More CREST Controversy: How Relevant Is Age in Treatment Decisions?

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Patients aged 64 and older appear to have an increasing risk of stroke with carotid artery stenting (CAS) that is not seen with carotid endarterectomy (CEA). The findings, from a subanalysis of the CREST trial, suggest that age may be an important component when discussing treatment options for patients with significant carotid stenosis. The paper was published online October 6, 2011, ahead of print in Stroke.

The main CREST (Carotid Revascularization Endarterectomy vs. Stenting Trial) study randomized 2,502 patients with symptomatic or asymptomatic disease to CEA or CAS. Overall, there was no difference in the estimated 4-year rates of the primary endpoint (composite of periprocedural stroke, MI, or death, or the incidence of ipsilateral stroke ≤ 4 years) between the 2 groups. However, there was a higher risk of stroke with stenting and a higher risk of MI with surgery.

Several previous substudies from CREST have been published, including those looking at gender and quality of life. For the newest subanalysis, researchers led by Thomas G. Brott, MD, of the Mayo Clinic (Jacksonville, FL), assessed the impact of age on relative efficacy of the 2 treatment options. The treatment groups were stratified into tertiles by age:

• Less than 65 (CAS, n = 404; CEA, n = 387)
• 65 to 74 (CAS, n = 525; CEA, n = 500)
• 75 or older (CAS, n = 333; CEA, n = 353)

Risk Increases with Age for CAS But Not CEA

For the primary endpoint at 4 years, there was evidence that age modified the treatment effect (P = 0.02). The relative risk of events increased with advancing age in CAS patients but remained mostly stable in CEA patients (table 1).

Table 1. Primary Endpoint at 4 Years

This increasing risk was driven by stroke, with a higher (P = 0.033) CAS vs. CEA risk across age groups. Stroke rates increased with age in the CAS group but not in the CEA group (table 2).

Table 2. Stroke at 4 Years

A similar pattern was observed during the periprocedural period for both the composite and stroke endpoints. However, these trends failed to reach statistical significance (P > 0.1)

On an interactivity analysis, the risk of the 2 procedures for the primary endpoint was approximately equal at age 70 years, with CAS showing superiority in younger patients and an increasing benefit for CEA in older patients. The risk for stroke was approximately equal at age 64.

In the CAS group, there was a 77% increase in risk of the primary endpoint (P < 0.0001; 95% CI 1.38-2.28) and a 76% increase (95% CI 1.35-2.31) in stroke events with each 10-year age increment. The effect of age was not mediated by differences in the prevalence of hypertension, diabetes, or dyslipidemia, or by differences in lesion characteristics or procedure duration.

In the CEA group, there was no evidence of any difference in risk across age groups for the primary endpoint (HR 1.16; 95% CI 0.89-1.50; P = 0.27) or for stroke (HR 1.12; 95% CI 0.82-1.54; P = 0.47).

Although degree of arterial tortuosity and lesion calcification were not available, the authors hypothesize that “the risk of embolization during CAS is increased during navigation of tortuous extracranial arteries, particularly in patients with heavily calcified vessels and ‘extended’ type II and III aortic arches.” This is bolstered, they add, by a longer observed fluoroscopy time in the elderly. 

Risk Assessment More Important Than Age

But Christopher J. White, MD, of the Ochsner Heart and Vascular Institute (New Orleans, LA), told TCTMD in a telephone interview that it would be a misinterpretation of the data to choose a cutoff for CAS based on age alone.

“We should not look at this and say [to a patient], ‘Oh, you are 2 days past age 64 and therefore you can’t have a stent,’” he said. “What this says is that there is something about the elderly that puts them at higher risk and something about younger folks that makes them do better. But individual risk assessment is still the key here. I prefer to think of this as a reminder that [clinicians] should be thinking about surgery in their older patients. But at the same time, you may have a 50-year-old who is better suited for surgery than a stent.”

Dr. White said that while the authors are correct about artery tortuosity hindering stenting, it is not true of all elderly patients.

“There are plenty of elderly patients who have healthy vessels that are not tortuous and not calcified,” he said. “There are ways to identify that, which is why you have to be selective and you have to be highly skilled. But it’s been shown over and over again that elderly patients can be treated safely [with stents].”

Exploratory at Best 

In a telephone interview with TCTMD, William A. Gray, MD, of Columbia University Medical Center (New York, NY), went even further in his criticism of the study, pointing out that the analysis was pre-planned, though not pre-specified.

“In a pre-specified analysis, all the questions, all the methodology, are defined before the study begins,” he said. “A pre-planned analysis doesn’t have to include specifics about how or what you are going to look at…it’s much more open to the potential for bias. Therefore, the statistical assumptions in this study should be considered exploratory and at best hypothesis-generating.”

Dr. Gray added that looking at the age data in tertiles, as the study authors did, is only the “bare minimum” needed to establish what would otherwise be considered a trend. In addition, the study authors used “best fit lines” to illustrate hazard, which Dr. Gray said is too simplistic for data such as these.

“We have done similar exploratory analyses that were presented to FDA looking at 5-year increments in age and we found no difference in outcomes by age,” he said. “In fact, over the age of 80, the hazard ratio for stenting and surgery was 1.00.”

According to Dr. Gray, the subanalysis provides no evidence to back the authors’ assertion that age should be a factor in deciding treatment.

“It’s wrong to conclude that from these data,” he said. “I’m not saying stenting is without risk, but this study does not give us definitive answers and does not appropriately address questions of age.” 

 

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Source:
Voeks JH, Howard G, Roubin GS, et al. Age and outcomes after carotid stenting and endarterectomy. The Carotid Revascularization Endarterectomy versus Stenting Trial. Stroke. 2011;Epub ahead of print.

 

 

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• CREST QOL Substudy: Early Advantage with Carotid Stenting Disappears Long-Term
• CREST Subanalysis Stirs Controversy Regarding Possible Gender Differences
• CREST Trial Results Continue to Cause Controversy