The second AREPA: AREPA2

Abstract

Cerebrovascular disease in adults is the second leading cause of mortality in Colombia and one of the most common causes of disability. Approximately three-quarters of all strokes are ischemic, and atrial fibrillation (AF) can be the underlying mechanism in up to 30.0% of cases. Anticoagulation is the antithrombotic therapy of choice for patients with ischemic stroke and AF; however, the residual risk of ischemic stroke in patients with AF, despite anticoagulation, may be as high as 7.2% per year.

In 2021, in a letter to the editor, we introduced the term AREPA: “Anticoagulated-patient Recurrent Event: stroke” (in Spanish, ACV recurrente en paciente anticoagulado). In that same correspondence, we proposed a diagnostic and therapeutic framework for AREPA.

Approximately five years have passed, and during this period new evidence has accumulated that supports several recommendations for the management of AREPA:

AREPA may result from an alternative pathophysiologic mechanism, poor adherence to anticoagulation, inappropriate anticoagulant dosing, uncontrolled vascular risk factors, or thromboembolic events due to yet-unidentified causes.

Large-artery atherosclerosis and small-vessel disease may account for up to 50.0% of ischemic strokes.

Long-term adherence to anticoagulation in patients with AF may be as low as 35.0%.

Up to 50.0% of elderly patients may receive inappropriate anticoagulant dosing.

Patients with AF frequently have comorbidities that themselves constitute vascular risk factors.

Finally, a variable but significant proportion of patients treated for suspected stroke ultimately receive a diagnosis of a stroke mimic.

Coagulation studies and measurement of anticoagulant levels may help identify the cause of AREPA; however, some of these laboratory assays are not available in Colombia. In the setting of AREPA, some clinicians may be inclined to modify the anticoagulation regimen. Observational data indicate that switching anticoagulants offers minimal reduction in the risk of recurrent ischemic stroke, and adding antiplatelet therapy may increase bleeding risk. Conversely, left atrial appendage occlusion may represent a therapeutic option for AREPA.

Given this landscape, we introduce the expanded term AREPA2 as a mnemonic to guide the evaluation of recurrent stroke in an anticoagulated patient (Table 1). Each letter represents a key component of the assessment:

A: Ascertain that the event is truly an ischemic stroke.
R: Review adherence, drug interactions, and anticoagulant dosing.
E: Evaluate the stroke’s underlying pathophysiologic mechanism.
P: Promote optimal control of vascular risk factors and comorbidities.
A2: Ask for input from other specialties.