Effect of sinus rhythm restoration on markers of thrombin generation in atrial fibrillation

Anja Wiedswang Horjen, Ingebjørg Seljeflot, Trygve Berge, Pål Smith, Harald Arnesen, Arnljot Tveit, Anja Wiedswang Horjen, Ingebjørg Seljeflot, Trygve Berge, Pål Smith, Harald Arnesen, Arnljot Tveit

Abstract

Background: Atrial fibrillation (AF) confers a hypercoagulable state; however, it is not clear whether restoration of sinus rhythm is associated with normalisation of markers of thrombogenesis. We studied the impact of sustained sinus rhythm on prothrombotic markers, and their predictive abilities in foreseeing rhythm outcome after cardioversion.

Methods: In a double blind, placebo-controlled study, 171 patients referred for electrical cardioversion of persistent AF were randomised to receive candesartan or placebo for 3-6 weeks before and 6 months after cardioversion. Endogenous thrombin potential (ETP), prothrombin fragment 1 + 2 (F1 + 2) and D-dimer were measured before cardioversion and at end of study. These markers were also measured in a reference group comprising 49 subjects without AF.

Results: The markers remained unchanged in those 28 patients who maintained sinus rhythm. Discontinuation of warfarin treatment in a subset of 13 low-risk patients in sinus rhythm was associated with significantly higher levels of D-dimer and F1 + 2 compared to the reference group; D-dimer (456 ng/mL (276, 763) vs. 279 ng/mL (192, 348), p = 0.002) and F1 + 2 (700 pmol/L (345, 845) vs. 232 pmol/L (190, 281), p < 0.001). None of the markers were associated with rhythm outcome after electrical cardioversion.

Conclusions: Sustained sinus rhythm for 6 months after cardioversion for AF had no impact on ETP, F1 + 2 or D-dimer levels. Discontinuation of warfarin in low-risk patients with sustained sinus rhythm was associated with significantly higher levels of D-dimer and F1 + 2 compared to the reference group. Our results suggest persistent hypercoagulability in AF patients despite long-term maintenance of sinus rhythm.

Trial registration: The CAPRAF study was registered at clinicaltrials.gov (NCT00130975) in August 2005.

Keywords: Atrial fibrillation; Cardioversion; Hypercoagulability; Thrombin generation.

Conflict of interest statement

The study was approved by the Regional Ethics Committee, and all patients provided written, informed consent in accordance with the revised Declaration of Helsinki.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Flow chart of the CAPRAF study and reference group recruited from the ACE 1950 study. Abbreviations: ACE, Akershus Cardiac Examination 1950 study; AF, atrial fibrillation; CAPRAF study, Candesartan in the Prevention of Relapsing Atrial Fibrillation study; n, number of patients; SR, sinus rhythm
Fig. 2
Fig. 2
Marker levels in patients with sustained SR and continued warfarin treatment. P-values derived from the Wilcoxon signed-rank test. Center lines show the medians; box limits indicate the 25th and 75th percentiles; whiskers extend 1.5 times the interquartile range from the 25th and 75th percentiles. Abbreviations: ETP, endogenous thrombin potential; F1 + 2, prothrombin fragment 1 + 2; SR, sinus rhythm
Fig. 3
Fig. 3
Marker levels in patients with sustained SR and discontinued warfarin treatment compared to reference group. P-values are derived from the Mann-Whitney U-test. Center lines show the medians; box limits indicate the 25th and 75th percentiles; whiskers extend 1.5 times the interquartile range from the 25th and 75th percentiles. Abbreviations: ETP, endogenous thrombin potential; F1 + 2, prothrombin fragment 1 + 2; SR, sinus rhythm

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