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

Endovascular versus Intravenous Thrombolysis Approaches

The Local versus Systemic Thrombolysis for Acute Ischemic Stroke (SYNTHESIS expansion) trial showed no benefit of endovascular treatment (pharmacological or mechanical intervention or both, at clinician's discretion) alone over intravenous thrombolysis alone (Ciccone et al., 2013). Similarly, the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) study, designed to identify people who might benefit from mechanical embolectomy using multimodal CT or MRI (NCT00389467) (, found embolectomy not to be significantly superior to standard care (intravenous thrombolysis) in patients with 'favourable' penumbral pattern or non-penumbral pattern, or overall (Kidwell et al., 2013). These results suggest the need for development of better endovascular therapies, or better patient selection strategies through meta-analysis of baseline patient metrics, but current evidence does not support endovascular therapy in acute ischaemic stroke patients eligible for intravenous thrombolysis (Jauch et al., 2013).

Bridging Therapies: Combination of Intravenous and Endovascular Approaches

Although both intravenous thrombolysis and endovascular strategies to recanalize could each be effective, the combination of these methods could be more synergistically beneficial following acute ischaemic stroke.

Combined Intravenous Thrombolysis–Intra-arterial Therapy. Combination therapy, also known as bridging therapy, is another approach to improved vessel recanalization through the early use of intravenous thrombolysis followed by local intra-arterial therapy. Bridging therapy potentially combines the advantages of each modality: the wide availability of early rapid intravenous thrombolysis and the potentially higher recanalization rates of intra-arterial therapy, allowing for better clinical outcomes in acute ischaemic stroke. The first pilot study of bridging therapy was the Emergency Management of Stroke (EMS) Bridging trial, a multicentre randomized controlled trial. Although recanalization of middle cerebral artery occlusions was greater with a combined intravenous/intra-arterial approach (82%) than with intra-arterial therapy alone (50%), with lower NIHSS at 3 months, there was a significantly higher mortality in the bridging therapy group (29% versus 5.5%), but the risk of symptomatic intracranial haemorrhage in both groups was similar (Lewandowski et al., 1999). Subsequent Interventional Management of Stroke (IMS I and II) trials demonstrated improved outcomes at 3 months with bridging therapy compared with NINDS' historical placebo-treated controls (IMS, 2004, 2007), although it would have been more appropriate to compare outcomes to current standard of care (i.e. intravenous thrombolysis). Recanalization rates of 56% in IMS I and 60% in IMS II, and symptomatic intracranial haemorrhage rates of 6.3% in IMS I and 11.8% in IMS II (IMS, 2004, 2007), led to IMS III, meant to assess whether bridging therapy is superior to intravenous thrombolysis alone when initiated within 3 h of onset. However, the study was stopped early, following Data and Safety Monitoring Board recommendation, because of futility. No serious safety concerns were identified, but the bridging therapy and intravenous thrombolysis patients had no significant difference in functional independence (modified Rankin Score ≤2) at 3 months, symptomatic intracranial haemorrhage rate, or mortality (Broderick et al., 2013).

In a recent meta-analysis of 15 studies using bridging therapy the pooled estimate was 69.6% (CI 63.9–75.0%) for recanalization rate, 48.9% (CI 42.9–54.9%) for favourable outcome, 8.6% (CI 6.8–10.6%) for symptomatic intracranial haemorrhage, and 17.9% (CI 12.7–23.7%) for mortality (Mazighi et al., 2012). Current evidence does not necessarily support bridging therapy in patients eligible for intravenous thrombolysis, absent better patient selection strategies.

Combined Intravenous Thrombolysis–Mechanical Thrombectomy. The REcanalization using Combined intravenous Alteplase and Neurointerventional ALgorithm for acute Ischemic StrokE (RECANALIZE) study, demonstrated higher recanalization rates in the combined intravenous thrombolysis-endovascular group (87%) (using intra-arterial alteplase, and mechanical procedures—snare or balloon angioplasty—if intra-arterial therapy failed) than in the intravenous thrombolysis alone group (52%) (adjusted relative risk 1.49, CI 1.21–1.84, P = 0.0002). The combined approach suggested advantages over intravenous thrombolysis alone in early neurological improvement (NIHSS ≤1 or a ≥4 point improvement) at 24 h (60 versus 39%; adjusted relative risk 1.36, CI 0.97–1.91, P = 0.07) and favourable outcome (modified Rankin Score 0–2) at 3 months (57 versus 44%; adjusted relative risk 1.16, CI 0.85–1.58, P = 0.35), although the symptomatic intracranial haemorrhage rate (9 versus 11%) and 90 day mortality (17% in both) were similar. (Mazighi et al., 2009). The Pragmatic Ischaemic Stroke Thrombectomy Evaluation (PISTE) is a planned randomized controlled trial to investigate whether additional mechanical thrombectomy can improve functional outcome in acute ischaemic stroke patients with large artery occlusion given intravenous thrombolysis as standard care (NCT01745692) (

Multimodal Reperfusion Therapy. Multimodal reperfusion therapy is another approach, combining pharmacological and several endovascular methods to achieve quick reperfusion and higher rates of recanalization after acute ischaemic stroke. Combining approaches, including mechanical thrombolysis, intra-arterial lytic drugs, clot retrieval, and angioplasty with stenting, is increasingly being used in some centres (Lin et al., 2003; Abou-Chebl et al., 2005; Gupta et al., 2006b; Leker et al., 2009; Cohen et al., 2011; Park et al., 2012). Evidence of the benefits of multimodal reperfusion therapy in improving recanalization is derived from case reports of middle cerebral artery and extracranial internal carotid artery occlusions with varying results (Abou-Chebl et al., 2005; Gupta et al., 2006b; Bunc et al., 2010). This approach is particularly promising for patients with large hemispheric infarcts (Leker et al., 2009), posterior circulation stroke, and basilar artery occlusion (Raphaeli et al., 2009), where high survival and good outcome rates have been demonstrated (Leker et al., 2009; Raphaeli et al., 2009).

Multimodal reperfusion therapy has been found to be safe and effective at recanalizing occluded cerebral vessels that fail to respond to thrombolysis, without increasing the risk of intracerebral haemorrhage (Abou-Chebl et al., 2005). In case series involving 12 patients in whom intravenous thrombolysis had failed, multimodal reperfusion therapy, consisting of GPIIb/IIIa antagonists, angioplasty and mechanical embolectomy, resulted in good recanalization in 11 patients, with only one patient at low perfusion post-multimodal reperfusion therapy. There was only one symptomatic intracranial haemorrhage, and half of patients had a favourable outcome (NIHSS ≤4) at discharge (Abou-Chebl et al., 2005). Further research into multimodal reperfusion therapy is warranted as the evidence for its benefit and safety is based only on case series.