Warfarin-Treated Patients at Higher Risk for ICH Following tPA for Stroke

Allison Gandey

March 10, 2010

March 10, 2010 — Patients taking warfarin are more likely to have an intracerebral hemorrhage after treatment of an acute ischemic stroke with tissue plasminogen activator (tPA), a new study suggests.

The surprising finding is calling current practice into question.

"Given there is a lack of prior evidence on the safety of tPA in patients taking warfarin, this study should give some pause and encourage further study," lead investigator Shyam Prabhakaran, MD, from Rush University Medical Center in Chicago, Illinois, said in an interview.

Dr. Prabhakaran points out there are no published data assessing the safety of tPA among warfarin-treated patients. These patients were excluded from the National Institute of Neurological Disorders and Stroke and European Cooperative Acute Stroke Study trials of tPA for stroke, and yet warfarin users represent an increasing group of patients.

This study should give some pause and encourage further study.

Still, American Heart Association and American Stroke Association guidelines permit intravenous tPA use in patients taking oral anticoagulants with a baseline international normalized ratio (INR) less than 1.7.

In this new study, published online March 8 in Archives of Neurology, the investigators report that warfarin-treated patients are at higher risk for stroke despite INRs in a safe range.

With the estimated prevalence of atrial fibrillation in the United States approaching 3 million and expected to double by 2050, the researchers point out that the prevalence of anticoagulant use among stroke patients is not trivial.

Investigators studied 107 ischemic stroke patients treated with tPA. Of these, 12.1% were taking warfarin at baseline.

The overall rate of symptomatic intracerebral hemorrhage was 6.5%. Dr. Prabhakaran says that his team was surprised to see that this rate was nearly 10-fold higher among patients taking warfarin.

Table. Risk of Symptomatic Intracerebral Hemorrhage

Outcome Warfarin at Baseline, % No Warfarin, % P Value
Stroke 30.8 3.2 .004


The researchers report that the stroke risk remained high even after adjusting for relevant covariates, including age, atrial fibrillation, National Institutes of Health Stroke Scale score, and INR.

Asked by Medscape Neurology to comment on the findings, Jacob Pendergrast, MD, from the Toronto General Hospital in Ontario, said, "Despite its small size and retrospective design, the observations in this study are so striking that some clinicians may be moved to change their practice."

Dr. Pendergrast says it is worth noting that patients who have been taking warfarin, even if their INR is nearly normal, are at significantly increased risk of experiencing an intracranial hemorrhage when receiving thrombolysis for ischemic stroke.

"However," he adds, "it would be a potentially dangerous overinterpretation of this finding to state that such patients therefore require aggressive coagulation factor replacement prior to tPa administration, as these patients may not, in fact, be coagulopathic and could be at increased bleeding risk for other reasons."

Despite its small size and retrospective design, the observations in this study are so striking that some clinicians may be moved to change their practice.

Dr. Pendergrast calls for larger observational studies with more extensive evaluation of the hemostatic changes observed before, during, and after thrombolysis in patients with a history of warfarin use. He also would like to see the details of all interventions performed to bring an elevated INR into acceptable range.

Dr. Prabhakaran and his team propose that the fibrinolytic effects of tPA may be enhanced by the anticoagulant effects of warfarin. Higher recanalization rates with this combination may lead to a greater rate of reperfusion hemorrhage into infarcted tissue.

They suggest that warfarin use may also be a marker for patients with cardioembolic stroke in whom hemorrhagic transformation is more common and infarct volume is greater.

Dr. Prabhakaran acknowledges that although there is reason to be concerned, this work should be considered hypothesis generating, and further study is necessary.

This study was funded by the National Institute of Neurological Disorders and Stroke. The researchers have disclosed no relevant financial relationships.

Arch Neurol. Published online March 8, 2010.