI, 2.7-5.0 events per 100 person-years) after intracerebral hemorrhage vs 1.1 events per 100 person-years (95% CI, 1.1-1.2 events per 100 person-years) among those without intracerebral hemorrhage. In adjusted models, intracerebral hemorrhage was associated with arterial ischemic events (hazard ratio [HR], 2.3; 95% CI, 1.7-3.1), ischemic stroke (HR, 3.1; 95% CI, 2.1-4.5), and myocardial infarction (HR, 1.9; 95% CI, 1.2-2.9). In sensitivity analyses, intracerebral hemorrhage was associated with arterial ischemic events when updating covariates in a time-varying manner (HR, 2.2; 95% CI, 1.6-3.0); when using incidence density matching (odds ratio, 2.3; 95% CI, 1.3-4.2); when including participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction (HR, 2.2; 95% CI, 1.6-2.9); and when using death as a competing risk (subdistribution HR, 1.6; 95% CI, 1.1-2.1).

Conclusions and Relevance  This study found that intracerebral hemorrhage was associated with an increased risk of ischemic stroke and myocardial infarction. These findings suggest that intracerebral hemorrhage may be a novel risk marker for arterial ischemic events.

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