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Secondary prevention in intracranial stenosis related stroke: a narrow path among evidence

By Giuseppe Reale, MD. Catholic University of the Sacred Heart, Rome.

Arterial stenosis due to large artery atherosclerosis (intracranial atherosclerotic arterial stenosis, ICAAS) causes 5–10% of strokes in white, 15–29% of TIA/strokes in black and up to 30–50% of strokes in Asian people1. The proposed underlying mechanisms for ICAAS causing stroke are basically three: 1) hemodynamic disfunction, with hypoperfusion distal to the stenosis; 2) artery-to-artery embolism; 3) plaque extension to penetrating vessels’ ostia, with subsequent occlusion (branch artery disease)1. Digital subtraction angiography is the gold standard for ICAAS diagnosis, but MRI-angiography, CT-angiography, transcranial color-coded duplex sonography (TCCS) and transcranial doppler (TD) are widely used in daily clinical practice2–4. While the diagnosis of ICAAS is quite standardized, secondary prevention is a real clinical challenge. In fact, the risk of recurrent stroke/TIA in case of symptomatic ICAAS is high5–8.

Several trials have investigated the best secondary prevention of ICAAS-related stroke.

The WASID trial compared warfarin versus aspirin in patients with recent (<90 days) TIA/non-disabling stroke due to ICAAS>50% (confirmed by DSA)6. There was no difference regarding the primary endpoint (ischemic stroke, brain haemorrhage, or death from vascular causes other than stroke). The recurrence of stroke in the same vascular territory was high in both groups (12% versus 15%), while the occurrence of death and major haemorrhages was significantly higher in the warfarin group6.

The SAMPRISS trial compared stenting plus aggressive medical therapy (three-months of aspirin + clopidogrel plus aggressive risk factor control) versus aggressive medical therapy in patients with recent (<30 days) TIA/non-disabling stroke caused by ICAAS>70% (verified by DSA)7. The primary endpoint (composite of stroke/death within 30 days after enrolment or ischemic stroke in the territory of the qualifying artery between beyond 30 days after enrolment) was significantly higher in the stenting group and the trial was stopped for concerns about safety. The occurrence of stroke in the same vascular territory was 10% at 1 year for the medical arm. Another trial on endovascular treatment, the VISSIT trial, compared balloon-expandable stenting plus aggressive medical treatment (the same approach as SAMPRISS) versus aggressive medical treatment alone in patients with recent (<30 days) minor stroke/TIA. This trial found efficacy and safety outcomes favouring the medical treatment and was stopped soon after the publication of SAMPRISS for safety concerns9.

The CLAIR trial had a non-clinical primary endpoint (number of transcranial doppler embolic signals in the territory of the extra- or intra-cranial carotid artery stenosis within 7 days after enrolment). Nevertheless, this trial compared double antiplatelet therapy (aspirin + clopidogrel) versus aspirin alone in patients with very acute minor ischemic stroke/TIA (<7 days)10. As found in a previous trial on extra-cranial carotid stenosis, CLAIR showed that the number of embolic signals in the double antiplatelet group was significantly lower than that in the aspirin group11.

Another randomized trial compared cilostazol plus aspirin versus aspirin alone and showed that the combination approach might reduce ICAAS progression on MR-angiography, but no conclusive data on secondary prevention are available12.

At the moment, there is no randomized controlled trial comparing single versus double antiplatelet therapy or other medical treatments to each other.

Of course, antithrombotic drugs are not the only tool we have. General lifestyle modifications (smoke cessation, weight reduction, regular exercise, Mediterranean diet…) are safe and effective13. Concerning blood pressure, several post-hoc analyses of the aforementioned trials have essentially shown that a systolic blood pressure target <140 mmHg lowers the risk of recurrence13,14. The same is said for LDL cholesterol, with a reasonable target <70 mg/dl13–15.

Putting all this together, until we have any definite answer about other approaches including the use of newer generations of stents, we can probably conclude that there is some evidence suggesting a potential benefit of a three-months course of double antiplatelet therapy (aspirin + clopidogrel) plus aggressive risk factor control for patients with a recent ischemic event (<30 days) and a symptomatic ICAAS >70%1.

We hope that further trials will shed light on this non-marginal topic.



  1. Holmstedt CA, Turan TN, Chimowitz MI. Atherosclerotic intracranial arterial stenosis: risk factors, diagnosis, and treatment. Lancet Neurol. 2013;12:1106–1114.
  2. Feldmann E, Wilterdink JL, Kosinski A, Lynn M, Chimowitz MI, Sarafin J, et al. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial. Neurology. 2007;68:2099–2106.
  3. Liebeskind DS, Kosinski AS, Saver JL, Feldmann E. Computed Tomography Angiography in the Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) Study. Interv. Neurol. 2014;2:153–159.
  4. Baumgartner RW, Mattle HP, Schroth G. Assessment of >/=50% and <50% intracranial stenoses by transcranial color-coded duplex sonography. Stroke. 1999;30:87–92.
  5. Famakin BM, Chimowitz MI, Lynn MJ, Stern BJ, George MG. Causes and Severity of Ischemic Stroke in Patients with Symptomatic Intracranial Arterial Stenosis. Stroke J. Cereb. Circ. 2009;40:1999–2003.
  6. Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N. Engl. J. Med. 2005;352:1305–1316.
  7. Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N. Engl. J. Med. 2011;365:993–1003.
  8. Liu L, Wong KSL, Leng X, Pu Y, Wang Y, Jing J, et al. Dual antiplatelet therapy in stroke and ICAS: Subgroup analysis of CHANCE. Neurology. 2015;85:1154–1162.
  9. Zaidat OO, Fitzsimmons B-F, Woodward BK, Wang Z, Killer-Oberpfalzer M, Wakhloo A, et al. Effect of a balloon-expandable intracranial stent vs medical therapy on risk of stroke in patients with symptomatic intracranial stenosis: the VISSIT randomized clinical trial. JAMA. 2015;313:1240–1248.
  10. Wong KSL, Chen C, Fu J, Chang HM, Suwanwela NC, Huang YN, 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. Lancet Neurol. 2010;9:489–497.
  11. Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, 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;111:2233–2240.
  12. Kwon SU, Cho Y-J, Koo J-S, Bae H-J, Lee Y-S, Hong K-S, et al. Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis. Stroke. 2005;36:782–786.
  13. Turan TN, Nizam A, Lynn MJ, Egan BM, Le N-A, Lopes-Virella MF, et al. Relationship between risk factor control and vascular events in the SAMMPRIS trial. Neurology. 2017;88:379–385.
  14. Chaturvedi S, Turan TN, Lynn MJ, Kasner SE, Romano J, Cotsonis G, et al. Risk factor status and vascular events in patients with symptomatic intracranial stenosis. Neurology. 2007;69:2063–2068.
  15. Amarenco P, Kim JS, Labreuche J, Charles H, Abtan J, Béjot Y, et al. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. N. Engl. J. Med. 2019;0:null.