New ischemic brain lesions seen on MRI-based diffusion-weighted imaging (DWI) after carotid artery stenting (CAS) appear to signal increased risk of future stroke or TIA, according to a study published in the February 17, 2015, issue of the Journal of the American College of Cardiology. However, such lesions detected after carotid endarterectomy (CEA) are not associated with cerebrovascular events—although few surgical patients were available for analysis.

 “Because most cerebral ischemic events present clinically within the first 6 months after carotid stenting, future trials should address whether patients with asymptomatic postprocedural ischemia benefit from more prolonged dual antiplatelet therapy [DAPT],” the study authors suggest.

In the MRI substudy of the International Carotid Stenting Study (ICSS-MRI), 231 patients with symptomatic carotid stenosis were randomized to CAS (n = 124; 41% with cerebral protection) or CEA (n = 107).

For the current analysis, investigators led by Leo H. Bonati, MD, of University Hospital Basel (Basel, Switzerland), studied 66 patients (37 CAS; 29 CEA) with 3T scanners and the rest with 1.5T scanners. Half of the CAS arm vs 16.8% of the CEA arm showed new ischemic brain lesions on DWI of scans obtained a median of 1 day after treatment (adjusted OR 5.21; 95% CI 2.78-9.79).

At baseline, patients with DWI lesions were a median 5 years older, smoked less often, and had lower total cholesterol levels and higher baseline scores on a scale of age-related white matter changes than those without new DWI lesions.

Over a median follow-up of 4.65 years, 5-year cumulative mortality rates among CAS patients were 16.5% in those with and 15.5% in those without new DWI lesions. The cumulative stoke/TIA risk was 15.1% in lesion-positive patients vs 3.2% in lesion-negative patients at 1 year—with a difference emerging during the first 6 months—and 22.8% vs 8.8%, respectively, at 5 years.

After adjustment for systolic blood pressure, the risk of stroke/TIA was tripled in DWI-positive CAS patients. The presence of DWI lesions made no difference for risk of ipsilateral stroke/TIA or stroke alone (table 1).

However, when analysis was based on lesion count, a higher number of periprocedural DWI lesions was associated with all 3 outcomes (table 2).

In the CEA group, there were no differences in baseline characteristics between DWI-positive and DWI-negative patients. Over a median follow-up of 4.02 years, 1 DWI-positive patient and 10 DWI-negative patients died. No link was seen between the presence or number of periprocedural DWI lesions and any outcomes in either the binary analysis or the lesion-count analysis.

None of the recurrent events in either the CAS or CEA groups was linked to residual or recurrent carotid stenosis, and none of the patients with recurrent events underwent repeat revascularization.

A Case for More Aggressive Antiplatelet Therapy

According to the study authors, the findings suggest “that periprocedural DWI lesions seen after CAS may be a marker of unstable atherosclerotic plaques, which increase the risk of cerebral embolism not only during the procedure but also in the first few months thereafter.”

Furthermore, unstable plaques might be present not only in the target artery but also in the access vasculature, including the aortic arch, they observe, and that may explain why recurrent events also occur outside the territory supplied by the treated carotid artery.

The timing of events in the study supports more aggressive and prolonged antiplatelet therapy in such patients, Dr. Bonati and colleagues comment. Indeed, because routine DWI scanning increases costs and new periprocedural brain lesions are common, that strategy might be justified for all patients undergoing CAS. However, they caution, the current results need confirmation in larger studies before such recommendations can be made.

Finally, “the small number of patients with new periprocedural DWI lesions after CEA precluded a meaningful analysis of the impact of these lesions on future risk of cerebrovascular events in the surgical arm,” the authors say.

Multiple Problems Detract From Conclusions

In an accompanying editorial, William A. Gray, MD, of Columbia University Medical Center (New York, NY), writes that efforts to predict outcomes based on clinical or procedural characteristics “are confounded by 1 simple, unassailable fact: the number of outcome events in carotid intervention is too small to achieve statistical significance in most cases.”

Lesions seen on DWI have been proposed as a surrogate for risk, Dr. Gray says, and—though their clinical import has remained elusive—“a generally small but numerically greater incidence of minor strokes after CAS compared with CEA raises the hope that if the excess of new MR-DWI lesions could be reduced, then the minor stroke rate might also be expected to drop.”

However, Dr. Gray contends, the results of analyses of ICSS are mitigated by the fact that the trial falls short of contemporary standards for CAS, with low requirements for operator experience and no embolic protection in about 60% of CAS patients. He also suggests that despite adjustment, baseline differences between lesion and no-lesion groups—especially with regard to hypertension—were potentially confounding.

In addition, A-fib, which could also have confounded the analysis, was neither reported nor adjusted for. Moreover, the sidedness of the lesions was not specified and thus could not be correlated with the intervention. This calls into question the mechanistic cause for the primary finding and thus the rationale for more aggressive DAPT, Dr. Gray asserts, adding that in light of the equipoise between CAS and CEA in hard endpoints and its small increased bleeding risk, “extended DAPT does not seem justified or advisable.

“Unfortunately,” he concludes, “the study… fails to shed light on the clinical relevance of MR-DWI abnormalities associated with carotid procedures or operations.”

Stented Patients Susceptible to Late Emboli

In a telephone interview with TCTMD, Joseph Rapp, MD, of the University of California, San Francisco (San Francisco, CA), said that although the study is far from definitive, it is interesting and the mechanism for creation of emboli is plausible.

Imaging studies have shown that endarterectomy produces emboli only in the periprocedural period, Dr. Rapp observed, whereas after stenting emboli continue to be shed. When emboli travel to the brain—even if they do not obstruct a vessel and cause ischemia—they can be incorporated into the vessel wall, he reported. “You may have some structural change in the intracranial circulation that makes you more susceptible to further emboli,” he speculated.

Dr. Rapp said that whether more liberal antiplatelet therapy would make a difference is unclear, but “if you’re more susceptible to late emboli and those emboli were platelet clumps, [ongoing] antiplatelet therapy would probably be worthwhile.”

Surgery produces fewer emboli than stenting, at least as currently practiced, Dr. Rapp said. But he added that use of flow reversal during the procedure is more effective at minimizing emboli than distal embolic protection devices. And a new direct stenting device that avoids the aortic arch holds promise, he said, adding, “Their DWI data are very good.”

Such advances in technology, together with interventionalists becoming smarter about patient selection—avoiding stenting bulky or calcified lesions—are reducing the overall burden of emboli, he suggested.

Still, Dr. Rapp concluded, “DWI lesions in the brain are not good, but how bad they are remains debatable.”

1. Gensicke H, van der Worp HB, Nederkoorn PJ, et al. Ischemic brain lesions after carotid artery stenting increase future cerebrovascular risk. J Am Coll Cardiol. 2015;65:521-529.

2. Gray WA. Flights from wonder: the search for meaning in diffusion-weighted brain lesions [editorial]. J Am Coll Cardiol. 2015;65:530-532.

Disclosures:

• ICSS was funded by grants from the European Commission, the Medical Research Council, Sanofi-Synthelabo, and the Stroke Association.
• Dr. Bonati reports receiving grants from the Swiss National Science Foundation and the University of Basel and serving on scientific advisory boards for Bayer.
• Drs. Gray and Rapp report no relevant conflicts of interest.

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