Most imaging-based risk assessments of stroke or TIA rely on the degree of arterial narrowing with the highest incidence of stroke associated with the most severe narrowing. The yearly incidence of stroke varies from approximately 1.2 to 5.9% per year for asymptomatic ICA stenosis5,17
to about 10% per year for symptomatic ICA occlusion21
. Though these estimates are integral to current treatment and stroke prevention paradigms, most consensus recommendations do not include assessments of cerebral hemodynamics in their management algorithms22
In this systematic review and meta-analysis of 1061 independent CVR tests in 991 unique patients with carotid stenosis or occlusion with a mean follow up of 32.7 months, baseline CVR impairment was associated with increased risk of stroke/TIA. Our findings suggest a positive relationship between baseline CVR impairment and future ischemic events, with a pooled odds ratio suggesting that patients with impaired CVR are approximately 4 times more likely to develop stroke or TIA. To our knowledge, though there have been two previous published meta-analyses of the role of CVR in predicting future stroke risk, one was limited in scope as it examined only 3 studies limited to patients with asymptomatic disease5
and another was performed in 1997 before a majority of the current studies in the meta-analysis were published and was focused instead on baseline CBF impairments6
. Our literature search found 5 studies limited to asymptomatic patients, and is the first study to evaluate the effect of CVR impairment across different disease characteristics and by combining studies that used different methods to measure CVR. Importantly, our study suggests that CVR impairment is strongly associated with stroke or TIA in both high grade stenosis and occlusion, as well as in asymptomatic and symptomatic patients. These findings suggest that, in combination or in addition to the risk of embolic stroke arising from carotid atheromatous plaque, these patients face stroke risk from hypoperfusion in vascular territories where vasodilatory capacity is maximally exhausted.
The choice of modality for evaluating CVR varies. We found the association between CVR impairment and risk of stroke conserved across testing modality (TCD or NM techniques) as well as the nature of the vasodilatory stimulus (acetazolamide or variation in inspired CO2 levels). TCD is relatively inexpensive and fairly widely available, but does not provide additional information of the brain parenchyma and is technically impossible in some cases due to lack of acoustic windows. Modalities which measure brain tissue perfusion, such as NM techniques, often have limited use in the clinical setting due to expense, availability, and low spatial and temporal resolution. Though there are radiation and cost considerations for newer cross sectional methods such as CT and MRI perfusion techniques, to our knowledge no prospective studies assessing CVR impairment and stroke risk have been performed with these newer modalities, so their utility requires further investigation.
Our study has some limitations that should be considered. Though no studies in the review described any differences in risk factors or treatment that might explain differences between normal and impaired CVR groups, an explicit statistical correction of these risk factors occurred in a majority (9 of 13) but not all of the studies. In addition, no methodology for blinding of investigators to the CVR results was explicitly made in a majority of the studies. Additional limitations inherent to the generalization of data for the purposes of pooled statistical analysis also should be acknowledged. Study endpoints (stroke or TIA) were defined variably by authors with many aggregating these outcomes and preventing distinction between them in our summary meta-analysis, and also preventing a distinction between minor versus disabling stroke. In addition, definitions of normal versus impaired CVR and symptomatic versus asymptomatic disease varied, and though some similarities existed, no one standard definition could be applied across all studies. Similarly, more precise description of the severity of stenosis (percentages) and timing of this measurement relative to CVR determination was reported in a variable fashion and was difficult to generalize. Lastly, due to the nature of the data available for statistical analysis, assessment of risk per unit of time as a hazard ratio could not be performed.
Despite these potential limits, the preservation of association between CVR impairment and risk of stroke/TIA is robust across many patient subsets and methods of CVR assessment suggesting an important potential role in stroke/TIA risk assessment. The feasibility of integrating routine CVR measurements into the care of patients with carotid stenosis or occlusion and validation of newer methods of CVR using cross-sectional imaging techniques requires continued investigation.