AHA/ASA Science Advisory Recommends Use of tPA Between 3 and 4.5 Hours After Stroke

Susan Jeffrey

May 28, 2009

May 28, 2009 — A new science advisory from the American Heart Association (AHA)/American Stroke Association (ASA) has given the green light to the use of tissue plasminogen activator (tPA) to treat acute ischemic stroke between 3 and 4.5 hours after symptom onset.

However, the advisory, published online May 28 in Stroke, still emphasizes that time is of the essence when it comes to treatment of stroke.

"Although a longer time window for treatment has been tested formally, delays in evaluation and initiation of therapy should be avoided," the authors stress. The writing group is chaired by Gregory J. del Zoppo, MD, from the University of Washington, in Seattle.


The advisory updates the current guidelines mainly on the basis of findings from the European Cooperative Acute Stroke Study 3 (ECASS 3), which showed a benefit from thrombolytic therapy in patients treated between 3 and 4.5 hours after symptom onset. Exclusion criteria for that trial — which followed exclusions mandated by European regulatory authorities for the approval of tPA there — now become exclusion criteria for these new recommendations.

"The eligibility criteria for treatment in this time period are similar to those treated at earlier time periods, with any 1 of the following additional exclusion criteria: patients older than 80 years, those taking oral anticoagulants with an international normalized ratio [INR] of  ≤ 1.7 [the guidelines for the under-three-hour patients excluded from treatment patients on warfarin with an INR > 1.7], those with a baseline National Institutes of Health Stroke Scale score > 25, or those with both a history of stroke and diabetes," the authors write. Thus, for this later time period, all patients receiving oral anticoagulants are excluded, regardless of their INR, they note.

"The efficacy of intravenous treatment with [recombinant tissue plasminogen activator] rtPA within 3 to 4.5 hours after stroke in patients with these exclusion criteria is not well established and requires further study," the document states. In addition, the relative utility of rtPA in this time window to other methods of recanalization such as thrombus dissolution or removal is considered "not well established."

Ancillary care for patients receiving tPA In this expanded window should be similar to what has been established in the current 2007 American Heart Association Stroke Council Guidelines, the authors note.

"These recommendations, which are based on peer-reviewed publications, should be reevaluated after the results of regulatory agency review of detailed, non–publicly available data are known," they conclude.

Do Not Hesitate to Treat

Asked for comment on the new advisory, Ralph Sacco, MD, from the Miller School of Medicine at the University of Miami, in Florida, and president-elect of the AHA, pointed out that on the basis of ECASS 3, the guidelines in Europe have already changed.

"The European Stroke Organization was quick to change the guidelines," Dr. Sacco said. "I think the American Heart Association has been more cautious about widening the window. One of our concerns is that we don't want people to hesitate, and if you all of a sudden widen the window, some people may feel they have a little more time, both patients waiting to call or healthcare professionals waiting to give tPA," he said.

"First and foremost to us is, the earlier you treat, the better; the earlier you recognize the symptoms, the better; and that's the only concern — that if we widen the window, will we lose some patients giving it later rather than earlier?"

This may allow many physicians to be more comfortable at least in treating those who arrive late in the already-approved 3-hour time window, he added.

Werner Hacke, MD, from the University of Heidelberg, in Germany, is the current president of the European Stroke Organization and was principal investigator of ECASS 3. He feels that the revised AHA/ASA statement is "correct, appropriate, and congruent to the European published change in guidelines."

The only difference, he notes, is that the European guidelines make the recommendation to treat within the 3- to 4.5-hour time window class I, level A importance, not level B, as the AHA/ASA document has done. "It is probably done here because of the fact that it is only 1 trial," he added, although he pointed out that the level-A recommendation in the current AHA/ASA guideline for the 3-hour time window is also based on 1 study, the National Institute of Neurological Disorders and Stroke (NINDS) trial.

"We in Europe take the pooled analysis that appeared in the Lancet, which was also cited in the [AHA/ASA] update as supportive, independent evidence from a meta-analysis, and therefore make it a level A," he told Medscape Neurology & Neurosurgery (SITS Investigators. Lancet 2008;372:1303-1309).

Phillip B. Gorelick, MD, from the University of Illinois College of Medicine at Chicago, was a reviewer on the new science advisory. "There are several key factors to keep in mind when contemplating administration of intravenous tPA, given the AHA/ASA advisory," he told Medscape Neurology & Neurosurgery. "One, treatment should not be delayed if it can be given sooner than the 3- to 4.5-hour time window."

In addition, the exclusions outlined above will also apply, he noted. "The advisory does not address the role of intra-arterial rtPA administration or the use of mechanical or other clot-extraction devices in the 3- to 4.5-hour time window," Dr. Gorelick said. "The role of these latter treatments in light of the expanded time-window advisory will need to be addressed in subsequent AHA/ASA guidelines on acute stroke therapy and in subsequent research."

The American Heart Association/American Stroke Association statement notes that the association receives funding "primarily from individuals and foundations, and corporations (including pharmaceutical, device manufacturers, and other companies) also make donations and fund specific association programs and events. The association has strict policies to prevent these relationships from influencing science content. Revenues from pharmaceutical and device corporations are disclosed at www.americanheart.org/corporatefunding ."

Dr. Del Zoppo reports no disclosures. Disclosure information for other members of the writing group and reviewers are included in the advisory.

Stroke. Published online May 28, 2009.