Voeks JH, Howard G, Roubin G, Farb R, Heck D, Logan W, et al. Mediators of the Age Effect in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). Stroke. 2015
The CREST trial demonstrated no significant difference between the efficancy of carotid stenting (CAS) versus carotid endarterectomy (CEA) overall, but when the effects of age were studied, older patients had better outcomes with CEA and younger patients with CAS. The biggest factor contributing to this difference in outcomes was that older patients had a higher risk of stroke or death with carotid stenting (CAS), both periprocedurally and during follow up, but the exact pathway for this is not well understood. Is it age itself, or some other factor that increases with age, which accounts for this increased risk? The overall goal, as with any treatment, is to select a group of patients who will benefit most with the least amount of risk. In order to do this, it is crucial to identify the direct contributors. In the case of older patients with worse outcomes after CAS, age is not thought to be a direct contributor, but an umbrella category which happens to include many patients with a certain vascular characteristic predisposing them to a worse outcome.
The authors undertook an analysis of possible factors which included those related to the patient (HTN, diabetes, hyperlipidemia) and those related to the arteries themselves (plaque length, eccentric plaque, ulcerated plaque, percent stenosis, peak systolic velocity, and location), among 1123 patients treated with CAS from the CREST study. The authors identified for each factor: the association it had with age, the association it had with periprocedural stroke or death risk, and for those factors contributing, the authors determined by how much the risk of stroke or death decreased when adjusted for that factor. The idea was that if certain factors mediated the effect significantly, then a select population of older patients (without these offending factors) could still undergo CAS and expect to do well.
Plaque length and tortuosity increased with age. Plaque length, eccentric plaque, ulcerated plaque, and sequential plaque were associated with risk of periprocedural stroke or death. Symptomatic status of the stenotic vessel was not an effect modifier. Unfortunately, only plaque length met all the criteria: it increased with age, was associated with increased risk, and significantly mediated the effect of age. However, adjusting for plaque length decreased the hazard ratio from 1.72 to 1.66 (per 10-years in age), a decrease in the risk by only 8%. Based on this, we are unable to select older patients with short plaques safely for CAS.
This analysis was well done, but limited by the small number of event rates. As baseline MRIs were not done in CREST, baseline white matter disease could not be quantified and included, though this would be an interesting factor to consider, as it is expected to increase with age and potentially worsen outcomes. A critical factor to consider would be the composition of the plaques, as mentioned by the authors. If the plaque hardens with age, this may make the plaques less amenable to CAS, increasing the periprocedural risk. Using new techniques to visualize and quantify the plaque composition, we would be able to determine whether this plays a role, and perform a similar analysis to the one presented here.