Hooman Kamel, MD, on Anticoagulation Therapy After Cryptogenic Stroke

About 25% of ischemic strokes do not have a root cause, even after testing. Treatment of these cryptogenic strokes—or embolic strokes of undetermined source (ESUS)—has been subject of debate over the past few years.

Though current guidelines recommend antiplatelet therapy for patients with ESUS, new research is examining the effect of anticoagulation therapy on patient outcomes. Researcher and associate professor of neurology at Weill Cornell Medical School in New York, New York, Hooman Kamel, MD, answers our questions about this debate.1

CARDIOLOGY CONSULTANT: What do current guidelines in the United States recommend for treating patients who have experienced cryptogenic stroke?

Hooman Kamel: Current guidelines2 from the American Heart Association recommend antiplatelet therapy, not anticoagulant therapy, for secondary stroke prevention in patients with cryptogenic stroke.

CARDIO CON: Can you tell us more about the NAVIGATE ESUS study? What have the results taught us so far?

HK: NAVIGATE ESUS3 was an international multicenter randomized trial of rivaroxaban vs aspirin for secondary stroke prevention in patients with embolic stroke of undetermined source (ESUS). Practically, ESUS is similar to cryptogenic stroke, but an ESUS label requires a minimum diagnostic evaluation (cervical and intracranial arterial vessel imaging to rule out atherosclerotic stenosis, echocardiography, and at least 24 hours of heart-rhythm monitoring to rule out atrial fibrillation), whereas a patient with an incomplete evaluation or multiple potential causes of stroke would be labeled as cryptogenic.

Among 7213 participants in the NAVIGATE ESUS trial, the annualized rate of recurrent stroke (composite of ischemic or hemorrhagic stroke) was 5.1% in the rivaroxaban group and 4.7% in the aspirin group (hazard ratio, 1.07; 95% CI, 0.87-1.33). These results, combined with similar results of the RE-SPECT ESUS trial4 of dabigatran vs aspirin, have taught us that anticoagulation is not beneficial in the overall ESUS population and that the current guideline-endorsed approach of aspirin therapy is good enough for now.

CARDIO CON: How might those results impact clinical practice and, potentially, how patients with cryptogenic stroke are treated?

HK: Based on the current available evidence, cryptogenic stroke patients should not be empirically anticoagulated, and the preferred antithrombotic approach for secondary stroke prevention is antiplatelet therapy.

CARDIO CON: What is the most common question you receive about the NAVIGATE ESUS trial?

HK: Does the ESUS concept remain useful? I believe it does, because it provides a clinically robust and practical diagnostic framework for evaluating ischemic stroke etiology. Are there potential patients with ESUS who may benefit from anticoagulant therapy? I believe there are. For example, a secondary analysis of NAVIGATE ESUS found a substantial benefit of rivaroxaban in the about 10% of trial participants with left atrial diameter of more than 4.7 cm. Whether this subset of ESUS patients who have atrial myopathy but have no evidence of atrial fibrillation benefit from anticoagulation is being tested in the ongoing ARCADIA trial.5

CARDIO CON: What is your key take-home message for cardiologists?

HK: For now, antithrombotic therapy for secondary stroke prevention in ESUS patients should be aspirin. These patients should generally be evaluated for underlying paroxysmal atrial fibrillation/flutter with some type of continuous heart-rhythm monitoring for at least a few weeks, and if atrial fibrillation/flutter is found, then most stroke specialists would favor switching to anticoagulation at that point.



  1. Kamel H. Should cryptogenic stroke patients get oral anticoagulation? NAVIGATE (ES)us! Paper presented at: 40th Heart Rhythm Scientific Sessions; May 8-11, 2019; San Francisco, CA.!/5753/presentation/31045.
  2. Kernan WN, Ovbiagele B, Black HR, et al; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2014;45(7):2160-2236.
  3. Hart RG, Sharma M, Mundl H, et al; NAVIGATE ESUS investigators. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med. 2018;378:2191-2201. doi:10.1056/NEJMoa1802686.
  4. Diener HC, Sacco RL, Easton JD, et al; RE-SPECT ESUS Steering Committee and Investigators. Dabigatran for prevention of stroke after embolic stroke of undetermined source. N Engl J Med. 2019;380:1906-1917. doi:10.1056/NEJMoa1813959.
  5. Atrial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke (ARCADIA) [ongoing trial].