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Recurrent Ischemic Stroke Despite Therapeutic Anticoagulation: Evidence of Dual Embolic Mechanisms
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Abstract:
Background: Ischemic stroke occurring despite effective oral anticoagulation, termed “breakthrough stroke,” represents a diagnostic and therapeutic challenge. It may indicate the presence of alternative or concomitant etiological mechanisms beyond the initially identified cause. Data regarding such situations remain limited in sub-Saharan Africa. We report a case of recurrent ischemic stroke despite therapeutic anticoagulation, revealing a dual embolic origin. Methods and Findings: A 50-year-old right-handed woman with poorly controlled hypertension was admitted for sudden onset left-sided hemiparesis (NIHSS score 13). Non-contrast brain CT scan showed a hypodensity in the territory of the right middle cerebral artery. Electrocardiogram revealed atrial fibrillation. Anticoagulation was initiated with enoxaparin followed by fluindione, achieving a therapeutic INR of 2.3. Initial evolution was favorable, with motor improvement at day 14 (NIHSS score 6). Three weeks later, the patient was readmitted for worsening neurological deficit despite good treatment adherence (INR 2.05). Follow-up CT scan showed extension of the infarction in the same vascular territory. Further etiological evaluation with Doppler ultrasound revealed significant right internal carotid artery stenosis with an unstable, ulcerated plaque. The coexistence of atrial fibrillation and carotid atherosclerosis suggested a dual embolic mechanism. The clinical course was unfavorable, with progressive neurological deterioration leading to death. Conclusions: This case illustrates the complexity of etiological reasoning in ischemic stroke. Stroke occurring despite adequate anticoagulation should prompt systematic reassessment for alternative or additional embolic mechanisms. In resource-limited settings, comprehensive etiological evaluation remains a major challenge requiring a pragmatic and individualized approach.
| [1] | Hart, R.G., Pearce, L.A. and Aguilar, M.I. (2007) Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation. Annals of Internal Medicine, 146, 857-867. https://doi.org/10.7326/0003-4819-146-12-200706190-00007 |
| [2] | Polymeris, A.A., Meinel, T.R., Oehler, H., H？lscher, K., Zietz, A., Scheitz, J.F., et al. (2022) Aetiology, Secondary Prevention Strategies and Outcomes of Ischaemic Stroke Despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation. Journal of Neurology, Neurosurgery & Psychiatry, 93, 588-598. https://doi.org/10.1136/jnnp-2021-328391 |
| [3] | Seiffge, D.J., De Marchis, G.M., Koga, M., Paciaroni, M., Wilson, D., Cappellari, M., et al. (2020) Ischemic Stroke Despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation. Annals of Neurology, 87, 677-687. https://doi.org/10.1002/ana.25700 |
| [4] | Ay, H., Furie, K.L., Singhal, A., Smith, W.S., Sorensen, A.G. and Koroshetz, W.J. (2005) An Evidence‐Based Causative Classification System for Acute Ischemic Stroke. Annals of Neurology, 58, 688-697. https://doi.org/10.1002/ana.20617 |
| [5] | Arsava, E.M., Ballabio, E., Benner, T., Cole, J.W., Delgado-Martinez, M.P., Dichgans, M., et al. (2010) The Causative Classification of Stroke System. Neurology, 75, 1277-1284. https://doi.org/10.1212/wnl.0b013e3181f612ce |
| [6] | Feigin, V.L., Stark, B.A., Johnson, C.O., Roth, G.A., Bisignano, C., Abady, G.G., et al. (2021) Global, Regional, and National Burden of Stroke and Its Risk Factors, 1990-2019: A Systematic Analysis for the Global Burden of Disease Study 2019. The Lancet Neurology, 20, 795-820. https://doi.org/10.1016/s1474-4422(21)00252-0 |
| [7] | Wolf, P.A., Abbott, R.D. and Kannel, W.B. (1991) Atrial Fibrillation as an Independent Risk Factor for Stroke: The Framingham Study. Stroke, 22, 983-988. https://doi.org/10.1161/01.str.22.8.983 |
| [8] | Kamel, H., Okin, P.M., Elkind, M.S.V. and Iadecola, C. (2016) Atrial Fibrillation and Mechanisms of Stroke: Time for a New Model. Stroke, 47, 895-900. https://doi.org/10.1161/strokeaha.115.012004 |
| [9] | Lip, G.Y.H., Nieuwlaat, R., Pisters, R., Lane, D.A. and Crijns, H.J.G.M. (2010) Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in Atrial Fibrillation Using a Novel Risk Factor-Based Approach: The Euro Heart Survey on Atrial Fibrillation. Chest, 137, 263-272. https://doi.org/10.1378/chest.09-1584 |
| [10] | Naylor, A.R., Ricco, J., de Borst, G.J., Debus, S., de Haro, J., Halliday, A., et al. (2018) Editor’s Choice—Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). European Journal of Vascular and Endovascular Surgery, 55, 3-81. https://doi.org/10.1016/j.ejvs.2017.06.021 |
| [11] | Redgrave, J.N.E., Lovett, J.K., Gallagher, P.J. and Rothwell, P.M. (2006) Histological Assessment of 526 Symptomatic Carotid Plaques in Relation to the Nature and Timing of Ischemic Symptoms. Circulation, 113, 2320-2328. https://doi.org/10.1161/circulationaha.105.589044 |
| [12] | Gupta, A., Baradaran, H., Schweitzer, A.D., Kamel, H., Pandya, A., Delgado, D., et al. (2013) Carotid Plaque MRI and Stroke Risk: A Systematic Review and Meta-Analysis. Stroke, 44, 3071-3077. https://doi.org/10.1161/strokeaha.113.002551 |
| [13] | Paciaroni, M., Agnelli, G., Caso, V., Tsivgoulis, G., Furie, K.L., Tadi, P., et al. (2017) Prediction of Early Recurrent Thromboembolic Event and Major Bleeding in Patients with Acute Stroke and Atrial Fibrillation by a Risk Stratification Schema: The ALESSA Score Study. Stroke, 48, 726-732. https://doi.org/10.1161/strokeaha.116.015770 |
| [14] | Blackshear, J.L. and Odell, J.A. (1996) Appendage Obliteration to Reduce Stroke in Cardiac Surgical Patients with Atrial Fibrillation. The Annals of Thoracic Surgery, 61, 755-759. https://doi.org/10.1016/0003-4975(95)00887-x |
| [15] | Khurram, I.M., Dewire, J., Mager, M., Maqbool, F., Zimmerman, S.L., Zipunnikov, V., et al. (2013) Relationship between Left Atrial Appendage Morphology and Stroke in Patients with Atrial Fibrillation. Heart Rhythm, 10, 1843-1849. https://doi.org/10.1016/j.hrthm.2013.09.065 |
| [16] | Sulague, R.M., Whitham, T., Danganan, L.M.L., Effiom, V., Candelario, K., Latif, N., et al. (2023) The Left Atrial Appendage and Atrial Fibrillation—A Contemporary Review. Journal of Clinical Medicine, 12, Article No. 6909. https://doi.org/10.3390/jcm12216909 |
| [17] | Kimura, K., Minematsu, K., Yamaguchi, T. and Japan Multicenter Stroke Investigators’ Collaboration (J-MUSIC) (2005) Atrial Fibrillation as a Predictive Factor for Severe Stroke and Early Death in 15 831 Patients with Acute Ischaemic Stroke. Journal of Neurology, Neurosurgery & Psychiatry, 76, 679-683. https://doi.org/10.1136/jnnp.2004.048827 |
| [18] | Ntaios, G., Baumgartner, H., Doehner, W., Donal, E., Edvardsen, T., Healey, J.S., et al. (2024) Embolic Strokes of Undetermined Source: A Clinical Consensus Statement of the ESC Council on Stroke, the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC. European Heart Journal, 45, 1701-1715. https://doi.org/10.1093/eurheartj/ehae150 |
| [19] | Veltkamp, R., Pearce, L.A., Korompoki, E., Sharma, M., Kasner, S.E., Toni, D., et al. (2020) Characteristics of Recurrent Ischemic Stroke after Embolic Stroke of Undetermined Source: Secondary Analysis of a Randomized Clinical Trial. JAMA Neurology, 77, 1233-1240. https://doi.org/10.1001/jamaneurol.2020.1995 |
| [20] | Ruff, C.T., Giugliano, R.P., Braunwald, E., Hoffman, E.B., Deenadayalu, N., Ezekowitz, M.D., et al. (2014) Comparison of the Efficacy and Safety of New Oral Anticoagulants with Warfarin in Patients with Atrial Fibrillation: A Meta-Analysis of Randomised Trials. The Lancet, 383, 955-962. https://doi.org/10.1016/s0140-6736(13)62343-0 |
| [21] | Benz, A.P., Carlin, S. and Eikelboom, J.W. (2026) Antithrombotic Therapy in Patients with Atrial Fibrillation: Unresolved Issues and Future Directions. Journal of Thrombosis and Haemostasis, 24, 1230-1241. https://doi.org/10.1016/j.jtha.2025.12.033 |
| [22] | McCabe, J.J., Cheung, Y., Foley, M., Brennan, S.O., Buckley, J., Renom, P.C., et al. (2025) Residual Risk of Recurrent Stroke Despite Anticoagulation in Patients with Atrial Fibrillation: A Systematic Review and Meta-Analysis. JAMA Neurology, 82, 696-705. https://doi.org/10.1001/jamaneurol.2025.1337 |
| [23] | Libby, P. and Pasterkamp, G. (2015) Requiem for the “Vulnerable Plaque”. European Heart Journal, 36, 2984-2987. https://doi.org/10.1093/eurheartj/ehv349 |
| [24] | Saba, L., Saam, T., J？ger, H.R., Yuan, C., Hatsukami, T.S., Saloner, D., et al. (2019) Imaging Biomarkers of Vulnerable Carotid Plaques for Stroke Risk Prediction and Their Potential Clinical Implications. The Lancet Neurology, 18, 559-572. https://doi.org/10.1016/s1474-4422(19)30035-3 |
| [25] | Murgia, A., Erta, M., Suri, J.S., Gupta, A., Wintermark, M. and Saba, L. (2020) CT Imaging Features of Carotid Artery Plaque Vulnerability. Annals of Translational Medicine, 8, 1261-1261. https://doi.org/10.21037/atm-2020-cass-13 |
| [26] | January, C.T., Wann, L.S., Calkins, H., Chen, L.Y., Cigarroa, J.E., Cleveland, J.C., et al. (2019) 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation. Journal of the American College of Cardiology, 74, 104-132. https://doi.org/10.1016/j.jacc.2019.01.011 |
| [27] | Owolabi, M.O., Sarfo, F., Akinyemi, R., Gebregziabher, M., Akpa, O., et al. (2018) Dominant Modifiable Risk Factors for Stroke in Ghana and Nigeria (SIREN): A Case-Control Study. The Lancet Global Health, 6, e436-e446. |
| [28] | Bonati, L.H., Kakkos, S., Berkefeld, J., de Borst, G.J., Bulbulia, R., Halliday, A., et al. (2021) European Stroke Organisation Guideline on Endarterectomy and Stenting for Carotid Artery Stenosis. European Stroke Journal, 6, I-XLVII. https://doi.org/10.1177/23969873211012121 |
| [29] | Lim, E.T.A., Ying, G., Bernau, O., Frampton, C. and Khashram, M. (2026) Medical Management of Patients with Symptomatic Carotid Artery Stenosis. Annals of Vascular Surgery, 124, 93-100. https://doi.org/10.1016/j.avsg.2025.11.003 |
| [30] | Rothwell, P.M., Eliasziw, M., Gutnikov, S., Warlow, C. and Barnett, H. (2004) Endarterectomy for Symptomatic Carotid Stenosis in Relation to Clinical Subgroups and Timing of Surgery. The Lancet, 363, 915-924. https://doi.org/10.1016/s0140-6736(04)15785-1 |
| [31] | Azhar, B., Wafi, A., Budge, J. and Loftus, I. (2020) Timing of Carotid Endarterectomy and Clinical Outcomes. Annals of Translational Medicine, 8, Article No. 1267. https://doi.org/10.21037/atm-20-1130 |
| [32] | Chisci, E., Lazzeri, E., Masciello, F., Troisi, N., Turini, F., Sapio, P.L., et al. (2022) Timing to Carotid Endarterectomy Affects Early and Long Term Outcomes of Symptomatic Carotid Stenosis. Annals of Vascular Surgery, 82, 314-324. https://doi.org/10.1016/j.avsg.2021.10.071 |
| [33] | Joglar, J.A., Chung, M.K., Armbruster, A.L., Benjamin, E.J., Chyou, J.Y., et al. (2024) 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation. Circulation, 149, e1-e156. |
| [34] | Martini, L., Lisi, M., Pompei, G., Arioti, M., Bendandi, F., Henein, M.Y., et al. (2025) Antiplatelet Therapy in Atrial Fibrillation Patients on Direct Oral Anticoagulants Undergoing Percutaneous Coronary Intervention: Which and How. Journal of Clinical Medicine, 14, Article No. 6331. https://doi.org/10.3390/jcm14176331 |
| [35] | Pennlert, J., Eriksson, M., Carlberg, B. and Wiklund, P. (2014) Long-Term Risk and Predictors of Recurrent Stroke beyond the Acute Phase. Stroke, 45, 1839-1841. https://doi.org/10.1161/strokeaha.114.005060 |
