The risk of intracerebral hemorrhage (ICH) in Alzheimer's disease (AD) patients undergoing anticoagulation (AC) remains unclear.
Objective
This nationwide cohort study assessed ICH risk in AC-treated AD patients.
Methods
Using Taiwan's National Health Insurance Research Database, we identified 1638 AC-treated AD patients and established four matched cohorts: AD with AC, AD without AC, non-AD with AC, and non-AD without AC. We applied inverse probability of treatment weighting (IPTW) and competing risks regression (CRR) to adjust for confounders and mortality risk. Cox proportional hazards regression estimated ICH risk.
Results
The ICH incidence per 100 person-years was 2.21 in AD patients with AC, 1.03 without AC, 1.71 in non-AD with AC, and 0.28 in non-AD without AC. After IPTW adjustment, compared to non-AD without AC, AD patients with AC had the highest ICH risk (aHR 1.94, 95% CI: 1.44–2.61), followed by non-AD with AC (aHR 1.84, 95% CI: 1.51–2.23) and AD without AC (aHR 1.74, 95% CI: 1.42–2.11). ICH risk in AC-treated AD patients was comparable to non-AD with AC. Subgroup analysis showed higher ICH risk in females and those with hyperlipidemia, diabetes, heart failure, chronic kidney disease, or cancer.
Conclusions
AD is associated with increased ICH risk, which is further elevated by AC use. These findings highlight the need for individualized risk-benefit evaluation, particularly in high-risk populations.
GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health2022; 7: e105–e125.
2.
JackCRJrAndrewsJSBeachTG, et al.Revised criteria for diagnosis and staging of Alzheimer's disease: alzheimer's Association Workgroup. Alzheimers Dement2024; 20: 5143–5169.
3.
ValenzuelaMJPascual-LeoneA. Lecanemab in early Alzheimer's disease. N Engl J Med2023; 388: 1630.
4.
SimsJRZimmerJAEvansCD, et al.Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA2023; 330: 512–527.
5.
SevignyJChiaoPBussiereT, et al.The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature2016; 537: 50–56.
6.
SelkoeDJHardyJ. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med2016; 8: 595–608.
7.
VeitchDPWeinerMWAisenPS, et al.Using the Alzheimer's Disease Neuroimaging Initiative to improve early detection, diagnosis, and treatment of Alzheimer's disease. Alzheimers Dement2022; 18: 824–857.
8.
BehlTKaurISehgalA, et al.The link between Alzheimer's disease and stroke: a detrimental synergism. Ageing Res Rev2024; 99: 102388.
9.
FontMAKrupinskiJArboixA. Antithrombotic medication for cardioembolic stroke prevention. Stroke Res Treat2011; 2011: 607852.
10.
RivardLFribergLConenD, et al.Atrial fibrillation and dementia: a report from the AF-SCREEN International Collaboration. Circulation2022; 145: 392–409.
11.
ChiNFChienLNKuHL, et al.Alzheimer disease and risk of stroke: a population-based cohort study. Neurology2013; 80: 705–711.
12.
ZhouJYuJTWangHF, et al.Association between stroke and Alzheimer's disease: systematic review and meta-analysis. J Alzheimers Dis2015; 43: 479–489.
13.
ShenYNieQXiangW, et al.The relationship between Alzheimer's disease and intracerebral hemorrhage based on Mendelian randomization. J Alzheimers Dis2025; 104: 1154–1166.
14.
LeeTLLiuCHChangYM, et al.The impact of antiplatelet use on the risk of intracerebral hemorrhage in patients with Alzheimer's disease: a nationwide cohort study. J Alzheimers Dis2020; 73: 297–306.
15.
YangYHWuMNChouPS, et al.Longitudinal neuropsychological outcome in Taiwanese Alzheimer's disease patients treated with medication. Curr Alzheimer Res2018; 15: 474–481.
16.
LiuCYHungYTChuangYL, et al.Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J Health Manag2006; 4: 1–22.
17.
SaccoRLKasnerSEBroderickJP, et al.An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke2013; 44: 2064–2089.
18.
AustinPC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res2011; 46: 399–424.
19.
RichardsonDBKaufmanJS. Estimation of the relative excess risk due to interaction and associated confidence bounds. Am J Epidemiol2009; 169: 756–760.
20.
FlahertyMLKisselaBWooD, et al.The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology2007; 68: 116–121.
21.
WuTLvCWuL, et al.Risk of intracranial hemorrhage with direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Neurol2022; 269: 664–675.
22.
ChanYHLeeHFLiPR, et al.Effectiveness, safety, and major adverse limb events in atrial fibrillation patients with concomitant diabetes mellitus treated with non-vitamin K antagonist oral anticoagulants. Cardiovasc Diabetol2020; 19: 63.
23.
ChangSHChouIJYehYH, et al.Association between use of non-vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA2017; 318: 1250–1259.
24.
EllisRJOlichneyJMThalLJ, et al.Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease: the CERAD experience, Part XV. Neurology1996; 46: 1592–1596.
25.
HonigLSSabbaghMNvan DyckCH, et al.Updated safety results from phase 3 lecanemab study in early Alzheimer's disease. Alzheimers Res Ther2024; 16: 105.
26.
OkumuraKAkaoMYoshidaT, et al.Low-dose edoxaban in very elderly patients with atrial fibrillation. N Engl J Med2020; 383: 1735–1745.
27.
BoulangerMPoonMTWildSH, et al.Association between diabetes mellitus and the occurrence and outcome of intracerebral hemorrhage. Neurology2016; 87: 870–878.
28.
AdelborgKSzepligetiSSundbollJ, et al.Risk of stroke in patients with heart failure: a population-based 30-year cohort study. Stroke2017; 48: 1161–1168.
29.
VanentKNLeasureACAcostaJN, et al.Association of chronic kidney disease with risk of intracerebral hemorrhage. JAMA Neurol2022; 79: 911–918.
30.
FalangaARussoLMilesiV. The coagulopathy of cancer. Curr Opin Hematol2014; 21: 423–429.
31.
ParkHJRanganathanP. Neoplastic and paraneoplastic vasculitis, vasculopathy, and hypercoagulability. Rheum Dis Clin North Am2011; 37: 593–606.
32.
LiYLiuYLiuS, et al.Diabetic vascular diseases: molecular mechanisms and therapeutic strategies. Signal Transduct Target Ther2023; 8: 152.
33.
ZiaeianBFonarowGC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol2016; 13: 368–378.
34.
SixIFlissiNLengletG, et al.Uremic toxins and vascular dysfunction. Toxins (Basel)2020; 12: 404.
35.
DurantonFCohenGDe SmetR, et al.Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol2012; 23: 1258–1270.
SprickJDNoceraJRHajjarI, et al.Cerebral blood flow regulation in end-stage kidney disease. Am J Physiol Renal Physiol2020; 319: F782–F791.
38.
LeeVJairamVYuJB, et al.Nationwide patterns of hemorrhagic stroke among patients hospitalized with brain metastases: influence of primary cancer diagnosis and anticoagulation. Sci Rep2020; 10: 10084.
39.
GuoXOsouliSShahripourRB. Review of cerebral radiotherapy-induced vasculopathy in pediatric and adult patients. Adv Biol (Weinh)2023; 7: e2300179.
40.
MallikarjunKSEldayaRWMiller-ThomasMM, et al.Good gone bad: complications of chemotherapy, immunotherapy, and radiotherapy on the CNS. Curr Probl Diagn Radiol2024; 53: 133–149.
41.
KaganAPopperJSRhoadsGG. Factors related to stroke incidence in Hawaii Japanese men. The Honolulu Heart Study. Stroke1980; 11: 14–21.
42.
UeshimaHIidaMShimamotoT, et al.Multivariate analysis of risk factors for stroke. Eight-year follow-up study of farming villages in Akita, Japan. Prev Med1980; 9: 722–740.
43.
SunLClarkeRBennettD, et al.Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults. Nat Med2019; 25: 569–574.
44.
ZhangXPatelAHoribeH, et al.Cholesterol, coronary heart disease, and stroke in the Asia Pacific region. Int J Epidemiol2003; 32: 563–572.
45.
PaciaroniMAgnelliGGiustozziM, et al.Risk factors for intracerebral hemorrhage in patients with atrial fibrillation on non-vitamin K antagonist oral anticoagulants for stroke prevention. Stroke2021; 52: 1450–1454.
46.
GoldsteinLBTothPPDearborn-TomazosJL, et al.Aggressive LDL-C lowering and the brain: impact on risk for dementia and hemorrhagic stroke: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol2023; 43: e404–e442.
KittnerSJSekarPComeauME, et al.Ethnic and racial variation in intracerebral hemorrhage risk factors and risk factor burden. JAMA Netw Open2021; 4: e2121921.
49.
LarssonSCChenJGillD, et al.Risk factors for intracerebral hemorrhage: genome-wide association study and Mendelian randomization analyses. Stroke2024; 55: 1582–1591.
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