Aggressive Medical Therapy Alone Is Not Adequate in Certain Patients With Severe Symptomatic Carotid Stenosis
- antihypertensive agents
- antiplatelet agents
- carotid stenosis
- clinical prediction rule
- transient ischemic attack
A 59-year-old woman presents 4 weeks after a transient ischemic attack (left-sided weakness). Carotid ultrasound shows 80% right internal carotid artery stenosis. She takes aspirin 81 mg and atorvastatin 20 mg daily.
Should the patient undergo carotid endarterectomy (CEA)?
Should clopidogrel be added to her therapy and the dose of atorvastatin increased to 80 mg instead of CEA?
Aggressive medical therapy alone is not adequate in certain patients with severe symptomatic carotid stenosis?
The results of the first European Carotid Surgery Trial (ECST) and the North American Symptomatic Carotid Endarterectomy Trial (NASCET) led to guidelines recommending carotid endarterectomy (CEA) for patients matching the trial characteristics, which are still current today. Thus, if you observe the guidelines, this patient should be referred for CEA. However, analysis of the trial data suggests that this is not necessarily the right decision. Rothwell et al1 developed a risk model using ECST data that predicted the future risk of stroke in patients allocated medical treatment alone and was validated in the NASCET dataset.1 The analyses showed that only patients with a 5-year risk of ipsilateral stroke of >20% benefited from CEA. The characteristics that predicted the risk of recurrent stroke included age, sex, symptom severity, time since symptoms, severity of stenosis, other vascular risk factors, and whether the stenosis was ulcerated, irregular, or smooth. A tool that uses this model is available online (http://www.stroke.ox.ac.uk/model/form1.html), and I have just used the tool to calculate the patient’s future risk of stroke. If I assume that she has a history of diabetes mellitus, myocardial infarction, and peripheral vascular disease and is found to be hypertensive and to have an irregular carotid plaque on imaging, then the model gives her a 1-year risk of ipsilateral stroke of 20% and a 5-year ipisilateral stroke risk of 45% if she is treated with medical therapy alone. The prediction assumes she would receive best medical therapy as applied in the original ECST and NASCET. However, even with modern intensive medical therapy, her risk is still likely to be substantially higher than the risks of surgery. Thus, if the model predicts such a high risk of stroke treated medically, she should certainly undergo CEA as soon as possible.
On the contrary, if I assume that the patient does not have a history of diabetes mellitus, myocardial infarction, or peripheral vascular disease and that her carotid plaque was smooth, the model gives her a much lower 1-year risk of ipsilateral ischemic stroke of <5% and a 5-year risk of <10%. These figures are so low that in this circumstance the risks of CEA are difficult to justify. All our patients with carotid stenosis are discussed at our multidisciplinary vascular meeting. I can hear an enthusiastic surgeon arguing that CEA is now so safe that surgery is justified even with such a low risk of stroke on medical treatment. It is true that the risks have declined, but the 30-day risk of stroke or death after CEA was still 3.4% in our recent trial, the International Carotid Stenting Study. Moreover, during the same time, medical treatment has improved substantially. Therefore, the data from ECST and NASCET used to calculate future stroke risk almost certainly overestimate the risk of recurrence with modern treatment, and if she has a low predicted risk of future stroke, she is likely to be better off avoiding surgery.
It might seem an attractive option to add clopidogrel to this woman’s aspirin. Combination antiplatelet therapy is effective at reducing asymptomatic embolization and probably reduces the rate of recurrent stroke in patients with carotid stenosis awaiting surgery.2 Recent results from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial also showed a benefit of aspirin plus clopidogrel given for 21 days after transient ischemic attack.3 However, there is undoubtedly an increased long-term risk of intracerebral hemorrhage in patients treated with aspirin plus clopidogrel, and this patient is now 4 weeks from her transient ischemic attack. Therefore, I would be inclined to swap her aspirin to clopidogrel or add dipyridamole to the aspirin rather than treat her with aggressive dual therapy.
The benefits of lowering cholesterol and blood pressure are probably greater than those of antiplatelet therapy. However, in the Heart Protection Study, simvastatin 40 mg daily reduced the risk of any major vascular event, but there was no significant reduction in stroke risk alone in patients with pre-existing cerebrovascular disease.4 In contrast, in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, patients with prior transient ischemic attack or stroke allocated high-dose atorvastatin 80 mg daily had a significant reduction in stroke risk. The benefit was particularly striking in those with known carotid stenosis.5 Simvastatin 40 mg is approximately equivalent to the atorvastatin 20 mg the patient is currently taking. Thus, it is logical to increase the dose of atorvastatin to 80 mg daily, as long as she does not develop side effects. I would also put her on a combination of a thiazide-type diuretic and an angiotensin-converting enzyme inhibitor. The perindopril protection against recurrent stroke study (PROGRESS) trial showed that this regime reduced the risk of recurrent stroke by ≈30%, even in nonhypertensive patients.6
Thus, I conclude that the patient should have her risk of future stroke assessed using the online prediction tool. If she has risk factors predicting a high risk of future stroke, she should have CEA. On the contrary, if she has a low future stroke risk, treating her with maximum medical therapy might reduce her risk of stroke down to ≈1% per year, obviating the need for CEA. I would put these figures to her, but I would explain that although the data suggest her risks may be low with medical treatment, there is considerable uncertainty about this because the model used to predict her risk of stroke is based on trials conducted >20 years ago. Moreover, although statins and blood pressure lowering are effective in the long term, we do not know whether they work quickly enough to prevent stroke from a recently symptomatic carotid plaque. I would, therefore, offer her randomization in the Second European Carotid Surgery Trial (http://www.ecst2.com). This is comparing optimized medical treatment alone versus optimized medical treatment plus immediate carotid revascularization in patients at low or intermediate risk of stroke, assessed using a recalibrated version of the risk model. As part of the trial, we would also image her carotid plaque using magnetic resonance and 3-dimensional ultrasound to see whether we can identify plaque characteristics that predict future stroke and surgical risk. When we have the results from the trial, this topic should no longer be controversial.
Dr Brown is the Chief Investigator of the Second European Carotid Surgery Trial (ECST-2) that is funded in the United Kingdom by the National Health Service (NHS) National Institute for Health Research (NIHR). University College London (UCL) receives additional funding for research on carotid stenosis from CORDA Preventing heart disease and stroke and the Department of Health’s NIHR Biomedical Research Centres funding scheme. Dr Brown’s Chair in Stroke Medicine at UCL is supported by the Reta Lila Weston Trust for Medical Research. Dr Brown has received consultancy fees and travel expense refunds from Bayer Healthcare to support membership of the ARRIVE trial Data Safety Monitoring Board.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part 1 of a 3-part article. Parts 2 and 3 appear on pages 2957 and 2959, respectively.
- Received March 30, 2013.
- Accepted August 6, 2013.
- © 2013 American Heart Association, Inc.
- Markus HS,
- Droste DW,
- Kaps M,
- Larrue V,
- Lees KR,
- Siebler M,
- et al
- Collins R,
- Armitage J,
- Parish S,
- Sleight P,
- Peto R
- Sillesen H,
- Amarenco P,
- Hennerici MG,
- Callahan A,
- Goldstein LB,
- Zivin J,
- et al