Safety of Intravenous Thrombolysis Among Patients Taking Direct Oral Anticoagulants

A Systematic Review and Meta-Analysis

Shima Shahjouei, MD, MPH; Georgios Tsivgoulis, MD, PhD, MSc, FESO; Nitin Goyal, MD; Alireza Sadighi, MD; Ashkan Mowla, MD; Ming Wang, MS, PhD; David J. Seiffge, MD; Ramin Zand, MD, MPH


Stroke. 2020;51(2):533-541. 

In This Article

Abstract and Introduction


Background and Purpose: There are scarce data regarding the safety of intravenous thrombolysis (IVT) in acute ischemic stroke among patients on direct oral anticoagulants (DOACs).

Methods: We performed a systematic review and meta-analysis of the current literature. Data regarding all adult patients pretreated with DOAC who received IVT for acute ischemic stroke were recorded. Meta-analysis was performed by comparing the rate of symptomatic intracerebral hemorrhage in these patients with (1) stroke patients without prior anticoagulation therapy and (2) patients on warfarin with international normalized ratio <1.7. Meta-analyses were further conducted in subgroups as follows: (1) administration of DOAC within 48 hours versus an unknown interval before IVT, (2) consideration of symptomatic intracerebral hemorrhage outcome according to the National Institute of Neurological Disorders (NINDS) versus the European Cooperative Acute Stroke Study II (ECASS-II) criteria.

Results: After reviewing 13 392 reports and communicating with certain authors of 12 published studies, a total of 52 823 acute ischemic stroke patients from 6 studies were enrolled in the present meta-analysis: DOACs: 366, warfarin: 2133, and 503 241 patients without prior anticoagulation. We detected no additional risk of symptomatic intracerebral hemorrhage following IVT among patients taking DOACs within 48 hours—DOACs-warfarin: NINDS (odds ratio [OR], 0.55 [95% CI, 0.19–1.59]), ECASS-II (OR, 0.77 [95% CI, 0.28–2.16]); DOACs-no-anticoagulation: NINDS (OR, 1.23 [95% CI, 0.46–3.31]), ECASS-II (OR, 0.87 [95% CI, 0.32–2.41]). Similarly, no additional risk was detected with no time limit between last DOAC intake—DOACs warfarin: NINDS (OR, 0.85 [95% CI, 0.49–1.45]), ECASS-II (OR, 1.11 [95% CI, 0.67–1.85]); DOACs-no-anticoagulation: NINDS (OR, 1.17 [95% CI, 0.43–3.15]), ECASS-II (OR, 0.87 [95% CI, 0.33–2.41]). There was no evidence of heterogeneity across included studies (I 2=0%). We also provided the details of 123 individual cases with or without reversal agents before IVT. There was no significant increase in the risk of hemorrhagic transformation (OR, 1.48 [95% CI, 0.50–4.38]), symptomatic hemorrhagic transformation (OR, 0.47 [95% CI, 0.09–2.55]), or early mortality (OR, 0.60 [95% CI, 0.11–3.43]) between cohorts who did or did not receive prethrombolysis idarucizumab.

Conclusions: The results of our study indicated that prior intake of DOAC appears not to increase the risk of symptomatic intracerebral hemorrhage in selected AIS patients treated with IVT.


Direct oral anticoagulants (DOACs) are direct thrombin or factor Xa inhibitors which are increasingly being administered for prevention of embolic events.[1,2] Randomized-controlled clinical trials reported either similar or superior efficacy of DOACs (dabigatran,[3] rivaroxaban,[4] apixaban,[5] and edoxaban[6]) in the prevention of ischemic stroke and thromboembolism in comparison with warfarin. Despite the potential benefit and safety of DOACs, there is 1% to 2% annual risk of stroke among these patients.[3–6]

An increasing number of patients under treatment with DOACs who received intravenous thrombolysis (IVT) are being reported from centers across the world.[7–12]

American Heart Association/American Stroke Association (AHA/ASA) latest 2018 guideline recommends thrombolytic therapy within 4.5 hours after the stroke onset among patients on warfarin only with the international normalized ratio (INR) <1.7.[13] AHA/ASA recommends against fibrinolytic therapy in ischemic stroke patients who are already on direct thrombin inhibitors or direct factor Xa inhibitors unless patients have been cleared after an extensive coagulation assessment (eg, activated partial thromboplastin time, INR, ecarin clotting time, thrombin time, or direct factor Xa activity) and >48 hours passed since the last dose intake.[13] In accordance with AHA/ASA guideline, French Vascular Neurology Society and French study Group on Hemostasis and Thrombosis in 2018[14] recommended that stroke management should not differ for patients who stopped taking DOACs >48 hours before IVT (with normal renal function). If the last dose intake of DOAC is earlier, French Vascular Neurology Society/French study Group on Hemostasis and Thrombosis encouraged considering mechanical thrombectomy. However, this guideline allowed IVT based on the administration of idarucizumab, or type of hospital, in addition to plasma concentration of DOACs and presence of standard coagulation tests. The 2018 national clinical guides on stroke thrombolysis for anticoagulated patients in Japan[15] recommended IVT when INR <1.7 and activated partial thromboplastin time <1.5× the baseline value (≤40). This guideline minimized the interval from last DOAC intake to 4 hours and recommended 0.6 mg/kg alteplase instead of the standard 0.9 mg/kg. In addition, idarucizumab is not recommended by this guideline either before IVT or mechanical thrombectomy.

To the best of our knowledge, there are 2 prior systematic reviews on the safety of endovascular therapy in patients anticoagulated with DOACs.[16,17] In the meta-analysis by Kurowski et al,[16] endovascular intervention in subjects on therapeutic anticoagulation has a similar rate of symptomatic intracranial hemorrhage (sICH) to patients, not on anticoagulation agents. This review presented the outcome of patients with either vitamin K antagonists or DOACs together. Besides, it has considered cases received intraarterial therapy in addition to the patients with intravenous therapy. Moreover, this study did not mention the interval between the last DOACs consumption and intervention. The second systematic review has been conducted by Jin et al.[17] The authors limited their literature search to PubMed and presented the details of 492 AIS patients pretreated with DOACs who received IVT. Due to the high risk of publication bias and lack of control groups the authors could not conduct a meta-analysis.

In view of the former considerations, the primary goal of this study was to conduct a systematic review and meta-analysis of available reports on the safety of IVT among AIS pretreated with DOACs in <48 hours before tPA (tissue-type plasminogen activator) bolus and in the absence of reversal agents. We also provided the result of subgroup meta-analysis when there was no time restrict between the last intake of DOAC and IVT and when sICH was defined according to National Institute of Neurological Disorders (NINDS) or ECASS-II criteria (European Cooperative Acute Stroke Study II). In addition to meta-analysis, we presented the details of individual cases with or without reversal agents before IVT in a separate section.