Can we apply thrombolysis for stroke in patients on non-vitamin K oral anticoagulants?

In patients who experience an ischaemic stroke while on effective anticoagulation, intravenous thrombolysis (IVT), is currently contraindicated due to concerns that the risk for major bleeding events, particularly intracranial hemorrhage (ICH), is particularly increased. Current guidelines do not recommend IVT in patients with acute ischaemic stroke who have taken a NOAC within 48 hours before the event (1). However, this assumption is not evidence-based. Up to 20% of all strokes occur while on effective NOAC treatment (2). As the spectrum of indications for NOACs is continuously expanding, it can be assumed that this proportion of patients who are withheld IVT on the basis of this paradigm will continue to grow and thus become even more relevant.

Previous studies did not indicate a substantial risk for bleeding events in thrombolysed patients who are taking a NOAC  (3, 4). In a current retrospective, international multi-center study led by the colleagues from Bern (Switzerland) and Heidelberg (Germany), Meinel et al. analysed data from patients who received IVT between 2008 and 2021 and had taken a NOAC within 48 hours before symptom onset of stroke (5). As control cohort, patients treated with IVT but not under effective anticoagulation were included, most of them recruited in the Thrombolysis in Ischaemic Stroke Patients (TRISP) collaboration. When available, the exact NOAC intake time before stroke was documented and categorised according to within 12 hours, 12-24 hours, or over 24 hours. Information on the respective regimen was also collected, i.e., to what extent NOAC plasma levels were measured or NOAC were antagonised before IVT. The primary endpoint was the occurrence of a symptomatic ICH (defined as worsening by 4 NIHSS points) within 36 hours after IVT. Secondary endpoints were any ICH on follow-up imaging and a favorable functional outcome according to a modified Rankin Scale of 0-2, which was assessed center-based at 90 days via a clinical or telephone visit. (5)

There were 832 patients with NOAC treatment and 32375 controls included. In the NOAC group, patients were older (79 vs. 72 years) and had higher stroke severity (median NIHSS 11 vs. 9), prevalence of proximal vessel occlusion (59% vs. 33%), and atrial fibrillation (90% vs. 25%). Dabigatran was the most common anticoagulant used (41%), followed by rivaroxaban (31%), apixaban (20%), and edoxaban (8%). Among NOAC-treated patients, antagonisation (idarucizumab for dabigatran) was performed in 30% and NOAC plasma levels were measured in 27%. In the NOAC group, the rate of symptomatic ICH was 2.5% compared with 4.1% in controls. The adjusted odds ratio (OR) for symptomatic ICH was 0.57 (95% confidence interval : 0.36-0.92). In prespecified sensitivity analyses using the different time intervals, this result was consistent, with the limitation of small number of cases. Patients who received NOAC but in whom neither plasma level measurement nor antagonisation could be performed (n=355) still had a nominally decreased risk of symptomatic ICH (aOR: 0.66 (95% CI: 0.35-1.25)) but an increased OR for any ICH (aOR: 1.58 (95% CI: 1.16-2.14)), although the precision of these estimates was quite low. (5)

The occurrence of secondary end points did not differ considerably between groups. (5)

This important study again plausibly challenges the paradigm of contraindication of thrombolysis by NOAC treatment. Contrary to the expectation, the risk of symptomatic ICH due to thrombolysis was even significantly reduced under existing NOAC treatment, which may be explained by improved thrombolytic properties and reduced blood-brain barrier disruption. (5)

The most important limitation of the study is its retrospective design and a probable selection bias: the treating colleagues will have selected suitable patients having low risks for hemorrhagic transformation of stroke in their routine practice. Subgroup analyses have shown similar trends but had too little statistical power to provide reliable estimates.

While a randomised-controlled trial on this topic is unlikely to ever be planned for financial and logistical reasons, a prospective registry of appropriate size seems to be warranted in order to change the current practice in favor of the many NOAC-treated patients. A particularly interesting group are patients for whom the practitioners are unaware of NOAC use, as no selection bias would be expected here.

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References:

1. Berge E, Whiteley W, Audebert H, De Marchis G, Fonseca AC, Padiglioni C, et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. European Stroke Journal. 2021;6(1):I-LXII.
2. Seiffge DJ, De Marchis GM, Koga M, Paciaroni M, Wilson D, Cappellari M, et al. Ischemic Stroke despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation. Ann Neurol. 2020;87(5):677-87.
3. Seiffge DJ, Hooff RJ, Nolte CH, Béjot Y, Turc G, Ikenberg B, et al. Recanalization therapies in acute ischemic stroke patients: impact of prior treatment with novel oral anticoagulants on bleeding complications and outcome. Circulation. 2015;132(13):1261-9.
4. Xian Y, Federspiel JJ, Hernandez AF, Laskowitz DT, Schwamm LH, Bhatt DL, et al. Use of Intravenous Recombinant Tissue Plasminogen Activator in Patients With Acute Ischemic Stroke Who Take Non-Vitamin K Antagonist Oral Anticoagulants Before Stroke. Circulation. 2017;135(11):1024-35.
5. Meinel TR, Wilson D, Gensicke H, Scheitz JF, Ringleb P, Goganau I, et al. Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants. JAMA Neurology. 2023.