No Extra Concerns for Stroke Treatment in Warfarin Users

Abstract

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, according to an observational study of more than 23,000 patients. The patients 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. Symptomatic intracranial hemorrhage (sICH) is associated with intravenous TPA and may occur more often in patients receiving warfarin, according to Dr. Ying Xian, who was lead investigator on the study 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 (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 nonwarfarin 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. In an accompanying editorial (JAMA 2012;307:2637–8), Dr. Mark J. Alberts wrote that the findings support the use of TPA for eligible patients. “The real risk is in not treating otherwise eligible patients, who may then have prolonged morbidity from their stroke,” said Dr. Alberts of Northwestern University in Chicago. Boehringer Ingelheim, Merck, Bristol-Myers Squibb, and Sanofi-Aventis have supported the Get With the Guidelines – Stroke program and Janssen Pharmaceutical Companies does currently. Several coauthors disclosed financial relationships with companies.