Standardized use of novel oral anticoagulants plasma level thresholds in a new thrombolysis decision making protocol

Abstract

Acute ischemic stroke (AIS) patients receiving non-vitamin-K antagonist oral anticoagulants (NOAC) are commonly excluded from thrombolytic therapy, as interpretation of coagulation tests remains unclear. We aimed to investigate the applicability of a novel institutional protocol for thrombolysis based on current expert recommendations and NOAC specific coagulation assessment. We included hospitalized AIS patients receiving NOAC for at least 24 h and consecutive AIS patients not receiving NOAC into a prospective study. We performed standard coagulation tests and specific tests for dabigatran, rivaroxaban and apixaban plasma levels. We studied 65 patients: mean age 72 ± 13 years, 30 (46 %) male, median NIHSS score 3 (IQR 6). Fifteen (23 %) were on NOAC treatment (5 dabigatran, 5 rivaroxaban, and 5 apixaban, respectively) and 50 (77 %) were not. In patients without NOAC, dabigatran was not detectable (0 ng/ml), and plasma levels of rivaroxaban (median: 10.0 ng/ml, IQR 7.0) and apixaban (7.2 ng/ml, IQR 6.7) were below our lower thresholds that allow thrombolysis. In patients with dabigatran pre-treatment, trough levels (58.0 ng/ml, IQR 143.0) were below our upper threshold that would allow thrombolysis in 3/5 patients. In patients receiving rivaroxaban, trough level (68.0 ng/ml, IQR 64.0) was below our predefined upper thresholds that would allow thrombolysis in 4/5 patients. In all patients on apixaban, trough level was above our predefined threshold of 40 ng/ml that precludes thrombolysis (98.2 ng/ml, IQR 84.3). Predefined thresholds of NOAC plasma levels in the decision of thrombolysis in NOAC treated AIS patients might supplement routine coagulation tests and should be validated in a larger study population.

Coagulation Testing in Acute Ischemic Stroke Patients Taking Non–Vitamin K Antagonist Oral Anticoagulants

“…12,13 The exploratory analysis was limited to patients presenting within a 4.5-hour time window. 7 The upper ranges of normal values of nonspecific coagulation tests, as well as peak and trough levels of NOACs, are summarized in the methods section in the online-only Data Supplement.…”

“…12,15,16 Following the protocol by Kepplinger et al, we used the INR threshold of <1.4 and performed a sensitivity analysis using an INR threshold of <1.2 to account for different thromboplastin reagents with different sensitivities. 13,17 …”

“…Table 3 summarizes the consequences if the suggested thresholds 12,13 had been applied for off-label thrombolysis in patients presenting within a 4.5-hour time window in RASUNOA. The number of patients theoretically eligible for intravenous thrombolysis based on coagulation parameters alone heavily depended on the decision protocol.…”

“…12,13 Notably, both protocols lack prospective validation of their safety. Post hoc application of these protocols to our cohort of NOAC-treated AIS patients showed large inter-and intraprotocol differences.…”

“…Mass spectrometry can provide reliable drug-level estimates but are usually unavailable in the emergency setting. 11 Importantly, although guidance for the interpretation of coagulation test result allowing safe thrombolysis in patients on NOAC treatment have been proposed, 12,13 data supporting their validity is limited. 11,14 The impact of time-consuming NOAC-specific coagulation testing in acute stroke management is currently unclear, and the actual use of these tests in clinical practice is unknown.…”