JAMA: Use of tPA for warfarin-treated patients is safe after stroke
The American Heart Association, American Stroke Association and the American Academy of Neurology recommend that patients on warfarin with INRs of 1.7 or lower who experience acute ischemic stroke receive intravenous tissue plasminogen activator (tPA), which has been shown to improve outcomes. But patients on warfarin may be at increased risk of intracranial hemorrhage when treated with tPA.
Exacerbating the problem is the fact that major clinical trials excluded warfarin-treated patients in their studies, and the observational studies that have examined tPA’s safety profile among these patients have been small, had conflicting results and may not be applicable to patients in the U.S., wrote Ying Xian, MD, PhD, of the Duke Clinical Research Institute in Durham, N.C., and colleagues.
Using the Get With the Guidelines-Stroke Registry database, Xian and colleagues designed a study to better understand what if any increased risks warfarin-treated patients faced with tPA, the association between INR and symptomatic intracranial hemorrhage in these patients and the percentage of eligible patients who go without treatment in current clinical practice.
They identified 23,437 patients from 1,203 hospitals with acute ischemic stroke and a baseline INR of 1.7 or lower who received intravenous tPA between 2009 and 2011. The primary outcome was symptomatic intracranial hemorrhage. The secondary outcomes were life-threatening or serious systemic hemorrhage within 36 hours, any tPA complication within 36 hours, in-hospital mortality, and discharge to skilled nursing facility or inpatient rehabilitation facility.
The researchers found that 7.7 percent of stroke patients administered tPA therapy were receiving warfarin. Those patients were typically older, sicker and had more severe strokes. The unadjusted symptomatic intracranial hemorrhage rate was higher in this group compared with those not on warfarin. But after risk adjustment and sensitivity analyses, there no longer were significant differences in symptomatic intracranial hemorrhage risk, serious systemic hemorrhage, tPA complications or in-hospital mortality.
Nor was the degree of anticoagulation among warfarin-treated patients with INRs of 1.7 or lower significantly associated with symptomatic intracranial hemorrhage risk. Overall, they calculated that 48.6 percent of patients on warfarin who were eligible for tPA treatment did not receive it.
“[A]lthough the risk of sICH [symptomatic intracranial hemorrhage ] increases marginally with higher INR levels, intravenous tPA appears to be safe in warfarin-treated patients with a baseline INR of 1.7 or lower,” Xian and colleagues wrote. “Collectively, these findings provide empirical support for current AHA/ASA guideline recommendations and confirm the safety profile of intravenous tPA in warfarin-treated patients with INRs of 1.7 or lower in routine clinical practice.”
They suggested that their findings may inform further studies and recommended that researchers examine the effectiveness and safety of tPA use in warfarin-treated patients whose INR values are outside the recommended range in guidelines. They raised the issue of new oral anticoagulants and their safety as well.
They pointed out that in their study at least 2,400 patients did not receive tPA treatment although they met guideline requirements. “We found the potential for substantial undertreatment, because up to 50 percent of warfarin-treated patients who might have been eligible for reperfusion therapy did not receive intravenous tPA,” they wrote. “These data provide empirical support of current AHA/ASA guideline recommendations and may help support future stroke quality improvement efforts.”
In an accompanying editorial, Mark J. Alberts, MD, of the stroke program at Northwestern University Feinberg School of Medicine, call the results reassuring but he also highlighted some limitations. He noted that many patients had INRs lower than 1.5. “Thus, it is not surprising that intravenous tPA was relatively safe in the overall cohort,” he wrote.
Hospitals participate voluntarily in the Get With the Guidelines-Stroke program, which Alberts wrote suggests they likely follow well-developed protocols for tPA usage and offer a high level of expertise and experience. He questioned if the results were generalizable to all hospitals and care settings.
“Despite these limitations, the study by Xian et al contributes important information regarding stroke care and raises further questions that should be examined,” he wrote. He added that the study provide evidence that supports current guidelines. “The results of the current study provide another chance to treat a serious and potentially disabling disease that has very few effective medical therapies.”