Haemorrhagic Transformation in Breakthrough Ischemic Stroke: Clinical Characteristics, Outcomes, and Anticoagulation Resumption Timing—Insights from the ASPERA-R Study
Lucio D'Anna, Matteo Foschi, Francesca Gabriele, Raffaele Ornello, Andrea Zini, Matteo Paolucci, Stefano Forlivesi, Mauro Gentile, Giacomo Urbinati, Angelo Cascio Rizzo, Maria Sessa, Ghil Schwarz, Rachele Tortorella, Gabriele Prandin, Ludovica Maria Miserocchi, Giorgia Balducci, Gaurav Desai, Leonardo Pantoni, Francesco Mele, Giuseppe Scopelliti, Ilaria Cova, Mariarosaria Valente, Giovanni Merlino, Domenico Maisano, Luca Antonelli, Maria Rosaria Bagnato, Giovanni Di Mauro, Francesca Bernocchi, Martina Gaia Di Donna, Barbara Casolla, Stephan Mbakop-Noukoua, Paolo Arnoffi, Sok-Sithikun Bun, Laura Gonzalez-Martín, Ricardo Rigual, Blanca Fuentes, Carlos Hervás, Paolo Candelaresi, Vincenzo Andreone, Antonio De Mase, Emanuele Spina, Diana Aguiar de Sousa, Mariana Almudi Souza, Alberto Fior, Miguel Serôdio, Pietro Caliandro, Aurelia Zauli, Giuseppe Reale, Ahmed Abdelalim, Sandra Mohamed Ahmed, Samah Ali Ismail, Liqun Zhang, Tara Latimer, Muhammad Elboghdany, Ahmed Elbassiouny, Tamer Roushdy, Hossam M Shokri, Federica Ferrari, Nicola Loizzo, Federico Mazzacane, Maria Guarino, Valentina Barone, Paola Forti, Giuseppe Rinaldi, Marco Rossi, Vincenzo Laterza, Giovanni Frisullo, Pier Andrea Rizzo, Aldobrando Broccolini, Marina Mannino, Valeria Terruso, Marcella Caggiula, Simona Scalise, Ana Catarina Gaspar Fonseca, Bernardo Antunes, Hrvoje Budinčević, Petra Crnac, Giovanna Viticchi, Mauro Silvestrini, Viktoria Musienko, Samir Abu-Rumeileh, Lorenzo Barba, Markus Otto, Piergiorgio Lochner, Benjamin Landau, Sandeep Buddha, Roumeisa Khalil, Maria Grazia Piscaglia, Marialuisa Zedde, Ahmed Nasreldein, Luisa Vinciguerra, Luís Rufo Costa, Ahmed Elsayed, Mona AlBanna, Laura Tudisco, Maria Giulia Mosconi, Federico De Santis, Simona SaccoBackground and Purpose.
The timing of anticoagulation resumption in patients who experience ischemic stroke despite ongoing anticoagulation and develop haemorrhagic transformation (HT) remains uncertain. We aimed to describe the characteristics and outcomes of patients with HT after a breakthrough ischemic stroke and to explore the association between anticoagulation resumption timing and the model-predicted balance of recurrent ischemic and bleeding risks in this high-risk population.
Methods.
We analysed data from patients with breakthrough ischemic stroke receiving anticoagulation therapy from the multicentre ASPERA-R registry. Analyses focused on patients with HT. HT was defined according to the Heidelberg Bleeding Classification based on brain imaging within 24 hours and categorized as haemorrhagic infarction (HI) or parenchymal hematoma (PH). Anticoagulation resumption and its timing were determined by treating clinicians and were not randomized. Landmark Cox regression models were used to evaluate recurrent ischemic events and moderate-to-severe bleeding after anticoagulation resumption. Restricted cubic spline models and exploratory net clinical benefit analyses integrating ischemic and bleeding risks were used to assess the relationship between anticoagulation resumption timing and model-predicted combined risk, overall and across clinically relevant subgroups.
Results.
Among 1,555 patients with breakthrough ischemic stroke, 269 (17.3%) developed HT, of whom 170 (63.2%) resumed anticoagulation and contributed to the restart-timing analyses. At 90 days, patients with HT had higher crude rates of recurrent ischemic events (27.1% vs 13.8%), moderate-to-severe bleeding (7.4% vs 2.8%), and mortality (34.2% vs 17.7%) compared with patients without HT. In landmark analyses, HT was not associated with recurrent ischemic events (HR 1.42, 95% CI 0.85–2.37) but remained strongly associated with moderate-to-severe bleeding (HR 3.39, 95% CI 1.61–7.13). Exploratory net clinical benefit analyses showed that the model-predicted combined risk reached its nadir at approximately 10 days after stroke in the overall HT population, with substantial uncertainty around this estimate.
Conclusions.
HT is a marker of poor prognosis in patients with breakthrough ischemic stroke, with an increased risk of bleeding after anticoagulation resumption. Among selected patients who resumed anticoagulation, exploratory modelling suggested that the combined predicted ischemic and bleeding risk reached its nadir at approximately 10 days after stroke. Given the non-randomized treatment timing and potential for treatment-selection bias, this estimate is hypothesis-generating and requires prospective validation.