Authors: Antonia Kleeberg, Peter A. Ringleb, Ioana Huber, Jessica Jesser, Markus Möhlenbruch, Jan C. Purrucker
Categories: Original Research, ischemic stroke, oral anticoagulation, thrombolysis
Source: Therapeutic Advances in Neurological Disorders
For patients experiencing ischemic stroke despite receiving therapy with direct oral anticoagulants (DOAC) and without endovascular treatment options, therapeutic prospects are currently dismal. Current guidelines recommend intravenous thrombolysis (IVT) only for patients who have received DOAC in very restricted settings, as an increased risk of bleeding is suspected. However, recent retrospective observational studies suggest that IVT is safe despite DOAC pretreatment.
To provide further evidence that IVT despite previous DOAC treatment is not associated with an increased risk of bleeding.
Observational retrospective study.
Demographic, clinical, and radiological data of patients who received IVT (+/− endovascular thrombectomy) despite DOAC pretreatment between June 2021 and January 2024 were analyzed using descriptive statistics, including DOAC plasma concentration at admission. Secondary intracranial hemorrhages and functional outcomes at 3 months were assessed. Since 2023, patients have been treated according to a modified local standard operating procedure at our hospital, allowing for IVT despite DOAC pretreatment regardless of DOAC plasma levels or the use of reversal agents.
Of 1821 patients treated with acute recanalization procedures during the study period, N = 35 had received IVT with (18) or without (17) additional endovascular therapy. Among these patients with a wide age range (42–97 years) and DOAC plasma concentrations up to 369 ng/ml, only one developed symptomatic intracranial hemorrhage. A favorable outcome (modified Rankin scale score 0–2) after 3 months was observed in 57% (20) of the patients.
IVT despite direct oral anticoagulation seems to be safe, even at advanced age and high DOAC plasma levels.
Keywords: ischemic stroke, oral anticoagulation, thrombolysis
Recent retrospective observational data have challenged the perception of an increased risk of intracranial hemorrhage in patients with acute ischemic stroke who were treated with intravenous thrombolysis (IVT) despite having received direct oral anticoagulants (DOAC).^1–6^ However, according to current guideline recommendations,^7,8^ IVT should only be performed in patients prescribed a DOAC if the last dose was taken more than 48 h prior to the stroke or if laboratory parameters indicate low plasma concentrations. In the largest cohort to date with documented intake of DOAC within the last 48 h, data were collected from 832 patients who received IVT despite DOAC treatment, including 355 patients who did not receive reversal treatment or were not selected by laboratory parameters prior to IVT.^ 2 ^ Compared to patients without prior DOAC treatment but who had received thrombolysis, no increased bleeding risk was observed.^ 2 ^ Based on these and further observational data^1–3,5,6^ and preclinical data,^9,10^ we liberalized our local standard operating procedures, which now allow thrombolysis despite DOAC treatment in patients within a 3-h time window, without waiting for laboratory results and regardless of the availability of reversal agents.^ 11 ^ In the absence of evidence from prospective randomized trials, data are now needed to confirm the previous observational data after the local standards were changed. Thus, we herein report additional safety data of patients treated with IVT despite being prescribed DOAC.
A prospective recanalization database was screened for consecutive patients with acute ischemic stroke who presented directly or were referred to our comprehensive stroke center (CSC) and received IVT and/or endovascular thrombectomy (EVT). The study period was limited to the period from June 2021 to January 2024 to generate a new cohort that was not included in the previously published multicenter analysis.^ 3 ^ All adult patients were included who had an acute ischemic stroke with an indication for IVT according to current guidelines and local treatment standards, and who had an ongoing prescription of DOAC with assumed or confirmed intake <24 h at the time of decision making for thrombolysis. We excluded patients who received EVT without intravenous or intraarterial thrombolysis. Patients were treated in our certified stroke unit or in the neurological intensive care unit.
In January 2023, our standard operating procedure (SOP) was updated to allow off-label IVT in patients known to have been prescribed DOAC (i.e. apixaban, dabigatran, edoxaban, or rivaroxaban). It now states that IVT can be considered despite oral anticoagulation with DOAC in case of ischemic stroke with disabling neurological deficits (which in most cases corresponds to a National Institutes of Health Stroke Scale (NIHSS) score of ⩾4) if the patient presents within an early time window (⩽3 h after symptom onset or last-seen-well), and if there is no history of major bleeding or severe microangiopathy. Prior to the update, we restricted thrombolysis to patients with an anti-Xa level of <30 ng/ml, in case of a factor Xa inhibitor treatment. In patients treated with the thrombin inhibitor dabigatran, the recommendation to administer the reversal agent idarucizumab prior to IVT was left unchanged. DOAC plasma concentrations are still routinely measured at hospital admission to determine the stroke etiology, but the results no longer influence the decision to perform thrombolysis or not.^ 11 ^
According to local standards and individual case characteristics, patients received a brain computer tomography (CT) or magnetic resonance imaging (MRI) prior to administering recanalization therapy and control brain imaging 12–24 h after therapy or earlier in case of clinical deterioration. Secondary intracranial hemorrhage was assessed by a board-certified neuroradiologist blinded to medical treatment and classified according to the Heidelberg Bleeding classification.^ 12 ^ Symptomatic intracranial hemorrhage (sICH) was defined according to the Safe Implementation of Thrombolysis in Stroke criteria.^ 13 ^ Functional outcomes before and after stroke were assessed using the modified Rankin scale score (mRS; range 0 (no symptoms) to 5 (severe disability, bedridden), or 6 (death)) by a rater not blinded to the therapy. Follow-up outcome 3 months after stroke was determined by outpatient assessments, standardized interviews, or rehabilitation reports, and the assessment was part of the prospective database. Neither age of >80 years nor pre-stroke disability constituted exclusion criteria for the recanalization therapies.
To characterize the demographic, clinical, and radiological data, we used descriptive statistics. For categorical data, the absolute and relative frequencies (count and percentage) are reported, and the distribution of continuous data is described as mean (SD) or median (interquartile ranges (IQRs)). The Kolmogorov–Smirnov test was used to ascertain the distribution of data. Due to the exploratory, observational character of the study, and owing to the relatively small patient groups, we refrained from statistical comparisons between the groups with and without thrombectomy. Analyses were conducted using IBM^®^ SPSS^®^ Statistics, V. 29.0.2. This study was performed in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.
Of N = 1821 patients treated with acute recanalization therapies during the 2.7-year study period, 281 (15.4%) were taking a DOAC. Of these, N = 35 (2%) were identified who had received IVT with (18) or without (17) additional EVT, despite ongoing prescription of a DOAC, and included in further analyses. See Figure 1 for the patient selection flow chart. In the 1.5-year period before liberalization of the local SOP, 9 patients were treated; in the 1.2-year period after liberalization, 26 patients were treated, a 3.7-fold increase.
Figure 1. Flow diagram of patient screening process.
Table 1 lists clinical and demographic characteristics. Briefly, the mean age was 77 (±13) years (range 42–97), 17 (49%) were women, and 26 (74%) had received factor Xa inhibitor treatment prior to IVT.
DOAC plasma concentrations were measured in 31 (89%), but the decision to perform thrombolysis did not depend on the results. Post hoc, admission plasma concentrations ⩾30 ng/ml were detected in 14 (45%) of the patients (IVTonly 59%, n = 10/17; IVT + EVT 29%, n = 4/14). The median DOAC plasma concentration was 24 ng/ml (IQR 6–80), range of 0.1–369 ng/ml, with median plasma concentrations of 40 ng/ml (12–103) in the group of IVT without EVT. Reversal treatment prior to IVT was only performed in patients receiving dabigatran, with idarucizumab administered in 8/9 (89%).
Any intracranial hemorrhage (aICH) developed in 7 (20%) (Table 2). Three of the seven ICH occurred in patients with a DOAC plasma concentration <30 ng/ml. One intracranial hemorrhage was classified as symptomatic (sICH) (3%, n = 1). In this patient, in whom thrombolysis was performed within a time window of less than 2 h and in whom a drug-specific anti-Xa level of 0.8 ng/ml was observed, a subarachnoid hemorrhage developed during thrombectomy of an M2-segment middle cerebral artery occlusion. Subsequently, in conjunction with further clinical deterioration due to a non-ST-segment elevation myocardial infarction, the best supportive care was offered and the patient died. Major extracranial bleeding and concomitant angioedema were observed in one patient with epistaxis, requiring otorhinolaryngology treatment. Post hoc, no relevant anti-Xa activity of the prescribed factor Xa inhibitor could be detected. Furthermore, two asymptomatic subarachnoid hemorrhages were observed, all of which occurred after thrombectomy.
In a sensitivity analysis excluding patients with prior reversal treatment (n = 8), the rate of sICH was 3.7% (1/27).
A favorable outcome (mRS 0–2) at 3 months was observed in 20 (57%) of the patients (see Table 3 for functional outcomes).
After the liberalization of local treatment standards, allowing now for IVT despite prior DOAC use with few remaining exceptions, the number of patients treated accordingly increased more than 3-fold. Nevertheless, despite no selection according to laboratory measurements prior to IVT, intracranial hemorrhage and especially sICH did not represent frequent complications. DOAC plasma levels were not associated with the occurrence of symptomatic or aICH.
Our findings are similar to reports from a mixed cohort of patients with and without selection or reversal approaches.^ 2 ^ In a multicenter retrospective analysis, we and others reported a rate of sICH within 36 h in 2.5% of patients who had recently taken DOAC (compared to 4.1% in the control group without DOAC).^ 2 ^ In the present study, the only symptomatic bleeding was attributed to the EVT approach in a distal segment of the middel cerebral artery, and no association with DOAC plasma levels was observed here. Furthermore, advanced age was not associated with increased bleeding risk in our cohort, the oldest patient treated with thrombolysis despite prior DOAC intake being 97 years of age. Functional independence was achieved in 57% of our population, whereas it was reached in 45% of DOAC intake patients in the aforementioned study, further supporting the safety and efficacy of IVT in patients with prior DOAC treatment.
In randomized clinical trials using alteplase for the treatment of acute ischemic stroke, symptomatic intracranial bleeding was observed in 3.7% after IVT, and fatal intracranial hemorrhage was reported in 2.7%.^ 14 ^ Compared to these data, our findings suggest no excess morbidity or mortality, despite off-label IVT treatment and inclusion of patients with more pre-stroke comorbidities and higher age. Recently, another observational study found no sICH in 49 patients treated with IVT despite DOAC use.^ 4 ^ Metanalyses of studies, including patients with wider time periods of last DOAC intake before IVT similarly suggest no increased risk of intracranial hemorrhage.^5,6^
Although more prospectively collected data are now needed to support these observations, all available evidence, including the data presented here, emphasizes the safety of offering IVT to patients despite DOAC treatment. Currently, the ACT-GLOBAL trial, a multicenter, randomized, open-label, blinded endpoint trial, is investigating the use of tenecteplase at different doses (the currently licensed dose of 0.25 mg/kg body weight and a reduced dose of 0.18 mg/kg body weight) or no IVT with and without additional EVT in patients receiving DOAC. This multifactorial trial aims to enroll 4000 patients and results will not be available until 2031 (ClinicalTrials.gov NCT06320431). Whether further randomized clinical trials, including alteplase, which is widely available and frequently used, are warranted despite any safety signals from observational data is still a matter of academic debate. However, trials across America and Europe are planned.
The strength of our study is that we provide real-world data, following up on a multicenter cohort study. Our study has limitations. The cohort size is small; thus, detailed statistical analyses are not possible, and the generalizability may be limited. Power analysis for sample size calculation was not performed since this is an observational study of all patients eligible from June 2021 to January 2024 in our CSC and the number of patients is limited. Further studies and collaborations with pooled analyses are needed to gain further insights into the validity of the results. Second, these data are only observational without a control group. There might also remain a residual selection bias, as the decision to perform off-label IVT is still an individual one, and factors influencing the decision are not available in detail for all patients. Furthermore, the median DOAC plasma concentration was relatively low and a significant part of patients (23%) received the reversal agent idarucizumab prior to IVT. However, previous studies have even shown an inverse association between DOAC plasma levels and the risk of bleeding after IVT.^ 2 ^ Even patients with actual non-intake or low plasma levels benefit from a liberalized approach since it avoids time-consuming waiting for laboratory tests prior to IVT.
Regarding the application of our findings for primary care physicians, they should be vigilant for breakthrough strokes in patients with DOAC intake and should not lose any time in admitting such patients to a primary or CSC to consider the use of IVT. Furthermore, patients hesitating to take a DOAC can be ensured that all medical treatment options for acute stroke remain—at least with liberalized local standard operating procedures.
The aim of gaining more data concerning the safety of IVT in patients taking DOAC is clinically highly relevant, as stroke despite DOAC pretreatment (“breakthrough stroke”) is a frequent event, and IVT remains the only established medical reperfusion therapy for acute stroke. Even though our study has limitations due to the small cohort size and retrospective design, the present data contribute to the increasing evidence that IVT is safe in patients taking DOAC.
The authors acknowledge Sherryl Sundell for language editing.
Antonia Kleeberg, Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
Peter A. Ringleb, Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany
Ioana Huber, Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
Jessica Jesser, Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
Markus Möhlenbruch, Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
Jan C. Purrucker, Department of Neurology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.