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. 2021 Jul 1;78(7):809-816.
doi: 10.1001/jamaneurol.2021.0925.

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

Santosh B Murthy  1 , Cenai Zhang  1 , Ivan Diaz  2 , Emily B Levitan  3 , Silvia Koton  4   5 , Traci M Bartz  6 , Janet T DeRosa  7   8 , Kevin Strobino  7   8 , Lisandro D Colantonio  3 , Costantino Iadecola  1 , Monika M Safford  9 , Virginia J Howard  3 , W T Longstreth Jr  10   11 , Rebecca F Gottesman  4   12 , Ralph L Sacco  13 , Mitchell S V Elkind  7   8 , George Howard  14 , Hooman Kamel  1   15
Affiliations

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

Santosh B Murthy et al. JAMA Neurol. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Murthy reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Levitan reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study; and grants from Amgen and personal fees from Novartis outside the submitted work. Ms Bartz reported receiving grants from the NIH during the conduct of the study. Ms DeRosa reported receiving grants from the National Institute of Neurological Disorders and Stroke (NINDS) during the conduct of the study. Dr Colantonio reported receiving grants from Amgen outside the submitted work. Dr Iadecola reported receiving personal fees for serving on the scientific advisory board for Broadview Ventures outside the submitted work. Dr Safford reported receiving grants from Amgen outside the submitted work. Dr V. J. Howard reported receiving grants from the NIH/NINDS during the conduct of the study. Dr Longstreth reported being a coinvestigator on the CHS and serving as a co–principal investigator for the NIH-funded ARCADIA (Atrial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke) trial, which receives in-kind study drug from the Bristol Myers Squibb (BMS)–Pfizer Alliance and ancillary funding from Roche Diagnostics. Dr Gottesman reported being the former Associate Editor for Neurology outside the submitted work. Dr Sacco reported receiving grants from the NIH Northern Manhattan Study during the conduct of the study; and grants from Florida Department of Health Florida Stroke Registry, NIH Miami Clinical Translational Science Institute, and NIH Transitions of Stroke Care outside the submitted work; and a stipend from the American Heart Association for work as Editor-in-Chief of Stroke. Dr Elkind reported serving as a principal investigator for the NIH-funded ARCADIA trial, which receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis and ancillary funding from Roche Diagnostics; and receiving royalties from UpToDate for chapters related to stroke. Dr Kamel reported serving as co–principal investigator for the NIH-funded ARCADIA trial, which receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics; serving as a steering committee member of Medtronic’s Stroke AF trial (uncompensated), serving on an endpoint adjudication committee for a trial of empagliflozin for Boehringer-Ingelheim, and having served on an advisory board for Roivant Sciences related to Factor XI inhibition. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flowchart Showing Inclusion Criteria for Analysis of Intracerebral Hemorrhage (ICH) and Subsequent Arterial Ischemic Events
MI indicates myocardial infarction.
Figure 2.
Figure 2.. Kaplan-Meier Analysis of the Risk of an Arterial Ischemic Event After Intracerebral Hemorrhage (ICH)
The number at risk is shown on the x-axis, with the corresponding failures (outcomes of interest) in parentheses.
Figure 3.
Figure 3.. Kaplan-Meier Analysis of the Risk of Ischemic Stroke and Myocardial Infarction (MI) After Intracerebral Hemorrhage (ICH)
The number at risk is shown on the x-axis, with the corresponding failures (outcomes of interest) in parentheses.
Figure 4.
Figure 4.. Subgroup Analyses of the Risk of an Arterial Ischemic Event After Intracerebral Hemorrhage (ICH)
ARIC indicates Atherosclerosis Risk in Communities study; CHS, Cardiovascular Health Study; HR, hazard ratio; NOMAS, Northern Manhattan Study; and REGARDS, Reasons for Geographic and Racial Differences in Stroke study.
See this image and copyright information in PMC

Comment in

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