How common is intracranial stenosis (ICS) in Caucasians, both in the general population and in patients with TIA and minor stroke?
Rob: There are few data from population-based studies of Caucasians on the prevalence of ICS and what is available is highly heterogeneous due to differing selection criteria, ICS definitions and imaging techniques.
The Atherosclerosis Risk in Communities Study (ARIC) in the US imaged 1,765 community-dwelling individuals and estimated a prevalence of ≥50% asymptomatic ICS in Caucasian 65-90 year olds as 8%. In the Barcelona-Asymptomatic Intracranial Atherosclerosis (Barcelona-AsIA) study the prevalence of asymptomatic ICS in stroke-free Caucasians with mean age 65 years and a moderate-high vascular risk was 8.6%.
In stroke and TIA patients, the prevalence is reported to be higher; a hospital-based study of 403 stroke patients admitted to a single French centre reported an ICS rate of 36.2%. We performed the first population-based study of Caucasian minor stroke and TIA patients and identified 50-99% asymptomatic or symptomatic ICS in 17%.
What are the current treatment options for symptomatic and for asymptomatic intracranial stenosis?
Rob: As demonstrated by randomised trials (SAMMPRIS and VISSIT), patients with recently symptomatic ICS should be treated with intensive medical management rather than percutaneous angioplasty/ stenting and we have validated these findings in a real-life population-based cohort. Medical management should comprise short-term dual anti-platelet therapy (DAPT; for example aspirin and clopidogrel for a month) followed by single anti-platelet therapy plus intensive risk factor management. The benefit of long-term DAPT has not yet been proven beneficial in patients with symptomatic ICS and we know from the MATCH and CHARISMA trials there is a significant risk of major haemorrhage.
There are no randomised data to guide the optimal management of patients with asymptomatic or remotely symptomatic ICS. These patients should be treated according to standard secondary prevention guidelines, namely long-term single anti-platelet therapy and intensive risk factor management.
Many centres around the world offer percutaneous angioplasty/ stenting for recurrent ischaemic cerebrovascular events on intensive medical therapy, but there is no randomised evidence to support this and it is not routinely performed in the UK. Our approach would be for a further short course of DAPT, re-assess and manage vascular risk factors and change aspirin to clopidogrel long-term monotherapy.
Can you briefly summarise the design and patient selection of the study?
Rob: We included consecutive patients with TIA or minor ischaemic stroke (NIHSS ≤3) ascertained to the population-based Oxford Vascular Study and followed up over a 7-year period. The majority (87%) of these patients underwent intracranial vascular imaging, preferentially with MR angiography (78% of imaged patients), but to minimise patient selection bias we also included patients with CT angiography and transcranial Doppler ultrasonography.
We calculated the age-specific prevalence of symptomatic and asymptomatic ≥50% ICS and the risk of subsequent ischaemic stroke during follow-up. We also performed a sensitivity analysis in patients with 70-99% symptomatic ICS and compared the prognosis with those in the medical (non-stenting) arms of SAMMPRIS and VISSIT in order to validate their results in a real-life, older population.
What are the key findings?
Rob: We identified symptomatic or asymptomatic ICS in 17% of our patients with highest rates at older ages. Although symptomatic ICS conveyed an increased risk of ischaemic stroke compared to no ICS (adjusted hazard ratio= 1.43, 95% CI 1.04-1.96), the risk of recurrent ischaemic stroke on intensive medical treatment was consistent with the non-stenting arms of SAMMPRIS and VISSIT supporting the generalisability of their results to routine practice.
Similarly, we found that asymptomatic ICS also increases steeply with age (OR per decade=1.96, 95% CI 1.69-2.27) and was greater than that of ≥50% asymptomatic carotid bifurcation stenosis. However, patients with only asymptomatic ICS had no increase in risk of ischaemic stroke compared to those with no ICS, with only eight (5.2%) first recurrent events during 506 patient-years of follow-up, and only three in the territory of the previously asymptomatic ICS (annualised risk= 0.59%, 0.12-1.73).
Should we change our current clinical practice based on the study?
Rob: The current guidelines for management of symptomatic ICS are supported by high quality trial evidence and we have validated this in a real-life population-based cohort of older Caucasian patients. There is no consensus on the utility of routine screening for ICS in secondary stroke prevention and patients with TIA or minor ischaemic stroke are often not screened. Our results show that patients with symptomatic ICS are a high-risk subgroup even when treated according to current guidelines and whilst there is no evidence to support a role for percutaneous stenting, the high stroke risk might justify routine screening to tailor risk factor management; for example intensive lipid-lowering with monoclonal antibodies or novel combinations of antithrombotic agents (as in the COMPASS trial).
Furthermore, no specific additional treatments or follow-up imaging is required for patients with asymptomatic ICS. Patients can be reassured that there is no increased risk of recurrent schaemic stroke, vascular event or death over and above those minor ischaemic stroke/ TIA patients without ICS.
Finally, our finding that ICS are prevalent in Caucasian patients will hopefully reinforce the need for intensive risk factor management. This is particularly relevant with regards to statin therapy given the increasing reluctance on the part of some patients to take statins, and of some clinicians to prescribe lipid-lowering drugs in the very elderly, in whom we found high rates of ICS.
Do we still need another randomised trial of intervention vs. best medical treatment for symptomatic intracranial stenosis?
Peter: I think that the scope for further trials is limited to relatively small subsets of patients, such as those with recurrent strokes despite best medical treatment and those with marked perfusion deficits.
What are your suggestions to clinicians and to patients with regards to asymptomatic intracranial stenosis?
Peter: In the absence of symptoms, the prognosis of incidental asymptomatic intracranial stenosis on best medical treatment appears to be relatively benign and so I don’t think that patients or clinicians should be unduly concerned.
Interviewed by Dr Linxin Li, Wolfson Centre for Prevention of Stroke and Dementia, University of Oxford, UK