Asymptomatic Carotid Disease

Introduction to asymptomatic carotid disease

Carotid artery disease can cause strokes and ministrokes (transient ischaemic attacks, TIAs). Once symptoms such as strokes and TIAs have developed and they are caused by narrowing in the carotid artery, it seems obvious that surgery to correct the narrowing is likely to be helpful.  This is correct in patients with greater than 50% narrowing of the carotid artery where carotid surgery and has been proven in large trials to be beneficial if undertaken in a timely fashion.

The next logical step is to suggest that it might be helpful to perform surgery to a narrowed carotid artery before any symptoms develop.  This also sounds like a logical extension of what we already know is beneficial to patients, but it is important to be sure that patients undergoing surgery really do benefit.  It is important not to forget that surgery has its own risks.

What is the risk of stroke in asymptomatic carotid disease?

This is crucial information in patients with no symptoms.  If patients had no risk of stroke from having a narrowing in the carotid artery then there would be nothing to gain from surgery.  As the risk of stroke increases there is obviously more to gain from surgery.

In the European Trial of symptomatic patients undergoing surgery, the investigators took the opportunity to examine the risks of stroke in the opposite carotid artery, that was not causing symptoms.  In this study, 2,295 patients were followed for 4.5 years.  In patients with the most severe narrowing, only 5.7% (5-6 in every 100) of patients suffered a stroke over 3 years.  There were only 9 fatal strokes in 2,295 patients over 3 years.

It is clear from this and many other studies that most patients with narrowing of the carotid artery and no symptoms will not have a stroke and even fewer will die because of their problem.

Can surgery reduce the stroke risk even further?

There are two major trials that have examined the effect of surgery to the carotid artery on the risk of subsequent stroke.  They are the Asymptomatic Carotid Atherosclerosis Study (ACAS) and the Asymptomatic Carotid Surgery Trial (ACST).

The ACAS study

The Asymptomatic Carotid Atherosclerosis Study (ACAS) was the first major study examining the role of carotid surgery in patients without symptoms.  This study reported in 1995 and looked at the benefits of surgery in patients with narrowing in the carotid artery in the range 60-99%.

The study showed that over 5 years the risk of stroke or stroke and death, caused by narrowing in the affected artery were reduced from 11% to 5.1%.  This means that only 5 patients in every hundred having surgery suffered a stroke or death over 5 years compared with 11 patients in every hundred in the group without surgery.  In other words the chances of having a stroke or dying over 5 years was halved, but the absolute risk of having a stroke is actually very low (approximately only a 1 in 10 risk of stroke over 5 years OR a 9 of 10 (90%) chance of not having a stroke over 5 years).  There was no evidence of any more or less benefit as the narrowing approached 99%.

The ACST study

The Asymptomatic Carotid Surgery Trial (ACST) reported 5 year results in the Lancet in May 2004. Comparing all patients without symptoms allocated immediate carotid endarterectomy (for 60-99% stenosis) versus all those allocated non-surgical management the net 5 year risk was 6.4% for all strokes or death in patients having carotid endarterectomy versus 11.8% with no surgery.  This was a net absolute gain of 5.4% (relative risk reduction 46%) and was a highly statistically significant benefit for surgery even with the risks attached to surgery.  The ACST trial also showed that patients having carotid endarterectomy were much less likely to have a fatal or disabling stroke (3.5% in the surgical group versus 6.1% in the no surgery group). 

Various subgroups of patients were analysed separately.  In men under the age of 75 years the benefit of surgery was clear cut (8.2% decrease in 5 year risk of stroke with surgery from 10.6% to 2.4%).  There were benefits in women, but these were less (4.1% decrease in 5 year risk of stroke with surgery from 7.5% to 3.4%). Continuing follow up studies indicate there is a clear benefit for women which appears close to or equivalent to the benefits for men.

The ACST study essentially confirms and extends the findings of the ACAS trial.  ACST confirms there is overall benefit from carotid surgery in patients with asymptomatic carotid narrowing of 60-99%.  It also shows that there is most benefit in patients under the age of 75 years.  In patients over the age of 75 years potential benefits are uncertain.  Probably most importantly the ACST study clearly showed a reduction in the risk of fatal or disabling stroke with carotid surgery.  The two studies together provide very strong evidence of a benefit for carotid surgery in selected patients with asymptomatic carotid disease.  Although many surgeons prefer to wait before intervening in asymptomatic carotid disease until the stenosis is greater than 70 or 80% there is little justification from these trials for that approach as they included patients with stenoses greater than 60%.

Are there problems with the asymptomatic trials?

There are no serious problems with ACAS or ACST in terms of trial design.  They are both well designed and conducted studies.  However, in every trial, no matter how well designed, there are points of interpretation and methodology that can be debated.

Data from ACAS indicate that only 21% of Duplex ultrasound machines attained acceptable sensitivity for the prediction of a 60% stenosis (Howard G et al, 1996). In ACAS most patients underwent angiography prior to surgery.  In 27 patients the narrowing in the carotid artery was found to be less than 60% at angiography (despite previous ultrasound examination) and these patients did not undergo surgery.  However, there were some problems associated with angiography in 1.2% of patients.  In the ACST study few patients, especially in later years, underwent angiography and the accuracy of a Duplex only approach can be questioned.  Whichever techniques are used to assess carotid stenosis they need to be reliable and consistent.

Patients in the ACST trial were eligible for inclusion if the carotid narrowing had not caused a stroke or TIA in the previous 6 months.  This does sound reasonable but patients who have previously had a stroke or TIA remain at a higher risk than true asymptomatic patients for up to 3 years after their initial stroke.  This was shown in the symptomatic carotid trials.  In the ACST study, 373 patients with previous symptoms more than 6 months before entry, were enrolled.  Surprisingly, carotid surgery did not make a statistically significant difference in this group, supposedly at higher risk than patients without any previous symptoms. This may be because there were insufficient patients to demonstrate significant differences, but this is nonetheless surprising.

The risk of stroke caused by disease in the affected artery was clearly reduced in the ACAS trial.  However, if ALL strokes and deaths or ALL major strokes and deaths were compared (surgery patients versus no surgery patients), and not just strokes/death related to the affected artery, then there was no proven benefit at 3 years.  In other words after 3 years there were just as many major strokes and deaths in the patients having carotid surgery as there were in the patients who did not undergo surgery.  The ACST study with larger numbers of patients was subsequently able to show a reduction in 5 year risk of peri-operative death or stroke death (2.1% with carotid surgery versus 4.2% with no surgery).  Surprisingly, the ACST study was able to demonstrate a difference not only in strokes on the side of the operated artery, but also in strokes from the opposite artery.

What is the real benefit of surgery in asymptomatic carotid disease?

In the ACAS trial surgical risk was very low and surgeons were very careful in patient selection e.g. 25 patients were screened for every one patient entered into the trial.  Trial findings may not always translate into similar actual benefits for individuals.  If we accept that all the benefits of the trial could be gained in the community, the ACAS authors rightly point out in their commentary, that 19 patients would require carotid surgery to prevent one stroke over 5 years.  Some authors (Benavente O et al. 1998 and Barnett HJM, 2004) suggest up to 50 patients or more would require carotid surgery to prevent one stroke (minor or major).

There is now good evidence to support the use of carotid endarterectomy in patients without symptoms, but only in carefully selected patients.  It is also important that patients considering carotid surgery understand their true risk of suffering a stroke. 

The statistics can be confusing but there is a 95% chance that operating in patients with asymptomatic disease will produce NO benefit, even though relatively the risk of further stroke is reduced by 50% (11% to 5%).  On an annual basis carotid endarterectomy for asymptomatic disease will reduce the risk of stroke from 2 chances in 100 down to 1 chance in 100.

Patients under the age of 75 years are most likely to benefit from carotid surgery in asymptomatic disease.

Despite all the information from the trials there is an increasing weight of evidence that with modern drug treatment of vascular risk factors the current risk of stroke in asymptomatic patients has dropped significantly and that surgery may have minimal benefit. This is particularly so for women who are unlikely to benefit from surgery when they have no symptoms. There is no definitive trial since 2004 that reverses the findings from the previous studies so my view is that surgery for asymptomatic disease still has a place. It is most useful in men under the age of 75 years who are reasonably fit and expected to live a further 4-5 years.

Useful links

http://neurosurgery.mgh.harvard.edu/neurovascular/cea.htm

http://general-medicine.jwatch.org/cgi/content/full/2011/915/1

References

The European Carotid Trialists Collaborative Group. Risk of stroke in the distribution of an asymptomatic carotid artery. Lancet 1995; 345: 209-212.
Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273: 1421-1428.
MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet 2004; 363: 1491-502.
Howard G, Baker WH, Chambless LE, Howard VJ, Jones AM, Toole JF et al. An approach for the use of Doppler ultrasound as a screening tool for hemodynamically significant stenosis (despite heterogeneity of Doppler performance). Stroke 1996;27:1951-1957.
Benavente O, Moher D, Pham B. Carotid endarterectomy for asymptomatic carotid stenosis: a meta-analysis. Brit Med J 1998; 317: 1477-1480.
Barnett HJM. Carotid endarterectomy. Lancet 2004; 363: 1486-87.