The Exact Science of Stroke Thrombolysis and the Quiet Art of Patient Selection

Joyce S. Balami; Gina Hadley; Brad A. Sutherland; Hasneen Karbalai; Alastair M. Buchan


Brain. 2013;136(12):3528-3553. 

In This Article

Interventional Endovascular Therapies

Intra-arterial Thrombolysis

Intra-arterial thrombolysis is another method for administering thrombolytic agents with several theoretical advantages over intravenous thrombolysis (Table 3). Intra-arterial thrombolysis is normally indicated for patients presenting within 6 h, those with large vessel occlusion like distal internal carotid artery and proximal middle cerebral artery, those with contraindications to intravenous rt-PA such as anticoagulated or postoperative patients, and those patients who do not improve after intravenous thrombolysis (Natarajan et al., 2009). The Prolyse in Acute Cerebral Thromboembolism (PROACT II) trial compared intra-arterial thrombolysis (with pro-urokinase) to heparin-only controls in acute ischaemic stroke patients. The intra-arterial thrombolysis group had significantly higher recanalization rates and more favourable outcomes (modified Rankin Score 0–2) at 3 months, with similar mortality but a 5× higher risk of intracerebral haemorrhage within 24 h of stroke onset (Furlan et al., 1999), which was attributed to the longer (6 h) time window, as well as greater baseline stroke severity. Despite these encouraging results (adjusted relative risk 15%, number needed to treat = 7), the FDA did not approve intra-arterial pro-urokinase for acute ischaemic stroke, requesting a confirmatory trial that has never been performed. Nevertheless, the success of PROACT II has led to a new era in intra-arterial thrombolysis for acute ischaemic stroke treatment.

In subsequent analysis of the PROACT II data, the patients were stratified by baseline ASPECTS, showing a significant adjusted relative risk of independent functional outcome at 3 months in patients with ASPECTS >7, relative to those with ASPECTS ≤7 (adjusted relative risk 3.2, CI 1.2–9.1 versus adjusted relative risk 1.0, CI 0.6–1.9), highlighting the importance of quantitative imaging metrics for patient selection in future intra-arterial thrombolysis trials (Hill et al., 2003b).

Meta-analysis of five randomized trials suggests that intra-arterial fibrinolysis substantially increases recanalization rates with good and excellent clinical outcomes relative to control (generally intravenous heparin) in acute ischaemic stroke (Lee et al., 2010), and in open clinical case series intra-arterial therapy had higher early recanalization rates (50–80%) than intravenous thrombolysis (30–50%) (Alexandrov et al., 2004). In addition to the benefit of intra-arterial therapy for treatment of acute ischaemic stroke due to middle cerebral artery occlusion (Fields et al., 2011), there is also evidence of benefit of intra-arterial therapy in vertebral or basilar occlusions up to 24 h after symptom onset (Macleod et al., 2005), with higher rates of recanalization in vertebrobasilar occlusion with intra-arterial therapy than intravenous thrombolysis (65 versus 53%) (Lindsberg and Mattle, 2006).

The majority of these favourable intra-arterial therapy studies used recombinant pro-urokinase. Unfortunately, recombinant pro-urokinase is currently not available for routine clinical use and intra-arterial therapy with rt-PA is not substantiated by randomized controlled trials, only observational and non-randomized data. Although intra-arterial rt-PA and urokinase are not approved by the FDA for acute ischaemic stroke treatment, some specialist centres have adopted protocols for their use in specific cases (Ahn et al., 2006; Sacco et al., 2007; Smith, 2007; Alberts et al., 2008).

Ultrasound Enhanced Therapies (Sonothrombolysis)

Ultrasound enhanced thrombolysis represents a new therapeutic approach that holds promise for improving recanalization rates and outcome. The mechanism of ultrasound enhanced thrombolysis involves reversible alteration of fibrin structure and microcavity formation in the shallow layers of thrombus, allowing increased penetration of alteplase into the clot and enhancing flow with microstreaming and vessel dilation (Suchkova et al., 1998; Alexandrov and Grotta, 2002; Labiche et al., 2003; Rubiera et al., 2005).

In the Combined Lysis of Thrombus in Brain Ischaemia Using Transcranial Ultrasound and Systemic rt-PA (CLOT-BUST) trial, continuous 2 MHz transcranial Doppler ultrasonography applied for 2 h augmented the rate of rt-PA induced arterial recanalization (Alexandrov et al., 2004). A meta-analysis of six randomized and three non-randomized studies of ultrasound enhanced thrombolysis in acute ischaemic stroke showed that the likelihood of complete recanalization was higher in patients receiving the combination of transcranial Doppler with intravenous thrombolysis compared with intravenous thrombolysis alone (pooled OR 2.99, CI 1.70–5.25, P = 0.0001) (Tsivgoulis et al., 2010). A pilot study showed enhanced recanalization and a trend toward better short- and long-term outcome with a combination of microbubbles (small microspheres filled with air or gas) and ultrasound enhanced thrombolysis compared with ultrasound enhanced thrombolysis or intravenous thrombolysis alone (Molina et al., 2006). Further phase 3 trials of combined ultrasound enhanced thrombolysis and intravenous thrombolysis are planned (NCT01098981) (

Mechanical Thrombectomy

The need for a wider therapeutic window to increase the proportion of acute ischaemic stroke patients who receive treatment has led to the advancement of endovascular intervention through mechanical thrombectomy, restoring cerebral blood flow by either removing or fragmenting the obstructing thrombus, with the theoretical advantage, over pharmacological thrombolysis, of avoiding systemic bleeding risks (Table 3). Mechanical thrombectomy offers the promise of efficacious treatment for patients who failed recanalization after thrombolysis, or in patients with pharmacological thrombolysis contraindications, such as recent surgery, abnormal haemostasis, or late presentation/unknown time of onset (Smith et al., 2005b, 2008; Nogueira and Smith, 2009). It is also usually indicated for large clot burdens or for clots containing large amounts of calcium, cholesterol or other debris resistant to thrombolytics (Halloran and Bekavac, 2004).

A myriad of devices have been developed, including retriever devices (e.g. Merci) (Smith et al., 2005b), Phenox (Henkes et al., 2006; Liebig et al., 2008), Alligator (Kerber et al., 2007), Revive (Rohde et al., 2011) and Trevo (Wahlgren, 2012), deployed distal to a thrombus for clot extraction, aspiration devices (e.g. Penumbra) (Bose et al., 2008), which apply a vacuum to the proximal aspect of the thrombus, with a potentially lower rate of embolic events (Nguyen et al., 2011), and stents (e.g. balloon angioplasty and stents) (Ueda et al., 1998; Nakano et al., 2002, 2004; Gupta et al., 2006a; Levy et al., 2006; Nogueira et al., 2008), and self-expandable stents such as Wingspan (Levy et al., 2009) and Solitaire (Roth et al., 2010; Koh et al., 2012). Stent retrievers (e.g. Trevo) are preferred under current AHA guidelines. Currently four devices have FDA clearance: Merci, Penumbra, Solitaire, and Trevo (Jauch et al., 2013).