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Observational Study
. 2025 Sep;10(3):775-783.
doi: 10.1177/23969873241307520. Epub 2025 Jan 9.

Statin therapy in ischemic stroke patients with atrial fibrillation: Efficacy and safety outcomes

Michele Marvardi  1 , Maurizio Paciaroni  1   2 , Valeria Caso  1 ; RAF and RAF NOAC-Investigators
Collaborators, Affiliations
Observational Study

Statin therapy in ischemic stroke patients with atrial fibrillation: Efficacy and safety outcomes

Michele Marvardi et al. Eur Stroke J. 2025 Sep.

Abstract

Introduction: The efficacy and safety of statins for secondary prevention in patients who have experienced a cardioembolic stroke are not well-defined. However, previous observational data reported hyperlipidemia as a risk factor for both ischemic and bleeding complications in patients with AF and previous stroke. Based on these premises, we conducted a sub-analysis of the RAF and RAF-NOAC studies to evaluate the efficacy and safety of statins in secondary prevention in patients with acute ischemic stroke and AF.

Materials and methods: We combined patient data from the RAF and RAF-NOAC studies, prospective observational studies conducted across Stroke Units in Europe, the United States, and Asia from January 2012 to June 2016. We included consecutive patients with AF who suffered an acute ischemic stroke with a follow-up of 90 days. Our outcomes were the combined endpoint, including stroke, transient ischemic attack, systemic embolism, symptomatic intracerebral hemorrhage, and major extracranial bleeding. Furthermore, both ischemic and hemorrhagic outcomes were evaluated separately.

Results: A total of 1742 patients were included (46% male), and 898 (52%) received statins after the index event, of whom 436 (48.6%) were already taking statins before the index event, 462 (51.4%) started treatment after. At multivariable analysis, statin use was statistically associated with age (OR 0.92, 95% CI 0.97-0.99, p = 0.001), male sex (OR 1.35, 95% CI 1.07-1.70, p = 0.013), anticoagulation (OR 2.53, 95% CI 1.90-3.36, p < 0.0001), hyperlipidemia (OR 5.52, 95% CI 4.28-7.12, p < 0.0001), paroxysmal AF (OR 1.40, 95% CI 1.12-1.75, p = 0.003), leukoaraiosis (OR 1.39, 95% CI 1.11-1.75, p = 0.004) and heart failure (OR 0.72, 95% CI 0.53-0.98, p = 0.034). Statin use was not associated with the combined outcome event (OR 0.84, 95% CI 0.58-1.23, p = 0.3) and ischemic outcome event (OR 1.17, 95% CI 0.73-1.88, p = 0.5) while was associated with a lower risk of hemorrhagic outcome event (OR 0.51, 95% CI 0.28-0.91, p = 0.02).

Discussion: Statins protect cerebral arterial vessels (particularly small vessels) from subacute damage due to hypertension, diabetes, and other harmful agents (such as reactive oxygen species, proinflammatory cytokines, etc.) due to their systemic anti-inflammatory and endothelium-protective effects.

Conclusions: Our data show that statins seem to protect against global bleeding events in cardioembolic stroke patients; this may be due to the pleiotropic effect of statins. More data are warranted to confirm these findings.

Keywords: atrial fibrillation; intracerebral hemorrhage; pleiotropy; prevention; stroke; tatin.

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Conflict of interest statement

Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M. Paciaroni received honoraria as a member of the speaker bureau of Sanofi-Aventis, Bristol Meyer Squibb, Daiiki Sankyo and Pfizer. C. Becattini received honoraria as a member of the speaker bureau of Bristol Meyer Squibb and Bayer. G. Agnelli received honoraria as a member of the speaker bureau of Boehringer Ingelheim and Bayer. P. Michel received Research Grant by Swiss National Science Foundation and Swiss Heart Foundation; he received speaker fees by Bayer, Boehringer Ingelheim, Covidien, St. Jude Medical; he received honoraria as advisory relationship by Pierre-Fabre, Bayer, Bristol Meyer Squibb, Amgen, and Boehringer Ingelheim. J. Putaala received honoraria for lectures related to atrial fibrillation and anticoagulants for Orion Pharma, Bristol Meyer Squibb, Pfizer, Bayer, and Boehringer Ingelheim. T. Tatlisumak received honoraria as consultant or advisory relationship by Lundbeck and Boehringer Ingelheim. G. Tsivgoulis has received funding for travel or speaker’s honoraria from Bayer, Pfizer, and Boehringer Ingelheim. He has served on scientific advisory boards for Bayer, Boehringer Ingelheim, and Daiichi Sankyo. D. Toni has received personal fees from Abbott, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, and Pfizer. V. Caso received honoraria as a member of the speaker bureau of Boehringer Ingelheim, Bayer, and Daiichi Sankyo (all fees were paid to Associazione Ricerca Stroke, Umbria). She received honoraria as consultant or advisory board member of Boehringer Ingelheim, Bayer, Daiichi Sankyo, and Pfizer. G. Ntaios reports speaker fees/advisory board/ research support from Bayer, Pfizer, Boehringer Ingelheim and Elpen. All fees are paid to his institution. S. Sacco has received personal fees as speaker or advisor from Abbott, Allergan, Astra Zeneca, Eli Lilly, Lundbeck, Novartis, NovoNordisk, Teva and research grants from Allergan, Novartis, and Uriach. J. Dawson as received honoraria as speaker from Medtronic, Daicchi Sankyo, BMS, Pfizer. Advisory board Astra Zeneca. L. Pantoni recieved consultation fees from Amicus and PIAM. M. Del Sette has received honoraria for speaking from Bayer and Boehringer Ingelheim. M. Zedde received speaking and consulting fees from Daiichi Sankyo, Amicus Therapeutics, Sanofi Genzyme, Abbott, and Takeda. M. Cappellari has received consulting fees from Boehringer Ingelheim, Pfizer – BMS, and Daiichi Sankyo. Y. Flomin has received personal fees from Boehringer Ingelheim, Bayer and Takeda, grants, personal fees and nonfinancial support from Pfizer, personal fees and nonfinancial support from Sanofi Genzyme. R. Ornello has received nonfinancial support from Novartis, Allergan, and Teva. S. Giannopoulos has received funding for travel from Bayer and speaker’s honoraria from Pfizer. The other authors report no conflicts.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Cox regression: statins as an independent predictive factor for hemorrhagic outcome.
Figure 2.
Figure 2.
Cox regression: statins as an independent predictor for symptomatic intracranial hemorrhage.
See this image and copyright information in PMC

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