Wireless Capsule Endoscopy to Diagnose Disorders of the Small Bowel, Esophagus, and Colon - CAM 60133

Description:
The wireless capsule endoscopy (CE) uses a noninvasive device to visualize segments of the gastrointestinal tract. Patients swallow a capsule that records images of the intestinal mucosa as it passes through the gastrointestinal (GI) tract. The capsule is collected after being excreted and images interpreted.

Summary of Evidence
Patients With Suspected GI Disorders
For individuals who have suspected small bowel bleeding (previously referred to as obscure GI bleeding) who receive wireless CE, the evidence includes numerous case series evaluating patients with a nondiagnostic standard workup. Relevant outcomes are test validity, other test performance measures, symptoms, and change in disease status. The evidence has demonstrated that CE can identify a bleeding source in a substantial number of patients who cannot be diagnosed by other methods, with a low incidence of adverse events. Because there are few other options for diagnosing obscure small bowel bleeding in patients with negative upper and lower endoscopy, this technique will likely improve health outcomes by directing specific treatment when a bleeding source is identified. The evidence is sufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals who have suspected small bowel Crohn disease (CD) who receive wireless CE, the evidence includes case series. Relevant outcomes are test validity, other test performance measures, symptoms, and change in disease status. Although the test performance characteristics and diagnostic yields of the capsule for this indication are uncertain, the diagnostic yields are as good as or better than other diagnostic options, and these data are likely to improve health outcomes by identifying some cases of CD and directing specific treatment. The evidence is sufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals who have suspected celiac disease who receive wireless CE, the evidence includes case series and diagnostic accuracy studies. Relevant outcomes are test validity, other test performance measures, symptoms, and change in disease status. The diagnostic characteristics of CE are inadequate to substitute for other modalities or to triage patients to other modalities. For other conditions (e.g., determining the extent of CD), direct evidence of improved outcomes or a strong indirect chain of evidence to improved outcomes is lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals who have unexplained chronic abdominal pain who receive wireless CE, the evidence includes case series and diagnostic accuracy studies. Relevant outcomes are test validity, other test performance measures, symptoms, and change in disease status. The diagnostic characteristics of CE are inadequate to substitute for other modalities or to triage patients to other modalities. For other conditions (e.g., determining the extent of CD), direct evidence of improved outcomes or a strong chain of evidence to improved outcomes is lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Patients With Confirmed GI Disorders
For individuals who have an established diagnosis of CD who receive wireless CE, the evidence includes diagnostic accuracy studies and a systematic review. Relevant outcomes are test validity, other test performance measures, symptoms, and change in disease status. A 2017 systematic review of 11 studies in patients with established CD found a similar diagnostic yield with CE and with radiography. Because there is evidence that the diagnostic yields are as good as or better than other diagnostic options, there is indirect evidence that CE is likely to improve health outcomes by identifying some cases of CD and directing specific treatment. The evidence is sufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals who have ulcerative colitis who receive wireless CE, the evidence includes case series and diagnostic accuracy studies. Relevant outcomes are test validity, other test performance measures, symptoms, and change in disease status. Several diagnostic accuracy studies have compared CE with colonoscopy to assess disease activity in patients with ulcerative colitis. Two of 3 studies were small (i.e., <50 patients) and thus data on diagnostic accuracy are limited. Direct evidence of improved outcomes and a strong chain of evidence to improved outcomes are lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals who have esophageal disorders who receive wireless CE, the evidence includes case series and diagnostic accuracy studies. Relevant outcomes are test validity, other test performance measures, symptoms, and change in disease status. Other available modalities are superior to CE. The diagnostic characteristics of CE are inadequate to substitute for other modalities or to triage patients to other modalities. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals who have hereditary GI polyposis syndromes who receive wireless CE, the evidence includes case series and diagnostic accuracy studies. Relevant outcomes are test validity, other test performance measures, symptoms, and change in disease status. The data are insufficient to determine whether evaluation with CE would improve patient outcomes. Further information on the prevalence and natural history of small bowel polyps in Lynch syndrome patients is necessary. At present, surveillance of the small bowel is not generally recommended as a routine intervention for patients with Lynch syndrome. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

For individuals who have portal hypertensive enteropathy who receive wireless CE, the evidence includes case series and diagnostic accuracy studies. Relevant outcomes are test validity, and other test performance measures, symptoms, and change in disease status. Systematic reviews of studies of CE’s diagnostic performance for this indicated have reported limited sensitivity and specificity. Due to insufficient data on diagnostic accuracy, a chain of evidence on clinical utility cannot be constructed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Acute Upper GI Bleeding
For individuals who have acute upper GI tract bleeding who receive wireless CE, the evidence includes an RCT and several cohort studies. Relevant outcomes are test validity, and other test performance measures, symptoms, hospitalizations, and resource utilization. The use of CE in the emergency department setting for suspected upper GI bleeding is intended to avoid unnecessary hospitalization or immediate endoscopy. Controlled studies are needed to assess further the impact of CE on health outcomes compared with standard management. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Colon Cancer Screening
For individuals who are screened for colon cancer who receive wireless CE, the evidence includes diagnostic accuracy studies and systematic reviews. Relevant outcomes are overall survival, disease-specific survival, test validity, and other test performance measures. Studies of CE in screening populations are necessary to determine the diagnostic characteristics of the test in this setting. Studies of diagnostic characteristics alone are insufficient evidence to determine the efficacy of CE for colon cancer screening. Because diagnostic performance is worse than standard colonoscopy, CE would need to be performed more frequently than standard colonoscopy to have comparable efficacy. Without direct evidence of efficacy in a clinical trial of colon cancer screening using CE, modeling studies using established mathematical models of colon precursor incidence and progression to cancer could provide estimates of efficacy in preventing colon cancer mortality. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Lower GI Tract Bleeding and Major Risks for Colonoscopy or Moderate Sedation
For individuals who are screened for colon polyps with evidence of lower GI tract bleeding and major risks for colonoscopy or moderate sedation who receive wireless CE, the evidence includes diagnostic accuracy studies. Relevant outcomes are overall survival, disease-specific survival, resource utilization, test validity, and other test performance measures. Studies of CE in the intended use population are necessary to determine the diagnostic characteristics of the test in the triage setting. Studies of diagnostic characteristics alone are insufficient evidence to determine the clinical utility of CE in this population, and no studies adequately assess the impact of findings on specific health outcomes or patient adherence. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Incomplete Colonoscopy
For individuals who are screened for colon polyps following an incomplete colonoscopy with adequate preparation who receive wireless CE, the evidence includes case series. Relevant outcomes are overall survival, disease-specific survival, resource utilization, test validity, and other test performance measures. Studies of CE compared to standard management with repeat colonoscopy in the intended use population are necessary to determine the diagnostic characteristics of the test in the triage setting. Studies of diagnostic characteristics alone are insufficient evidence to determine the clinical utility of CE in this population, and no studies adequately assess the impact of findings on specific health outcomes or patient adherence. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Patency Capsule for Patients with Bowel Stricture
For individuals who are scheduled to undergo CE for known or suspected small bowel stricture who receive a patency capsule, the evidence includes case series. Relevant outcomes are test validity, symptoms, change in disease status, and treatment-related morbidity, The available studies have reported that CE following a successful patency capsule test results in high rates of success with low rates of adverse events. The capsule is also associated with adverse events. Because of the lack of comparative data to other diagnostic strategies, it is not possible to determine whether the use of the patency capsule improves the net health outcome. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

Additional Information
Not applicable.

Background
Wireless Capsule Endoscopy
WirelessCE is performed using the PillCam Given Diagnostic Imaging System (previously called M2A), which is a disposable imaging capsule manufactured by Given Imaging. The capsule measures 11 by 30 mm and contains video imaging, self-illumination, and image transmission modules, as well as a battery supply that lasts up to 8 hours. The indwelling camera takes images at a rate of two frames per second as peristalsis carries the capsule through the gastrointestinal tract. The average transit time from ingestion to evacuation is 24 hours. The device uses wireless radio transmission to send the images to a receiving recorder device that the patient wears around the waist. This receiving device also contains localizing antennae sensors that can roughly gauge where the image was taken over the abdomen. Images are then downloaded onto a workstation for viewing and processing. 

CE hasbeen proposed as a method for identifying Crohn disease. There is no single criterion standard diagnostic test for Crohn disease; rather, diagnosis is based on a constellation of findings.1 Thus it is difficult to determine the diagnostic characteristics of various tests used to diagnose the condition and difficult to determine a single comparator diagnostic test to CE.

Regulatory Status
Table 1 summarizes various wireless CE devices with clearance by the U.S. Food and Drug Administration.

Code used: NEZ

Table 1. Wireless Capsule Endoscopy Devices Cleared by the Food and Drug Administration

Device

Manufacturer

Date Cleared

510(k) No.

Indication

CapsoCam Plus (SV-3)

CapsoVision Inc.

4/19/2019

K183192

For visualization of the small bowel mucosa in adults. It may be used as a tool in the detection of abnormalities of the small bowel.

Olympus Small Intestinal Capsule Endoscope System

Olympus Medical Systems Corp.

3/5/2019

K183053

For visualization of the small intestine mucosa.

MiroCam Capsule Endoscope System

IntroMedic Co. Ltd.

11/8/2018

K180732

May be used as a tool in the detection of abnormalities of the small bowel and this device is indicated for adults and children from two years of age.

Olympus Small Intestinal Capsule Endoscope System

Olympus Medical Systems Corp.

3/13/2018

K173459

May be used in the visualization and monitoring of lesions that may indicate Crohn's disease not detected by upper and lower endoscopy. - It may be used in the visualization and monitoring of lesions that may be a source of obscure bleeding (either overt or occult) not detected by upper and lower endoscopy. It may be used in the visualization and monitoring of lesions that may be potential causes of iron deficiency anemia (IDA) not detected by upper and lower endoscopy. The Red Color Detection Function is intended to mark frames of the video suspected of containing blood or red areas.

PillCam Patency System

Given Imaging Ltd.

3/8/2018

K180171

Intended to verify adequate patency of the gastrointestinal tract prior to administration of the PillCam video capsule in patients with known or suspected strictures.

MiroCam Capsule Endoscope System

IntroMedic Co. Ltd.

1/30/2018

K170438

For visualization of the small intestine mucosa.

PillCam SBC capsule endoscopy system PilCam Desktop Software 9.0

Given Imaging Ltd.

9/1/2017

K170210

For visualization of the small intestine mucosa.

RAPID Web

Given Imaging Ltd.

5/26/2017

K170839

Intended for visualization of the small bowel mucosa.

AdvanCE capsule endoscope delivery device

United States Endoscopy Group Inc.

3/10/2017

K163495

Intended for visualization of the small bowel mucosa.

OLYMPUS SMALL INTESTINAL CAPSULE ENDOSCOPE SYSTEM

OLYMPUS MEDICAL SYSTEMS CORP.

1/19/2017

K163069

Intended for visualization of the small bowel mucosa.

CapsoCam Plus (SV-3) Capsule Endoscope System

CapsoVision Inc

10/21/2016

K161773

Intended for visualization of the small bowel mucosa.

CapsoCam (SV-1)

CapsoVision Inc.

2/9/2016

K151635

For use in diagnosing disorders of the small bowel, esophagus, and colon.

PillCam TM COLON

2

Given®

Imaging

01/14/2016

K153466

Detection of colon polyps in patients after an

incomplete colonoscopy and a complete

evaluation of the colon was not technically

possible, and for detection of colon polyps in

patients with evidence of GI bleeding of lower

GI origin with major risks for colonoscopy or

moderate sedation.

MiroCam Capsule Endoscope System

INTROMEDIC CO. LTD

3/17/2015

K143663

Intended for visualization of the small bowel mucosa.

ENDOCAPSULE SOFTWARE 10; ENDOCAPSULE SOFTWARE 10 LIGHT

OLYMPUS MEDICAL SYSTEMS CORP.

2/8/2015

K142680

Intended for visualization of the small bowel mucosa.

GI: gastrointestinal.

Policy:
Wireless capsule endoscopy of the small bowel may be considered MEDICALLY NECESSARY for the following indications

  • Initial diagnosis in patients with suspected Crohn's disease without evidence of disease on conventional diagnostic tests such as small-bowel follow-through (SBFT) and upper and lower endoscopy.
  • In patients with an established diagnosis of Crohn's disease, when there are unexpected change(s) in the course of disease or response to treatment, suggesting the initial diagnosis may be incorrect and re-examination may be indicated.
  • Obscure gastrointestinal (GI) bleeding suspected of being of small bowel origin, as evidenced by prior inconclusive upper and lower gastrointestinal endoscopic studies performed during the current episode of illness.
  • For surveillance of the small bowel in patients with hereditary GI polyposis syndromes, including familial adenomatous polyposis and Peutz-Jeghers syndrome.

Other indications of wireless capsule endoscopy are investigational and/or unproven and are therefore consdidered NOT MEDICALLY NECESSARY, including, but not limited to:

  • Evaluation of the extent of involvement of known Crohn's disease or ulcerative colitis
  • Evaluation of the esophagus, in patients with gastroesophageal reflux (GERD) or other esophageal pathologies
  • Evaluation of other gastrointestinal diseases and conditions not presenting with GI bleeding, including, but not limited to, celiac sprue, irritable bowel syndrome, Lynch syndrome, portal hypertensive enteropathy, small bowel neoplasm and unexplained chronic abdominal pain
  • Evaluation of the colon, including, but not limited to, detection of colonic polyps or colon cancer.
  • Initial evaluation of patients with acute upper GI bleeding
  • Evaluation of patients with evidence of lower GI bleeding and major risks for colonoscopy or moderate sedation.
  • Evaluation of patients following incomplete colonoscopy.

The patency capsule is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY, including use to evaluate patency of the gastrointestinal tract before wireless capsule endoscopy.

Policy Guidelines
See the Codes table for details. 

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all FDA-approved services may not be considered investigational, and, thus, these services may be assessed only on the basis of their medical necessity.

Rationale
This evidence review was created in February 2002 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through September 21, 2020.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be tTechnically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Suspected Small Bowel Bleeding
Clinical Context and Test Purpose
The purpose of wireless capsule endoscopy (CE) for patients who have suspected small bowel bleeding is to confirm a diagnosis and inform a decision to proceed to appropriate treatment.

The question addressed in this evidence review is: Does the use of wireless CE improve the net health outcome in patients with suspected small bowel bleeding?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with suspected small bowel bleeding. Suspected small bowel bleeding, previously referred to as obscure gastrointestinal (GI) tract bleeding, is defined as bleeding from the GI tract that persists or recurs without an obvious etiology after imaging with upper and lower endoscopy and radiologic evaluation of the small bowel. Recurrent or persistent iron-deficiency anemia, positive fecal occult blood test, or visible bleeding with no bleeding source found at original endoscopy are other indicators of obscure GI tract bleeding. Examples of etiologies for small bowel bleeding include angiodysplasia, tumor, medication-induced, infections, Crohn disease (CD), Meckel diverticulum, Zollinger-Ellison syndrome, vasculitis, radiation enteritis, jejunal diverticula, and chronic mesenteric ischemia.

Interventions
The intervention of interest is wireless CE.

Comparators
The following practice is currently being used to diagnose small bowel bleeding: a standard workup without wireless CE and, with or without direct endoscopic procedures or specialized GI imaging. A “true” reference standard for suspected small bowel bleeding is difficult or impossible to achieve because the bleeding source may resolve and invasive techniques (e.g., surgery) cannot be justifiably used.

Patients with suspected small bowel bleeding are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Outcomes
The outcomes of interest for diagnostic accuracy include test validity (i.e., sensitivity, specificity). The primary outcomes of interest are symptoms and disease status that would change due to patient management decisions following wireless CE.

Wireless CE would be performed prior to surgical exploration if conventional endoscopy has been inconclusive. Follow-up for further diagnostic evaluation and surveillance for recurrence of symptoms would be immediate to weeks if no etiology is identified. Follow-up of weeks to months would be based on the disease condition identified by CE.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria
Below are selection criteria for studies to assess whether a test is clinically valid. These will be applied to all of the indications reviewed in this policy. 

  • The study population represents the population of interest. Eligibility and selection are described.

  • The test is compared with a credible reference standard.

  • If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

  • Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operator curve, area under the receiver operator curve, c-statistic, likelihood ratios) may be included but are less informative.

  • Studies should also report reclassification of the diagnostic or risk category.

Systematic Reviews
Tables 2 and 3 summarize the characteristics and results of selected systematic reviews, which have evaluated a number of case series that compared the diagnostic accuracy of CE with alternative procedures such as intraoperative endoscopy or mesenteric angiography.

Table 2. Characteristics of Systematic Reviews Evaluating CE for Iron-Deficient Anemia

Study Dates Trials Participants N (Range) Design QUADAS Assessment of Included Trials
Koulaouzidis et al. (2012)2 2004-2011 24 Patients with iron-deficiency anemia who had SBCE and at last 1 lower and upper GI endoscopy prior to CE 1960 (35-652) Observational Low-to-moderate quality

CE: capsule endoscopy; GI: gastrointestinal; SBCE: small bowel capsule endoscopy.

Table 3. Results of Systematic Reviews Evaluating CE for Iron-Deficient Anemia

Study Overall Diagnostic Yielda Diagnostic Yield of Patients With IDAb I2, % Diagnostic Yield, n (%)c
Koulaouzidis et al. (2012)2        
Total N 1960 264  
  • Angioectasias: 293 (45.9)
  • Inflammatory lesions: 126 (19.7)
  • Polyp/mass lesions: 42 (6.6)
  • Not classified: 177 (27.7)
Pooled effect (95% CI), % 47 (42 to 52) 66.6 (61.0 to 72.3) 78.8  
p     <0.001  

CE: capsule endoscopy; CI: confidence interval; IDA: iron-deficient anemia.
a Per-patient analysis.
b From 4 studies (n=264 patients; 13.47% of total).
c Patients with positive SBCE findings.

Randomized Controlled Trials
A small RCT compared CE with mesenteric angiography in patients with acute melena or hematochezia. While CE had a higher diagnostic yield, secondary outcomes such as transfusion, hospitalization, and mortality did not differ significantly between groups. Tables 4 and 5 summarize the characteristics and results of selected RCTs.

Table 4. Characteristics of RCT Evaluating CE for Obscure GI Bleeding

Study Countries Sites Dates Participants Interventions
          Active Comparator
Leung et al. (2012)3 China 1 2005-2007 Consecutive adults with active overt obscure GI bleeding 30 randomized to CE 30 randomized to mesenteric angiography

CE: capsule endoscopy; GI: gastrointestinal; RCT: randomized controlled trial.

Table 5. Results of RCT Evaluating CE for Obscure GI Bleeding

Study Diagnostic Yield (95% CI), %a Rebleeding Rates
(95% CI), %
Hospitalization Rate, n (%) Transfusion Rate, n (%) Mean Follow-Up (SD), mo
Leung et al. (2012)3          
CE 53.3 (36.1 to 69.8) 16.7 (7.3 to 33.6) 5 (16.7) 3 (10) 48.5 (20.9)
Angiography 20 (9.5 to 37.3) 33.3 (19.2 to 51.2) 5 (16.7) 3 (10)  
Difference 33.3 (8.9 to 52.8) 16.7 (-5.3 to 36.8)      
p 0.016 0.23 1.0 1.0  

CI: confidence interval; CE: capsule endoscopy; GI: gastrointestinal; RCT: randomized controlled trial; SD: standard deviation.
a Percentage identified with a high probability of bleeding.

The purpose of the limitations tables (see Tables 6 and 7) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement.

Table 6. Study Relevance Limitations of RCT Evaluating CE for Obscure GI Bleeding

Study Populationa Interventionb Comparatorc Outcomesd Duration of Follow-Upe
Leung et al. (2012)3 2. It is possible patients with moderate bleeding would not undergo angiography in clinical setting
4. Patients with overt but nonmassive bleeding may not be ideal for CE or angiography
  2. A criterion standard is lacking for evaluation of obscure GI bleeding    

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
CE: capsule endoscopy; GI: gastrointestinal; RCT: randomized controlled trial.
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity, and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Table 7. Study Design and Conduct Limitations of RCT Evaluating CE for Obscure GI Bleeding

Study Allocationa Blindingb Selective Reportingc Follow-Upd Powere Statisticalf
Leung et al. (2012)3         3. Study underpowered to detect significant difference in clinical outcome  

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
CE: capsule endoscopy; RCT: randomized controlled trial.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Follow-Up key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f Statistical key: 1. Intervention is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Intervention is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Case Series
Tables 8 and 9 summarize the characteristics and results of selected case series.

Table 8. Characteristics of Case Series Evaluating CE for Obscure GI Bleeding

Study Country Participants Treatment Delivery Follow-Up (Range), mo
Hartmann et al. (2005)4 Germany 47 patients >18 y with obscure GI bleeding Patients received CE and criterion standard, intraoperative endoscopy NR
Pennazio et al. (2004)5 Italy 100 patients ≥18 y with obscure GI bleeding 51 patients received CE and PE before or after the procedure Mean: 18 (5-25)

CE: capsule endoscopy; GI: gastrointestinal; NR: not reported; PE: push enteroscopy.

Table 9. Results of Case Series Evaluating CE for Obscure GI Bleeding

Study Treatment Locating Bleeding
With CE, %
Diagnostic Yield for Positive Lesions, % PPV of CE, % NPV of CE %
    Sensitivity Specificitya      
Hartmann et al. (2005)4 CE and intraoperative endoscopy 95 75 Both procedures: 76.6 95 86
Pennazio (2004)5 CE and PE 89 95 67 (95% CI, 54 to 80) 97 82.6

CE: capsule endoscopy; PPV: positive predictive value; NPV: negative predictive value; PE: push enteroscopy; CI: confidence interval
a CE results confirmed by intraoperative endoscopy or other reference standards.

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs assessing the clinical utility of wireless CE for this indication were identified.

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Based on evidence that CE isolates the source of bleeding at least as well as other diagnostic tools and that few diagnostic options are available to patients with suspected small bowel bleeding, a chain of evidence can be constructed to support the clinical utility of CE for this indication.

Section Summary: Suspected Small Bowel Bleeding
A small RCT compared CE with mesenteric angiography in patients with acute melena or hematochezia. While CE had a higher diagnostic yield, secondary outcomes such as transfusion, hospitalization, and mortality did not differ significantly between groups. A large number of uncontrolled studies have evaluated the use of CE in the evaluation of patients with suspected small bowel bleeding. These studies have consistently reported that a substantial proportion of patients receive a definitive diagnosis following this test when there are few other diagnostic options. A meta-analysis of 24 studies estimated that the diagnostic yield in this patient population was approximately half of the included patients and was higher in patients with documented iron-deficiency anemia. CE appears to locate the source of bleeding at least as well as other diagnostic methods and direct treatment to the source of bleeding.

Suspected Crohn Disease
Clinical Context and Test Purpose
The purpose of wireless CE for patients with suspected CD is to confirm a diagnosis and inform a decision to proceed to appropriate treatment.

The question addressed in this evidence review is: Does the use of wireless CE improve the net health outcome in patients with suspected CD?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with suspected CD. CD is 1 of the 2 types of inflammatory bowel disease, Crohn disease can involve the entire GI tract and is characterized by transmural inflammation.

Interventions
The test being considered is wireless CE.

Patients with suspected CD are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Comparators
The following tests are currently being used to diagnose CD: Ileocolonoscopy, barium small bowel follow-through, computed tomography enterography (CTE), magnetic resonance enterography (MRE).

Patients with suspected CD are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Outcomes
The general outcomes of interest are test validity, other test performance measures, symptoms, and change in disease status.

The diagnosis of CD requires confirmatory imaging when the disease is prominent on the differential diagnosis list. The imaging study would be performed and promptly followed by appropriate treatment. CD is a chronic condition requiring long-term follow-up.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria
Below are selection criteria for studies to assess whether a test is clinically valid. These will be applied to all of the indications reviewed in this policy.

  • The study population represents the population of interest. Eligibility and selection are described.

  • The test is compared with a credible reference standard.

  • If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

  • Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operator curve, area under the receiver operator curve, c-statistic, likelihood ratios) may be included but are less informative.

  • Studies should also report reclassification of the diagnostic or risk category.

Results from a meta-analysis by Choi et al (2017), which compared CE with various modalities for diagnosing CD, are summarized in Tables 10 and 11. The reference standards varied for the selected studies, so quantitative data were not synthesized for diagnostic accuracy. In the pooled analysis, in patients with suspected CD, the sensitivity of CE ranged from 89.6% to 92.0% and the specificity was 100% 

Table 10. Characteristics of Systematic Reviews Assessing the Diagnostic Yield of CE vs Other Modalitiesa 

Study Dates Trials Participants N (Range) Design
Choi et al. (2017)6 2002-2013 24 Patients with suspected or established CD NR RCT, nonrandomized, and diagnostic accuracy studies

CD: Crohn disease; CE: capsule endoscopy; NR: not reported; RCT: randomized controlled trial.
a Other modalities include small bowel follow-through, enteroclysis, computed tomography enterography, and magnetic resonance enterography.

Table 11. Results of Systematic Reviews Assessing the Diagnostic Yield of CE vs Other Modalities

Study CE vs SBFTa CE vs ECb CE vs CTEb CE vs MREb
Choi et al. (2017)6      
N 94      
Diagnostic yield, % 66 vs 21.3 75.7 vs 29.4 72.5 vs 22.5 85.7 vs 100
Weighted incremental yield (95% CI) 0.44 (0.29 to 0.59) 0.50 (0.21 to 0.79) 0.36 (0.18 to 0.90) -0.16 (-0.63 to 0.32)
I2, % 30 52 68 44

CE: capsule endoscopy; CI: confidence interval; CTE: computed tomography enterography; EC: enteroclysis; MRE: magnetic resonance enterography; SBFT: small bowel follow-through.
a From 4 studies (3 included in meta-analysis).
b From 2 studies.

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs assessing the clinical utility of wireless CE for this indication were identified.

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Based on evidence that CE can provide a diagnosis of CD when other tests cannot, a chain of evidence can be constructed to support the clinical utility of CE for this indication.

Section Summary: Suspected Crohn Disease
For patients with suspected CD who cannot be diagnosed by other modalities, CE can confirm the diagnosis in a substantial number of patients.

Suspected Celiac Disease
Clinical Context and Test Purpose
The purpose of wireless CE for patients who have suspected celiac disease is to confirm a diagnosis and inform a decision to proceed to appropriate treatment.

The question addressed in this evidence review is: Does the use of CE endoscopy improve the net health outcome in patients with suspected celiac disease?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with suspected celiac disease. Celiac disease, or gluten-sensitive enteropathy, is an immune-mediated condition of the small intestine. Serologic markers of the disease have good sensitivity and specificity in triaging patients to endoscopy.

Interventions
The test being considered is wireless CE. CE has been evaluated as an alternative method of diagnosing celiac disease, assessing the extent of disease, and in the evaluation of celiac disease unresponsive to treatment.

Patients with suspected celiac disease are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Comparators
The following test is currently being used to diagnose celiac disease: endoscopy with biopsy. The criterion standard for the diagnosis of celiac disease is obtained through small bowel biopsies obtained during endoscopy.

Patients with suspected celiac disease are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Outcomes
The general outcomes of interest are test validity, other test performance measures, symptoms, and change in disease status.

The diagnosis of celiac disease requires confirmatory imaging when the disease is prominent on the differential diagnosis list. The imaging study would be performed and promptly followed by appropriate treatment. Celiac disease is a chronic condition requiring long-term follow-up.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria
Below are selection criteria for studies to assess whether a test is clinically valid. These will be applied to all of the indications reviewed in this policy.  

  • The study population represents the population of interest. Eligibility and selection are described.

  • The test is compared with a credible reference standard.

  • If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

  • Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operator curve, area under the receiver operator curve, c-statistic, likelihood ratios) may be included but are less informative.

  • Studies should also report reclassification of the diagnostic or risk category.

Systematic Reviews
A meta-analysis by El-Matary et al. (2009) compared the diagnostic performance of CE with a reference standard of duodenal biopsy.7 The pooled analysis of 3 studies showed a sensitivity of 83% and a specificity of 98%. Another meta-analysis by Rokkas and Niv (2012) also compared the diagnostic performance of CE with biopsy, summarizing 6 studies (total n=166 subjects).8 The overall pooled sensitivity was 89%, and the specificity was 95%.

CE detected involvement of intestines beyond the duodenum; however, the clinical significance of detecting the extent of celiac disease is uncertain. Given the less than 90% sensitivity of CE for celiac disease, it does not appear to be an adequate alternative method of making an initial diagnosis.

Nonrandomized Studies
In a study by Kurien et al. (2013), 62 patients with an equivocal diagnosis of celiac disease and 69 patients with the confirmed celiac disease who were unresponsive to standard treatment were evaluated with CE.9 Results were combined with human leukocyte antigen typing and response to gluten challenge, with the final diagnosis made by 3 expert physicians who received the information from all 3 sources. The main outcome was the increase in diagnostic yield after CE combined with the other tests. The diagnostic yield was greatest in cases with antibody-negative villous atrophy where a diagnosis of celiac disease was made in 9 (28%) of 32 patients. In 8 (12%) of the 69 nonresponsive celiac disease patients, CE identified 2 cases of enteropathy-associated lymphoma, 4 type 1 refractory disease cases, 1 fibroepithelial polyp, and 1 case of ulcerative jejunitis. This study was limited by the small sample size and use of other tests in conjunction with CE to ascertain a final diagnosis.

The role of CE in nonresponsive celiac disease has been evaluated in only a few studies. One case series by Culliford et al. (2005) evaluated 47 patients with complicated celiac disease and found unexpected additional findings in 60% of patients, most of which were ulcerations.10 However, the definition of “complicated” celiac disease included other factors such as evidence of blood loss, itself an indication for CE. The impact on patient management and outcomes is unclear.

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs assessing the clinical utility of wireless CE for this indication were identified.

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of wireless CE for diagnosing celiac disease has not been established, a chain of evidence supporting the test’s clinical utility for this indication cannot be constructed.

Section Summary: Suspected Celiac Disease
In cases where the diagnosis of celiac disease is equivocal, CE can sometimes reveal morphologic changes in the small bowel consistent with celiac disease. However, it is unlikely that the appearance of small bowel on CE is itself sufficient to make a definitive diagnosis of celiac disease. Small bowel biopsy, celiac serologies, and human leukocyte antigen typing remain the standard tests for confirming celiac disease and have a higher sensitivity and specificity for this purpose. Case series of patients with unresponsive celiac disease undergoing CE have shown some yield of actionable diagnoses that have the potential to improve patient outcomes. Larger studies are needed to better determine the diagnostic yield of CE in these patients.

Unexplained Chronic Abdominal Pain
Clinical Context and Test Purpose
The purpose of wireless CE for patients who have unexplained chronic abdominal pain is to confirm a diagnosis and inform a decision to proceed to appropriate treatment.

The question addressed in this evidence review is: Does the use of wireless CE improve the net health outcome in patients with unexplained chronic abdominal pain?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with unexplained chronic abdominal pain.

Interventions
The test being considered is wireless CE.

Patients with unexplained chronic abdominal pain are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Comparators
The following practice is currently being used to diagnose chronic abdominal pain: standard workup for abdominal pain without CE.

Patients with unexplained chronic abdominal pain are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Outcomes
The general outcomes of interest are test validity, other test performance measures, symptoms, and change in disease status.

The diagnosis of chronic abdominal pain is often one of exclusion after a comprehensive clinical evaluation including empirical treatment. Imaging studies are used during initial and follow-up evaluations. Continued follow-up would be based on a definitive or working diagnosis, which would typically occur over weeks to months.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria
Below are selection criteria for studies to assess whether a test is clinically valid. These will be applied to all of the indications reviewed in this policy. 
 

  • The study population represents the population of interest. Eligibility and selection are described.

  • The test is compared with a credible reference standard.

  • If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

  • Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operator curve, area under the receiver operator curve, c-statistic, likelihood ratios) may be included but are less informative.

  • Studies should also report reclassification of the diagnostic or risk category.

Systematic Reviews
Xue et al. (2015) reported on a systematic review of 21 studies (total N=1520 patients) evaluating CE for unexplained chronic abdominal pain.11 The pooled diagnostic yield was 20.9% (95% CI, 15.9% to 25.9%). The most commonly identified findings were inflammatory lesions (78.3%) and tumors (9.0%). Studies in the review were highly heterogeneous. Limitations in interpreting the findings included retrospective study designs, different durations of abdominal pain, and the use of different tests before CE.

Case Series
In a study not included in the systematic review, Yang et al (2014) reported on a case series evaluating 243 patients with CE for unexplained chronic abdominal pain.12 The diagnostic yield of CE was 23.0%. Identified findings included 19 (7.8%) patients with CD, 15 (6.2%) with enteritis, 11 (4.5%) with idiopathic intestinal lymphangiectasia, 5 (2.1%) with uncinariasis, 5 (2.1%) with abnormal transit time and other findings (eg, small bowel tumor, ascariasis, anaphylactoid purpura).

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs assessing the clinical utility of wireless CE for this indication were identified.

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of wireless CE for diagnosing unexplained chronic abdominal pain has not been established, a chain of evidence supporting the test’s clinical utility for this indication cannot be constructed.

Section Summary: Unexplained Chronic Abdominal Pain
While CE diagnosed unexplained chronic abdominal pain in a proportion of patients reported in retrospective studies, the sequence and chronology of testing and treatment recommended before CE needs to be defined to determine whether CE had utility to diagnose the condition.

Established Crohn Disease
Clinical Context and Test Purpose
The purpose of wireless CE for patients who have established diagnosis of CD is to inform management decisions based on disease status.

The question addressed in this evidence review is: Does the use of wireless CE improve the net health outcome in patients diagnosed with CD?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with CD.

Interventions
The intervention of interest is wireless CE.

Patients with an established diagnosis of Crohn disease are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Comparators
The following test is currently being used to monitor CD: Ileocolonoscopy, barium small bowel follow-through, CTE, and MRE.

An international consensus statement indicated that radiographic imaging should take precedence over CE because of the capability to detect obstructive strictures as well as extraluminal and transmural disease.1 The consensus statement identified some studies in which CE had a higher percentage of positive findings than alternative tests in patients with established CD, but it is not clear how these findings correlated with either symptoms or outcomes of the therapeutic intervention. A 2013 European consensus statement indicated MRE or CTE is usually preferred to CE in patients with known CD patients.13 The 2013 consensus also indicated CE should be limited in patients with CD to the evaluation of unexplained symptoms, unexplained iron-deficiency, or obscure GI bleeding after other investigations are inconclusive.

Patients with an established diagnosis of Crohn disease are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Outcomes
The beneficial outcome of a true test result, if correctly classified as low disease activity, is the avoidance of endoscopy and unnecessary medications.

Wireless CE would be performed to monitor patients with CD.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria
Below are selection criteria for studies to assess whether a test is clinically valid. These will be applied to all of the indications reviewed in this policy.

  • The study population represents the population of interest. Eligibility and selection are described.

  • The test is compared with a credible reference standard.

  • If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

  • Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operator curve, area under the receiver operator curve, c-statistic, likelihood ratios) may be included but are less informative.

  • Studies should also report reclassification of the diagnostic or risk category.

Systematic Reviews
Kopylov et al. (2017) published a systematic review of studies evaluating the use of CE for CD.14 Reviewers included prospective studies comparing CE with MRE and/or small bowel contrast ultrasound in patients who had suspected and/or established CD. In pooled analyses of the 11 studies that included patients with established CD, the diagnostic yield of CE was similar to that of MRE (odds ratio [OR], 1.88; 95% CI, 0.53 to 1.48; I2=48%) and to ultrasound (OR=0.57; 95% CI, 0.27 to 1.20; I2=67%).

Diagnostic Accuracy Studies
Bruining et al. (2020) reported results from the multicenter, prospective BLINK trial comparing the diagnostic accuracy of CE compared to ileocolonoscopy (IC) and/or magnetic resonance enterography (MRE) in patients with established CD.15 The per-protocol analysis included 99/158 enrolled subjects with 16 patients tested by all 3 modalities. Major reasons for exclusion from analysis included patency failure or MRE stricture and major protocol violations.The reference standard was defined as the presence or absence of inflammation as designated by the modality-specific scoring system at prospective interpretation by expert central readers. In cases of discrepant findings for any bowel segment, all modalities were reviewed and resolved by a consensus panel consisting of 3 gastroenterologists. Overall sensitivity, specificity, PPV, and NPV were 94% (95% CI, 86 to 98%), 74% (95% CI, 55 to 87%), 91% (95% CI, 82 to 96%), 83% (95% CI, 64 to 94%) for CE compared to 100% (95% CI, 95 to 100%), 22% (95% CI, 10 to 41%), 77% (95% CI, 68 to 85%), and 100% (95% CI, 54 to 100) for IC and/or MRE. Sensitivity of CE was significantly higher compared to MRE for enteric inflammation in the proximal small bowel (97% vs 71%, P=0.021) and similar in the terminal ileum and colon (P=0.500-0.625). Discrepant reads between the proximal small bowel, terminal ileum, and colon were 57%, 49%, and 81%, respectively. In the proximal small bowel, the majority consensus panel decision was agreement with CE.

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs assessing the clinical utility of wireless CE for this indication were identified.

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Based on evidence that CE has a similar diagnostic yield as radiography when used to monitor CD and CE can be used when radiography cannot, a chain of evidence can be constructed to support the clinical utility of CE for this indication.

Section Summary: Established Crohn Disease
A 2017 systematic review of 11 studies in patients with established CD found a similar diagnostic yield with CE compared with radiography. A diagnostic accuracy study of CE compared with IC and/or MRE for the detection of active inflammatory CD in patients with established CD found a comparable sensitivity, higher specificity and PPV, and lower NPV compared to IC and/or MRE. Differences may be attributed to high rates of discrepant reads between modalities and high consensus panel agreement with CE results in cases of discrepancy. International consensus statements have suggested that radiographic imaging has advantages (e.g., ability to detect obstructive strictures) and that CE should be limited to certain situations (e.g., unexplained symptoms or other inconclusive investigations).

Ulcerative Colitis
Ulcerative colitis is an inflammatory disease of the large intestine. CE has been proposed as an alternative method for assessing the extent and severity of disease activity in those with known ulcerative colitis.

Clinical Context and Test Purpose
The purpose of wireless CE for patients who have ulcerative colitis is to inform management decisions based on disease status.

The question addressed in this evidence review is: Does the use of wireless CE improve the net health outcome in patients with ulcerative colitis?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with ulcerative colitis.

Interventions
The test being considered is wireless CE.

Patients with ulcerative colitis are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Comparators
The following test is currently being used to manage ulcerative colitis: optical colonoscopy.

Patients with ulcerative colitis are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Outcomes
The general outcomes of interest are test validity, other test performance measures, symptoms, and change in disease status.

Wireless CE would be performed to monitor patients after a confirmed diagnosis of ulcerative colitis.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria
Below are selection criteria for studies to assess whether a test is clinically valid. These will be applied to all of the indications reviewed in this policy.  

  • The study population represents the population of interest. Eligibility and selection are described.

  • The test is compared with a credible reference standard.

  • If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

  • Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operator curve, area under the receiver operator curve, c-statistic, likelihood ratios) may be included but are less informative.

  • Studies should also report reclassification of the diagnostic or risk category.

A number of prospective observational studies have evaluated the diagnostic accuracy of CE in patients with ulcerative colitis. Tables 12 and 13 summarize the characteristics and results of these studies.

Table 12. Characteristics of Observational Comparative Studies Assessing CE for UC 

Study Study Type Country Dates Participants Treatment Follow-Up
Shi et al. (2017)16 Single-center prospective observational China 2014-2016 Patients 18-80 y with UC requiring colonoscopy 150 patients underwent CE-2 and colonoscopy NR
San Juan-Acosta et al. (2014)17 Single-blind prospective comparative Spain 2010-2012 Patients 18-70 y with UC with flare in disease activity or due for CRC screening 23 underwent CE-1, 19 had CE-2; all followed by colonoscopy NR
Oliva et al. (2014)18 Prospective observational Spain 2011-2012 Patients 6-18 y with a diagnosis at least 3 mo prior to enrollment 30 patients underwent CE-2, followed by colonoscopy NR
Sung et al. (2012)19 Prospective cohort China and Singapore 2000-2008 Patients with suspected or known UC 100 patients underwent CE and same-day colonoscopy NR

CE-1:first-generation capsule endoscopy CE-2:second-generation capsule endoscopy; CRC: colorectal cancer; NR: not reported; UC: ulcerative colitis.

Table 13. Results of Observational Comparative Studies Assessing CE for Ulcerative Colitis  

Study Active Colonic
Inflammation, %
PPV, % NPV, % Correlation Between Colon CE and Colonoscopy
  Sensitivitya Specificity     Disease Severity Extent of Inflammation
Shi et al. (2017)16          
N 150 150 150   150 150
Mucosal inflammation (MES >0) 97     94-95    
M-to-S inflammation (MES >1) 94          
Postinflammatory polyps 100 91        
ICC (95% CI)         0.69
(0.46 to 0.81)a
0.64
(0.38 to 0.78)b
p         <0.001 <0.001
San Juan-Acosta et al. (2014)17          
N 42 42 42   42 42
CE vs colonoscopy            
Disease activity 77.78 95.83 93.33 85.19    
Disease extent 68.75 96.15 91.67 83.33    
κ (95% CI)         0.79
(0.62 to 0.96)
0.71
(0.52 to 0.90)
Oliva et al. (2014)18          
N 30 30 30      
% (95% CI) 96
(79 to 99)
100
(61 to 100)
100
(85 to 100)
85
(49 to 97)
   
Sung et al. (2012)19          
N 100 100 100      
% (95% CI) 89
(80 to 95)
75
(51 to 90)
93
(84 to 97)
65
(43 to 83)
   

CE: capsule endoscopy; CI: confidence interval; ICC: intraclass correlation coefficient; MES: Mayo Endoscopic Subscore; M-to-S: moderate to severe; NPV: negative predictive value; PPV: positive predictive value.
a MES.
b Ulcerative Colitis Endoscopic Index of Severity.

In the study by San Juan-Acosta et al (2014), although the correspondence between the 2 methods was reasonably good, it is uncertain whether management changes based on 1 or the other test would result in similar or different patient outcomes.17

Oliva et al. (2014) evaluated 30 patients with known ulcerative colitis with both CE and colonoscopy to assess disease activity.18 The reference standard for disease activity was a Matts score greater than 6 as judged by colonoscopy. Although the 2 methods had a high concordance at this cutoff level of disease in this study, patient outcomes linked to these assessments of disease activity cannot be determined.

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs assessing the clinical utility of wireless CE for this indication were identified.

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of wireless CE for monitoring ulcerative colitis has not been established, a chain of evidence supporting the test’s clinical utility for this indication cannot be constructed.

Section Summary: Ulcerative Colitis
Several diagnostic accuracy studies have compared CE with colonoscopy to assess disease activity in patients with ulcerative colitis. Two of 4 studies were small (i.e., <50 patients) and thus data on diagnostic accuracy are limited. Because there are insufficient data on diagnostic accuracy, a chain of evidence on clinical utility cannot be constructed.

Esophageal Disorders
Clinical Context and Test Purpose
The purpose of wireless CE for patients who have esophageal disorders is to inform management decisions based on disease status.

The question addressed in this evidence review is: Does the use of wireless CE improve the net health outcome in patients with esophageal disorders?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with esophageal disorders. Gastrointestinal reflux disease and chronic sequelae such as Barrett esophagus may require diagnostic and surveillance interventions.

Interventions
The test being considered is wireless CE. In the esophagus, the capsule camera has been proposed as a screening technique for Barrett esophagus associated with gastroesophageal reflux disease. Evaluation of the esophagus requires limited transit time, and it is estimated that the test takes 20 minutes to perform.

CE can visualize several types of esophageal conditions. It could substitute for traditional upper endoscopy for several indications and may have the advantage of comfort and convenience. However, interventional procedures and biopsies cannot be performed with CE.CE could triage patients for endoscopy if either the sensitivity or the specificity is high. Traditional endoscopy could then be performed on the appropriate group to determine false-positives or false-negatives, having spared the group with a high positive predictive value an endoscopy procedure.

Patients with esophageal disorders are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Comparators
The following test is currently being used to manage esophageal disorders: upper GI endoscopy.

Outcomes
The general outcomes of interest are test validity, other test performance measures, symptoms, and change in disease status.

Wireless CE would be performed to monitor patients after a confirmed diagnosis of an esophageal disorder.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria
Below are selection criteria for studies to assess whether a test is clinically valid. These will be applied to all of the indications reviewed in this policy. 

  • The study population represents the population of interest. Eligibility and selection are described.

  • The test is compared with a credible reference standard.

  • If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

  • Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operator curve, area under the receiver operator curve, c-statistic, likelihood ratios) may be included but are less informative.

  • Studies should also report reclassification of the diagnostic or risk category.

Most studies have shown that CE has inferior diagnostic characteristics compared with traditional upper endoscopy for a variety of esophageal conditions. A meta-analysis by Guturu et al (2011) evaluated 9 studies comparing CE with traditional endoscopy for detecting esophageal varices and calculated a sensitivity of 83% and specificity of 85%.20 A meta-analysis by Bhardwaj et al (2009) assessed 9 studies comparing CE with traditional endoscopy for detecting Barrett esophagus and reported a sensitivity of 77% and specificity of 86%.21  Because of the lower sensitivity and specificity of that test, CE cannot substitute for traditional endoscopy nor can it be used to triage patients to endoscopy.

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs assessing the clinical utility of wireless CE for this indication were identified.

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of wireless CE for monitoring esophageal disorders has not been established, a chain of evidence supporting the test’s clinical utility for this indication cannot be constructed.

Section Summary: Esophageal Disorders
Other available modalities are superior to CE for monitoring esophageal disorders. The diagnostic characteristics of CE are inadequate to substitute for other modalities or to triage patients to other modalities.

Hereditary GI Polyposis Syndromes
Clinical Context and Test Purpose
The purpose of wireless CE for patients who have hereditary GI polyposis syndromes is to inform management decisions based on disease status.

The question addressed in this evidence review is: Does the use of wireless CE improve the net health outcome in patients with hereditary GI polyposis syndromes?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with hereditary GI polyposis syndromes, including Lynch syndrome and Peutz-Jeghers syndrome (PJS).

Interventions
The test being considered is wireless CE.

Patients with hereditary GI polyposis syndromes are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Comparators
The following tests and practices are currently being used to manage hereditary GI polyposis syndromes: ileocolonoscopy, barium small bowel follow-through, CTE, and MRE, which are performed by a gastroenterologist in an outpatient setting.

Outcomes
The general outcomes of interest are, test validity, other test performance measures, symptoms, and change in disease status.

Wireless CE would be performed to monitor patients after a confirmed diagnosis with hereditary GI polyposis syndromes.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria
Below are selection criteria for studies to assess whether a test is clinically valid. These will be applied to all of the indications reviewed in this policy.
 

  • The study population represents the population of interest. Eligibility and selection are described.

  • The test is compared with a credible reference standard.

  • If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

  • Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operator curve, area under the receiver operator curve, c-statistic, likelihood ratios) may be included but are less informative.

  • Studies should also report reclassification of the diagnostic or risk category.

Persons with familial adenomatous polyposis and PJS are genetically at high-risk of small bowel polyps and tumors. Urquhart et al. (2014) compared CE with MRE in 20 patients with PJS.22 CE identified more polyps 10 mm or larger (47 polyps) than MRE (14 polyps; p=0.02). However, subsequent balloon enteroscopy in 12 patients showed a poor correlation of findings between techniques, with a 100%positive predictive value of finding a polyp on balloon enteroscopy with MRE vs 60% for CE. A study by Brown et al (2006) in 19 patients showed a greater number of polyps identified with CE than with barium follow-through examinations.23, Mata et al (2005) studied the role of CE in 24 patients with hereditary GI polyposis syndromes, including familial adenomatous polyposis (n=20) or PJS (n=4).24, Compared with barium studies using small bowel enteroclysis, CE identified 4 additional patients with small bowel polyps, which were subsequently removed with endoscopic polypectomy. Although these studies were small, they demonstrated that CE can identify additional lesions compared with other diagnostic methods in persons with disease syndromes at high-risk for such lesions.

The lifetime risk of small bowel cancer in Lynch syndrome has been estimated at 5%. Although not extremely high, this risk is greatly increased compared with the general population. There are a few case series of the prevalence of neoplastic lesions in asymptomatic patients in patients with Lynch syndrome. Haanstra et al. (2015), 200 patients with Lynch syndrome underwent CE.25 Small bowel neoplasia was detected in the duodenum in 2 patients (1 adenocarcinoma, 1 adenoma). These lesions would have been in the reach of a gastroduodenoscope. In a smaller study by Saurin et al. (2010), 35 asymptomatic patients with Lynch syndrome underwent colon CE.26 Small bowel neoplasms were diagnosed in 3 (8.6%) patients (1 adenocarcinoma, 2 adenomas with low-grade dysplasia).

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs assessing the clinical utility of wireless CE for this indication were identified.

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of wireless CE for monitoring hereditary GI polyposis syndromes has not been established, a chain of evidence supporting the test’s clinical utility for this indication cannot be constructed.

Section Summary: Hereditary GI Polyposis Syndromes
Although studies have shown at least a low prevalence of small bowel neoplasms, these data are insufficient to determine whether evaluation with CE would improve patient outcomes. Additional data on the prevalence and natural history of small bowel polyps in Lynch syndrome patients are necessary. At this time, surveillance of the small bowel is not generally recommended as a routine intervention for patients with Lynch syndrome.

Portal Hypertensive Enteropathy
Patients with liver cirrhosis and portal hypertension can develop portal hypertensive enteropathy, which may lead to GI bleeding. CE has been considered as a diagnostic tool for portal hypertensive enteropathy.

Clinical Context and Test Purpose
The purpose of wireless CE for patients who have portal hypertensive enteropathy is to inform management decisions based on disease status.

The question addressed in this evidence review is: Does the use of wireless CE improve the net health outcome in patients with portal hypertensive enteropathy?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with portal hypertensive enteropathy.

Interventions
The test being considered is wireless CE, which is performed in an outpatient setting by a gastroenterologist.

Comparators
The following test is currently being used to manage portal hypertensive enteropathy: upper and lower endoscopy, which are performed in an outpatient setting by a gastroenterologist.

Outcomes
The general outcomes of interest are test validity, other test performance measures, symptoms, and change in disease status.

Wireless CE would be performed to monitor patients after a confirmed diagnosis with portal hypertensive enteropathy.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria
Below are selection criteria for studies to assess whether a test is clinically valid. These will be applied to all of the indications reviewed in this policy.  

  • The study population represents the population of interest. Eligibility and selection are described.

  • The test is compared with a credible reference standard.

  • If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

  • Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operator curve, area under the receiver operator curve, c-statistic, likelihood ratios) may be included but are less informative.

  • Studies should also report reclassification of the diagnostic or risk category.

Several systematic reviews, including a Cochrane review, have been published. Tables 14 and 15 summarize the characteristics and results of select systematic reviews.

Table 14. Characteristics of Systematic Reviews Assessing CE for Portal Hypertensive Enteropathy  

Study Dates Trials Participants N (Range) Design
McCarty et al. (2017)27 2005-2015 17 Patients with portal hypertension 1328 (8-330) NR
Colli et al. (2014)28 2005-2014 16 Adults with cirrhosis 936 (NR) Cohort

NR: not reported.

Table 15. Results of Systematic Reviews Assessing CE for Portal Hypertensive Enteropathy 

Study CE, % Likelihood Ratios Diagnostic Accuracy
  Sensitivity Specificity Positive Negative CE Medium-to-Large Varices
McCarty et al. (2017)27        
N 1328 1328 1328    
PE (95% CI), % 83
(76 to 89)
85
(75 to 91)
5.4
(3.3 to 9.0)
0.20
(0.14 to 0.28)
90
(88 to 93)
92
(90 to 94)
Studies with low risk of bias, n          
PE (95% CI), % 80
(81 to 88)
86
(68 to 94)
  85
(81 to 88)
92
(89 to 94)
Colli et al. (2014)28          
N 936 936 936    
PE (95% CI), % 84.8
(77.3 to 90.2)
84.3
(73.1 to 91.4)
5.4
(3.1 to 9.5)
0.18
(0.12 to 0.27)
   
Studies with low risk of bias, n 396 396 396    
PE (95% CI), % 79.7
(73.1 to 85.0)
86.1
(64.5 to 95.5)
5.8
(2.1 to 16.1)
0.24
(0.18 to 0.31)
   

CI: confidence interval; CE: capsule endoscopy; PE: pooled effect.

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs assessing the clinical utility of wireless CE for this indication were identified.

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of wireless CE for monitoring portal hypertensive enteropathy has not been established, a chain of evidence supporting the test’s clinical utility for this indication cannot be constructed.

Section Summary: Portal Hypertensive Enteropathy
CE has been used to diagnose portal hypertensive enteropathy. Systematic reviews of studies of its diagnostic performance have reported limited sensitivity and specificity. Because neither the sensitivity nor the specificity was high for identifying esophageal varices, CE should not be used instead of esophagogastroduodenoscopy nor should it be used to triage patients to esophagogastroduodenoscopy. Based on these diagnostic characteristics, the test does not appear to have clinical utility.

Acute Upper GI Tract Bleeding
Clinical Context and Test Purpose
The purpose of wireless CE for patients who have acute upper GI tract bleeding is to inform management decisions based on disease status.

The question addressed in this evidence review is: Does the use of wireless CE improve the net health outcome in patients with acute upper GI tract bleeding?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with acute GI tract bleeding.

Interventions
The intervention of interest is wireless CE.

The test would be performed in an urgent care or emergency department setting.

Comparators
The following practices are currently being used to manage acute upper CI tract bleeding: standard workup of acute bleeding without wireless CE and, with or without direct endoscopic procedures or specialized GI imaging.

The tests would be performed in an urgent care or emergency department setting.

Outcomes
The primary outcomes of interest for clinical utility are symptoms and disease status that would change due to patient management decisions following wireless CE. Other outcomes of interest are the avoidance of hospitalizations and reductions in resource utilization (eg, need for additional testing or procedures).

Wireless CE would be performed as soon as possible after acute bleeding is identified. Wireless CE would be performed to monitor patients after a confirmed diagnosis with acute GI tract bleeding.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria
Below are selection criteria for studies to assess whether a test is clinically valid. These will be applied to all of the indications reviewed in this policy. 
 

  • The study population represents the population of interest. Eligibility and selection are described.

  • The test is compared with a credible reference standard.

  • If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

  • Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operator curve, area under the receiver operator curve, c-statistic, likelihood ratios) may be included but are less informative.

  • Studies should also report reclassification of the diagnostic or risk category.

Randomized Controlled Trials
Sung et al. (2016) reported on a prospective RCT to evaluate the use of CE in the emergency department for patients with suspected upper GI bleeding.29 CE was used to determine whether patients would be admitted to the hospital or sent home, vs an alternative strategy of admitting all patients. Eligible patients presented with signs and/or symptoms of acute upper GI bleeding but were without hemodynamic shock or conditions likely to preclude the use of the capsule endoscope. Seventy-one patients were randomized to CE in the emergency department (n=37), followed by monitoring for upper GI bleeding, or standard care (n=34), which included mandatory hospital admission. Seven CE patients with active bleeding or endoscopic findings were admitted, with the remainder discharged home. There were no deaths or morbid outcomes in either group, indicating that CE could result in equivalent patient outcomes with many patients safely avoiding emergency hospitalization.

Tables 16 and 17 summarize the characteristics and results of select RCTs.

Table 16. Characteristics of RCTs Assessing CE for Acute GI Tract Bleeding 

Study Countries Sites Dates Participants Interventions
          Active Comparator
Sung et al. (2016)29 China NR 2013-2014 Patients presenting to ED with symptoms suggestive of UGIB 37 randomized to CE; admission determined by CE 34 randomized to SOC; admission determined by GBS
Gutkin et al. (2013)30 U.S. 3 NR Patients ≥18 y with history suggestive of acute UGIB ≤48 h prior to ED presentation 12 randomized to VCE prior to endoscopy 12 randomized to endoscopy

CE: capsule endoscopy; ED: emergency department; GI: gastrointestinal; GBS: Glasgow Blatchford score; NR: not reported; RCT: randomized controlled trial; SOC: standard of care; UGIB: upper gastrointestinal bleeding; VCE: video capsule endoscopy.

Table 17. Results of RCTs Assessing CE for Acute GI Tract Bleeding  

Study Active Bleeding or Endoscopic Findings, n Hospitalization, n Mortality, n GBS Score Agreement Between CE and EGD
Sung et al. (2016)29        
N 68 68 68 68 68
CE
  • “Coffee ground” material: 2
  • Peptic ulcer with Forrest Ib stigmata: 2
  • Forrest IIa: 2
  • Esophageal varix: 1
7 0
  • 6 patients: 0
  • 3 patients: 1
  • 25 patients: ≥2
 
SOC
  • Peptic ulcer: 14
  • Duodenal ulcer: 12
  • Gastritis/duodenitis: 10
  • Gastric or duodenal erosions: 5
  • Mallory Weiss tear: 1
34 0
  • No patients scored 0
  • 7 patients: 1
  • 27 patients: ≥2
 
Gutkin et al. (2013)30        
N 24       24
VCE 8 (67.7%) had positive findings confirmed by endoscopy; for these patients, average Rockall score was 3; average Blatchford score was 13       VCE data identical to EGD results (P=1.0)

CE: capsule endoscopy; EGD: esophagogastroduodenoscopy; GI: gastrointestinal; GBS: Glasgow Blatchford score; RCT: randomized controlled trial; RR: relative risk; SOC: standard of care; VCE: video capsule endoscopy.

The purpose of the limitations tables (see Tables 18 and 19) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement.

Table 18. Study Relevance Limitations 

Study Populationa Interventionb Comparatorc Outcomesd Duration of Follow-Upe
Sung et al. (2016)29          
Gutkin et al. (2013)30          

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity, and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Table 19. Study Design and Conduct Limitations 

Study Selectiona Blindingb Delivery of Testc Selective Reportingd Data Completenesse Statisticalf
Sung et al. (2016)29           3. As a feasibility study, confidence intervals and p values were not reported
Gutkin et al. (2013)30         2. Small sample size based on pilot/ feasibility study  

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Selection key: 1. Selection not described; 2. Selection not random or consecutive (i.e., convenience).
b Blinding key: 1. Not blinded to results of reference or other comparator tests.
c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.
d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.
f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.

Cohort Studies
Two 2013 studies with small cohorts of patients (range, 49-83 patients) have reported on the use of CE before upper endoscopy for acute GI bleeding, to triage and/or risk-stratify patients in the emergency department or hospital.31,32 These studies reported that CE provides useful information, such as identifying gross bleeding and inflammatory lesions in a substantial proportion of patients and in stratifying patients into high- or low-risk categories. However, the yield of CE in localizing the bleeding source was lower than for esophagogastroduodenoscopy, which is the standard initial evaluation for acute upper GI bleeding.

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs assessing the clinical utility of wireless CE for this indication were identified.

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of wireless CE for diagnosing acute upper GI tract bleeding has not been established, a chain of evidence supporting the test’s clinical utility for this indication cannot be constructed.

Section Summary: Acute Upper GI Tract Bleeding
Use of CE in the emergency department setting for suspected upper GI bleeding is based on efficiency (avoiding hospitalization, avoiding immediate endoscopy). Controlled studies are needed to assess further the impact of CE on health outcomes compared with standard management. Patients should be followed to their ultimate diagnosis to determine whether the use of CE vs other triage strategies or immediate endoscopy results in lower health care resource utilization.

Colon Cancer Screening
Clinical Context and Test Purpose
The purpose of wireless CE for patients who are being screened for colon cancer is to confirm a diagnosis and inform a decision to proceed to appropriate treatment.

The question addressed in this evidence review is: Does the use of wireless CE improve the net health outcome in patients undergoing colon cancer screening?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients who are undergoing colon cancer screening.

Interventions
The intervention of interest is wireless CE, which is performed by gastroenterologists in an outpatient setting. Patients screened for colon cancer are actively managed by oncologists, gastroenterologists, radiologists, surgeons, and primary care providers in an outpatient setting.

Comparators
The following test is currently being used to diagnose colon cancer: standard workup using optical colonoscopy, which is performed by gastroenterologists in an outpatient setting. Patients screened for colon cancer are actively managed by oncologists, gastroenterologists, radiologists, surgeons, and primary care providers in an outpatient setting.

Outcomes
The outcomes of interest for diagnostic accuracy include test validity (ie, sensitivity, specificity). The primary outcomes of interest for clinical utility are overall mortality and disease-specific mortality from colon cancer.

Wireless CE would be performed after an initial clinical examination. Though not completely standardized, follow-up for screening for colon cancer would be based on guidelines for asymptomatic screening or for follow-up of significant screening findings.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria
Below are selection criteria for studies to assess whether a test is clinically valid. These will be applied to all of the indications reviewed in this policy. 

  • The study population represents the population of interest. Eligibility and selection are described.

  • The test is compared with a credible reference standard.

  • If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

  • Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, receiver operator curve, area under the receiver operator curve, c-statistic, likelihood ratios) may be included but are less informative.

  • Studies should also report reclassification of the diagnostic or risk category.

Several studies have assessed the accuracy of CE for detecting colonic lesions. Spada et al. (2016) reported on a systematic review and meta-analysis of the diagnostic accuracy of CE for detecting colorectal polyps with stratified results for first- and second-generation capsules.33 Across the 14 eligible studies, the indications for endoscopy included colorectal cancer screening (n=1261 [47%]), postpolypectomy surveillance or family history of colorectal cancer (n=636 [24%]), symptoms suggestive of cancer and/or fecal occult blood test positivity (n=619 [23%]), positive imaging tests (n=136 [5%]), or other indication (24 [1%]). There were no missed cancers (n=11) in the series using second-generation CE (per-patient sensitivity, 100%). In series using the first-generation CE, 6 of 26 proven cancers were missed on CE (per-patient sensitivity, 77%).

Kjolhede et al. (2020) reported on a systematic review and meta-analysis of the diagnostic accuracy of CE compared to colonoscopy with stratified results for polyps of any size, polyps ≥ 6mm, and polyps ≥ 10 mm.34 Across analyzed patients in the 12 eligible studies, the indications for endoscopy included colorectal cancer screening or history of polyps or colorectal cancer (n=1200 [63.2%]), positive fecal immunochemical test (n=493 [26%]), first-degree relatives of patients with colorectal cancer (n=177 [9.3%]), or unspecified (n=28 [1.5%]). The rate of patients with an adequate bowel preparation ranged from 40% to 100%. The rates of complete CE transits ranged from 57% to 100%. The authors note that the relatively high rate of incomplete CE investigations limits the utility of CE in the colorectal cancer setting. All but 1 study was assessed to have a high risk of bias and applicability concerns for the reference standard.

Characteristics of the systematic reviews and their main findings are summarized in Tables 20 and 21, respectively.

Table 20. Characteristics of Systematic Review Assessing CE for Colon Cancer Screening 

Study Dates Trials N (Range) Design Outcome
Spada et al. (2016)33 2006-2015 14 2681 (40-884) Diagnostic accuracy studies Per-patient sensitivity of CCE for different categories of polyp size and for cancer
Kjolhede et al. (2020)34 2009-2020 12 2199 (20-884) Diagnostic accuracy studies Per-patient sensitivity of CCE for various polyp size thresholds

CCE: colon capsule endoscopy.

Table 21. Results of Systematic Review Assessing CE for Colon Cancer Screening 

Random-Effects Model Trials N Outcomes Effect Size 95% CI I2, %
Spada et al. (2016)33            
For ≥10 mm polyps 10 NR Diagnostic accuracy for ≥10 mm polyps Sens=80.0%
Spec=96.2%
PLR=18.6
NLR=0.22
DOR=90.4
66% to 90.3%;
94.0% to 97.6%
12.0 to 28.2
0.13 to 0.34
44 to 163
53.4
31.3
For ≥6 mm polyps 7 NR Diagnostic accuracy for ≥6 mm polyps using 1st-generation CCE Sens=58%
Spec=85.7%
PLR=3.7
NLR=0.51
DOR=7.4
44% to 70%
80.2% to 90.0%
65
For ≥6 mm polyps 6 NR Diagnostic accuracy for ≥6 mm polyps using 2nd-generation CCE Sens=86%
Spec=88.1%
PLR=7.9
NLR=0.16
DOR=50.5
82% to 89%
74.2% to 95.0%
3.7 to 16.1
0.12 to 0.21
20.3 to 107.0
0
For ≥10 mm polyps 3 NR Diagnostic accuracy for ≥6 mm polyps using 1st-generation CCE Sens=54%
Spec=97.4%
PLR=NR
NLR=NR
DOR=NR
29% to 77%
96.0% to 98.3%
76.2
0
For ≥10 mm polyps 6 NR Diagnostic accuracy for ≥6 mm polyps using 2nd-generation CCE Sens=88%
Spec=95.3%
PLR=NR
NLR=NR
DOR=NR
81% to 91%
91.5% to 97.5%
0
67
Kjolhede et al. (2020)34            
For polyps of any size 4 338 Diagnostic accuracy for polyps of any size Sens=85%
Spec=85%
PLR=NR
NLR=NR
DOR=30.5
73% to 92%
70% to 93%


16.2 to 57.2
NR
For polyps ≥ 6 mm 6 1324 Diagnostic accuracy for polyps ≥ 6 mm Sens=87%
Spec=88%
PLR=NR
NLR=NR
DOR=51.1
83% to 90%
75% to 95%


19.8 to 131.8
NR
For polyps ≥ 10 mm 7 1577 Diagnostic accuracy for polyps ≥ 10 mm Sens=87%
Spec=95%
PLR=NR
NLR=NR
DOR=136.0
82% to 90%
92% to 97%


70.6 to 262.1
NR

CCE: colon capsule endoscopy; CI: confidence interval; DOR: diagnostic odds ratio; NLR: negative likelihood ratio; NR: not reported; PLR: positive likelihood ratio; Sens: sensitivity; Spec: specificity.

Prospective Studies
Other recent studies by Saito et al. (2015), Morgan et al. (2016), and Parodi (2018) have evaluated the diagnostic characteristics of CE, using subsequently performed colonoscopy as the reference standard.35,36,37 In the Saito et al. (2015) study, of 66 evaluable patients, per-patient sensitivity for the detection of polyps was 94% (95% CI, 88.2% to 99.7%). In the Morgan et al. (2016) study, for lesions 10 mm or larger, sensitivity of CE was 100% (95% CI, 56.1% to 100%), with a specificity of 93.0% (95% CI, 79.9% to 98.2%). For lesions 6 mm or larger, sensitivity was 93.3% (95% CI, 66.0% to 99.7%) and the specificity was 80.0% (95% CI, 62.5% to 90.9%). The Parodi (2018) study included 177 first-degree relatives of individuals with colorectal cancer and found, for lesions 6 mm or larger, a sensitivity of 91% (95% CI, 81% to 96%) and a specificity of 88% (95% CI, 81% to 93%).37

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs assessing the clinical utility of wireless CE for this indication were identified.

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of wireless CE for diagnosing colon cancer has not been established, a chain of evidence supporting the test’s clinical utility for this indication cannot be constructed.

Section Summary: Colon Cancer Screening
Studies of diagnostic characteristics alone are insufficient evidence to determine the efficacy of CE for colon cancer screening. Because diagnostic performance is worse than standard colonoscopy, CE would need to be performed more frequently than standard colonoscopy to have comparable efficacy. Without direct evidence of efficacy in a clinical trial of colon cancer screening using CE, modeling studies using established mathematical models of colon precursor incidence and progression to cancer could provide estimates of efficacy in preventing colon cancer mortality. Studies of CE in screening populations are necessary to determine the diagnostic characteristics of the test in this setting.

Lower GI Tract Bleeding and Major Risks for Colonoscopy or Moderate Sedation
Clinical Context and Test Purpose
The purpose of wireless CE for patients with evidence of gastrointestinal bleeding of lower GI origin and major risks for colonoscopy or moderate sedation is to visualize the colon for the detection of polyps or other sources of lower GI bleeding and inform a decision to proceed to further treatment and testing.

The question addressed in this evidence review is: Does the use of wireless CE improve the net health outcome in patients with evidence of gastrointestinal bleeding of lower GI origin and major risks for colonoscopy or moderate sedation?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with evidence of gastrointestinal bleeding of lower GI origin and major risks for colonoscopy or moderate sedation, but who could tolerate colonoscopy and moderate sedation in the event a clinically significant colon abnormality was identified with wireless CE.

Interventions
The intervention of interest is wireless CE for the visualization of the colon and detection of polyps or other sources of lower GI bleeding, which is performed by gastroenterologists in an outpatient setting. Symptomatic patients assessed for colorectal polyps may be actively managed by gastroenterologists, radiologists, surgeons, and primary care providers in an outpatient setting.

Comparators
The following reference standard is currently being used to detect colon polyps: standard workup using optical colonoscopy, which is performed by gastroenterologists in an outpatient setting. Symptomatic patients assessed for colorectal polyps may be actively managed by gastroenterologists and primary care providers in an outpatient setting.

Outcomes
The outcomes of interest for diagnostic accuracy include test validity. The primary outcomes of interest are symptoms, disease status, and resource utilization that would change due to patient management decisions following wireless CE.

Beneficial outcomes resulting from a true-negative test result are avoiding unnecessary subsequent testing. Harmful outcomes resulting from a false-positive test result are unnecessary testing or therapeutic intervention. Harmful outcomes resulting from a false-negative test result are increased risk of further disease progression and missed colorectal disease.

Therefore, in the evaluation of wireless CE as a triage test, the test would need to identify precisely a group of patients that could safely forgo additional testing; therefore, the sensitivity, specificity, negative predictive value and negative likelihood ratio are key test validity characteristics.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Study Selection Criteria
Below are selection criteria for studies to assess whether a test is clinically valid. These will be applied to all of the indications reviewed in this policy.  

  • The study population represents the population of interest. Eligibility and selection are described.

  • The test is compared with a credible reference standard.

  • If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

  • Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-negative results are ideal. Studies reporting other measures (eg, receiver operator curve, area under the receiver operator curve, c-statistic, likelihood ratios) may be included but are less informative.

  • Studies should also report reclassification of the diagnostic or risk category.

Diagnostic Accuracy Studies
Several studies have evaluated the diagnostic characteristics of CE for the detection of colon polyps in patients with evidence of lower GI bleeding (e.g., hematochezia, positive fecal occult blood test [FOBT]). Study characteristics and results are described in Table 22 and 23.

Table 22. Study Characteristics of Clinical Validity

Study Study Population Reference Standard Threshold for Positive Index Test Timing of Reference and Index Tests Blinding of Assessors Comments
Kobaek-Larsen et al. (2017)38 FOBT-positive individuals participating in a CRC screening program in Denmark (N=253; median age, 64 y) OC adjusted by any findings from all follow-up procedures; repeat colonoscopy was offered for suspected missed polyps Polyps >9 mm within ±50% of CE measure OC performed 1 day after CE Investigators were blinded to both CE and OC; in the case of a second endoscopy, investigator was unblinded to CE findings. RS adjusted in 75 patients due to follow-up procedures; only 50% (126) had complete OC and CE
Rondonotti et al .(2014)39 FOBT-positive individuals participating in a CRC screening program in Italy (N=54; age range, 50-69) OC followed by colon segment re-inspection if double unblinding to CTC and CE results revealed a disparity Polyps ≥6 mm CTC and OC performed 15 days after CE Initial blinding to CE and CTC results followed by double-unblinding and opportunity for re-inspection and adjustment of RS 4 patients excluded from analysis (consent withdrawal [2], endoscopist not blinded [2])
Eliakim et al. (2009)40 Individuals with known or suspected colonic disease in Israel; 21% of patients had hematochezia or positive FOBT (N=104; mean age, 49.8) OC Polyps ≥6 mm and ≥10 mm within +50% of CE measure OC performed within 10 hours of CE Investigators blinded to both OC and CE. 6 patients excluded from analysis (did not complete bowel prep [2], withdrawal [1], could not ingest capsule [1], capsule retention [1], technical failure [1])

CE: capsule endoscopy; CRC: colorectal cancer; CTC: computed tomography colonography; FOBT: fecal occult blood test; OC: optical colonoscopy; RS: reference standard.

Table 23. Study Results of Clinical Validity 

Study N CE Completion Rate, % (95% CI) Sensitivity, % (95% CI)1 Specificity, % (95% CI)1 PLR; NLR Adverse Events
Kobaek-Larsen et al. (2017)38           None related to OC or CE.

All patients; CE >9mm

253 54 (48 to 60) 87 (83 to 91) 92 (89 to 95) NR  
Complete CE and OC; CE >9 mm 126 --- 97 (94 to 100) 90 (85 to 95) NR  
All patients; OC > 9 mm 253 90 (86 to 94) 88 (84 to 92) 100 (100) NR  
Complete CE and OC; OC > 9 mm 126 --- 89 (84 to 94) 100 (100) NR  
Rondonotti et al. (2014)39           None related to OC or CE. 10 cases of mild abdominal pain and 2 cases of significant pain during CTC.
CE ≥6 mm 50 100 88.2 (62.2 to 97.9) 87.8 (70.8 to 96.0)