Table 1 List of thrombolytic trials in acute ischemic stroke based on time-window

TIME WINDOW 0–3 HOURS

NINDS [4, 231] (n = 624)

Time window: 0–3 h, 3–6 h

Endpoints: A favourable outcome was defined as recovery with minimal or no deficit 3 months after treatment using four outcome measures: the BI ≥95, mRS seven ≤1, Glasgow Outcome Scale 8 of 1, and NIHSS score ≤ 1.

Results: Treatment with tPA within 3 h of the onset led to the improved clinical outcome at 3 months, and increase in the incidence of symptomatic ICH.

SITS-MOST [232] (n = 6483)

Time window: 0–3 h

Endpoints: Primary outcomes were symptomatic (a deterioration in NIHSS score of ≥4) ICH type 2 within 24 h and mortality at 3 months. Functional independence (defined by an mRS score of 0–2 at 90 days) was a secondary outcome.

Results: Treatment with Alteplase is safe and effective when used within 3 h of stroke onset.

TESPI [64, 233] (n = 248)

Time window: 0–3 h

Endpoints: Primary endpoint for efficacy was the disability at day 90, dichotomized as a favourable outcome (mRS 0–2) or unfavourable outcome (mRS 3–6) [64]. The end-point for safety is symptomatic ICH radiologically confirmed on the 22–36 h post-treatment scan combined with neurological deterioration leading to an increase of ≥1 point/s on the NIHSS scale.

Results: Higher mortality in patients aged >80 years than younger patients treated with IV-rtPA. No significant differences in symptomatic ICH nor for a favourable outcome. Thrombolytic therapy should not be a priori denied for appropriately selected >80-year old patients [233].

SITS-NEW [234] (n = 591)

Time window: 0–3 h

Endpoints: Primary endpoints were symptomatic (deterioration in NIHSS score ≥ 4 or death within the first 24 h) intracerebral haemorrhage type 2 22–36 h after the thrombolysis, and mortality at 90 days follow-up. The secondary outcome was functional independence (mRS 0–2) at three-months [234].

Results: IV alteplase is safe and efficient in the treatment of ischaemic stroke in Asian population in congruence to the observations of SITS trials performed on European population.

TIME WINDOW 3–4.5 HOURS

ECASS-III [11] (n = 821)

Time window: 3–4.5 h

Endpoints: Primary outcome was a disability at 3 months, assessed by the mRS as either favourable (score of 0 or 1) or unfavourable (score of 2 to 6). Secondary end-points included combined BI and RS, Scandinavian Stroke Scale (SSS) at 90 days, and 30 day mortality. Tertiary outcomes included early neurologic recovery (SSS) and duration of in-hospital stay.

Results: Significant benefit of IV-rtPA when administered up to 4·5 h. Symptomatic ICH is significantly more likely with alteplase than with placebo. No difference in mortality between the groups.

CASES [20] (n = 1112)

Time window: 3–4.5 h, 0–3 h

Endpoints: The primary endpoints were mRS at 90 days, mortality and symptomatic ICH. An mRS 0–1 at 90 days was defined as a favourable outcome.

Results: IV alteplase is efficacious in treating AIS patients in 3–4.5 h window; however, there is a tendency towards increased risk of symptomatic ICH in the later time window.

SITS-ISTR [21] (n = 23,942)

Time window: 3–4.5 h

Endpoints: Primary endpoints were functional independence at 3 months, and incidence of symptomatic ICH.Results: Safety and the functional outcome less favourable after 3 h.

TIME WINDOW 4.5–6 HOURS

ATLANTIS-B [18] (n = 613)

Time window: 3–5 h

Endpoints: Primary efficacy endpoint was an excellent neurologic recovery at day 90 (NIHSS ≤1); Secondary endpoints included remarkable recovery on functional outcome measures (BI, mRS, and Glasgow Outcome Scale) at days 30 and 90. Serious adverse events such as symptomatic ICH were also assessed.

Results: No significant rtPA benefit on the 90 day efficacy endpoints in patients treated between 3 and 5 h. A significant increase in the risk of symptomatic ICH with treatment using IV-rtPA.

ECASS-II [17] (n = 800)

Time window: 0–3 h and 3–6 h

Endpoints: The primary outcome was the mRS at 90 days, dichotomised for favourable (score 0–1) and unfavourable (score 2–6) outcome.

Results: Trend towards benefit for alteplase, though not statistically significant. Increased risk of symptomatic ICH (8.6% alteplase-group vs. 3.4% placebo-group).

ATLANTIS-A [19] (n = 142)

Time window: 0–6 h

Endpoints: Primary efficacy endpoints were the number of patients with a decrease of ≥ points on the NIHSS scale at 24 h and day 30, along with infarct volume at day 30. Secondary outcomes included mortality and functional status on the BI and mRS scales at days 30 and 90.

Results: Significantly higher proportion of 4-point NIHSS improvement at 24 h for rtPA groups (40%) vs. placebo (21%). The trend reversed at 30 days with more improvement observed in placebo (75%) vs. rtPA patients (60%). rtPA is strongly correlated with an increased risk of ICH, especially in patients treated between 5 and 6 h after onset.

IST-3 [15] (n = 3035)

Time window: 0–6 h

Endpoints: Primary outcome was the proportion of patients who were alive and independent (defined by an Oxford Handicap Score (OHS) of 0–2) at 6 months. Symptomatic ICH recorded at 7 days, and at 6 months.

Results: Higher proportion of symptomatic ICH at 7 days in the rtPA group (7%) vs. control group (1%), and deaths at 7 days in rtPA (11%) vs. control group (7%). A similar number of fatalities in either rtPA or control groups (27% each). Despite early hazards, IV alteplase improved functional outcome.