Stroke is the leading cause of disability in the elderly, and i.v. alteplase (recombinant tissue plasminogen activator) is the only Food and Drug Administration (FDA)-approved thrombolytic agent for the treatment of AIS. FDA still recommends the use of Alteplase in patients of AIS within 3 h of the onset of symptoms. But, the professional stroke organizations extended the recommended time between symptom onset and administration of alteplase from 3 to 4.5 hours on the basis of reports published in September 2008 from two large international studies which had demonstrated that therapy with i.v. alteplase remains safe and effective when given 3–4.5 hours after AIS onset.
One of the trials (1) the compared efficacy and safety of alteplase (0.9 mg of alteplase per kilogram), administered intravenously (with an upper limit of 90 mg) administered between 3 and 4.5 hours after the onset of a stroke with placebo.
In the second study (2) the comparison was between the patients treated between 3 h and 4•5 h versus those treated within 3 h. Alteplase remained safe when given at 3—4•5 h after ischaemic stroke, offering an opportunity for patients who cannot be treated within the standard 3-h timeframe.
Now, the September issue of Lancet Neurology3 has reported an updated analysis of the implementation of the wider time window, its effect on the admission-to-treatment time, and safety and functional outcome in patients recorded in SITS-ISTR.
The patients treated according to the criteria of the European Summary of Product Characteristics, except for the time window, were included. Patients were grouped according to whether they were registered into SITS-ISTR before or after October, 2008. The admission-to-treatment time and rates of symptomatic intracerebral haemorrhage, mortality, and functional independence at 3 months were measured.
Results:
The proportion of patients treated within 3-4.5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 [22%] vs 67 of 1023 [7%]).
The median admission-to-treatment time was 65 min both for patients registered before and after October, 2008 (p=0.94). 352 (2%) of 21 204 patients treated within 3 h and 52 (2%) of 2317 treated within 3-4.5 h of stroke had symptomatic intracerebral haemorrhage at 3 months (adjusted odds ratio [OR] 1.44, 95% CI 1.05-1.97; p=0.02).
2287 (12%) of 18 583 patients who were treated within 3 h and 218 (12%) of 1817 who were treated within 3-4.5 h had died by the 3-month follow-up (adjusted OR 1.26, 95% CI 1.07-1.49; p=0.005); 10 531 (57%) of 18 317 patients treated within 3 h of stroke and 1075 (60%) of 1784 who were treated within 3-4.5 h were functionally independent at 3 months.
The authors concluded that since October, 2008, thrombolysis within 3-4.5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased.
Safety and functional outcomes are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier.
Thrombolysis should be initiated within 4.5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset.
The evidence supports a wider treatment window and professional organizations recommend it. Nevertheless, time is brain, and eligible patients should be treated as soon as possible.Earlier is better.
1.http://www.nejm.org/doi/pdf/10.1056/NEJMoa0804656
2.http://www.thelancet.com/journals/lancet/article/PIIS0140673608613392/abstract
3. Ahmed N et al. Implementation and outcome of thrombolysis with alteplase 3–4.5 h after an acute stroke: An updated analysis from SITS-ISTR. Lancet Neurol 2010 Sep; 9:866.
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