Art of Anticoagulation After Recent Ischemic Stroke

David J. Seiffge, MD; Martina Goeldlin, MD

Disclosures

Stroke. 2020;51(9):2618-2619. 

Atrial fibrillation is a major risk factor for stroke and accounts for roughly 20% of ischemic stroke cases. Although therapy with direct oral anticoagulants (DOAC) and vitamin K antagonists (VKA) is well established, the question when and how to start therapy—the art of anticoagulation after a recent stroke—is a huge unmet need in current stroke medicine.[1]

The risk of early recurrent ischemic stroke is high among patients with a recent stroke and atrial fibrillation. Early initiation of anticoagulation is thought to protect patients from further damage due to early recurrence. However, recently infarcted brain tissue is vulnerable and anticoagulation might increase the risk of hemorrhagic transformation leading to increased morbidity and mortality.

All recent large randomized controlled trials comparing DOACs and VKA in patients with atrial fibrillation excluded patients with a recent stroke.[2] Furthermore, trial populations are only marginally representative for patients with acute stroke treated at stroke units and stroke centers.[3] In contrast, the HAEST trial,[4] published 20 years ago, enrolled patients with atrial fibrillation early and within 30 hours after recent stroke. They compared aspirin and low molecular weight heparin (LMWH) and found that LMWH increases the risk of intracerebral hemorrhage without reducing the risk of early recurrent stroke. Finally, current guideline recommendations are rather based on expert consensus than on high-quality data.

In this issue of Stroke, Yaghi et al[5] present data on this important topic, helping to guide clinical decisions. They analyzed data from 1289 consecutive patients with ischemic stroke and atrial fibrillation enrolled in prospective local stroke registries from 8 comprehensive stroke centers in the United States. They addressed 2 different questions: First, they investigated whether bridging (defined as LMWH or heparin before introduction of oral anticoagulants) compared with no bridging (no LMWH/heparin) before starting oral anticoagulation after a recent ischemic stroke is beneficial. They found that bridging was associated with an increased risk of delayed symptomatic intracranial hemorrhage (hazard ratio, 2.74 [95% CI, 1.01–7.42], P=0.047) but did not reduce the risk of recurrent ischemic stroke. Second, they compared DOAC and VKA-therapy and found that DOAC treatment was associated with a lower rate of recurrent ischemic events within 90 days (5.3% versus 10.0%; hazard ratio, 0.51 [95% CI, 0.29–0.87]; P=0.015) without a significant difference in rate of symptomatic intracranial hemorrhage (1.2% versus 2.0%; hazard ratio, 0.57 [95% CI, 0.22–1.48]; P=0.246). They thus conclude that DOACs without prior bridging therapy seem to have the most favorable risk-benefit-profile in patients with ischemic stroke and AF.

The authors should be complimented for running this collaborative, comprehensive study that reflects current practice in specialized centers in the United States. They analyzed a rich dataset and adjusted for many relevant (known) confounders including high-risk cardiac abnormalities (ie, presence of cardiac thrombus). However, unmeasured factors (such as infarct location and poststroke blood pressure control) and bias by indication may have influenced the results. Interestingly, roughly 15% of the patients received bridging therapy before starting any anticoagulation.

Their findings have direct clinical implications: (1) bridging with LMWH/heparin should be generally avoided. However, further studies enrolling more patients with high-risk cardiac abnormalities are needed to identify whether particular subgroups might have a benefit from bridging, accounting for the pharmacokinetic differences between unfractionated heparin and LMWH. (2) DOAC should be preferred over VKA after a recent stroke due to the growing body of evidence that they are associated with better outcomes. Interestingly and in contrast to another recent study from Europe and Japan[6] that found DOACs to be associated with lower risk of intracerebral hemorrhage but no difference in the risk of recurrent stroke, Yaghi et al[5] found that DOAC therapy decreased the risk of early recurrence but did not find any difference in rates of symptomatic intracranial hemorrhage. These conflicting results are possibly related to differing observational periods (90 days in Yaghi et al[5] and up to 5.4 years in the European/Japanese study) and diverging development of the risk of hemorrhage and stroke over time. However, both studies found that DOACs were associated with better outcomes compared to VKA.

Although the study by Yaghi et al[5] helps us with the how—avoid bridging, use DOACs—the when is still a matter of debate. Currently, 4 large randomized controlled trials—ELAN (Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischemic Stroke Patients With Atrial Fibrillation; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03148457), OPTIMAS (Optimal Timing of Anticoagulation After Acute Ischemic Stroke; URL: http://www.isrctn.com; Unique identifier: ISRCTN17896007), TIMING (TIMING of Oral Anticoagulant Therapy in Acute Ischemic Stroke With Atrial Fibrillation; URL: https://www.clinicaltrials.gov; Unique identifier: NCT02961348), and START (Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03021928)[1]—are enrolling >10 000 patients all together explore the optimal timing of DOAC therapy after a recent stroke. Their results are eagerly awaited.

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