Non-vitamin K-dependent Oral Anticoagulants Have a Positive Impact on Ischaemic Stroke Severity in Patients With Atrial Fibrillation

Simon Hellwig; Ulrike Grittner; Heinrich Audebert; Matthias Endres; Karl Georg Haeusler


Europace. 2018;20(4):569-574. 

In This Article


One of the major findings of this study is that only half of the patients with known AF and a CHA2DS2-VASc score ≥ 2 before stroke were taking oral anticoagulation despite given indication. This finding underlines the present shortcomings in primary and secondary stroke prevention in AF patients and furthermore demonstrates subsequent complications. However, we analysed only AF patients with acute ischaemic stroke; therefore, we cannot draw conclusions on the quality of stroke prevention in AF patients in the general population.

Compared with AF patients without antithrombotic medication before stroke (Table 2), self-reported NOAC intake pre-admission lowered the probability of severe ischaemic stroke on hospital admission, as similarly observed for phenprocoumon patients with an INR ≥ 2 on admission. In accordance with previous publications, there was no significant effect of VKA intake with an INR < 2 or the intake of platelet inhibitors on stroke severity on admission.[8,20] NOAC intake also lowered the probability of worse functional outcome at hospital discharge (Table 2), despite of a higher rate of previous stroke and a lower rate of thrombolysis in patients taking a NOAC when compared with AF patients without antithrombotic medication (Table 1). A similar effect on stroke severity at hospital discharge was observed in VKA patients with an INR ≥ 2 on admission (Table 2). Adjusted for various confounders, the multiple relations of stroke severity on admission, thrombolysis as well as endovascular treatment on functional outcome at hospital discharge are depicted in the Supplementary material online, Figure S1. As demonstrated, the NIHSS score on admission significantly impacts on the mRS score at discharge. Moreover, intake of phenprocoumon or NOAC was inversely related to stroke severity on admission, as indicated by the negative estimates.

NOACs are effective in primary and secondary stroke prevention without need for routine coagulation monitoring.[4] However, a non-temporal correlation was reported between (single) plasma concentrations of dabigatran and edoxaban and cerebrovascular events during follow-up of the respective phase III clinical trials.[21,22] Just recently, a single-centre case series including 19 patients admitted for acute stroke while taking dabigatran demonstrated that plasma concentrations of dabigatran were higher in four patients with intracerebral haemorrhage compared with 15 patients with ischaemic stroke.[23] Because NOAC plasma concentrations on admission or measurements of calibrated anti-Xa activity were not available in our stroke cohort, coagulation tests on hospital admission were analysed (as similarly reported in a German registry).[24] Despite uncertain sensitivity and specificity, these tests provide useful information to assess a residual anticoagulant effect of NOACs—in patients with abnormal results—indicating a recent intake.[25] Of note, NOAC patients with elevated routine coagulation tests had a significantly lower probability of severe stroke when compared to patients without antithrombotic medication on admission. This was not the case for NOAC patients without elevated routine coagulation tests. With regard to the published phase III randomized trials, the reduced dose of rivaroxaban as well as apixaban was more often prescribed in our stroke cohort (Supplementary material online, Table S1).

Limitations of the Present Study

Beside the reported strengths, our study has weaknesses that mitigate the validity of its results. First, this is a retrospective single-centre analysis and we cannot exclude that undocumented factors have influenced the physicians' choice of medical stroke prevention in an individual patient pre-stroke. Second, there are limitations in terms of statistical power to the various comparisons due to comparably small patient subgroups. Third, there were significant differences between patient subgroups regarding baseline characteristics and acute stroke treatment. Despite statistical adjustment, residual bias may still be present. Fourth, we were unable to assess the adherence to NOAC intake and the actual anticoagulatory effect at the time of stroke onset in more detail because specific tests like calibrated anti-Xa activity are not part of clinical routine so far.[24] We addressed this issue by comparing NOAC patients with and without altered routine coagulation tests to those patients without medical stroke prevention. Fifth, due to retrospective data assessment we were unable to assess the impact of pre-hospital time in therapeutic range (TTR) on stroke severity. Since the half-life of phenprocoumon is much longer compared to warfarin, we believe that INR on admission is sufficient to assess the quality of anticoagulation in the last week before stroke.[26] Finally, we missed an additional follow-up 3 months after stroke that would have strengthened our results. Therefore, our findings have to be validated in larger cohorts of stroke patients with known AF as suggested previously.[13]