A long clot, defined by a low (0-6) clot burden score (CBS) assessed by T2*-MR sequence, is associated with worse clinical outcome after intravenous thrombolysis (IVT) for acute ischemic stroke than is a small clot (CBS, 7-10). The added benefit of mechanical thrombectomy (MT) might be higher in patients with long clot. The aim of this pre-specified
Of 414 patients randomized in the THRACE trial, 281 patients were included in this analysis. Associations between T2*-CBS and clinical outcome on the modified Rankin Scale (mRS) at 3 months were tested.
High T2*-CBS, i.e., small clot, was associated with a shift toward better outcome on the mRS; proportional odds ratio (POR) per point CBS was 1.19 (95% confidence interval [CI], 1.05 to 1.34) in the whole population, 1.34 (95% CI, 1.13 to 1.59) in IVT group, and 1.04 (95% CI, 0.87 to 1.23) in IVTMT group. After adjustment for baseline prognostic variables, the effect of the full scale T2*-CBS was not statistically significant in the whole population and for the IVTMT group but remains significant for the IVT group (POR, 1.32; 95% CI, 1.11 to 1.58).
A small clot, as assessed using T2*-CBS, is associated with improved outcome and may be used as a prognostic marker. Despite the worst outcome with long clot, the relative benefit of MT over IVT seemed to increase with low T2*-CBS and longer clot.
Recanalization of the arterial occlusion is the cornerstone of treatment in acute ischemic stroke (AIS) patients. Several randomized clinical trials (RCTs) [
Despite its compelling efficacy, up to half of AIS-LVO patients do not regain functional independence after MT [
Brain magnetic resonance imaging (MRI), using the T2*-MRI sequence, is a powerful tool to identify thrombus in AIS patients, based on the presence of a susceptibility vessel sign (SVS) [
With more than 300 patients included with pre-treatment MRI, the THRombectomie des Artères CErebrales (THRACE) trial (ClinicalTrials.gov, number NCT01062698) offers a unique opportunity to study the associations between T2*-CBS, successful recanalization rate and functional independence. The purpose of this prespecified
THRACE was a randomized controlled trial done in 26 centers in France. Study design and protocol have been previously detailed [
The primary outcome in the THRACE trial was the proportion of patients with a score of 0–2 on the modified Rankin Scale (mRS), indicating functional independence, at 3 months after the intervention. Secondary outcomes nonexhaustively included, successful recanalization, defined as a modified Thrombolysis in Cerebral Infarction (mTICI) score ≥2b [
MRI images and angiograms before and after MT were reviewed by four experienced neuroradiologists, who were masked to randomization group and patient clinical outcome. Baseline examinations included the determination of the Alberta Stroke Program Early CT Score (ASPECTS) [
All primary outcome analyses were performed according to the intention-to-treat principle. For this study, the primary effect variable was the proportional adjusted common odds ratio for a shift in the direction of better outcome on the 3-month mRS. The association between full-scale or dichotomized T2*-CBS (0–6 vs. 7–10) with shift in the direction of better outcome on the mRS was assessed using ordinal logistic regression respectively.
For all outcome parameters, two models were generated as previously used [
Patient characteristics are reported for groups with and without SVS and patient with long (T2*-CBS 0–6) and small clot (T2*-CBS 7–10). Continuous variables were compared with Student t-test, a Mann-Whitney test, or Median test, as appropriate. Categorical variables were compared using chisquare or Fisher exact test, as appropriate.
For all statistical analyses,
Among 414 patients randomized in the THRACE trial (
Among 281 patients included in 19 centers, 234 (83.3%) demonstrated presence of SVS, 118 (50.4%) in the IVT group, and 116 (49.6%) in the IVTMT group. Overall, the median T2*-CBS was 7 (interquartile range, 6 to 8), similar in IVT and IVTMT groups (
The primary outcome was assessed in 281 patients (
Proportion of small clot was significantly higher in patients with favorable (97/144 patients, 67.4%) than in patients with unfavorable outcome (73/137, 53.3%; OR, 1.81; 95% confidence interval [CI], 1.12 to 2.94;
Successful recanalization was observed in 66 of 91 patients (72.5%) in the IVTMT group who received MT treatment. There was no association between the presence of SVS and recanalization result (
In this prespecified
We found a significant interaction between treatment allocation and clot length as measured using T2*-CBS. In the recent RCTs [
The greater beneficial effect in IVTMT group accounts for the paradoxical finding of increasing relative benefit of MT despite the overall worse outcome associated with longer thrombi. This finding illustrates the difference between prognostic and therapeutic imaging biomarkers; in AIS-LVO patients, long clot is simultaneously a negative prognostic biomarker and a positive therapeutic biomarker with regards to MT (i.e., clot length modifies the differential treatment effect of MT or IVT). The detrimental effect of low CBS on clinical outcome is most likely attributable to greater difficulty of recanalizing longer and/or multisegment thrombi [
In line with THERAPY trial results [
Recently, randomized comparison of first-line MT with ADAPT technique versus SR did not result in an increased successful revascularization rate [
The strength of our study is that, beyond the demonstration of a LVO, no other imaging criteria was used to select patients in the THRACE trial. Hence, patients with unfavorable clinical and imaging profiles were included, resulting in generalizable findings. The present study was based on the largest to date AIS-LVO population initially included based on brain MRI data in a RCT and allows for a less biased assessment of the efficacy of baseline imaging prognostic biomarkers to select patients for future studies.
A few points may require clarification. First, 59 patients randomized to the intervention arm did not receive MT. When evaluating imaging biomarker of efficacy for MT, it could add to the sensitivity of the analysis to only include the patients who actually received MT. A second limitation is that T2*-CBS likely underestimates full clot extent, given that the susceptibility effect depends on thrombus composition and age [
Clot length, as assessed using the MRI based T2*-CBS is independently associated with functional outcome in patients with AIS caused by a LVO, and may be used as prognostic biomarker. Despite the worst outcome with long clot, the relative benefit of MT over IVT seemed to increase with low T2*-CBS.
Supplementary materials related to this article can be found online at
The authors have no financial conflicts of interest.
The funder of the study (French Ministry for Health) had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
THRACE investigators: Alain Bonafé (Department of Neuroradiology, Gui de Chauliac Hospital, Montpellier, France), Xavier Leclerc (Department of Radiology, University Hospital of Lille, Lille, France), Nelly Agrinier (Department of Clinical Epidemiology INSERM CIC-EC 1433, University of Lorraine and University Hospital of Nancy, Nancy, France), Serge Bakchine (Department of Neurology, University Hospital of Reims, Reims, France), Flore Baronnet (Stroke Unit, Pitié-Salpêtrière Hospital Group and Paris 6 University—Pierre et Marie Curie, Paris, France), Marine Beaumont (Department of INSERM CIC-IT, University of Lorraine and University Hospital of Nancy, Nancy, France), Yannick Bejot (Department of Neurology, University Hospital of Dijon, Dijon, France), Jerome Berge (Department of Interventional and Diagnostic Neuroradiology, University Hospital of Bordeaux, Bordeaux, France), Marc Bintner (Department of Neuroradiology Sud-Reunion Hospital Group, Saint Pierre, France), Romain Bourcier (Department of Interventional and Diagnostic Neuroradiology, University Hospital of Nantes, Nantes, France), Tae Hee Cho (Department of Neurology, University Hospital of Lyon, Lyon, France), Frédéric Clarencon (Department of Interventional Neuroradiology Pitié-Salpêtrière Hospital Group and Paris 6 University—Pierre et Marie Curie, Paris, France), Julien Cogez (Department of Neurology, University Hospital of Caen, Caen, France), Charlotte Cordonnier (Department of Neurology, University Hospital of Lille, Lille, France), Christian Denier (Department of Neurology, University Hospital of Bicêtre, Le Kremlin-Bicêtre, France), Anne Laure Derelle (Department of Diagnostic and Interventional Neuroradiology, University Hospital of Nancy, Nancy, France), Olivier Detante (Department of Neurology, University Hospital of Grenoble, Grenoble, France), Anthony Faivre (Department of Neurology, Hôpital d’Instruction des Armées, Sainte Anne, Toulon, France), Anne Ferrier, (Department of Neurology, University Hospital Gabriel-Montpied, Clermont-Ferrand, France), Laetitia Gimenez (Department of Neurology, University Hospital of Limoges, Limoges, France), Sophie Godard (Department of Neurology, University Hospital of Angers, Angers, France), Gregoire Boulouis (Department of Neuroradiology, Sainte-Anne Hospital and Paris- Descartes University, INSERM U894, Paris, France), Benoit Guillon (Department of Neurology, University Hospital of Nantes, Nantes, France), Emmanuel Houdart (Department of Neuroradiology, University Hospital Lariboisière, Paris, France), Bertrand Lapergue (Department of Neurology, Foch Hospital, Suresnes, France), Mariano Musacchio (Department of Neuroradiology, Pasteur Hospital, Colmar, France), Olivier Naggara (Department of Neuroradiology, Sainte-Anne Hospital and Paris-Descartes University, INSERM U894, Paris, France), Jean Philippe Neau (Department of Neurology, University Hospital of Poitiers, Poitiers, France), Michael Obadia (Department of Neurology, Rothschild Ophthalmological Foundation, Paris, France), Anne Pasco-Papon (Department of Radiology, University Hospital of Angers, Angers, France), Michel Piotin (Department of Interventional Neuroradiology [MP] Rothschild Ophthalmological Foundation, Paris, France), Laurent Pierot (Department of Neuroradiology, University Hospital of Reims, Reims, France), Helene Raoult (Department of Neuroradiology, University Hospital of Rennes, Rennes, France), Sébastien Richard (Department of Neurology University Hospital of Nancy, Nancy, France), Frederic Ricolfi (Department of Neuroradiology, University Hospital of Dijon, Dijon, France), Thomas Ronziere (Department of Neurology, University Hospital of Rennes, Rennes, France), Guillaume Saliou (Department of Neuroradiology, University Hospital of Bicêtre, Le Kremlin-Bicêtre, France), Igor Sibon (Department of Neurology, University Hospital of Bordeaux, Bordeaux, France), Sebastien Soize (Department of Neuroradiology, University Hospital of Reims, Reims, France), Jacques Sedat (Department of Radiology, University Hospital of Nice, Nice, France), Christian Stapf (Department of Neurology, University Hospital Lariboisière, Paris, France), Laurent Suissa (Department of Neurology, University Hospital of Nice, Nice, France), Marie Tisserand (Department of Neuroradiology, Sainte-Anne Hospital and Paris- Descartes University, INSERM U894, Paris, France), Francis Turjman (Department of Interventional Neuroradiology, University Hospital of Lyon, Lyon, France), and Stephane Velasco (Departments of Radiology, University Hospital of Poitiers, Poitiers, France).
The T2*-clot burden score (T2*-CBS). (A) A score of 10 is normal, implying absence of susceptibility vessel sign (SVS) on T2*. Three points (as indicated) are subtracted for SVS found in the supraclinoid internal carotid artery (ICA), 2 points for SVS in each of the proximal and distal halves of the middle cerebral artery trunk (M1), 1 point for SVS in the A1–A4 segment and 2 points for SVS in the M2–M4 branches. A score of 0 implying complete multisegment vessel occlusion. (B) Patient 1, distal occlusion with T2*-CBS=9 (SVS in 1 left M2 branch). (C, D) Patient 2, proximal occlusion with T2*-CBS=3 (SVS in right supraclinoid ICA, proximal and distal halves of M1).
Flow chart study. CT, computerized tomography; MRI, magnetic resonance imaging; CBS indicates clot burden score; mRS, modified Rankin Scale; IVT, intravenous thrombolysis; IVTMT, intravenous thrombolysis mechanical thrombectomy.
Modified Rankin Scale distribution for the intra-arterial treatment and control arms for T2*-CBS groups (0–6) and (7–10). CBS, clot burden score; IVT, intravenous thrombolysis; and IVTMT, intravenous thrombolysis mechanical thrombectomy.
Baseline patient characteristics according to dichotomized T2*-CBS groups
Characteristic | T2*-CBS (7–10) | T2*-CBS (0–6) | |
---|---|---|---|
Number | 170 | 111 | |
IVTMT randomization group | 87 (51.2) | 52 (46.8) | 0.48 |
Undergo IVTMT | 57 (33.5) | 43 (38.7) | 0.37 |
Age (yr) | 61.8±14.2 | 65.4±13.4 | 0.01 |
≤70 | 109 (64.1) | 50 (45.0) | 0.002 |
>70 | 61 (35.9) | 61 (55.0) | |
Sex | 0.32 |
||
Male | 93 (54.7) | 54 (48.6) | |
Female | 77 (45.3) | 57 (51.4) | |
Comorbidities | |||
Hypertension | 84 (49.7) | 57 (52.3) | 0.67 |
Diabetes mellitus | 20 (11.8) | 5 (4.6) | 0.04 |
History of stroke | 9 (5.5) | 9 (8.3) | 0.37 |
Hypercholesterolemia | 79 (53.0) | 50 (50.5) | 0.70 |
Current tobacco use | 43 (28.3) | 14 (14.1) | 0.009 |
Coronary disease | 20 (12.4) | 20 (18.7) | 0.16 |
Etiology of cerebral infarction | 0.41 |
||
Large-artery atherosclerosis | 25 (15.3) | 13 (13.0) | |
Cardioembolism | 64 (39.3) | 51 (51.0) | |
Small-vessel occlusion | 1 (0.6) | 0 (0) | |
Other determined etiology | 10 (6.1) | 5 (5.0) | |
Undetermined etiology | 63 (38.7) | 31 (31.0) | |
Baseline NIHSS score | 18 (13–21) | 17 (14–20) | 0.69 |
ASPECTS at baseline | 7 (5–9) | 7 (4–8) | 0.72 |
ASPECTS (0–4) | 25 (14.7) | 28 (25.2) | 0.04 |
ASPECTS (5–7) | 73 (42.9) | 35 (31.5) | |
ASPECTS (8–10) | 72 (42.4) | 48 (43.2) | |
Baseline occlusion location (%) | <0.001 |
||
ICA | 13 (7.6) | 30 (27.0) | |
M1 | 155 (91.2) | 81 (73.0) | |
M2 | 2 (1.2) | 0 (0) | |
Workflow time (min) | |||
From stroke onset to imaging | 112 (88–135) | 112 (89–142) | 0.91 |
From stroke onset to IVT | 146 (124–170) | 154 (120–180) | 0.49 |
From stroke onset to recanalization | 239 (208–270) | 261 (204–291) | 0.44 |
ASPECTS at 24 hours | 7 (4–8) | 6 (3–8) | 0.40 |
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
CBS, clot burden score; IVTMT, intravenous thrombolysis mechanical thrombectomy; NIHSS, National Institutes of Health Stroke Scale; ASPECTS, Alberta Stroke Program Early CT Score; ICA, internal carotid artery; IVT, intravenous thrombolysis.
Chi-square test;
Mann-Whitney test;
Median test;
Fisher exact test.
Patient characteristics of dichotomized mRS groups
Characteristic | mRS ≤2 | mRS >2 | |
---|---|---|---|
Number | 144 | 137 | |
IVTMT randomization group | 79 (54.9) | 60 (43.8) | 0.06 |
Age (yr) | 60.1±14.6 | 66.5±12.7 | <0.001 |
≤70 | 97 (67.4) | 62 (45.3) | <0.001 |
>70 | 47 (32.6) | 75 (54.7) | |
Sex | 0.94 |
||
Male | 75 (52.1) | 72 (52.6) | |
Female | 69 (47.9) | 65 (47.4) | |
Comorbidities | |||
Hypertension | 61 (43.0) | 80 (58.8) | 0.01 |
Diabetes mellitus | 10 (7.0) | 15 (11.1) | 0.23 |
History of stroke | 11 (7.8) | 7 (5.3) | 0.41 |
Hypercholesterolemia | 68 (52.3) | 61 (51.7) | 0.92 |
Current tobacco use | 30 (21.7) | 27 (23.9) | 0.69 |
Coronary disease | 16 (11.4) | 24 (18.8) | 0.09 |
Baseline NIHSS score | 16 (12–19) | 19 (16–22) | <0.001 |
ASPECTS at baseline | 7 (6–9) | 6 (4–8) | <0.01 |
ASPECTS (0–4) | 16 (11.1) | 37 (27.0) | 0.002 |
ASPECTS (5–7) | 58 (40.3) | 50 (36.5) | |
ASPECTS (8–10) | 70 (48.6) | 50 (36.5) | |
Baseline occlusion location (%) | <0.001 |
||
ICA | 10 (6.9) | 33 (24.1) | |
M1 | 133 (92.4) | 103 (75.2) | |
M2 | 1 (0.7) | 1 (0.7) | |
Workflow time (min) | |||
From stroke onset to imaging | 111 (85–140) | 114 (93–137) | 0.80 |
From stroke onset to IVT | 146 (120–179) | 150 (125–175) | 0.53 |
From stroke onset to recanalization | 240 (204–280) | 250 (208–281) | 0.57 |
SVS (+) | 120 (83.3) | 114 (83.2) | 0.98 |
SVS length | 14.3 (10.6–18.7) | 17.4 (12.9–23.6) | <0.04 |
T2 |
97 (67.4) | 73 (53.3) | 0.02 |
Recanalizers (TICI ≥2b) | 43 | 25 | <0.001 |
ASPECTS at 24 hours | 8 (6–9) | 5 (2–7) | <0.001 |
NIHSS score at 24 hours | 5 (2–9) | 18 (14–22) | <0.001 |
Values are presented as number (%), mean±standard deviation, or median (interquartile range).
mRS, modified Rankin Scale; IVTMT, intravenous thrombolysis mechanical thrombectomy; NIHSS, National Institutes of Health Stroke Scale; ASPECTS, Alberta Stroke Program Early CT Score; ICA, internal carotid artery; IVT, intravenous thrombolysis; SVS, susceptibility vessel sign; CBS, clot burden score; TICI, Thrombolysis in Cerebral Infarction.
Chi-square test;
Mann-Whitney test;
Median test;
Fisher exact test.
Estimates of POR of T2*-CBS using ordinal logistic regressions explaining lower modified Rankin Scale score at 3 months
Proportional odds ratio for | POR |
APOR |
||||
---|---|---|---|---|---|---|
IVT subgroup | IVTMT subgroup | All | IVT subgroup | IVTMT subgroup | All | |
Increase of 1 point of CBS | 1.34 | 1.04 | 1.19 | 1.32 | 0.94 | 1.12 |
(1.13–1.59) |
(0.87–1.23) | (1.05–1.34) |
(1.11–1.58) |
(0.79–1.12) | (0.99–1.27) | |
CBS >6 vs. CBS ≤6 | 3.19 | 0.93 | 1.73 | 3.06 | 0.71 | 1.48 |
(1.75–5.82) |
(0.51–1.7) | (1.13–2.65) |
(1.63–5.74) |
(0.38–1.32) | (0.95–2.30) |
Adjustment on age, National Institutes of Health Stroke Scale (NIHSS), glycemia, and Alberta Stroke Program Early CT Score (ASPECTS).
POR, proportional odds ratio; CBS, clot burden score; APOR, adjusted proportional odds ratio; IVT, intravenous thrombolysis; IVTMT, intravenous thrombolysis mechanical thrombectomy.
Statistically significant (
POR of lower mRS for T2*-CBS (with 95% confidence interval) estimated by Model A, i.e., without adjustment;
APOR of lower mRS for T2*-CBS (with 95% confidence interval) estimated by Model B.