Bahar M. Beaver, MD

Macha K, Marsch A, Siedler G, Breuer L, Strasser EF, Engelhorn T, et al. Cerebral Ischemia in Patients on Direct Oral Anticoagulants: Plasma Levels Are Associated With Stroke Severity. Stroke. 2019;50:873–879.

Although anticoagulation is standard of care for secondary prevention in patients with cardioembolic stroke and non-valvular atrial fibrillation (a-fib), we often see recurrent strokes in patients taking vitamin K antagonists (VKA) or direct oral anticoagulants (DOACs). This group of authors at the University Medical Center in Erlangen, Germany, performed an observational study using a patient registry in order to correlate oral anticoagulant activity and plasma levels with severity of ischemic stroke.

From the Erlangen Registry of Patients on Oral Anticoagulation (ER-NOAC), 460 patients with acute ischemic stroke while on oral anticoagulation for a-fib were selected from November 2014 to October 2017. Of these, 234 (50.9%) were on DOAC, and 226 (49.1%) were on VKA. Functional plasma levels were assessed in the patients on DOAC, and the results were broken down by low (<50 ng/ML), intermediate (50-100 ng/mL), and high (>100 ng/mL). For patients on VKA, the threshold INR was set at 1.7. From the 226 patients on VKA, 41.2% had an INR below 1.7. The investigators correlated the various lab findings to NIHSS at time of presentation.

The study found that lower plasma levels of DOAC correlated with higher stroke severity. Similarly, patients on VKA with INR <1.7 had higher NIHSS at time of presentation. Moreover, the occurrence rates of large vessel occlusions (LVO) were higher in patients whose plasma levels and INR were low or subtherapeutic, respectively. They also concluded that low antithrombotic activity is an independent predictor of vessel occlusion, whereas high plasma levels are protective against it.

This observational study has several limitations. First, the investigators did not further break down INR beyond the set threshold of 1.7. There was no quantitative information on what INR best correlated with protection against ischemic stroke, or at what point the rate of hemorrhagic complications increased. Second, the total sample size of 460 is rather small. Though the results of the study are somewhat intuitive and help to support the notion that compliance with antithrombotics is protective against ischemic strokes, a larger cohort would be necessary to further solidify this. Lastly, the authors did not account for other medications, including antiplatelets, statins, or antihypertensives — all of which could also impact risk of ischemic stroke.

Despite these limitations, however, this is an important study to highlight that the level of antithrombotic activity does impact risk of ischemic stroke in patients with nonvalvular afib. One interesting point about this article from Germany is that the breakdown of anti-Xa levels is based on their institutional policy for decision making regarding IV tPA administration in patients on DOACs. Though this is not a validated scale, it would be interesting to see more studies specifically geared toward investigating these levels and their impact on outcomes with IV tPA. One final consideration is whether these values could later be used to gauge DOAC activity and efficacy and help guide dose titrations. Although one advantage of DOACs over VKA is the lack of routine blood monitoring, it may be beneficial to have a validated scale for those patients whose renal function affects their ability to metabolize DOACs, which could lead to more personalized dosing of the medications.