History of Intra-arterial Thrombolysis

Fig. 7.1

The history of thrombolysis. Prolyse in Acute Cerebral Thromboembolism (PROACT) II trial; The Mechanical Embolus Removal in Cerebral Ischemia (MERCI); Interventional Management of Stroke [IMS] III; Local Versus Systemic Thrombolysis for Acute Ischemic Stroke [SYNTHESIS] Expansion; Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy [MR RESCUE]; Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands [MR CLEAN]; Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness [ESCAPE]; Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial [EXTEND-IA]; Solitaire With the Intention For Thrombectomy as Primary Endovascular Treatment [SWIFT PRIME]; Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 h [REVASCAT]

Table 7.1

Summary of landmark trials of endovascular therapy for AIS

	Number, active group	Study design	Occluded vessels	Duration of symptoms (h)	Baseline NIHSS, median	Successful recanalization TIMI 2–3/TICI 2b–3 (%)	Good clinical outcomes, 90-day mRS 0–2 (%)	Mortality at 90 days (%)	sHT (%)
IAT with thrombolytic agent
PROACT I	26	RCT, IA pro UK + IV heparin vs. IV heparin	MCA (M1/M2)	<6	17	58	58	27	15
PROACT II	121	RCT, IA pro UK + IV heparin vs. IV heparin	MCA (M1/M2)	<6	17	66	40	25	10
MELT	57	RCT, IA UK vs. control	MCA (M1/M2)	<6	14	NA	49	5	9
Combined IV and IA thrombolysis (bridging therapy)
EMS	17	RCT, IV rt-PA + IA rt-PA vs. IA rt-PA	MCA (M1/M2), ICA	<3	16	54	NA	29	12
IMS I	62	Single-arm study, IV rt-PA + IA rt-PA	MCA (M1/M2), ICA, VBA	<3	18	56	43	16	6
IMS II	55	Single-arm study, IV rt-PA + IA rt-PA/EKOS	MCA (M1/M2), ICA, VBA	<3	19	58	46	16	10
IMS III	434	RCT, IV rt-PA + EVT/IA rt-PA vs. IV rt-PA	MCA (M1/M2), ICA, VBA	<3	17	65–81	41	19	6
Endovascular mechanical IAT
MERCI	151	Single-arm study, IA MERCI, IAT	MCA (M1/M2), ICA, VBA	<8	22	46	28	44	8
Multi-MERCI	164	Single arm, IA MERCI, IAT + IV rt-PA	MCA (M1/M2), ICA, VBA	<8	19	68	36	34	10
Penumbra pivotal trial	125	Single arm, IA Penumbra, IV rt-PA	MCA (M1/M2), ICA, VBA	<8	18	82	25	33	11
SWIFT (Solitaire)	58	RCT, Solitaire vs. MERCI	MCA (M1/M2), ICA, VBA	<8	17	83	36	17	2
TREVO 2 (TREVO)	88	TREVO vs. MERCI	MCA (M1/M2), ICA, VBA	<8	19	85	40	33	7
SYNTHESIS	181	RCT, ET vs. IV rt-PA	NA	<4.5	13	NA	42	8	6
MR-RESCUE^a	34; 30	RCT, ET vs. medical therapy	MCA (M1/M2), ICA	<8	17;19	67;77	21;17	18;20	9;0

Abbreviations: NIHSS National Institutes of Health Stroke Scale score, TICI thrombolysis in cerebral infarction, TIMI thrombolysis in myocardial infarction, mRS modified Rankin Scale, SHT symptomatic hemorrhagic transformation, RCT randomized controlled trial, Pro-UK pro-urokinase, IV rt-PA intravenous recombinant tissue plasminogen activator, IAT intra-arterial thrombolysis, MCA middle cerebral artery, VBA vertebrobasilar artery, ICA internal carotid artery, NA not available

^aEmbolectomy patients with good penumbral pattern on magnetic resonance imaging (MRI); embolectomy in patients without good penumbral pattern on MRI

7.1 History of Local Chemical IAT

Earlier endovascular therapies attempted using IAT with thrombolytic agents. IA application of thrombolytic agents can deliver a higher dose of drug directly into the clot, thus increasing the chances for recanalization. The lower systemic exposure and smaller dose of thrombolytic agents used with IAT makes treatment possible in ineligible patients for treatment of IV rt-PA. Other advantages of IAT include direct angiographic visual assessment of treatment efficacy and the extension of the time window. The thrombolytic agents for IAT in AIS include urokinase (UK), pro-urokinase (pro-UK), streptokinase, alteplase, and reteplase [1].

7.1.1 The Prolyse in Acute Cerebral Thromboembolism (PROACT) (1998, N = 46)

The PROACT I study was a phase II, double-blind, randomized, placebo-controlled trial that compared IA r-pro-UK (6 mg) and low-dose IV heparin with IA placebo and low-dose IV heparin for symptomatic M1 and M2 middle cerebral artery (MCA) occlusion within 6 h of stroke onset [2]. The PROACT I trial was terminated early because the Food and Drug Administration (FDA) approved IV rt-PA. A total of 40 patients were recruited before premature termination. The recanalization of an occluded vessel, defined as a Thrombolysis in Myocardial Infarction (TIMI) score of 2 or 3, was significantly more likely in the pro-UK group versus the placebo group (57.7% vs. 14.3%, respectively). The overall risk of symptomatic hemorrhagic transformation (SHT) was also higher in the pro-UK group to 15.4% compared to 7.1% in the placebo group.

7.1.2 The PROACT II (1999, N = 180)

The PROACT II study was a phase III, open-label, randomized controlled trial of assessing the efficacy and safety of IA pro-UK (9 mg) plus IV heparin compared with IV heparin alone in patients presenting within 6 h of stroke onset and with angiographically confirmed MCA occlusions [3]. In PROACT II trial, the primary clinical outcome of a modified Rankin Scale (mRS) score of 0–2 at 90 days was achieved in a higher percentage of the IA pro-UK group (40%) compared with the heparin-only control group (25%). The successful recanalization, defined as TIMI grade 3, was also higher in the pro-UK group (19%) compared to the control group (4%) [3]. SHT was increased in the pro-UK group (10% vs. 2%), but these increases of SHT did not affect mortality rates (25% in the pro-UK group vs. 27% in the control group) [3].

7.1.3 The Middle Cerebral Artery Embolism Local Fibrinolytic Intervention (MELT) (2007, N = 114)

The Japanese MELT study was a randomized, controlled trial examining the safety and efficacy of IA infusion of UK in patients with symptomatic M1 or M2 MCA occlusion of less than 6 h of stroke onset [4]. This trial was terminated after the approval of IV rt-PA in Japan. In the MELT trial, preliminary results did not show significance in primary efficacy outcome (mRS score 0–2) at 90 days. However, there was significantly more patients with excellent functional outcome (mRS score of 1 less) and the National Institute of Health Stroke Scale (NIHSS) score 0 or 1 at 3 months in the UK group than the control group.

The PROACT II trial is the only randomized controlled trial of IA thrombolytic agents to date, which verified statistically significant clinical benefit. Because of the small size and marginal significance, The FDA did not approve a stroke label for IA r-pro-UK and requested a confirmatory efficacy trial that has not yet been conducted. Furthermore, there have been no direct comparative trials to examining the safety and efficacy of IAT versus IV rt-PA in AIS. The disadvantages of IAT include additional time required to activate the interventional team and to transport patients to the specialized hospitals available to IAT.

7.2 History of Combined IV and IA Thrombolysis (Bridging Therapy)

Several studies have investigated the feasibility, safety, and efficacy of combined IV rt-PA and IAT in AIS patients. The rationale for combined IVT and IAT came from the concern that the delayed time of initiation with the IAT may negate the potential benefits of more efficacious recanalization as well as that proximal intracranial artery occlusions with larger clot burdens may benefit most from IAT. The bridging therapy came from the efforts of the combined advantages of IVT (wide availability, fast administration) and IAT (higher recanalization, extended time window).

7.2.1 Combined IV and IA Administration of rt-PA

7.2.1.1 The Emergency Management of Stroke (EMS) Bridging Trial (1999, N = 34)

The EMS was a double-blind, randomized, placebo-controlled, multicenter phase I pilot trial, which randomized patients to the IV/IA group [low-dose IV rt-PA (0.6 mg/kg) followed by local IA rt-PA via microcatheter] or the placebo/IA group (IV placebo followed local IA of rt-PA via microcatheter) [5]. Based on the subanalysis of the 22 patients with a persistent clot on angiography, the IV/IA bridging approach yielded significantly higher rates of recanalization (54% vs. 10%, respectively) but no difference in the clinical and functional outcomes [5]. The rates of death, SHT, and the life-threatening extracranial bleeding complications were higher in the IV/IA group than in the placebo/IA group but not statistical significance [5].

7.2.1.2 The International Management of Stroke (IMS) I (2004, N = 80)

The IMS I and II studies were a prospective, multicenter, open-label, single-arm pilot trial, with the aim of assessing the feasibility and safety of a combined low-dose IV rt-PA and IA rt-PA administered in patients with persistent clot after the bolus of IV rt-PA [6]. These IMS studies included patients with intracranial internal carotid artery (ICA) occlusion, vertebrobasilar artery (VBA) occlusion, as well as M1 and M2 MCA occlusion [6]. In IMS I, 34 (43%) of the 80 enrolled patients achieved an mRS ≤ 2 at 90 days compared with 39% and 28% of the patients in the rt-PA and placebo groups of the National Institute of Neurological Disorders and Stroke (NINDS) trial, respectively [6]. The partial or complete recanalization, defined as TIMI 2–3, was achieved in 35 (56%) of the 62 patients who underwent combined IVT and IAT. The rate of SHT (6.3%) in IMS subjects was comparable with the IV rt-PA group (6.6%) but higher than the rate in the placebo group (1.0%) in the NINDS trial. The 90-day mortality in IMS subjects (16%) was lower but not statistically different from the mortality rate of the rt-PA group (21%) or the placebo group (24%) in the NINDS trial [6].

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