Thrombolytic use in select stroke patients with recent direct oral anticoagulant (DOAC) ingestion did not raise the risk of the most feared bleeding complication, according to the largest-yet observational dataset.
In fact, the 832 such patients receiving off-label IV thrombolysis within the standard time window for ischemic stroke actually experienced a lower incidence of symptomatic intracranial hemorrhage (sICH) within 36 hours compared with controls without anticoagulant use in the prior 48 hours (2.5% vs 4.1%; adjusted OR 0.57, 95% CI 0.37-0.92), reported David Seiffge, MD, of Bern University Hospital in Switzerland, and colleagues.
This “counterintuitive” finding was consistent across the different selection strategies for IV thrombolysis — DOAC-level measurements, DOAC reversal with idarucizumab (Praxbind), or neither. It also held up in people with very recent DOAC intake and persisted after accounting for mechanical thrombectomy, large vessel occlusion, and concomitant antiplatelet therapy, the investigators reported in JAMA Neurology.
“Given the established benefits of IV thrombolysis and the absence of any signal for harm in our study or in other clinical studies or preclinical investigations, future guideline updates need to reconsider recent DOAC ingestion as a contraindication to IV thrombolysis for acute ischemic stroke,” they urged.
In theory, recent DOAC use — taken for stroke prevention or a growing list of other indications — might protect against sICH through mechanisms related to faster recanalization, smaller infarct volumes, and thrombin inhibition against sICH, Seiffge and colleagues suggested.
They reported that recent users of DOACs who received IV thrombolysis had first been given reversal agents in 30.3% of cases, had measurement of DOAC levels in 27.0%, and neither in 42.7%.
“Notwithstanding the small number of patients in each group, it is reassuring to see that rates of sICH were comparable among these selection strategies,” commented Eva Mistry, MBBS, MSCI, a vascular neurologist at the University of Cincinnati.
“However, the study lacks data on recently emerging anti Xa measurement-based selection for thrombolysis. Anti-Xa level measurement is potentially more widely available compared to DOAC level measurement and correlates well with drug levels,” she wrote in an accompanying editorial.
The retrospective cohort study spanned 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand and included consecutive adult patients with ischemic stroke from 2008 to 2021. Thrombolysis consisted of alteplase (Activase) in the bulk of cases, with few individuals receiving tenecteplase (TNKase).
Included were 832 patients who had used a DOAC within 48 hours of thrombolysis — a fairly large addition to the limited literature — compared against 32,375 controls without recent anticoagulant use. Notably, the control population was treated across a somewhat different time frame than the thrombolysis patients and came only from European centers, some of which did not contribute to the DOAC arm of the study, Mistry cautioned.
The overall study cohort had a median age of 73 years and 43.5% women. Median NIH Stroke Scale score was 9, and time from stroke onset to thrombolysis was 138 minutes.
Compared with controls, patients with recent ingestion of DOACs were older and had a higher prevalence of hypertension but less smoking, had greater pre-stroke disability and more severe strokes, waited longer for treatment, and were more likely to have a large vessel occlusion.
The DOACs that had most commonly been ingested prior to stroke were dabigatran (Pradaxa, 41%), rivaroxaban (Xarelto, 31%), and apixaban (Eliquis, 20%).
The study’s nonrandomized design left room for potential confounding and bias, the authors acknowledged.
“Despite the limitations of the study design and enrolled population, these data may be used by clinicians to make individualized decisions regarding thrombolysis among patients with recent DOAC use. Importantly, this study lays the foundation for prospective, well-powered studies that definitively determine the safety of thrombolysis in this population,” according to Mistry.
However, Seiffge and colleagues said a randomized trial designed to assess the safety of thrombolytics in patients with recent ingestion of DOACs is unlikely to be financed or completed in a timely fashion.
The study was supported by a grant from the Bangerter-Rhyner Foundation
Seiffge reported personal fees from Bayer, Alexion, and VarmX.
Mistry disclosed receiving grant funding from the National Institute of Neurological Disorders and Stroke and consulting for RAPID AI.
Source Reference: Meinel TR, et al “Intravenous thrombolysis in patients with ischemic stroke and recent ingestion of direct oral anticoagulants” JAMA Neurol 2022; DOI: 10.1001/jamaneurol.2022.4782.
Source Reference: Mistry EA “Building evidence on safety of thrombolysis for patients undergoing direct oral anticoagulant treatment” JAMA Neurol 2022; DOI: 10.1001/jamaneurol.2022.4765.