What's the Right TIMING for NOAC After Ischemic Stroke?

Erik Greb

September 14, 2021

Early initiation of treatment with novel oral anticoagulants (NOAC) was noninferior to delayed initiation of treatment among patients with ischemic stroke and atrial fibrillation, new research shows.

In a randomized controlled study, the difference between treatment arms in the risk of a composite outcome that included recurrent ischemic stroke was 1.79%, favoring the group that underwent early initiation of NOAC.

Dr Signild Åsberg

"Based on these results, we believe that in most patients with an ischemic stroke in the setting of atrial fibrillation, it is reasonable to initiate NOAC within 4 days after stroke onset," investigator Signild Åsberg, MD, PhD, senior consultant at the stroke unit of Uppsala University Hospital, Uppsala, Sweden, told Medscape Medical News.

Åsberg and co-investigator Jonas Oldgren, MD, PhD, senior consultant in cardiology at Uppsala, presented the findings at the European Stroke Organization Conference (ESOC) 2021, which was held online.

Registry-Based Study

The literature contains little evidence from randomized controlled trials about the optimal time to start oral anticoagulation in patients with stroke and atrial fibrillation, the researchers point out. Guidelines do not provide evidence-based recommendations on this question.

The early initiation of highly effective anticoagulants with fast treatment onset, such as NOAC, could reduce the risk of recurrent ischemic stroke, but also carries the risk of intracerebral bleeding, they note.

The investigators conducted the TIMING study to investigate the efficacy and safety of early vs delayed initiation of NOAC. They used the Swedish Stroke Register to enroll patients at 34 stroke units into their noninferiority, open-label, blinded-endpoint study. Eligible patients were age 18 years or older, within 72 hours after ischemic stroke onset, and had atrial fibrillation.

The researchers randomly assigned patients in equal groups to early or delayed initiation of NOAC. Early initiation was defined as initiation within 4 or fewer days. Delayed initiation was defined as initiation within 5 to 10 days. The choice of NOAC was at the discretion of the investigator.

The study's primary outcome was a composite of first recurrent ischemic stroke, symptomatic intracerebral hemorrhage (sICH), or all-cause mortality within 90 days.  

In addition to the study population, the investigators registered a control cohort of patients with acute ischemic stroke and atrial fibrillation who received early or delayed NOAC within 10 days without randomization.

No Patient Had sICH

From April 2017 to December 2020, the researchers enrolled 888 patients and randomly assigned them to early or later treatment. The population's mean age was 78 years, and 46% were female. The control cohort included 9321 patients (also 46% female) with a mean age of 79 years. Follow-up duration was at least 90 days for all patients.

NOAC was most commonly started at day 2 to day 3 in the early-treatment group and at day 5 to day 6 in the delayed-treatment group.

There were 31 primary outcome events in the early group and 38 in the delayed group. The risk of the primary outcome was 6.89% in the early group and 8.68% in the delayed group. The difference in risk between groups was -1.79% in favor of the early group.

"Early start was shown noninferior to delayed start regarding the primary outcome," said Åsberg. "Importantly, no patient experienced sICH, and no patients were lost to follow-up at 90 days."

In addition, the rates of major bleeding events were low, the investigators note. There were 11 bleeding events overall, seven of which occurred in the early arm.

Dr Jonas Oldgren

"TIMING is the first large, randomized controlled study in the acute phase following atrial-fibrillation-associated ischemic stroke evaluating timing of initiation of only NOACs and assessing hard clinical endpoints," Oldgren told Medscape Medical News. The study addresses a gap in knowledge that has been identified in international guidelines and in the Stroke Action Plan for Europe, he added.

By conducting a registry-based investigation, the researchers "could combine the advantages of a prospective, randomized study design with the strengths of a national comprehensive clinical quality register," said Oldgren. Other areas of cardiovascular medicine previously have used this method successfully.

The investigators plan to explore the short- and long-term results of TIMING further. These efforts will include an examination of nonrandomized patients with acute ischemic stroke and atrial fibrillation who were registered in the Swedish Stroke Register but did not participate in TIMING.

"We hope that similar, currently ongoing randomized trials are successful, and we have, together with the primary investigators of those trials, already pre-planned a meta-analysis of our results in the future," said Åsberg.

No Algorithm for Anticoagulation

"The findings are consistent with prior retrospective studies showing the safety of early NOAC use in the setting of ischemic stroke," said Shadi Yaghi, MD, assistant professor of neurology at Brown University in Providence, Rhode Island, who commented on the study for Medscape Medical News.

A weakness of the study is that it included no algorithm for starting anticoagulation. "In practice, we typically start early in small strokes and delay anticoagulation in large strokes," said Yaghi. Yet the study benefited from its randomized design, blinded outcome assessment, and large sample size, he added.

The findings may have ramifications for neurologists' clinical practice. "Early NOAC use — four days or less from stroke onset — is potentially safe in most patients with acute cardioembolic stroke," said Yaghi. "The efficacy of early initiation needs testing in larger studies."

Dr Pooja Khatri

The decision about when to start direct oral anticoagulants (DOAC) is always a challenge, because the risk of recurrent stroke is higher earlier on, but the risk of hemorrhagic transformation of the ischemic stroke is also higher early on, said Pooja Khatri, MD, professor of neurology at the University of Cincinnati, Cincinnati, Ohio, who also commented on the findings for Medscape Medical News.

"Clinicians have to make a judgment based on the volume of the incident stroke, as larger strokes have greater risk, and typically start anticoagulation sooner for smaller strokes and later for larger strokes," she said.

In addition, the TIMING findings support those of earlier comparisons of various anticoagulants. "Prior nonrandomized data suggested that we could more safely start DOACs sooner than warfarin, in terms of risk of hemorrhage, and the results of the TIMING trial reinforced this," said Khatri.

The publication of additional details about the study could inform clinical practice, she added. "It would be very helpful to know the extent of infarct volumes — or stroke severity by NIHSS, if infarct volumes are not available —in the enrolled participants, compared to those not enrolled into TIMING within the registry." This information could clarify how generalizable these data are to individual patients, said Khatri.

"It would also be helpful to explore how infarct volume interacted with safety and specific timing of DOAC initiation to guide our clinical reasoning," she concluded.

The study was funded by the Swedish Research Council. Neither Åsberg nor Oldgren accepted any personal fees. Åsberg's institution received a research grant and lecture fees from AstraZeneca and Boehringer Ingelheim. Oldgren's institution has received lecture fees, and Oldgren has served as a consultant to or on advisory boards for, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Novartis, Pfizer, Portola, Roche Diagnostics, and Sanofi. Yaghi had no disclosures. Khatri had no disclosures.

Follow Erik Greb on Twitter: @MedscapeErik .

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