0319-Feature-Stroke-guidelines_BlogGiving the drug Alteplase to stroke patients more than three hours after stroke does not provide a clear benefit and may increase the risk of death, according to a new opinion paper published this week in BMJ.

The authors of the opinion paper called for a re-evaluation of American Heart Association/American Stroke Association Guidelines recommending the drug be given to some patients from three to 4.5 hours after stroke.

Alteplase belongs to a class of drugs known as tissue plasminogen activators and is used to break up blood clots blocking the brain’s blood vessels that cause an acute ischemic stroke.

“We believe that current guidance is based on uncertain evidence and that urgent reconsideration of the available data is essential to guide policy decisions on use of Alteplase to manage acute stroke,” wrote Brian Alper, M.D., lead author of the article.

Alper’s team evaluated data used in the AHA/ASA 2013 guidelines, studies that were included in a 2014 Cochrane review, a 2014 study published in the medical journal Lancet about the effect of delayed treatment, and other studies that included some patients treated in the extended timeframe.

Although all three of these systematic reviews concluded that that giving Alteplase from three to 4.5 hours after the first symptoms of ischemic stroke was beneficial, Alpers and colleagues disagreed.

The AHA/ASA guidelines recommend tPA be given from three to  4.5 hours after stroke to highly selected patients, including under age 80 who aren’t on oral anticoagulant medications, have a baseline score less than 25 on the National Institutes of Health Stroke Scale and don’t have a history of combined stroke and diabetes.

Jeffrey Saver, M.D., a national spokesperson for the AHA/ASA stands by the guidelines.

“The article oddly attempts to impugn the AHA guidelines, using data that don’t directly cover the patients specified in the guidelines, from a trial that’s structurally weaker than the other trials upon which the guidelines are based,” said Saver, who’s also professor of neurology at the Geffen School of Medicine at University of California, Los Angles, and the director of the UCLA Comprehensive Stroke Center. “Moreover, it’s already out there that we want more data, so this article is merely echoing what we’ve already said.”

The organization’s guidelines rate the Level of Evidence for use of tPA in the three to 4.5 hour window as Level B, not Level A, acknowledging the limitations of the data supporting extending the treatment window for tPA beyond three hours, said Saver.

Saver also noted that the AHA/ASA experts recognized that tPA neither reduced or increased death after stroke in the three to 4.5 hour window, because they considered all causes of mortality that tPA might affect, including both brain swelling and bleeding into the brain. The BMJ article focused on only the bleeding subset of fatal events.

Alper, who is vice president for DynaMed in Ipswich, Maryland, discussed that some findings about treatment in the three to 4.5 hour window from the Third International Stroke Trial appeared to not show a benefit of therapy, unlike earlier trials.

Saver noted that the trial, known as IST-3, has not reported data specific to the population specified in the AHA Guideline. For example, the AHA Guideline is confined to patients under age 80, while more than 53 percent of the IST-3participants were over age 80, the age group excluded from receiving tPA during the extended timeframe under AHA/ASA Guidelines.

IST-3 also was the only trial to specifically instruct physicians to for exclude patients whom they thought likely would benefit from the drug, an approach that is known to bias studies toward finding less benefit than actually exists for a treatment. In addition, IST-3 was the only trial that was not a blind study, meaning physicians and patients knew who had received tPA, which could lead to bias.

Alper said the key to resolving uncertainty about the benefits and harms of Alteplase between three and  4.5 hours after stroke, “lies in publishing more of the underlying data forming the basis of the 2014 meta-analysis and reanalyzing them transparently,” an idea Saver supports.

Providing raw data from studies of giving tPA beyond three hours after stroke, “would provide deeper insight into the benefits and risks of therapy in this time window,” said Saver. He added that guidelines for giving tPA to stroke patients within the first three  hours after stroke symptoms was fortified by public reporting of raw data from two major stroke trials.

“Unless and until there are data showing unequivocal benefits to outweigh known harms, we believe that there should not be any strong recommendation or encouragement for use of Alteplase beyond three hours after stroke,” Alper said.

Saver said that current evidence indicates that the benefits for patients getting tPA in the extended time window substantially outweigh the risk, but more evidence is needed.

Despite this, people should not be unnecessarily concerned.

“Patients should be reassured that tPA within three hours of onset is a well-proven therapy,” he said. “It’s important to emphasize that this article is only bringing up questions about the 15 percent of patients who are getting tPA within the extended time window — 85 percent of patients who get tPA get it with the three-hour window, for which data are unassailable.”