Author Reply to “Intravenous thrombolysis in patients taking direct oral anticoagulants (European stroke organisation intravenous thrombolysis guidelines comment)

Dear Editors,

We read with interest the letter by Seiffge et al. on the European Stroke Organisation (ESO) intravenous thrombolysis (IVT) guideline. ¹ The letter addressed two expert consensus statements – first, the use of coagulation tests to select patients taking a non-Vitamin K antagonist oral anticoagulants (NOAC) for IVT; second, the use of the NOAC reversal agents prior to IVT.

The ESO guidelines make evidence-based recommendations based on a systematic literature review and critical appraisal with GRADE methodology, prior to making any expert consensus statement. There was insufficient evidence to make an evidence-based recommendation either for or against IVT based on coagulation test results, for patients who had taken a NOAC during the last 48 h and presented within 4.5 h of stroke onset, or for the use of idarucizumab before IVT in patients taking dabigatran. However, the use of IVT in patients taking a NOAC was a pre-specified question asked by the ESO guideline board.

In the absence of high quality, randomised evidence, we made an expert statement. As the inadequate current evidence can be interpreted in a number of ways, it is unsurprising that expert members came to different conclusions.

Ideally, we would have both (i) a widely available and rapid gold standard to measure NOAC concentration and (ii) prospectively validated NOAC cut‐offs to decide whether to administer IVT based on patients randomly allocated to IVT or not. Unfortunately, neither is the case. The gold standard to quantitate NOAC concentrations –liquid chromatography coupled with mass spectrometry– is time-consuming, expensive, and not practical for urgent decisions on IVT. The modest number of patients (n = 38) included in studies with a uniform NOAC-activity assessment prior to IVT is insufficient to validate different NOAC-activity cut-offs to decide for or against IVT.^2–4

We are not suggesting using the uncalibrated anti-Xa-activity for factor Xa inhibitors. Instead, the guideline mentions the calibrated anti-Xa-activity. The question is, rather, calibrated for what? Anti-Xa-activity can be calibrated for heparin or for the specific NOACs that inhibit factor Xa (apixaban, rivaroxaban or edoxaban). When calibrated for heparin, the results are expressed in units per milliliter, and, when calibrated for the Xa inhibiting NOACs, in nanograms per milliliter. ⁵ The correlation between heparin-calibrated Anti-Xa activity and apixaban- or rivaroxaban-calibrated anti-Xa assays lies above 96%. ⁶ Given its accuracy and broader availability across Europe, we chose a cut-off based on the heparin-calibrated Anti-Xa activity. The cut-off of <0.5 U/ml corresponds to low Xa inhibiting NOACs concentrations (<50–100 ng/ml). ⁷ Concerning the measuring of dabigatran concentrations, it is correct that a thrombin time <60 s may be too conservative, as patients with dabigatran concentrations ≤30 ng/ml can well have thrombin times ≥60 s. ⁸ We wish to underscore, however, that even the cut-off of dabigatran concentration ≤30 ng/ml has not been prospectively validated to decide on IVT.

The number of NOAC specific coagulation tests is increasing – we encourage their use and validation in the emergency setting. The five different dabigatran specific assays cited by the letter authors have not been compared to each other in the emergency setting. ⁹ In summary, we encourage the use of NOAC specific tests, but we deem necessary to (1) assess their comparative performance in the emergency setting including acute stroke, and (2) establish if any and which test cut-off is indeed associated with the risk of symptomatic intracranial hemorrhage.

We came to different voting results between idarucizumab and andexanet mainly because of their different speeds of administrations. Idarucizumab, the dabigatran reversal agent, can be administered as two bolus infusions, no more than 15 min apart ¹⁰ , while andexanet, the reversal agent of apixaban and rivaroxaban requires a bolus over a period of 15–30 minutes followed by a 2-h infusion ¹¹ , leading to a considerable delay in the door-to-IVT times. Therefore, we voted in favour of idarucizumab, but not in favour of andexanet prior to IVT. Additional arguments are the very high cost of andexanet, casting doubts to its cost/benefit ratio and limiting its availabily. ¹² We share the hope that point-of-care testing (POCT) for NOAC could help tailor the indication for IVT. Point-of-care testing could also help tailoring the dosing of reversal agents, but all these strategies will need to be evaluated in randomized-controlled clinical trials.

In summary, there is considerable uncertainty about the use of thrombolytic agents in patients taking NOACS who have had an acute ischaemic stroke. Registry studies and “real-world evidence” are generally of limited use when making decisions about the effectiveness of treatments. The way to better inform clinicians and patients is through randomised controlled trials that are simple enough to implement in everyday practice. ¹³