Recurrent Ischemic Stroke and Bleeding in AF Patients Experiencing Stroke on NOACs

Quick Takes

  • A 13.4% annual risk of recurrent thromboembolic and bleeding events was observed in patients with atrial fibrillation who had experienced a cerebrovascular event on nonvitamin K antagonist oral anticoagulant treatment.
  • Predictive factors for ischemic events included higher CHA2DS2-VASc score after the ischemic event and hypertension, whereas predictive factors for hemorrhagic events included age, history of major bleeding, and addition of an antiplatelet.

Study Questions:

How common are ischemic and bleeding events after an acute ischemic stroke in patients with atrial fibrillation (AF) while on treatment with nonvitamin K antagonist oral anticoagulants (NOACs)?


RENO-EXTEND was a prospective multicenter observational cohort study including 1,240 patients with AF experiencing an acute cerebrovascular ischemic event at one of 43 stroke units across the United States and Europe between January 2018–December 2020 who were taking a NOAC at the time of the event. Patients were excluded if anticoagulant therapy had been suspended for at least 24 hours prior to the ischemic event or adherence could not be guaranteed. Cause of stroke was characterized using atherosclerosis, small vessel disease, cardiac pathology, other causes, and dissection (ASCOD) classification. The primary outcome was the composite of ischemic stroke, systemic embolism, intracranial bleeding, and major extracranial bleeding. Multivariable logistic regression was used to identify predictors of outcome events. The risk of primary outcome events in patients who did or did not have their anticoagulation regimen changed was also examined.


Cardioembolic strokes made up 74.2% of the index events. A total of 69.9% of patients were treated with low-dose NOAC before the index event, with 30.3% of those patients being treated with a nonlabel low dose. An annual rate of outcome events of 13.4% was observed during the mean follow-up time of 15 ± 10.9 months. These 207 outcome events observed in 15.5% of patients included 111 ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings.

Predictive factors for thromboembolic and bleeding events were history of major bleeding (odds ratio [OR], 4.1; 95% confidence interval [CI], 2.2-7.6; p = 0.0001), addition of an antiplatelet to NOAC (OR, 1.7; 95% CI, 1.1-2.9; p = 0.03), age (OR, 1.2; 95% CI, 1-1.4; p = 0.045 for each decade increase), male gender (OR, 1.5; 95% CI, 1-2.2; p = 0.04), and hypertension (OR, 2.2; 95% CI, 1.1-4.2; p = 0.02). Predictive factors for ischemic stroke and systemic embolism included CHA2DS2-VASc score after the index event and hypertension, whereas predictive factors for intracranial and major extracranial bleeding included age, history of major bleeding, and the addition of an antiplatelet. Patients who changed their NOAC treatment (n = 490) showed no difference in the rate of the primary outcome events compared to those who did not change (n = 527) their regimen (OR, 1.1; 95% CI, 0.8-1.4).


Patients with AF experiencing a stroke despite being on NOAC therapy are at high risk of recurrent thromboembolic and bleeding events.


This real-world prospective cohort study supports prior observational reports of elevated risk of thromboembolic and bleeding events in patients with AF who experienced a stroke while on NOAC therapy compared to that seen in clinical trials. Notably, this study observed that adding antiplatelet therapy to a NOAC was associated with an enhanced bleed risk without an observed reduction in ischemic events, and changing anticoagulant regimens was not associated with a difference in primary outcome events (though the study was not powered to detect differences in these two groups). This study highlights that better risk stratification is needed to improve secondary prevention therapy decisions and reduce this residual risk.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Hypertension

Keywords: Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Embolism, Hemorrhage, Hypertension, Intracranial Hemorrhage, Hypertensive, Ischemic Stroke, Patient Care Team, Platelet Aggregation Inhibitors, Primary Prevention, Secondary Prevention, Stroke, Thromboembolism, Vascular Diseases

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