Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial.


Few data are available from randomised trials about the effect of thrombolysis with alteplase on long-term functional outcome in patients who have had acute ischaemic stroke and no trial has reported effects on health-related quality of life. A secondary objective of the third International Stroke Trial (IST-3) was to assess the effect of thrombolysis on such outcomes at 18 months.


In this open-label, international, multicentre, randomised, controlled trial, 3035 patients with ischaemic stroke from 12 countries were randomly allocated within 6 h of onset via a secure central system to either intravenous alteplase (0·9 mg/kg; n=1515) plus standard care or standard care alone (control; n=1520). 2348 patients were scheduled for 18-month follow-up. For our main analysis, survivors were assessed at 18 months with the Oxford handicap scale (OHS; the primary outcome was the adjusted odds of OHS score 0—2). We also used the EuroQoL (EQ) instrument and asked questions about overall functioning and living circumstances. We analysed the OHS and the five EQ domains by ordinal logistic regression and calculated the mean difference between treatment groups in EQ utility index and visual analogue scale score. Analyses were adjusted for key baseline prognostic factors. This study is registered with controlled-trials.com, number ISRCTN25765518.


At 18 months, 408 (34·9%) of 1169 patients in the alteplase group versus 414 (35·1%) of 1179 in the control group had died (p=0·85). 391 (35·0%) of 1117 patients versus 352 (31·4%) of 1122 had an OHS score of 0—2 (adjusted odds ratio [OR] 1·28, 95% CI 1·03—1·57; p=0·024). Treatment was associated with a favourable shift in the distribution of OHS grades (adjusted common OR 1·30, 95% CI 1·10—1·55; p=0·002). Alteplase treatment was associated with significantly higher overall self-reported health (adjusted mean difference in EQ utility index 0·060; p=0·019). The differences between the groups in visual analogue scale score and the proportion living at home were not significant.


IST-3 provides evidence that thrombolysis with intravenous alteplase for acute ischaemic stroke does not affect survival, but does lead to statistically significant, clinically relevant improvements in functional outcome and health-related quality of life that are sustained for at least 18 months.

Source: Lancet



More Information on Thrombolysis Benefits for Ischemic Stroke.

Two studies using large databases provide details on timing and outcomes.

Clinical trials of thrombolysis for acute ischemic stroke typically have included fewer than 1000 patients. Two new studies involved larger datasets, allowing investigators to analyze important clinical issues in greater detail.

Saver and colleagues analyzed data from the national Get With The Guidelines–Stroke (GWTG-Stroke) database on 58,353 patients (median age, 72; 50.3% women) treated with tissue plasminogen activator (TPA) within 4.5 hours of symptom onset over a 9-year period. The median time from symptom onset to TPA administration was 144 minutes. Factors associated with earlier treatment included greater stroke severity, arrival by ambulance, and arrival during regular hours. Intracranial hemorrhage occurred in 4.9% of patients; 38.6% were discharged home. Earlier treatment, measured in 15-minute increments, was associated significantly with reduced mortality (odds ratio, 0.96), reduced intracranial hemorrhage (OR, 0.96), increased chance of independent ambulation at discharge (OR, 1.04), and increased rate of discharge to home (OR, 1.03).

The IST-3 collaborative group examined the effects of thrombolysis on 18-month quality-of-life and functional outcomes. Among more than 2300 patients from 10 countries who were randomized to usual care or thrombolysis within 6 hours of stroke, the adjusted odds of being alive and independent at 18 months were 28% greater with thrombolysis. Survival at 18 months did not differ. On a scale measuring mobility, self care, activity, pain, and anxiety, patient or caregiver reports of wellbeing improved significantly more between 6 and 18 months after stroke, and were better at 18 months, in the thrombolysis group, although anxiety was not lower.


The data from the large GWTG-Stroke database emphasize the importance of timely intervention for acute ischemic stroke. Currently, fewer than one third of patients are treated with thrombolysis with a door-to-needle time of <60 minutes (Stroke 2011; 42:2983). The Target: Stroke initiative of the American Heart Association/American Stroke Association aims to improve this rate to 50% in the next few years. Accelerating the pace of treatment will have multiple important benefits, including lower mortality and improved functional outcomes.

The study from the IST-3 investigators shows long-term benefits for functional status with prior thrombolytic therapy. Although multiple factors can affect health status 18 months after stroke (such as cardiac issues and infectious complications), the persisting improvements in functional status with prior thrombolytic therapy are reassuring.