Stroke: if in doubt, opt for lysis therapy
23.07.2012 12:42
Significantly more stroke patients than before should receive lysis therapy. This is the core message of the world's largest thrombolysis study IST-3 and a meta-analysis of several scientific papers that were recently published in the renowned journal The Lancet. “These data support our recommendation to anchor lysis even more in routine therapy,” comments Professor Martin Grond, board member of both the DGN (German Society for Neurology) and the DSG (German Stroke Society). “So far, people have tended to look for reasons not to carry out lysis - but we should consider lysis as the standard instead of selecting the indicated patients.”
Patients with severe strokes and patients over 80 also benefit
With lysis, neurologists in the stroke units dissolve a thrombus in the brain after a stroke that led to a cerebral infarction. The decision to undergo lysis therapy requires a detailed examination of the patient to ensure that no undesirable side effects such as increased bleeding occur. The studies now show that lysis therapy with alteplase can be used with sufficient safety even if the decision for or against this therapy is not covered by the previous approval. In some of the patients who are excluded, success rates similar to those for standard indications are achieved. This applies, for example, to patients with severe strokes, for whom the approval of the drug has so far imposed great reservations, or to patients who are not allowed to be treated accordingly due to their age over 80. Professor Didier Leys, Director of the Neurological Clinic at the University of Lille, France, confirms in his commentary in The Lancet: “The IST-3 study suggests that many patients from subgroups that would otherwise be excluded from lysis therapy can now receive alteplase.”
Facilitation of off-label indications – but no change in standards
Stroke expert Professor Werner Hacke, director of the Heidelberg University Neurological Clinic, points out that the study showed no significant difference between the treatment groups. All positive results come from secondary or post hoc analyses. Nevertheless, the key messages that can be derived from the study are helpful: The results are consistent with those of previous studies, although the inclusion criteria were much broader. This means they provide greater security for off-label indications - but the standards of lysis therapy would not have to be changed by IST-3. “It is still true that the benefit of thrombolysis therapy is greatest in the first 90 minutes after the ischemic insult,” emphasizes Professor Hacke expressly. The study results once again impressively demonstrated the effectiveness and safety of this therapy, even in the borderline areas of the applicable indications. In general, all stroke patients should receive adequate thrombolysis therapy as early as possible. Under no circumstances should the new data be interpreted to mean that there is now a longer time window of up to 6 hours in which lysis can be used as routine therapy, Professor Hacke continued.
The IST-3 study
Between 2000 and 2011, a total of 3,035 stroke patients from 12 countries were included in the IST-3 study (International Stroke Trial 3). 53 percent of the test subjects were over 80 years old. 1515 people were treated with alteplase, the recombinant tissue plasminogen activator rt-PA (0.9 mg/kg), and 1520 were assigned to the control group. The time window between the appearance of the first symptoms and lysis has been extended from the previous 4.5 hours to 6 hours. The primary aim of the study was to determine the number of surviving patients after 6 months who were also able to cope with everyday life largely independently. After this period, 37 percent in the rt-PA group and 35 percent in the control group were alive and able to care for themselves. The lysis therapy therefore did not achieve any significant improvement in the primary endpoint. Looking at the improvement across the entire spectrum of disability levels, this was 27 relative percent greater with lysis therapy (OR 1.27; 95 percent CI 1.10–1.47; p=0 001). Within the first seven days after the stroke, mortality after lysis was higher (11 percent) than in the control group (7 percent). This was primarily attributed to the significant increase in intracranial bleeding (7 percent versus 1 percent). After 6 months there was no longer any difference; In both groups, 27 percent of the patients died. In the subgroup analyses, there was no indication of an unfavorable benefit/risk ratio for patients over 80 years of age, patients with very severe strokes and patients who were only treated after 4.5 hours. “However, this contradicts the last pooled analysis (Lees KR et al, The Lancet 2010), in which all studies carried out up to that point were of much higher data quality,” states Professor Hacke, co-author of this study. There, a significantly increased risk of mortality after 3 months was described in patients treated between 4.5 and 6 hours.
Meta-analysis with corresponding results
A meta-analysis in which twelve rt-PA studies, including the IST-3 study, with data from a total of 7012 patients were evaluated, confirmed the results of the pooled analysis. All subjects had received rt-PA within the first 6 hours after stroke. After 6 months, 46.3 percent of the rt-PA group were alive and able to care for themselves; in the control group, this only applied to 42.1 percent of patients. The greatest benefit was seen in patients treated within three hours: 40.7 percent versus 31.7 percent in the control group. The mortality rate in the control group was 18.5 percent, almost the same as in the rt-PA arm (19.1 percent). The treatment was just as effective for those over 80 as it was for younger patients.