Dr David SeiffgeDavid Seiffge, MD
Results from a recent study suggest that direct oral anticoagulant (DOAC) therapy started early after recent atrial fibrillation-related ischemic stroke is associated with a lower risk for poor clinical outcomes, including intracerebral hemorrhage (ICH) and death, compared with vitamin K antagonists (VKA).

The study, led by Gian Marco De Marchis, PD, MD, MSc, of University Hospital Basel, provides class 2A and Level B evidence that DOAC therapy started in a median of 5 days following ischemic stroke in patients with atrial fibrillation is beneficial compared with VKA therapy.

“Our study has important clinical implications as it closes a gap,” said first author David Seiffge, MD, Stroke Research Center, department of brain repair and rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, in London. “There was no evidence about the risks and benefits of DOACs vs. VKA in patients with a recent ischemic stroke. The results of our study suggest that in patients with atrial fibrillation who had a recent stroke, DOACs should be used,” Seiffge told NeurologyLive. 

A pooled analysis of individual patient data from 7 prospective observational cohort studies was used to compare the clinical benefit of DOAC and VKA therapy in patients with atrial fibrillation who had an ischemic stroke or transient ischemic attack between Jan. 1, 2012 and July 2017. Only studies with a planned follow-up of at least 3 months after index event were included.

The cohort comprised 4912 patients treated with oral anticoagulants after recent cerebral ischemia related to atrial fibrillation; the median age was 78 years and 47.5% (n=2331) patients were female.

In 96.5% (n=4739) patients, the index event was ischemic stroke, and prior to the index event 54.1% (n=2658) of patients had no antithrombotic treatment, 8.7% (n=429) patients were on antiplatelet agents, 12.4% (n=607) were on VKA, and 23.5% (n=1153) were on a DOAC. Among the 2656 patients that were given a DOAC, 27.2% (n=723) took apixaban, 36.1% (n=959) dabigatran, 0.4% (n=11) edoxaban, and 33.1% (n=880) rivaroxaban; in 3.1% (n=83) of patients, the DOAC was not specified.

After the index event, 45.9% (n=2256) of patients received VKA therapy and 54.1% (n=2656) received any DOAC. The median time from index event to starting oral anticoagulation was 5 days for both groups. Overall, 81.3% (n=3993) of patients began VKA or DOAC therapy within the first 14 days after index stroke.

The primary outcome measure focused on time to occurrence of the composite endpoint of recurrent acute ischemic stroke, ICH, and mortality, while the secondary endpoints were the number of occurrence of each of these factors separately. The total follow-up time was 5970 patient-years; 3382 patient-years in the VKA group and 2588 patient-years in the DOAC group. Over the course of follow-up, 262 patients had acute ischemic stroke, 71 had ICH, and 439 patients died.

Compared to VKA, treatment with DOAC was associated with reduced risks for the composite endpoint (P = .05) and notably ICH (P <.01); however, there was no difference found for the risk of recurrent acute ischemic stroke (P = .05) and mortality (P = .09).
 
Dr Gian Marco De MarchisGian Marco De Marchis, PD, MD, MSc
These results reveal that treatment with DOACs started a median of 5 days after the index event is associated with lower risk of adverse outcomes compared to treatment with VKAs. The benefit was found to be consistent across subgroups, including those with either minor or severe strokes at baseline, those 80 years of age or older, those started on anticoagulants ≤7 days since index stroke, and those treated with acute recanalization therapies for index stroke.

“Our paper found that, DOACs started early after a recent ischemic stroke in patients with atrial fibrillation was associated with lower odds for a composite endpoint of recurrent stroke, ICH and death compared to VKA,” Seiffge explained. “This difference was mainly driven by a lower risk of ICH. We also provide evidence, that this finding was consistent among many important subgroups including patients with large strokes, elderly patients and those who received intravenous thrombolysis. This finding was expected as DOACs showed to have a favorable risk-benefit profile compared to VKA in many other indications but patients with a recent stroke had been excluded from all randomized controlled trials because they were feared to have an increased risk of ICH. Interestingly, the risk of ICH was very low in our study and significantly lower among patients who received DOACs.”

While the risk for ICH is low in patients with atrial fibrillation treated with DOACs for secondary prevention early after ischemic stroke, the optimal timing to initiate oral anticoagulation is unclear and is currently being investigated in 4 ongoing controlled clinical trials: ELAN (NCT03148457), TIMING (NCT02961348), OPTIMAS (EudraCT, 2018- 003859-38), and START (NCT03021928), Seiffge added.
REFERENCE
Seiffge D, Paciaroni M, Wilson D, et al. DOAC vs. VKA after recent ischemic stroke in patients with atrial fibrillation. Ann Neurol. 2019. doi: 10.1002/ana.2
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