Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study

Maurizio Paciaroni^#^{1

2}, Valeria Caso^#², Giancarlo Agnelli², Maria Giulia Mosconi², Michela Giustozzi², David Julian Seiffge^{3

4}, Stefan T Engelter³, Philippe Lyrer³, Alexandros A Polymeris³, Lilian Kriemler³, Annaelle Zietz³, Jukka Putaala⁵, Daniel Strbian⁵, Liisa Tomppo⁵, Patrik Michel⁶, Davide Strambo⁶, Alexander Salerno⁶, Suzette Remillard⁶, Manuela Buehrer⁶, Odessa Bavaud⁶, Peter Vanacker^{7

8

9}, Susanna Zuurbier^{7

8}, Laetitia Yperzeele^{7

8}, Caroline M J Loos^{7

8}, Manuel Cappellari¹⁰, Andrea Emiliani¹⁰, Marialuisa Zedde¹¹, Azmil Abdul-Rahim¹², Jesse Dawson¹², Robert Cronshaw¹², Erika Schirinzi¹³, Massimo Del Sette¹³, Christoph Stretz¹⁴, Narendra Kala¹⁴, Michael Reznik¹⁴, Ashley Schomer¹⁴, Brian Mac Grory^{14

15}, Mahesh Jayaraman¹⁴, Ryan McTaggart¹⁴, Shadi Yaghi¹⁴, Karen L Furie¹⁴, Luca Masotti¹⁶, Elisa Grifoni¹⁶, Danilo Toni¹⁷, Angela Risitano¹⁷, Anne Falcou¹⁸, Luca Petraglia¹⁷, Enrico Maria Lotti¹⁹, Marina Padroni¹⁹, Lucia Pavolucci¹⁹, Piergiorgio Lochner²⁰, Giorgio Silvestrelli²¹, Alfonso Ciccone²¹, Andrea Alberti², Michele Venti², Laura Traballi², Chiara Urbini², Odysseas Kargiotis²², Alessandro Rocco²³, Marina Diomedi²³, Simona Marcheselli²⁴, Pietro Caliandro²⁵, Aurelia Zauli²⁶, Giuseppe Reale²⁶, Kateryna Antonenko²⁷, Eugenia Rota²⁸, Tiziana Tassinari²⁹, Valentina Saia²⁹, Francesco Palmerini³⁰, Paolo Aridon³¹, Valentina Arnao³², Serena Monaco³², Salvatore Cottone³², Antonio Baldi³³, Cataldo D'Amore³³, Walter Ageno³⁴, Samuela Pegoraro³⁴, George Ntaios³⁵, Dimitrios Sagris³⁵, Sotirios Giannopoulos³⁶, Maria Kosmidou³⁶, Evangelos Ntais³⁶, Michele Romoli³⁷, Leonardo Pantoni³⁸, Silvia Rosa³⁹, Pierluigi Bertora³⁸, Alberto Chiti⁴⁰, Isabella Canavero^{41

42}, Carlo Emanuele Saggese⁴³, Maurizio Plocco⁴³, Elisa Giorli⁴⁴, Lina Palaiodimou⁴⁵, Eleni Bakola⁴⁵, Georgios Tsivgoulis⁴⁵, Fabio Bandini⁴⁶, Antonio Gasparro⁴⁷, Valeria Terruso⁴⁷, Marina Mannino⁴⁷, Alessandro Pezzini⁴⁸, Raffaele Ornello⁴⁹, Simona Sacco⁴⁹, Nemanja Popovic⁵⁰, Umberto Scoditti⁵¹, Antonio Genovese⁵¹, Licia Denti⁵², Yuriy Flomin⁵³, Michelangelo Mancuso⁵⁴, Elena Ferrari⁵⁴, Maria Chiara Caselli⁵⁴, Leonardo Ulivi⁵⁴, Nicola Giannini⁵⁴, Gian Marco De Marchis³

Affiliations

¹ Neurology, Stroke Unit, IRCCS MultiMedica, Milano, Italy (M. Paciaroni).
² Stroke Unit, Division of Cardiovascular Medicine, University of Perugia, Italy (M. Paciaroni, V.C., G.A., M.G.M., M.G., A.A., M.V., L.T., C.U.).
³ Department of Neurology, Stroke Center, University Hospital Basel, University of Basel, Switzerland (D.J.S., S.T.E., P. Lyrer, A.A.P., L.K., A. Zietz, G.M.D.M.).
⁴ Department of Neurology, Inselspital University Hospital, University of Bern, Switzerland (D.J.S.).
⁵ Department of Neurology, Helsinki University Hospital and Neurosciences University of Helsinki, Finland (J.P., D. Strbian, L.T.).
⁶ Stroke Center, Neurology Service, Department of Clinical Neuroscience, Lausanne University Hospital, University of Lausanne, Switzerland (P.M., D. Strambo, A. Salerno, S.R., M.B., O.B.).
⁷ NeuroVascular Center, Stroke Unit Antwerp, Department of Neurology, Antwerp University Hospital, Belgium (P.V., S.Z., L.Y., C.M.J.L.).
⁸ Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium (P.V., S.Z., L.Y., C.M.J.L.).
⁹ Groeninge Hospital, Kortrijk, Belgium (P.V.).
¹⁰ Stroke Unit, DAI di Neuroscienze, Azienda Ospedaliera Universitaria Integrata, Verona, Italy (M.C., A.E.).
¹¹ Neurology Unit, AUSL - IRCCS of Reggio Emilia, Italy (M.Z.).
¹² Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.A.-R., J.D., R.C.).
¹³ Struttura Complessa di Neurologia, Ente Ospedaliero Ospedali Galliera, Genoa, Italy (E.S., M.D.S.).
¹⁴ Department of Neurology, The Warren Alpert Medical School of Brown University, Providence, RI (C.S., N.K., M. Reznik, A. Schomer, B.M.G., M.J., R.M., S.Y., K.L.F.).
¹⁵ Department of Neurology, Duke University School of Medicine, Durham, NC (B.M.G.).
¹⁶ Internal Medicine, San Giuseppe Hospital, Empoli, Italy (L.M., E. Grifoni).
¹⁷ Department of Human Neurosciences, Sapienza University of Rome, Italy (D.T., A. Risitano, L. Petraglia).
¹⁸ Stroke Unit, Emergency Department, Policlinico Umberto I, Rome, Italy (A.F.).
¹⁹ U.O. Neurologia Presidio Ospedaliero di Ravenna Azienda USL della Romagna, Italy (E.M.L., M. Padroni, L. Pavolucci).
²⁰ Department of Neurology, Saarland University, Medical Center, Homburg, Germany (P. Lochner).
²¹ S.C. di Neurologia e S.S. di Stroke Unit, ASST di Mantova, Italy (G.S., A. Ciccone).
²² Stroke Unit, Metropolitan Hospital, Piraeus, Greece (O.K.).
²³ Stroke Unit, Department of Systems Medicine, University of Tor Vergata, Rome, Italy (A. Rocco, M.D.).
²⁴ Humanitas Clinical and Research Center - IRCCS, Rozzano, Milano, Italy (S. Marcheselli).
²⁵ Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (P.C.).
²⁶ Department of Geriatrics, Neurosciences and Orthopedics, Università Cattolica del Sacro Cuore, Rome, Italy (A. Zauli, G.R.).
²⁷ Department of Neurology, Bogomolets National Medical University, Kyiv, Ukraine (K.A.).
²⁸ S.C. Neurologia-Stroke Unit, Novi Ligure/Tortona, ASL Alessandria, Italy (E.R.).
²⁹ Department of Neurology, Stroke Unit, Santa Corona Hospital, Pietra Ligure (Savona), Italy (T.T., V.S.).
³⁰ Istituto Ospedaliero Fondazione Poliambulanza, Brescia, Italy (F.P.).
³¹ Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, Italy (P.A.).
³² Neurologia-Stroke Unit ARNAS Civico, Palermo, Italy (V.A., S. Monaco, S.C.).
³³ Stroke Unit, Ospedale di Portogruaro, Venice, Italy (A.B., C.D.).
³⁴ Department of Medicine, University of Insubria, Ospedale di Circolo, Varese, Italy (W.A., S.P.).
³⁵ Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece (G.N., D.S.).
³⁶ Department of Neurology, University of Ioannina School of Medicine, Greece (S.G., M.K., E.N.).
³⁷ Neurology and Stroke Unit, Department of Neuroscience, Bufalini Hospital, Cesena, Italy (M. Romoli).
³⁸ L. Sacco' Department of Biomedical and Clinical Sciences, University of Milan, Italy (L. Pantoni, P.B.).
³⁹ Neurology Unit, ASST Fatebenefratelli - Sacco, Milan, Italy (S.R.).
⁴⁰ Neurologia, Ospedale Apuano, Massa Carrara, Italy (A. Chiti).
⁴¹ Emergency Neurology, IRCCS Casimiro Mondino Foundation, Pavia, Italy (I.C.).
⁴² Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta," Milano, Italy (I.C.).
⁴³ Unità di Terapia Neurovascolare. Ospedale "Fabrizio Spaziani," Frosinone, Italy (C.E.S., M.P.).
⁴⁴ Stroke Unit, Department of Neurology, Sant'Andrea Hospital, La Spezia, Italy (E. Giorli).
⁴⁵ Second Department of Neurology, "Attikon" University Hospital, National and Kapodistrian University of Athens, School of Medicine, Greece (L. Palaiodimou, E.B., G.T.).
⁴⁶ Department of Neurology, Ospedale San Paolo, Savona, Italy (F.B.).
⁴⁷ Neurologia, Ospedali Riuniti, Palermo, Italy (A. Gasparro, V.T., M. Mannino).
⁴⁸ Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Italy (A.P.).
⁴⁹ Neuroscience Section, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Italy (R.O., S.S.).
⁵⁰ Clinic of Neurology, Clinical Center of Vòsvodina, University of Novi Sad, Serbia (N.P.).
⁵¹ Emergency Department (U.S., A. Genovese), Stroke Unit, University of Parma, Italy.
⁵² Dipartimento Geriatrico Riabilitativo (L.D.), Stroke Unit, University of Parma, Italy.
⁵³ Stroke and Neurorehabilitation Unit, MC Universal Clinic 'Oberig' Kyiv, Ukraine (Y.F.).
⁵⁴ Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Italy (M. Mancuso, E.F., M.C.C., L.U., N.G.).

^# Contributed equally.

PMID: 35543133
DOI: 10.1161/STROKEAHA.121.038239

Free article

Observational Study

Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study

Maurizio Paciaroni et al. Stroke. 2022 Aug.

Free article

. 2022 Aug;53(8):2620-2627.

doi: 10.1161/STROKEAHA.121.038239. Epub 2022 May 11.

Authors

Affiliations

¹ Neurology, Stroke Unit, IRCCS MultiMedica, Milano, Italy (M. Paciaroni).
² Stroke Unit, Division of Cardiovascular Medicine, University of Perugia, Italy (M. Paciaroni, V.C., G.A., M.G.M., M.G., A.A., M.V., L.T., C.U.).
³ Department of Neurology, Stroke Center, University Hospital Basel, University of Basel, Switzerland (D.J.S., S.T.E., P. Lyrer, A.A.P., L.K., A. Zietz, G.M.D.M.).
⁴ Department of Neurology, Inselspital University Hospital, University of Bern, Switzerland (D.J.S.).
⁵ Department of Neurology, Helsinki University Hospital and Neurosciences University of Helsinki, Finland (J.P., D. Strbian, L.T.).
⁶ Stroke Center, Neurology Service, Department of Clinical Neuroscience, Lausanne University Hospital, University of Lausanne, Switzerland (P.M., D. Strambo, A. Salerno, S.R., M.B., O.B.).
⁷ NeuroVascular Center, Stroke Unit Antwerp, Department of Neurology, Antwerp University Hospital, Belgium (P.V., S.Z., L.Y., C.M.J.L.).
⁸ Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium (P.V., S.Z., L.Y., C.M.J.L.).
⁹ Groeninge Hospital, Kortrijk, Belgium (P.V.).
¹⁰ Stroke Unit, DAI di Neuroscienze, Azienda Ospedaliera Universitaria Integrata, Verona, Italy (M.C., A.E.).
¹¹ Neurology Unit, AUSL - IRCCS of Reggio Emilia, Italy (M.Z.).
¹² Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.A.-R., J.D., R.C.).
¹³ Struttura Complessa di Neurologia, Ente Ospedaliero Ospedali Galliera, Genoa, Italy (E.S., M.D.S.).
¹⁴ Department of Neurology, The Warren Alpert Medical School of Brown University, Providence, RI (C.S., N.K., M. Reznik, A. Schomer, B.M.G., M.J., R.M., S.Y., K.L.F.).
¹⁵ Department of Neurology, Duke University School of Medicine, Durham, NC (B.M.G.).
¹⁶ Internal Medicine, San Giuseppe Hospital, Empoli, Italy (L.M., E. Grifoni).
¹⁷ Department of Human Neurosciences, Sapienza University of Rome, Italy (D.T., A. Risitano, L. Petraglia).
¹⁸ Stroke Unit, Emergency Department, Policlinico Umberto I, Rome, Italy (A.F.).
¹⁹ U.O. Neurologia Presidio Ospedaliero di Ravenna Azienda USL della Romagna, Italy (E.M.L., M. Padroni, L. Pavolucci).
²⁰ Department of Neurology, Saarland University, Medical Center, Homburg, Germany (P. Lochner).
²¹ S.C. di Neurologia e S.S. di Stroke Unit, ASST di Mantova, Italy (G.S., A. Ciccone).
²² Stroke Unit, Metropolitan Hospital, Piraeus, Greece (O.K.).
²³ Stroke Unit, Department of Systems Medicine, University of Tor Vergata, Rome, Italy (A. Rocco, M.D.).
²⁴ Humanitas Clinical and Research Center - IRCCS, Rozzano, Milano, Italy (S. Marcheselli).
²⁵ Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (P.C.).
²⁶ Department of Geriatrics, Neurosciences and Orthopedics, Università Cattolica del Sacro Cuore, Rome, Italy (A. Zauli, G.R.).
²⁷ Department of Neurology, Bogomolets National Medical University, Kyiv, Ukraine (K.A.).
²⁸ S.C. Neurologia-Stroke Unit, Novi Ligure/Tortona, ASL Alessandria, Italy (E.R.).
²⁹ Department of Neurology, Stroke Unit, Santa Corona Hospital, Pietra Ligure (Savona), Italy (T.T., V.S.).
³⁰ Istituto Ospedaliero Fondazione Poliambulanza, Brescia, Italy (F.P.).
³¹ Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, Italy (P.A.).
³² Neurologia-Stroke Unit ARNAS Civico, Palermo, Italy (V.A., S. Monaco, S.C.).
³³ Stroke Unit, Ospedale di Portogruaro, Venice, Italy (A.B., C.D.).
³⁴ Department of Medicine, University of Insubria, Ospedale di Circolo, Varese, Italy (W.A., S.P.).
³⁵ Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece (G.N., D.S.).
³⁶ Department of Neurology, University of Ioannina School of Medicine, Greece (S.G., M.K., E.N.).
³⁷ Neurology and Stroke Unit, Department of Neuroscience, Bufalini Hospital, Cesena, Italy (M. Romoli).
³⁸ L. Sacco' Department of Biomedical and Clinical Sciences, University of Milan, Italy (L. Pantoni, P.B.).
³⁹ Neurology Unit, ASST Fatebenefratelli - Sacco, Milan, Italy (S.R.).
⁴⁰ Neurologia, Ospedale Apuano, Massa Carrara, Italy (A. Chiti).
⁴¹ Emergency Neurology, IRCCS Casimiro Mondino Foundation, Pavia, Italy (I.C.).
⁴² Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta," Milano, Italy (I.C.).
⁴³ Unità di Terapia Neurovascolare. Ospedale "Fabrizio Spaziani," Frosinone, Italy (C.E.S., M.P.).
⁴⁴ Stroke Unit, Department of Neurology, Sant'Andrea Hospital, La Spezia, Italy (E. Giorli).
⁴⁵ Second Department of Neurology, "Attikon" University Hospital, National and Kapodistrian University of Athens, School of Medicine, Greece (L. Palaiodimou, E.B., G.T.).
⁴⁶ Department of Neurology, Ospedale San Paolo, Savona, Italy (F.B.).
⁴⁷ Neurologia, Ospedali Riuniti, Palermo, Italy (A. Gasparro, V.T., M. Mannino).
⁴⁸ Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Italy (A.P.).
⁴⁹ Neuroscience Section, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Italy (R.O., S.S.).
⁵⁰ Clinic of Neurology, Clinical Center of Vòsvodina, University of Novi Sad, Serbia (N.P.).
⁵¹ Emergency Department (U.S., A. Genovese), Stroke Unit, University of Parma, Italy.
⁵² Dipartimento Geriatrico Riabilitativo (L.D.), Stroke Unit, University of Parma, Italy.
⁵³ Stroke and Neurorehabilitation Unit, MC Universal Clinic 'Oberig' Kyiv, Ukraine (Y.F.).
⁵⁴ Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Italy (M. Mancuso, E.F., M.C.C., L.U., N.G.).

^# Contributed equally.

PMID: 35543133
DOI: 10.1161/STROKEAHA.121.038239

Abstract

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain.

Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment.

Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA₂DS₂-VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0-1.3] for each point increase; P=0.05) and hypertension (OR, 2.3 [95% CI, 1.0-5.1]; P=0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0-1.2] for each year increase; P=0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4-14.2]; P=0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4-5.5]; P=0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8-1.7]).

Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

Keywords: anticoagulants; atrial fibrillation; hypertension; ischemic stroke; recurrence.

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Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study

Affiliations

Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study

Authors

Affiliations

Abstract

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Medical