Doppler ultrasound, CT angiography, MR angiography, and contrast‐enhanced MR angiography versus intra‐arterial angiography for moderate and severe carotid stenosis in symptomatic patients

Abstract

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows:

The primary objective is to determine the accuracy of colour DUS, CT angiography, MR angiography, and contrast‐enhanced MR angiography in comparison with intra‐arterial angiography in patients with symptoms attributable to carotid stenosis (transient ischaemic attack, minor stroke, retinal artery occlusion, or amaurosis fugax). To reflect clinical practice, the review will consider each of the four index tests used singly, and also colour DUS followed by any of the four index tests.

This work is based on an earlier systematic review (Wardlaw 2006). We therefore know that many articles do not report the data needed to investigate the heterogeneity due to differences in the patient population (age, gender, whether the symptom affected the eye or brain), differences in the expertise of the people making the diagnoses, and the time interval between the index and reference tests. We had also investigated generation of technology (using year of publication as a proxy) and did not find evidence that it was a significant source of heterogeneity.

Background

Rationale for the review

Patients with severe, symptomatic carotid stenosis due to atheroma in the carotid artery are at a high risk of stroke. Stroke is the most common cause of severe disability in the UK (Stroke Association 2006) and consumes around 10% of NHS resources (Isard 1992). Two large randomised controlled trials, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) (ECST 1998; NASCET 1991) have shown that carotid endarterectomy (surgical removal of the atheroma) reduces the risk of stroke in patients with 70%‐99%  stenosis by the NASCET criteria and possibly also in those with 50%‐69% stenosis also (Barnett 1998; ECST 1998) A recent reanalysis of data from both the NASCET and ECST trials found that carotid endarterectomy could also benefit patients with 50%‐69% stenosis provided the operation were carried out soon after the symptoms occurred (Rothwell 2004). However, the overall net benefit is delicately balanced. On average, carotid endarterectomy prevents two strokes and causes one stroke for every 10 operations (Rothwell 2003). These trials used intra‐arterial angiography to measure carotid stenosis, an invasive method that carries a 1%‐2% risk of stroke or death (Davies 1993). Since the early 1990s when the trials were carried out, non‐invasive imaging methods have developed, are more widely available, and are commonly used in place of intra‐arterial angiography to diagnose carotid stenosis. These non‐invasive methods include colour Doppler ultrasound (DUS), computer tomography (CT) angiography, magnetic resonance (MR) angiography, or contrast‐enhanced MR angiography. It is essential to know how these non‐invasive methods compare to intra‐arterial angiography if the net effect of carotid endarterectomy is not to be obscured. Misdiagnosis of carotid stenosis may lead to patients being unnecessarily exposed to the risk of surgery or to patients not being offered surgery and so suffering preventable strokes.

The risk of stroke is greatest in the first few days after the occurrence of symptoms (Rothwell 2006). Therefore carotid endarterectomy is most effective if performed as soon as possible. However arranging intra‐arterial angiography introduces significant delays – for example most patients with symptomatic carotid disease may require hospital admission to avoid any adverse effects of intra‐arterial angiography, and so wait for a bed. In general the non‐invasive methods can be performed much more quickly and do not require admission.

Given that intra‐arterial angiography has significant morbidity and mortality, and that its use imposes delays during which preventable strokes will occur, it is critical to know if it could be replaced by colour DUS, CT angiography, MR angiography, or contrast‐enhanced MR angiography whether used singly or in combination. In general, colour DUS is the first investigation performed to investigate carotid territory symptoms, because of its ready accessibility. Colour DUS was able to identify the patients with less than 50% stenosis who did not need further investigation. Those with more than 50% stenosis, or possible occlusion, and who were candidates for carotid endarterectomy, were commonly referred for intra‐arterial angiography to confirm and provide a precise measure of the stenosis and exclude any additional abnormalities (e.g. tandem stenosis) that would influence surgery. However intra‐arterial angiography has gradually been dropped in favour of combinations of non‐invasive tests, or even a single DUS alone, as confidence in the accuracy of non‐invasive imaging, and awareness of the need for rapid assessment and treatment, have increased. Thus recent surveys in the UK suggest that an initial ultrasound may be followed by either a second confirmatory ultrasound, or an MR angiography, or a CT angiography or a contrast‐enhanced MR angiography, with intra‐arterial angiography being reserved for the occasional situation in which the non‐invasive tests disagree, or where an angioplasty is planned. It is unusual to use CT angiography or MR angiography or contrast‐enhanced MR angiography as the first line test as, in general, they are less available and much more expensive. 

Target condition being diagnosed

Stenosis caused by atheroma in the carotid artery can be graded in various ways. The methods used in the literature to define carotid stenosis are the NASCET method, the ECST method, and the Common Carotid Artery (CCA) method. All these methods measure the width of the artery where the stenosis is greatest, i.e. at the narrowest point (distance A in Figure 1) and assess the reduction in width either in comparison to the internal carotid artery (NASCET method), the carotid bulb (ECST method), or the common carotid artery (CCA) method.

Figure 1.

Methods of measuring stenosis

Severe and moderate symptomatic carotid stenosis can be defined as a stenosis of 70%‐99% or 50‐69% respectively as measured by the NASCET method (Barnett 1998) (or 80% to 99% and 70% to 79% by the ECST and CCA methods (Rothwell 1994)) in patients with symptomatic carotid territory ischaemia. Symptoms include transient ischaemic attacks, minor strokes, retinal artery occlusion, and amaurosis fugax. Transient ischaemic attacks occur when the blood supply to a part of the brain is temporarily reduced and any signs or symptoms resolve within 24 hours. Minor strokes have the same symptoms as transient ischaemic attacks but do not resolve within 24 hours, but the patient is not left disabled by the stroke. The symptoms of minor strokes and transient ischaemic attacks can include weakness or numbness on one side of the body, language difficulties, problems with swallowing, and loss of balance. Retinal artery occlusion and amaurosis fugax both cause loss of vision in one eye. Patients have described the loss as a shutter coming down over the eye. Amaurosis fugax typically lasts for only a few minutes, but retinal artery occlusion is permanent.

Index test(s)

Index tests and reference test

The index tests are colour DUS, CT angiography, MR angiography, and contrast‐enhanced MR angiography. These tests are chosen as they are currently used to diagnose carotid stenosis, but there is wide variation in practice and in the availability of each test (Wardlaw 2006). DUS is widely available in most imaging departments, but experience with carotid artery examinations may be confined to centres associated with vascular surgery or stroke services. CT angiography is widely available in general radiology departments, and MR angiography and contrast‐enhanced MR angiography are available in many general radiology departments as well as in regional clinical neuroscience centres.

Traditionally, carotid imaging investigations were performed by specialists in carotid imaging. However, the increasing availability of these machines in general departments means that increasingly these tests may be performed by non‐experts in carotid imaging or stroke. All these tests are less invasive and have less severe side‐effects than the reference standard intra‐arterial angiography.

The reference test is either digital subtraction intra‐arterial angiography or cut‐film intra‐arterial angiography, but not rotational intra‐arterial angiography as the latter is a recent development.

Objectives

The primary objective is to determine the accuracy of colour DUS, CT angiography, MR angiography, and contrast‐enhanced MR angiography in comparison with intra‐arterial angiography in patients with symptoms attributable to carotid stenosis (transient ischaemic attack, minor stroke, retinal artery occlusion, or amaurosis fugax). To reflect clinical practice, the review will consider each of the four index tests used singly, and also colour DUS followed by any of the four index tests.

This work is based on an earlier systematic review (Wardlaw 2006). We therefore know that many articles do not report the data needed to investigate the heterogeneity due to differences in the patient population (age, gender, whether the symptom affected the eye or brain), differences in the expertise of the people making the diagnoses, and the time interval between the index and reference tests. We had also investigated generation of technology (using year of publication as a proxy) and did not find evidence that it was a significant source of heterogeneity.

Methods

Criteria for considering studies for this review

Types of studies

All prospective diagnostic studies with blind comparison of index and reference tests i.e. where the index test was read without knowledge of the reference test and vice versa, with sufficient data to extract the following will be considered for inclusion:

• The number of true positives (TP), i.e. patients categorised as diseased by both the reference and index test

• The number of false negatives (FN), i.e. patients categorised as diseased by the reference test, but as non‐diseased by the index test

• The number of true negatives (TN), i.e. patients categorised as non‐diseased by both the reference and index tests

• The number of false positives (FP), i.e. patients categorised as non‐diseased by the reference test, but as diseased by the index test

We will also restrict the studies to those that used the index and reference tests within six months of each other to limit bias due to changes in patients’ stenoses over time. Patients will be from an unbiased sample, e.g. a random sample or a consecutive series. There will be no language restriction imposed, though it is recognised that resources may not allow for all non‐English language studies to be translated or included. Initially, we will limit the review to studies with 20 or more patients, and only include the smaller studies if resources allow.

Participants

The patient group will be people presenting with symptoms consistent with a transient ischaemic attack, minor stroke, amaurosis fugax, or retinal artery occlusion. They may or may not have had a prior ultrasound test. The settings are dedicated transient ischaemic attack and minor stroke services, neurology services, vascular services, geriatric services, and A & E departments. Studies using asymptomatic patients, or a mixture of symptomatic and asymptomatic patients where the proportion of symptomatic patients is less than 90%, will be excluded.

Index tests

The index tests are colour (DUS) (but not power Doppler or B‐flow imaging), CT angiography, MR angiography, and contrast‐enhanced MR angiography in the assessment of severe carotid stenosis.

Colour DUS is non‐invasive, requiring no injections. A probe is held on the skin over the carotid arteries with a gel on the skin to provide acoustic coupling, and images of the carotid and vertebral arteries, as well as readings of the blood velocities at different points in the blood vessels obtained. Colour DUS depends on the skill and experience of the operator and provides limited images for others to review independently. The completeness of the examination may be restricted by the patient physique, the jaw may prevent visualisation of the carotid bifurcation. CT angiography and contrast‐enhanced MR angiography both require intravenous injections routinely given by mechanical pumps timed to coincide with rapid imaging through the carotid arteries as the contrast agent is carried through as a bolus in the blood. Both require post‐processing techniques to provide anatomical images of the artery outlines and subtract the veins which can obscure the arteries. CT contrast agents may be precluded in patients with allergies, heart failure, renal failure or diabetes (all common in older people). MR angiography uses special properties of flowing blood to “magnetically tag the blood” and allows visualisation without intravenous injections. It also requires post‐processing. MR angiography and contrast‐enhanced MR angiography produce images which many others can view independently so do not have the same operator dependence but are best performed in units with regular and sufficient patient throughput to develop proficiency.

Target conditions

Severe carotid stenosis is defined as 70%‐99% NASCET (80%‐99% ECST) and moderate stenosis as 50%‐69% NASCET (70%‐79% ECST) method (ECST 1998; NASCET 1991). Studies without data consistent with this definition, or which could not be converted to it, will be excluded. The data from studies using the ECST or CCA method to define stenosis will be transformed to 70%‐99% or 50%‐69% by the NASCET method using ECST or CCA = 0.6NASCET + 40% (Rothwell 1994).

Reference standards

Intra‐arterial angiography (including digital subtraction and cut film but not rotational intra‐arterial angiography). This investigation is no longer routinely performed in many centres because of the morbidity associated with arterial puncture. Also the need for inpatient stay amongst older patients creates delays. Intra‐arterial angiography was the test used to measure carotid stenosis in all the carotid endarterectomy trials. It is therefore the technique that links stenosis to stroke risk and is thus the reference standard against which all other imaging techniques are judged. It produces high definition anatomical outlines of the arteries and the disease.

Search methods for identification of studies

Electronic searches

Electronic searches will be made in MEDLINE and EMBASE from 1990 to end 2005 using the search strategies given in Appendix 1. The earlier review found no relevant and methodologically robust articles prior to 1990 (Wardlaw 2006). The search strategies used in MEDLINE and EMBASE incorporated a diagnostic studies filter to reduce the retrieval of non‐relevant studies, as otherwise the number of studies was unworkable. However, great care was taken to ensure that relevant studies were not lost by this process. The search strategies were validated by comparison with handsearching, and experts in the field were asked to give details of any missing references.

Searching other resources

The bibliographies of review articles will be checked for extra references.

The search strategy will be revalidated by handsearching of the following key journals: Radiology, Neuroradiology, American Journal of Roentgenology, Stroke, and European Journal of Vascular and Endovascular Surgery from 1990 to 2005 inclusive. The search strategy was used in an earlier systematic review (Wardlaw 2006), where only one extra reference was found by handsearching alone, and this reference was not included in the final analysis.

Data collection and analysis

Selection of studies

Two reviewer authors will independently select abstracts for inclusion in the review using the above criteria. Abstracts will be sorted into “definitely exclude” and “possibly include” categories, recognising that sometimes it will not be possible to judge from the abstract whether a reference will fulfil the criteria or not. All abstracts selected by at least one review author will be in the “possible include” category.

Data extraction and management

For each study, the numbers of TP, FN, TN, and FP will be extracted. A positive test result will be defined as 70%‐99% stenosis by the NASCET method. Where possible, TP, FN, TN, and FP will also be extracted using 50%‐69% stenosis by the NASCET method as the definition of a positive test result. These data will be extracted by one review author and checked by a second. Other data to be recorded are:

• all items from the QUADAS checklist (spectrum of patients, reference test, time period between reference and index tests, if the results of the index test influenced whether patients underwent the reference test, whether patients received different forms of the reference test, whether the results of the index test formed part of the final diagnosis, whether the index test was read blind to the result of the reference test and vice versa, what clinical data were available to the readers of the tests, how were uninterpretable or intermediate tests reported, how were dropouts reported).

• imaging modality

• age range of patients

• symptoms of patients

• male to female ratio of the patients

• any prior selection by US was used to decide if patients were to enter the study or not, and if so, the degree of stenosis required for inclusion

• whether patients contributed data from both the symptomatic and asymptomatic sides

• the proportion of and total number of patients accounted for in the analysis, and any reports of adverse events due to the tests.

• the method of defining stenosis: NASCET, ECST, or CCA

• study setting

We will record data in Microsoft Excel initially, prior to importing into other packages such as SAS.

Assessment of methodological quality

Two review authors will independently assess the full‐text of each study in the “possible include” category. Discrepancies will be referred to a third author. As abstracts may not give the information necessary to decide whether a study fulfils the inclusion criteria or not, studies will also be excluded at this stage if the full‐text version shows they do not fulfil the inclusion criteria for considering studies for review as outline above. The review authors will use the QUADAS checklist (Whiting 2006) to assess the susceptibility to bias of the studies (Appendix 2), with additional questions on imaging and patient population.

Statistical analysis and data synthesis

Given the adverse effects and cost of intra‐arterial angiography, we need to know whether the less invasive tests can replace the reference test, whether singly or in combination. Reflecting current clinical practice, the combinations of index tests will be DUS followed by another less invasive test (DUS, CT angiography, MR angiography, and contrast enhanced MR angiography).

Providing statistical modelling assumptions are met, the data will be combined using the empirical Bayes hierarchical summary ROC curve method (Macaskill 2004) as this method can be used to produced both ROC curves and point estimates of sensitivity and specificity, and also to investigate the effect of sources of heterogeneity on diagnostic accuracy.

If possible, we will analyse the data from studies where more than one non‐invasive modality has been used on the same patient group, i.e. direct comparison of non‐invasive modalities. In a separate analysis, we will compare diagnostic accuracy using data from studies that used a single non‐invasive test, i.e. make an indirect comparison of diagnostic accuracy.

Investigations of heterogeneity

The investigations are primarily concerned with exploring heterogeneity in sensitivity and specificity as these are the quantities we hope to estimate. Therefore, we will use:

• Forest plots to look for evidence of heterogeneity within sensitivity and within specificity

• ROC plots to look for evidence of a threshold effect and heterogeneity due to differences in accuracy.

• Plots of logit‐transformed sensitivity and specificity as described by Moses et al (Moses 1993) to assess variation in diagnostic odds with change in diagnostic threshold.

Sensitivity analyses

In many centres, ultrasound is used to identify patients with stenosis, and only patients with potentially significant degrees of stenosis are referred for further testing. We will therefore also investigate how screening with prior ultrasound affects diagnostic accuracy as the non‐invasive tests may perform differently in patients who have been shown to have a significant stenosis. We will also investigate the effect of missing data, i.e. where patients have been recruited into the study, but are not included in the final analysis as these may be patients for whom the tests did not work. The analyses will be done by adding covariates to the nonlinear mixed model used in the hierarchical summary ROC curve method.

Appendices

Appendix 1.  Electronic database search strategies

Carotid stenosis Medline strategy

1. carotid stenosis/

2. carotid stenosis.tw.

3. carotid stenoses.tw.

4. carotid artery stenosis.tw.

5. carotid artery stenoses.tw.

6. carotid arteries stenosis.tw.

7. carotid arteries stenoses.tw.

8. (narrow$ adj carotid).tw.

9. carotid artery plaque$.tw.

10. carotid plaque$.tw.

11. (carotid adj2 narrow$).tw.

12. carotid ulcer$.tw.

13. ica.tw.

14. islets of langerhans/

15. immunohistochemistry/

16. calcium channels/

17. 13 not (14 or 15 or 16)

18. or/1‐12,17

19. carotid artery diseases/

20. carotid arteries/

21. carotid artery, common/

22. carotid artery, internal/

23. carotid artery, external/

24. carotid.tw.

25. carotid sinus/

26. or/19‐25

27. stenosis.tw.

28. stenoses.tw.

29. constriction, pathologic/

30. arteriosclerosis/

31. arterial occlusive diseases/

32. regional blood flow/

33. atheroscleros$.tw.

34. blood flow velocity/

35. or/27‐34

36. plaque$1.tw.

37. morphology.tw.

38. heterogenous.tw.

39. homogenous.tw.

40. homogeneity.tw.

41. echolucent.tw.

42. echogenic.tw.

43. echogenicity.tw.

44. hyperechoic.tw.

45. hypoechoic.tw.

46. isoechoic.tw.

47. surface characteristic$.tw.

48. unstable.tw.

49. or/36‐48

50. endarterectomy, carotid/

51. carotid endarterectomy.tw.

52. carotid artery endarterectomy.tw.

53. cea.tw.

54. carcinoembryonic antigen.tw.

55. (central nucleus adj2 amygdala).tw.

56. carcinoembryonic antigen/

57. neoplasm.mp.

58. neoplasms.mp.

59. or/54‐58

60. 53 not 59

61. or/50‐52,60

62. patient selection/

63. patient selection.tw.

64. work‐up.tw.

65. or/62‐64

66. 61 and 65

67. magnetic resonance angiography/

68. mr angiograph$.tw.

69. mr angiogram$.tw.

70. mri angiograph$.tw.

71. mri angiogram$.tw.

72. magnetic resonance angiograph$.tw.

73. magnetic resonance angiogram$.tw.

74. mra.tw.

75. angio mr$1.tw.

76. or/67‐75

77. magnetic resonance imaging/

78. magnetic resonance.tw.

79. mri.tw.

80. mr imaging.tw.

81. mr image$1.tw.

82. mr.tw.

83. mri scan$.tw.

84. mr scan$.tw.

85. nmr.tw.

86. nuclear magnetic resonance, biomolecular/

87. magnetic resonance spectroscopy/

88. 85 not (86 or 87)

89. or/77‐84,88

90. angiography/

91. angiography, digital subtraction/

92. angiograph$.tw.

93. angiogram$.tw.

94. cerebral angiography/

95. or/90‐94

96. 89 and 95

97. doppler.tw.

98. ultrasonics/

99. ultrasonography, doppler/

100. ultrasonography, doppler, duplex/

101. ultrasonography, doppler, pulsed/

102. ultrasonography, doppler, color/

103. ultrasonography, doppler, transcranial/

104. ultrasonography/

105. duplex sonography.tw.

106. duplex sonographic.tw.

107. duplex sonogram$.tw.

108. duplex ultra$.tw.

109. ultrasound.tw.

110. ultrasonogra$.tw.

111. transducers/

112. dus.tw.

113. or/97‐112

114. ct scan$.tw.

115. cat scan$.tw.

116. tomography, x‐ray computed/

117. computer tomograph$.tw.

118. computer tomogram$.tw.

119. tomography/

120. tomography scanners, x‐ray computed/

121. tomography, x‐ray/

122. computer assisted tomograph$.tw.

123. computer assisted tomogram$.tw.

124. ct angiography.tw.

125. cta.tw.

126. tomodensitomet$.tw.

127. 3d‐cta.tw.

128. three dimensional‐ct.tw.

129. multi‐slice.tw.

130. single slice.tw.

131. ct.tw.

132. or/114‐131

133. image enhancement/

134. imaging, three‐dimensional/

135. radiographic image enhancement/

136. transducers/

137. image processing, computer assisted/

138. exp contrast media/

139. or/133‐138

140. di.fs.

141. du.fs.

142. 139 and (140 or 141)

143. intra‐arterial angiograph$.tw.

144. intra‐arterial angiogram$.tw.

145. catheter angiography.tw.

146. catheter angiogram$.tw.

147. catheterization/

148. intra‐arterial catheter$.tw.

149. or/143‐148

150. diagnostic imaging/

151. diagnosis, differential/

152. diagnostic errors/

153. false negative reactions/

154. false positive reactions/

155. observer variation/

156. diagnosis, computer‐assisted/

157. image interpretation, computer‐assisted/

158. radiographic image interpretation, computer‐assisted/

159. "sensitivity and specificity"/

160. sensitivity.tw.

161. specificity.tw.

162. predictive value of tests/

163. roc curve/

164. roc.tw.

165. receiver operating characteristic.tw.

166. receiver operator characteristic.tw.

167. reproducibility of results/

168. diagnosis/

169. "diagnostic techniques and procedures"/

170. pre‐test odds.tw.

171. pretest odds.tw.

172. pre‐test probabilit$.tw.

173. pretest probabilit$.tw.

174. post‐test odds.tw.

175. posttest odds.tw.

176. post test probabilit$.tw.

177. posttest probabilit$.tw.

178. likelihood ratio$.tw.

179. positive predictive value$.tw.

180. negative predictive value$.tw.

181. false negative.tw.

182. false positive.tw.

183. true negative$.tw.

184. true positive$.tw.

185. misdiagnosis.tw.

186. misdiagnoses.tw.

187. or/150‐185

188. carotid stenosis/ra

189. carotid stenosis/us

190. 188 or 189

191. 18 and 76 and 187

192. 26 and 35 and 76 and 187

193. 26 and 49 and 76 and 187

194. 66 and 76 and 187

195. 18 and 96 and 187

196. 26 and 35 and 96 and 187

197. 26 and 49 and 96 and 187

198. 66 and 96 and 187

199. 18 and 113 and 187

200. 26 and 35 and 113 and 187

201. 26 and 49 and 113 and 187

202. 66 and 113 and 187

203. 18 and 132 and 187

204. 26 and 35 and 132 and 187

205. 26 and 49 and 132 and 187

206. 66 and 132 and 187

207. 18 and 142 and 187

208. 26 and 35 and 142 and 187

209. 26 and 49 and 142 and 187

210. 66 and 142 and 187

211. 18 and 149 and 187

212. 26 and 35 and 149 and 187

213. 26 and 49 and 149 and 187

214. 66 and 149 and 187

215. 187 and 190

216. or/191‐215

Carotid stenosis Embase strategy

1. carotid artery obstruction/

2. carotid artery thrombosis/

3. internal carotid artery occlusion/

4. carotid stenosis.tw.

5. carotid stenoses.tw.

6. carotid artery stenosis.tw.

7. carotid artery stenoses.tw.

8. carotid arteries stenosis.tw.

9. carotid arteries stenoses.tw.

10. (narrow$ adj carotid).tw.

11. carotid artery plaque$.tw.

12. carotid plaque$.tw.

13. (carotid adj2 narrow$).tw.

14. or/1‐13

15. carotid artery disease/

16. carotid artery bifurcation/

17. carotid artery bruit/

18. carotid artery/

19. internal carotid artery/

20. carotid sinus/

21. common carotid artery/

22. carotid.tw.

23. or/15‐22

24. stenosis/

25. artery occlusion/

26. blood vessel occlusion/

27. "stenosis, occlusion and obstruction"/

28. occlusion/

29. obstruction/

30. blood flow velocity/

31. ulcer/

32. brain blood flow/

33. artery blood flow/

34. blood flow/

35. artery dissection/

36. stenosis.tw.

37. stenoses.tw.

38. arteriosclerosis/

39. atherosclerosis/

40. or/24‐39

41. carotid artery flow/

42. carotid artery pulse/

43. 41 or 42

44. atherosclerotic plaque/

45. artery intima proliferation/

46. morphology/

47. echolucent.tw.

48. echogenic.tw.

49. echogenicity.tw.

50. hyperechoic.tw.

51. hypoechoic.tw.

52. isoechoic.tw.

53. surface characteristic$.tw.

54. surface property/

55. unstable.tw.

56. heterogenous.tw.

57. homogenous.tw.

58. homogeneity.tw.

59. or/44‐58

60. carotid endarterectomy/

61. carotid endarterectomy.tw.

62. carotid artery endarterectomy.tw.

63. cea.tw.

64. amygdaloid nucleus/

65. carcinoembryonic antigen.mp.

66. (cancer or tumour or tumor or neoplasm).tw.

67. 63 not (64 or 65 or 66)

68. or/60‐62,67

69. preoperative evaluation/

70. treatment indication/

71. patient selection/

72. work‐up.tw.

73. or/69‐72

74. magnetic resonance angiography/

75. magnetic resonance angiograph$.tw.

76. magnetic resonance angiogram$.tw.

77. mr angiograph$.tw.

78. mr angiogram$.tw.

79. mri angiograph$.tw.

80. mri angiogram$.tw.

81. mra.tw.

82. angio mr$1.tw.

83. or/74‐82

84. nuclear magnetic resonance imaging/

85. magnetic resonance.tw.

86. mri.tw.

87. mr scan.tw.

88. mr scan$.tw.

89. mr imaging.tw.

90. mr image$.tw.

91. mr.tw.

92. nuclear magnetic resonance imaging agent/

93. or/84‐92

94. angiography/

95. angiograph$.tw.

96. angiogram$.tw.

97. digital subtraction angiography/

98. brain angiography/

99. or/94‐98

100. ultrasound/

101. real time echography/

102. intravascular ultrasound/

103. color ultrasound flowmetry/

104. doppler flowmetry/

105. doppler flowmeter/

106. doppler echography/

107. echography/

108. ultrasound transducer/

109. ultrasound scanner/

110. transducer/

111. duplex sonograph$.tw.

112. duplex sonogram$.tw.

113. doppler.tw.

114. dus.tw.

115. b scan/

116. duplex sonographic.tw.

117. ultrasound.tw.

118. ultrasonogra$.tw.

119. or/100‐118

120. spiral computer assisted tomography/

121. computer assisted tomography/

122. tomography/

123. ct scan$.tw.

124. cat scan$.tw.

125. cta.tw.

126. 3d‐cta.tw.

127. 3d‐ct.tw.

128. ct.tw.

129. single slice.tw.

130. multi‐slice.tw.

131. tomodensitomet$.tw.

132. ct angiograph$.tw.

133. ct angiogram$.tw.

134. computer tomograph$.tw.

135. computerised tomograph$.tw.

136. computerized tomograph$.tw.

137. computer tomogram$.tw.

138. computerised tomogram$.tw.

139. computerized tomogram$.tw.

140. computed tomography scanner/

141. x‐ray tomograph$.tw.

142. x‐ray tomogram$.tw.

143. computer assisted tomograph$.tw.

144. computer assisted tomogram$.tw.

145. computer assisted impedance tomography/

146. or/120‐145

147. image reconstruction/

148. image processing/

149. image analysis/

150. three dimensional imaging/

151. contrast enhancement/

152. image quality/

153. contrast medium/

154. imaging/

155. image intensifier/

156. image enhancement/

157. or/147‐156

158. blood vessel catheterization/

159. artery catheterization/

160. artery catheter/

161. "catheters and tubes"/

162. catheter/

163. intra‐arterial angiograph$.tw.

164. intra‐arterial angiogram$.tw.

165. catheter angiographic.tw.

166. catheter angiography.tw.

167. catheter angiogram$.tw.

168. balloon catheter/

169. intra‐arterial catheter$.tw.

170. or/158‐169

171. diagnostic value/

172. diagnostic imaging/

173. diagnostic accuracy/

174. "sensitivity and specificity"/

175. receiver operating characteristic/

176. roc curve/

177. sensitivity.tw.

178. specificity.tw.

179. roc.tw.

180. receiver operator.tw.

181. receiver operating.tw.

182. diagnostic error/

183. quantitative diagnosis/

184. qualitative diagnosis/

185. computer assisted diagnosis/

186. diagnostic procedure/

187. diagnostic test/

188. diagnostic approach route/

189. differential diagnosis/

190. false negative$.tw.

191. false positive$.tw.

192. true negative$.tw.

193. true positive$.tw.

194. pre‐test odds.tw.

195. pretest odds.tw.

196. pre‐test probabilit$.tw.

197. pretest probabilit$.tw.

198. post‐test odds.tw.

199. posttest odds.tw.

200. post‐test probabilit$.tw.

201. posttest probabilit$.tw.

202. likelihood ratio$.tw.

203. positive predictive value$.tw.

204. negative predictive value$.tw.

205. diagnosis/

206. misdiagnosis.tw.

207. misdiagnoses.tw.

208. observer variation/

209. artifact reduction/

210. non‐invasive measurement/

211. or/171‐210

212. 14 and 83 and 211

213. 23 and 40 and 83 and 211

214. 43 and 83 and 211

215. 23 and 59 and 83 and 211

216. 68 and 73 and 83 and 211

217. 14 and 93 and 99 and 211

218. 23 and 40 and 93 and 99 and 211

219. 43 and 93 and 99 and 211

220. 23 and 59 and 93 and 99 and 211

221. 68 and 73 and 93 and 99 and 211

222. 14 and 119 and 211

223. 23 and 40 and 119 and 211

224. 43 and 119 and 211

225. 23 and 59 and 119 and 211

226. 68 and 73 and 119 and 211

227. 14 and 146 and 211

228. 23 and 40 and 146 and 211

229. 43 and 146 and 211

230. 23 and 59 and 146 and 211

231. 68 and 73 and 146 and 211

232. 14 and 157 and 211

233. 23 and 40 and 157 and 211

234. 43 and 157 and 211

235. 23 and 59 and 157 and 211

236. 68 and 73 and 157 and 211

237. 14 and 170 and 211

238. 23 and 40 and 170 and 211

239. 43 and 170 and 211

240. 23 and 59 and 170 and 211

241. 68 and 73 and 170 and 211

242. or/212‐241

Appendix 2. Assessment of QUADAS items

Item no.	Item	Assessment
1	Was the spectrum of patients representative of the patients who will receive the test in practice?	Patients who receive the test in practice are those with symptoms of carotid stenosis, i.e. transient ischaemic attack, minor stroke, amaurosis fugax, and retinal occlusion. Patients may or may not have had prior tests for carotid stenosis. If the selection criteria are consistent with the above score as ‘yes’. Studies unable to be scored as ‘yes’ should be excluded.
2	Were the selection criteria clearly described?	In particular, studies should state whether symptoms were an inclusion criteria, and if prior tests were used, what degree of stenosis was used to include or exclude patients.
3	Is the reference standard likely to correctly classify the target condition?	The reference standard must be digital subtraction or cut‐film intra‐arterial angiography.
4	Is the time period between reference standard and index test short enough to be reasonably sure that the target condition did not change between the two tests?	The time period between index and reference tests must be less than six months to avoid discrepancies between the index and reference tests being caused by development of the disease. Score as ‘yes’ if the time is less that six months for all patients. Score as ‘no’ if some patients definitely waited more than six months. Otherwise score as ‘unclear’.
5	Did the whole sample or a random selection of the sample, receive verification using a reference standard of diagnosis?	Investigators should report the reasons for any discrepancies between the number of patients recruited into the study and the number of arteries in the 2x2 table.  If there are discrepancies but no explanation given, score as ‘unclear’. If an explanation is given, and the exclusions are not related to the degree of stenosis, score as ‘yes’, if the exclusions are related, score as ‘no’.
6	Did patients receive the same reference standard regardless of the index test result?	Only one reference standard is acceptable (intra‐arterial angiography) and all other studies should be excluded.
7	Was the reference standard independent of the index test (i.e. the index test did not form part of the reference standard)?	Not applicable. The index tests and reference standard are different procedures.
8	Was the execution of the index test described in sufficient detail to permit replication of the test?	Studies should describe equipment, contrast agent and dose if applicable, and in particular which criteria (NASCET, ECST, or CCA) was used to measure the degree of stenosis. DUS studies should give the velocity criteria.
9	Was the execution of the reference standard described in sufficient detail to permit its replication?	Studies should describe equipment and the number of views taken.
10	Were the index test results interpreted without knowledge of the results of the reference standard?	This is scored ‘yes’ if it is stated that the index test was performed blind to the results of the reference standard or if the index test was performed prior to the reference standard. Note that studies where it is unclear whether the index test was performed blind should be excluded.
11	Were the reference standard results interpreted without knowledge of the results of the index test?	Investigators should state that the reference standard was performed blind to the results of the index test. Otherwise score as ‘no’ or ‘unclear’ as appropriate.
12	Were the same clinical data available when test results were interpreted as would be available when the test is used in practice?	If studies report whether or not the readers knew symptoms, side of symptoms, etc, score ‘yes’ or ‘no’ as appropriate. Otherwise score ‘unclear’.
13	Were uninterpretable /intermediate test results reported?	The number of arteries in the 2x2 table should match the number of patients recruited into the study. If the number of arteries does match the number of patients, or if any discrepancies are explained, score as ‘yes’. If no mention is made of reasons for missing arteries, score as ‘no’, otherwise ‘unclear’.
14	Were withdrawals from the study explained?	If the number of patients contributing to the 2x2 table does not match the number of patients recruited and no explanation is given, score as ‘no’. If the study does not report the number of patients recruited, score as ‘unclear’. Otherwise score as ‘yes’

What's new

Last assessed as up‐to‐date: 7 August 2008.

Date	Event	Description
13 February 2017	Amended	Withdrawn

Contributions of authors

This protocol has been commented on by Prof Constantine Gatsonis and two review authors selected by the Stroke Cochrane Review Group.

Sources of support

Internal sources

• Chief Scientist Office of the Scottish Government Health Directorates, UK.

External sources

• No sources of support supplied

Declarations of interest

None known

Notes

This protocol has been published since 2008 but it has not progressed to the full review. After due consideration, it was agreed by the Cochrane Stroke Group Editorial Board that the protocol be withdrawn from publication.

Withdrawn from publication for reasons stated in the review