The International CVT Summit 2023 was initiated by the International cerebral venous thrombosis Consortium and took place in the Room Mate Aitana hotel in Amsterdam on 1 and 2 June 2023. The aims of the meeting were to define an international research agenda for cerebral venous thrombosis (CVT) and to strengthen global collaboration in this field. We welcomed 45 invited participants from 15 countries, among whom 35 clinical researchers, four patient representatives, three industry representatives, and two representatives from non-profit granting organizations.

Six pre-specified themes were discussed during the summit: 1. Epidemiology and clinical features, 2. Life after CVT, 3. Neuroimaging and diagnosis, 4. Pathophysiology, 5. Treatment – medication, and 6. Treatment – endovascular. All themes were introduced by a speaker who presented the respective current state of knowledge, summarized ongoing research activities and proposed topics for future research. After this presentation, the meeting participants, led by four selected panel members, provided their first thoughts and ideas on the proposed research directions. The meeting participants were then split in break-out sessions, where they further discussed the theme and listed concrete research questions in order of importance. These concrete research questions were discussed again with the whole group in a second plenary discussion, after which the research questions were finalized. This resulted in 3 to 4 research questions per theme which the group of participants agreed upon should be the focus of research in the coming years. These questions are currently being bundled in a position paper with a research agenda, which we plan to finalize within the coming weeks and submit for publication to an international medical journal. We envision that researchers worldwide will use this position paper to: 1. Prioritize which research questions require answering; 2. Increase the quality of research; 3. Strengthen international collaboration; 4. Help to secure national and international funding for research on CVT.

An important part of the meeting was formed by the presentations by the patients’ representatives. Two women from different countries who had suffered a CVT in the past shared their impressive story on how CVT affected their lives and shared their view on priorities for future research directions for CVT. Both patients have extensive networks among CVT patients in their countries, allowing them to speak on behalf of a large group of CVT survivors. The meeting program also included talks about the European Stroke Organisation and American Heart and American Stroke Association guidelines on CVT and education on behalf of the World Stroke Academy, which all contributed to a comprehensive overview of the current position of CVT research.

The CVT summit was fully funded by the following non-profit organizations: European Joint Programme on Rare Diseases (EJP RD), ZonMw, Amsterdam Neuroscience, Dr. C.J. Vaillantfonds, Dutch Brain Foundation, Dutch Thrombosis Foundation, Dutch Heart Foundation. No profit organization was involved in the design or funding of the summit.

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Oral anticoagulants (OAC) are highly efficient in secondary prevention after ischaemic stroke or transient ischaemic attack (TIA) in patients with atrial fibrillation (AF). However, there was still uncertainty whether an early application of OAC does not only prevent recurrent ischaemic events but is also safe concerning haemorrhagic complications (1). Especially in patients with acute stroke of larger infarct sizes, haemorrhagic transformation is feared and thus it is common sense to delay starting OAC in these patients, although the evidence for this reasoning is low.

Randomized controlled trials (RCTs) that led to the approval of non-vitamin K antagonist oral anticoagulants (NOAC) excluded patients with recent ischemic stroke and observational studies on this topic yielded heterogonous findings. Thus, the international guidelines are currently based on expert opinions. One pragmatic and often applied approach is the 1 – 3 – 6 – 12 days rule which is based on the clinical stroke severity.

Four RCTs were initiated to provide us with evidence on the common dilemma of the timing of anticoagulation in the early phase of acute stroke due to AF: TIMING (2), START (3), OPTIMAS (4) and ELAN (5). The TIMING study has been presented at the European Stroke Organisation Conference (ESOC) in 2021 and was published in Circulation last year (6). Importantly, TIMING showed that an early initiation (i.e. ≤4 days) was noninferior to a later start (5–10 days) with NOACs. Moreover, none of the patients in both groups suffered a symptomatic intracranial haemorrhage (6).

At the recent ESOC 2023 in Munich, Professor Urs Fischer presented the results of the ELAN trial, which were simultaneously published in the New England Journal of Medicine (7). ELAN (“Early versus Late initiation of direct oral Anticoagulants in post-ischaemic stroke patients with atrial fibrillation”) is an investigator-initiated, international RCT that enrolled 2,013 patients with recent ischaemic stroke and AF. The patients were randomised in a 1:1 fashion to an early start of anticoagulation depending on infarct size, i.e. within 48 hours after a minor or moderate stroke and on day 6-7 after a major stroke, respectively, or to a later start, i.e. on day 3-4 for minor, on day 6-7 for moderate or on day 12-14 after a major stroke (5). Importantly, the severity of stroke was assessed by imaging: Minor strokes were defined as lesions of ≤1.5 cm in the anterior or posterior circulation. Moderate strokes were defined as lesions in a cortical superficial branch of the anterior or posterior circulation or in the internal border zone and major strokes were defined as lesions involving a complete vascular territory, lesions of ≥1.5 cm in the brainstem or cerebellum or multiple moderate lesions. Of note, the study design did not incorporate a formal statistical test for superiority or non-inferiority but rather had a descriptive approach.

The primary outcome, which was defined as a composite of ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial haemorrhage, or vascular death within 30 days after randomisation, was observed in 29 (2.9%) of the patients in the early treatment and in 41 (4.1%) patients in the later treatment group, translating to a risk difference of −1.18 percentage points with a 95% confidence interval of −2.84 to 0.47. Two patients in each group suffered a symptomatic intracranial haemorrhage. The odds of a recurrent ischemic stroke by 30 days was almost halved in patients with an early application of anticoagulation (odds ratio, 0.57; 95% confidence interval: 0.29 to 1.07). Taken together, the trial found no evidence that initiation of a NOAC earlier than currently suggested by guidelines in patients with acute ischemic stroke and AF, based on a simple visual assessment of brain imaging, increases the risk of haemorrhagic complications. On the contrary, a clinically important reduction in the risk for the composite endpoint and, in particular, for recurrent ischemic events was found at 30 days after randomisation.

In conclusion, ELAN is a landmark trial that provides further evidence that an early initiation of NOACs after acute ischaemic stroke is likely safe and contributes to a reduction in recurrent ischemic events. It will be very exciting to see if START and OPTIMAS will show similar results. In addition to these RCTs, results from large observational studies like PRODAST (n=10,000) (8) and RASUNOA-prime (n=3,000) (9) will additionally provide us with “real-world” evidence on the ideal timing of anticoagulation following acute stroke due to AF.

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1. Seiffge DJ, Werring DJ, Paciaroni M, Dawson J, Warach S, Milling TJ, et al. Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. Lancet Neurol. 2019;18(1):117-26.
2. Åsberg S, Hijazi Z, Norrving B, Terént A, Öhagen P, Oldgren J. Timing of oral anticoagulant therapy in acute ischemic stroke with atrial fibrillation: study protocol for a registry-based randomised controlled trial. Trials. 2017;18(1):581.
3. King BT, Lawrence PD, Milling TJ, Warach SJ. Optimal delay time to initiate anticoagulation after ischemic stroke in atrial fibrillation (START): Methodology of a pragmatic, response-adaptive, prospective randomized clinical trial. International Journal of Stroke. 2019;14(9):977-82.
4. Best JG, Arram L, Ahmed N, Balogun M, Bennett K, Bordea E, et al. Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): Protocol for a randomized controlled trial. Int J Stroke. 2022;17(5):583-9.
5. Fischer U, Trelle S, Branca M, Salanti G, Paciaroni M, Ferrari C, et al. Early versus Late initiation of direct oral Anticoagulants in post-ischaemic stroke patients with atrial fibrillatioN (ELAN): Protocol for an international, multicentre, randomised-controlled, two-arm, open, assessor-blinded trial. European Stroke Journal. 2022;7(4):487-95.
6. Oldgren J, Åsberg S, Hijazi Z, Wester P, Bertilsson M, Norrving B. Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study. Circulation. 2022;146(14):1056-66.
7. Fischer U, Koga M, Strbian D, Branca M, Abend S, Trelle S, et al. Early versus Later Anticoagulation for Stroke with Atrial Fibrillation. N Engl J Med. 2023.
8. Grosse GM, Weimar C, Kuklik N, Hüsing A, Stang A, Brinkmann M, et al. Rationale, Design and Methods of the Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) Study. European Stroke Journal. 2021;6(4):438-44.
9. Haas K, Purrucker JC, Rizos T, Heuschmann PU, Veltkamp R. Rationale and design of the Registry of Acute Stroke Under Novel Oral Anticoagulants-prime (RASUNOA-prime). Eur Stroke J. 2019;4(2):181-8.

Micro-emboli detection by transcranial Doppler is a non-invasive examination that can identify micro-emboli signals (MES) in the middle cerebral artery. MES are visualized as high-intensity transient signals (HITS) and may represent solid micro-emboli, gaseous particles, or artifacts.¹ The clinical significance of micro-emboli detection has been disputed and widespread use of this examination has not been fully established. Importantly, MES may indicate an ongoing asymptomatic cerebral embolization and besides risk stratification, it may also have a therapeutic significance for ischemic stroke. MES are usually detected in the acute phase of ischemic stroke, often decreasing over time either spontaneously or in response to adequate secondary prevention. There is evidence that MES may be used as an independent predictor of early stroke recurrence in some stroke subtypes and possibly as a measure of inadequate secondary prevention.²

Most of the studies aimed at patients with acute ischemic stroke caused by large artery disease. Ipsilateral MES are present in up to 40% of cases with symptomatic internal carotid stenosis (ICAS) and risk features including recent ischemic event, unstable plaque, or high-grade stenosis are strongly associated with MES.² Patients with symptomatic ICAS along with ipsilateral MES have approximately 15% risk of an early recurrence compared with a 1% risk in patients without MAS and may therefore help in selecting candidates for surgical intervention.³ MES are less commonly detected in asymptomatic ICAS, although their presence may identify high-risk patients within this group.⁴ The presence of MAS may also select patients for intensified medical therapy. In these patients, dual antiplatelet therapy, as well as intensified statin therapy, may reduce MAS burden.^5-6 There are, however, no data on safety and stroke recurrence since big randomized trials are lacking.

Contrary to cardioembolism, MAS are detected rarely in patients with small vessel diseases without proximal emboli source. Approximately 10% of patients with atrial fibrillation have MES detected bilaterally. This number decreases significantly in those who are on anticoagulation.⁸ Micro-emboli detection in multi-territory ischemic stroke, which is often attributed to cardioembolism, might be a useful examination in the diagnostic work-up and therapeutic approach. Micro-emboli detection may be also used in rare but high-risk stroke etiologies such as active cancer, CNS vasculitis, moyamoya diseases, infective endocarditis, or antiphospholipid syndrome. Initial but also follow-up examinations may facilitate the type, intensity, and duration of therapeutic measures.⁹

Micro-emboli detection is a relatively simple, repeatable, and low-cost examination which may contribute to risk stratification in the stroke subtypes with a proximal source of embolism. It may also facilitate the therapeutic decision-making and eventual adjustment of secondary prevention. Its potential could be underestimated, and clinical trials are warranted to examine the yield of micro-emboli detection in routine clinical practice.

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1. Devuyst, G., et al. Automatic classification of HITS into artifacts or solid or gaseous emboli by a wavelet representation combined with dual-gate TCD. Stroke, 2001, 32.12: 2803-2809.
2. King, A.; Markus, H. S. Doppler embolic signals in cerebrovascular disease and prediction of stroke risk: a systematic review and meta-analysis. Stroke, 2009, 40.12: 3711-3717.
3. Spence, J. David, et al. Absence of microemboli on transcranial Doppler identifies low-risk patients with asymptomatic carotid stenosis. Stroke, 2005, 36.11: 2373-2378.
4. Zhang, Chunmei, et al. Microembolic signals and carotid plaque characteristics in patients with asymptomatic carotid stenosis. Scandinavian Cardiovascular Journal, 2009, 43.5: 345-351.
5. Wong, Ka Sing Lawrence, et al. Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blinded-endpoint trial. The Lancet Neurology, 2010, 9.5: 489-497.
6. Markus, Hugh S., et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation, 2005, 111.17: 2233-2240.
7. Safouris, Apostolos, et al. Statin pretreatment and microembolic signals in large artery atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology, 2017, 37.7: 1415-1422.
8. Tinkler, Kerry, et al. Asymptomatic embolisation in non-valvular atrial fibrillation and its relationship to anticoagulation therapy. European journal of ultrasound, 2002, 15.1-2: 21-27.
9. Kargiotis, Odysseas, et al. The role of transcranial Doppler monitoring in patients with multi‐territory acute embolic strokes: a review. Journal of Neuroimaging, 2019, 29.3: 309-322.

Performing mechanical thrombectomy (MT) in acute ischaemic stroke (AIS) is progressively expanding and becoming more streamlined by the introduction of newer devices and indications.¹ Patient history as well as initial CT/MRI scan can provide a clue of the thrombus composition and thus potentially allow for a more adequate initial MT strategy. In previous randomised control trials, using first-line catheter aspiration (CA) versus first-line stent-retriever (SR) demonstrated similar recanalisation rates and favorable outcomes.^2,3 However, a more nuanced MT approach may potentially provide better outcomes. Along with occlusion location, presumed thrombus composition and stroke etiology, occlusion appearance on the initial angiogram may be the last decisional factor influencing initial MT strategy.

Four different angiographic patterns have been described on the initial angiogram, at the interface between the proximal end of occluding thrombi and the patent arterial segment^4,5 (Fig. 1, upper panel):

1. Cut-off appearance: abrupt interruption of contrast, without generating any specific shape.
2. Tapered appearance: gradual luminal narrowing, forming an acute angle over the superior/inferior vessel wall.
3. Meniscus appearance: abrupt interruption of contrast delineating a concavity towards the proximal lumen.

3.1 Claw-sign appearance⁶: variation of the meniscus occlusion, in which the protrusion length of the contrast on each side of the thrombus convexity was more than half of the parent vessel diameter (Fig. 1, lower panel).

4. Tram-track appearance: a partially occlusive lesion, with visible distal contrast filling the lumen and several pieces of thrombotic material serially positioned. The extended linear contrast can be observed on one or both arterial walls.

Alternatively, Consoli et al. classified acute occlusions as either regular (corresponding to cut-off occlusions, as per description) and irregular (encompassing all other patterns).⁷

Although there is no published study concomitantly comparing all described occlusion patterns and their association with efficiency of MT method, several features emerge:

• The cut-off and tapered occlusion types were considered as fully occlusive, the meniscus and tram-track appearances might rather suggest a sub-occlusive⁴
• The cut-off pattern seemed the most refractory to MT, requiring one supplementary passage on average (2.7 vs. 1.7 for tapered and vs. 1.9 for meniscus/tram-track occlusions, p 0.01). Furthermore, the cut-off or regular pattern was also more responsive to first-line CA (100% vs. 33.3%, p 0.001).⁷
• In contrast, successful recanalisation was more frequently achieved after first-line SR for irregular occlusions (73.9% vs. 38.4%, p 0.036).⁷
• The tapered pattern was associated with intracranial stenosis (54.8% vs. 18%) and re-occlusion, truncal type occlusion and use of rescue therapy such as permanent stenting.⁵
• A meniscus/tram-track pattern in the posterior circulation^8,9 as well as the ‘claw-sign’ positive occlusions⁶ were associated with a higher rate of recanalisation (89.3% vs. 63.6%, p 0.004 and an OR of 12.50 95% CI 1.50-103.00, p 0.019, respectively), as well as a higher first pass effect in the former (even higher for first-line CA than SR).

In conclusion, as MT will be performed more extensively owing to expanded indications, the experience regarding different angiographic patterns and their relative ‘responsiveness’ to MT techniques will increase. This knowledge, along with patient history and emergent cerebral imaging, may determine a tailored MT approach for intracranial large vessel occlusions.

Fig 1: Upper panel, from left to right: Cut-off, tapered, meniscus and tram-track occlusion patterns. Reproduced with permission from Pr. Ashfaq Shuaib, Department of Medicine (Neurology), University of Alberta, Edmonton, AB, Canada; Lower panel: ‘Claw-sign’ positive occlusion pattern with contrast protrusion length on each side estimated at more than half of the parent vessel diameter. Reproduced with permission from Dr. Yuki Yamamoto, Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan.

References

1. Jovin TG, Li C, Wu L, et al. Trial of Thrombectomy 6 to 24 Hours after Stroke Due to Basilar-Artery Occlusion. N Engl J Med. 2022;387(15):1373-1384. doi:10.1056/NEJMoa2207576
2. Lapergue B, Blanc R, Gory B, et al. Effect of Endovascular Contact Aspiration vs Stent Retriever on Revascularization in Patients With Acute Ischemic Stroke and Large Vessel Occlusion: The ASTER Randomized Clinical Trial. JAMA. 2017;318(5):443-452. doi:10.1001/jama.2017.9644
3. Turk AS, Siddiqui A, Fifi JT, et al. Aspiration thrombectomy versus stent retriever thrombectomy as first-line approach for large vessel occlusion (COMPASS): a multicentre, randomised, open label, blinded outcome, non-inferiority trial. Lancet. 2019;393(10175):998-1008. doi:10.1016/S0140-6736(19)30297-1
4. Mönch S, Boeckh-Behrens T, Berndt M, et al. Angiographic Baseline Proximal Thrombus Appearance of M1/M2 Occlusions in Mechanical Thrombectomy. Clin Neuroradiol. 2021;31(1):189-196. doi:10.1007/s00062-019-00863-4
5. Garcia-Bermejo P, Patro SN, Ahmed AZ, et al. Baseline occlusion angiographic appearance on mechanical thrombectomy suggests underlying etiology and outcome. Front Neurol. 2019;10(MAY):1-7. doi:10.3389/fneur.2019.00499
6. Yamamoto Y, Yamamoto N, Kanematsu Y, et al. The Claw Sign: An angiographic Predictor of Recanalization After Mechanical Thrombectomy for Cerebral Large Vessel Occlusion. J Stroke Cerebrovasc Dis. 2019;28(6):1555-1560. doi:10.1016/j.jstrokecerebrovasdis.2019.03.007
7. Consoli A, Rosi A, Coskun O, et al. Thrombectomy for M1-middle cerebral artery occlusion: Angiographic aspect of the arterial occlusion and recanalization: A preliminary observation. Stroke. 2018;49(5):1286-1289. doi:10.1161/STROKEAHA.117.018987
8. Baik SH, Jung C, Kim BM, Han K, Kim DJ. Clot meniscus sign: An angiographic clue for choosing between stent retriever and contact aspiration in acute basilar artery occlusion. Am J Neuroradiol. 2021;42(4):732-737. doi:10.3174/AJNR.A6988
9. Baik SH, Kim JW, Kim BM, Kim DJ. Significance of angiographic clot meniscus sign in mechanical thrombectomy of basilar artery stroke. J Neurointerv Surg. 2020;12(5):477-482. doi:10.1136/neurintsurg-2019-015321

Intracranial arterial dolichoectasia (IADE) is defined as an increase in the diameter and length of at least one intracranial artery. This pathology affects the posterior circulation in 80% of cases, causing a malformation of the basilar artery, which is showed elongated, dilatated and often tortuous.¹ This vascular alteration is particularly relevant because it seems to be related to a higher risk of stroke and it is found in about 12% of stroke patients.¹

To date, the diagnostic criteria are not clearly established, mostly because of insufficient data about the cutoffs between normal and pathological dilatation and elongation of intracranial arteries. Smoker and colleagues well defined these aspects for the basilar artery and their criteria are recognised as having a good accuracy value in the diagnosis of basilar dolichoectasia. Therefore, a basilar artery is defined as dilated with a diameter greater than 4,5 mm on MRI axial sections, while it is elongated if it crossed over to the margin of the dorsum sellae or if its bifurcation was above the plane of the suprasellar cistern. ² On the contrary, no validated criteria are available for the anterior circulation.

Differently from the atherosclerotic process, which is caused by the infiltration of inflammatory cells and lipidic cells in the arterial wall intima, IADE involves the tunica media and the internal elastic lamina, with impairment of extracellular matrix (ECM) and smooth muscle cells. In patients with IADE, modifications of ECM may be the result of an imbalanced matrix metalloproteinases (MMP) activity, particularly demonstrated by lower MMP-3 plasma concentrations. Similarly, MMP-3 levels are associated with ectasia of coronary arteries.³ Metabolic disorders involving smooth muscle cells (e.g. Pompe’s disease, Fabry’s disease) or elastic fibres (e.g. Marfan’s syndrome, mutations in the collagen IV alpha 1 or 2 genes) also can be associated with IADE. Specifically, in Fabry’s and Pompe’s disease, the lipid accumulation in endothelial and smooth muscle cells weakens the arterial wall leading to tortuosity and dilatation.

The main neurological manifestations of IADE are ischaemic stroke or transient ischaemic attack (34%), compression of surrounding structures (cranial nerve/brainstem/third ventricle with hydrocephalus) (28%), and intracerebral haemorrhage or subarachnoid haemorrhage (7%).⁴ IADE is also correlated with systemic arterial dilatations, like enlarged descending thoracic aorta, abdominal aortic aneurysm, saccular aneurysm, and coronary artery ectasia.

An interesting work by Del Brutto and colleagues has tried to clarify the clinical correlates of IADE and acute ischaemic stroke. IADE is likely responsible for a percentage of strokes initially categorised as of undetermined aetiology or as related to small-artery occlusion.⁵ Supporting that, IADE is demonstrated to be linked to lacunar infarcts, in particular at pons, where perforating arteries arising from the dolichoectatic basilar artery could be occluded by vessel distortion or intraluminal thrombus formation. In addition, several studies have highlighted the possible correlation between IADE and cerebral small vessel disease. These two entities may share the previously exposed pathophysiologic models based on MMP dysregulation and genetic mutations.⁶

In conclusion, a considerable part of stroke cases may be due to IADE (the prevalence ranges from 3 to 17%⁷), which should be considered in the diagnostic workup. Surely, further studies are necessary to better establish the diagnostic criteria. Moreover, because of the link with different pathologies (e.g. cardiac infarction, aortic aneurysm, metabolic and genetic diseases), when IADE is suspected, it is important to screen the patient for relevant comorbidities to find the best therapeutic approach.

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References

 

1. Pico F, Labreuche J, Amarenco P. Pathophysiology, presentation, prognosis, and management of intracranial arterial dolichoectasia. Lancet Neurol. 2015 Aug;14(8):833-845. doi: 10.1016/S1474-4422(15)00089-7. PMID: 26194931
2. Smoker WR, Price MJ, Keyes WD, Corbett JJ, Gentry LR. High-resolution computed tomography of the basilar artery: 1. Normal size and position. AJNR Am J Neuroradiol. 1986 Jan-Feb;7(1):55-60. PMID: 3082144; PMCID: PMC8334772.
3. Pico F, Jacob MP, Labreuche J, Soufir N, Touboul PJ, Benessiano J, Cambien F, Grandchamp B, Michel JB, Amarenco P. Matrix metalloproteinase-3 and intracranial arterial dolichoectasia. Ann Neurol. 2010 Apr;67(4):508-15. doi: 10.1002/ana.21922. PMID: 20437586.
4. Shapiro M, Becske T, Riina HA, Raz E, Zumofen D, Nelson PK. Non-saccular vertebrobasilar aneurysms and dolichoectasia: a systematic literature review. J Neurointerv Surg. 2014 Jun;6(5):389-93. doi: 10.1136/neurintsurg-2013-010793. Epub 2013 Jul 10. PMID: 23843444.
5. Del Brutto VJ, Gutierrez J, Goryawala MZ, Sacco RL, Rundek T, Romano JG. Prevalence and Clinical Correlates of Intracranial Dolichoectasia in Individuals With Ischaemic Stroke. Stroke. 2021 Jul;52(7):2311-2318. doi: 10.1161/STROKEAHA.120.032225. Epub 2021 May 13. PMID: 33980042; PMCID: PMC8238812.
6. Zhang DP, Yin S, Zhang HL, Li D, Song B, Liang JX. Association between Intracranial Arterial Dolichoectasia and Cerebral Small Vessel Disease and Its Underlying Mechanisms. J Stroke. 2020 May;22(2):173-184. doi: 10.5853/jos.2019.02985. Epub 2020 May 31. PMID: 32635683; PMCID: PMC7341005.
7. Del Brutto VJ, Ortiz JG, Biller J. Intracranial Arterial Dolichoectasia. Front Neurol. 2017 Jul 17;8:344. doi: 10.3389/fneur.2017.00344. PMID: 28769872; PMCID: PMC5511833

Mechanical thrombectomy, when performed within 24 hours after symptom onset in patients with small-to-moderate acute ischemic strokes due to an occlusion of a large vessel, has been shown to significantly improve functional outcome at 90 days. The results of previous trials, however, do not apply to patients with large strokes, which until now mostly have been excluded from treatment. Just recently, two trials on endovascular therapy for acute ischemic stroke with large infarct have demonstrated evidence of a benefit in this subgroup of patients.

We talked about the results and clinical implications of ANGEL-ASPECT¹ and SELECT2², both published in the NEJM a few days ago, with Prof Götz Thomalla who is the neurological PI of the TENSION trial.

Märit Jensen: Many thanks for taking the time for this interview. What is your opinion, will ANGEL-ASPECT and SELECT2 have an impact on clinical practice of thrombectomy?

Götz Thomalla: Indeed, I am pretty sure that the results of these trials will change clinical practice. The publication of the two trials has immediately stimulated lively discussions among stroke physicians around the world. From now on, there is no longer a reason to withhold thrombectomy in patients with large vessel occlusion based on large ischemic core. In many cases, this will make treatment decisions easier.

 

MJ: Both trials randomized patients with large ischemic core up to 24 hours to either thrombectomy or medical management. ANGEL-ASPECT enrolled 456 patients and SELECT2 enrolled 352 patients. Can you briefly summarize the results of the trials?

GT: Results were straight-forward and similar in both trials: Thrombectomy was associated with a higher odds ratio for better functional outcome assessed by the mRS at 90 days (ANGEL-ASPECT: OR 1.37 [95% CI 1.11-1.69]; SELECT2: OR 1.51 [95% 1.20-1.89]). Mortality was similar among treatment groups and there was no excess of symptomatic intracranial hemorrhage with thrombectomy. In brief, thrombectomy is safe and effective even in patients with large core.

 

MJ: SELECT2 was conducted at sites across the US, Canada, Europe, Australia, and New Zealand, while ANGEL-ASPECT was exclusively involved Chinese sites. What are the differences between both trials?

GT: There are some differences in design and results. The definition of a large ischemic core differed slightly. ANGEL-ASPECT used the definition of ASPECTS 3-5 or core volume of 70-100 ml. In SELECT2, the definition was ASPECTS 3-5 or core volume >50 ml. Both trials mainly enrolled patients with occlusion of the M1 or the intracranial internal carotid artery. Patients in SELECT2 had more severe strokes reflected by a median NIHSS of 19 as compared to 15-16 in ANGEL-ASPECT.

There were also differences in outcomes, as overall patients in ANGEL-ASPECT showed better outcomes. In SELECT2, rates of functional independence (mRS 0-2) wer 20% in the thrombectomy group and 7% in the medical-care group. In the Chinese trial, functional independence was achieved by 30% vs. 11%. Mortality was higher in SELECT2 (38% vs. 42%) than in ANGEL-ASPECT (22% vs. 20%). In SELECT2, up to 20% of patients had procedure-related complications, such as dissection, vasospasms, or vessel perforation. As to medical management, in both trials rates of intravenous thrombolysis were rather low, approximately 20% in SELECT2 and less than 30% in ANGEL-ASPECT. Despite differences both trials were consistent in the clear benefit of thrombectomy over medical management alone.

MJ: Did the subgroup analyses provide additional insights?

GT: The analysis of subgroups did not bring any surprises. Subgroup analysis in both trials were supportive and consistent with the main findings. There was no significant heterogeneity of the treatment effect for any relevant subgroup, but, of course, both trials were not powered for subgroup analysis.

 

MJ: You are involved in the TENSION study which addresses a very similar clinical question. Will these results influence your trial?

GT: This is a good question, and within the TENSION team we have asked ourselves this question immediately. The TENSION Steering Committee had an ad hoc meeting after the trial results were published. As of now, TENSION has randomized 252 patients. We decided to suspend randomization in TENSION until the results of ANGEL-ASPECT and SELECT2 have been discussed by our DSMB, which will meet by the end of February. At that time, we will also have the results of a pre-planned interim analysis of the first 222 patients randomized in TENSION available, and based on the recommendations of the DSMB, the Steering Committee will then make a final decision.

 

MJ: It appears, as if the most burning scientific questions concerning stroke thrombectomy have been answered, including thrombectomy for basilar artery occlusion, and just now also for large core. What is next to come?

GT: This is another good question. It remains to be elucidated, whether thrombectomy is also effective in distal occlusions, e.g., M3, A2, P2 and beyond, and we are looking forward to the results of the DISTAL trial. With the momentum stemming from of ESCAPE-NA1³, I also expect further trials of neuroprotection or other add-on treatments together with endovascular stroke treatment. Maybe the results of the recently completed ESCAPE-NEXT trial will be presented at ESOC 2023 in Munich. Finally, probably the most important next step will be to transfer these findings from clinical trials into guidelines and clinical practice and make this effective treatment available to as many patients as possible across the world.

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References

1. Huo X, Ma G, Tong X, Zhang X, Pan Y, Nguyen TN, et al. Trial of endovascular therapy for acute ischemic stroke with large infarct. New England Journal of Medicine. 2023
2. Sarraj A, Hassan AE, Abraham MG, Ortega-Gutierrez S, Kasner SE, Hussain MS, et al. Trial of endovascular thrombectomy for large ischemic strokes. New England Journal of Medicine. 2023
3. Hill MD, Goyal M, Menon BK, Nogueira RG, McTaggart RA, Demchuk AM, et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (escape-na1): A multicentre, double-blind, randomised controlled trial. Lancet. 2020;395:878-887

Current ESO recommendations regarding extended time-window reperfusion treatment require the use of advanced cerebral imaging. A favorable revascularisation decision thus relies on the mismatch between core and penumbra (on both CT and MRI) or between Diffusion Weighted Imaging (DWI) and Fluid-Attenuated Inverse Recovery (FLAIR) sequences on MRI.^1,2 However, other radiological markers may influence and nuance the decision to administer acute reperfusion treatment.

The FLAIR sequence often demonstrates the extent of acute stroke (considered beyond potential salvation); however, it takes several hours for the infarcted parenchyma to become hyperintense. A more precocious finding is represented by the FLAIR hyperintense vessel sign (FHVs), corresponding to vessels situated downstream an arterial occlusion.³ This sign is often readily identifiable on the FLAIR sequence considering the low signal from surrounding cerebrospinal fluid.

First described in 2000 by Kamran et al.,⁴ it was identified in 10% of a series of retrospectively analysed MRI examinations performed for acute ischaemic stroke. Almost all patients presenting this sign had large vessel occlusion or severe stenosis. When performed, angiography demonstrated corresponding slow-flow. Lastly, on MRI scans performed shortly after stroke debut, FHVs was present while parenchymal hyperintensity was absent.⁴

Following this initial study, two questions progressively emerged regarding FHVs: firstly, does it rather represent insufficient collateralisation or, on the contrary, increased leptomeningeal collateralisation, both in the context of altered cerebral hemodynamics caused by acute occlusion or stenosis? Secondly, does it have a clinical predictive value?

In a retrospective cohort study on 62 patients with acute ischaemic stroke and large and medium-vessel occlusion, patients with extensive FHVs had larger baseline lesions with a higher initial NIHSS and a more pronounced diffusion-perfusion mismatch.³ In all, extensive FHVs presence was predictive of severe hypoperfusion which was further associated with a worse 3-months functional outcome. The authors concluded that extensive FHVs probably indicates insufficiency of leptomeningeal collateralisation to maintain perfusion over a large area of cerebral ischaemia.³

Moreover, a more recent study attempted to nuance the leptomeningeal collateral status by analysing the pattern of FHVs with regard to initial DWI lesion extent.⁵ Thus, in patients with FHVs situated inside the borders of the DWI lesion, regional cerebral blood flow and volume as well as collateral grade were significantly lower on the CTA/CTP examination than in patients with FHVs identified outside of the lesion. The authors suggested that the FHVs-out pattern may represent a cerebral perfusion reserve stage,⁵ being associated with relatively improved cerebral perfusion and thus, adequate, but temporary leptomeningeal collaterals.

Finally, a recent study on acute large-vessel occlusion strokes treated by mechanical thrombectomy analysed the FHVs-DWI mismatch score, representing the number of cortical areas (classified using the DWI-ASPECTS, comprising only the insular component and M1-M6 territories) that involved the presence of FHVs without a DWI lesion.⁶ After analysing around 200 patients, the study identified that an increase in the FHVs-DWI mismatch score was associated with an increase in 3-months favorable outcome.

In summary, the FHVs is a precocious radiological marker identified on MRI FLAIR sequence, demonstrating an alteration of cerebral hemodynamics downstream a severe stenosis or occlusion. It is generally believed to represent an area of ischaemic penumbra (and thus with salvageable potential), probably stemming from insufficient or temporary leptomeningeal collateralisation. Lastly, its prognostic value seems to be dependent on its relationship with the DWI lesion extent, with FHVs situated outside of positive DWI lesions being most informative of the reserve of salvageable cerebral tissue.

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References:

1. Berge E, Whiteley W, Audebert H, et al. European Stroke Organisation (ESO) Guidelines on Intravenous Thrombolysis for Acute Ischaemic Stroke. Vol 6.; 2021. doi:10.1177/2396987321989865
2. Turc G, Bhogal P, Fischer U, et al. European Stroke Organisation (ESO)- European Society for Minimally Invasive Neurological Therapy (ESMINT) guidelines on mechanical thrombectomy in acute ischemic stroke. J Neurointerv Surg. 2019;11(6):535-538. doi:10.1136/neurintsurg-2018-014568
3. Kufner A, Galinovic I, Ambrosi V, et al. Hyperintense vessels on FLAIR: Hemodynamic correlates and response to thrombolysis. Am J Neuroradiol. 2015;36(8):1426-1430. doi:10.3174/ajnr.A4320
4. Kamran S, Bates V, Bakshi R, Wright P, Kinkel W, Miletich R. Significance of hyperintense vessels on FLAIR MRI in acute stroke [1]. Neurology. 2001;56(9):1248. doi:10.1212/WNL.56.9.1248
5. Huang X, Shi X, Yang Q, et al. Topography of the hyperintense vessel sign on fluid-attenuated inversion recovery represents cerebral hemodynamics in middle cerebral artery occlusion: a CT perfusion study. Neuroradiology. 2019;61(10):1123-1130. doi:10.1007/s00234-019-02231-y
6. Tokunaga K, Tokunaga S, Hara K, et al. Fluid-attenuated inversion recovery vascular hyperintensity-diffusion-weighted imaging mismatch and functional outcome after endovascular reperfusion therapy for acute ischemic stroke. Interv Neuroradiol. July 2022:15910199221113900. doi:10.1177/15910199221113900

In patients who experience an ischaemic stroke while on effective anticoagulation, intravenous thrombolysis (IVT), is currently contraindicated due to concerns that the risk for major bleeding events, particularly intracranial hemorrhage (ICH), is particularly increased. Current guidelines do not recommend IVT in patients with acute ischaemic stroke who have taken a NOAC within 48 hours before the event (1). However, this assumption is not evidence-based. Up to 20% of all strokes occur while on effective NOAC treatment (2). As the spectrum of indications for NOACs is continuously expanding, it can be assumed that this proportion of patients who are withheld IVT on the basis of this paradigm will continue to grow and thus become even more relevant.

Previous studies did not indicate a substantial risk for bleeding events in thrombolysed patients who are taking a NOAC  (3, 4). In a current retrospective, international multi-center study led by the colleagues from Bern (Switzerland) and Heidelberg (Germany), Meinel et al. analysed data from patients who received IVT between 2008 and 2021 and had taken a NOAC within 48 hours before symptom onset of stroke (5). As control cohort, patients treated with IVT but not under effective anticoagulation were included, most of them recruited in the Thrombolysis in Ischaemic Stroke Patients (TRISP) collaboration. When available, the exact NOAC intake time before stroke was documented and categorised according to within 12 hours, 12-24 hours, or over 24 hours. Information on the respective regimen was also collected, i.e., to what extent NOAC plasma levels were measured or NOAC were antagonised before IVT. The primary endpoint was the occurrence of a symptomatic ICH (defined as worsening by 4 NIHSS points) within 36 hours after IVT. Secondary endpoints were any ICH on follow-up imaging and a favorable functional outcome according to a modified Rankin Scale of 0-2, which was assessed center-based at 90 days via a clinical or telephone visit. (5)

There were 832 patients with NOAC treatment and 32375 controls included. In the NOAC group, patients were older (79 vs. 72 years) and had higher stroke severity (median NIHSS 11 vs. 9), prevalence of proximal vessel occlusion (59% vs. 33%), and atrial fibrillation (90% vs. 25%). Dabigatran was the most common anticoagulant used (41%), followed by rivaroxaban (31%), apixaban (20%), and edoxaban (8%). Among NOAC-treated patients, antagonisation (idarucizumab for dabigatran) was performed in 30% and NOAC plasma levels were measured in 27%. In the NOAC group, the rate of symptomatic ICH was 2.5% compared with 4.1% in controls. The adjusted odds ratio (OR) for symptomatic ICH was 0.57 (95% confidence interval : 0.36-0.92). In prespecified sensitivity analyses using the different time intervals, this result was consistent, with the limitation of small number of cases. Patients who received NOAC but in whom neither plasma level measurement nor antagonisation could be performed (n=355) still had a nominally decreased risk of symptomatic ICH (aOR: 0.66 (95% CI: 0.35-1.25)) but an increased OR for any ICH (aOR: 1.58 (95% CI: 1.16-2.14)), although the precision of these estimates was quite low. (5)

The occurrence of secondary end points did not differ considerably between groups. (5)

This important study again plausibly challenges the paradigm of contraindication of thrombolysis by NOAC treatment. Contrary to the expectation, the risk of symptomatic ICH due to thrombolysis was even significantly reduced under existing NOAC treatment, which may be explained by improved thrombolytic properties and reduced blood-brain barrier disruption. (5)

The most important limitation of the study is its retrospective design and a probable selection bias: the treating colleagues will have selected suitable patients having low risks for hemorrhagic transformation of stroke in their routine practice. Subgroup analyses have shown similar trends but had too little statistical power to provide reliable estimates.

While a randomised-controlled trial on this topic is unlikely to ever be planned for financial and logistical reasons, a prospective registry of appropriate size seems to be warranted in order to change the current practice in favor of the many NOAC-treated patients. A particularly interesting group are patients for whom the practitioners are unaware of NOAC use, as no selection bias would be expected here.

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References:

1. Berge E, Whiteley W, Audebert H, De Marchis G, Fonseca AC, Padiglioni C, et al. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. European Stroke Journal. 2021;6(1):I-LXII.
2. Seiffge DJ, De Marchis GM, Koga M, Paciaroni M, Wilson D, Cappellari M, et al. Ischemic Stroke despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation. Ann Neurol. 2020;87(5):677-87.
3. Seiffge DJ, Hooff RJ, Nolte CH, Béjot Y, Turc G, Ikenberg B, et al. Recanalization therapies in acute ischemic stroke patients: impact of prior treatment with novel oral anticoagulants on bleeding complications and outcome. Circulation. 2015;132(13):1261-9.
4. Xian Y, Federspiel JJ, Hernandez AF, Laskowitz DT, Schwamm LH, Bhatt DL, et al. Use of Intravenous Recombinant Tissue Plasminogen Activator in Patients With Acute Ischemic Stroke Who Take Non-Vitamin K Antagonist Oral Anticoagulants Before Stroke. Circulation. 2017;135(11):1024-35.
5. Meinel TR, Wilson D, Gensicke H, Scheitz JF, Ringleb P, Goganau I, et al. Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants. JAMA Neurology. 2023.