Antithrombotic agents and effect on outcomes in ischemic stroke with atrial fibrillation and large artery atherosclerosis: a real-world study

What is your competent? doctor's EXACT PROTOCOL to prevent the next stroke from atrial fibrillation? Oh, doesn't have one? So, you DON'T have a functioning stroke doctor, do you?

 Antithrombotic agents and effect on outcomes in ischemic stroke with atrial fibrillation and large artery atherosclerosis: a real-world study

Jilu Chen¹Jianhua Cheng²Qiang Ye²Yuntao Liu²Yanlei Zhang²Zheng Zhang^2*

• ¹The First School of Clinical Medicine, Wenzhou Medical University, Wenzhou, China
• ²Department of Neurology, Wenzhou Medical University First Affiliated Hospital, Wenzhou, China

Introduction: The optimal antithrombotic regimen for preventing recurrent stroke in patients who experience ischemic stroke due to atrial fibrillation (AF) and atherosclerotic large-vessel stenosis remains unclear(Well then, contact stroke leadership and get research done and a PROTOCOL CREATED! Doing nothing is grounds for firing!) The present study aimed to evaluate the effect of multiple antithrombotic therapies on outcomes after ischemic stroke due to ≥ 2 causes.

Methods: Data from 632 patients at a single hospital, who experienced ischemic stroke due to AF and large-artery atherosclerosis. Patients were categorized into 3 groups according to antithrombotic therapy at discharge: antiplatelets (APT), oral anticoagulant(s) (OAC), and APT plus OAC. Study outcomes included recurrent ischemic stroke and composite outcomes for cardiovascular events, death and major bleeding. Propensity scores (PS) were used to balance APT and OAC groups.

Results: Among 632 patients, 158 (25.0%) were treated with APT, 447 (70.7%) with OAC, and 27 (4.3%) with both APT and OAC. After applying PS, only OAC had a significant beneficial effect on the composite outcome (hazard ratio [HR] 0.41 [95% confidence interval (CI) 0.19–0.83]; p = 0.01) and death (HR 0.12 [95% CI 0.01–1.0]; p = 0.05). However, there was no significant difference in one-year recurrent stroke events or risk for bleeding between the APT and OAC groups. Further analysis of the relationship between the dose of OAC and outcome revealed no significant difference between reduced and standard doses of OAC.

Conclusion: This study demonstrated that OAC monotherapy was associated with a lower risk for composite outcomes and death after ischemic stroke due to AF and atherosclerotic stenosis, although the OAC dose had no effect on clinical outcomes.

1 Introduction

Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, which is often fatal or disabling. Long-term oral anticoagulant(s) (OAC) therapy is usually recommended to reduce the recurrence of embolic events in patients diagnosed AF (1–5). However, the development of acute ischemic stroke (AIS) in patients with AF undergoing OAC treatment has become an increasingly important issue in clinical practice. One of the reasons for this is AF-unrelated stroke, since it has been estimated that one-third of the patients with ischemic stroke and AF may also have concomitant large-artery atherosclerosis (LAA) or small-vessel disease (SVD) (6–9). Emerging evidence suggests that AF and atherosclerosis exhibit a bidirectional pathophysiological interplay beyond shared traditional risk factors. Mechanistically, atherosclerotic lesions induce atrial electrical remodeling, thereby facilitating AF initiation and perpetuation. Conversely, AF exacerbates atherosclerosis via two key pathways: endothelial dysfunction and systemic inflammation. This positive feedback mechanism creates a vicious cycle, wherein AF and atherosclerosis mutually reinforce disease progression (10). Notably, the coexistence of atherosclerosis and AF confers a synergistic elevation in thromboembolic risk (11). Due to the lack of randomized clinical trials, there are no guidelines for antithrombotic treatment in patients with AIS and simultaneous AF and LAA. There are broadly 3 alternative antithrombotic regimens: monotherapy with OAC, monotherapy with an antiplatelet (APT) agent and combined OAC and APT agent. The present real-world study aimed to investigate and compare the therapeutic efficacy of AIS, AF, and LAA in patients, who experienced recurrent ischemic stroke over a period of 1 year.

2 Materials and methods

2.1 Study population

This retrospective study enrolled consecutive patients diagnosed with AIS, nonvalvular atrial fibrillation (NVAF) and LAA between January 2017 and December 2022 at The First affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Data from patients diagnosed with AIS (within 7 days of symptom onset) between January 2017 and December 2022 due to ≥ 2 potential causes (NVAF and LAA > 50% in the relevant intracranial or extracranial vessels) according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification (12), were included. After excluding non-atherosclerotic etiologies, intracranial large artery atherosclerosis (LAA) with ≥ 50% luminal stenosis was confirmed by digital subtraction angiography (DSA), computed tomography angiography (CTA), or magnetic resonance angiography (MRA), consistent with the diagnostic criteria for atherosclerotic stenosis in relevant intracranial arteries. Patients who met the following criteria were excluded: non-AF/LAA causes, incomplete imaging/ECG data, poor follow-up feasibility, treatment conflicts (anticoagulation intolerance, prior revascularization), vascular malformations, pregnancy, or ambiguous findings (stenosis <50%, unverified AF episodes). In addition, discharge medications prescribed after stroke, documented in hospital records, were also analyzed.

The data involved in this study are anonymous retrospective data, which are exempted from ethical review after being reviewed by the Ethics Review Committee of the First Affiliated Hospital of Wenzhou Medical University. The research strictly follows the principles of Helsinki Declaration to protect the privacy of subjects. Requirements for informed consent were waived by the Institutional Review Board of the First Affiliated Hospital of Wenzhou Medical University due to the retrospective design of the study and the use of anonymized data.

2.2 Baseline characteristics and clinical information

Baseline characteristics analyzed included the following: age, sex, vascular risk factors (hypertension [HT], diabetes mellitus [DM], dyslipidemia [DL], coronary artery disease [CAD], AF, previous stroke/transient ischemic attack [TIA], and smoking). Clinical information for acute stroke management included the following: initial National Institutes of Health Stroke Scale (NIHSS) score (13); stroke mechanisms; thrombolytic therapy including intravenous (IV) thrombolysis, and endovascular recanalization therapy (EVT); hemorrhage transformation after stroke; length of hospitalization; CHA₂DS₂-Vasc (2 points for history of stroke or age > 75 years, and 1 point each for congestive heart failure, HT, DM, vascular disease, age 65 to 74 years, and female sex) and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio [INR], Elderly, Drugs/Alcohol Concomitantly) score after the index ischemic stroke were calculated (14, 15). Information regarding discharge medications, including APT agents, OACs (warfarin and direct OAC) or both, was also collected. Patients were categorized into 3 groups according to the prescribed antithrombotic therapy at discharge: APT agents only; OACs only; and APT agents plus OACs. The APT group was selected as the reference group because it was expected to be the least effective treatment option among the 3 regimens. The doses of non-vitamin K antagonist OACs (NOACs) were recorded because low dose NOACs may be associated with high crude adverse event rates, particularly in patients who should have received standard NOAC dosing. Low dose dabigatran was considered to be labeled for elderly patients (age ≥ 80 years), patients with moderate renal impairment (creatinine clearance, 30–49 mL/min), and those with concomitant use of interacting drugs (eg, verapamil). Low dose rivaroxaban was considered to be labeled for patients with moderate or severe renal impairment (creatinine clearance, 15–49 mL/min) (16).

2.3 Outcomes

The primary outcomes were composite outcomes, including recurrent ischemic stroke, intracerebral hemorrhage (ICH), myocardial infarction (MI), and gastrointestinal bleeding (GI) and all-cause death 1 year after the index stroke. Secondary outcomes were major bleeding including ICH and GI. Patient status was assessed by telephone interview(s) or clinic visits, when possible.

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