London, UK - Results of an observational monitoring study of tPA for the treatment of stroke in clinical European practice shows similar rates of intracerebral hemorrhage (ICH) but lower death rates, compared with those seen in the major clinical trials of tPA for patients treated within three hours of symptom onset [1].

The researchers hope the results will spur permanent licensing for alteplase in the treatment of ischemic stroke by European Union regulators, the European Medicines Evaluation Agency (EMEA). To date, the EMEA has granted only provisional approval.

"One thing that's very important is that 50% of our centers had no previous experience with thrombolysis and stroke, and that's a very strong message, because it means that even in those centers, the treatment is safe," lead author Dr Nils Wahlgren (Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden) said. "The main important message of this paper is the treatment is safe and it's efficacious, and now it's time to see that patients get this treatment when they have a stroke."

The results, from the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), are published in the January 27, 2007 issue of the Lancet.

Subsequent to results of the major clinical trials of tPA during the early 1990s, alteplase was approved for use in the United States in 1996 and in Canada in 1999 for ischemic stroke patients treated within three hours of symptom onset. However, European authorities were more conservative, giving only provisional approval for the treatment in 2002. One of two conditions for licensing was that an observational study be implemented to assess the safety profile of tPA in routine clinical practice vs that seen in the randomized trials. SITS-MOST is that safety study.

Between 2002 and 2006, 6483 patients were recruited from 285 centers in 14 European countries; 50% of these had little previous experience using thrombolysis for stroke. SITS-MOST was a prospective, open, monitored observational study embedded in a larger thrombolysis registry called SITS-International Stroke Thrombolysis Register (SITS-ISTR).

Importantly, patients were not eligible for inclusion in this monitoring study if they received tPA outside of the product recommendations for tPA; all had to receive treatment within three hours of symptom onset, be between 18 and 80 years of age, and not have contraindications for thrombolytic treatment such as a severe stroke (National Institutes of Health Stroke Scale [NIHSS] score of 25 or higher).

Primary outcomes of interest were symptomatic intracerebral hemorrhage type 2, defined as a deterioration in NIHSS score of > 4 within 24 hours of treatment, and mortality at three months.

At 24 hours, symptomatic ICH (SICH) according to the SITS-MOST protocol occurred in 1.7%, or 107, of 6444 patients. At seven days, the proportion of patients with SICH by the Cochrane definition was 7.3%, vs 8.6% in the pooled randomized tPA trials.

At three months, the mortality rate was lower than that seen in the randomized trials.

"Although there are still unanswered questions with regard to the role of stroke thrombolysis beyond the limitations of this study, our data suggest that thrombolysis should now be considered a part of routine care of suitable stroke patients," the authors conclude. "We hope that these findings will encourage the uptake of routine thrombolytic therapy for suitable patients in stroke centers, whether experienced or new to stroke thrombolysis."

A second condition for the European licensing in 2002 was that a randomized trial be carried out comparing treatment with alteplase vs placebo in patients with ischemic stroke treated between three and 4.5 hours after symptom onset, Wahlgren said. That study, the European Cooperative Acute Stroke Study 3 (ECASS-3), is still ongoing.

"We are not quite certain whether the European regulators will take the message of SITS-MOST right now and provide a permanent license or if they are going to await the results of the randomized trial," Wahlgren said.

In an accompanying Commentary [2], Drs Gregory Albers and Jean-Marc Olivot (Stanford Stroke Center at Stanford University Medical Center, Palo Alto, CA) write, "SITS-MOST imparts a strong message to European regulators that permanent approval of alteplase for appropriate stroke patients in suitable settings is justified." However, they raise some concern about the study's methodology, specifically that the SITS-MOST data include outcomes only on selected patients.

"Overall it's clearly a very positive experience, showing that a wide variety of hospitals across Europe were able to give tPA to appropriately selected patients," Albers said. However, he noted, "this registry captured only the patients who met prespecified criteria that included age, stroke severity, and blood pressure within a particular range."

Normally, this type of phase 4 monitoring study takes all comers who receive a particular treatment and looks at their outcomes, he said. "If you select only the ones who meet the prespecified criteria, it does provide a bias in which you're kind of picking the best patients."

He said that it would be important for the SITS-MOST researchers to publish the data pertaining to these other patients to give the best overall picture of the drug's safety and efficacy.