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Screening for Asymptomatic Carotid Artery Stenosis: A Systematic Review and Meta-analysis for the U.S. Preventive Services Task ForceScreening for Carotid Artery Stenosis FREE

Daniel E. Jonas, MD, MPH; Cynthia Feltner, MD, MPH; Halle R. Amick, MSPH; Stacey Sheridan, MD, MPH; Zhi-Jie Zheng, MD, MPH, PhD; Daniel J. Watford, MD, MPH; Jamie L. Carter, MD, MPH; Cassandra J. Rowe, MPH; and Russell Harris, MD, MPH
[+] Article and Author Information

This article was published online first at www.annals.org on 8 July 2014.


From Cecil G. Sheps Center for Health Services Research and Gillings School of Global Public Health, University of North Carolina, and University of North Carolina School of Medicine, Chapel Hill, and Research Triangle Institute International, Research Triangle Park, North Carolina.

Disclaimer: The views expressed in this article do not represent and should not be construed to represent a determination or policy of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Acknowledgment: The authors thank the following persons for their support, commitment, and contributions to this project: Tracy Wolff, MD, MPH, Agency for Healthcare Research and Quality Medical Officer; Kirsten Bibbins-Domingo, PhD, MD, Jessica Herzstein, MD, MPH, and Michael LeFevre, MD, MSPH, U.S. Preventive Services Task Force leads; Evelyn Whitlock, MD, MPH, Kaiser Permanente Research Affiliates Evidence-based Practice Center Director; Tracy Beil, MS, Kaiser Permanente Research Affiliates Evidence-based Practice Center; Carol Woodell, BSPH, Research Triangle Institute–University of North Carolina Evidence-based Practice Center Project Manager; Meera Viswanathan, PhD, Research Triangle Institute–University of North Carolina Evidence-based Practice Center Director; Christiane Voisin, MSLS, Evidence-based Practice Center Librarian; Claire Baker, research assistant; Laura Small, Evidence-based Practice Center editor; and Loraine Monroe, Evidence-based Practice Center publications specialist.

Financial Support: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services (contract HHSA290201200015iTO2).

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0530.

Requests for Single Reprints: Daniel E. Jonas, MD, MPH, Department of Medicine, University of North Carolina at Chapel Hill, 5034 Old Clinic Building, CB 7110, Chapel Hill, NC 27599; e-mail, daniel_jonas@med.unc.edu.

Current Author Addresses: Drs. Jonas, Feltner, and Sheridan: Department of Medicine, University of North Carolina at Chapel Hill, 5034 Old Clinic Building, CB 7110, Chapel Hill, NC 27599.

Ms. Amick, Drs. Carter and Harris, and Ms. Rowe: Cecil G. Sheps Center for Health Services Research, CB 7590, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7590.

Dr. Zheng: Research Triangle Institute International, 6110 Executive Boulevard, Suite 902, Rockville, MD 20852-3907.

Dr. Watford: Jackson Memorial Hospital, 1611 Northwest 12th Avenue, Miami, FL 33136-1096.

Author Contributions: Conception and design: D.E. Jonas, C. Feltner, H.R. Amick, S. Sheridan, Z.J. Zheng, J.L. Carter, R. Harris.

Analysis and interpretation of the data: D.E. Jonas, C. Feltner, H.R. Amick, S. Sheridan, Z.J. Zheng, D.J. Watford, J.L. Carter, R. Harris.

Drafting of the article: D.E. Jonas, C. Feltner, H.R. Amick, S. Sheridan, Z.J. Zheng, D.J. Watford.

Critical revision of the article for important intellectual content: D.E. Jonas, C. Feltner, H.R. Amick, S. Sheridan, Z.J. Zheng, D.J. Watford, J.L. Carter, R. Harris.

Final approval of the article: D.E. Jonas, C. Feltner, S. Sheridan, Z.J. Zheng, R. Harris.

Provision of study materials or patients: Z.J. Zheng.

Statistical expertise: D.E. Jonas, C. Feltner.

Obtaining of funding: D.E. Jonas.

Administrative, technical, or logistic support: D.E. Jonas, C. Feltner, H.R. Amick, Z.J. Zheng, D.J. Watford, C.J. Rowe.

Collection and assembly of data: D.E. Jonas, C. Feltner, H.R. Amick, S. Sheridan, Z.J. Zheng, D.J. Watford, J.L. Carter, C.J. Rowe.


Ann Intern Med. 2014;161(5):336-346. doi:10.7326/M14-0530
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Background: Approximately 10% of ischemic strokes are caused by carotid artery stenosis (CAS). Estimated prevalence of asymptomatic CAS is 1%.

Purpose: To evaluate evidence on screening and treating asymptomatic adults for CAS.

Data Sources: MEDLINE, the Cochrane Library, EMBASE, and trial registries through September 2013; MEDLINE through March 2014 for trials.

Study Selection: Good- or fair-quality trials of screening, carotid endarterectomy (CEA), or stenting compared with medical therapy or of intensification of medical therapy; systematic reviews; multi-institution studies reporting harms; and externally validated risk-stratification tools.

Data Extraction: Dual extraction and quality assessment.

Data Synthesis: No trials compared screening with no screening or stenting with medical therapy or assessed intensification of medical therapy, and no externally validated, reliable risk-stratification tools were found. Given the specificity of ultrasonography (range, 88% to 94% for CAS ≥50% to ≥70%), its use in low-prevalence populations would yield many false-positive results. Absolute reduction of nonperioperative strokes was 5.5% (95% CI, 3.9% to 7.0%; 3 trials; 5223 participants) over approximately 5 years for CEA compared with medical therapy. The 30-day rates of stroke or death after CEA in trials and cohort studies were 2.4% (CI, 1.7% to 3.1%; 6 trials; 3435 participants) and 3.3% (CI, 2.7% to 3.9%; 7 studies; 17 474 participants), respectively. Other harms of interventions included myocardial infarction, nerve injury, and hematoma.

Limitations: Trials may have overestimated benefits and used highly selected surgeons. Medical therapy used in trials was outdated, and stroke rates have declined in recent decades. Harms may have been underreported.

Conclusion: Current evidence does not establish incremental overall benefit of CEA, stenting, or intensification of medical therapy. Potential for overall benefit is limited by low prevalence and harms.

Primary Funding Source: Agency for Healthcare Research and Quality.


Stroke is a leading cause of death and disability (1). An estimated 7 million U.S. adults have had a stroke, and roughly 75% were first attacks (2). Ischemic strokes account for nearly 90% of all strokes in the United States (3). Carotid artery stenosis (CAS) causes approximately 10% of ischemic strokes (4).

Carotid artery stenosis refers to atherosclerotic narrowing of the extracranial carotid arteries—specifically, the internal carotid arteries or the common and internal carotid arteries. The best available data for the prevalence of asymptomatic CAS from large U.S.-based studies of the general population were published in the 1990s and enrolled adults aged 65 years or older (56). Data published in 1992 showed a prevalence of just more than 1% for CAS of 75% to 99% (6), and those published in 1998 suggested a prevalence of 0.5% for CAS of 70% to 99% (5).

Several studies have attempted to estimate the rate of progression of asymptomatic CAS and predict neurologic events (5, 711). The best available data from large U.S.-based studies of the general population revealed a 5-year risk for ipsilateral stroke of 5% for CAS of 70% or greater (5441 participants) (5).

The main purpose of this review is to evaluate the current evidence on whether screening asymptomatic adults for CAS reduces the risk for ipsilateral stroke and on harms associated with screening and interventions for CAS. We also evaluated evidence on the incremental benefit of medical therapy and on risk-stratification tools. Despite a D recommendation from the U.S. Preventive Services Task Force in 2007 (12), many surgeries or interventions for asymptomatic CAS continue to be performed, and free or “cash-on-the-barrel” screenings are offered in public locations across the country (13).

We developed an analytic framework (Supplement 1) and key questions (Table 1 of Supplement 2) that guided the review. Detailed methods and additional results are publicly available in our full evidence report (www.uspreventiveservicestaskforce.org) (14).

Data Sources and Searches

We searched MEDLINE, the Cochrane Library, and EMBASE for English-language articles published through September 2013 (Tables 2 and 3 of Supplement 2). We conducted a targeted update search of MEDLINE for trials published through 31 March 2014 and searched clinical trial registries for unpublished literature. To supplement electronic searches, we reviewed reference lists of included studies and literature suggested by reviewers.

Study Selection

Two investigators independently reviewed abstracts and full-text articles against prespecified eligibility criteria (Table 4 of Supplement 2). We included studies that focused on asymptomatic adults with CAS and studies that analyzed the asymptomatic group separately. We included randomized, controlled trials (RCTs) of screening for CAS, RCTs and systematic reviews of treatment effectiveness, multi-institution trials or cohort studies that reported harms, and studies that attempted to externally validate risk-stratification tools. For evaluation of accuracy and reliability of ultrasonography, we focused on systematic reviews but also included primary studies that were published after the literature search cutoff of the most recent good-quality systematic review.

Data Extraction and Quality Assessment

One investigator extracted pertinent information from each article. Another investigator reviewed extractions for completeness and accuracy. Two independent investigators assigned quality ratings (good, fair, or poor) for each study using predefined criteria (1415). Disagreements were resolved with team discussion. Poor-quality studies are described in the full report (14).

Data Synthesis and Analysis

We qualitatively synthesized findings for each key question by summarizing the characteristics and results of included studies in tabular or narrative format. To determine whether meta-analyses were appropriate, we assessed the clinical and methodological heterogeneity of the studies following established guidance (16). We conducted meta-analysis of RCTs that compared carotid endarterectomy (CEA) with medical therapy for relevant outcomes reported by several studies. We used DerSimonian–Laird random-effects models to estimate pooled effects (17) and calculated risk differences between CEA and medical therapy to show the absolute differences between groups. Absolute measures are more easily interpreted, show more directly relevant information, and better allow decision makers to assess tradeoffs between benefits and harms (1820). We calculated chi-square and I2 statistics to assess statistical heterogeneity in effects among studies (2122).

To allow the comparison of rates of perioperative harms reported in RCTs with those from sources that may be more representative of real-world clinical practice, we conducted meta-analyses of cohort studies that reported perioperative (30-day) stroke or death rates. We also conducted meta-analyses of such rates reported in trials that involved CEA or carotid angioplasty and stenting (CAAS), regardless of the comparator.

We conducted sensitivity analyses using profile likelihood random-effects methods when our meta-analyses included few studies (2326). We did not include poor-quality studies in our analyses. Analyses were conducted using Stata, version 11.1 (StataCorp).

Role of the Funding Source

The Agency for Healthcare Research and Quality funded the review. Members of the U.S. Preventive Services Task Force and Agency for Healthcare Research and Quality assisted in developing the review's scope and reviewed draft manuscripts, but the authors are solely responsible for the content.

We included 78 published articles that reported on 56 studies (Figure 1) .

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Figure 1.

Summary of evidence search and selection.

WHO ICTRP = World Health Organization International Clinical Trials Registry Platform.

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Direct Evidence that Screening Reduces Ipsilateral Stroke

We found no eligible studies that provided evidence on whether screening reduced ipsilateral stroke.

Accuracy and Reliability of Duplex Ultrasonography

We included 3 meta-analyses (2729) and 1 fair-quality primary study (30) (Table 5 of Supplement 2). The most recent good-quality meta-analysis (28) included 47 studies published through 2003 that used digital subtraction angiography as the reference standard. It reported sensitivity and specificity for detecting stenosis of 50% or greater (1716 participants) of 98% (95% CI, 97% to 100%) and 88% (CI, 76% to 100%), respectively. Sensitivity and specificity for detecting stenosis of 70% or greater (2140 participants) were 90% (CI, 84% to 94%) and 94% (CI, 88% to 97%). Using data from this meta-analysis, the last evidence report for the U.S. Preventive Services Task Force estimated the sensitivity and specificity for detecting stenosis of 60% or greater as 94% and 92%, respectively (31). The meta-analysis reported wide, clinically important variation in measurement properties among laboratories (28). The findings of the other meta-analyses were generally consistent with these results, but specificity in the primary study was lower (66% for detecting CAS of 70% to 99% [CI, 63% to 71%]; 503 participants) (30). Additional results are provided in our full report (14).

Benefits of CEA or CAAS Beyond Medical Therapy

We included 3 RCTs (Table 1) described in 12 publications (3243) that compared CEA with medical therapy and 3 systematic reviews described in 5 publications (31, 4447). We found no eligible studies that compared CAAS with medical therapy and no studies that compared CEA with current standard medical therapy.

Table Jump PlaceholderTable 1. Characteristics and Main Results of Included Fair- or Good-Quality Randomized, Controlled Trials of CEA Compared With MM for Asymptomatic CAS* 

The ACAS (Asymptomatic Carotid Atherosclerosis Study) and the VACS (Veterans Affairs Cooperative Study) were conducted in North America; the ACST (Asymptomatic Carotid Surgery Trial) involved 30 countries, primarily in Europe. Medical therapy varied across trials and was often not clearly defined or standardized. Surgeons with a history of low complication rates were selected. They submitted records of their last 50 cases or previous 24 months of experience with CEA and were selected on the basis of review by a committee or morbidity and mortality rates less than 3%.

Our meta-analyses found that fewer persons treated with CEA had perioperative stroke or death or subsequent ipsilateral stroke, perioperative stroke or death or any subsequent stroke, any stroke or death, nonperioperative ipsilateral stroke, and any nonperioperative stroke than those in medical therapy groups (Table 2 and Figure 2). For all-cause mortality, we found no significant difference. Results for sensitivity analyses using profile likelihood methods were very similar to those of our main analyses, with only minor variation in width of CIs (Table 2).

Table Jump PlaceholderTable 2. Summary of Main Results of Meta-analyses 
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Figure 2.

Meta-analyses of randomized, controlled trials comparing CEA with medical therapy, by outcome.

ACAS = Asymptomatic Carotid Atherosclerosis Study; ACST = Asymptomatic Carotid Surgery Trial; CEA = carotid endarterectomy; MM = medical management; RD = risk difference; VACS = Veterans Affairs Cooperative Study.

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In the ACST, more than one half (57.8% [166 of 287]) of nonperioperative strokes were disabling or fatal, and the proportional reduction in disabling or fatal stroke (relative risk, 0.61 [CI, 0.41 to 0.92]) was similar to that for any stroke (relative risk, 0.54 [CI, 0.43 to 0.68]) (37). Subgroup analyses of the ACAS showed a statistically significant reduction for men (relative risk reduction, 66% [CI, 36% to 82%]) but not for women (relative risk reduction, 17% [CI, −96% to 65%]) for estimated 5-year rate of perioperative stroke or death and subsequent ipsilateral stroke. In the ACST, reduction in the rate of first nonperioperative strokes was statistically significant for both sex subgroups.

Two of the 3 systematic reviews were conducted before the most recent ACST publication (37) and thus had preliminary ACST data (31, 44). The third review compared management strategies for asymptomatic CAS and included a meta-regression to evaluate the effect of time (to reflect improvements in medical therapy) on incidence rates of stroke (46). The investigators found that the incidence rate of ipsilateral stroke was lower in studies that completed recruitment from 2000 to 2010 than in those that completed recruitment in earlier years (1.1% vs. 2.4% per year; P < 0.001) (46).

Incremental Benefit of Additional Medications Beyond Current Standard Medical Therapy

We found no eligible studies that assessed benefits of additional medications beyond current standard medical therapy.

Harms Associated With Screening

Potential harms of screening include harms associated with false-positive results and harms of any confirmatory work-up, such as angiography. We found no studies on anxiety or labeling among persons with false-positive results. Two RCTs reported strokes after angiography. In the ACAS (33), 1.2% of patients (5 of 414) who had angiography had strokes; 1 patient died subsequently. In the VACS (42), 0.4% of patients (3 of 714) had nonfatal strokes after angiography.

Harms Associated With CEA or CAAS

We included 3 RCTs that compared CEA with medical therapy and 24 additional good- or fair-quality multi-institutional trials or cohort studies. Most studies reported perioperative death or stroke and did not report on other harms (such as nerve injuries, other postoperative harms, or psychological harms).

Trial Characteristics

The RCTs that compared CEA with medical therapy have been described. Characteristics of other included trials, as well as threats to internal and external validity, are presented in Table 6 of Supplement 2 (4856). In brief, these included 1 RCT that compared CEA with a control group (nearly one half of participants received CEA [48]), 1 RCT that compared CEA with low-dose aspirin (49), 2 RCTs that compared CEA with CAAS (5052), 2 uncontrolled trials that used postmarketing surveillance data for CAAS (5354, 56), and 1 study that pooled data from 2 uncontrolled trials of CAAS (55). Further details are provided in our full report (14).

Observational Study Characteristics

Eight fair-quality, multi-institution cohorts reported perioperative (30-day) harms of CEA (Table 6 of Supplement 2) (5768). All 8 used Medicare claims or enrollment databases. Harms were identified using both claims data and medical chart review. Most studies were conducted among Medicare beneficiaries of single states (5763, 6668); 2 used data from 10 states (6465).

One cohort from the credentialing phase of CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) reported rates of harms after CAAS (1151 participants with asymptomatic CAS ≥70%) (69).

An additional 8 fair-quality studies reported in-hospital (but not 30-day) perioperative events after CEA or CAAS from state discharge databases (7072) or the Nationwide Inpatient Sample (Table 6 of Supplement 2) (7377). Results are provided in Table 7 of Supplement 2 but are not included in this article because they capture only in-hospital events.

CEA Compared With Medical Therapy

Our meta-analysis found that 1.9% (CI, 1.2% to 2.6%) more participants treated with CEA had perioperative (30-day) stroke or death than those in medical therapy groups (Table 2 and Figure 2).

Two trials reported perioperative (30-day), nonfatal myocardial infarctions (MIs). The ACST found that 0.6% more participants treated with CEA had events than those treated with medical therapy (10 events vs. 1 event). The VACS reported 4 events in the CEA group and none in the medical therapy group.

Rates of Perioperative (30-Day) Death or Stroke

The main results of relevant studies are summarized in Table 7 of Supplement 2. Our meta-analysis of 7 cohort studies (17 474 participants) using Medicare claims data and medical records found a rate of perioperative (30-day) death or stroke of 3.3% (CI, 2.7% to 3.9%) after CEA (Table 2 and Figure 3). Among all trials that included a CEA group, regardless of the comparator, the rate was 2.4% (CI, 1.7% to 3.1%) (Table 2 and Figure 3).

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Figure 3.

Rates of perioperative death or stroke after CEA, by study design.

ACAS = Asymptomatic Carotid Atherosclerosis Study; ACST = Asymptomatic Carotid Surgery Trial; CASANOVA = Carotid Artery Stenosis with Asymptomatic Narrowing: Operation Versus Aspirin; CEA = carotid endarterectomy; CREST = Carotid Revascularization Endarterectomy Versus Stenting Trial; IA = Iowa; MACE = Mayo Asymptomatic Carotid Endarterectomy; MC = Medicare; NY = New York; OH = Ohio; OK = Oklahoma; VACS = Veterans Affairs Cooperative Study.

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One cohort study (6932 participants from 150 hospitals in New York) reported rates by comorbid condition level after CEA; 7.1% of persons with high comorbid condition levels versus 2.7% of those with low levels had perioperative death or stroke (62). A high comorbid condition level was defined as any end-stage disease, severe disability, or 3 or more Revised Cardiac Risk Index risk factors.

Rates varied significantly across states and by hospital volume (Table 7 of Supplement 2) (5758, 6465).

For CAAS, 1 cohort study (CREST credentialing phase) found a rate of 3.8% (CI, 2.9% to 5.1%) and higher rates for persons older than 75 years than for those aged 75 years or younger (7.5% vs. 2.4%) (69). Our meta-analysis of 2 trials found a rate of 3.1% (CI, 2.7% to 3.6%; 6152 participants) (Table 2).

Rates of Perioperative (30-Day) MIs

Studies of 1378 Medicare beneficiaries in New York (59) and 1002 in Georgia (63) conducted during the 1990s reported perioperative (30-day) rates of 0.9% for nonfatal MI and 0.8% for MI (0.6% for MI-related death) after CEA, respectively. One RCT (CREST) reported a 2.2% rate of any MI after CEA and 1.2% after CAAS (51).

Nerve Injuries, Infection, and Other Harms

In the VACS, 3.8% of persons who had CEA (8 of 211) had cranial nerve injuries with complete functional recovery. One multicenter trial conducted in Germany reported rates of 1.4% for pulmonary embolism, 4.2% for permanent cranial nerve damage, 1.4% for pneumonia, and 2.8% for local hematoma requiring surgery among 206 patients who were randomly assigned to the immediate surgical group (48). The total frequency of major complications (such as death, stroke, minor stroke, MI, or permanent cranial nerve damage) in that group was 7.9%. The Mayo Asymptomatic Carotid Endarterectomy study reported a 1.1% rate of minor cranial nerve injury after CEA (36 participants) (49).

Risk-Stratification Tools

For distinguishing persons more or less likely to have CAS, we found 1 study (78) that attempted to externally validate 2 tools using a cohort of 5449 participants from the Cardiovascular Health Study (7880). We rated the quality of one of the attempted external validations as poor; thus, we focus on the other one here. The tool (79) assigned 1 point each for the presence of several risk factors (coronary artery disease, smoking, hypertension, and high cholesterol) to predict the likelihood of CAS of 50% or greater. The tool's overall discrimination (its ability to correctly assign those with CAS ≥50% to a higher score than those with lesser CAS) was not much better than chance (c-statistic, 0.60 [CI, 0.56 to 0.64]) (78).

We found no eligible studies that distinguished persons at decreased or increased risk for stroke caused by CAS or for harms from CEA or CAAS. Some publications reported risk-stratification tools to predict increased risk for complications from CEA or CAAS, but those tools have not been externally validated (8187).

Duplex ultrasonography is a widely available, noninvasive screening test. Reliability of ultrasonography is questionable because accuracy can vary considerably among laboratories. Its use in a low-prevalence population would result in many false-positive test results—for example, for a population of 100 000 adults with a prevalence of 1%, it would result in 940 true-positive results and 7920 false-positive results (using a specificity of 92%). If no confirmatory tests are done, many unnecessary interventions and harms would occur. If all positive test results were followed by angiography (which is not typically done in clinical practice), as many as 1.2% of persons would have a resulting stroke (33). If all positive test results were followed by magnetic resonance angiography (95% sensitivity and 90% specificity [29]), many patients would still be sent for unnecessary intervention—in the previous example, 792 false-positive results would still be sent for intervention.

If externally validated, reliable risk-stratification tools were available to distinguish subgroups of persons who were more likely to have CAS, then the ratio of true-positive results to false-positive results would improve. However, the only study that attempted external validation of such a tool found inadequate discrimination.

An accurate estimate of potential benefit for the current primary care population is difficult to obtain. Although our meta-analyses of RCTs that compared CEA with medical therapy found a reduction in perioperative stroke or death or any subsequent stroke (and other outcomes), the applicability of the evidence to current practice is substantially limited. Medical therapy was often not clearly defined or standardized; was not kept constant during the study; and would not have included treatments now considered to be current standard medical therapy, including aggressive management of blood pressure and lipids. Current standard therapy to reduce stroke risk includes use of statins, antihypertensives (including newer classes, such as angiotensin-converting enzyme inhibitors), glycemic control for persons with diabetes, and use of antiplatelet drugs for vascular diseases and risk reduction.

To address some applicability limitations of previous studies, the new CREST-2 trial (88) (to begin later this year) will compare both CAAS plus medical therapy versus medical therapy alone and CEA plus medical therapy versus medical therapy alone. None of the trials we identified focused on a population identified by screening in primary care. Definitions of asymptomatic status varied across the trials and included persons with a history of contralateral stroke or TIA (25% in the ACAS and 32% in the VACS), ipsilateral symptoms that were not recent, and previous contralateral CEA.

The trials that compared CEA with medical therapy used highly selected surgeons, requiring low rates of complications to allow participation. A relatively low perioperative stroke or death rate of less than 3% is required for CEA to have a reasonable likelihood of resulting in more benefit than harm for persons with asymptomatic CAS. Although our meta-analyses of trial data found rates less than 3%, observational data show higher rates and reveal a wide range of rates across states (more than 6% in some states) (65).

The potential benefits of CEA or CAAS depend on the risk for an asymptomatic lesion eventually resulting in a stroke. Evidence suggests that this risk has decreased in recent decades, most likely due to advances in medical therapy (46, 89). The best recent evidence suggests that the incidence rate of ipsilateral stroke is nearing 1% per year (46), approaching the rate achieved in the surgical groups of trials that compared CEA with medical therapy. This would significantly reduce the potential benefits of surgery. Medical intervention has also been estimated to be 3 to 8 times more cost-effective (89).

In theory, patients at greater risk for ipsilateral stroke may be more likely to benefit from surgery or intervention. However, no externally validated, reliable risk-stratification tools are available that can distinguish persons with asymptomatic CAS who are at decreased or increased risk for stroke caused by CAS despite current standard medical therapy or those who are at decreased or increased risk for harms from CEA or CAAS. One may expect that persons with greater reduction of the carotid diameter would have greater potential for benefit, but subgroup analyses from trials that compared CEA with medical therapy found no significant difference by CAS percentage (33, 37).

Of note, the main estimates of overall benefit from the trials that compared CEA with medical therapy do not include some important harms, such as nonfatal MI, permanent cranial nerve damage, pulmonary embolism, pneumonia, wound infection, acute renal failure, deep venous thrombosis, and local hematoma requiring surgery. The CAS screening cascade also has potential psychological harms (14). Most studies we reviewed did not report on harms other than perioperative stroke or death. Thus, lack of reporting or underreporting of some harms is possible.

Timing of events and life expectancy are also important considerations when assessing the potential for benefit. The consolidation of all stroke and death events together into one composite outcome does not reflect different values that patients may have for a stroke or death caused by surgery than for one caused by natural progression. Based on the data from RCTs, a life expectancy of at least 5 to 10 years would be needed to have a reasonable chance of benefit from CEA. Potential for benefit decreases with advanced age (older than 75 years) because of competing hazards. The mean age of patients in trials that compared CEA with medical therapy was 65 to 68 years. However, the mean age of Medicare patients who have CEA is 75 years (90), raising the question of whether many persons who have surgical intervention are likely too old to benefit.

The limitations of this review primarily reflect the published literature, and most key issues limiting applicability of the evidence have been described. Changes in technology, standard medical therapy, surgical procedures, and stroke rates may not be reflected in the included literature (because much of the data is from the 1990s). Our review did not evaluate the use of carotid intima–media thickness in assessing coronary heart disease risk, but a previous review for the U.S. Preventive Services Task Force concluded that evidence does not support its use (91).

Asymptomatic CAS has low prevalence in the general adult population. Noninvasive screening with ultrasonography would result in many false-positive results. Externally validated, reliable risk-stratification tools to distinguish persons who are more likely to have CAS are not available.

Current evidence does not sufficiently establish incremental overall benefit of CEA beyond current standard medical therapy, primarily because medical therapy for trials was ill-defined, varying, and often lacked treatments that are now standard and have reduced the rate of stroke in persons with asymptomatic CAS in recent decades. Externally validated, reliable risk-stratification tools that can distinguish persons with asymptomatic CAS who have increased or decreased risk for ipsilateral stroke or harms after CEA or CAAS are not available.

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Figures

Grahic Jump Location
Figure 1.

Summary of evidence search and selection.

WHO ICTRP = World Health Organization International Clinical Trials Registry Platform.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Meta-analyses of randomized, controlled trials comparing CEA with medical therapy, by outcome.

ACAS = Asymptomatic Carotid Atherosclerosis Study; ACST = Asymptomatic Carotid Surgery Trial; CEA = carotid endarterectomy; MM = medical management; RD = risk difference; VACS = Veterans Affairs Cooperative Study.

Grahic Jump Location
Grahic Jump Location
Figure 3.

Rates of perioperative death or stroke after CEA, by study design.

ACAS = Asymptomatic Carotid Atherosclerosis Study; ACST = Asymptomatic Carotid Surgery Trial; CASANOVA = Carotid Artery Stenosis with Asymptomatic Narrowing: Operation Versus Aspirin; CEA = carotid endarterectomy; CREST = Carotid Revascularization Endarterectomy Versus Stenting Trial; IA = Iowa; MACE = Mayo Asymptomatic Carotid Endarterectomy; MC = Medicare; NY = New York; OH = Ohio; OK = Oklahoma; VACS = Veterans Affairs Cooperative Study.

Grahic Jump Location

Tables

Table Jump PlaceholderTable 1. Characteristics and Main Results of Included Fair- or Good-Quality Randomized, Controlled Trials of CEA Compared With MM for Asymptomatic CAS* 
Table Jump PlaceholderTable 2. Summary of Main Results of Meta-analyses 

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Letters

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Comments

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This USPSTF recommendation neglects the benefits of statins
Posted on July 8, 2014
David L. Keller, MD
none
Conflict of Interest: None Declared
I wish to answer to the question of what to do for an asymptomatic patient with a 70-99% ICA obstruction, discovered on a screening carotid ultrasound ordered, perhaps, by a clinician who disagrees with the USPSTF advice not to perform this screen.

First, I would take a very careful history and perform as diligent a neurological examination as I can, to discern if the patient has perhaps had a small stroke with subtle signs and symptoms. Any evidence of neurological deficits consistent with stroke would change the patient's category to symptomatic, and mandate further workup.

Second, if the patient is truly asymptomatic, I would classify him as having a coronary artery disease equivalent. If he is not taking a statin, I would prescribe him a strong statin (as recently defined in the 2014 AHA/ACC guidelines). If he is taking a weak statin, I would increase it to a strong statin. I would obtain consultation from a neurologist (to confirm my negative neurological exam) and discuss whether low-dose aspirin and aggressive blood pressure control are indicated. I would teach the patient extensively about the signs and symptoms of stroke, to engage him in his own care.

Internists should not adhere to recommendations from the USPSTF in a blind or unquestioning fashion. The 16 primary care physicians on that committee are not responsible for the well-being of my patients. I am. The data from carotid stenosis trials which did not even look at high dose statin therapy does not apply in this new era. Atherosclerosis is a systemic disease, so it is proper to apply the findings from the heart disease studies for the benefit of our patients, pending definitive disproof of any benefit from statins for patients with carotid stenosis.
In Reponse
Posted on September 3, 2014
J. David Spence M.D., FRCPC, FAHA
Robarts Research Institute, Western University
Conflict of Interest: None Declared

The recent report of the U.S. Preventive Services Task Force on screening for carotid stenosis(1) recommended against this practice. However, carotid ultrasound is a two-edged sword.

With modern medical therapy the risk of stroke or death among patients with asymptomatic carotid stenosis is now well below the risk of carotid stenting or endarterectomy; the annual risk of ipsilateral stroke is now ~ 0.5%(2-5). Even in the most recent randomized trial comparing stenting and endarterectomy (the Carotid Revascularization Endarterectomy vs. Stenting Trial, CREST) (6), the 30-day risk of stroke or death for asymptomatic patients was 2.5% for stenting and 1.4% for endarterectomy; the 4-year risk was 4.5% with stenting and 2.7% with endarterectomy. In Medicare patients, Wang et al (7) reported that a 1-year risk of stroke or death of 16.7% for stenting and 11% for endarterectomy.

Most patients with asymptomatic carotid stenosis (~ 90) would be better off with medical therapy, and the ~ 10% at high enough risk to benefit from intervention can be identified by the presence of microemboli on transcranial Doppler(8;9).

It is therefore appropriate to recommend against screening for asymptomatic carotid stenosis if the purpose is to find victims for inappropriate intervention that is more likely to harm than help them. On the other hand, there is good reason to assess preclinical atherosclerosis to better target intensive medical therapy to high-risk patients. Most cardiovascular events occur among patients with a low risk predicted by scores such as the Framingham score(10), and measuring carotid plaque burden can significantly improve risk stratification(11-13), better than measuring carotid intima-media thickness (IMT)(14).

It is important to recognize that measurement of plaque burden (as total plaque area(15) or plaque volume, which is highly correlated with coronary calcium score(16)) is distinct from measuring IMT. IMT adds little to risk scores(17), and progression of IMT does not predict risk(18). Among patients attending a vascular prevention clinic, carotid plaque burden strongly predicted risk: after adjustment for age, sex, blood pressure, cholesterol, smoking, diabetes, homocysteine and treatment of blood pressure and cholesterol, patients with a total plaque area in the top quartile (> 119 mm2) had a nearly 40% five-year risk of stroke, death or myocardial infarction, and patients in the third quartile (47-118 mm2) had a 20% five-year risk of those events(15). Those findings were validated in a large (>6000 participants) population-based study in Norway(19;20).

Among prevention clinic patients, despite treatment according to guidelines, carotid plaque progression doubled risk after adjustment for the same risk factors listed above, and it was half the patients who had progression of plaque(15). The recognition that guideline-based therapy was failing half the patients led to a new approach, “treating arteries instead of treating risk factors”(21). This approach markedly reduced risk among patients with asymptomatic carotid stenosis: the 2-year risk of stroke dropped from 8.8% to 1%, and that of myocardial infarction from 7.6% to 1%(4). Clinical trials are now being designed to test the generalizability of that approach to other clinic populations. This cannot be done with IMT or coronary calcium, because the annual change within individuals is too small to adjust therapy in clinically meaningful time frames(22).

In summary, screening for asymptomatic carotid stenosis in order to find victims for inappropriate stenting or endarterectomy is inappropriate. Assessing preclinical atherosclerosis for the purpose of improving medical therapy is entirely appropriate.

Reference List

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(14) Inaba Y, Chen JA, Bergmann SR. Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: A meta-analysis. Atherosclerosis 2011; 220(1):128-133.
(15) Spence JD, Eliasziw M, DiCicco M, Hackam DG, Galil R, Lohmann T. Carotid Plaque Area: A Tool for Targeting and Evaluating Vascular Preventive Therapy. Stroke 2002; 33:2916-2922.
(16) Sillesen H, Muntendam P, Adourian A, Entrekin R, Garcia M, Falk E et al. Carotid Plaque Burden as a Measure of Subclinical Atherosclerosis: Comparison With Other Tests for Subclinical Arterial Disease in the High Risk Plaque BioImage Study. JACC Cardiovasc Imaging 2012; 5(7):681-689.
(17) Den Ruijter HM, Peters SA, Anderson TJ, Britton AR, Dekker JM, Eijkemans MJ et al. Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis. JAMA 2012; 308(8):796-803.
(18) Lorenz MW, Polak JF, Kavousi M, Mathiesen EB, Volzke H, Tuomainen TP et al. Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. Lancet 2012; 379(9831):2053-2062.
(19) Johnsen SH, Mathiesen EB, Joakimsen O, Stensland E, Wilsgaard T, Lochen ML et al. Carotid atherosclerosis is a stronger predictor of myocardial infarction in women than in men: a 6-year follow-up study of 6226 persons: the Tromso Study. Stroke 2007; 38(11):2873-2880.
(20) Mathiesen EB, Johnsen SH, Wilsgaard T, Bonaa KH, Lochen ML, Njolstad I. Carotid Plaque Area and Intima-Media Thickness in Prediction of First-Ever Ischemic Stroke: A 10-Year Follow-Up of 6584 Men and Women: The Tromso Study. Stroke 2011; 42(4):972-978.
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(22) Spence JD. Carotid plaque measurement is superior to IMT Invited editorial comment on: Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: A meta-analysis-Yoichi Inaba, M.D., Jennifer A. Chen M.D., Steven R. Bergmann M.D., Ph.D. Atherosclerosis 2011; 220(1):34-35.

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