Advances in Medical Revascularisation Treatments in Acute Ischemic Stroke

Table 2

Summary of articles.

Study	Design	Patient groups^*	Baseline NIHSS	Time from onset	Time to treatment	Symptomatic ICH%	Mortality%; (90-day)	Functional outcome at 3 months
Tissue plasminogen activator (tPA)
NINDS: parts 1 and 2 (1995) [16]	RCT	= 624; Part 1: improvement >4 in NIHSS within 24 hours; Part 2: clinical outcome at 3 months; G1: IV tPA (0.9 mg/kg, max 90 mg); G2: placebo	Median (range); Part 1: G1: 14; (1–37); G2: 14; (1–32); Part 2: G1: 14; (2–37); G2: 15; (2–33)	Within 3 hours	0–90 mins; G1: 50%; G2: 46%; 91–180 mins; G1: 50%; G2: 54%	Within 36 hours: G1: 6.4%; G2: 0.6% ( < 0.001)	G1: 17%; G2: 21% ( = 0.30)	mRS 0-1; 0–90 mins; G1: 40%; G2: 28%; ( = 0.035); 91–180 mins; G1: 45%; G2: 25%; ( < 0.001)
ECASS 3 (2009) [17]	RCT	= 821; G1: IV-tPA (0.9 mg/kg, max 90 mg); G2: placebo	Mean (SD); G1: 10.7 (5.6); G2: 11.6 (5.9)	Between 3 and 4.5 hours	Mean; mins; G1: 239; G2: 238	G1: 2.4%; G2: 0.2% ( = 0.008)	G1: 7.7%; G2: 8.4%; ( = 0.68)	mRS 0-1; G1: 52.4%; G2: 45.2%; ( = 0.04)
IST-3 (2012) [18]	RCT	= 3035; G1: IV tPA; G2: control	G1: 0–5 20%; 6–10 28%; 11–15 20%; 16–20 18%; >20 14%; G2: 0–5 20%; 6–10 28%; 11–15 19%; 16–20 18%; >20 14%	Within 6 hours	Mean; mins; G1: 252 (72); G2: —	Within 7 days; G1: 7%; G2: 1% (≤ 0.0001)	Within 7 days; G1: 11% G2: 7%, = 0.001; Between 7 days and 6 months: G1: 16% G2: 20%, ( = 0.002)	Independent patients (Oxford Handicap score of 0–6) and alive at 6 months: G1: 37%; G2: 35% ( = 0.181)
SITS-ISTR (2013) [19]	Observational registry	= 29618; IV tPA in different treatment times; G1: 4.5–6 hours; G2: 3–4.5 hours; G3: within 3 hours	Median (IQR); G1: 9; (6–15); G2: 9; (6–15); G3: 12; (7–17)	Within 3, 4.5, or 6 hours	Median (IQR) mins; G1: 295 (289–315); G2: 210 (195–235); G3: 138 (112–162)	G1: 2.6%; ( = 0.17); G2: 1.8%; ( = 0.27); G3: 1.5%	G1: 11.8%; ( = 0.99); G2: 11.1%; ( = 0.21); G3: 11.8%	mRS 0–2; G1: 61.3%; ( = 0.4); G2: 62.7%; ( < 0.01); G3: 58.4%
ARTIS (2012) [20]	RCT	= 642,; G1: 300 mg IV aspirin; 90 mins after IV tPA; G2: standard treatment	Median (IQR); G1: 9; (5–12); G2: 9; (5–14)	Within 4.5 hours	Mean (SD) mins; G1: 124.4 (54); G2: 127.9 (57.6)	G1: 7.4%; G2: 0.7%; ( = 0.006)	G1: 11.2%; G2: 9.7%; ( = 0.54)	mRS 0–2; G1: 54%; G2: 57.2%; ( = 0.42)
Other thrombolytic agents
Parsons et al. (2012) [21]	RCT	= 75; G1: alteplase (0.9 mg/kg); G2: tenecteplase (0.1 mg/kg); G3: tenecteplase (0.25 mg/kg)	G1: 14 (2.3); G2: 14.5 (2.3); G3: 14.6 (2.3)	Within 6 hours	Mean (SD); hours; G1: 2.7 (0.8); G2: 3.1 (0.9); G3: 3; (0.7)	G1: 12%; G2+3: 4%; ( = 0.33)	G1: 12%; G2+3: 8%; ( = 0.68)	mRS 0–2; G1: 44%; G2+3: 72%; ( = 0.02); Reperfusion on MRI at 24 hr; G1: 55.4% (38.7); G2+3: 79.3% (28.8); ( = 0.004); Complete recanalisation at 24 hr; G1: 36%; G2+3: 58%; ( = 0.09)
DIAS (2005) [22]	RCT	= 104 patients with perfusion/diffusion mismatch on MRI treated with IV desmoteplase or placebo; Part 1 ( = 47) trial terminated prematurely due to high rates of sICH (23.5%–30.8%).; Part 2 ( = 57) had lower weight adjusted doses; G1: 62.5 ug/kg; G2: 90 ug/kg; G3: 125 ug/kg; G4: placebo	G1: 13; G2: 12; G3: 12; G4: 8	Between 3 and 9 hours	Mean; mins; G1: 360; G2: 400; G3: 295; G4: 340	Within 72 hr; G1: 0%; G2: 6.7%; G3: 0%; G4: 0%	G1+2+3: 4.4%; G4: 9.1%	Favourable clinical outcome (composite score) at 90 days; G1: 13.3% ( = 0.757); G2: 46.7% ( = 0.054); G3: 60% ( = 0.009); G4: 18.2%; Early reperfusion at 4- to 8-hour (reduction ≥30% mean transit time or ≥2; point improvement in TIMI); G1: 23.1% ( = 0.390); G2: 46.7% ( = 0.035); G3: 71.4% ( = 0.0012); G4: 20%; Favourable clinical outcome associated with reperfusion, 53% versus 25% ( = 0.0028)
DEDAS (2006) [14]	RCT	= 37 patients with perfusion/diffusion mismatch on MRI treated with IV desmoteplase or placebo; G1: 90 ug/kg; G2: 125 ug/kg; G3: placebo	Median (range); G1: 10; (4–18); G2: 9; (5–19); G3: 12; (6–18)	Between 3 and 9 hours	Median (range); mins; G1: 477 (393–568); G2: 420 (222–531); G3: 443 (220–516)	G1: 0%; G2: 0%; G3: 0%	G1: 7.1%; G2: 6.7%; G3: 12.5%	Favourable clinical outcome (composite score); G1: 37.5% ( = 0.20); G2: 72.7% ( = 0.022); G3: 16.7%; Early; reperfusion at 4- to 8-hour (reduction ≥30%; mean transit time or ≥2 point improvement in TIMI); G1: 16.7% ( = 0.74); G2: 63.6% ( = 0.12); G3: 33.3%
DIAS II (2009) [4]	RCT	= 193 patients diffusion mismatch on MRI treated with IV desmoteplase or placebo; G1: 90 ug/kg; G2: 125 ug/kg; G3: placebo	Median (IQR); G1: 9; (7–14); G2: 9; (7–15); G3: 9; (6–14)	Between 3 and 9 hours	Mean (SD); mins; G1: 388 (88); G2: 402 (88); G3: 391 (92)	G1: 3.5%; G2: 4.5%; G3: 0%	G1: 11%; G2: 21%; G3: 6%	Favourable clinical outcome (composite score); G1: 47%; G2: 36%; G3: 46%; ( = 0.47)
STAT (2000) [23]	RCT	= 500; G1: ancrod 0.167 IU/kg iv per hour for over 72 hours, followed by 0.125 and 0.082 IU/kg over 1 hour at 96 and 120 hours depending on plasma fibrinogen level (target 1.18 to 2.03 micromole/L); G2: placebo	Mean (SD); G1: 23.8 (10); G2: 24.4 (11)	Within 3 hours	Mean (SD); hours; G1: 2.7 (0.4); G2: 2.7 (0.5)	G1: 5.2%; G2: 2%; ( = 0.06)	G1: 25.4%; G2: 23%; ( = 0.62)	Favourable outcome (Barthel Index >95); G1: 41.1%; G2: 35.3%; ( = 0.04)
SaTIS (2011) [24]	RCT	= 260; G1: tirofiban infusion (0.4 ug/kg/min over 30 mins + continuous infusion 0.1 ug/kg/min for 48 hr); G2: placebo	Median (range); G1: 6; (4–18); G2: 6; (4–18)	Between 3 and 22 hours	Median; hours; G1: 9.25; G2: 10.7	Haemorrhagic transformation/parenchymal haemorrhage within 7 days; G1: 30%; G2: 26.6%; ( = 0.665)	Mortality at 5 months: G1: 2%; G2: 8%; ( = 0.03)	Mean mRS after 5 months: G1: 1.9; G2: 2.2; ( = 0.3)
AbESTT-II (2008) [25]	RCT	= 808; trial terminated prematurely due to unfavourable risk-benefit profile; Primary cohort; G1: abciximab; G2: placebo; 5-6 hr cohort; G3: abciximab; G4: placebo; Wake-up cohort; G5: abciximab; G6: placebo	Mean (SD); G1: 9.9 (5.2); G2: 9.6 (5); G3: 9.5 (4.8); G4: 9.4 (4.9); G5: 10.4 (5); G6: 10 (5)	Primary cohort: within 5 hours; 5-6 hr cohort; Wake-up cohort: within 3 hours of awakening	Mean; hours; G1: 3.6; G2: 3.8; G3: 5; G4: 5; G5: 10.8; G6: 12.1	Within 5 days/discharge; G1: 5.5%; G2: 0.5%; ( = 0.002); G3: 1.9%; G4: 0.6%; ( = 0.309); G5: 13.6%; G6: 5%; ( = 0.347)	G1: 15.8%; G2: 11.5%; ( = 0.167); G3: 11.3%; G4: 10.7%; ( = 0.887); G5: 27.3%; G6: 14.3%; ( = 0.298)	mRS 0-1; G1: 42.5%; G2: 44.5%; ( = 0.679); G3: 36.3%; G4: 40.3%; ( = 0.462); G5: 9.1%; G6: 28.6%; ( = 0.101)
CLEAR-ER (2013) [26]	RCT	= 126; G1: combination IV 0.6 mg/kg tPA + eptifibatide (135 mcg/kg bolus + 0.75 mcg/kg/min infusion for 2 hr); G2: standard IV tPA	Median (IQR); G1: 12; (9–20); G2: 17 (11–22)	Within 3 hours	Median (IQR) mins; G1: 113 (99–135); G2: 129 (90–141)	Within 36 hours; G1: 2%; G2: 12%; ( = 0.053)	G1: 19.8%; G2: 4% ( = 0.78)	mRS 0-1 or return to baseline mRS; G1: 49.5%; G2: 36%; ( = 0.23)
ARGIS-1 (2004) [27]	RCT	= 171; G1: IV argatroban (100 ug/kg bolus) + infusion 3 ug/kg/min PT time × 2.5; G2: IV argatroban (100 ug/kg bolus) + infusion 1 ug/kg/min PT time × 1.75; G3: placebo	Median (IQR); G1: 9 (5–22); G2: 10 (5–22); G3: 9 (5–20)	Within 12 hours	N/A	G1: 5.1% ( = 0.18); G2: 3.4% ( = 0.5); G3: 0%	G1: 11.1%; G2: 19.3%; G3: 9.3%	mRS 0–2; G1: 51% ( = 0.58); G2: 45% ( = 0.61); G3: 54%
ARTTS (2012) [28]	Single arm prospective trial	= 65; During standard IV tPA, IV argatroban given (100 ug/kg bolus) + infusion for 2 days with target PT time × 1.75	Median (range); 13 (3–25)	Within 4.5 hours	Median (IQR) mins; 128 (94–170)	4.6%	7-day mortality; 10.8%	7-day mRS 0-1; 29%; Complete recanalisation (TIMI 3) at 24 hr; 63%
Penumbra neuroimaging
DEFUSE 2 (2012) [29]	Prospective cohort study	= 138; (98 had endovascular treatment; 104 had MRI profile); G1: = 78 had target mismatch; G2: = 26 had no target mismatch	Median (IQR); G1: 14 (11–20); G2: 18 (12–19)	Within 12 hours	Median (IQR) hours; G1: 6.2 (4.9–8.1); G2: 3.6 (2.5–4.9)	G1: 7%; G2: 19%; ( = 0.15)	N/A	mRS 0–2; G1; Reperfused 57%; No reperfusion; 31%; ( = 0.04); G2; Reperfused 25%; No reperfusion 22% ( = 1.0); Median (core) lesion growth (IQR) mL; G1 Reperfused; 30 (5–67); No reperfusion 73 (32–127); ( = 0.005); G2 Reperfused; 96 (68−159); No reperfusion 34 (4–147) ( = 0.21)
DEFUSE (2006) [30]	Prospective cohort study	= 74; IV TPA 0.9 mg/kg; G1: target mismatch; G2: no target mismatch	Median (IQR); 11.5 (8)	Between 3 and 6 hours	Median (IQR) mins; 328 (40)	G1; Reperfused 22%; No reperfusion 6.3%; G2; Reperfused 25%; No reperfusion 0%; Malignant profile 50%	N/A	mRS 0–2; G1 Reperfused 50%; No reperfusion 13%; G2 Reperfused 25%; No reperfusion 71%; Malignant profile: 17%; Mismatch with early reperfusion OR 5.4 (CI 1.1–25.8) for favourable clinical response ( = 0.039)
EPITHET (2008) [31]	RCT	= 101; G1: alteplase; G2: placebo; 86% of patients had perfusion mismatch	Median (range); G1: 14; (4–26); G2: 10; (5–25)	Between 3 and 6 hours	Mean (SD); mins; G1: 297 (42); G2: 294 (50)	Within 36 hours; G1: 7.7%; G2: 0%	G1: 25%; G2: 14%; ( = 0.161)	mRS 0-1; G1: 35%; G2: 24%; ( = 0.153); Reperfusion (>90% reduction between baseline and day 3 PWI volume); G1: 56%; G2: 26%; ( = 0.01); Infarct growth in geometric mean at 90 days; G1: 1.24; G2: 1.78; ( = 0.239)
Adjuvant/experimental treatments
CLOTBUST: phase 2 (2004) [32]	RCT	= 126 patients; Proximal arterial occlusion on TCD; G1: IV 0.9 mg/kg TPA and 2 MHz TCD with max 750 mW power for 2 hours at the target lesion; G2: placebo	Median; G1: 16; G2: 17	Within 3 hours	Median; mins; G1: 150; G2: 130	Within 72 hours; G1: 4.8%; G2: 4.8%	G1: 15%; G2: 18% ( = 0.4)	mRS 0-1; G1: 42%; G2: 29%; ( = 0.2); Complete recanalisation (TIMI 3) at 2 hours; G1: 29%; G2: 11% ( < 0.001)
TUCSON (2009) [33]	RCT	= 35; Receiving IV tPA with proximal intracranial occlusion; G1: microS (MRX-801) infusion over 90 minutes (1.4 mL); G2: microS (MRX-801) infusion over 90 minutes (2.8 mL); G3: control	Median (IQR); G1: 10; (4–14); G2: 16; (9–21); G3: 25; (7–14)	Within 3 hours	Mean; (SD) mins; G1: 139 (33); G2: 130 (32); G3: 126 (46)	G1: 0%; G2: 27%; G3: 0%; ( = 0.028)	G1: 0%; G2: 30%; G3: 0%; ( = 0.022)	mRS 0-1; G1: 75%; G2: 50%; G3: 36% ( = 0.167); Complete recanalisation; G1: 67%; G2: 45%; G3: 33%; ( = 0.255)

G = study groups.