Risk of recurrent stroke in patients with atrial fibrillation treated with oral anticoagulants alone or in combination with anti-platelet therapy
Authors:   RAF and RENO-EXTEND Investigators, Caliandro Pietro , Cancelloni Virginia , Marco Moci , Reale Giuseppe , Zauli Aurelia , Agnelli Giancarlo , Caso Valeria , Becattini Cecilia , Calabresi Paolo , Giulia Mosconi Maria , Giustozzi Michela , Tsivgoulis Georgios , Julian Seiffge David , Engelter Stefan T. , Lyrer Philippe , Polymeris Alexandros A. , Dittrich Tolga , Zietz Annaelle , Marco De Marchis Gian , Putaala Jukka , Strbian Daniel , Tomppo Liisa , Michel Patrik , Strambo Davide , Salerno Alexander , Remillard Suzette , Buehrer Manuela , Bavaud Odessa , Vanacker Peter , Zuurbier Susanna , Yperzeele Laetitia , Loos Caroline M.J. , Cappellari Manuel , Emiliani Andrea , Zedde Marialuisa , Abdul-Rahim Azmil , Dawson Jesse , Cronshaw Robert , Schirinzi Erika , Del Sette Massimo , Stretz Christoph , Kala Narendra , Reznik Michael , Schomer Ashley , Mac Grory Brian , Jayaraman Mahesh , McTaggart Ryan , Yaghi Shadi , Furie Karen L. , Masotti Luca , Grifoni Elisa , Toni Danilo , Risitano Angela , Falcou Anne , Petraglia Luca , Maria Lotti Enrico , Padroni Marina , Pavolucci Lucia , Lochner Piergiorgio , Silvestrelli Giorgio , Ciccone Alfonso , Alberti Andrea , Venti Michele , Leone De Magistris Ilaria , Kargiotis Odysseas , Rocco Alessandro , Diomedi Marina , Marcheselli Simona , Antonenko Kateryna , Rota Eugenia , Tassinari Tiziana , Saia Valentina , Palmerini Francesco , Aridon Paolo , Arnao Valentina , Monaco Serena , Cottone Salvatore , Baldi Antonio , D’Amore Cataldo , Ageno Walter , Pegoraro Samuela , Ntaios George , Sagris Dimitrios , Giannopoulos Sotirios , Kosmidou Maria , Ntais Evangelos , Romoli Michele , Pantoni Leonardo , Rosa Silvia , Bertora Pierluigi , Chiti Alberto , Canavero Isabella , Emanuele Saggese Carlo , Plocco Maurizio , Giorli Elisa , Palaiodimou Lina , Bakola Eleni , Bandini Fabio , Gasparro Antonio , Terruso Valeria , Mannino Marina , Pezzini Alessandro , Ornello Raffaele , Sacco Simona , Popovic Nemanja , Scoditti Umberto , Genovese Antonio , Denti Licia , Flomin Yuriy , Mancuso Michelangelo , Ferrari Elena , Chiara Caselli Maria , Ulivi Leonardo , Giannini Nicola , Vadikolias Kostantinos , Liantinioti Chrysoula , Chondrogianni Maria , Halvatsiotis Panagiotis , Carletti Monica , Karagkiozi Efstathia , Athanasakis George , Makaritsis Kostantinos , Lanari Alessia , Tatlisumak Turgut , Acciarresi Monica , Vannucchi Vieri , Lorenzini Gianni , Tassi Rossana , Guideri Francesca , Acampa Maurizio , Martini Giuseppe , Sohn Sung-Il , Mumoli Nicola , Tadi Prasanna , Letteri Federica , Maccarrone Miriam , Poli Loris , Magoni Mauro , Galati Franco , Tiseo Cindy , Gourbali Vanessa , Orlandi Giovanni , Giuntini Martina , Corea Francesco , Bellesini Marta , Girardi Laura , Maimone Baronello Mario , Karapanayiotides Theodore , Rueckert Christina , Csiba Laszló , Szabó Lilla , Rigatelli Alberto , Imberti Davide , Zabzuni Dorjan , Pieroni Alessio , Barlinn Kristian , Pallesen Lars-Peder , Barlinn Jessica , Doronin Boris , Volodina Vera , Deleu Dirk , Bonetti Bruno , Porta Cesare , Gentile Luana , Eskandari Ashraf , Paciaroni Maurizio 
Published: July 2023

Introduction: Ischaemic stroke patients with atrial fibrillation (AF) are at high risk of stroke recurrence despite oral anticoagulation therapy. Patients with cardiovascular comorbidities may take both antiplatelet and oral anticoagulation therapy (OAC/AP). Our study aims to evaluate the safety and efficacy of OAC/AP therapy as secondary prevention in people with AF and ischaemic stroke. Patients and methods: We performed a post-hoc analysis of pooled individual data from multicenter prospective cohort studies and compared outcomes in the OAC/AP cohort and patients on DOAC/VKA anticoagulation alone (OAC cohort). Primary outcome was a composite of ischaemic stroke, systemic embolism, intracranial bleeding, and major extracranial bleeding, while secondary outcomes were ischaemic and haemorrhagic events considered separately. A multivariable logistic regression analysis was performed to identify independent predictors for outcome events. To compare the risk of outcome events between the two cohorts, the relation between the survival function and the set of explanatory variables were calculated by Cox proportional hazard models and the results were reported as adjusted hazard ratios (HR). Finally another analysis was performed to compare the overall risk of outcome events in both OAC/AP and OAC cohorts after propensity score matching (PSM). Results: During a mean follow-up time of 7.5 ± 9.1 months (median follow-up time 3.5 months, interquartile range ±3), 2284 stroke patients were on oral anticoagulants and 215 were on combined therapy. The multivariable model demonstrated that the composite outcome is associated with age (OR: 1.03, 95% CI: 1.01–1.04 for each year increase) and concomitant antiplatelet therapy (OR: 2.2, 95% CI: 1.48–3.27), the ischaemic outcome with congestive heart failure (OR: 1.55, 95% CI: 1.02–2.36) and concomitant antiplatelet therapy (OR: 1.93, 95% CI: 1.19–3.13) and the haemorrhagic outcome with age (OR: 1.03, 95% CI: 1.01–1.06 for each year increase), alcoholism (OR: 2.15, 95% CI: 1.06–4.39) and concomitant antiplatelet therapy (OR: 2.22, 95% CI: 1.23–4.02). Cox regression demonstrated a higher rate of the composite outcome (hazard ratio of 1.93 [95% CI, 1.35–2.76]), ischaemic events (HR: 2.05 [95% CI: 1.45–2.87]) and bleeding outcomes (HR: 1.90 [95% CI, 1.06–3.40]) in OAC/AP cohort. After PSM analysis, the composite outcome remained more frequent in people treated with OAC + AP (RR: 1.70 [95% CI, 1.05–2.74]). Discussion: Secondary prevention with combination of oral anticoagulant and antiplatelet therapy after ischaemic stroke was associated with worse outcomes in our cohort. Conclusion: Further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischaemic stroke in patients with atrial fibrillation.