In the current era of intensive medical therapy, carotid artery disease rarely progresses to occlusion and, when it does, patients’ risk of ipsilateral stroke is very low, according to an observational study published online September 21, 2015, ahead of print in JAMA Neurology.

In fact, endarterectomy and carotid stenting both carry higher stroke risk, say J. David Spence, MD, of Western University (London, Canada), and colleagues. “Progression of stenosis, although often touted as a reason for intervention, is of limited use in identifying patients who should have intervention,” they assert.

The researchers looked at 3,681 asymptomatic patients who underwent annual carotid ultrasound evaluation at the stroke prevention clinics of 2 Canadian hospitals between 1990 and 2012; the last date of follow-up was August 2014. They identified 316 patients (mean age 66.4 years; 71.2% men) who developed carotid occlusion that had not been seen on surveillance within the previous 18 months.

In this cohort of patients with new blockages, 77.8% were hypertensive and 68.4% had hyperlipidemia. Three patients had no significant plaque or stenosis before the index occlusion, suggesting that the occlusion may have been due to dissection or embolism. Prior asymptomatic occlusion on the contralateral side was present in 10 patients.

The proportion of patients who progressed to occlusion declined markedly after the implementation of more intensive medical therapy in 2002-2003, reaching a plateau of less than 0.1% in 2005.

Before the index occlusion, 13.3% of patients had a previous MI, 20.6% had diabetes, and 74.6% were current or former smokers. Patients with more severe stenosis were more likely to have diabetes and lower LDL levels than those with lesser degrees of artery narrowing. There were no differences in baseline characteristics between patients with vs without prior contralateral occlusion.

Stenosis Severity, Contralateral Occlusion Do Not Predict Outcome

One patient (0.32%) had an ipsilateral stroke at the time of occlusion, and 3 patients (0.9%) had such a stroke over a mean follow-up of 2.56 years. Overall, 71 patients died, at a mean 7.2 years after the index occlusion. In only 1 case was the cause of death determined to be stroke.

Even on the conservative assumption that all 16 deaths of unknown cause were due to stroke, in Kaplan-Meier analyses neither the severity of stenosis before occlusion nor previous contralateral occlusion predicted survival free of the combination of ipsilateral

stroke, ipsilateral TIA, or death from ipsilateral stroke or unknown cause (primary endpoint). Carotid plaque burden, measured as total plaque area, predicted reduced event-free survival (P = .006).

On Cox regression analysis, older age (P = .02), male sex (P = .01), and increased total plaque area (P = .006) predicted patients’ likelihood of experiencing a primary endpoint event.

“Among patients receiving intensive medical therapy, the risk of stroke at the time of a carotid occlusion is … much lower than the risk of intervention,” the authors say, noting that the 30-day rates of stroke or death in the CREST trial were 2.5% for stenting and 1.4% for endarterectomy and “much higher” in real-world practice.

Moreover, the current study confirms that the burden of carotid atherosclerosis is a stronger predictor of outcomes than percent stenosis, they say.

The authors suggest that the approximately 10% of patients with asymptomatic carotid stenosis who might benefit from endarterectomy can be identified by the presence of microemboli on transcranial Doppler ultrasound or by reduced cerebrovascular reserve. Other methods of singling out high-risk asymptomatic stenosis—such as ulceration on 3-D ultrasound, echolucency, or intraplaque hemorrhage on MRI—are under development, they add.

Data Support Need for CREST 2

In an accompanying editorial, Seemant Chaturvedi, MD, and Ralph L. Sacco, MD, MS, both of the University of Miami Miller School of Medicine (Miami, FL), observe that the randomized ACAS and ACST trials, which showed a 0.5% to 1% per year absolute reduction in ipsilateral stroke with endarterectomy vs medical therapy alone, have led to “a surge in carotid revascularization procedures in recent years.”

However, they add, the low rates of progression to occlusion and stroke in asymptomatic patients treated with contemporary medical therapy seen in the current study and other analyses “provide further support for the rationale of new trials to reassess the evidence for revascularization in such cases.”

Fortunately, Drs. Chaturvedi and Sacco say, the National Institute of Neurological Disorders and Stroke has funded the CREST 2 trial, which features parallel tracks comparing endarterectomy and carotid stenting with intensive medical management. They encourage neurologists and other clinicians to support enrollment in the trial “because our patients deserve to know whether carotid revascularization for asymptomatic stenosis is superior to contemporary medical therapies.”

Inference From Retrospective Data

But William A. Gray, MD, of Columbia University Medical Center (New York, NY), questioned the study findings and thus the premise of the authors’ arguments. “I don’t see good science here,” he told TCTMD in a telephone interview.

Though the investigators assert that medical therapy improved after 2002-2003 on the basis of plaque measurements, they do not document specific medication changes or correlate them with control of risk factors such as LDL or blood pressure, he said. Moreover, there is no guarantee that the populations treated before and after the initiation of intensive medical therapy were comparable.

“We already know that occlusion leads to stroke or TIA in only a minority of patients,” Dr. Gray said, but the study finding that only 1 in 316 patients had an ipsilateral stroke at the time of occlusion and only 3 did so over follow-up “raises a question in my mind about whether they had reasonable stroke surveillance. I would submit that they substantially underestimated because there was an ascertainment problem. [The incidence of] occlusion-related stroke should be about 10%. The 1% rate they observed is lower than anything that has ever been reported before.”

Dr. Gray also noted that in the ACST trial, endarterectomy reduced stroke risk by 50% over 5 years despite the fact that medical therapy improved substantially over the course of the study.

He granted that within the trial’s broad population of asymptomatic patients, some subgroups might have fared equally well with medical therapy, but he stressed that that possibility has not been evaluated in a prospective, randomized trial.

“My problem is that they take very poorly controlled retrospective data and draw inferences about the treatment paradigms that we should be following,” he concluded. “That should be left to prospective, randomized trials.”

Sources: 
1. Yang C, Bogiatzi C, Spence JD. Risk of stroke at the time of carotid occlusion. JAMA Neurol. 2015;Epub ahead of print.
2. Chaturvedi S, Sacco RL. Are the current risks of asymptomatic carotid stenosis exaggerated? Further evidence supporting the CREST 2 trial [editorial]. JAMA Neurol. 2015;Epub ahead of print.

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