No Extra Concerns for Stroke Treatment in Warfarin Users

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Supports TPA Use in Eligible Patients

"These results are surprising, yet reassuring, because patients receiving warfarin were in general older and more likely to have atrial fibrillation and overall had more risk factors for intracranial hemorrhage," Dr. Mark J. Alberts wrote in an accompanying editorial.

The study was limited in part by the fact that the majority of the patients had INRs lower than 1.5. "The overall suggestion of slightly higher rates of intracranial hemorrhage among patients with higher INRs warrants further monitoring," he noted.

The findings, however, support the use of TPA for eligible patients, Dr. Alberts said. "The real risk is in not treating otherwise eligible patients, who may then have prolonged morbidity from their stroke."

Dr. Alberts is with the stroke program at Northwestern University in Chicago. He reported serving as a consultant for and receiving honoraria from Genentech and Boehringer Ingelheim, and serving as a consultant for Janssen and the Joint Commission. His comments are derived from an editorial accompanying the warfarin-TPA study (JAMA 2012;307:2637-8).



Thrombolysis with intravenous tissue plasminogen activator for the treatment of acute ischemic stroke does not increase the risk of brain hemorrhage in patients who are also taking warfarin, based on data from an observational study of more than 23,000 patients.

The patients in the study had an international normalized ratio (INR) of 1.7 or lower, which is the same population of warfarin-treated patients for whom intravenous tissue plasminogen activator (TPA) is recommended in the current American Heart Association/American Stroke Association guidelines.

Dr. Ying Xian

Symptomatic intracranial hemorrhage (sICH) is an adverse event associated with intravenous TPA that may occur more often in patients receiving warfarin, according to Dr. Ying Xian, who was lead investigator on the study, published June 26 in JAMA. But "the true absolute risk of sICH in this population remains a matter of significant debate," and previous studies of bleeding risk associated with warfarin have been small, with inconsistent results, wrote Dr. Xian of the Duke Clinical Research Institute in Durham, N.C. and his colleagues.

The investigators reviewed data from 23,437 adults in the American Heart Association’s Get With the Guidelines - Stroke Registry. The study participants were treated with intravenous TPA at 1,203 registry hospitals between April 2009 and June 2011 (JAMA 2012;307:2600-8).

A total of 1,802 (8%) of the patients were receiving warfarin at the time of treatment with TPA. A total of 1,107 patients (5%) developed sICH after TPA.

Although the unadjusted rate of hemorrhage was significantly higher in warfarin-treated patients, compared with non-warfarin patients (6% vs. 5%, P less than .001), there was no significant difference in hemorrhage rates after risk adjustment (adjusted odds ratio, 1.01). The results were similar regardless of whether or not the patients’ scores on the National Institutes of Health Stroke Scale (NIHSS) were excluded from the risk adjustment, the researchers noted.

Similarly, there was no significant difference in the rates of life-threatening or serious systemic hemorrhage between the warfarin and non-warfarin groups (0.9% for both) and no significant differences between the two groups in TPA complications (11% vs. 8%, respectively) or in-hospital mortality (11% vs. 8%, respectively).

"We found the potential for substantial undertreatment, because up to 50% of warfarin-treated patients who might have been eligible for reperfusion therapy did not receive intravenous TPA," the researchers wrote.

The results also indicated that there was no significant relationship between warfarin use and sICH in a subgroup analysis of patients with INRs between 1.5 and 1.7 or in an exploratory analysis of patients with INRs of 2.0 or lower.

The higher unadjusted incidence of sICH in warfarin patients may be a result of the differences in risk profiles between the warfarin and non-warfarin patients, because those receiving warfarin were significantly older and had higher NIHSS scores, the researchers noted.

The study was limited by several factors, including its retrospective design and a lack of NIHSS information for all patients. More research is needed to explore the effectiveness of intravenous TPA for patients with INRs outside of the range recommended by the guidelines, they added.

The study was supported in part by the American Heart Association – Pharmaceutical Roundtable and from David and Stevie Spina. Dr. Xian had no financial conflicts to disclose. Several coauthors disclosed financial relationships with multiple companies, including Boehringer Ingelheim, Merck, Bristol-Myers Squibb, and Sanofi-aventis, which have supported the Get With the Guidelines – Stroke Program in the past, and Janssen Pharmaceutical Companies of Johnson & Johnson, which currently supports it. Boehringer Ingelheim markets TPA in the United States as Activase.

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