Starting DOACs Early After Ischemic Stroke Appears Safe

Starting direct oral anticoagulant (DOAC) therapy shortly after an acute ischemic stroke or TIA linked to atrial fibrillation (AF) seems to be an acceptable approach, a pooled analysis of eight observational studies suggests, although randomized trials are still needed to define the best timing.

Patients started on a DOAC within the first 5 days after an ischemic stroke or TIA did not have increased risks of intracranial hemorrhage (ICH) or recurrent infarct compared with those put on anticoagulation at a later time point, according to researchers led by Gian Marco De Marchis, MD (University Hospital Basel, Switzerland).

“The sevenfold higher risk of recurrent acute ischemic than ICH—with almost half of these occurring before DOAC-start—suggests that early DOAC start after AF-related acute ischemic stroke might be reasonable,” they write in a paper published recently online in the Journal of Neurology, Neurosurgery, and Psychiatry.

But conclusions drawn from observational analyses can only go so far, and De Marchis pointed out that a more-concrete answer will come from clinical trials like ELAN, OPTIMAS, TIMING, and START.

“The bottom line would be randomize, randomize, randomize,” De Marchis told TCTMD, “because we really need these randomized trials to give us the answer. Many physicians may be scared of randomizing people in a trial to an early start, and our results provide reassurance that it is not dangerous to randomize people in these trials because they don’t seem to bleed a lot.”

Mollie McDermott, MD (University of Michigan, Ann Arbor), who was not involved in the study, agreed. “This is reassuring that we are not hurting patients by starting anticoagulation early after acute ischemic stroke when patients have A-fib, but we won’t know for sure what the best thing to do is until we get the results of these randomized controlled trials,” she cautioned.

Timing Uncertainty

When to begin or restart anticoagulation with a vitamin K antagonist (VKA) or DOAC after an acute ischemic stroke to best balance the benefits of stroke prevention with the risks of bleeding remains uncertain. A recent study indicated that it isn’t harmful to initiate anticoagulation early on, hinting that the interval from 7 to 10 days after the stroke might be best.

A common rule of thumb, De Marchis said, is that anticoagulation can be started within a day of a TIA, a few days after a minor stroke, 6 days after a moderate stroke, and 12 days or later after a large ischemic stroke. But, he added, “this is not validated and it stems from the VKA era when you had a higher bleeding risk, and because of that the current practice varies a lot.”

The primary advantage that DOACs have over VKAs is a roughly 50% lower risk of ICH, although the pivotal trials of the newer agents excluded patients with recent ischemic strokes. Nevertheless, a prior meta-analysis of observational studies suggested that DOACs maintain an edge over VKAs early after an ischemic stroke.

To delve into the timing issue, De Marchis and his colleagues pooled data from eight prospective studies conducted in Europe and Japan. The analysis included 2,550 patients (median age 77 years; 47% women) with acute ischemic stroke or TIA related to AF who had DOAC therapy newly initiated or restarted within 30 days of the event. The researchers compared recurrent stroke and ICH risks in the 53% of patients who began treatment within the first 5 days with risks in the 47% of patients who initiated therapy after 5 days.

The overall rate of recurrent acute ischemic stroke within 30 days was 1.5%, with 43% of those infarcts occurring before DOAC therapy could be initiated. Just 0.2% of patients had an ICH, all after DOAC initiation.

After propensity-score matching, there were no differences between the late and early initiation groups in terms of recurrent ischemic stroke (adjusted HR 1.2; 95% CI 0.5-2.9), ICH (adjusted HR 6.0; 95% CI 0.6-56.3), or any stroke (adjusted HR 1.44; 95% CI 0.66-3.33).

Moreover, risk of a composite of recurrent ischemic stroke, ICH, or all-cause mortality was not influenced by the timing of anticoagulation, which was consistent across subgroups defined by stroke severity, age, kidney failure, and use of recanalization therapies.

An Individualized Decision

McDermott said that despite the possibility of confounding, this is a well-conducted observational study. She added that “the results are encouraging in that the risk of ICH after starting DOAC was very low in both groups, suggesting that early initiation of a DOAC is probably safe,” and that they support the need for the ongoing RCTs exploring the optimal timing.

In practice, the decision about when to initiate anticoagulation after a stroke is very much individualized, McDermott said, highlighting consideration of patient factors and the size and location of the infarct. If patients are immobile and at risk for blood clots, clinicians might want to start anticoagulation earlier, she said. On the flip side, for patients who have a stroke in their brain stem or have scans showing minor hemorrhaging in the infarct bed, it might make sense to push anticoagulation later.

De Marchis also highlighted imaging findings that go into the decision, noting that physicians will generally wait longer to start anticoagulation in patients with more microbleeds or white matter disease. They’ll also be more cautious in patients who have been treated with IV thrombolysis for the initial stroke or who have a generally elevated bleeding risk.

Both McDermott and De Marchis said they were surprised by the low event rates in the study, and McDermott saw that as having research implications. “It does impact the RCTs that are going on because the lower the rates of both outcomes, the more patients you have to enroll,” she said. “So it suggests that these trials are going to have to be large trials in order to answer the question that they’re trying to answer.”

One of the trials, TIMING, reported results in September at the virtual European Stroke Organisation Conference, showing that initiation of DOAC therapy within the first 4 days was noninferior to starting 5 to 10 days after a stroke. But the findings have not yet been published, and the field awaits the conclusion of the other RCTs.

“I think that the direction is pointing towards an earlier start, . . . but I really want to encourage people to randomize into these trials,” De Marchis said.