Professor Dr. Hans-Christoph Diener

Professor Dr. Hans-Christoph Diener

A conversation with Professor Dr. Hans-Christoph Diener, Faculty of Medicine at the University of Duisburg-Essen, on the recently published randomized clinical trials assessing the safety and efficacy of non-vitamin K oral anticoagulants (NOACs) in patients with embolic strokes of undetermined source (ESUS), and on the future of anticoagulation in the secondary prevention of cryptogenic cerebral ischemia.

Interviewed by Aristeidis H. Katsanos, Research Fellow at the Department of Neurology, Ruhr University of Bochum.

They will be discussing the paper “Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source,” published in the May 16, 2019 issue of the New England Journal of Medicine.

Dr. Katsanos: Can you please summarize for the readers of the blog the main hypothesis and findings of the RE-SPECT ESUS trial?

Prof. Diener: Patients with ESUS (embolic stroke of undetermined source) have high risk of recurrent stroke, and the risk of recurrent stroke per year is about 5%. We assume that the majority of these recurrent strokes have an embolic source. Therefore, oral anticoagulation should be superior to antiplatelet therapy in patients with ESUS.

Dr. Katsanos: Do the results of the RE-SPECT ESUS trial uncover any potential reasons for the lack of efficacy of anticoagulation in patients with ESUS?

Prof. Diener: The rate of recurrent stroke, which was about 5% per year, was not statistically significantly different between patients treated with dabigatran compared to aspirin. This was, in particular, true for the first year of the observation period. In the second half of the study, dabigatran was more effective than aspirin. Overall, the trial was neutral. An important result of the RE-SPECT ESUS study was the fact that the risk of major bleeding was not different between dabigatran and aspirin.

Dr. Katsanos: Were there any subpopulations within the RE-SPECT ESUS trial which seem to benefit from anticoagulation?

Prof. Diener: In the RE-SPECT ESUS trial, we had two subgroups which seemed to benefit from dabigatran over aspirin. The first group included patients above the age of 75 years who were treated with the lower dose of dabigatran (110 mg twice daily). This group of patients had a statistically significant reduction in the risk of recurrent stroke compared to aspirin. The second subgroup which had a benefit was patients from Asia. The benefit of dabigatran over aspirin almost reached statistical significance. For the 594 patients recruited in Japan, the benefit of dabigatran over aspirin was significant.

Dr. Katsanos: A very interesting finding in the RE-SPECT ESUS trial was an equal risk of intracranial haemorrhage between patients randomized to dabigatran intake and those randomized to antiplatelet treatment. Taking into account the significantly higher risk of intracranial haemorrhage of patients randomized to rivaroxaban compared to antiplatelet intake in the NAVIGATE-ESUS trial, do you think that the difference could be attributed to the different mechanisms of the two drugs, study populations, or both?

Prof. Diener: If we look at the results of NAVIGATE ESUS and RE-SPECT ESUS, it seems that in the NAVIGATE ESUS trial, rivaroxaban had a significantly higher risk of major bleeding compared to aspirin, including intracranial bleeding. If we compare the two trials, it turns out that the risk of major bleeding was almost identical with dabigatran and rivaroxaban. The difference between the two studies was the rate of major bleeding on aspirin. This rate was much lower in the NAVIGATE ESUS compared to the RE-SPECT ESUS. We have to admit that we have no good explanation for the different bleeding rates on aspirin in the two trials.

Dr. Katsanos: Considering the negative result of both the RE-SPECT ESUS and NAVIGATE ESUS trials, one could argue that the potential clinical utility of the ESUS concept is challenged. What is your comment on this criticism?

Prof. Diener: We have to admit that at present, we have two neutral trials for the comparison of non-vitamin K oral anticoagulants (NOACs) in comparison to aspirin in patients with embolic stroke of undetermined source. However, we have two ongoing trials (ATTICUS, AR-CARDIA), and at least one of the trials only selects patients who have a high risk to develop atrial fibrillation. The ESUS concept most probably has to be modified. ESUS patients at high risk of atrial fibrillation will still need long-term ECG monitoring.

Dr. Katsanos: Do you believe that the ESUS definition needs to be reformatted to identify a subgroup of patients who could benefit from anticoagulation therapy?

Prof. Diener: The ESUS concept has to be modified. First, patients with patent foramen ovale have to be removed from the ESUS group because we have now evidence from randomized trials that the interventional closure of the patent foramen ovale in patients below the age of 60 years has a benefit over antithrombotic therapy. We need to include in the ESUS concept parameters to identify patients with a high risk to develop atrial fibrillation. These include biomarkers like high sensitivity BNP and the size of the left atrium in echocardiography.

Dr. Katsanos: What is your prediction regarding the future of cryptogenic stroke management?

Prof. Diener: I think the ESUS concept has to be modified, and we have to wait for the results of the ongoing studies which compare apixaban and aspirin in patients with ESUS. Unfortunately, I do not see a real prospect for additional studies investigating the benefit of NOACS for the prevention of recurrent stroke in ESUS.

Dr. Katsanos: Thank you very much for your time and answers.