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Ischemic stroke
Intra-arterial or intravenous thrombolysis for acute ischemic stroke? The SYNTHESIS pilot trial
  1. A Ciccone1,
  2. L Valvassori2,
  3. M Ponzio3,
  4. E Ballabio4,
  5. R Gasparotti5,
  6. M Sessa6,
  7. F Scomazzoni7,
  8. P Tiraboschi1,
  9. R Sterzi1,
  10. the SYNTHESIS Investigators
  1. 1Department of Neurology, Stroke Unit, ‘Niguarda Ca' Granda’ Hospital, Milan, Italy
  2. 2Department of Neuroradiology, ‘Niguarda Ca' Granda’ Hospital, Milan, Italy
  3. 3Department of Health Sciences, Section of Epidemiology and Medical Statistics, University of Pavia, Pavia, Italy
  4. 4Neurological Clinic, ‘Policlinico’ Hospital, University of Milan, Italy
  5. 5Neuroradiology Unit, Spedali Civili, University of Brescia, Brescia, Italy
  6. 6Stroke Unit, ‘S Raffaele’ Hospital, Milan, Italy
  7. 7Neurointerventional Unit, ‘S Raffaele’ Hospital, Milan, Italy
  1. Correspondence to Dr A Ciccone, Department of Neurosciences, Stroke Unit, ‘Niguarda Ca' Granda’ Hospital, Piazza Ospedale Maggiore 3, 20164 Milano, Italy; alfonso.ciccone{at}ospedaleniguarda.it

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; p=0.067). SICH occurred in 2/25 patients on IAT and in 4/29 on IVT (OR 0.5; CI 0.1 to 3.3; p=0.675). Mortality at day 7 was 5/25 (IAT) compared with 4/29 (IVT) (OR 1.6; CI 0.4 to 6.7; p=0.718). 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.

https://doi.org/10.1136/jnis.2009.001388

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    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 segment4 and the proximal (M1) segment of the middle cerebral artery.5 6

    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 outcome8 and there are data suggesting that in patients with large vessel occlusions reperfusion rates with IAT are superior to those obtained with IVT.1 7 8

    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.11 As a result, IAT, even though performed for more than 25 years, is still a niche therapy for stroke victims. Moreover, there have been no trials that have compared only IAT with only IVT with alteplase.

    SYNTHESIS is a pragmatic RCT whose purpose was to compare the clinical efficacy and safety of IAT versus IVT and whose design specifically accounted for the following issues:

    1. patients randomized to IAT were treated as soon as possible within 6 h (as opposed to ≤3 h in the intravenous arm) of symptom onset, as a comparison of IAT and IVT should account for the time used to prepare the former;

    2. patients were randomized before angiogram because the risks associated with angiogram, not inherent in IVT, were considered in the global evaluation of IAT efficacy.

    Methods

    Study design and hypothesis

    SYNTHESIS is an open label, RCT, with blinded follow-up. Its primary aim was to assess whether a greater proportion of stroke patients treated with IAT (experimental arm), compared with those on IVT (control arm), had reached independent survival at 90 days. Patients with a modified Rankin Scale (mRS) score of 0 or 1 at 3 months were considered independent. Its secondary aims were a between group comparison of both the severity of the neurological deficit (as expressed by the patient's National Institutes of Health Stroke Scale (NIHSS) score12) on day 7 and treatment safety (as measured by the occurrence of symptomatic intracranial hemorrhage (ICH), fatal and non-fatal strokes, death from any cause and neurological deterioration within the first week).

    Standard protocol approvals, registrations and patient consent

    The study protocol and all amendments were approved by each of the four participating centers' institutional review board. Patients or proxies13 14 gave written informed consent before enrolment.

    Patient selection

    The study was pragmatically based on the ‘uncertainty principle’ between IAT and IVT for patients eligible for IVT with alteplase in accordance with the current European labeling15: a patient was randomized if the clinician was uncertain about the balance of risks and benefits between IAT and IVT with alteplase. There were no pre-specified clinical (such as NIHSS cut-off) or instrumental (such as the demonstration of arterial occlusion with non-invasive procedures) criteria to further select a patient already eligible for IVT with alteplase. Clinical, CT and laboratory exclusion criteria are summarized in table 1. Additional exclusion criteria were previous disability (mRS score>2), very poor prognosis regardless of therapy, known allergy to intravenous contrast and expected problems with keeping in contact with the participating center during follow-up.

    View this table:
    Table 1

    Major inclusion and exclusion criteria

    Patients who were eligible for IVT but not randomized were entered into a stroke registry where their initials, sex, age, date of observation and reasons for exclusion were reported. These patients were not followed-up.

    Randomization

    Random assignment to treatment was stratified per center and prepared in a ratio 1:1 with casual numbers by a person not involved in the recruitment and not operating in any of the recruiting centers. This person prepared opaque, sealed envelopes that were sequentially opened by the randomizing investigators.

    Treatment comparison

    IAT

    The procedure included a preliminary angiogram. Intravenous heparin was initiated with a 2000 U bolus followed by an infusion of 500 U/h until termination of the angiography. An infusion microcatheter (<3.0 F) with a single end hole had to be placed into the middle of the thrombus using a steerable microguidewire. If it was not possible to position the infusion catheter into the thrombus, the tip of the catheter had to be placed as close as possible to the proximal face of the thrombus before starting with alteplase infusion. A super-selective angiogram had to be performed through the microcatheter to document exactly where the catheter was placed (figure 1). Alteplase infusion could then be started at a rate of about 0.9 mg/kg/h (maximum 90 mg/h) while the catheter was withdrawn from the proximal surface of the thrombus. Contrast was injected though the guide catheter every 15 min to verify the occurrence and progression of lysis so as to reposition the microcatheter when necessary. In case of unsuccessful recanalization, injection of potential collateral vessels was attempted. The alteplase infusion continued for a maximum of 1 h and the overall dose did not exceed 0.9 mg/kg body weight (maximum 90 mg). If complete lysis occurred, the infusion was stopped. Mechanical thrombus disruption was possible during the procedure passing through the thrombus with the infusion microcatheter. Clot retrieval, but not balloon angioplasty, was allowed.

    Figure 1
    Figure 1

    Cerebral angiography during endovascular treatment with alteplase and CT scan. Angiography (A–C) in a 39-year-old man with acute right hemiparesis and aphasia. The study begins 3.5 h after symptom onset. (A) The angiograms (frontal view, right carotid artery injection) confirms a proximal left M1 occlusion (arrow). (B) A microcatheter is taken beyond the clot and contrast is injected by hand to check the flow arrest due to middle cerebral artery occlusion (arrow). Alteplase is then infused, slowly, beyond, inside and proximal to the clot. (C) At 4.5 h, carotid artery injection shows complete clot lysis with normal distal flow. (D–G) Baseline CT scan at 48 h after treatment shows an ischemic lesion in the left frontal lobe and in the region of the external capsule. After 4 days, only a mild aphasia persisted. Further neurological improvement was registered in the following weeks. At 3 months, the patient was neurologically intact.

    IVT

    Patients allocated to IVT had to receive alteplase in a dose of 0.9 mg/kg body weight (maximum 90 mg), started within 3 h of ischemic stroke onset. Of the total dose, 10% was administered as a bolus and the remainder was given by continuous intravenous infusion over a period of 60 min.

    Patients allocated to IAT and IVT were treated in the same way in all other respects.

    Clinical assessment, follow-up and measures of outcome

    Initial assessments included a physical examination, brain CT and quantification of any neurological deficit with the use of the NIHSS, a 15 item scale that measures the level of neurologic impairment. Total scores on the NIHSS range from 0 to 42, with higher values reflecting more severe stroke.12 Examiners were trained and certified in the use of the NIHSS examination.

    Patients were observed during the 7 days after randomization, and compliance with trial treatments, protocol deviations and occurrence of major inhospital events or death were evaluated. A second CT scan was performed on all patients during this period, preferably on day 2. CT was repeated if a new stroke or neurologic deterioration (defined as any major change in the level of consciousness and/or any substantial change in degree of motor deficit and/or new deficits that were clinically significant and persistent or that led to death within 7 days) occurred. Neurologic deficit was re-scored with NIHSS on day 7 or discharge, whichever occurred first. The possible causes of neurologic deterioration were classified as follows: (1) symptomatic ICH (any neurologic deterioration due to ICH); (2) cerebral edema (any neurologic deterioration due to the development of significant mass effect of the recent lesion); (3) new ischemic stroke (any neurologic deterioration not due to ICH or cerebral edema from the previous ischemic lesion); and (4) unknown (any neurologic deterioration unknown if due to ICH or cerebral edema).

    The patient's long term clinical condition was evaluated by telephone call after 90 days from randomization by a single trained neurologist, blinded to treatment allocation, using the mRS score. The interviewer used a checklist of activities of daily living as a guide in questioning the patient.16 17 In case of unavailability of the patient, a proxy was interviewed. The use of the mRS by telephone instead of direct examination appears to be reliable.16 18

    Statistical analysis

    All analyses were based on the intention to treat principle.

    The time variable was expressed as median and IQR, and differences in time variables between treatment groups were analyzed using the Mann–Whitney U test.

    NIHSS outcome was analyzed by comparing the median value between baseline and day 7 within each group using the Wilcoxon test for matched pairs, or by categorizing the variables' decrease in score (change of 4 or more points from baseline to 7 days) between groups using a Fisher exact test.

    mRS outcome was described as an ordinal variable (distribution of score on the 0 to 6 mRS scale) and analyzed as a binary mRS that treats scores of 0–1 as positive (favorable outcome) and scores of 2–6 as negative (unfavorable outcome).

    The severity of stroke at baseline was considered by dividing the baseline NIHSS score into three categories: <10, 10–20 and ≥20; stroke severity was entered into the analysis as strata.

    Logistic regression analysis was used to compare treatment arms with regard to primary outcome (a binary mRS at 90 days) controlling for severity score at baseline and age (cut-off 55 years).

    Safety, mortality and rate of adverse events at 7 days were compared between the two treatment groups using a Fisher exact test and calculating the OR with CI at 95%. Neurologic deterioration was evaluated both as an increase of 4 or more points from baseline to 7 days in NIHSS score and as the presence of any neurologic deterioration (symptomatic ICH or cerebral edema or new ischemic stroke or unknown) during the first 7 days. In both cases the difference between groups was analyzed using a Fisher exact test.

    All analyses were performed using Stata V.10.

    Sample size

    The study was designed to detect or disprove (α level of 0.05 and power of 80%) a 15% absolute difference in the percentage of patients with a favorable outcome (mRS score 0–1) between the two treatment groups. Enrolment was to be completed with 350 randomized patients.

    Results

    Recruitment

    Recruitment started in January 2004 and was stopped early with 54 randomized patients on 1 February 2008 when analysis of the data to explore the feasibility of undertaking a large trial was required in order to access an Italian Agency of Drugs (AIFA) grant for an expansion phase of the study. At the same time, decisions were made to upgrade the protocol and reorganize the study, at the request of the AIFA. Therefore, the study presented here can be considered a pilot phase of a larger study on IAT versus IVT.

    During the study, 161 patients were identified as eligible for IVT but only 54 were randomized (25 to intra-arterial alteplase and 29 to intravenous alteplase). Reasons for exclusion are reported in figure 2. There were no follow-up losses or dropouts from the study.

    Figure 2
    Figure 2

    Patient selection and follow-up. The randomized/eligible patient ratios were distributed among recruiting centers as follows: ‘Niguarda’ 40/67 (60%) over a 48 month period; ‘San Raffaele’ 2/41 (5%) over a 35 month period; ‘Como Valduce’ 7/14 (50%) over a 20 month period; and ‘Brescia’ 5/39 (13%) over a 32 month period.

    Baseline characteristics

    The two groups were generally well matched with regard to baseline characteristics (table 2). Two patients suffered from seizure mimicking stroke so that only 52 had a diagnosis of definite ischemic stroke.

    View this table:
    Table 2

    Baseline characteristics of the randomized patients

    Treatment modality

    Among the randomized patients, six IAT and one IVT (p<0.001) did not receive any treatment (figure 2). Median time from stroke onset to the start of alteplase infusion was 195 min for IAT (IQR 170–240 min) and 155 min for IVT (IQR 135–170 min) (p<0.001).

    For the 19 patients treated with IAT, the procedures were as follows: for 10 patients alteplase was delivered with the microcatheter positioned as close as possible to the thrombus without any mechanical maneuver; for seven patients pharmacological thrombolysis was aided by mechanical thrombus disruption through manipulations of the microcatheter tip and advancements of the microguide; in one case extracranial stenting and intracranial pharmacological thrombolysis were used to work out an occluding embologenic dissection; and in a further case of carotid T occlusion the procedural choice involved suction thrombectomy, clot extraction by retrieval device, pharmacological thrombolysis and mechanical action of the microcatheter tip.

    Median alteplase dose was 50 mg (IQR 45–70) for the 19 IAT patients and 66.5 mg (IQR 58–72) for the 28 allocated IVT (p=0.022).

    Efficacy

    For the primary efficacy analysis, 48% (12/25) of IAT and 28% (8/29) of IVT patients had a mRS score of 1 or less at 90 days after stroke (figure 3). Controlling for stroke severity and age at baseline, we observed a prevalence OR favoring IAT treatment (OR 3.2; 95% CI 0.9 to 11.4; p=0.067).

    Figure 3
    Figure 3

    Distribution of modified Rankin Scores (mRS) on 90 day of the follow-up assessment. A score of 0–1 (yellow–orange) on the mRS scale indicates a favorable outcome of slight or no disability. A score of 6 represents death. IAT, intra-arterial thrombolysis; IVT, intravenous thrombolysis.

    As shown in table 3, there were no group differences with regard to all secondary outcome measures.

    View this table:
    Table 3

    Secondary outcomes

    Safety

    Complications in the 7 days following randomization in the IAT and IVT groups included mild extracranial bleeding, 0% versus 7% (2/29); new ischemic stroke, 8% (2/25) versus 7% (2/29); and cerebral edema, 20% (5/25) versus 24% (7/29). Two cases of groin hematoma, not requiring surgical excision, were observed among the 25 patients in the IAT group. Symptomatic ICH occurred in 8% (2/25) of IAT patients and in 14% (4/29) of IVT patients (OR 0.5; 95% CI 0.1 to 3.3; p=0.675). Mortality was 20% (5/25) for the IAT group and 14% (4/29) for the IVT group (OR 1.6; 95% CI 0.4 to 6.7; p=0.718). Causes of death are reported in table 3.

    Discussion

    SYNTHESIS is the first randomized controlled trial comparing IAT to IVT with alteplase in acute ischemic stroke. Our main finding was that, despite a significantly longer mean interval between stroke onset and beginning of treatment (median time 3 h 15 min vs 2 h 35 min), twice as many patients on IAT as those on IVT were independent at 3 months. However, due to the width of the CI, the possibility that IAT could cause an excess of dead or dependent patients cannot be ruled out.

    Concerning the implications for practice, at present IAT cannot be substituted for IVT with alteplase for acute ischemic stroke. However, these data have important implications for research. Indeed, the main question is to establish whether it is ethically and scientifically justified to proceed with further RCTs on IAT for stroke and in particular to randomize a patient to IAT versus IVT. This issue deserves consideration.

    Firstly, one of the most impressive difference between the current study and previous trials6 9 10 was the quicker time to IAT (median 2 h earlier). IAT trials that treat at later time windows would be unlikely to replicate our results.

    Secondly, as in the National Institute of Neurological Disorders and Stroke (NINDS)19 and European Cooperative Acute Stroke Study (ECASS) III trials,20 we chose mRS ≤1 rather than mRS ≤2 as the primary outcome measure because our primary aim was to assess the efficacy of IAT compared with today's standard therapy of acute ischemic stroke which is actually based on the NINDS trial results. If SYNTHESIS data were analyzed using the same cut-off of mRS ≤2 that has been used in other IAT stroke trials,6 9 10 the results of the primary outcome measures would yield a statistically significant result (OR 4.56; 95% CI 1.20 to 17.37; p=0.026—data not shown in the results).

    Thirdly, the trend toward a more favorable effect of IAT compared with IVT was not associated with any excess of complications.

    Fourthly, the magnitude of the result obtained for the primary outcome is compatible with the initial hypothesis of the study that was designed to detect or disprove a 15% absolute difference between treatment groups in the percentage of patients with a favorable outcome. A recently published paper on a non-randomized comparison of the two approaches21 suggested an efficacy of IAT over IVT of an even greater magnitude in a subset of ischemic stroke patients with hyperdense middle cerebral artery signs.

    Therefore, the implications for research of SYNTHESIS are that an RCT is urgently needed to verify whether IAT is more effective that standard therapy with intravenous alteplase. On this basis, we continued with a new study (SYNTHESIS Expansion) of the former.

    Study weakness

    In evaluating the study results, it should be taken into account that six out of 25 patients randomized to IAT compared with only one on IVT were not treated accordingly (reasons given in figure 2). Possible hypotheses include the following: (1) IAT allocation oriented the decision not to treat (because of more chances of symptoms resolving while waiting for angiogram and/or waiver of treatment on the basis of angiographic findings); (2) intravenous heparin used during the angiographic procedure favored recanalization; and (3) more patients on IAT improved spontaneously for a chance effect. On the basis of our data, we are unable to determine which of these hypotheses is true. However, if only patients treated per protocol were considered for the primary efficacy analysis (data not shown in the results section), the resulting OR, controlling for stroke severity at baseline and age, would still favor IAT treatment (8/19 vs 8/28; OR 2.14; 95% CI 0.57 to 8.07; p=0.260).

    Another aspect of the per protocol analysis is mortality, which was much higher in the IAT than in the IVT group (6/19 vs 5/28). This could be just a chance effect or an effect of IAT. The potential risks associated with IAT justify the need for all centers that currently perform IAT for acute ischemic stroke to participate in randomized trials.

    The SYNTHESIS hypothesis was that the disadvantage of intra-arterial therapy in terms of time spent, compared with that required for intravenous treatment, might be compensated by a greater efficacy of the former. The Interventional Management of Stroke III Trial is testing the alternative hypothesis of the combined approach, which consists of starting with intravenous therapy immediately while intra-arterial therapy is organized.22 Both the single and combined approaches have their advantages and disadvantages and need to be tested in an RCT.11 22 23 In all probability, the combined approach is more indicated where the preparation of IAT has a considerable delay, while immediate IAT is more indicated where local organization allows quick access to angiography.

    The feasibility of the study has been shown, mainly in one out of the four centers. The great heterogeneity in the randomization rate among the four centers involved in this study, that ranged from 60%—in the leading center—to 5%, points to the fact that the presence of a robust organizational network, beyond the endowment of endovascular treatment facilities, is a conditio sine qua non for performing endovascular treatments in emergency situations.

    Acknowledgments

    We would like to thank Dr Carlo Alberto Defanti, who was Head of the Department of Neurosciences of ‘Niguarda Cà Ganda’ Hospital in Milan when SYNTHESIS was carried out.

    Appendix

    Principal Investigator: A Ciccone, MD; Safety and Monitoring Committee: L Candelise, MD (University of Milan, Italy), G del Zoppo, MD (University of Washington, Seattle, USA), P Sandercock, MD (University of Edinburgh, UK); Monitor: E Ballabio, MD (University of Milan, Italy); Follow-up: T Cantisani, MD (Silvestrini Hospital, Perugia, Italy); Randomization: C Coppola, MD (University of Naples, Italy); Statistician: M Ponzio, PhD (University of Pavia, Italy).

    Co-investigators: The following persons and institutions participated in the SYNTHESIS trial in Italy. ‘Niguarda Cà Granda’ Hospital, Milan, Stroke Unit: A Ciccone, MD, A Gatti, MD, A Guccione, MD, I Santilli, MD, R Sterzi, MD; Neurology: S Jann, MD, A Protti, MD, M Rizzone, MD; Interventional Neuroradiology: E Boccardi, MD, L Valvassori, MD. ‘Valduce’ Hospital, Como, Stroke Unit: M Guidotti, MD, N Checcarelli, MD, F Muscia, MD; Interventional Radiology: A Martegani, MD. ‘Spedali Civili’, Brescia, Stroke Unit: M Magoni, MD, A Costa, MD; Interventional Neuroradiology: R Gasparotti, MD, M. Pavia, MD. ‘San Raffaele’ Hospital, Stroke Unit: M. Sessa, MD; Interventional Neuroradiology: F Scomazzoni, MD.

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    Footnotes

    • The SYNTHESIS co-investigators are listed in the Appendix.

    • Statistical analysis The statistical analysis was conducted by Dr Michela Ponzio, PhD, Department of Health Sciences, Section of Epidemiology and Medical Statistics, University of Pavia, Pavia, Italy.

    • Competing interests None.

    • Ethics approval This study was conducted with the approval of the Niguarda Ca Granda Hospital, Milan, Italy, Spedali Civili, University of Brescia, Brescia, Italy and ‘S Raffaele’ Hospital, Milan, Italy.

    • Patient consent Obtained.

    • Provenance and peer review Not commissioned; not externally peer reviewed.

    • Contributors AC conceived and wrote most of this manuscript, which was checked and discussed with the other authors who approved the final version. LV prepared the parts concerning the description of intra-arterial thrombolysis. EB checked the quality of the data and helped MP who performed the statistical analysis. AC, EB and FS prepared the introduction. RG, MS, RS and PT in particular, reviewed and discussed the manuscript with AC and participated in the final version.