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Dabigatran Treatment in Embolic Stroke of Undetermined Source and Elevated Biomarkers: the RE-SPECT ESUS Trial

Open AccessPublished:January 04, 2023DOI:https://doi.org/10.1016/j.cjco.2022.12.013

      Abbreviations:

      (ESUS) (Embolic stroke of undetermined source), (Hs-TnT) (High sensitivity troponin), (nt-proBNP) (N-terminal pro brain natriuretic peptide)
      Embolic stroke of undetermined source (ESUS) is a stroke subtype with no readily attributable cause. A significant percentage of ESUS patients develop atrial fibrillation, up to 40%

      Kitsiou, Alkisti, et al. "Atrial fibrillation in patients with embolic stroke of undetermined source during 3 years of prolonged monitoring with an implantable loop recorder." Thrombosis and Haemostasis AAM (2021).

      , making anticoagulation a possible treatment option. However, two trials

      Diener, Hans-Christoph, et al. "Dabigatran for prevention of stroke after embolic stroke of undetermined source." New England Journal of Medicine 380.20 (2019): 1906-1917.

      ,

      Hart, Robert G., et al. "Rivaroxaban for stroke prevention after embolic stroke of undetermined source." New England Journal of Medicine 378.23 (2018): 2191-2201.

      showed no benefit with anticoagulation in ESUS. The purpose of this study was to determine if a subgroup of ESUS patients with risk factors for both atrial fibrillation and recurrent stroke would benefit from anticoagulation. We analyzed post-hoc patients with elevated cardiac biomarkers, namely, high sensitivity troponin T (Hs-TnT) and n-terminal pro brain natriuretic peptide (nt-proBNP), which have been shown to associate with stroke as well as development of atrial fibrillation

      Hijazi, Ziad, et al. "The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation." European heart journal 37.20 (2016): 1582-1590.

      .

      Methods

      Anonymized data was used from the RE-SPECT ESUS trial comparing dabigatran with aspirin. Informed, written consent was obtained from all participants. The ABC score

      Hijazi, Ziad, et al. "The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation." European heart journal 37.20 (2016): 1582-1590.

      was calculated for individual subjects. This is an established clinical risk score used to identify patients with atrial fibrillation who benefit from anticoagulation. The score aggregates the two biomarkers Hs-TnT and nt-proBNP, as well as age, into a single index. Treatment effects were evaluated using cox proportional hazards regression. Adjusted Kaplan-meier analysis adjusting for the competing risk of death was performed. All analyses were done using SAS 9.4 (Cary, NC). The study was approved by the Beaumont Health institutional review board.

      Results

      1134 participants from the RE-SPECT ESUS population underwent biomarker evaluation. 1051 were analyzed, 524 to aspirin and 527 to dabigatran. Median, baseline Hs-TnT and nt-proBNP were 7.23 ng/L (IQR 4.98, 10.90) and 565 pg/mL (IQR 246, 1130). Average age was 64 years, 36% were female, 20.6% had diabetes, 4.9% had heart failure and 4.9% had chronic kidney disease. The rate of recurrent stroke, systemic embolism and transient ischemic attack was 10.8% and 9.9% in the dabigatran and aspirin arms respectively, hazard ratio of 1.13 (0.77, 1.62) P>0.05) There was no interaction between treatment effect with dabigatran and biomarker levels or ABC score in unadjusted and mortality adjusted analysis. (P>0.05). (Figure 1). ABC score was significantly associated with event rates, hazard ratio 1.39 (1.14, 1.70) (p=0.001).
      Figure thumbnail gr1
      Figure 1Survival free of stroke or systemic embolism according to quartiles of ABC score. Hazard ratios for dabigatran treatment effect were similar across quartiles. There was no interaction between quartile and treatment effect (p= 0.962)

      Discussion

      Cardiac biomarkers compiled with age into the ABC risk score were significantly associated with cerebral ischemic event rate in this population of ESUS patients. However, there was no interaction between score and treatment effect with dabigatran. Despite the association between risk score and events, power was limited to detect an interaction with treatment effect due to small sample size, as only a subgroup, accounting for 21% of the entire RE-SPECT ESUS trial population, underwent biomarker measurement. Given the significant association between these cardiac biomarkers and outcomes in ESUS, future trials in this population should test baseline biomarker levels routinely and continue to explore their interaction with treatment effect.

      Acknowledgments

      This publication is based on research using data from data contributors Boehringer Ingelheim that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication.

      References

      1. Kitsiou, Alkisti, et al. "Atrial fibrillation in patients with embolic stroke of undetermined source during 3 years of prolonged monitoring with an implantable loop recorder." Thrombosis and Haemostasis AAM (2021).

      2. Diener, Hans-Christoph, et al. "Dabigatran for prevention of stroke after embolic stroke of undetermined source." New England Journal of Medicine 380.20 (2019): 1906-1917.

      3. Hart, Robert G., et al. "Rivaroxaban for stroke prevention after embolic stroke of undetermined source." New England Journal of Medicine 378.23 (2018): 2191-2201.

      4. Hijazi, Ziad, et al. "The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation." European heart journal 37.20 (2016): 1582-1590.