Are Thrombolytics for Stroke Safe for Patients on NOACs?

Recent use of non-vitamin K antagonist oral anticoagulants (NOACs) is not associated with increased risk for bleeding following treatment with intravenous alteplase for ischemic stroke, new data suggest.

In a prespecified, retrospective analysis of data from the GWTG-Stroke and ARAMIS registries, the risk for symptomatic intracranial hemorrhage (sICH) was not significantly different between patients who had been taking NOACs and those who had not (adjusted odds ratio, 0.88).

Dr Ying Xian

The data suggest that administering IV alteplase to patients with stroke who have been taking NOACs in the past 7 days is safe, investigator Ying Xian, MD, PhD, section head of research in stroke and cerebrovascular diseases, University of Texas Southwestern Medical Center, Dallas, told Medscape Medical News. "I don't think that this should be an absolute contraindication," for tissue plasminogen activator (t-PA).

The data were published online February 10 in the Journal of the American Medical Association.

GWTG-Stroke and ARAMIS

Although NOACs effectively prevent ischemic stroke associated with nonvalvular atrial fibrillation, each year a small proportion of patients taking these medications has a stroke. Current guidelines advise against IV alteplase, the standard reperfusion therapy, in patients who have recently taken NOACs, because of a perceived increased risk for sICH. Yet few studies have assessed the safety of alteplase in patients who took NOACs before their strokes.

The current investigators analyzed GWTG-Stroke and ARAMIS data to examine this question. GWTG-Stroke collects data on consecutive patients with ischemic stroke who are admitted to the hospital. ARAMIS includes patients who had an ischemic stroke while taking long-term anticoagulation therapy.

This analysis focused on patients who received IV alteplase within 4.5 hours of ischemic stroke onset between April 2015 and March 2020. Patients who were taking warfarin, an anticoagulant other than a NOAC, or several anticoagulants were excluded.

The primary endpoint was sICH within 36 hours after IV alteplase in patients who were taking NOACs, compared with those who weren't. Secondary safety endpoints included inpatient mortality and life-threatening or serious systemic hemorrhage within 36 hours. The investigators also assessed secondary functional outcomes, including independent ambulation, discharge location, freedom from disability (modified Rankin Scale score of 0 to 1), and functional independence (mRS of 0 to 2).

NOACs and Functional Outcomes

The current analysis included 163,038 patients (median age, 70 years; 50.9% men). Overall, 1.4% of patients were taking NOACs before the stroke, and 98.6% were not.

Patients who were taking NOACs were older (median age, 75 years) than those who were not (median age, 70 years). Patients who were taking NOACs also had a higher prevalence of comorbidities (such as atrial fibrillation or coronary artery disease) and had more severe strokes than those who were not (median NIH Stroke Scale [NIHSS] score, 10 vs 7). Finally, patients taking NOACs were more likely to receive endovascular therapy than whose who were not (18.8% vs 11.5%).

The unadjusted rate of sICH was 3.7% in patients taking NOACs and 3.2% in patients not taking anticoagulants. When investigators adjusted the data for NIHSS score and clinical factors, they found no significant difference in this outcome between groups. Similarly, there were no significant differences between groups in the secondary safety outcomes after data adjustments.

The secondary functional endpoints favored patients who were taking NOACs. These patients were significantly more likely to walk independently at discharge (aOR, 1.25), be discharged home (aOR, 1.17), be free of disability at discharge (aOR, 1.22), and be functionally independent at discharge (aOR, 1.27) than patients who were not taking anticoagulants.

One limitation of the study is that the time of the last NOAC dose was unknown, wrote David J. Seiffge, MD, senior physician in the department of neurology, Inselspital University Hospital, Bern, Switzerland, in an accompanying editorial. IV alteplase is considered safe if the last NOAC dose was taken more than 48 hours earlier.

In addition, the fact that less than 9% of otherwise eligible patients taking NOACs received alteplase raises concerns about selection bias. "It remains unclear whether additional selection criteria for patients with prior NOAC use are needed, and if so, which may be best," Seiffge notes.

Still, the results suggest that patients who were taking NOACs within 7 days before stroke and who received IV alteplase had better outcomes than patients who were not on oral anticoagulants before stroke. "This really emphasizes that there's a lot of opportunity to help these patients and save them from lifelong disability after stroke," said Xian.

The researchers are conducting a meta-analysis of individual patient-report data from around the world to determine whether IV alteplase is safe in patients who were taking NOACs within 2 days before stroke. "In our study, we only have 25 patients in that category," said Xian. "Hopefully, in the future, we will provide a more definitive answer for t-PA in the NOAC population."

A "Comprehensive" Study

The study was well done, thoughtful, and comprehensive, said Philip B. Gorelick, MD, adjunct professor of neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, who commented on the findings for Medscape Medical News. The large database that the researchers analyzed was one of the study's strengths, he said.

Dr Philip Gorelick

In addition to the small number of patients who received NOACs during the 48-hour period before stroke, a weakness of the study is the possibility of residual confounding, said Gorelick, who was not involved with the research. This weakness results from the nature of this observational registry study. "If we want to get more definitive results, we need to put the hypothesis of interest to a clinical trial format," he said.

Over time, data have suggested that it may be possible to loosen some of the original t-PA trial eligibility criteria established by the National Institute of Neurological Disorders and Stroke. "Practitioners should be giving some consideration to the use of alteplase when NOACs have been administered," said Gorelick. "It's really a case-by-case decision that has to be made, given the devastating consequences of stroke."

The GWTG-Stroke program is sponsored, in part, by Alexion Pharmaceuticals, AstraZeneca, Bayer, Johnson & Johnson, Novo Nordisk, Sanofi, and the Novartis, Boehringer Ingelheim, and Eli Lilly Diabetes Alliance. The ARAMIS registry is sponsored by Daiichi Sankyo, Genentech, and Janssen. Xian reported receiving grants from Genentech, Janssen, Daiichi Sankyo, the American Heart Association, and the National Institute on Aging and receiving personal fees from Boehringer Ingelheim.

JAMA. Published online February 10, 2022. Abstract, Editorial

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