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Friday, February 23, 2018

ONLINE FIRST: In the Clinic-Intracerebral Hemorrhage: In-Hospital ICH Mortality Worse with Warfarin than NOACs, Researchers Find


The odds of surviving an in-hospital intracerebral hemorrhage appear to be better for patients who have taken newer oral anticoagulants than those treated with warfarin, although not as good as for treatment-naïve patients, according to a new analysis of outcomes in a large stroke registry published in the February 6 issue of the Journal of the American Medical Association.

The researchers conducted a retrospective analysis of data in the American Heart/Stroke Association's Get with the Guidelines-Stroke (GWTG) database including 141,311 patients with ICH admitted from October 2013 to December 2016, at 1,662 GWTG stroke hospitals. GWTG-Stroke is an ongoing voluntary, continuous registry.

While prior use of warfarin or non-vitamin K antagonist oral anticoagulants (NOACs) was associated with a higher risk of a fatal intracerebral hemorrhage (ICH) compared with no prior use, patients who had taken NOACs were more likely to have favorable in-hospital mortality and disability outcomes, especially if warfarin was used together with antiplatelet therapy. Patients who had previously used NOACs were more likely to be discharged home and have better functional outcomes at discharge than those with prior use of warfarin.

The unadjusted in-hospital mortality rates were 32.6 percent for warfarin, 26.5 percent for NOACs, and 22.5 percent for no oral anticoagulants. Three month mortality for patients treated with warfarin was 52 percent compared with 25.8 percent for patients not receiving warfarin, and the risk increased further if warfarin dosages were at the higher limits of the accepted (INR) range.

Although NOACs are increasingly used to prevent thromboembolic disease, there are limited data on NOAC-related ICH. Currently approved NOACs include dabigatran, rivaroxaban, apixaban, and edoxaban.

"This is one of the largest studies of real-world clinical experience with anticoagulation-related ICH to date," said coauthor Gregg C. Fonarow, MD, the Corday Chair in Cardiovascular Medicine and Science and director of the Cardiomyopathy Center at the University of California Los Angeles Medical Center.

 "We found significantly increased odds of in-hospital mortality among patients with prior warfarin and antiplatelet therapy, but the difference was not seen in patients with prior NOAC treatment alone," he told Neurology Today. The difference was most pronounced if NOAC patients had also received antiplatelet treatment, although the number of such patients in the registry was small.

Even so, the findings may support using NOACs when a combination strategy is indicated, he said. "Many physicians are reluctant to prescribe NOACs rather than warfarin because they are new, and warfarin can be reversed with vitamin K. There has also been speculation that ICH severity might be worse in patients treated with NOACs, but we found little difference in stroke severity across the three groups of patients," he said.

While 63 percent of the ICH patients were admitted prior to the 2015 approval of the NOAC rescue agent idarucizumab, preceding use of NOACs was associated with lower odds of mortality and disability compared with prior use of warfarin for which an established reversal strategy could be applied.

"Patients with prior use of NOACs had worse ICH mortality than those without any history of NOACs, but even after considering comorbid conditions, mortality was much worse with warfarin," Dr. Fonarow said.


"This study provides important real-world data extending single center observational studies that have suggested that NOAC-related ICH is less severe when compared to warfarin-related ICH. That's the real message," said Kevin N. Sheth, MD, FAAN, chief of the division of neurocritical care and emergency neurology and director of the Neurosciences Intensive Care Unit at Yale School of Medicine and Yale New Haven Hospital in New Haven, CT.

This helps to explain the very strong safety and efficacy profiles seen in the many studies of atrial fibrillation-related stroke prevention comparing NOACs to warfarin, Dr. Sheth told Neurology Today. "The risk/benefit profile of NOACs in high-risk conditions needs to be studied in prospective trials, but this study helps to underscore the appropriate use of NOACs as the potential anticoagulation of choice."

Magdy H. Selim, MD, PhD, FAAN, professor of neurology and chief of the division of stroke and cerebrovascular diseases at Beth Israel Deaconess Medical Center in Boston, said the GWTG database lacks important information that needs to be included in evaluating mortality.

"The problem with GWTG is what is excluded from the database, and there are a number of factors that may have affected the results," he told Neurology Today. "One of the most important ones is the lack of information on whether or not a patient had a preexisting do-not-resuscitate order that could have limited whether they would have received aggressive care."

The GWTG database also does not include information on the size or location of the hemorrhage, also very important factors in ICH survival, he said, and there is a lack of information on whether reversal of coagulopathy was attempted in the patients.

"When patients come in on blood thinners, we usually do something to try to reverse the effects of these medications. This could have an impact on mortality, but there were no data on this."

Basically, the findings reaffirm what is already known about NOACs and warfarin risks, Dr. Selim continued.

"As neurologists, we already know that the mortality of anticoagulation-related ICH is high. The reluctance of some physicians to prescribe NOACs is largely because there hasn't been a reversal agent, but that is rapidly changing. Previous small studies have indicated that survival is better in patients who have been taking NOACs compared to warfarin. I think the main message here is that we should use NOACs because the risk of ICH is lower, not because they are associated with lower mortality after ICH."


Inohara T, Xian Y, Liang L, et al. Association of intracerebral hemorrhage among patients taking non-vitamin K antagonist vs vitamin-K antagonist oral anticoagulants with in-hospital mortality. JAMA 2018;319(5):463-473.​​