Song J. Kim, MD

Giustozzi M, Acciarresi M, Agnelli G, Caso V, Bandini F, Tsivgoulis G, Yaghi S, Furie KL, Tadi P, Becattini C, et al. Safety of Anticoagulation in Patients Treated With Urgent Reperfusion for Ischemic Stroke Related to Atrial Fibrillation. Stroke. 2020;51:2347–2354.

While the optimal timing of initiating or resuming anticoagulation in patients with acute strokes is said to be generally within 3-14 days, a treating neurologist may pause to consider the impact of recent IV thrombolysis or mechanical revascularization. Pharmacological thrombolysis carries an increased risk of brain hemorrhage, and reperfusion injury is a concern in the latter group of patients. At the same time, these potential adverse events must be weighed against the risk of recurrent thromboembolic events while anticoagulation is being held.

To address this issue, Giustozzi et al. set out to examine the incidence of both ischemic and hemorrhagic events in patients receiving anticoagulation following reperfusion therapies, as compared to untreated patients. The authors tapped into the RAF and RAF-NOAC datasets, which are prospective observational studies of patients receiving anticoagulation following stroke due to non-valvular atrial fibrillation. Primary outcome was the composite of any ischemic strokes and symptomatic intracranial hemorrhages, as well as other systemic embolism and bleeding events at 90 days. Furthermore, the authors conducted a multivariate logistic regression models to identify independent predictors of increased risk for the primary outcomes.

The treated group (n= 564, receiving IV thrombolysis, mechanical thrombectomy, or both) were more likely to be younger, with history of diabetes, previous strokes, CHADS-VASC >5, lower lesion volume and greater NIHSS at presentation compared to the untreated group (n=1595). Percentage receiving oral anticoagulation was comparable between the groups (90% vs. 81%, p=0.147) and started at a similar time interval from the index event (7.6 vs. 7.0 days, p=0.287). At 90 days, there was no difference between the two groups in the composite primary outcome (Adjusted OR, 0.85; 95% CI, 0.53–1.36), or in the secondary outcomes of ischemic and hemorrhagic event separately examined. After propensity score 1:1 matching to adjust for baseline differences, acute reperfusion treatment did not increase the primary outcome, nor the secondary outcome of ischemic and hemorrhagic event. When the analysis was limited to patients receiving IV thrombolysis only, there was a significant lower risk of primary outcome than compared to the non-treatment group. In the multivariable analysis, small infarcts (<1.5 cm) were less likely to result in hemorrhagic complications (OR 0.43; 05% CI, 0.22-0.85, p=0.013), and higher CHADS-VASC score was associated with ischemic events (OR 1.29; 95% 1.07-1.56, p=0.008).

The authors conclude that in patients started on oral anticoagulation for recent strokes due to A-fib, acute reperfusion therapies did not appear to increase early recurrence or major bleeding. However, the number of experiencing adverse events was relatively low, and only a small subset of patients underwent mechanical thrombectomy (57 out of 564), thus limiting our interpretation of the findings with regards to a growing number of patients who undergo endovascular reperfusion. The multivariable analysis also revealed a trend toward favorable outcome in small lesion size (<1.5 cm). However, the infarct volume was drawn from an unspecified point (pre-treatment vs. post-treatment?); the dichotomously reported lesion volume at a very small threshold is also too simplified for a variable that is perhaps the most important patient factor in determining the timing of anticoagulation. Also, notably absent from the analysis was the final post-treatment NIHSS. Use of final infarct volume and post-treatment NIHSS — factors used to determine timing of early anticoagulation — would be better aligned with real-life clinical decision-making.

There are currently 4 randomized prospective trials ongoing (ELAN, TIMING, OPTIMAS, START) in investigating the optimal timing of anticoagulation in acute stroke. Giustozzi’s work forms the basis to further examine the role of reperfusion therapies on the outcome of early anticoagulation as we await the results of these trials.