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Thrombolytics within 6 hours for stroke: no difference after 6 months (IST-3)

Clinical Question:
Does treatment with recombinant tissue plasminogen activator within 6 hours of acute ischemic stroke improve 6-month outcomes?

Bottom Line:
Although treatment with recombinant tissue plasminogen activator (rtPA) within 6 hours of acute ischemic stroke increases 7-day mortality and the rate of symptomatic intracranial hemorrhage, the mortality rate eventually evens out so there is no significant increase in the proportion of patients who are alive and independent 6 months after treatment. (LOE = 2b)

IST-3 collaborative group, Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012;379(9834):2352-2363.  [PMID:22632908]

Study Design:
Randomized controlled trial (nonblinded)



Inpatient (any location) with outpatient follow-up

The use of rtPA in patients with acute ischemic stroke is controversial, requiring balancing very real harms against the benefit of long-term independence. Additionally, the medication is expensive and the window to administer it safely is narrow. Nonetheless, many believe that rtPA is underused and have campaigned for broadening its eligibility to patients older than 80 years and for extending its administration time limits. Among the objectives of the researchers in this study, the first was to "establish the balance of benefits and harms of thrombolytic therapy with rtPA in patients who did not exactly meet the (European) license criteria." The study included patients if they had symptoms and signs of acute stroke; the time of stroke onset was known; treatment could be started within 6 hours of symptom onset; and CT or MRI had excluded both intracranial hemorrhage and structural brain lesions that could mimic stroke. The researchers randomized approximately 3000 patients to receive 0.9 mg/kg of intravenous rtPA (to a maximum of 90 mg) or control treatment. All patients had a CT or MRI brain scan before randomization and a follow-up scan at 24 to 48 hours. Repeat imaging was required if the patient deteriorated neurologically or intracranial hemorrhage was suspected. The follow-up imaging was read by radiologists masked to treatment allocation. All other study personnel and all the patients were aware of the treatment assignment. Initially, the study was designed to recruit 6000 patients in order to be able to detect a 3% absolute difference in event rates. However, after several years, the researchers reported that this was no longer feasible and that having 3000 patients would permit detecting a 5% absolute reduction in events. The outcomes were analyzed by intention to treat. After 6 months, the proportion of patients alive and independent was similar between the groups (37% for rtPA-treated patients and 35% for control patients; P = 0.18). The authors overstate the "benefit" of intervention and ignore both the lack of statistical significance and the fact that the difference could be due to random events rather than treatment. Additionally, the 6-month death rate in each group was the same (27%). Among patients who died in the first 7 days, 11% received rtPA while only 7% were control patients (P = .001; number needed to treat to harm [NNTH] = 27; 95% CI, 18 - 59). However, for the remainder of the 6 months, the death rate was higher in the control group (20% vs 16%; P = .002; number needed to treat to prevent one death = 28; 16 - 120). Symptomatic intracranial hemorrhage occurred in 7% of treated patients and only 1% of controls (NNTH = 18; 14 - 23).


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