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

Abstract

Background: Thrombolysis is of net benefit in patients with acute ischaemic stroke, who are younger than 80 years of age and are treated within 4·5 h of onset. The third International Stroke Trial (IST-3) sought to determine whether a wider range of patients might benefit up to 6 h from stroke onset.

Methods: In this international, multicentre, randomised, open-treatment trial, patients were allocated to 0·9 mg/kg intravenous recombinant tissue plasminogen activator (rt-PA) or to control. The primary analysis was of the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0-2 at 6 months. The study is registered, ISRCTN25765518.

Findings: 3035 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0-2; adjusted odds ratio [OR] 1·13, 95% CI 0·95-1·35, p=0·181; a non-significant absolute increase of 14/1000, 95% CI -20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1·27 (95% CI 1·10-1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07-11·8; absolute excess 58/1000, 95% CI 44-72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1·60, 95% CI 1·22-2·08, p=0·001; absolute increase 37/1000, 95% CI 17-57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group).

Interpretation: For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients.

Funding: UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, Arbetsmarknadens Partners Forsakringsbolag (AFA) Insurances Sweden, Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, the Australian Heart Foundation, Australian National Health and Medical Research Council (NHMRC), Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita, Regione dell'Umbria, Italy, and Danube University.

Figure 1

Trial profile rt-PA=recombinant tissue plasminogen activator. OHS=Oxford Handicap Score. *Of the patients allocated to control, seven actually received some rt-PA. Appendix pp 4–5 gives more detail of treatment actually received and background care.

Figure 2

Outcome at 6 months: Oxford Handicap Scale (OHS) by treatment group For the ordinal analysis, which was adjusted for age, National Institutes of Health Stroke Scale (NIHSS), delay (all linear), and and presence or absence of visible acute ischaemic change on baseline scan as judged by the expert reader, the statistical analysis plan prespecified that OHS levels 4, 5, and 6 were grouped and 0, 1, 2, 3 remained discrete. In that analysis, the common odds ratio was 1·27 (95% CI 1·10–1·47; p=0·001). An ordinal analysis with OHS levels 0, 1, 2, 3, 4, 5, and 6 all discrete, adjusted in the same way, gave an odds ratio of 1·17 (95% CI 1·03–1·33; p=0·016). rt-PA=recombinant tissue plasminogen activator.

Figure 3

Adjusted effect of treatment on the primary outcome (alive and independent, Oxford Handicap Score 0, 1, or 2) in subgroups The key predefined subgroups were age 80 years or younger, age older than 80 years, time from stroke onset to randomisation (0–3·0 h, 3·0–4·5 h, 4·5–6·0 h), initial stroke severity as measured by National Institutes of Health stroke score, and the appearance of the baseline brain scan on expert read for each subgroup (whether ischaemic change is visible or not). The treatment odds ratio in each subgroup has been adjusted for the linear effects of the other key variables (age, NIHSS, and delay) but not for the presence or absence visible ischaemic change. It is for this reason that the adjusted odds ratio in the “Total” row at the bottom of the table does not exactly agree with the odds ratio in table 2. The choice of cut-points to define certain subgroups is slightly different to those given in table 1. On the graph, for each subgroup, the horizontal line represents the 99% CI, the diamond is centred on the overall estimate and it represents the 95% CI. The graph was generated with R (version 2.11.1). rt-PA=recombinant tissue plasminogen activator. NIHSS=National Institutes of Health Stroke Scale. TACI=total anterior circulation infarct. PACI=partial anterior circulation infarct. LACI=lacunar infarct. POCI=posterior circulation infarct.