Editor's Note: Commentary based on Seiffge DJ, Hooff RJ, Nolte CH, et al. Recanalization Therapies in Acute Ischemic Stroke Patients: Impact of Prior Treatment With Novel Oral Anticoagulants on Bleeding Complications and Outcome. Circulation 2015;132:1261-9.

Background

Anticoagulation with warfarin or a non-vitamin K oral anticoagulant (NOAC) has been shown to lower the risk of ischemic stroke in patients with atrial fibrillation (AF).¹ NOACs have demonstrated a favorable risk-benefit profile in comparison to warfarin,² and are frequently used in clinical practice. Despite the efficacy of NOACs, patients with AF treated with a NOAC may still experience an ischemic stroke. Although current guidelines provide recommendations for the use of intravenous (IV) thrombolytics or intra-arterial treatment in patients who suffer an ischemic stroke while on warfarin,³ the appropriate therapy for NOAC-treated patients who experience an ischemic stroke is less clear.

Methods

The Novel Oral Anticoagulants in Stroke Patients (NOACISP) Study Group conducted a multicenter, observational pilot study to evaluate the safety of IV thrombolytics or intra-arterial treatments in patients with ischemic stroke on NOACs.⁴ The 78 NOAC-treated patients were compared with 441 patients treated with a vitamin K antagonist (VKA), as well as 8,938 non-anticoagulated patients at the time of ischemic stroke. The primary outcomes of the study were occurrence of intracranial hemorrhage (ICH) or death at three months. The three groups were compared using propensity score matching.

Results

Of the 78 NOAC-treated patients (apixaban n=2, dabigatran n=29, rivaroxaban n=47), 51 received IV thrombolytics. The median time between last NOAC dose and IV thrombolytic/intra-arterial treatment was 13 hours (interquartile range [IQR] 8-22). In VKA-treated patients, median international normalized ratio (INR) prior to IV thrombolytics/intra-arterial treatment was 1.3 (IQR 1.1-1.6).

ICH occurred in 18.4% of NOAC-treated patients, 26.8% in VKA-treated patients, and 17.4% in patients not on oral anticoagulation. After three months, 23% of NOAC-treated patients versus 26.9% of VKA-treated patients, and 13.9% of non-anticoagulated patients died. Propensity score matching for both outcomes revealed no significant differences between groups.

In the 21 patients taking rivaroxaban, the decision to treat with IV thrombolytics was based on calibrated anti-factor Xa assay, with a mean level of 21 ng/mL. In each of these patients, anti-factor Xa levels were < 100ng/mL.

Conclusion

In carefully selected NOAC-treated patients who experience an ischemic stroke, the use of IV thrombolytics/intra-arterial treatments has a similar safety and outcome profile to the use of IV thrombolytics/intra-arterial treatments in patients with sub-therapeutic vitamin K antagonism or those not on prior anticoagulation.

Commentary/Perspective

As the frequency of NOAC use continues to rise, the development of appropriate evidence-based treatment algorithms for recanalization strategies in acute stroke will become paramount. The NOACISP Study Group takes an important first step by providing crucial pilot data demonstrating the safety and feasibility of IV thrombolytics/intra-arterial treatments for select patients taking NOACs treated at experienced stroke centers. They also report the potential utility of specific coagulation tests in helping to identify which patients are suitable candidates for recanalization therapy.

The recently U.S. Food and Drug Administration (FDA)-approved reversal agent for dabigatran, idarucizumab (Praxbind), along with the anticipated arrival of other reversal agents for the remaining NOACs, may make recanalization therapy (particularly IV thrombolytics) safer and more widely available for patients who experience an ischemic stroke while taking a NOAC.

The authors appropriately acknowledge the small sample size and cite heterogeneity as important limitations, and thus encourage cautious interpretation of the results, highlighting the need for further research before these results can be generalized to routine practice. The authors have taken the next step forward and recently set up the NOACISP ACUTE prospective, multicenter registry to further evaluate the management of NOAC-treated patients who experience an acute ischemic stroke.

Until more data are available, based on the current stroke guidelines and the results of this pilot study,^3,4 it would be reasonable to treat patients who present with an acute ischemic stroke while on a NOAC in the following fashion: 1) for patients who have taken a NOAC within the last 12 hours, thrombolytic therapy should be avoided and mechanical thrombectomy should be considered if available; 2) for patients who have taken a NOAC in the last 12 to 48 hours, thrombolytic therapy may be considered (depending on the NOAC and the patient's renal function), particularly in the setting of normal sensitive laboratory coagulation tests.

References

1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1-76.
2. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955-62.
3. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870-947.
4. Seiffge DJ, Hooff RJ, Nolte CH, et al. Recanalization Therapies in Acute Ischemic Stroke Patients: Impact of Prior Treatment With Novel Oral Anticoagulants on Bleeding Complications and Outcome. Circulation 2015;132:1261-9.

Keywords: Algorithms, Anticoagulants, Atrial Fibrillation, Benzimidazoles, Cytarabine, Factor Xa, Fibrinolytic Agents, International Normalized Ratio, Intracranial Hemorrhages, Morpholines, Pilot Projects, Propensity Score, Prospective Studies, Pyrazoles, Pyridones, Registries, Sample Size, Stroke, Thiophenes, Thrombectomy, Thrombolytic Therapy, Vitamin K, Warfarin, beta-Alanine

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