Tissue More Important Than Time for tPA Treatment in Stroke?

May 16, 2014

NICE, France — Treating patients with thrombolysis should not be based purely on time, and a stronger predictor of who will benefit most is the amount of dead tissue in the brain as visible on contrast computed tomography (CT), a new registry study suggests.

The study was presented at the XXIII European Stroke Conference (ESC) by Andrew Bivard, PhD, imaging scientist at Newcastle University, John Hunter Hospital, Australia.

Results showed that in a group of 650 patients in the current under-4.5-hour time window for tissue plasminogen activator (tPA) treatment, the volume of the acute core on perfusion CT was by far the strongest predictor of outcome in both treated and untreated patients.

"While we agree that patients should be treated as quickly as possible, our results strongly suggest valuable information implying treatment responsiveness can be obtained by measuring pretreatment tissue status on perfusion CT," Dr. Bivard said.

"The focus should now be on streamlining routine multimodal CT assessment in acute stroke patients so as not to delay thrombolytic treatment but to ensure optimal patient selection," he concluded.

Imaging Controversial?

Commenting on the study for Medscape Medical News, Ralph Sacco, MD, professor and Olemberg Chair of Neurology, chief of neurology at the Jackson Memorial Miller School of Medicine, University of Miami, Florida, said, "Hyperacute imaging with perfusion CT or even MRI can add important information to help with selection of patients for acute therapies. In this study, they confirm that the perfusion CT size is an excellent indicator of prognosis. 

"However, using these imaging criteria to exclude some patients with small perfusion deficits from thrombolysis is very controversial," he added. "Even a small perfusion deficit in a strategic place in the brain could have devastating consequences.   

"In prior studies we have tried to use hyperacute imaging information to potentially select patients beyond the traditional 4.5-hour window who could still benefit from thrombolysis," Dr. Sacco added. "Unfortunately, the correct set of imaging studies to identify ways to extend the time window has not yet been definitely identified and more work is needed."

Dr. Bivard responded, "Dr. Sacco is correct that this topic is controversial. However, we are only treating patients within the current time window."

Dr. Andrew Bivard

For the study, 650 patients eligible for tPA treatment based on noncontrast CT were evaluated with perfusion imaging. Results suggested that tPA would be beneficial in only 380 patients who were treated. The rest were designated as not eligible.

"That is one third of patients without much potential for benefit and possible potential for harm," Dr. Bivard pointed out. "People think spending an extra few minutes doing a perfusion scan is a waste of time, but by doing such a scan we can save one third of patients from having unnecessary tPA. That is not a waste of time."

Using this analysis approach, Dr. Bivard and colleagues demonstrated that patients with a small acute perfusion lesion did not benefit from tPA treatment and made up a substantial number of patients in the database. Patients not administered thrombolysis with small perfusion lesions had high rates of excellent outcome (76%). The patients with a small perfusion lesion also had clinically significant stroke symptoms (mean National Institutes of Health Stroke Scale score of 8) and as such are likely to be included in many randomized controlled trials being currently run, he noted.

Not Best Treatment

Coauthor, Mark Parsons, MD, a neurologist at the John Hunter Hospital, explained that thrombolysis is not the best treatment for patients who have had very large or very small strokes.

"If the patient has had a very large stroke, reperfusion can actually be harmful. If a large area of the brain has already died, giving tPA can cause more harm than good," Dr. Parsons said. "If the perfusion deficit is more than 50 mL the benefit really drops off, and there is absolutely no point in giving tPA with a deficit of 70 mL or more. Patients with a very small perfusion deficit do very well without tPA. They often reperfuse spontaneously," he noted. Noncontrast CT, which is routinely performed on stroke patients before administration of tPA to rule out hemorrhagic stroke, is poor at discerning the amount of brain affected by the stroke in the early time window, Dr. Parsons continued.

Dr. Mark Parsons

"We are saying that with modern technology we can perform both noncontrast CT and the perfusion CT with the same scanner. The addition of a perfusion scan can identify patients who should not be given tPA. These patients cannot be identified with standard noncontrast scans," he added.

He noted that most centers don't do perfusion CT because they don't want to spend extra time doing a second scan. "But, while we need fast treatment, the haste to get patients to thrombolysis means that advanced imaging with perfusion CT is going out the window. But adding in a perfusion CT would only take an extra 5 to 10 minutes to process the results."

Dr. Parsons commented: "Most hospitals using IV [intravenous] tPA for stroke will have access to a multislice CT scanner, but most just do noncontrast CT as this is what the guidelines advise. But you can't tell what is happening in the brain without a perfusion CT — it should be the standard approach. Most doctors are worried about treating outside the guidelines, but we believe you have to use your clinical judgement and not just religiously follow the guidelines."

What about MR-RESCUE?

Also commenting for Medscape Medical News, Larry B. Goldstein, MD, Duke Stroke Center, Durham, North Carolina, said: , "Although intriguing, this was a retrospective cohort study without randomization to treatment or nontreatment based on imaging criteria. The most recent randomized trial, MR-RESCUE, failed to show benefit of advanced imaging as a predictor of patient response to reperfusion treatment."

In response, Dr. Bivard pointed out that the MR-RESCUE trial had a mean acute infarct core volume of 60 mL. "Patients with such large deficits are unlikely to benefit from reperfusion. So this trial included patients that were far too severe and beyond helping."

He added that other negative trials of advanced imaging had not selected patients with appropriate thresholds to define tissue pathophysiology.

"But the phase 2A DEFUSE-2 trial did show highly positive results with advanced imaging in the setting of intra-arterial tPA and has done much to advance the field," he added.

For the current study, the researchers designated certain imaging criteria as signifying questionable value of treatment with tPA. These were a small perfusion lesion (<10 mL), no mismatch (<10 mL penumbra), and a large infarct core (>60 mL). From the database, 271 patients met these criteria, of whom 116 were treated with recombinant tPA.

There were 140 patients with an acute perfusion lesion less than 10 mL, 38 of whom were treated. Untreated patients with a small perfusion lesion had a high rate of excellent outcome (modified Rankin scale score [mRS], 0 to 1) compared with those treated, with an odds ratio (OR) of 0.08. They also showed a better rate of a good outcome (mRS score, 0 to 2) with an OR 0.15.

Of the 96 patients with a large acute core (>60 mL), 59 were untreated. The OR for an excellent outcome in this group was 1.0, showing exactly the same result for treated or untreated patients, while the odds of a poor outcome (mRS score, 5 to 6) were increased with treatment (OR, 1.73).

Of the 35 patients with no mismatch, 19 were untreated. These patients also had a higher chance of an excellent outcome without treatment (OR, 0.23).

"Our results suggest that patients with a small acute lesion on advanced imaging had a 32% increased risk of a poor outcome if treated with tPA, while those who were not treated had nearly double the chance of a good outcome," Dr. Bivard said. "Also, patients with a large acute lesion showed no benefit from treatment with tPA at all, presumably because of the extent of the existing injury."

The researchers noted that several other centers are now adopting this approach, and contrast CT technology is being used to assess eligibility for treatment in an ongoing study of tenecteplase vs tPA in stroke patients (TASTE) being coordinated by the John Hunter Hospital team.

Another study (EXTEND) is using contrast CT to select patients for thrombolysis after the current 4.5-hour treatment window.

XXIII European Stroke Conference (ESC). Presented May 8, 2014.

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