Dabigatran Anticoagulation to Reduce Stroke Recurrence

I evaluated a patient after a recent hospitalization for ischemic stroke. Work up did not reveal any atrial fibrillation or intracardiac thrombus, only the presence of insignificant carotid stenosis (1%-19%). The patient is taking low-dose aspirin daily because patients who have had stroke or transient ischemic attack are at increased risk for recurrent stroke with up to 10% recurrence rate in the first year.

Should anticoagulation such as dabigatran be considered in lieu of aspirin to reduce recurrent stroke risk?

Strokes are broadly classified as ischemic or hemorrhagic, with ischemic stroke accounting for greater than 80%. Ischemic strokes can be due to large-artery atherosclerosis (embolus or thrombosis), small vessel occlusion (lacunar), cardioembolism, or an unknown cause (cryptogenic, generally thought to be embolic and of undetermined cause). Cryptogenic strokes are thought to account for 20% to 30% of ischemic strokes.

In secondary stroke prevention, patients are assessed and treated for modifiable risk factors such as tobacco use, hypertension, lipid profile, hypercoagulable states, physical activity, and the presence of carotid stenosis and atrial fibrillation. Antiplatelet therapy reduces the risk of ischemic stroke recurrence. Can anticoagulants do the same in patients with embolic stroke of undetermined origin?

To find out, investigators randomized patients with embolic stroke of undetermined source to receive oral dabigatran (150 mg or 110 mg twice daily) or aspirin (100 mg once daily). The results showed that dabigatran did not reduce the risk of recurrent stroke and increased the risk of clinically relevant nonmajor bleeding (but not major bleeding) in patients with recent history of embolic stroke of undetermined origin.

Regarding the patient described above without atrial fibrillation or intracardiac thrombus, this study indicates that he should not receive dabigatran in lieu of aspirin because it provides no clinical benefit over aspirin and increases the risk of bleeding.

The following NEJM Journal Watch summary explains the study in further detail.

Anthony S. Kim, MD reviewing Diener HC et al. N Engl J Med 2019 May 16

Oral anticoagulants have an established role in preventing cardioembolic stroke in patients with known nonvalvular atrial fibrillation. But even if the infarct pattern suggests an embolic mechanism, current guidelines recommend antiplatelet therapy over presumptive anticoagulation unless a specific embolic source is identified. Availability of newer oral anticoagulants has renewed interest in evaluating the suitability of presumptive anticoagulation.

In the industry-sponsored RE-SPECT ESUS trial, 5390 ESUS patients were randomly assigned to dabigatran or aspirin. ESUS was defined as a nonlacunar stroke without significant extracranial or intracranial atherosclerosis with less than 6 minutes of atrial fibrillation demonstrated during at least 20 hours of monitoring.

Results of the primary efficacy analysis were neutral: Annualized rates of first recurrent stroke were 4.1% with dabigatran (177 events) and 4.8% with aspirin (207 events; P=0.10); nearly all events were ischemic stroke. The annualized rate of major bleeding was similar in the two groups: 1.7% with dabigatran (77 events) and 1.4% with aspirin (64 events); more clinically relevant nonmajor bleeding episodes occurred with dabigatran (70 versus 41).

Comment: This is the second neutral trial of newer anticoagulants for ESUS. The NAVIGATE ESUS trial evaluating rivaroxaban versus aspirin was terminated early for futility and for excess bleeding with rivaroxaban (NEJM JW Neurol Jul 2018 and N Engl J Med 2018; 378:2191) The authors of RE-SPECT ESUS do not report the same risk for major bleeding with dabigatran as was seen with rivaroxaban in NAVIGATE ESUS. Post hoc subgroup analyses suggest that closer evaluation of efficacy in the second year of follow-up and for preventing recurrent stroke may be fruitful. A modified concept of ESUS that focuses on thrombogenic atrial cardiopathy (as tested in the ongoing ARCADIA trial [NCT03192215]) looks especially promising.

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James Yeh, MD MPH is an internist and assistant in medicine at the Massachusetts General Hospital and an instructor in medicine at Harvard Medical School. His clinical and academic interests are in evidence-based medicine, medical education, continuing medical education, cardiopulmonary diseases, cardiovascular risk reduction, critical illness, care transition, polypharmacy, and health communication. He was a NEJM editorial fellow in 2015-2016.