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Assessment of Incidence and Risk Factors of Intracerebral Hemorrhage Among Participants in the Framingham Heart Study Between 1948 and 2016

Educational Objective
To evaluate whether the incidence of intracerebral hemorrhage decreased over time and to determine risk factors for deep vs lobar intracerebral hemorrhage.
1 Credit CME
Key Points

Question  Is the incidence of intracerebral hemorrhage decreasing over time, and do risk factor profiles for intracerebral hemorrhage located in the deep vs lobar brain regions differ?

Findings  In this cohort study of 10 333 participants from the Framingham Heart Study, a generally stable age-adjusted intracerebral hemorrhage incidence rate was found between 1985 and 2016; an age-stratified analysis indicated a continued increase in the incidence rate among those 75 years and older, coinciding with a 3-fold increase in the use of anticoagulant medications. Hypertension was associated with intracerebral hemorrhage located in both the deep and lobar brain regions.

Meaning  Results of this study suggest that, although the intracerebral hemorrhage incidence rate has stabilized in the last 30 years in this cohort, it has not substantially decreased; the cumulative burden is likely to continue to increase.


Importance  Intracerebral hemorrhage (ICH) has the highest mortality of all stroke types and is the most serious complication of anticoagulation. Data regarding trends in ICH incidence and location-specific risk factors on the population level are conflicting.

Objective  To assess long-term population-based trends in the incidence of ICH, examine incidence rates stratified by deep and lobar locations, and characterize location-specific risk factors.

Design, Setting, and Participants  This longitudinal prospective community-based cohort study comprised 10 333 original participants (n = 5209; age range, 28-62 years) and offspring participants (n = 5124; age range, 5-70 years) from the Framingham Heart Study who were followed up from January 1, 1948, to December 31, 2016. Original and offspring patient cohorts were confirmed to have experienced a spontaneous ICH event through imaging or pathologic testing. A total of 129 participants were identified with a primary incident of ICH. After exclusions, the remaining 99 patients were divided into 2 nested case-control samples, which were created by stratifying the first incident of ICH by brain region (lobar ICH or deep ICH), with 55 patients included in the lobar ICH sample and 44 patients included in the deep ICH sample. Patients were matched by age and sex (1:4 ratio) with 396 individuals without any stroke event (the control group). No participant in the patient samples was excluded or approached for consent, as their initial consent to participate in the Framingham Heart Study included consent to follow-up of cardiovascular outcomes. Data were analyzed in October 2019.

Main Outcomes and Measures  The unadjusted and age-adjusted ICH incidence rates, assessed in 3 periods (period 1, from 1948-1986; period 2, from 1987-1999; and period 3, from 2000-2016) to study incidence trends. Nested case-control samples were used to examine baseline risk factors and medication exposures with the incidence of ICH events located in the lobar and deep brain regions within the 10 years before participants experienced a stroke event.

Results  Of 10 333 original and offspring participants in the Framingham Heart Study, 129 patients (72 women [55.8%]; mean [SD] age, 77 [11] years) experienced a primary ICH incident during a follow-up period of 68 years (301 282 person-years), with an incidence rate of 43 cases per 100 000 person-years. The unadjusted incidence rate increased over time, but the age-adjusted incidence rate decreased slightly between periods 2 and 3. An age-stratified analysis indicated a continued increase in ICH incidence among patients 75 years and older, reaching 176 cases per 100 000 person-years in period 3. A concurrent 3-fold increase in the use of anticoagulant medications was observed, from 4.4% in period 2 to 13.9% in period 3. The incidence rate increased substantially with age for both lobar and deep ICH. Higher systolic and diastolic blood pressure and statin medication use (odds ratio [OR], 4.07; 95% CI, 1.16-14.21; P = .03) were associated with the incidence of deep ICH. Higher systolic blood pressure and apolipoprotein E ε4 allele homozygosity (OR, 3.66; 95% CI, 1.28-10.43; P = .02) were associated with the incidence of lobar ICH.

Conclusions and Relevance  This study found that the incidence of ICH increased in the oldest patients. Hypertension is a treatable risk factor for both deep and lobar ICH, while the use of statin medications is associated with the risk of a deep ICH event.

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Article Information

Accepted for Publication: March 15, 2020.

Corresponding Author: Vasileios-Arsenios Lioutas, MD, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215 (

Published Online: June 8, 2020. doi:10.1001/jamaneurol.2020.1512

Author Contributions: Drs Romero and Seshadri contributed equally and are considered co–last authors of this work. Drs Lioutas and Beiser had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lioutas, Beiser, Selim, Romero, Seshadri.

Acquisition, analysis, or interpretation of data: Lioutas, Beiser, Aparicio, Himali, Romero, Seshadri.

Drafting of the manuscript: Lioutas.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Lioutas, Beiser, Himali.

Obtained funding: Seshadri.

Administrative, technical, or material support: Seshadri.

Supervision: Romero, Seshadri.

Conflict of Interest Disclosures: Dr Lioutas reported receiving grants from the National Institutes of Health and the National Institute on Aging during the conduct of the study and personal fees from Qmetis outside the submitted work. Dr Himali reported receiving grants from the National Institutes of Health during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was supported by grants NS017950 and UH2 NS100605 from the National Institute of Neurological Disorders and Stroke; grants R01 AG054076, R01 AG049607, R01 AG033040, R01 AG063507, R01 AG059725, RF1 AG052409, RF1 AG061872, U01 AG049505, and AG058589 from the National Institute on Aging; and grants N01-HC-25195, HHSN268201500001I, and 75N92019D00031 from the National Heart, Lung, and Blood Institute.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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