Intra-arterial or intravenous thrombolysis for acute ischemic stroke? The SYNTHESIS pilot trial

Abstract

Objective To assess the feasibility, safety and preliminary efficacy of intra-arterial thrombolysis (IAT) compared with standard intravenous thrombolysis (IVT) for acute ischemic stroke. Methods Eligible patients with ischemic stroke, who were devoid of contraindications, started IVT within 3 h or IAT as soon as possible within 6 h. Patients were randomized within 3 h of onset to receive either intravenous alteplase, in accordance with the current European labeling, or up to 0.9 mg/kg intra-arterial alteplase (maximum 90 mg), over 60 min into the thrombus, if necessary with mechanical clot disruption and/or retrieval. The purpose of the study was to determine the proportion of favorable outcome at 90 days. Safety endpoints included symptomatic intracranial hemorrhage (SICH), death and other serious adverse events. Results 54 patients (25 IAT) were enrolled. Median time from stroke onset to start to treatment was 3 h 15 min for IAT and 2 h 35 min for IVT (p,0.001). Almost twice as many patients on IAT as those on IVT survived without residual disability (12/25 vs 8/29; OR 3.2; 95% CI 0.9 to 11.4; p50.067). SICH occurred in 2/25 patients on IAT and in 4/29 on IVT (OR 0.5; CI 0.1 to 3.3; p50.675). Mortality at day 7 was 5/25 (IAT) compared with 4/29 (IVT) (OR 1.6; CI 0.4 to 6.7; p50.718). There was no significant difference in the rate of other serious adverse events. Conclusions Rapid initiation of IAT is a safe and feasible alternative to IVT in acute ischemic stroke. Trial registration number NCT00540527.Although intravenous alteplase administered within 3 h of symptom onset is the only approved medication for the treatment of acute ischemic stroke, 1 this approach has known limitations. A major issue is that intravenous alteplase may be ineffective in patients with occlusions of the large arteries, such as the internal carotid artery, 2 3 carotid T segment 4 and the proximal (M1) segment of the middle cerebral artery. Intra-arterial thrombolysis (IAT) offers some theoretical advantages over intravenous thrombolysis (IVT) 7 : (a) angiographic planning allows customization of treatment strategy; (b) locoregional injection allows a much higher concentration of the drug where needed and the overall dosage administered to the patient is limited to the minimum necessary; (d) mechanical devices may either speed up the recanalization process or make it possible in drug resistant cases.Recanalization rates have been related to improved clinical outcome 8 and there are data suggesting that in patients with large vessel occlusions reperfusion rates with IAT are superior to those obtained with IVT. However, compared with IVT, intra-arterial treatment requires more time consuming and invasive procedures, and expensive techniques that are available only in highly specialized centers with a neurointerventional team. Although previous randomized controlled trials (RCTs) on IAT provided promising results, 6 9 10 their generalization remains questionable as they were performed in highly selected patients. 11As a result, ...

Acute Ischemic Stroke

“…In this small study (n=54), 3-month good functional outcomes (mRS, 0-2) were achieved in 56% of patients treated with IA-tPA compared with 31% of those treated with IV-tPA. 33 The selection of patients more likely to have a vascular occlusion allows the effect of timely reperfusion to be demonstrated.…”

“…30 The issue is well illustrated by the original SYNTHESIS pilot trial. 33 In this study, patients more likely to have a target lesion were enrolled. The NIHSS of endovascular patients was 17 (median), with a range of 7 to 23 indicating exclusion of patients with mild strokes unlikely to have vascular occlusions.…”

Endovascular Treatment for Acute Ischemic Stroke

“…The study was designed to verify or refute an absolute difference of 15 percentage points between the proportions of patients with a favorable outcome in the two treatment groups. The rationale for this effect size was based on the results of the pilot phase of the trial, 19 which showed a nonsignificant absolute difference of 20 percentage points in favor of endovascular treatment over intravenous t-PA; the favorable data on recanalization rates with endovascular treatment (a difference of 17 to 37 per-centage points in indirect comparisons with intravenous t-PA 10 ); and the need for a clinical effect sufficiently large to justify the switching from a well-established and simple procedure to one that is newer, more expensive, and more difficult to perform. We calculated that we would need to enroll at least 172 patients per study group, assuming that 40% of those treated with intravenous t-PA would have a favorable outcome.…”

“…Many case series and observational cohort studies of endovascular treatment have shown encouraging clinical results, but there have been concerns about selection and publication biases. 18 To investigate whether endovascular treatment, including the options of a mechanical device and intraarterial t-PA, is more effective than the currently available treatment with intravenous t-PA, we randomly assigned a total of 362 patients to the two treatment options, after a pilot study showed that prompt initiation of endovascular treatment is a safe and feasible alternative to intravenous t-PA. 19 …”

Evolving Treatments for Acute Ischemic Stroke

“…Again safety and efficacy were demonstrated with no significant differences in adverse events. 109 With the technological advances in imaging, the REcanalization using Combined intravenous Rt-PA and Neurointerventional ALgorithm for acute Ischemic StrokE (RECANALISE) study, a cohort study, required CTA or magnetic resonance angiography to identify intracranial occlusions. Recanalization rates at 24 hours were 52% in the intravenous group, when compared with 87% in the intraarterial alteplase group, independent of the site of occlusion.…”