Neurological complications in patients with infective endocarditis (IE), such as ischemic and hemorrhagic stroke, are well described; however, predicting which patients are most likely to experience stroke remains uncertain.
Aims:
We conducted a systematic review and meta-analysis to identify the factors associated with the risk of stroke in patients hospitalized with IE.
Methods:
A systematic search of Ovid MEDLINE, EMBASE, and Web of Science up to 27 June 2024 was conducted. Articles evaluating risk of acute ischemic stroke (AIS) or intracranial hemorrhage (ICH) in patients with IE were included. Meta-analysis of odds ratios was feasible for only some predictive factors due to study heterogeneity. Cochrane’s Risk of Bias in Non-Randomized Studies of Exposure tool was used for risk-of-bias assessment.
Summary of Review:
Of 3538 studies identified, 35 were included: 9 prospective and 26 retrospective cohort. Staphylococcus aureus infection (odds ratio (OR) 3.05; 95% CI, 1.96–4.73, I2 = 77.2%; 9 studies) and 1-mm increment in vegetation size (OR, 1.26; 95% CI, 1.02–1.55, I2 = 90.1%; 3 studies) were associated with a higher risk of AIS, after adjusting for other covariates. High-intensity signals on transcranial Doppler, and comorbidities such as hypertension, atrial fibrillation, and hyperlipidemia were also found to be associated with a higher risk of AIS. The risk of ICH was increased by thrombocytopenia, mycotic aneurysms, prior ICH or AIS, and cerebral microbleeds.
Conclusion:
Our study has identified factors which are associated with increased stroke risk in IE and may help physicians predict risk. While echocardiographic and neuroimaging findings may be particularly informative, underlying comorbidities and various laboratory values may also contribute to predicting IE-associated strokes.
HabibGErbaPAIungB, et al. Clinical presentation, aetiology and outcome of infective endocarditis. Results of the ESC-EORP EURO-ENDO (European Infective Endocarditis) registry: a prospective cohort study. Eur Heart J2019; 40: 3222–3232.
2.
KimJHLeeHJKuNS, et al. Infective endocarditis at a tertiary care hospital in South Korea. Heart2021; 107: 135–141.
3.
SalaunETouilAHubertS, et al. Intracranial haemorrhage in infective endocarditis. Arch Cardiovasc Dis2018; 111: 712–721.
4.
GrecuNTiuCTerecoasaE, et al. Endocarditis and stroke. Maedica (Bucur)2014; 9: 375–381.
5.
HessAKleinIIungB, et al. Brain MRI findings in neurologically asymptomatic patients with infective endocarditis. AJNR Am J Neuroradiol2013; 34: 1579–1584.
6.
YangATanCDanemanN, et al. Clinical and echocardiographic predictors of embolism in infective endocarditis: systematic review and meta-analysis. Clin Microbiol Infect2019; 25: 178–187.
7.
MohananeyDMohadjerAPetterssonG, et al. Association of vegetation size with embolic risk in patients with infective endocarditis: a systematic review and meta-analysis. JAMA Intern Med2018; 178: 502–510.
8.
MoherDLiberatiATetzlaffJ, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med2009; 151: 264–269.
9.
LeeSJOhSSLimDSHongSKChoiRKParkJS.Usefulness of anticoagulant therapy in the prevention of embolic complications in patients with acute infective endocarditis. Biomed Res Int2014; 2014: 254187.
10.
PathickalSMParkTESharmaR.Clinical outcomes associated with the use of anticoagulant and antiplatelet agents in patients undergoing treatment for infective endocarditis: a pilot study. Clin Ther2020; 42: 1828–1838.
11.
ScheggiVMenaleSToniettiB, et al. Impact of septic cerebral embolism on prognosis and therapeutic strategies of infective endocarditis: a retrospective study in a surgical centre. BMC Infect Dis2022; 22: 554.
12.
Snygg-MartinUGustafssonLRosengrenL, et al. Cerebrovascular complications in patients with left-sided infective endocarditis are common: a prospective study using magnetic resonance imaging and neurochemical brain damage markers. Clin Infect Dis2008; 47: 23–30.
13.
Snygg-MartinURasmussenRVHassagerCBruunNEAnderssonROlaisonL.The relationship between cerebrovascular complications and previously established use of antiplatelet therapy in left-sided infective endocarditis. Scand J Infect Dis2011; 43: 899–904.
14.
Snygg-MartinURasmussenRVHassagerCBruunNEAnderssonROlaisonL.Warfarin therapy and incidence of cerebrovascular complications in left-sided native valve endocarditis. Eur J Clin Microbiol Infect Dis2011; 30: 151–157.
15.
HeiroMNikoskelainenJEngblomE, et al. Neurologic manifestations of infective endocarditis: a 17-year experience in a teaching hospital in Finland. Arch Intern Med2000; 160: 2781–2787.
16.
SursalTClareKFeldsteinE, et al. Significant increase in mortality and risk of acute ischemic stroke in infective endocarditis patients with subarachnoid hemorrhage secondary to mycotic aneurysms. J Neurol Sci2023; 451: 120670.
17.
OkazakiSSakaguchiMHyunB, et al. Cerebral microbleeds predict impending intracranial hemorrhage in infective endocarditis. Cerebrovasc Dis2011; 32: 483–488.
18.
García-CabreraEFernández-HidalgoNAlmiranteB, et al. Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study. Circulation2013; 127: 2272–2284.
19.
IungBTubianaSKleinI, et al. Determinants of cerebral lesions in endocarditis on systematic cerebral magnetic resonance imaging: a prospective study. Stroke2013; 44: 3056–3062.
20.
XuNFuYWangSLiSCaiD.High level of D-dimer predicts ischemic stroke in patients with infective endocarditis. J Clin Lab Anal2020; 34: e23206.
21.
OkazakiSYoshiokaDSakaguchiMSawaYMochizukiHKitagawaK.Acute ischemic brain lesions in infective endocarditis: incidence, related factors, and postoperative outcome. Cerebrovasc Dis2013; 35: 155–162.
22.
Di SalvoGHabibGPergolaV, et al. Echocardiography predicts embolic events in infective endocarditis. J Am Coll Cardiol2001; 37: 1069–1076.
23.
SongSJKimJHKuNS, et al. Vegetation size, multiplicity, and position in patients with infective endocarditis. Ann Thorac Surg2022; 114: 2253–2260.
24.
NitschLShirvani SamaniOSilaschiM, et al. Infective endocarditis and stroke: when does it bleed? A single center retrospective study. Neurol Res Pract2023; 5: 13.
25.
DavisKAHuangGPettySATanWAMalaverDPeacockJEJr.The effect of preexisting anticoagulation on cerebrovascular events in left-sided infective endocarditis. Am J Med2020; 133: 360–369.
26.
ValenzuelaIHunterMDSundheimK, et al. Clinical risk factors for acute ischaemic and haemorrhagic stroke in patients with infective endocarditis. Intern Med J2018; 48: 1072–1080.
27.
KaliappanTShukkoorAAAnandanPK, et al. Mural vegetation in infective endocarditis–Is it a predictor for embolism?J Cardiovasc Dis Res2021; 12: 1–6.
28.
LinYWJiangMWeiXB, et al. Prognostic value of D-dimer for adverse outcomes in patients with infective endocarditis: an observational study. BMC Cardiovasc Disord2021; 21: 279.
29.
Durante MangoniEAdinolfiLETripodiMF, et al. Risk factors for “major” embolic events in hospitalized patients with infective endocarditis. Am Heart J2003; 146: 311–316.
30.
SchuermannHvon RennenbergRRieglerC, et al. Characteristics associated with occurrence of stroke in patients with infective endocarditis—a retrospective cohort study. Neurol Res Pract2024; 6: 22.
31.
YuanBWangCFanZ, et al. A Bayesian network-based approach for identifying risk factors and predicting ischemic stroke in infective endocarditis patients. Front Cardiovasc Med2023; 10: 1294229.
32.
DasASMcKeownMJordanSALiKRegenhardtRWFeskeSK.Neurological complications and clinical outcomes of infective endocarditis. J Stroke Cerebrovasc Dis2022; 31: 106626.
33.
FabriJJrIssaVSPomerantzeffPMA, et al. Time-related distribution, risk factors and prognostic influence of embolism in patients with left-sided infective endocarditis. Int J Cardiol2006; 110: 334–339.
34.
KelesogluŞInciSGulM, et al. Value of increased CRP/albumin ratio in predicting embolic events in patients with infective endocarditis. Biomark Med2023; 17: 613–621.
KupferwasserLIHafnerGMohr-KahalySErbelRMeyerJDariusH.The presence of infection-related antiphospholipid antibodies in infective endocarditis determines a major risk factor for embolic events. J Am Coll Cardiol1999; 33: 1365–1371.
37.
Selton-SutyCMaigratCHDevignesJ, et al. Possible relationship between antiphospholipid antibodies and embolic events in infective endocarditis. Heart2018; 104: 509–516.
38.
OhiraSDoiKKawajiriH, et al. Prediction of early postoperative cerebral hemorrhage in infective endocarditis patients using magnetic resonance imaging. Gen Thorac Cardiovasc Surg2014; 62(10): 608–613.
39.
İleriMKanatSOrhanG, et al. Increased mean platelet volume in patients with infective endocarditis and embolic events. Cardiol J2015; 22: 37–43.
40.
ÖzkanUGürdoğanM.A novel potential biomarker for predicting the development of septic embolism in patients with infective endocarditis: systemic coagulation inflammation index. Turk Kardiyol Dern Ars2024; 52: 36–43.
41.
HsuRBLinFY.Methicillin resistance and risk factors for embolism in Staphylococcus aureus infective endocarditis. Infect Control Hosp Epidemiol2007; 28: 860–866.
42.
ChengXMengJChenY, et al. Analysis of clinical features and outcomes of infective endocarditis with very large vegetations: a retrospective observational study from 2016 to 2022. Rev Cardiovasc Med2022; 23: 264.
43.
HubertSThunyFResseguierN, et al. Prediction of symptomatic embolism in infective endocarditis: construction and validation of a risk calculator in a multicenter cohort. J Am Coll Cardiol2013; 62: 1384–1392.
44.
ThunyFDi SalvoGBelliardO, et al. Risk of embolism and death in infective endocarditis: prognostic value of echocardiography: a prospective multicenter study. Circulation2005; 112: 69–75.
45.
BaddourLMWilsonWRBayerAS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation2015; 132: 1435–1486.
46.
YoshiokaDTodaKSakaguchiT, et al. Valve surgery in active endocarditis patients complicated by intracranial haemorrhage: the influence of the timing of surgery on neurological outcomes. Eur J Cardiothorac Surg2014; 45: 1082–1088.
47.
KinneyKJStachJMKulhankovaKBrownMSalgado-PabónW.Vegetation Formation in staphylococcus aureus endocarditis inversely correlates with RNAIII and sarA expression in invasive clonal complex 5 isolates. Front Cell Infect Microbiol2022; 12: 925914.
48.
ChoIJKimJSChangHJ, et al. Prediction of hemorrhagic transformation following embolic stroke in patients with prosthetic valve endocarditis. J Cardiovasc Ultrasound2013; 21: 123–129.
49.
ArregleFMartelHPhilipM, et al. Infective endocarditis with neurological complications: delaying cardiac surgery is associated with worse outcome. Arch Cardiovasc Dis2021; 114: 527–536.
50.
HabibGLancellottiPAntunesMJ, et al. 2015 ESC Guidelines for the management of infective endocarditis: the task force for the management of infective endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J2015; 36: 3075–3128.
51.
PowersWJRabinsteinAAAckersonT, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke2018; 49: e46–e110.
52.
FischerUKogaMStrbianD, et al. Early versus later anticoagulation for stroke with atrial fibrillation. N Engl J Med2023; 388: 2411–2421.
53.
JumahAFuSAlbannaAJ, et al. Early vs late anticoagulation in acute ischemic stroke with indications outside atrial fibrillation. J Stroke Cerebrovasc Dis2024; 33: 107757.
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