Incidence and Risk Factors of Intracerebral Hemorrhage Among Framingham Heart Study Participants | Cardiology | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

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.

Abstract

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.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

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 (vlioutas@bidmc.harvard.edu).

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.

References
1.
Krishnamurthi  RV , Moran  AE , Forouzanfar  MH ,  et al; Global Burden of Diseases, Injuries, and Risk Factors 2010 Study Stroke Expert Group.  The global burden of hemorrhagic stroke: a summary of findings from the GBD 2010 study.   Glob Heart. 2014;9(1):101-106. doi:10.1016/j.gheart.2014.01.003 PubMedGoogle ScholarCrossref
2.
Krishnamurthi  RV , Feigin  VL , Forouzanfar  MH ,  et al; Global Burden of Diseases, Injuries, Risk Factors Study 2010 (GBD 2010); GBD Stroke Experts Group.  Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the Global Burden of Disease Study 2010.   Lancet Glob Health. 2013;1(5):e259-e281. doi:10.1016/S2214-109X(13)70089-5 PubMedGoogle ScholarCrossref
3.
Jolink  WM , Klijn  CJ , Brouwers  PJ , Kappelle  LJ , Vaartjes  I .  Time trends in incidence, case fatality, and mortality of intracerebral hemorrhage.   Neurology. 2015;85(15):1318-1324. doi:10.1212/WNL.0000000000002015 PubMedGoogle ScholarCrossref
4.
Lovelock  CE , Molyneux  AJ , Rothwell  PM ; Oxford Vascular Study.  Change in incidence and aetiology of intracerebral haemorrhage in Oxfordshire, UK, between 1981 and 2006: a population-based study.   Lancet Neurol. 2007;6(6):487-493. doi:10.1016/S1474-4422(07)70107-2 PubMedGoogle ScholarCrossref
5.
Carlsson  M , Wilsgaard  T , Johnsen  SH ,  et al.  Temporal trends in incidence and case fatality of intracerebral hemorrhage: the Tromso Study 1995-2012.   Cerebrovasc Dis Extra. 2016;6(2):40-49. doi:10.1159/000447719 PubMedGoogle ScholarCrossref
6.
Giroud  M , Delpont  B , Daubail  B ,  et al.  Temporal trends in sex differences with regard to stroke incidence: the Dijon Stroke Registry (1987-2012).   Stroke. 2017;48(4):846-849. doi:10.1161/STROKEAHA.116.015913 PubMedGoogle ScholarCrossref
7.
van Asch  CJ , Luitse  MJ , Rinkel  GJ , van der Tweel  I , Algra  A , Klijn  CJ .  Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis.   Lancet Neurol. 2010;9(2):167-176. doi:10.1016/S1474-4422(09)70340-0 PubMedGoogle ScholarCrossref
8.
Appelros  P , Stegmayr  B , Terent  A .  Sex differences in stroke epidemiology: a systematic review.   Stroke. 2009;40(4):1082-1090. doi:10.1161/STROKEAHA.108.540781 PubMedGoogle ScholarCrossref
9.
Martini  SR , Flaherty  ML , Brown  WM ,  et al.  Risk factors for intracerebral hemorrhage differ according to hemorrhage location.   Neurology. 2012;79(23):2275-2282. doi:10.1212/WNL.0b013e318276896f PubMedGoogle ScholarCrossref
10.
Biffi  A , Anderson  CD , Battey  TW ,  et al.  Association between blood pressure control and risk of recurrent intracerebral hemorrhage.   JAMA. 2015;314(9):904-912. doi:10.1001/jama.2015.10082 PubMedGoogle ScholarCrossref
11.
Rodrigues  MA , Samarasekera  N , Lerpiniere  C ,  et al.  The Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage associated with cerebral amyloid angiopathy: model development and diagnostic test accuracy study.   Lancet Neurol. 2018;17(3):232-240. doi:10.1016/S1474-4422(18)30006-1 PubMedGoogle ScholarCrossref
12.
Tsao  CW , Vasan  RS .  Cohort profile: the Framingham Heart Study (FHS): overview of milestones in cardiovascular epidemiology.   Int J Epidemiol. 2015;44(6):1800-1813. doi:10.1093/ije/dyv337 PubMedGoogle ScholarCrossref
13.
Kannel  WB , Feinleib  M , McNamara  PM , Garrison  RJ , Castelli  WP .  An investigation of coronary heart disease in families. the Framingham offspring study.   Am J Epidemiol. 1979;110(3):281-290. doi:10.1093/oxfordjournals.aje.a112813 PubMedGoogle ScholarCrossref
14.
Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure.  The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V).   Arch Intern Med. 1993;153(2):154-183. doi:10.1001/archinte.1993.00410020010002 PubMedGoogle ScholarCrossref
15.
Andersson  C , Johnson  AD , Benjamin  EJ , Levy  D , Vasan  RS .  70-Year legacy of the Framingham Heart Study.   Nat Rev Cardiol. 2019;16(11):687-698. doi:10.1038/s41569-019-0202-5 PubMedGoogle ScholarCrossref
16.
Satizabal  CL , Beiser  AS , Chouraki  V , Chene  G , Dufouil  C , Seshadri  S .  Incidence of dementia over three decades in the Framingham Heart Study.   N Engl J Med. 2016;374(6):523-532. doi:10.1056/NEJMoa1504327 PubMedGoogle ScholarCrossref
17.
Carandang  R , Seshadri  S , Beiser  A ,  et al.  Trends in incidence, lifetime risk, severity, and 30-day mortality of stroke over the past 50 years.   JAMA. 2006;296(24):2939-2946. doi:10.1001/jama.296.24.2939 PubMedGoogle ScholarCrossref
18.
Drury  I , Whisnant  JP , Garraway  WM .  Primary intracerebral hemorrhage: impact of CT on incidence.   Neurology. 1984;34(5):653-657. doi:10.1212/WNL.34.5.653 PubMedGoogle ScholarCrossref
19.
Bejot  Y , Bailly  H , Graber  M ,  et al.  Impact of the ageing population on the burden of stroke: the Dijon Stroke Registry.   Neuroepidemiology. 2019;52(1-2):78-85. doi:10.1159/000492820 PubMedGoogle ScholarCrossref
20.
Feigin  VL , Lawes  CM , Bennett  DA , Barker-Collo  SL , Parag  V .  Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review.   Lancet Neurol. 2009;8(4):355-369. doi:10.1016/S1474-4422(09)70025-0 PubMedGoogle ScholarCrossref
21.
Liotta  EM , Prabhakaran  S .  Warfarin-associated intracerebral hemorrhage is increasing in prevalence in the United States.   J Stroke Cerebrovasc Dis. 2013;22(7):1151-1155. doi:10.1016/j.jstrokecerebrovasdis.2012.11.015 PubMedGoogle ScholarCrossref
22.
Salami  JA , Warraich  H , Valero-Elizondo  J ,  et al.  National trends in statin use and expenditures in the US adult population from 2002 to 2013: insights from the Medical Expenditure Panel Survey.   JAMA Cardiol. 2017;2(1):56-65. doi:10.1001/jamacardio.2016.4700 PubMedGoogle ScholarCrossref
23.
Goldstein  LB , Amarenco  P , Szarek  M ,  et al; SPARCL Investigators.  Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study.   Neurology. 2008;70(24, pt 2):2364-2370. doi:10.1212/01.wnl.0000296277.63350.77 PubMedGoogle ScholarCrossref
24.
Collins  R , Armitage  J , Parish  S , Sleight  P , Peto  R ; Heart Protection Study Collaborative Group.  Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions.   Lancet. 2004;363(9411):757-767. doi:10.1016/S0140-6736(04)15690-0 PubMedGoogle ScholarCrossref
25.
Park  HS , Gu  JY , Yoo  HJ ,  et al.  Thrombin generation assay detects moderate-intensity statin-induced reduction of hypercoagulability in diabetes.   Clin Appl Thromb Hemost. 2018;24(7):1095-1101. doi:10.1177/1076029618766254 PubMedGoogle ScholarCrossref
26.
Vergouwen  MD , de Haan  RJ , Vermeulen  M , Roos  YB .  Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease.   Stroke. 2008;39(2):497-502. doi:10.1161/STROKEAHA.107.488791 PubMedGoogle ScholarCrossref
27.
Gaist  D , Goldstein  LB , Cea Soriano  L , Garcia Rodriguez  LA .  Statins and the risk of intracerebral hemorrhage in patients with previous ischemic stroke or transient ischemic attack.   Stroke. 2017;48(12):3245-3251. doi:10.1161/STROKEAHA.117.019141 PubMedGoogle ScholarCrossref
28.
Stone  NJ , Robinson  JG , Lichtenstein  AH ,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.   J Am Coll Cardiol. 2014;63(25, pt B):2889-2934. doi:10.1016/j.jacc.2013.11.002 PubMedGoogle ScholarCrossref
29.
Biffi  A , Sonni  A , Anderson  CD ,  et al; International Stroke Genetics Consortium.  Variants at APOE influence risk of deep and lobar intracerebral hemorrhage.   Ann Neurol. 2010;68(6):934-943. doi:10.1002/ana.22134 PubMedGoogle ScholarCrossref
30.
Franklin  SS , Gustin  W  IV , Wong  ND ,  et al.  Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study.   Circulation. 1997;96(1):308-315. doi:10.1161/01.CIR.96.1.308 PubMedGoogle ScholarCrossref
31.
Mitchell  GF , van Buchem  MA , Sigurdsson  S ,  et al.  Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility—Reykjavik study.   Brain. 2011;134(pt 11):3398-3407. doi:10.1093/brain/awr253 PubMedGoogle ScholarCrossref
32.
Moulin  S , Labreuche  J , Bombois  S ,  et al.  Dementia risk after spontaneous intracerebral haemorrhage: a prospective cohort study.   Lancet Neurol. 2016;15(8):820-829. doi:10.1016/S1474-4422(16)00130-7 PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close