Consensus Guides on Stroke Thrombolysis for Anticoagulated Patients from Japan: Application to Other Populations

Abstract

Development of direct oral anticoagulants and their antidotes has led to the need to reconsider the eligibility of acute stroke patients who have been taking oral anticoagulants for intravenous thrombolysis. Officially authorized Japanese guidelines on this issue were revised twice at the time of approval for clinical use of direct oral anticoagulants and idarucizumab, a specific reversal agent for dabigatran. A unique recommendation in the latest Japanese clinical guides was that thrombolysis can be recommended if the time of the last dose of direct oral anticoagulants exceeds 4 hours and if commonly available anticoagulation markers are normal or subnormal, i.e., international normalized ratio of prothrombin time <1.7 and activated partial thromboplastin time <1.5 times the baseline value (≤40 seconds only as a guide). These criteria are partly supported by the findings of domestic multicenter and single-center surveys that symptomatic or asymptomatic intracranial hemorrhage following thrombolysis was rare under the conditions of the criteria. Even for dabigatran users, stroke thrombolysis can be considered without pretreatment by idarucizumab if patients meet the above criteria. If not, direct mechanical thrombectomy can be considered without pretreatment by idarucizumab or thrombolysis, and use of idarucizumab, followed immediately by thrombolysis, can be considered only when thrombectomy cannot be quickly performed. These clinical guides are practical and to some extent economical, but they have some limitations, including lack of corroborating information from sufficient numbers of relevant cases. The guides will be further modified based on the results of future research.

Idarucizumab for Emergency Reversal of Anticoagulant Effects of Dabigatran: Interim Results of a Japanese Post-Marketing Surveillance Study

“…Several case reports suggest that thrombolysis and thrombectomy can be performed safely after dabigatran reversal with idarucizumab [22,23]. Although these data are limited, recommendations have been published regarding acute reperfusion therapy with idarucizumab for patients with ischemic stroke receiving dabigatran [24,25].…”

MRI characteristics in acute ischemic stroke patients with preceding direct oral anticoagulant therapy as compared to vitamin K antagonists

“…Antiplatelet prescription did not affect group assignment. For the sensitivity analysis, we further defined confirmed therapeutic OAC as specific drug activity > 50 ng/ml in patients taking DOAC [11][12][13][14][15] and INR > 1.7 in VKA patients. If no specific drug activity was available in patients taking DOAC, confirmed therapeutic OAC was defined as reported previously [16].…”

Guidelines for Intravenous Thrombolysis (Recombinant Tissue-type Plasminogen Activator), the Third Edition, March 2019: A Guideline from the Japan Stroke Society

“…The above-mentioned nationwide questionnaire revealed that asymptomatic intracranial hemorrhage occurred in eight of 13 patients when IV thrombolysis or endovascular therapy was performed within 4 h after the last dosing of DOAC, suggesting that the incidence was higher than treatment beyond 4 h performed in four of 39 patients, and the potential risks were posed to provide IV thrombolysis early after the last dosing. 57) A single-center study also demonstrated that intracranial hemorrhage occurred in three of 11 patients treated with IV thrombolysis within 6 h after the last dosing of DOACs and in one of 11 patients receiving treatment beyond 6 h. 56) The third edition recommended that patients should be ineligible for IV thrombolysis if it is confirmed that thrombolysis is performed within 4 h of the last dose of DOACs, regardless of coagulation marker levels.…”

“…Of 48 reported patients treated with dabigatran who received IV thrombolysis followed by idarucizumab until February 2018, 30 were considered to show improvement in the mRS score of 0–2, and 3 were dead. 56) In Europe, where was reported in 35 of 48 patients, a growing body of clinical guides based on the expert opinion were published to recommend IV thrombolysis followed by idarucizumab. 58,59) The Consensus Guides on Stroke Thrombolysis and Thrombectomy for Anticoagulated Patients indicated detailed recommendations on acute reperfusion therapy in patients treated with dabigatran taking account of preceding guides from Europe and eligibility criteria on coagulation markers in Japan (Fig.…”

“…Cited from Special Working Group in the Committee on Medical Improvement and Social Insurance, Japan Stroke Society 6) and Toyoda et al 56) …”