1.1.1 Clinical Presentation

A 64-year-old male presented to the emergency department 100 minutes after acute onset of aphasia, right hemisyndrome, and hemineglect. Clinical examination was suggestive of a partial left middle cerebral artery (MCA) syndrome with National Institutes of Health Stroke Scale (NIHSS) 13.

1.1.2 Imaging Workup and Investigations

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  Noncontrast computed tomography (CT) was performed shortly after presentation to the emergency department (135 minutes after symptom onset) revealing early infarction.

  
  
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  CT angiography revealed occlusion of the distal left M1 segment of the MCA and left MCA bifurcation. There is slow filling of the distal left MCA branches via leptomeningeal collaterals (Fig. 1.1).

  

1.1.3 Diagnosis

Partial occlusion of the left M1 segment, with early involvement of the MCA territory.

1.1.4 Management

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  The patient had no contraindication to intravenous (IV) thrombolysis based on clinical history, clinical assessment, and CT findings.

  
  
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  He received an initial bolus and infusion of tissue plasminogen activator (tPA) commencing 170 minutes after symptom onset, then subsequently bolus of intra-arterial (IA)-tPA.

1.1.5 Technique

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  A 6-Fr guide catheter was placed into the left internal carotid arteries.

  
  
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  A microcatheter and 014-in wire were placed into the left M1 segment.

  
  
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  Mechanical clot disruption with a wire and catheter was performed. This was interspersed with IA-tPA. The left M1 segment and upper branch of the left MCA were completely opened after a total of 19 mg of IA-tPA.

  
  
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  The inferior MCA branch had some residual clot. Supraselective catheterization with mechanical clot disruption was performed with an addition of 5 mg of tPA in this vessel.

  
  
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  After termination of the procedure, the entire left MCA circulation was open. The patient can now move her right side, whereas she was densely hemiplegic prior to thrombolysis.

  
  
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  The long, 6-Fr sheath was exchanged with a shorter 6-Fr sheath.

  
  
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  However, the patient had significant oozing around the second sheath and it was decided to remove the sheath. After compression, the bleeding stopped. No other complications were noted.

1.1.6 Outcome

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  Successful complete thrombolysis of left M1 partial thrombus.

  
  
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  Discharged 4 days after admission to a rehabilitation hospital, with a modified Rankin score of 3.

1.1.7 Discussion

Prior to 1995, no consensus existed on the treatment of acute ischemic stroke. The first treatment to be approved was alteplase, a recombinant human tPA. With the understanding that stroke is caused by arterial occlusion, thrombolysis of thrombus would thus achieve recanalization and salvage ischemic cerebral tissue.

The monumental National Institute of Neurological Disorders and Stroke (NINDS) trial in 1995 randomized patients with acute ischemic stroke to receive either IV alteplase or placebo. ¹ This study was divided into two discrete parts. Part 1 demonstrated no significant difference between the groups in neurological improvement at 24 hours, but a significant benefit was observed for the treatment group at 3 months in terms of 4-point improvements in the NIHSS. In part 2, patients were assessed for improvements in the Barthel index, modified Rankin scale (mRS), Glasgow outcome scale, and NIHSS at 3 months. It was discovered that patients were at least 30% more likely to have a favorable outcome as measured by these scales (odds ratio [OR] = 1.7; 95% confidence interval [CI]: 1.2–2.6). Thus, NINDS study suggested that the use of IV-tPA within 3 hours of stroke onset has a definite long-term benefit for patients with acute ischemic stroke. However, symptomatic intracerebral hemorrhage (SICH) within 36 hours of symptom onset occurred more frequently in treated patients (6.4 vs. 0.6, p < 0.001), suggesting that the use of tPA was not without its risks. ¹ Thus, the risks and benefits of this approach must be balanced for optimal treatment. Nevertheless, based on the conclusive results of this trial, the Food and Drug Administration (FDA) approved the use of IV-tPA for the treatment of acute ischemic strokes in 1996.

Elsewhere around the world, similar investigations were underway. The European Cooperative Acute Stroke Study (ECASS) I, II, and III also investigated the use of alteplase for the treatment of acute ischemic stroke. ^{2 ,​ 3 ,​ 4} ECASS I was a double-blind randomized controlled trial (RCT) that randomized 620 patients to receive alteplase or placebo within 6 hours of stroke onset. The trial used both intention-to-treat (ITT) and explanatory analyses for the study’s target population (TP). The TP was defined as patients 18 to 80 years old with stable moderate-to-severe hemispheric stroke and few early infarct signs on CT. There was no difference discovered in the primary endpoint after ITT analysis. However, there was a significant difference in the mRS after post-hoc TP analysis. Moreover, Barthel Index and mRS were in favor of treated patient. No mortality differences were detected, but there was a significant increase in the occurrence of large parenchymal hemorrhages in treated patients. ² The results of this trial served as a reminder that treatment with tPA is associated with hemorrhagic complications, and careful patient selection must be done to exclude those who are unlikely to benefit from treatment.

ECASS II was another RCT that tested the efficacy and safety of a decreased dose of alteplase (0.9 mg/kg body weight from 1.1 mg/kg body weight in ECASS I) in the hope of lowering rates of intracranial hemorrhage. There was still more frequent symptomatic intracranial hemorrhage in the alteplase group, though mortality was not significantly different. The primary endpoint of mRS (0–1) was not significant between the groups, but a post-hoc analysis found less death or dependence (mRS: 3–6) in the treatment group, leaving the benefit of alteplase within 6 hours of stroke onset rather inconclusive. ³

The more conclusive result came from ECASS III, which specifically examined the administration of alteplase between 3 and 4.5 hours after stroke onset. The trial randomized 821 patients to receive either alteplase or placebo. More patients were found to have a favorable clinical outcome of mRS (0–1) with alteplase (52.4 vs. 42.2%, OR: 1.34, 95% CI: 1.02–1.76). The secondary endpoint of global OR was also in favor of the treatment group. Moreover, similar to the NINDS and ECASS I and II, treatment was associated with higher intracranial hemorrhage but not higher mortality rates. The ECASS III trial demonstrated the safety and efficacy of alteplase use within the window of 3 to 4.5 hours after stroke onset, extending the effective usage time of 3 hours from NINDS. ⁴

Since the approval of tPA, treatment data revealed that alteplase is able to achieve better recanalization rates and long-term clinical benefit (mRS ≤ 1) with distal occlusions rather than proximal ones. ^{5 ,​ 6} In fact, only half of the number of patients with proximal MCA occlusion achieved a good clinical outcome (mRS ≤ 1) as compared to those with distal occlusions. ⁵ Moreover, recanalization rate in proximal MCA was 26.1% as compared with 38.1% distally. ⁶ The next decade of research in acute ischemic stroke treatment tackled the possibility of delivering thrombolytic drugs intra-arterially to the site of vessel occlusion, in the hopes of achieving better results in proximal occlusions as well as distal ones.

The first RCT exploring the efficacy and safety of IA delivery method was PROACT I, a phase II study conducted between 1994 and 1995 that tested the use of recombinant pro-urokinase (rpro-UK) against placebo within 6 hours of stroke onset in patients with MCA occlusions. The study had a relatively smaller sample size, with 26 in the rpro-UK group and 14 in the placebo group. There was a significantly higher recanalization rate achieved with IA delivery of rpro-UK as compared to placebo (57.7 vs. 14.3%, p = 0.017). Moreover, there was a 10 to 20% absolute increase observed in neurological outcomes at 90 days as measured by the Barthel index, mRS, and NIHSS. Yet, perhaps owing to the small sample size, this difference was not statistically significant. As for safety measures, though there was a higher frequency of SICH observed in the treatment group versus placebo (15.4 vs. 7.1%), this difference was also not statistically significant. ⁷ The higher recanalization rate achieved in patients treated with rpro-UK, along with early indications of safety, prompted further exploration of the usage of IA delivery methods.

The PROACT II study was conducted in 1996, and in 1998 the phase III follow-up to PROACT I took place. In this study, 180 patients with acute ischemic stroke with angiographically proven occlusion of MCA were randomized to receive IA rpro-UK or placebo within 6 hours of stroke onset. The primary outcome was mRS of 2 or less, and this was achieved in 40% of rpro-UK patients as compared to 25% of control patients (p = 0.04). The recanalization rate was also higher for the treatment group, at 66% versus only 18% in the control group (p < 0.001). This trial was the first to demonstrate a clinical efficacy of IA thrombolysis in treating patients with acute ischemic stroke within 6 hours of symptom onset. Similar to PROACT I, the rate of SICH was higher in the intervention group within 24 hours (10% in intervention vs. 2% in controls). However, this result was still statistically insignificant (p = 0.06). ⁸

Another trial performed later in Japan also studied the efficacy of IA thrombolysis against placebo, but the results were more equivocal. The MELT trial conducted between 2002 and 2005 randomized 114 patients with MCA occlusions to either receive IA infusion of urokinase (UK) or no therapy, with the exception of osmotic diuretics only if indicated by high intracranial pressure. The trial was stopped early as the primary endpoint failed to achieve significance, and IV-rtPA was approved in Japan for the treatment of acute ischemic stroke in 2005. As of the study’s termination, the primary end point of the rate of achieving a good functional outcome (mRS ≤ 2) at 90 days was not significant (p = 0.345). Similarly, the difference in proportion of patients with a Barthel Index ≥95 was also not significant (p = 0.128). However, there was a higher proportion of patients who achieved an excellent functional outcome at day 90 in the treatment group than in the control (42.1 vs. 22.8%, p = 0.045). This trial suggested that the clinical benefits of IA thrombolysis with UK were still not clear at the time, and further research was required to elucidate the benefits of IA thrombolysis. ⁹

Several trials also looked at a combined IV and IA approach. One such trial was the EMS trial in 1999. This pilot double-blinded RCT randomized patients receiving IA-tPA to either receive IV-tPA or IV placebo within 3 hours of stroke onset. Though recanalization rates were significantly better (p = 0.03), the combined approach was not associated with a better clinical outcome. Although no clinical benefits were observed and trial size was relatively small (n = 35), the EMS trial demonstrated the feasibility of the combined approach. ¹⁰

The combined approach was explored further in the IMS I and II trials. ^{11 ,​ 12} IMS I compared a single arm of 80 patients who received both IV and IA-rtPA with historical controls of IV-tPA and placebo subjects from the 1995 NINDS trial. As compared to the placebo historical controls, all measures of clinical outcome at 3 months were better in the combined intervention group, including the primary endpoint of mRS of 0 to 1. However, the combined intervention group had a similar 3-month outcome in comparison with IV-tPA historical controls. Mortality rates were comparable in both placebo and tPA NINDS subjects, and SICH was higher than placebo controls but similar to NINDS tPA subjects. The IMS I trial demonstrated the safety and efficacy of combined IA/IV-tPA approach and better clinical outcomes in comparison to placebo. ¹¹ However, there was still no evidence that this is a superior approach than IV-tPA alone. IMS II was similar in design to IMS I, as it compared another 80 patients treated with combined IA and IV-tPA to NINDS controls. Yet, this time around, the researchers employed the use of an EKOS microinfusion system to deliver the IA bolus. This system uses low-energy ultrasound to alter the structure of clots, allowing for easier access. Perhaps owing to the advance in delivery method, there was a benefit detected in Barthel Index and Global Test Statistic scores at 90 days for patients treated with the combined approach as compared to NINDS tPA patients. The IMS II was the first study to demonstrate better clinical outcomes of the combined IA and IV approach over IV-tPA alone. ¹²

The efficacy of the combined approach was yet again investigated in the RECANALISE study in 2009. This prospective study treated patients in two phases within 3 hours of stroke onset. In phase I, 56 patients were treated with IV-tPA only. In phase II, 107 patients received a combined approach of IV/IA-tPA. In addition, if recanalization was not achieved with IA thrombolysis, patients were eligible to receive further mechanical thrombectomy including the 4-mm snare or balloon angioplasty. The efficacy of the combined approach was clearly evident as recanalization rates were significantly higher in the group receiving the combined approach (87 vs. 52%, RR = 1.49, p = 0.0002). Safety was also demonstrated since mortality and SICH rates were similar between the two groups. However, though neurological improvement (mRS: 0–2) at 90 days was achieved by more patients in the combined approach group (60 vs. 39%), the difference was not significant (p = 0·07). In RECANALISE, though the combined IV/IA approach resulted in greater recanalization rates, the clinical outcomes did not reveal a clear benefit. ¹³

Overall, the combined approach was shown to have better recanalization rates than IV-tPA alone. ¹³ Yet the clinical benefit of the combined approach was still not clear, with IMS II demonstrating better outcomes on some measures, and IMS I and RECANALISE finding no significant differences. ^{11 ,​ 12 ,​ 13}

From no standard treatment to the combined IV/IA approach, the management of acute ischemic stroke has come a long way. Moreover, around the same time, more exciting techniques were being developed in the treatment of acute ischemic stroke in the field of mechanical thrombectomy.