Screening for asymptomatic carotid artery stenosis: a systematic review and meta-analysis for the U.S. Preventive Services Task Force.

Review

Annals of Internal Medicine

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

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; multiinstitution studies reporting harms; and externally validated riskstratification 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 ⱖ50% to ⱖ70%), its use in low-prevalence populations would yield many false-positive results. Absolute reduc-

S

troke 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 (5, 6). 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). See also: Related article. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356 Editorial comment. . . . . . . . . . . . . . . . . . . . . . . . . . 370 Web-Only Supplements

336 2 September 2014 Annals of Internal Medicine Volume 161 • Number 5

tion 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. Ann Intern Med. 2014;161:336-346. doi:10.7326/M14-0530 www.annals.org For author affiliations, see end of text. This article was published online first at www.annals.org on 8 July 2014.

Several studies have attempted to estimate the rate of progression of asymptomatic CAS and predict neurologic events (5, 7–11). 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).

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

Screening for Carotid Artery Stenosis

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.

Figure 1. Summary of evidence search and selection.

Records identified (n = 5563) Database searching: 5076 PubMed: 2879 EMBASE: 1805 Cochrane: 392 Other sources: 487 Suggestions from peer and public comments: 46 ClinicalTrials.gov, Cochrane trials registry, and WHO ICTRP: 345 Reference lists of published articles: 96

Duplicates removed (n = 1625)

Records screened (n = 3938)

Records excluded (n = 3461)

Full-text articles assessed for eligibility (n = 477)

Full-text articles excluded (n = 399) Wrong publication type: 8 Wrong population: 113 Wrong screening/intervention: 25 Wrong comparator: 90 Wrong outcome: 31 Wrong setting: 2 Wrong study design: 130

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 (14, 15). 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 metaanalysis 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 (18 – 20). We calculated chi-square and I 2 statistics to assess statistical heterogeneity in effects among studies (21, 22). 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 conwww.annals.org

Review

Articles reporting on 56 studies included in qualitative synthesis (n = 78) Studies included in quantitative synthesis: 21

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

ducted 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 (23–26). We did not include poorquality 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. 2 September 2014 Annals of Internal Medicine Volume 161 • Number 5 337

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

CAS Percentage

Sample Demographic Characteristics

Sample Comorbid Conditions at Enrollment

Source of Patients

Follow-up, y

ACAS (32–35)

ⱖ60%

Participants: 1662 Mean age: 67 y Men: 66% White: 95%

Ultrasonography laboratories; practitioners who found bruits or CAS during evaluation for peripheral vascular surgery or contralateral CEA

Median: 2.7

ACST (36–40)

ⱖ60%

Participants: 3120 Mean age: 68 y Men: 66% White: NR

Medical and surgical clinics

Median in survivors: 9

VACS (41–43)

ⱖ50%

Participants: 444 Mean age: 65 y Men: 100% White: 87%

DM: 23% Hypertension: 64% Hypercholesterolemia: NR Smoker: 26% CAD: 69% Previous contralateral CEA: 20% Contralateral occlusion: 9% Contralateral TIA/stroke: 25% DM: 20% Hypertension: 65% Hypercholesterolemia: 27% Smoker: NR CAD, non-DM: 27% Previous contralateral CEA: 24% Contralateral occlusion: 9% Contralateral TIA/stroke: NR DM: 28% Hypertension: 64% Hypercholesterolemia: NR Smoker: 50% History of MI: 26% Previous contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: 32%

11 VAMCs; patients scheduled for surgery with unilateral symptomatic lesions found to have contralateral asymptomatic stenosis or with incidental bruits and positive noninvasive screening test results

Mean: 4

ACAS ⫽ Asymptomatic Carotid Atherosclerosis Study; ACST ⫽ Asymptomatic Carotid Surgery Trial; ARR ⫽ absolute risk reduction; CAD ⫽ coronary artery disease; CAS ⫽ carotid artery stenosis; CEA ⫽ carotid endarterectomy; DM ⫽ diabetes mellitus; MI ⫽ myocardial infarction; MM ⫽ medical management; NR ⫽ not reported; RR ⫽ relative risk; TIA ⫽ transient ischemic attack; VACS ⫽ Veterans Affairs Cooperative Study; VAMC ⫽ Veterans Affairs medical center. * Requirements for asymptomatic status differed slightly across the trials. For example, the ACST enrolled persons with no TIA or stroke attributable to the ipsilateral artery for the past 6 mo, and the ACAS enrolled those with no history of cerebrovascular events in the distribution of the ipsilateral carotid artery or the vertebrobasilar system and no symptoms referable to the contralateral artery for the past 45 d. † During the perioperative period, 2.3% of surgical patients (n ⫽ 19) had a stroke or died (95% CI, 1.28%–3.32%) compared with 0.4% of patients in the medical group (CI, 0.0%– 0.8%). It was estimated that if all 724 patients receiving CEA had arteriography as part of the ACAS (some had angiography in the 60 d before the study), 2.7% of surgical patients would have had a stroke or died as a result of the procedure. ‡ At study entry, 17% of participants randomly assigned in 1993 to 1996 were receiving lipid-lowering therapy. That percentage increased to 58% in 2000 to 2003. At the last follow-up in 2002 to 2003, more than 90% of the survivors received antiplatelet therapy, 81% received antihypertensives, and 70% received lipid-lowering therapy. At follow-up in 2002 or 2003, mean blood pressure was 148/79 mm Hg in both groups (41). § 2.9% (44 of 1532 CEAs performed) was the rate of perioperative stroke or death for persons in the immediate CEA group; when those in the delayed group who had CEA were included, the rate was 3.0% (95% CI, 2.4%–3.9%).

RESULTS We included 78 published articles that reported on 56 studies (Figure 1). 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 (27–29) and 1 fairquality 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 metaanalysis, the last evidence report for the U.S. Preventive Services Task Force estimated the sensitivity and specificity 338 2 September 2014 Annals of Internal Medicine Volume 161 • Number 5

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 metaanalyses 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 (32– 43) that compared CEA with medical therapy and 3 systematic reviews described in 5 publications (31, 44 – 47). We found no eligible studies that compared CAAS with medical therapy and no studies that compared CEA with current standard medical therapy. 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 counwww.annals.org


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Table 1—Continued

Medical Therapy Description

Rate of Perioperative Stroke/Death and Any Subsequent Stroke

Rate of Perioperative Stroke/Death and Subsequent Ipsilateral Stroke

Rate of Any Stroke or Death

Perioperative (30-Day) Stroke or Death, %

Aspirin, 325 mg daily; also had risk factor discussion and modification at random assignment, subsequent interviews, and telephone follow-up

Observed events: MM: 10.3% CEA: 7.3% ARR: 3.0% 5-y estimate: MM: 17.5% CEA: 12.4% ARR: 5.1% MM: 13.1% CEA: 9.2% RR: 0.7 (95% CI, 0.6–0.9) ARR: 3.9%

Observed events: MM: 6.2% CEA: 4.0% ARR: 2.2% 5-y estimate: MM: 11% CEA: 5.1% ARR: 5.9% MM: 6.9% CEA: 5.3% RR: 0.8 (95% CI, 0.6–1.0) ARR: 1.6%

Observed events: MM: 18.6% CEA: 15.4% ARR: 3.2% 5-y estimate: MM: 31.9% CEA: 25.6% ARR: 6.3% MM: 49.4% CEA: 47.2% RR: 0.95 (95% CI, 0.89–1.03)

2.7†

MM: 12.9% CEA: 10.4% RR: 0.8 (95% CI, 0.5–1.4) ARR: 2.5%

MM: 10.3% CEA: 6.6% RR: 0.64 (95% CI, 0.34–1.21) ARR: 3.7%

MM: 44.2% CEA: 41.2% RR: 0.9 (95% CI, 0.7–1.2)

4.7

Left to discretion of clinicians; usually included antiplatelet and antihypertensive therapy; in later years of the trial, lipid-lowering therapy was common‡

Aspirin, 650 mg twice daily, reduced to 325 mg daily if not tolerated

tries, 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 sub-

2.9§

sequent 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). 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

Table 2. Summary of Main Results of Meta-analyses Participants*, n

Effect Measure†

Estimate From Main Analysis (95% CI), %

I2, %

PL Estimate From Sensitivity Analysis (95% CI), %

RD RD RD RD RD RD RD

⫺2.0 (⫺3.3 to ⫺0.7) ⫺3.5 (⫺5.1 to ⫺1.8) 1.0 (⫺2.0 to 3.0) ⫺2.7 (⫺5.1 to ⫺0.3) ⫺4.1 (⫺5.4 to ⫺2.7) ⫺5.5 (⫺7.0 to ⫺3.9) 1.9 (1.2 to 2.6)

0 0 13 0 23 0 0

⫺2.0 (⫺3.6 to ⫺0.7) ⫺3.5 (⫺5.2 to ⫺1.5) 0.7 (⫺2.4 to 3.8) ⫺2.7 (⫺5.4 to ⫺0.1) ⫺3.9 (⫺5.8 to ⫺2.8) ⫺5.5 (⫺7.1 to ⫺3.8) 1.9 (1.2 to 2.8)

68 30

NA‡ NA‡

Outcome

Studies, n

CEA vs. medical therapy Perioperative stroke/death or subsequent ipsilateral stroke Perioperative stroke/death or any subsequent stroke All-cause mortality Any stroke or death Ipsilateral stroke (nonperioperative) Any nonperioperative stroke Perioperative stroke/death

3 3 3 3 3 3 3

5223 5223 5223 5223 5223 5223 5223

CEA Perioperative stroke/death rate from observational studies Perioperative stroke/death rate from trials

7 6

17 474 3435

Rate Rate

3.3 (2.7 to 3.9) 2.4 (1.7 to 3.1)

CAAS Perioperative stroke/death rate from trials

2

6152

Rate

3.1 (2.7 to 3.6)

0.1

3.1 (2.2 to 3.7)

CAAS ⫽ carotid angioplasty and stenting; CEA ⫽ carotid endarterectomy; NA ⫽ not applicable; PL ⫽ profile likelihood; RD ⫽ risk difference. * Participants who contributed to the meta-analysis. † RDs represent absolute differences over approximately 5 y. Negative RDs favor CEA. ‡ Analyses did not have small numbers of studies. www.annals.org

2 September 2014 Annals of Internal Medicine Volume 161 • Number 5 339

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Figure 2. Meta-analyses of randomized, controlled trials comparing CEA with medical therapy, by outcome. Study, Year (Reference)

CEA Events/ MM Events/ Participants, n/N Participants, n/N

RD (95% CI)

Perioperative stroke/death or any ipsilateral stroke ACAS, 1995 (33)

33/825

52/834

–0.02 (–0.04 to –0.00)

ACST, 2004 (38) and 2010 (37)

82/1560

108/1560

–0.02 (–0.03 to 0.00)

VACS, 1993 (42)

14/211

24/233

–0.04 (–0.09 to 0.01)

Subtotal (I2 = 0.0%; P = 0.74)

–0.02 (–0.03 to –0.01)

Perioperative stroke/death or any stroke ACAS, 1995 (33) ACST, 2004 (38) and 2010 (37) VACS, 1993 (42)

60/825

86/834

–0.03 (–0.06 to –0.00)

143/1560

204/1560

–0.04 (–0.06 to –0.02)

22/211

30/233

–0.02 (–0.08 to 0.04)

Subtotal (I2 = 0.0%; P = 0.83)

–0.03 (–0.05 to –0.02)

All-cause mortality ACAS, 1995 (33) ACST, 2004 (38) and 2010 (37) VACS, 1993 (42)

83/825

89/834

610/1560

570/1560

0.03 (–0.01 to 0.06)

70/211

78/233

–0.00 (–0.09 to 0.08)

–0.01 (–0.04 to 0.02)

Subtotal (I2 = 13.1%; P = 0.32)

0.01 (–0.02 to 0.03)

Any stroke or death ACAS, 1995 (33)

127/825

155/834

–0.03 (–0.07 to 0.00)

ACST, 2004 (38) and 2010 (37)

736/1560

771/1560

–0.02 (–0.06 to 0.01)

87/211

103/233

VACS, 1993 (42)

–0.03 (–0.12 to 0.06)

Subtotal (I2 = 0.0%; P = 0.93)

–0.03 (–0.05 to –0.00)

Ipsilateral stroke (nonperioperative) ACAS, 1995 (33)

14/825

49/834

ACST, 2004 (38) and 2010 (37)

38/1560

92/1560

–0.03 (–0.05 to –0.02)

5/211

22/233

–0.07 (–0.11 to –0.03)

VACS, 1993 (42)

–0.04 (–0.06 to –0.02)

Subtotal (I2 = 22.7%; P = 0.27)

–0.04 (–0.05 to –0.03)

Any nonperioperative stroke ACAS, 1995 (33)

41/825

83/834

–0.05 (–0.07 to –0.02)

ACST, 2004 (38) and 2010 (37)

99/1560

188/1560

–0.06 (–0.08 to –0.04)

VACS, 1993 (42)

13/211

28/233

–0.06 (–0.11 to –0.01)

Subtotal (I2 = 0.0%; P = 0.90)

–0.05 (–0.07 to –0.04)

Perioperative stroke or death ACAS, 1995 (33)

19/825

3/834

0.02 (0.01 to 0.03)

ACST, 2004 (38) and 2010 (37)

44/1560

16/1560

0.02 (0.01 to 0.03)

9/211

2/233

0.03 (0.00 to 0.06)

VACS, 1993 (42) Subtotal (I2 = 0.0%; P = 0.60)

0.02 (0.01 to 0.03) –0.10

–0.05

Favors CEA

0

0.05

0.10

Favors Medical Therapy

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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(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 multiinstitutional 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 (48 –56). 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 (50 –52), 2 uncontrolled trials that used postmarketing surveillance data for CAAS (53, 54, 56), and 1 study that pooled data from 2 www.annals.org

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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) (57– 68). 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 (57– 63, 66 – 68); 2 used data from 10 states (64, 65). 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 ⱖ70%) (69). An additional 8 fair-quality studies reported inhospital (but not 30-day) perioperative events after CEA or CAAS from state discharge databases (70 –72) or the Nationwide Inpatient Sample (Table 6 of Supplement 2) (73–77). 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). 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) (57, 58, 64, 65). For CAAS, 1 cohort study (CREST credentialing phase) found a rate of 3.8% (CI, 2.9% to 5.1%) and 2 September 2014 Annals of Internal Medicine Volume 161 • Number 5 341

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Figure 3. Rates of perioperative death or stroke after CEA, by study design. Study, Year (Reference)

Source

Study Period

Quality

Events/ Participants, n/N

Event Rate (95% CI)

Cohort study Bratzler et al, 1996 (57)

MC, OK

1993–1994

Fair

13/347

3.70 (2.20–6.30)

Cebul et al, 1998 (58)

MC, OH

1993–1994

Fair

4/167

2.40 (0.94–6.00)

1994

Fair

6/159

3.80 (1.74–7.99)

Kresowik et al, 2000 (66) MC, IA Kresowik, 2004 (64)

MC, 10 states 1995–1996

Fair

160/3891

4.10 (3.53–4.78)

Kresowik, 2004 (64)

MC, 10 states 1998–1999

Fair

156/4093

3.80 (3.27–4.44)

Halm et al, 2005 (60)

MC, NY

1997–1998

Fair

31/1378

2.28 (1.59–3.18)

Halm et al, 2007 (62) and 2009 (61)

MC, NY

1998–1999

Fair

209/6932

3.01 (2.64–3.44)

Subtotal (I2 = 67.0%; P = 0.006)

3.32 (2.73–3.91)

Trial CASANOVA, 1991 (48)

CASANOVA

1982–1988

Fair

7/216

3.20 (1.58–6.54)

VACS, 1993 (42)

VACS

1983–1987

Good

9/211

4.30 (2.26–7.91)

ACAS, 1995 (33)

ACAS

1987–1993

Good

19/825

2.30 (1.48–3.56)

MACE, 1992 (49)

MACE

1987–1990

Fair

1/36

4.00 (0.49–14.17)

ACST, 2004 (38) and 2010 (37)

ACST

1993–2003

Fair

44/1560

2.80 (2.11–3.77)

Brott et al, 2010 (50)

CREST

2000–2008

Fair

8/587

1.40 (0.69–2.67)

Subtotal (I2 = 30.3%; P = 0.21)

2.41 (1.71–3.12) 0

2

4

6

8

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.

higher rates for persons older than 75 years than for those aged 75 years or younger (7.5% vs. 2.4%) (69). Our metaanalysis of 2 trials found a rate of 3.1% (CI, 2.7% to 3.6%; 6152 participants) (Table 2).

The Mayo Asymptomatic Carotid Endarterectomy study reported a 1.1% rate of minor cranial nerve injury after CEA (36 participants) (49). Risk-Stratification Tools

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%. 342 2 September 2014 Annals of Internal Medicine Volume 161 • Number 5

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 (78 – 80). 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 ⱖ50% 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 (81– 87). www.annals.org


DISCUSSION 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 falsepositive 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 truepositive 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 www.annals.org

Review

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. 2 September 2014 Annals of Internal Medicine Volume 161 • Number 5 343

Review


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. 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. 344 2 September 2014 Annals of Internal Medicine Volume 161 • Number 5

Requests for Single Reprints: Daniel E. Jonas, MD, MPH, Depart-

ment of Medicine, University of North Carolina at Chapel Hill, 5034 Old Clinic Building, CB 7110, Chapel Hill, NC 27599; e-mail, [email protected]. Current author addresses and author contributions are available at www .annals.org.

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Annals of Internal Medicine Current Author Addresses: Drs. Jonas, Feltner, and Sheridan: Depart-

Author Contributions: Conception and design: D.E. Jonas, C. Feltner,

ment 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.

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.

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2 September 2014 Annals of Internal Medicine Volume 161 • Number 5

Supplement 1: Analytic Framework for Screening for Asymptomatic Carotid Artery Stenosis KQ 1

Asymptomatic adults KQ 2

Risk of CAS 60%-99% A : Decreased B : Average C: Increased

Screening +/confirmatory tests KQ 3

CAS 60%-99%

KQ 4

Risk of ipsilateral stroke or harms A: Decreased B: Average C: Increased

Treatment KQs 5 , 6

Reduced number of ipsilateral strokes /deaths

KQ 8

KQ 7 Harms of screening/ confirmatory tests

Harms of CEA or CAAS

Abbreviations: CAS = carotid artery stenosis; CAAS = carotid angioplasty and stenting; CEA = carotid endarterectomy; ; KQ = key question

Note: The scope and methods of this report differ from earlier U.S. Preventive Services Task Force (USPSTF) reviews on this topic by 1) using systematic methods for all key questions; 2) addressing new key questions about the availability of valid, reliable risk stratification tools to identify people most likely to benefit from screening and treatment; 3) adding carotid angioplasty and stenting (CAAS) to the included interventions; 4) adding a question about the incremental benefit of medical therapy; and 5) conducting quantitative synthesis for many outcomes.

.

Supplement 2: Tables Supplement Table 1. Key Questions for the Systematic Review Supplement Table 2. Main Search Strategy for MEDLINE Supplement Table 3. Additional Search Strategy for MEDLINE for Studies Addressing Incremental Benefit of Medications Beyond Current Standard Medical Therapy (KQ 6) Supplement Table 4. Inclusion/Exclusion Criteria Supplement Table 5. Included Good- or Fair-Quality Studies on Accuracy of Screening With Duplex Ultrasonography to Detect CAS Supplement Table 6. Characteristics of Additional Studies Rated as Good or Fair Quality and Reporting Rates of Peri-Procedural Complications of CEA or CAAS for Adults With Asymptomatic Carotid Artery Stenosis Supplement Table 7. Results From Additional Studies Rated as Good or Fair Quality and Reporting Rates of Peri-Procedural Complications of CEA or CAAS for Adults With Asymptomatic Carotid Artery Stenosis

Supplement Table 1. Key Questions for the Systematic Review 1. Is there direct evidence that screening adults with duplex ultrasonography, computerized tomographic angiography (CTA), and/or magnetic resonance angiography (MRA) for asymptomatic carotid artery stenosis (CAS) reduces fatal or nonfatal ipsilateral stroke? a. Is there direct evidence for persons at decreased risk? b. Is there direct evidence for persons at average risk? c. Is there direct evidence for persons at increased risk? d. Does the evidence differ for subgroups defined by age, sex, race, or ethnicity? 2. Are externally validated, reliable risk stratification tools available that distinguish people who are more or less likely to have CAS? 3a. What are the accuracy and reliability of screening with duplex ultrasonography, used alone or followed by CTA or MRA, to detect potentially clinically important CAS? 3b. Do the accuracy and reliability differ for subgroups defined by age, sex, race, or ethnicity? 4a. Are externally validated, reliable risk stratification tools available that distinguish people with asymptomatic CAS who are at decreased or increased risk of ipsilateral stroke caused by CAS? 4b. Are externally validated, reliable risk stratification tools available that distinguish people with asymptomatic CAS who are at decreased or increased risk of harms from CEA or carotid angioplasty and stenting (CAAS)? 5. For people with asymptomatic CAS, does intervention with carotid endarterectomy (CEA) or CAAS provide incremental benefit beyond current standard medical therapy for reduction of fatal or nonfatal ipsilateral stroke? a. Is there incremental benefit for persons at decreased risk for ipsilateral stroke caused by CAS? b. Is there incremental benefit for persons at average risk for ipsilateral stroke caused by CAS? c. Is there incremental benefit for persons at increased risk for ipsilateral stroke caused by CAS? d. Does the evidence differ for subgroups defined by age, sex, race, or ethnicity? 6. For people with asymptomatic CAS, does the addition of medications (e.g., aspirin, statins) provide incremental benefit beyond current standard medical therapy that includes treatment of traditional risk factors (e.g., hypertension, hypercholesterolemia) for reduction of fatal or nonfatal ipsilateral stroke? a. Is there incremental benefit for persons at decreased risk for ipsilateral stroke caused by CAS? b. Is there incremental benefit for persons at average risk for ipsilateral stroke caused by CAS? c. Is there incremental benefit for persons at increased risk for ipsilateral stroke caused by CAS? d. Does the evidence differ for subgroups defined by age, sex, race, or ethnicity? 7a. What are the harms associated with screening or confirmatory testing for asymptomatic CAS? 7b. Do the harms differ for subgroups defined by age, sex, race, or ethnicity? 7c. Do the harms differ for subgroups defined by comorbidities? 8a. What are the harms associated with CEA or CAAS for the treatment of asymptomatic CAS? 8b. Do the harms differ for subgroups defined by age, sex, race, or ethnicity? 8c. Do the harms differ for subgroups defined by comorbidities? Abbreviations: CAAS = carotid angioplasty and stenting; CAS = carotid artery stenosis; CEA = carotid endarterectomy; CTA = computerized tomographic angiography; MRA = magnetic resonance angiography

Supplement Table 2. Main Search Strategy for MEDLINE Search Query #1 Search ("Carotid Stenosis"[Mesh] OR "carotid stenosis" OR "carotid artery stenosis") #2 Search asymptomatic #3 Search (#1 and #2) #4 Search "Mass Screening"[Mesh] #5 Search (#3 and #4) #6 Search "Carotid Stenosis/ultrasonography"[Mesh] #7 Search "Ultrasonography"[Mesh] #8 Search (#3 and #7) #9 Search "Endarterectomy, Carotid"[Mesh] #10 Search (#3 and #9) #11 Search "Angioplasty"[Mesh] #12 Search (#3 and #11) #13 Search "Magnetic Resonance Angiography"[Mesh] #14 Search (#3 and #13) #15 Search ("Angioplasty, Balloon"[Mesh] OR "balloon dilation") #16 Search (#3 and #15) #17 Search "Stents"[Mesh] #18 Search (#3 and #17) #19 Search ("CT angiography"[tiab] OR “computed tomographic angiography”[tiab]) #20 Search (#3 and #19) #21 Search "Carotid Stenosis/radiography"[Mesh] #22 Search (#3 and #21) #23 Search (#5 or #6 or #8 or #10 or #12 or #14 or #16 or #18 or #20 or #22) #24 Search ("Randomized Controlled Trial"[Publication Type] OR "Single-Blind Method"[MeSH] OR "Double-Blind Method"[MeSH] OR "Random Allocation"[MeSH] OR trial[tiab]) #25 Search (#23 and #24) #26 Search ("review"[Publication Type] AND "systematic"[tiab]) OR "systematic review"[All Fields] OR ("review literature as topic"[MeSH] AND "systematic"[tiab]) OR "meta-analysis"[Publication Type] OR "meta-analysis as topic"[MeSH Terms] OR "meta-analysis"[All Fields]) #27 Search (#23 and #26) #28 Search (#25 or #27) #29 Search ("stroke"[MeSH Terms] OR "stroke"[All Fields] OR "brain infarction"[All Fields] OR "cerebrovascular disorder"[All Fields] OR "cerebrovascular disease"[All Fields] OR "CVA"[All Fields] OR "cerebral infarction"[All Fields] OR "ischemic stroke"[All Fields] OR (("stroke"[MeSH Terms] OR "stroke"[All Fields]) AND ("ischemia"[MeSH Terms] OR "ischemia"[All Fields] OR "ischemic"[All Fields])) OR "cerebrovascular accident"[All Fields]) #30 Search ("risk"[MeSH Terms] OR "risk assessment"[MeSH Terms] OR "risk adjustment"[MeSH Terms] OR "risk assessment"[MeSH Terms] OR ("risk"[All Fields] AND "assessment"[All Fields]) OR "risk assessment"[All Fields] OR ("assessment"[All Fields] AND "benefit"[All Fields] AND "risk"[All Fields]) OR ("assessments"[All Fields] AND "benefit"[All Fields] AND "risk"[All Fields])) #31 Search (#3 and #29 and #30) #32 Search (#31 and #24) #33 Search ("Case-Control Studies"[MeSH] OR "Cohort Studies"[MeSH] OR "comparative study"[pt] OR "Epidemiologic Studies"[MeSH] OR "Cross-Over Studies"[MeSH] OR "Follow-Up Studies"[MeSH] OR “observational study” OR “observational studies” OR "cohort"[tw] OR "case control"[tw]) #34 Search (#31 and #33) #35 Search (#32 or #34) #36 Search (#5 or #6 or #8 or #14 or #20 or #22) #37 Search (#36 and #26) #38 Search ("Endarterectomy, Carotid/statistics and numerical data"[Mesh]) #39 Search "Endarterectomy, Carotid/adverse effects"[Mesh] #40 Search (#23 or #38 or #39) #41 Search (harm OR harms OR adverse effect* OR adverse event* OR complication* OR death OR stroke OR "Myocardial Infarction"[Mesh] OR “myocardial infarction” OR (unnecessary AND “carotid endarterectomy”) OR "Kidney Failure, Chronic"[Mesh] OR "Renal Insufficiency"[Mesh] OR "Cranial Nerve Diseases"[Mesh] OR "Cranial Nerve Injuries"[Mesh] OR (neck AND hematoma*)) #42 Search (#40 and #41)

#43 #44 #45 #46 #47 #48 #49 #50 #51 #52 #53 #54 #55 #56 #57 #58 #59 #60 #61

Search (comment[pt] OR editorial[pt] OR letter[pt] OR news[pt]) Search (#25 or #27) Filters: Humans Search (#25 or #27) Filters: Humans; English Search (#25 or #27) Filters: Humans; English; Adult: 19+ years Search (#46 NOT #43) Search (#32 or #34) Filters: Humans Search (#32 or #34) Filters: Humans; English Search (#32 or #34) Filters: Humans; English; Adult: 19+ years Search (#50 NOT #43) Search (#36 and #26) Filters: Humans Search (#36 and #26) Filters: Humans; English Search (#36 and #26) Filters: Humans; English; Adult: 19+ years Search (#54 NOT #43) Search (#40 and #41) Filters: Humans Search (#40 and #41) Filters: Humans; English Search (#40 and #41) Filters: Humans; English; Adult: 19+ years Search (#58 NOT #43) Search (#47 or #51 or #55 or #59) Search (#21 or #31 or #42)

Supplement Table 3. Additional Search Strategy for MEDLINE for Studies Addressing Incremental Benefit of Medications Beyond Current Standard Medical Therapy (KQ 6) Search Query #1 Search ("Carotid Stenosis"[Mesh] OR "carotid stenosis" OR "carotid artery stenosis") #2 Search asymptomatic #3 Search (#1 and #2) #4 Search ("Aspirin"[Mesh] OR "Hydroxymethylglutaryl-CoA Reductase Inhibitors" [Pharmacological Action] OR "HydroxymethylglutarylCoA Reductase Inhibitors" [Mesh] OR statins[tiab] OR "Platelet Aggregation Inhibitors"[Mesh] OR "Drug Therapy"[Mesh] OR "drug therapy"[subheading]) #5 Search (#3 and #4) #6 Search ("Chemicals and Drugs Category"[Mesh]) #7 Search (#3 and #6) #8 Search (#7 NOT #5) #9 Search ("Randomized Controlled Trial"[Publication Type] OR "Single-Blind Method"[MeSH] OR "Double-Blind Method"[MeSH] OR "Random Allocation"[MeSH] OR trial[tiab]) #10 Search (#8 and #9) #11 Search (#8 and #9) Filters: Humans #12 Search (#8 and #9) Filters: Humans; English #13 Search (#8 and #9) Filters: Humans; English; Adult: 19+ years #14 Search ("review"[Publication Type] AND "systematic"[tiab]) OR "systematic review"[All Fields] OR ("review literature as topic"[MeSH] AND "systematic"[tiab]) OR "meta-analysis"[Publication Type] OR "meta-analysis as topic"[MeSH Terms] OR "meta-analysis"[All Fields])) Filters: Humans; English; Adult: 19+ years #15 Search (#8 and #14) Filters: Humans; English; Adult: 19+ years #16 Search (Chlorthalidone[mesh] AND #8) #17 Search (Chlorthalidone[mesh] AND #3) #18 Search (Hydrochlorothiazide[mesh] AND #3) #19 Search (#18 AND (#9 or #14)) #20 Search (#18 AND (#9 or #14)) Filters: Humans #21 Search (#18 AND (#9 or #14)) Filters: Humans; English #22 Search (#18 AND (#9 or #14)) Filters: Humans; English; Adult: 19+ years #23 Search (#22 NOT (#5 or #13)) Filters: Humans; English; Adult: 19+ years #24 Search ("Lisinopril"[Mesh] AND #3) Filters: Humans; English; Adult: 19+ years #25 Search ("Metoprolol"[Mesh] AND #3) Filters: Humans; English; Adult: 19+ years #26 Search (#5 and (#9 or #14)) Filters: Humans; English; Adult: 19+ years #27 Search (#13 or #22 or #26) Filters: Humans; English; Adult: 19+ years #28 Search (#13 or #22 or #26)

Supplement Table 4. Inclusion/Exclusion Criteria Inclusion Asymptomatic adults with CAS that is potentially clinically important (defined as 60% to 99% Populations stenosis). Asymptomatic indicates that patients have no significant neurologic symptoms referable to the carotid artery and have not experienced a cerebrovascular event (i.e., a stroke or transient ischemic attack). We will include studies that enroll both symptomatic and asymptomatic adults, but that analyze the asymptomatic group separately. Among asymptomatic participants, some trials enroll a minority of participants who have not had symptoms for some specified time period (e.g., the past 180 days), but who had prior symptoms or cerebrovascular events. Although our focus is on people who have never had cerebrovascular events, we will include such studies if they enroll 70% or more participants who never had symptoms referable to the carotid artery and never had a cerebrovascular event into the “asymptomatic” group. Setting Screening

Treatment/ Management Interventions Comparisons

Outcomes

Study Designs

Studies conducted in developed countries Screening with carotid duplex ultrasonography, used alone or followed by CTA or MRA with or without confirmatory testing with angiography. Studies that use a single screening test as well as those that use multiple tests in series (e.g., ultrasonography followed by MRA for persons with potentially significant ultrasound findings) will be included. CEA, CAAS, medical therapy (e.g., aspirin, statins, antiplatelet medications)

KQ 1: screened versus nonscreened groups. KQ 2: studies must determine/compare those at increased, average, or decreased risk, or those at higher and lower risk of CAS 60-99%. KQ 3: studies on accuracy of screening must include a comparison with angiography; studies on reliability of screening must include measures of reproducibility (e.g., test-retest, comparison between different labs or readers). KQ 4: studies must determine/compare those at increased, average, or decreased risk, or those at higher and lower risk of ipsilateral stroke (KQ 4a) or periprocedural harms from CEA or CAAS (KQ 4b). KQ 5: medical treatment/usual care. KQ 6: studies must compare the addition of one or more medications to current standard medical therapy (that includes treatment of traditional risk factors) versus the addition of placebo to current standard medical therapy (that includes treatment of traditional risk factors) KQ 7: screened versus nonscreened groups or those having angiography versus not having angiography or non-comparative studies reporting rates of harms. KQ 8: medical treatment/usual care or noncomparative studies reporting rates of harms. KQs 1, 5 and 6, health outcomes: CAS-related fatal or nonfatal stroke. Quality of life and functional status. KQ 2 (assessment of risk stratification tools): adjusted hazard ratio (or risk ratio or odds ratio), discrimination, calibration, reclassification; tools must be externally validated. KQ 3 (diagnostic accuracy and reliability of screening tests): sensitivity and specificity. KQ 4 (assessment of risk stratification tools): adjusted hazard ratio (or risk ratio or odds ratio), discrimination, calibration, reclassification; tools must be externally validated. KQ 7 (harms of screening or confirmatory tests): false positives leading to unnecessary treatment, nonfatal stroke, fatal stroke, persistent neurological complications, renal failure. KQ 8 (harms of CEA or CAAS): perioperative complications including stroke, death, nonfatal myocardial infarction, cranial nerve injuries. KQ 1: randomized controlled trials (RCTs) that compare screened versus nonscreened groups. KQ 2: cohort studies that develop risk stratification tools and then validate the tools using an external population. Studies must follow a cohort of asymptomatic people to develop a tool, derived from a multivariate analysis, predicting risk of CAS. Risk stratification tools (or “risk prediction tools”) must combine multiple variables and allow us to calculate risk for individual patients.

Exclusion Children and adolescents; symptomatic adults with CAS; adults with history of transient ischemic attacks or stroke; studies of people with carotid occlusion; studies of people undergoing CABG and others confined to a focused population, such as those with radiation exposure or PVD; people with remote CEA or CAAS undergoing surveillance for restenosis. Physical examination for carotid bruit

No comparison; nonconcordant historical controls; comparative studies of CEA versus CAAS.

Restenosis, quality-adjusted life years.

All other designs; studies enrolling both symptomatic and asymptomatic patients that do not analyze them separately.

Language

Inclusion KQ 3: systematic reviews that compare screening tests (ultrasonography, MRA, or CTA) with angiography. Primary studies comparing screening tests with angiography that were published after the included systematic reviews will be included (i.e., bridge searches will be performed to determine what is new since the systematic reviews and whether it is consistent with the systematic reviews). KQ 4: cohort studies that develop risk stratification tools for adults with asymptomatic CAS and then validate the tools using an external population. Studies must follow a cohort of people with asymptomatic CAS 60-99% to develop a tool, derived from a multivariate analysis, predicting risk of ipsilateral stroke (KQ 4a) or periprocedural harms (KQ 4b). Risk stratification tools (or “risk prediction tools”) must combine multiple variables and allow us to calculate risk for individual patients. Risk stratification tools may include clinical factors (e.g., age, diabetes) and anatomic or imaging predictors (e.g., plaque area or morphology, silent embolic events, contralateral disease). KQ 5: systematic reviews and RCTs of CEA or CAAS comparing surgical/interventional treatment with medical treatment. KQ 6: systematic reviews and RCTs. KQ 7: systematic reviews or multi-institution studies (RCTs or cohort studies) that report harms of screening or confirmatory tests. KQ 8: systematic reviews or multi-institution studies (RCTs or cohort studies) that report 30day or longer harms for asymptomatic patients undergoing CEA or CAAS. English

Exclusion

Non-English

Note: For the population of interest, we will not rigidly consider those with 60-99% CAS as a single homogeneous cohort. Rather, we will include studies enrolling participants beyond that degree of CAS (e.g., 50-99% CAS), and we will evaluate the available evidence for various subgroups within that cohort. For example, we will evaluate evidence for those with 80-99% CAS, if available. The settings are limited to developed countries to find evidence most applicable to the United States. Other settings are unlikely to have screening and interventions comparable to those in the United States. Physical examination for carotid bruit is not included as a screening method under evaluation because an earlier review for the USPSTF (1996) concluded that auscultation for carotid bruits is imperfect, with low sensitivity and specificity and considerable interobserver variation in the interpretation of key auditory characteristics. We scanned the literature published since the 1996 review and found no compelling evidence to suggest that auscultation has become any better as a screening tool to detect clinically significant levels of asymptomatic CAS. Our search identified 51 references, of which 4 reported on the accuracy of screening for CAS by auscultation of the carotid artery. Those studies used varying cutoffs for CAS; minimum cutoff values ranged from 50% to 70%. All studies used ultrasound as the gold standard. The reported sensitivities ranged from 46% to 77%, and specificities ranged from 71% to 98%. Notably, only two of the studies were of patients from the general population (one in the United States and the other in France); one study included Swedish patients referred to a hospital for carotid surgery investigation, and the fourth study was among Chinese patients with peripheral vascular disease. Abbreviations: CAAS = carotid angioplasty and stenting; CABG = coronary artery bypass grafting; CAD = coronary artery disease; CAS = carotid artery stenosis; CEA = carotid endarterectomy; CTA = computed tomography angiogram; KQ = Key Question; MRA = magnetic resonance angiography; PVD = peripheral vascular disease; RCT = randomized controlled trial.

Supplement Table 5. Included Good- or Fair-Quality Studies on Accuracy of Screening With Duplex Ultrasonography to Detect CAS Study, Year Study N Degree of Method of Proportion of Mean % Sensitivity (95% Specificity (95% (Reference) Design Stenosis Classification (e.g., Arteries Age (Y) Men CI) CI) NASCET, ECST) Asymptomatic Jahromi et al, 2005 SR/MA 1,716 ≥50%; PSV ≥ NASCET NR 66 70 98% (97% to 100%) 88% (76% to 100%) (28) patients 130 cm/s 2,140 ≥ 70%; PSV ≥ 90% (84% to 94%) 94% (88% to 97%) patients 200 cm/s Nederkoorn et al, 2003 SR/MA NR 70-99% NASCET NR NR NR 86% (84% to 89%) 87% (84% to 90%) (29) Blakely et al, 1995 SR/MA 3,989 >50% NASCET NR 62 65 91% (85% to 93%)* 92% (88% to 93%)* (27) arteries 2,646 88% (83% to 91%)* 91% (87% to 94%)* arteries >70% Sabeti et al, 2004 (30) Cross1,006 70-99%; NASCET NR 70 69 97% (95% to 99%) 66% (63% to 71%) sectional arteries; PSV>250 cm/s 503 patients *Values estimated from figure. Abbreviations: ACAS, Asymptomatic Carotid Atherosclerosis Study; CC, common carotid; CI, confidence interval; ECST, European Carotid Surgery Trial; MA, metaanalysis; NASCET, North American Symptomatic Carotid Endarterectomy Trial; RCT, randomized controlled trial; SR, systematic review; VACS, Veterans’ Affairs Cooperative Study; y, years

Quality

Good

Fair Good

Fair

Supplement Table 6. Characteristics of Additional Studies Rated as Good or Fair Quality and Reporting Rates of Peri-Procedural Complications of CEA or CAAS for Adults With Asymptomatic Carotid Artery Stenosis Study, Year Design Procedure Setting and Sample Selection Criteria Sample Participants’ Characteristics* Threats to Internal and Quality (Reference) Source External Validity Study period N Total Population (N asymp) Cohort studies Bratzler et al, Cohort study CEA Oklahoma Medicare claims used to identify Median Age: 73 May have missed nonfatal Fair 1996 (57) Medicare all CEA cases. White: NR neurologic events occurring 1/1993813 (347); 774 Beneficiaries, 8 Female: NR after discharge that did not 12/1994 patients hospitals DM: 26% result in another Asymptomatic defined as no CAD: 67% hospitalization; no prior TIA or stroke in the COPD: 20% comprehensive exam by distribution of the operated HF: 10% neurologist for outcome carotid artery. HTN: 71% assessment; definition of Smoker: 26% symptomatic CAS required Stenosis: 96% >60% CAS documentation of past TIA Prior contralateral CEA: NR or stroke in the distribution Contralateral occlusion: NR of the carotid being operated Contralateral TIA/stroke: NR on. Cebul et al, Cohort study CEA Ohio non-HMO Medicare part A claims used to Mean Age: 73 May have missed nonfatal Fair 1998 (58) Medicare identify all non-HMO Medicare White: 94% neurologic events occurring beneficiaries, 115 beneficiaries who underwent Female: 46% after discharge that did not 7/1993-6/1994 678 (167) hospitals and at CEA; random sample of the DM: 26% result in another least 478 4120 CEAs performed. CAD: NR hospitalization; no surgeons COPD: 15% comprehensive exam by HF: 9% neurologist for outcome Asymptomatic if no record of HTN: 71% assessment; interrater any neurologic symptoms or reliability for determining signs; categorized as nonspecific Smoker: 31% indication for surgery (TIA, symptoms if had nonlateralizing Stenosis: NR Prior contralateral CEA: NR stroke, asymptomatic or symptoms or signs (e.g., Contralateral occlusion: NR nonspecific symptoms) of dizziness, dementia). Contralateral TIA/stroke: NR 77% (kappa 0.69).

Study, Year (Reference)

Giacovelli et al, 2010 (70)

Design

Study period N Total (N asymp) Cohort study CEA & CAAS 2005-2007

Giles et al, 2010 (73)

Procedure

Cohort study 10/200412/2007

47,752 total CAAS + CEA (42,236)

Setting and Source Population

NY and CA state ICD-9 codes to identify patients hospital discharge who had CAAS or CEA. Uses “present on admission” (POA) databases flag in discharge diagnoses to identify symptom status.

4,919 (4,353) used in the matched propensity analysis comparing CAAS and CEA CEA & CAAS NIS database‡ 538,958 (52.937) CAAS: 56,564 (49,126) CEA: 482,394 (436,895)

Sample Selection Criteria

ICD-9 codes from NIS database Patients with symptomatic carotid stenosis were identified by ICD-9 diagnosis codes of TIA, amaurosis fugax, or stroke. Patients also classified as CMS high risk based on prespecified criteria.

Sample Participants’ Characteristics*

Threats to Internal and External Validity

Quality

Mean Age† CEA: 73; CAAS: 71 White: CEA: 86%; CAAS: 77% Female: CEA: 43%; CAAS: 39% DM: CEA: 27%; CAAS: 30% CAD/HF: CEA: 44%; CAAS: 57% COPD: CEA: 14%; CAAS: 13% HTN: CEA: 71%; CAAS: 74% Smoker: NR Stenosis: NR Prior contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: NR

Used present on admission Fair designations to determine symptom status at baseline; used ICD-9 codes only for outcome ascertainment; no supplementation with review of medical records; inhospital outcomes only.

Mean Age: CEA: 71; CAAS: 70 White: NR Female: CEA: 43%; CAAS: 40% DM: NR CAD (Previous MI): CEA: 11%; CAAS: 10% COPD: CEA: 22%; CAAS: 19% HF: CEA: 7%; CAAS: 11% HTN: NR Smoker: NR Stenosis: NR Prior contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: NR

Used ICD-9 codes only for Fair outcome ascertainment; no supplementation with review of medical records; inhospital outcomes only; potential for bias due to misclassification of symptom status and whether stroke was the indication or a perioperative harm.


Design

Procedure

Study period N Total (N asymp) Cohort study CEA


Halm et al, 2003 (59); Rockman et 1/1997al, 2005 (68); 12/1998 Halm et al, 2005 (60); Press et al, 2006 (67)

6 hospitals in New York (4 2,124 (1,413) university and 2 (N varies slightly community across hospitals); 67 publications) surgeons

Halm et al, 2007 (62); Halm et al, 2009 (61)

CEA

Cohort study (NYCAS)

9,588 (6,932) 1/1998-6/1999




Used administrative databases from 6 hospitals; consecutive CEAs (identified by ICD-9 codes).

Mean Age: 72 White: 87%% Female: 43% DM: 29%% CAD: 55%% COPD: 9%% HF: 8%% HTN: 73% Smoker: NR% Stenosis: 90.1% had 70-99% CAS Prior contralateral CEA: NR Contralateral occlusion: 6% Contralateral TIA/stroke: NR Mean Age: 75 White: 93% Female: 44% DM: 30% CAD: 62% COPD: 19% HF: 10% HTN: 79% Smoker: NR Stenosis: 94% with 70-99%; 1% with 100% occlusion; 2.9% with 60-69% Prior contralateral CEA: NR Contralateral occlusion: 5% with 100%; 24% with 70-99%; 5% with 60-69% Contralateral TIA/stroke: NR

May have missed Fair readmissions to other hospitals (only included readmissions to the index hospital); data from 1 region of New York; no comprehensive exam by neurologist for outcome assessment.

Indication for surgery based on acuity of the presenting neurologic symptoms in the 12 months before surgery (strokein-evolution, stroke, carotid TIA, asymptomatic, etc.).

NY State Any NY state Medicare claims Medicare for CEA and NY state hospital beneficiaries; 166 discharge database. hospitals; 488 surgeons

Quality

May have missed nonfatal Fair neurologic events occurring after discharge that did not result in another hospitalization; no comprehensive exam by neurologist for outcome assessment. Data abstractors had to pass a series of quality assurances and inter-rater reliability tests. Data reported had kappa from 0.60 to 1.0.


Design

Procedure

Study period N Total (N asymp) Hopkins et al, Cohort study CAAS 2010 (69) (lead-in/ credentialing phase of 1,565 (1,151) CREST) 11/20004/2008

Karp et al, 1998 (63)

Cohort study

CEA

1/199312/1993

1,945 (1,002)



Lead-in case data was reviewed prospectively for 427 potential interventionalists

Asymptomatic participants had to have >70% stenosis by angiography. Ascertainment of symptom status is unclear; cases were submitted by potential interventionalists to a multidisciplinary committee for review.


Mean Age: 70 White: 88% Female: 37% DM: 33% CAD: 24% with previous CABG COPD: NR HF: NR HTN: 84% Smoker: 18% Stenosis: 79% Prior contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: NR Georgia Medicare Georgia Medicare Claims; ICD- Mean Age: 72 beneficiaries 9 codes used to identify patients White: 91% who underwent CEA. Female: 47% DM: 20% Asymptomatic defined CAD: NR following ACAS (absence of symptoms in distribution of the COPD: 24% HF: 8% operated carotid artery). HTN: NR Smoker: NR Stenosis: 22% had 56-75%; 70% had >75% Prior contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: NR


Quality

Unclear whether cases are representative of the source population.

Fair

May have missed nonfatal Fair neurologic events occurring after discharge that did not result in another hospitalization; no comprehensive exam by neurologist for outcome assessment.


Kresowik et al, 2000 (66)

Kresowik, 2001 (65)

Design

Procedure



Iowa Medicare beneficiaries, 30 1/19942,063 CEAs (671 hospitals; 79 12/1994 and CEAs; 1994 only: surgeons 6/1995-5/1996 159)

Cohort study

CEA

6/1995-5/1996 10,561 (3,891); 10,030 patients


Claims for CEA (ICD-9) from Medicare Provider Analysis and Review (MEDPAR) Part A claims; Part B files for CPT codes also used. Considered asymptomatic if no history prior to CEA of CV symptoms or events in either the anterior or posterior circulations.


Median Age: 74 White: NR Female: 40-41% DM: NR CAD: NR COPD: NR HF: NR HTN: NR Smoker: NR Stenosis: NR Prior contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: NR Medicare Used ICD-9 code for CEA Mean age: 74 beneficiaries from among Medicare Provider White: NR Analysis and Review Female: 43% 10 US states§ (MEDPAR) Part A claims. DM: NR Considered asymptomatic if no CAD: NR COPD: NR history prior to CEA of CV symptoms or events in either the HF: NR anterior or posterior circulations. HTN: NR Smoker: NR Stenosis: NR Prior contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: NR


Quality





Design

Procedure




Medicare ICD-9 code for CEA among beneficiaries from Medicare Provider Analysis and Review (MEDPAR) Part A 6/1995-5/1996 19,690 10 US states§ claims. and 6/1998 – (1995-96: 3,891; 1998-99: 4,093) 5/1999 Considered asymptomatic if there was no history prior to CEA of CV symptoms or events in either the anterior or posterior circulations.

McPhee et al, Cohort study 2007 (74) 1/200312/2004


Median Age: 74 White: NR Female: 43-44% DM: NR CAD: NR COPD: NR HF: NR HTN: NR Smoker: NR Stenosis: NR Prior contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: NR CEA and CAAS NIS (Nationwide ICD-9 codes from NIS database Mean Age: CEA: 71; CAAS: 71 Inpatient Median Age: CEA: 72; CAAS: 72 259,080 CEAs / Sample)‡ White: NR CAASs Female: CEA: 43%; CAAS: 41% (238,389 CEAs / DM: CEA: 25%; CAAS: 26% CAASs) CAD/MI: CEA: 12%; CAAS: 12% COPD: CEA: 19%; CAAS: 15% 245,045 CEAs HF: CEA: 6%; CAAS: 9% (226,111 CEAs); HTN: CEA: 71%; CAAS: 67% Smoker: NR 14,035 CAASs Stenosis: NR (12,278 CAASs) Prior contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: NR


Quality


Before 10/2004 no specific Fair CAAS ICD-9 code existed, so required 2-step method to identify CAAS procedures with potential for misclassification. Used ICD-9 codes only for outcome ascertainment; no supplementation with review of medical records; inhospital outcomes only; potential for bias due to misclassification of symptom status and whether stroke was the indication or a perioperative harm.


Design

Procedure

Study period N Total (N asymp) McPhee et al, Cohort study CEA and CAAS 2008 (75) 2005 135,701 (122,986)



NIS database‡

ICD-9 codes from NIS database Mean age†: CEA: 71; CAAS: 72 White: NR Female: CEA: 43%; CAAS: 37% DM: CEA: 27%; CAAS: 27% CAD/MI: CEA: 11%; CAAS: 12% COPD: CEA: 21%; CAAS: 18% HF: CEA: 7%; CAAS: 11% HTN: CEA: 72%; CAAS: 66% Smoker: NR Stenosis: NR Prior contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: NR ICD-9 codes from NIS database Median age: CEA: 72; CAAS: 72 White: NR Female: CEA: 43%; CAAS: 38% DM: CEA: 29%; CAAS: 28% Previous MI: CEA: 12%; CAAS: 11% COPD: CEA: 21%; CAAS: 18% HF: CEA: 8%; CAAS: 12% HTN: CEA: 76%; CAAS: 69% Smoker: NR Stenosis: NR Prior contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: NR

CEA: 122,786 (111,684) CAAS: 12,914 (11,302)

Timaran et al, Cohort study 2009 (76) 2005

CEA & CAAS CAAS: 13,093 (11,836) CEA:122,984 (113,514)

NIS database‡



Quality




Vouyouka et al, 2012 (71)

Design

Procedure

Study period N Total (N asymp) Cohort study CEA and CAAS 2007-2009


NY and FL state discharge 20,613 CEAs / databases to CAASs (18,519) identify women who underwent CEA: 18,320 CEA or CAAS (16,576) CAAS: 2,263 (1,943)

Young et al, 2011 (77)

Cohort study

CEA & CAAS

2006-2007

249,592 (all asymptom-atic) CAAS: 31,197 (all) CEA: 218,395 (all)

NIS database‡



Mean Age:† 72 White: 90% Female: 100% DM: 30% CAD: 37% COPD: 2% HF: 6% HTN: 80% Smoker: NR Stenosis: NR Prior contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: NR ICD-9 codes from NIS database Mean age: 71; CEA: 71; CAAS: 71 Asymptomatic precerebral White: 66%; CEA: 65%; CAAS: 68% stenosis codes as indication for Female: 43%; CEA: 43%; CAAS: 40% CAS/CEA, excluding TIA as DM: 31%; CEA: 31%; CAAS: 30% indication for CAAS/CEA CAD (previous MI): 50%; CEA: 49%; CAAS: Also stratified patients by age 57% 70: CEA: 66%; CAAS: 62% White: CEA; 90%; CAAS: 83% 2005-2009 30,317 (all Female: CEA: 43%; CAAS: 44% asymptom-atic) DM, complicated: CEA: 5%; CAAS: 4% Previous MI: NR CAAS: 3,476 COPD: CEA: 20%; CAAS: 17% (all) HF: CEA: 8%; CAAS: 11% HTN, complicated: CEA: 10%; CAAS: 11% Smoker: NR CEA: 26,841 (all) Stenosis: NR Prior contralateral CEA: NR Contralateral occlusion: NR Contralateral TIA/stroke: NR RCT CEA and CAAS Multicenter (117 Asymptomatic patients had to CEA/CAAS‖ (CREST) sites) have at least 60% stenosis by Mean age: 70/69 CEA angiography, at least 70% by White: 95%/94% 12/20001,240 ultrasound or at least 80% by Female: 33%/36% 7/2008; (587) CT or MR angiography (if the DM: 34%/33% asymptomatic stenosis by ultrasound was CAD: 44% patients were CAAS initially read as 50-60%). COPD: NR only included 1,262 Asymptomatic defined as HF: NR from 2005 (594) symptoms referable only to the HTN: 88%/88% forward hemisphere contralateral to the Smoker: 22%/26% target vessel or symptoms in Stenosis: 92%/93% with =/>70% stenosis either hemisphere >180 days Prior contralateral CEA: NR prior to randomization, or Contralateral occlusion: 3%/2% vertebrobasilar symptoms only. Contralateral TIA/stroke: NR


Quality

Used present on admission Fair designations to determine symptom status at baseline; used ICD-9 codes only for outcome ascertainment; no supplementation with review of medical records; inhospital outcomes only

Unclear whether cases are Fair representative of the source population. A comprehensive training and credentialing process was required of participating interventionalists; only those with low complication rates were invited to participate in the study.


Design

Procedure

Study period N Total (N asymp) CASANOVA RCT CEA study group, 1991 (48) 1982-1988 410 (all)


Uncontrolled trial (CAPTURE2)

CAAS 5,297 (4,337)

3/2006-1/2009 50% and 70% Prior contralateral CEA: 27% Contralateral occlusion: NR Contralateral TIA/stroke: NR Asymptomatic pts had to have > Mean age: 73¶ 80% stenosis to have CAAS. White: NR Asymptomatic patients had no Female: 39% TIA, amaurosis fugax, or stroke DM: 37% in the territory supplied by the CAD: 74% COPD: 23% target vessel within 180 days. HF: 19% HTN: 89% Smoker: 22% Stenosis: 86% Prior contralateral CEA: 17% Contralateral occlusion: 17% Contralateral TIA/stroke: NR


Quality

Patient population Asymptomatic stenosis >50% recruited from and 80% stenosis. All participants had to have one high risk criteria (e.g. severe pulmonary disease, age >80).

Data for follow-up years, age are mean unless otherwise specified. *Sample characteristics are of entire cohort (symptomatic and asymptomatic patients) unless otherwise noted. † Characteristics are for the asymptomatic subgroup, not whole sample.

Quality

Unclear whether cases are Fair representative of the source population. Highly selected surgeons and interventionalists; participating interventionalists had to demonstrate a low complication rate with CEA or CAAS in order to participate in the trial. Unclear whether symptom status was determined using valid and reliable methods.

‡

Database of abstracted discharge data from national survey of 20% of all nonfederal hospitals in US; linked to AHA annual survey of hospitals; asymptomatic if principal discharge diagnosis was CAS “without mention of stroke” with no accompanying secondary diagnoses for TIA. § Arkansas, Georgia, Illinois, Indiana, Iowa, Kentucky, Michigan, Nebraska, Ohio, and Oklahoma. ‖ Patient characteristics are given for asymptomatic patients. ¶ These are for the asymptomatic patient population. Abbreviations: Asymp = asymptomatic; CAAS = carotid angioplasty and stenting; CAD = coronary artery disease; CAS = carotid artery stenosis; CEA = carotid endarterectomy; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; CPT = current procedural terminology; CV = cerebrovascular; DM = diabetes mellitus; HF = heart failure; HTN = hypertension; MI = myocardial infarction; N = sample size; NR = not reported; RCT = randomized controlled trial; TIA = transient ischemic attack; U/S = ultrasound; y = years.

Supplement Table 7. Results From Additional Studies Rated as Good or Fair Quality and Reporting Rates of Peri-Procedural Complications of CEA or CAAS for Adults With Asymptomatic Carotid Artery Stenosis Study, Year Method of Outcome Assessment In-Hospital Rates 30-Day Rates Cohort Studies Bratzler et al, Standard data collection form; abstractors used administrative data and NR Combined* stroke or death: 1996 (57) medical records; also used MedPRO data to identify patients who died or Overall: 3.7% were readmitted with a principal diagnosis of stroke within 30 days. High† volume hospitals: 3.5% Low-volume hospitals: 5.2% Stroke: Overall: 2.6% High-volume hospitals: 2.8% Low-volume hospitals: 1.7%

Cebul et al, 1998 (58)

Administrative data and chart review; trained nurse reviewers to identify outcomes during hospitalization; Medicare Provider Analysis and Review claims to identify all deaths and readmissions within 30 days of CEA, and the records of those were reviewed for occurrence of strokes.

NR

Giacovelli et al, 2010 (70)

ICD-9 codes

Postoperative stroke (propensity matched): CEA: 1.8%; CAAS: 2.0% Postoperative TIA (Propensity matched): CEA: 0.3%; CAAS: 0.3% Postoperative mortality (propensity matched): CEA: 0.4%; CAAS: 0.6% Combined postoperative stroke/death (propensity matched): CEA: 1.9%; CAAS: 2.4%

Death: Overall: 1.2% High-volume hospitals: 0.7% Low-volume hospitals: 3.4% Stroke or death: Overall: 2.4% High-volume hospitals: 0% Low-volume hospitals: 4.9% Being operated on in a higher-volume hospital conferred a 71% reduction in risk for 30-day stroke or death, controlling for indications, comorbid conditions, and surgeon’s volume: OR 0.3; 95% CI, 0.1 to 0.7). Outcomes did not differ significantly by surgeon volume. NR

Study, Year Giles et al, 2010 (73)

Method of Outcome Assessment ICD-9 codes

In-Hospital Rates Postoperative stroke: CEA: 0.6%; CAAS: 1.0% Postoperative mortality: CEA: 0.4%; CAAS: 0.8% Combined postoperative stroke/death: CEA: 0.9%; CAAS: 1.6% NR

30-Day Rates NR

Halm et al, 2003 (59); Rockman et al, 2005 (68); Halm et al, 2005 (60); Press et al, 2006 (67) Halm et al, 2007 (62); Halm et al, 2009 (61)

Abstracted from inpatient and outpatient medical records, including all readmissions; 2 investigators independently reviewed records of all those who sustained strokes or TIAs, including 1 neurologist.

Medicare claims; ICD-9 codes; hospital records. Research nurses abstracted data from index admission and all readmissions within 30 days of surgery for death, stroke, or TIA. Confirmed by 2 study physicians (including a neurologist). Disagreements resolved by consensus.

NR

Stroke severity was judged by a single physician based on chart review.

NR

Death and stroke: 3.0% Death or stroke in those with high comorbidity: 7.1%‡ Death or stroke rate in those without high comorbidity: 2.7%‡ Death, stroke and MI: 4.8% Death, any stroke: 3.8% Death, major stroke: 1.8% Death: 0.5% Major stroke: 1.6% Minor stroke: 2.0%

Hopkins et al, 2010 (69); CREST (lead-in/ credentialing)

Death: 0.6 Nonfatal stroke: 1.7 Death/stroke: 2.3 Nonfatal MI: 0.9

Age ≤75/age>75 Death, stroke and MI: 3.3%/9.1% Death, any stroke: 2.4%/7.5% Death, major stroke: 1.2%/3.2% Death: 0.5%/0.7% Major stroke: 1.1%/2.9% Minor stroke: 1.2%/4.3%

Study, Year Karp et al, 1998 (63)

Method of Outcome Assessment Claims and medical records. Trained medical abstractors pulled from medical records; a physician reviewed all records in which the abstractor determined that the patient had a stroke to verify and to determine the severity; deaths from Medicare claims and from Social Security files if the patient died at home.


Abstraction from medical records by trained abstractors for index hospitalization and any readmissions; Medicare beneficiary data set to identify deaths within 30 days.


MEDPAR files; ICD-9 codes; Medicare Enrollment Database to identify deaths; comprehensive review of all medical records for the index hospitalization and all admissions within 30 days by trained abstractors.

In-Hospital Rates NR

Combined stroke or death: Overall: 2.8% ’94: 2.5% ’95-’96: 2.9% NR

30-Day Rates All strokes:§ 2.4% Moderate/severe strokes: 1.0% Stroke-related death: 0.2% MI: 0.8% MI-related death: 0.6% Statistically significant increase in morbidity, mortality, and less severe complications at hospitals performing 10 or fewer CEAs. Combined stroke or death: Overall: 3.4% ’94: 3.8% ’95-’96: 3.3% Combined stroke or death: ’95-’96: 4.1% ’98-’99: 3.8% Death: ’95-’96: 1.1% ’98-’99: 1.0%


MEDPAR files; ICD-9 codes; Medicare Enrollment Database to identify deaths; comprehensive review of all medical records for the index hospitalization and all admissions within 30 days by trained abstractors; independent review of strokes by 2 clinicians with expertise in stroke; subset of those classified as having no stroke was also independently reviewed by 2 clinicians.

NR

McPhee et al, 2007 (74)

ICD-9 codes

Postoperative stroke: CEA: 0.9%; CAAS: 1.8% Postoperative mortality: CEA: 0.3%; CAAS: 0.4% Postoperative MI: CEA: 1.7%; CAAS: 2.0%

Combined stroke and death rates (’98-’99) ranged from 1.4% to 6.0% across 10 states; 3 states differed significantly from the mean. Combined stroke or death: 3.7%‖ Death: 1.1% Combined stroke and death rates ranged from 2.3% to 6.7% across 10 states; 2 states differed significantly from the mean. Mortality rate ranged from 0.5% to 2.5% across 10 states; 1 state differed significantly from the mean. NR

Study, Year McPhee et al, 2008 (75)

Timaran et al, 2009 (76)

Method of Outcome Assessment ICD-9 codes

ICD-9 codes

In-Hospital Rates In-hospital mortality CEA: 0.4%; CAAS: 0.6% Postoperative stroke CEA: 0.9%; CAAS:1.6% Postoperative stroke: CEA: 1.0%; CAAS: 1.8%

30-Day Rates NR

NR

In-hospital mortality: CEA: 0.5%; CAAS: 0.7% Vouyouka et al, 2012 (71)

ICD-9 codes

Young et al, 2011 (77)

ICD-9 codes

Yuo et al, 2013 (72)

ICD-9 codes

Trials

Postoperative stroke: CEA: 1.5%; CAAS: 2.6%; Propensity matched: CEA: 2.1%; CAAS: 2.7% Postoperative mortality: CEA: 0.3%; CAAS: 0.8%; Propensity matched: CEA: 0.4%; CAAS: 0.8% Combined postoperative stroke/death: CEA: 1.7%; CAAS: 3.1%; propensity matched: CEA: 2.2%; CAAS: 3.1% In-hospital stroke: CEA: 0.9%; CAAS: 1.3% In-hospital death: CEA: 0.4%; CAAS: 0.6% Combined in-hospital stroke/death: CEA: 1.2%; CAAS: 1.7% In-hospital cardiac complications: CEA: 1.9%; CAAS: 2.2% Combined in-hospital stroke/death/cardiac complications: CEA: 2.9%; CAAS: 3.7% In-hospital stroke: CEA: 1.5%; CAAS: 3.2% In-hospital death: CEA: 0.5%; CAAS: 1.4% Combined in-hospital stroke/death: CEA: 1.8%; CAAS: 4.1%

NR

NR

NR

Study, Year Brott et al, 2010 (50); Silver et al, 2011 (51)

CASANOVA study group, 1991 (48)

Method of Outcome Assessment Neurological examination, including NIHSS assessment and TIA - stroke questionnaire. Study committees unaware of treatment assignment adjudicated stroke and MI events.

CT scan, neurologic consultant blinded to group assignment.

In-Hospital Rates NR

NR

30-Day Rates CAAS: All pts/pts

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