Warfarin-treated patients have an increased risk for symptomatic intracerebral hemorrhage after treatment with IV t-PA, even if their blood-clotting function appears normal, according to researchers.
Patients treated with warfarin are more likely than those not receiving warfarin to have symptomatic intracerebral hemorrhage following treatment with IV t-PA for acute ischemic stroke, according to a study in the March 8 online Archives of Neurology. The finding was observed even though patients had a baseline international normalized ratio (INR) less than 1.7, per American Heart Association/American Stroke Association guidelines, Shyam Prabhakaran, MD, and colleagues reported.
Warfarin After t-PA for Stroke
Dr. Prabhakaran’s group conducted their retrospective study involving 107 consecutive patients with acute ischemic stroke who were treated with IV t-PA. All subjects (mean age, 69.2; 43.9% men; 26.1% white) had undergone acute revascularization therapies, including IV t-PA, intra-arterial t-PA, and mechanical embolectomy. Data collection included baseline demographic characteristics, medical history, initial NIH Stroke Scale (NIHSS) score, CT imaging findings, and onset-to-treatment time for IV t-PA. Warfarin use was defined as self-report or family report of current use prior to admission.
The investigators compared the frequency of symptomatic intracerebral hemorrhage among warfarin-treated patients to those who did not receive warfarin with use of the Fisher exact test. “Because baseline imbalances between those treated with warfarin and those not treated with warfarin may confound this relationship, we also assessed differences between patients with and without prior warfarin therapy using univariable tests as appropriate,” stated Dr. Prabhakaran, of the Department of Neurological Sciences, Rush University Medical Center in Chicago, and colleagues.
The median initial NIHSS score among participants was 14, and the median time to treatment with t-PA was 140 minutes. The median INR was 1.04 (range, 0.82 to 1.61). Thirteen subjects (12.1%) were using warfarin at baseline, and all had INRs less than 1.7 prior to t-PA administration (median INR, 1.21). Patients receiving warfarin were older than those who were not taking warfarin (mean age, 80.6 vs 67.6, respectively), more likely to have atrial fibrillation (69.2% vs 19.1%), and more likely to have a higher initial INR (mean, 1.21 vs 1.03).
The researchers observed seven cases of symptomatic intracerebral hemorrhage (6.5%) and three incidents of asymptomatic intracerebral hemorrhage (2.8%) within 36 hours after t-PA administration.
“The frequency of symptomatic intracerebral hemorrhage was higher among warfarin-treated patients than among patients not taking warfarin (30.8% vs 3.2%, respectively),” the authors wrote. “Patients with symptomatic intracerebral hemorrhage compared with those without symptomatic intracerebral hemorrhage also had higher trends for higher initial NIHSS scores (median, 18 vs 13, respectively) and longer onset-to-treatment times (mean, 159 vs 137 minutes, respectively). In an exploratory logistic regression model adjusting for age, NIHSS score, atrial fibrillation, and initial INR, baseline warfarin use remained strongly associated with symptomatic intracerebral hemorrhage.”
At Risk for Symptomatic Intracerebral Hemorrhage
“We found that baseline warfarin use, despite an INR less than 1.7, increased the risk of symptomatic intracerebral hemorrhage,” the authors commented. “Controlling for some potential confounders, warfarin use remained strongly associated with symptomatic intracerebral hemorrhage. Our preliminary data raise potential safety concerns regarding the currently accepted guideline of IV t-PA use in warfarin-treated patients presenting with acute ischemic stroke in whom the baseline INR is less than 1.7. Larger prospective studies to confirm our preliminary findings are warranted.”
Dr. Prabhakaran’s group speculated on reasons that may explain their findings. One theory is that fibrinolytic effects of t-PA may be enhanced by the anticoagulant effects of warfarin, even at subtherapeutic levels. “Second,” according to the investigators, “warfarin maintains its anticoagulant effect for three days, on average, following the last dose; therefore, the INR may continue to rise to therapeutic levels in the hours following treatment with IV t-PA…. Third, overall fibrinolysis and coagulation status may be insufficiently estimated using the INR, which measures the extrinsic pathway only. Lastly, there are rare case reports of coagulopathy caused by t-PA itself, an unusual pharmacologic effect that may be exacerbated in patients taking vitamin K antagonists.”
The researchers also pointed out limitations to their study, including a small sample size and tertiary referral bias toward a “sicker” cohort than is typically admitted to community hospitals. “Further analyses including more extensive adjustment for confounding variables in larger data sets may prove useful,” they commented.
—Colby Stong