International Stroke Conference
February 6–8, 2019
Kat Dakay, DO
As direct oral anticoagulants have gained increasingly widespread use and expanding indications, there has been a growing interest in their efficacy, pharmacokinetics, and reversal. At ISC 2019, an invited symposium focusing on this topic was co-moderated by Dr. Bruce Ovbiagele, MD, MSc, MAS, MBA, from USCF and Dr. Kazunori Toyoda, MD, from the National Cerebral and Cardiovascular Center in Osaka, Japan.
The first speaker, Dr Maurizio Paciaroni, MD, of the University of Perugia, discussed the efficacy and risk of DOACs using real-world data; he discussed many factors contributing to patients who have acute ischemic stroke while on a DOAC. One factor discussed was patient compliance; unfortunately, by one year post-DOAC initiation, about half of patients are not compliant with their medication at least 80% of the time. Another factor discussed were patients with very high CHADS-2-vasc scores who have a high cardiovascular risk. In some patients, the dosage prescribed may be lower than what is indicated given their renal function and weight, and this may provide inadequate protection. He discussed that there is limited data regarding when to initiate a DOAC in a patient who has had a recent stroke and an indication for anticoagulation, as the clinical trials did not enroll patients with very recent strokes.
Dr. Truman Milling, MD, associate professor at Dell Medical Center and deputy director of the Seton/UT Southwestern Clinical Research Institute, spoke about reversal agents in patients with an intracerebral hemorrhage who are anticoagulated. Earlier that day, Dr. Milling had presented the full study results of the ANNEXA-4 study, a prospective open-label study of andaxanet alfa, a reversal agent administered to patients with life-threatening hemorrhage (both systemic and intracranial) who are anticoagulated on a Xa inhibitor, at the main session. The study, published on NEJM (https://www.nejm.org/doi/full/10.1056/NEJMoa1814051?query=featured_home) demonstrated pharmacologic and clinical efficacy in hemostasis by twelve hours in a majority of patients. He discussed studies demonstrating superiority of PCC to plasma in reversal of vitamin K antagonists (Sarode et al Circulation 2013, Goldstein et al Lancet 2015). Ciraparantag, a small molecule reversal agent for DOACs and heparins that is currently under investigation for anticoagulant reversal, was briefly mentioned as well. An emergency medicine physician as well as a clinical researcher, Dr. Milling urged the audience to be as fast as possible with regards to reversal agents — most hematoma expansion happens shortly after the inciting event, and it isn’t just the mechanical injury that causes damage but also the inflammation caused by reactive oxygen species and blood brain barrier breakdown that leads to neurologic injury.
Dr. Ashkan Shoamanesh, MD, from McMaster University, echoed these sentiments — he warned the audience that an anticoagulated patient with an intracerebral hemorrhage that appears clinically well is at a risk of deterioration, and reversal should be initiated quickly. He advised the attendees on systems of care measures that could help reduce the time to reversal — these included having a point-of-care INR test available, a readily available printed protocol, and having PCC on stock. He illustrated the importance of early reversal with clinical cases, showing the potential for a good outcome in a patient who presented shortly after symptoms who was expeditiously reversed. I found the inclusion of practical quality improvement information to be very helpful to those of us trying to improve speed of anticoagulant reversal.
Lastly, Dr. David Seiffge, MD, from Basel University Hospital in Switzerland, spoke about the opposite scenario — patients who suffer an ischemic stroke while on Xa inhibitors, and whether these patients could be considered for thrombolysis. He talked about the wide practice variability with regards to this topic, and polled the audience about their opinions on a patient scenario. The heterogeneity of the audience responses indicated that there is a need for more data and research on this issue. He discussed the differences in pharmacokinetics between reversal of Vitamin K antagonists with PCC, which is repleting coagulation factors, and reversal of Xa antagonists with the newly developed antidotes — which bind to the drug with high affinity preventing its biological activity rather than by enhancing coagulation directly. He summarized some research regarding tPA in patients on rivaroxaban (Seiffge et al J Stroke 2017, Touze et al European Journal Neurology 2018). Additionally, the circulating dose of DOACs measured in the blood may be lower than therapeutic range in many patients (Seiffge et al Ann Neurol 2018). He also highlighted the multitude of biological effects of thrombin aside from its most notorious role in the coagulation cascade; in addition, it is also cytotoxic, increases vascular permeability, and can lead to microthrombosis of distal vessels. The ARTSS-2 trial was briefly mentioned; this was an exploratory study of argatroban plus tPA in patients with acute ischemic stroke which showed no increase in ICH risk. However, it was not designed to evaluate the efficacy of this treatment. Further studies are needed to evaluate the utility of this approach; although not mentioned in this talk, the MOST trial is a forthcoming multi center randomized controlled trial studying the effects of adding additional antithrombotic medications to tPA, and one of the arms is evaluating argatroban.
As one may tell from reading the above, this was a very informative symposium about the data surrounding DOACs, both on ischemic and hemorrhagic stroke, and it was presented in a very accessible manner. This was a very clinically relevant and focused discussion on a very important topic; although there has been a considerable body of research on the impact of DOACs in patients with ischemic and hemorrhagic stroke, more data is needed in particular with the issue of tPA consideration in patients on DOACs.