Alteplase may have benefit 3-6 hours after stroke: significant advantage seen over placebo when the smallest lesions were excluded from analysis.

Ishemic stroke patients with an area of hypoperfusion larger than the area of infarct and cytotoxic damage may still benefit from alteplase 3-6 hours after stroke onset, according to a study presented at the International Stroke Conference 2008 in New Orleans.

The trial failed to show a statistically significant difference between alteplase and placebo in its primary measure of efficacy, the geometric mean relative growth of infarct volume. But it did show statistically significant differences in a number of secondary measures.

The EPITHET study (Echoplanar Imaging Thrombolytic Evaluation Trial) was a phase II prospective, randomized, controlled trial conducted in Australia, New Zealand, Belgium, and the United Kingdom. The researchers hypothesized that alteplase given 3-6 hours after the onset of stroke symptoms might benefit patients in whom MRI identified an area of hypoperfusion surrounding a central infarct region--and thus would be most likely to have regions that could be saved from damage.

When the investigators limited the analysis to exclude the smallest lesions, however, the primary measure was significantly better with alteplase, said Dr. Stephen M. Davis of the department of neurology at Royal Melbourne Hospital, Melbourne, and colleagues (Lancet Neurol. 2008 Feb. 22 [Epub doi:10.1016/Sl474-4422(08)70044-9]).

To conduct the study, the investigators screened 3,908 patients with stroke symptoms and enrolled about 100 subjects, largely because they wanted patients more than 3 hours after onset but less than 6 hours after. Most of the patients screened had symptoms longer than 6 hours.

Enrolled patients were at least 18 years old, and had to have a National Institutes of Health Stroke Scale (NIHSS) score of more than 4 and a premorbid modified Rankin score of 2 or less. Likely candidates were given a CT scan to rule out acute hemorrhage and major early ischemic change.

Enrolled patients underwent an MRI, with diffusion-weighted and perfusion-weighted imaging sequences. They were treated with alteplase--0.9 mg/kg, up to a maximum of 90 mg, given over an hour, with 10% initially given as a bolus. MRI scans were repeated at 3-5 days and at 90 days.

A total of 101 patients were enrolled; 52 were randomized to alteplase and 49 to placebo. Average age of all patients was 71.6 years, and the median NIHSS score was 13.

A total of 80 patients--37 of the 52 patients in the alteplase group (71%) and 43 of the 49 patients in the placebo group (88%)--showed a mismatch between their diffusion-weighted MRI volume and the perfusion-weighted MRI volume. The percentage of patients with a mismatch was greater than the investigators expected, as a previous study had found only 54% of patients with a mismatch, Dr. Davis and colleagues wrote.

Among those 80 patients with a mismatch, the investigators found that at 90 days after treatment, the geometric mean relative growth of the infarct region in the treated group was only about two-thirds that of the placebo group (1.24 vs. 1.78, respectively), though the difference was not statistically significant (P = .24).

The investigators did find a statistically significant difference, however, if they excluded 11 patients (6 in the alteplase group, 5 in the placebo group) with small infarcts (5 mL or less). That exclusion may be legitimate, Dr. Davis and colleagues said, because small lesions are thought to be prone to measurement errors.

Median relative infarct growth among the 80 mismatch patients was 1.18 with alteplase, versus 1.79 with placebo, although the difference fell just short of statistical significant (P = .054). Median absolute growth was smaller in the alteplase group than in the placebo group, 4.1 mL vs. 28.7 mL, though the difference was not statistically significant.

Fifty-four percent of the alteplase-treated mismatch patients had some infarct growth, versus 77% of the placebo-treated mismatch patients, a statistically significant difference.

Reperfusion of greater than 90% was seen in 56% of the alteplase mismatch group, compared with only 26% of those in the placebo mismatch group, a difference that was statistically significant. Those with reperfusion were found to be more likely to have what the study defined as a good neurologic and a good functional outcome, the investigators wrote, though those differences were not statistically significant.

Four patients in the overall alteplase group had intracerebral hemorrhage, versus none of those treated with placebo.

The results suggest there is a benefit when the intravenous recombinant tissue plasminogen activator alteplase is given outside the 3-hour window, and indicate that further study is needed, Dr. Davis and colleagues said.

In a commentary accompanying the study, Dr. Peter D. Schellinger agreed.

The study had a number of problems, including the failure to demonstrate a statistically significant difference in its primary outcome, noted Dr. Schellinger, a professor of neurology at the University of Erlangen (Germany). However, it did appear to show that late reperfusion occurred in a greater percentage of patients treated with alteplase. It also appeared to demonstrate that reperfusion was associated with reduced infarct growth, which in turn was associated with better neurologic and functional outcome.

The findings give "hope that alteplase might be beneficial after the 3-hour time window," he wrote (Lancet Neurol.2008 Feb. 22 [Epub doi:10.1016/s1474-4422(08)70045-0]).

The Australian National Health and Medical Research Council, the Australian National Stroke Foundation, and the Heart Foundation of Australia supplied grants to support the researchers. Boehringer Ingelheim supplied alteplase and placebo, but was not involved in the study's design, management, or analysis.

BY TIMOTHY F. KIRN

Sacramento Bureau