Improving imaging to optimize screening strategies for carotid artery stenosis

    Improving Imaging to Optimize Screening Strategies for Carotid Artery Stenosis Ankur Pandya, Ajay Gupta PII: DOI: Reference:

S0899-7071(15)00161-8 doi: 10.1016/j.clinimag.2015.07.004 JCT 7856

To appear in:

Journal of Clinical Imaging

Received date: Revised date: Accepted date:

31 March 2015 9 June 2015 6 July 2015

Please cite this article as: Pandya Ankur, Gupta Ajay, Improving Imaging to Optimize Screening Strategies for Carotid Artery Stenosis, Journal of Clinical Imaging (2015), doi: 10.1016/j.clinimag.2015.07.004

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Improving Imaging to Optimize Screening Strategies for Carotid Artery Stenosis

T

Ankur Pandya, PhD1 and Ajay Gupta, MD2,3 1

RI P

Department of Health Policy and Management, Harvard School of Public Health, Boston, MA, USA

2

SC

Department of Radiology, Weill Cornell Medical College, New York, NY, USA

3

NU

Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY USA

Email address for corresponding author: [email protected]

MA

Address for correspondence:

ED

Ankur Pandya, PhD

Assistant Professor of Health Decision Science

PT

Department of Health Policy and Management

CE

Center for Health Decision Science

AC

Harvard School of Public Health 718 Huntington Ave., 2nd Floor Boston, MA 02115

1

ACCEPTED MANUSCRIPT

Abstract Carotid stenosis is a major risk factor for ischemic stroke. Recently, the United States Preventive Services

RI P

T

Task Force issued a recommendation against screening for carotid stenosis in the general population. There is the potential for efficient risk-stratifying or staged screening approaches that identify

SC

individuals at highest risk for carotid stenosis and stroke, but these tools have yet to be proven effective in external validation studies. In this paper we review how medical imaging can be used to detect

NU

carotid stenosis and highlight several areas that could be improved to identify potentially efficient

AC

CE

PT

ED

MA

screening strategies for carotid stenosis.

2

ACCEPTED MANUSCRIPT

Background Stroke is a leading cause of mortality, morbidity, and healthcare costs in the United States and

RI P

T

across the globe.(1) Ischemic stroke, which occur as a result of blocked blood vessels to the brain, accounts for 90% of all strokes. Carotid stenosis, which is the narrowing of the carotid arteries, is

SC

responsible for approximately 20% of ischemic strokes. (2) Carotid stenosis can come to clinical attention most frequently when it gives rise to a stroke or transient ischemic attack ipsilateral to the

NU

side of vessel narrowing. In such cases of symptomatic carotid artery stenosis of greater than 50%

MA

luminal narrowing, several randomized controlled trials have demonstrated that revascularization of the narrowed carotid artery via carotid endarterectomy reduces the future risk of recurrent stroke (3-5).

ED

The guidelines for the management of asymptomatic carotid stenosis, however, are much more controversial, largely because of vast recent improvements in medical therapy which have brought into

PT

question the need for relatively riskier surgical treatments in such patients.(6, 7) Asymptomatic carotid artery stenosis (ACAS) is a significant public health concern as

CE

approximately 400,000 people in the United States are believed to harbor a significant asymptomatic

AC

carotid artery stenosis. ACAS often presents in one of two ways. First, in a primary care setting, it can be incidentally detected by an abnormal blowing or swishing sound (a “bruit”) heard by auscultating the carotid arteries with stethoscope. Perhaps more commonly, carotid stenosis can be detected by any number of imaging studies (Doppler ultrasound of the neck, CT angiogram of the neck, MR angiography, or cerebral angiogram) done for other purposes. Despite carotid stenosis being a major risk factor for stroke, the United States Preventive Services Task Force (USPSTF) recently issued a recommendation against screening for carotid stenosis in the general population.(8) We will summarize the evidence that led to the USPSTF recommendation and propose a potential roadmap to guide the imaging community to more actively engage in stroke prevention research in carotid disease.

3

ACCEPTED MANUSCRIPT Screening for ACAS in the general population The USPSTF authors performed a systematic review of carotid stenosis screening approaches to

T

inform their recommendation.(8) They focused their search on randomized controlled trials, systematic

RI P

reviews, and cohort studies for screening approaches for carotid stenosis. Their search resulted in three good quality meta-analyses and one fair quality primary cross-sectional study that evaluated the

SC

performance of carotid artery stenosis with duplex ultrasound.(9-12) The USPSTF authors judged quality

NU

based on threats to internal and external validity, which included issues related to patient selection, outcome assessment, inter-rater reliability, and the representativeness of patient population

MA

analyzed.(8)

The most recent good quality meta-analysis included 1,716 patients with degree of stenosis

ED

>50% and 2,140 patients with degree of stenosis >70%.(12) The test characteristics for duplex ultrasound were compared an angiography reference standard based on the North American

PT

Symptomatic Carotid Endarterectomy Trial (NASCET) method. Sensitivity for duplex ultrasound (95%

CE

confidence interval) for detecting >50% stenosis was 98% (97-100%) and specificity was 88 (76%-100%); for detecting >70% stenosis these values were 90% (84-94%) and 94% (88-97%), respectively. The other

AC

three studies also compared duplex ultrasound to the NASCET criteria as a reference standard, with sensitivity point estimates ranging from 86-97% and specificity point estimates ranging from 66-92%.(911) Despite the seemly strong test characteristics for duplex ultrasound for detecting carotid stenosis, the USPSTF recommended against general ACAS screening in part due to a low underlying prevalence of carotid stenosis in asymptomatic adults. Sensitivity and specificity are conditional on presence or absence of the disease of interest; the probability of having the disease (i.e., ACAS) conditional on a positive test results depends on both the operating characteristics (i.e., sensitivity and specificity) of the test and the general overall prevalence of the disease. Therefore, a positive duplex

4

ACCEPTED MANUSCRIPT ultrasound result could still imply that the updated risk of having ACAS is too low, and that there are too many false positive test results, to justify screening for ACAS in the general population.

T

Staged screening approaches for ACAS in the general population

RI P

There are two ways staged screening approaches can potentially reduce the number of false positive ACAS findings: 1) limiting general population ACAS screening to individuals to high-risk

SC

individuals (based on clinical characteristics); and 2) second line testing to confirm positive test results

NU

from initial carotid duplex ultrasound studies. We summarize the evidence for each approach below. Unfortunately, the USPSTF authors did not find enough compelling evidence to recommend either

MA

staged screening approach.

There was one risk-stratification tool that met the USPSTF inclusion criteria, which externally

ED

validated a clinical risk score to identify patients at high risk for ACAS.(13) The study used data from the Cardiovascular Health Study (CHS) to assess the performance of a risk score (based on age >65 years,

PT

current smoking status, coronary heart disease, hypercholesterolemia, and hypertension)(14) that

CE

predicted ACAS (>50% and >75% as determined by carotid Doppler ultrasound) in the general population. The risk score had a c-statistic of 0.60 for both >50% and >75% carotid stenosis (with 95%

AC

confidence intervals of 0.56-0.64 and 0.52-0.68, respectively), which is higher than a useless test (which would have a c-statistic of 0.50) but still far from a theoretically perfect test (c-statistic of 1.0). Angiography could be used as a second-line test to confirm positive test results from initial carotid duplex ultrasound studies, which could reduce the number of false positive findings.(15) The problem with this approach is that angiography carries a stroke risk of 0.4-1.2% itself, which is close to the annual rate of stroke for ACAS patients.(7) ] Less invasive imaging techniques, such as CT angiography or MR angiography, would be more commonly used second-line tests instead of conventional catheter angiography nowadays in most imaging centers, but even these less invasive tests carry their own risks (such as renal dysfunction) and imperfect specificity.(15, 16)

5

ACCEPTED MANUSCRIPT Risk-stratifying individuals with ACAS for stroke risk As discussed in the preceding sections, the value of detecting new ACAS cases in the general

T

population is largely dependent on the ability to identify the subgroup of patients most likely to develop

RI P

future stroke. If this subgroup of ACAS could be reliably identified, then a more systematic effort to screen in either the general population or in a targeted fashion might be warranted. As of 2015, the best

SC

estimates of annual stroke risk in carotid stenosis of ≥50% is on the order of approximately 1% per year

NU

in patients on intensive medical therapy, which the most recent data suggesting that the annual risk may even be less than 1%. (6, 7, 17) Clearly, the use of luminal stenosis measures alone as an imaging

MA

risk biomarker is inadequate to isolate the subset of asymptomatic carotid stenosis patients most likely to develop ipsilateral stroke and in whom revascularization procedures might be most beneficial.

ED

Advances in neuroimaging in recent years have allowed a much more detailed and mechanistic assessment of stroke risk in carotid artery disease. The two main pathophysiologic factors contributing

PT

to stroke risk in carotid disease are plaque instability and hemodynamic impairment.(18) There is

CE

converging evidence that stroke risk assessment can be improved in carotid disease patients using techniques which interrogate these more specific risk features which provide data beyond luminal

AC

stenosis. For example, there are recent meta-analyses of nonrandomized prospective observational studies showing that impairment in the brain’s cerebrovascular reserve, detectable with transcranial Doppler techniques, confers a 3 to 4-fold increased risk of ipsilateral stroke amongst patients with carotid artery stenosis(19, 20). Similarly, meta-analyses of nonrandomized observational studies of patients obtaining high resolution MRI of carotid plaque has shown similar future prognostic value in stroke prediction.(21, 22) For example, the presence of complicated atherosclerotic lesions containing intraplaque hemorrhage, lipid-rich necrotic core, or fibrous cap abnormalities appears to confer a 3 to 6fold increased risk of future stroke in patients with hemodynamically significant carotid stenosis. Even when relatively simple-to-assess measures of plaque vulnerability such as the predominance of

6

ACCEPTED MANUSCRIPT echolucent (rather than echorich) plaque are present in patients with ≥50% stenosis, such plaque features are associated with a ~2.5 times increase relative risk of stroke.(23) Similarly, more recent

T

studies are revisiting the potential value of extracting plaque risk information from routinely acquired

RI P

cross-sectional MR angiography and CT angiography studies, which also hold significant promise as potential stroke risk assessment tools once cases of carotid stenosis are actually identified.(24-28)

SC

These emerging data suggest that these newer technologies are potentially effective and cost-

NU

effective stroke risk predictors.(29) Further validation with randomized controlled treatment trials and/or high quality observational cohort studies on patients receiving modern intensive medical therapy

approaches into clinical practice.(17)

MA

are needed to validate these techniques and provide enough evidence to routinely integrate these

ED

Stroke prevention and the optimal role for imaging

All of the providers that deal with carotid stenosis (including neuroradiologists, neurologists,

PT

vascular surgeons) should share the same goal, which is to prevent strokes.(30) At a policy level,

CE

however, the ultimate goal for carotid stenosis imaging should be to develop a screening algorithm that leads to the optimal balance of true positives and true negatives in terms of overall health benefits,

AC

risks, and healthcare costs. The USPSTF recommendations on carotid stenosis screening resonate with these policy goals. In their conclusion, the USPSTF authors highlighted the uncertain benefit-risk profile of revascularization options for carotid stenosis patients and the low prevalence of carotid stenosis and stroke in this population as driving forces behind their Grade D recommendation for carotid stenosis screening. In other words, the overall value of detecting carotid stenosis – even for imaging tests with high sensitivity and specificity values – is directly tied to the prior risk of disease and uncertainty surrounding the clinical decision at hand (medical therapy versus revascularization). If medical therapy is safer, cheaper, and (arguably) just as effective as revascularization for asymptomatic patients, then there is no value of information from carotid stenosis screening.

7

ACCEPTED MANUSCRIPT Does this mean that radiologists should abandon carotid screening as an area of clinical investigation? Our simple answer is no. Consider the following quote from the USPSTF statement: “If

T

externally validated, reliable risk-stratification tools were available…” “then the ratio of true-positive

RI P

results to false-positive results would improve.” The USPSTF authors went on to note that external validation studies for targeted imaging approaches were lacking. In theory, focusing general population

SC

screening on individuals that are most likely to have carotid stenosis would save imaging costs and

NU

reduce false positive carotid stenosis cases. Similarly, identifying carotid stenosis patients who are most likely to have a stroke could be used to target revascularization procedures on patients most likely to

MA

benefit, thus resulting in a better benefit-risk ratio compared to less selective revascularization strategies. These approaches might be cost-effective(29) but they did not meet the external validation

ED

eligibility criterion to be considered as part of the USPSTF recommendation.(8) Carotid stenosis imaging researchers should therefore focus on establishing the reliability of

PT

their risk-stratifying approaches to avoid the problem of developing a multitude of potentially useful

CE

tools, none of which are trusted enough to be used in general clinical practice. Additionally, although stroke prevention decisions are traditionally handled by non-radiologists, radiologists should consider

AC

the magnitude of patient stroke risk and the relevant treatment alternatives before recommending or performing carotid stenosis screening tests. If the results of the imaging tests do not change the optimal stroke prevention strategy, there is no value to the carotid stenosis screening. On the other hand, if riskstratifying can efficiently select patients for more (revascularization) and less (medical therapy or do nothing) invasive management strategies, then radiologists can use carotid stenosis screening as an example of how imaging can produce high-value care that has the potential to improve patient outcomes while controlling healthcare costs.(31)

8

ACCEPTED MANUSCRIPT References

AC

CE

PT

ED

MA

NU

SC

RI P

T

1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Executive summary: heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation. 2014;129(3):399-410. 2. Petty GW, Brown RD, Jr., Whisnant JP, Sicks JD, O'Fallon WM, Wiebers DO. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke; a journal of cerebral circulation. 1999;30(12):2513-6. 3. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. The New England journal of medicine. 1991;325(7):445-53. 4. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet. 1998;351(9113):1379-87. 5. Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. The New England journal of medicine. 1998;339(20):1415-25. 6. Abbott AL. Medical (nonsurgical) intervention alone is now best for prevention of stroke associated with asymptomatic severe carotid stenosis: results of a systematic review and analysis. Stroke; a journal of cerebral circulation. 2009;40(10):e573-83. 7. Raman G, Moorthy D, Hadar N, Dahabreh IJ, O'Donnell TF, Thaler DE, et al. Management strategies for asymptomatic carotid stenosis: a systematic review and meta-analysis. Annals of Internal Medicine. 2013;158(9):676-85. 8. Jonas DE, Feltner C, Amick HR, Sheridan S, Zheng ZJ, Watford DJ, et al. Screening for Asymptomatic Carotid Artery Stenosis: A Systematic Review and Meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2014. 9. Sabeti S, Schillinger M, Mlekusch W, Willfort A, Haumer M, Nachtmann T, et al. Quantification of internal carotid artery stenosis with duplex US: comparative analysis of different flow velocity criteria. Radiology. 2004;232(2):431-9. 10. Nederkoorn PJ, van der Graaf Y, Hunink MG. Duplex ultrasound and magnetic resonance angiography compared with digital subtraction angiography in carotid artery stenosis: a systematic review. Stroke; a journal of cerebral circulation. 2003;34(5):1324-32. 11. Blakeley DD, Oddone EZ, Hasselblad V, Simel DL, Matchar DB. Noninvasive carotid artery testing. A meta-analytic review. Ann Intern Med. 1995;122(5):360-7. 12. Jahromi AS, Cina CS, Liu Y, Clase CM. Sensitivity and specificity of color duplex ultrasound measurement in the estimation of internal carotid artery stenosis: a systematic review and metaanalysis. J Vasc Surg. 2005;41(6):962-72. 13. Suri MF, Ezzeddine MA, Lakshminarayan K, Divani AA, Qureshi AI. Validation of two different grading schemes to identify patients with asymptomatic carotid artery stenosis in general population. J Neuroimaging. 2008;18(2):142-7. 14. Jacobowitz GR, Rockman CB, Gagne PJ, Adelman MA, Lamparello PJ, Landis R, et al. A model for predicting occult carotid artery stenosis: screening is justified in a selected population. J Vasc Surg. 2003;38(4):705-9. 15. Weyer GW, Davis AM. Screening for asymptomatic carotid artery stenosis. Jama. 2015;313(2):192-3. 16. Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary. A 9

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

MA

NU

SC

RI P

T

report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Circulation. 2011;124(4):489-532. 17. Abbott AL, Nicolaides AN. Improving Outcomes in Patients With Carotid Stenosis: Call for Better Research Opportunities and Standards. Stroke; a journal of cerebral circulation. 2014. 18. Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Archives of Neurology. 1998;55(11):1475-82. 19. Reinhard M, Schwarzer G, Briel M, Altamura C, Palazzo P, King A, et al. Cerebrovascular reactivity predicts stroke in high-grade carotid artery disease. Neurology. 2014. 20. Gupta A, Chazen JL, Hartman M, Delgado D, Anumula N, Shao H, et al. Cerebrovascular reserve and stroke risk in patients with carotid stenosis or occlusion: a systematic review and meta-analysis. Stroke; a journal of cerebral circulation. 2012;43(11):2884-91. 21. Saam T, Hetterich H, Hoffmann V, Yuan C, Dichgans M, Poppert H, et al. Meta-analysis and systematic review of the predictive value of carotid plaque hemorrhage on cerebrovascular events by magnetic resonance imaging. Journal of the American College of Cardiology. 2013;62(12):1081-91. 22. Gupta A, Baradaran H, Schweitzer AD, Kamel H, Pandya A, Delgado D, et al. Carotid plaque MRI and stroke risk: a systematic review and meta-analysis. Stroke; a journal of cerebral circulation. 2013;44(11):3071-7. 23. Gupta A, Kesavabhotla K, Baradaran H, Kamel H, Pandya A, Giambrone AE, et al. Plaque echolucency and stroke risk in asymptomatic carotid stenosis: a systematic review and meta-analysis. Stroke; a journal of cerebral circulation. 2015;46(1):91-7. 24. Gupta A, Baradaran H, Kamel H, Mangla A, Pandya A, Fodera V, et al. Intraplaque high-intensity signal on 3D time-of-flight MR angiography is strongly associated with symptomatic carotid artery stenosis. AJNR American journal of neuroradiology. 2014;35(3):557-61. 25. Qiao Y, Etesami M, Malhotra S, Astor BC, Virmani R, Kolodgie FD, et al. Identification of intraplaque hemorrhage on MR angiography images: a comparison of contrast-enhanced mask and time-of-flight techniques. AJNRAmerican journal of neuroradiology. 2011;32(3):454-9. 26. Gupta A, Mtui EE, Baradaran H, Salama G, Pandya A, Kamel H, et al. CT Angiographic Features of Symptom-Producing Plaque in Moderate-Grade Carotid Artery Stenosis. AJNR American journal of neuroradiology. 2015;36(2):349-54. 27. Trelles M, Eberhardt KM, Buchholz M, Schindler A, Bayer-Karpinska A, Dichgans M, et al. CTA for screening of complicated atherosclerotic carotid plaque--American Heart Association type VI lesions as defined by MRI. AJNRAmerican journal of neuroradiology. 2013;34(12):2331-7. 28. Gupta A, Baradaran H, Kamel H, Pandya A, Mangla A, Dunning A, et al. Evaluation of computed tomography angiography plaque thickness measurements in high-grade carotid artery stenosis. Stroke; a journal of cerebral circulation. 2014;45(3):740-5. 29. Pandya A, Gupta A, Kamel H, Navi BB, Sanelli PC, Schackman BR. Carotid Artery Stenosis: Costeffectiveness of Assessment of Cerebrovascular Reserve to Guide Treatment of Asymptomatic Patients. Radiology. 2015;274(2):455-63. 30. Naylor AR. A surgeon's view on endarterectomy and stenting in 2011: lest we forget, it's all about preventing stroke. Cardiovascular and interventional radiology. 2012;35(2):225-33. 31. Seltzer SE, Lee TH. The transformation of diagnostic radiology in the ACO era. Jama. 2014;312(3):227-8.

10