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Stroke Patients on Warfarin with Higher INR May Be Able to Safely Get tPA Why Some Stroke Neurologists Disagree

Fitzgerald, Susan

doi: 10.1097/01.NT.0000547817.85926.41
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A new study suggests that stroke patients on warfarin whose higher INRs would normally preclude IV thrombolysis can be given an infusion to reverse vitamin K antagonist-induced anticoagulation and then be immediately treated with recombinant tissue plasminogen activator.

Despite the widespread adoption in recent years of intravenous thrombolysis (IVT) to treat acute ischemic stroke, one group of patients poses a dilemma to doctors: those with atrial fibrillation who are taking a vitamin K antagonist such as warfarin. IVT is not recommended for stroke patients on anticoagulants if they have an international normalized ratio (INR) greater than 1.7 because they have an elevated bleeding risk.

A new study from France suggests a possible solution. It found that stroke patients on warfarin whose higher INRs would normally preclude IVT can be given an infusion to reverse vitamin K antagonist (VKA)-induced anticoagulation and then be immediately treated with recombinant tissue plasminogen activator.

The study, published September 7 as a brief report in Stroke, involved only 26 patients at a single center and was not a randomized-controlled trial, but it suggested that the approach was feasible and safe, and did not elevate the risk for intracerebral bleeding or other complications.

“Although based on a small series, our results are positive, offering a new potential therapeutic way if confirmed,” said lead investigator Nicolas Chausson, MD, PhD, of Paris Sud University and the Stroke Unit at Centre Hospitalier Sud-Francilien.

According to background in the study, vitamin K antagonists, including warfarin, remain the only recommended oral treatment for patients with mechanical heart valves.

Despite the availability of direct oral coagulants, VKA including warfare are still widely used for atrial fibrillation and remain the only recommended oral treatment for patients with mechanical heart valves, said Dr. Chausson, whose collaborators included Didier Smadja, MD.

However, the annual acute IS risk is as high as (approximately) 1.7 percent for VKA-treated atrial fibrillation patients, occurring despite 30 percent of them having an international normalized ratio (INR) greater than or equal to 2, the study authors wrote. Guidelines from the American Heart Association/American Stroke Association do not recommend IVT for AIS patients with an INR greater than 1.7.

The researchers said animal studies have suggested that IVT could be dangerous for patients with an INR >1.7, though the possiility has not been clearly evaluated in humans.

The introduction of mechanical thrombectomy (MT) has provided a new treatment option for patients whose clots are reachable with the endovascular stent retriever therapy, making INR levels not such a deciding factor in how to treat a stroke patient. But mechanical thrombectomy is not available in many hospitals and when it is, it may be used in combination with IVT.

“MT is universally considered as the first option in patients with a proximal occlusion, whether they take VKA or not and whatever the INR level is,” said Dr. Chausson in an email to Neurology Today. But in VKA patients with an INR >1.7 and whose brain clots are not reachable by MT, a drug reversal technique could allow for the administration of IVT, he said.

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The researchers tested the technique on 26 patients who otherwise would have been eligible for IVT except that their INR values were >1.7. The study group had an average age of 77.8 and an average INR of 2.3.

To reverse the Vitamin K antagonist, patients were given an infusion of four-factor prothrombin complex concentrate and Vitamin K. IVT was then immediately initiated without waiting to see the results of INR testing following the reversal. INR levels were on average 1.3 immediately post-reversal, and levels were also measured at five minutes, four to six hours, and 24 hours past VKA-reversal. Addition reversal therapy was given if INR values remained high.

The patients were assessed clinically and by brain imaging (magnetic resonance imaging and computed tomography), electrocardiography, and hemoglobin levels.

The researchers reported that no symptomatic intracranial hemorrhage or thrombotic events occurred during the first three days, although two of 26 patients (7.7 percent) had recurrent acute ischemic stroke before restarting anticoagulation. (Researchers said that was inconsistent with what is expected.) One patient developed major systemic hemorrhoidal bleeding on day two that required blood transfusion.





At three months, 61.5 percent of the patients were considered independent based on a modified Rankin Scale score of < or equal to 2.

Dr. Chausson said his team is planning a large controlled study to confirm “our encouraging first results,” and they hope it will be carried out at multiple centers.

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Sara K. Rostanski, MD, assistant professor of neurology at NYU Langone Medical Center and medical director of stroke at Bellevue Hospital, said “the results of this study provide an intriguing basis for a larger randomized trial.” But she cautioned, “I wouldn't recommend a change in current practice based on these findings.”

Dr. Rostanski noted that the reversal approach, if proven to be safe and effective in a larger trial, would only apply to a small subset of patients, since patients who are on warfarin with an INR >1.7 are candidates for mechanical thrombectomy if their stroke is due to a large vessel occlusion. She said the use of warfarin is declining as newer anticoagulants come along, though it is used for mechanical heart valves.

Joseph Schindler, MD, associate professor of neurology and neurosurgery at Yale University School of Medicine, said “physicians face complex decision-making when treating an acute ischemic stroke patient while on anticoagulation. The major dilemma is whether the benefits of IV alteplase administration outweigh the risk of symptomatic hemorrhage.”

He said the new study using drugs to reverse VKA, followed by IVT, was done between 2012 and 2015, before mechanical thrombectomy was more widely available. He said many of the patients in the study, particularly those with large vessel occlusions, today would be given that procedure

“It is premature to incorporate this (reversal method) into clinical practice,” Dr. Schindler, director of the Yale-New Haven Comprehensive Stroke Center and Telestroke Services, said in an email to Neurology Today. “Patients are on warfarin for a myriad of conditions and there is likely to be an increased risk of thrombosis reversing patients who have a hypercoagulable state from a blood disorder. In my experience, patients who develop clots in the setting of therapeutic anticoagulation have an advanced or severe underlying disease state, and IV alteplase may not alter the outcome.”

AHA/ASA guidelines for early management of acute ischemic stroke set >1.7 INR as the cutoff for IVT, he said, but the reversal technique is worth further study in patients with distal embolic occlusion, who likely can't benefit from mechanical thrombectomy.

Mark J. Alberts, MD, professor of neurology at University of Connecticut Medical School, said there are studies in the medical literature showing “increased bleeding risks with INR >1.7,” and he doubts the reversal technique combined with tPA administration, would gain much traction in the US.

“It is outside our guidelines,” he said, of using tPA on patients with an elevated INR. “And unlike Europe, we have a lot of lawyers looking for business.”





Dr. Alberts, chief of the department of neurology at Hartford Hospital, also questioned the sensibility of the reversal approach. “Reversing warfarin to then use tPA seems illogical to me. Plus, it takes time to reverse the INR. Time is brain,” he said in an email.

The average door-to-needle time reported in the French study was 82 minutes; stroke onset to treatment time was 238 minutes, just under four hours.

Eric Peterson, MD, professor of medicine at Duke University, said: “The new therapy is promising, but there are potential downsides to the strategy described in the French study, including time delay to obtain and administer the reversal agent, the expense of the agent, and the potential for causing a thrombotic event as a result of restoring coagulation.”

He headed a large study published in the Journal of the American Medical Association in 2017 that looked at the risk of intracranial hemorrhage among AIS patients treated with tPA who were on warfarin (some with INRs 2.0 or greater).

“While the study was non-randomized, even those with elevated INR generally did well,” Dr. Peterson said.

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•. Chausson N, Soumah D, Aghasaryan M, et al Reversal of vitamin K antagonist therapy before thrombolysis for acute ischemic stroke Stroke 2018; 49(10):2526–2528.
© 2018 American Academy of Neurology