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Imaging of critical limb ischemia
Jens, S.
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critical limb ischemia. Boxpress.
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ImagIng of
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Isbn 978-94-6295-116-7
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SJRD kaft.indd 1 05-03-15(w10) 09:14
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Imaging of Critical Limb Ischemia
Sjoerd Jens
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This thesis was prepared at the Department of Radiology,
Academic Medical Center, University of Amsterdam, the
Netherlands.
Copyright 2015 © Sjoerd Jens, Amsterdam, the NetherlandsNo part
of this thesis may be reproduced, stored, or transmitted in any
form or by any means, without prior permission of the author.
Financial support by the Dutch Heart Foundation for the
publication of this thesis is gratefully acknowledged.Printing of
this thesis was financially supported by the Department of
Radiology and Surgery (Academic Medical Center, Amsterdam, the
Netherlands), Intersocks, JR Foundation, Cheng Shin Tire,
Amsterdamsche Football Club, ChipSoft and ABN Amro.
Cover: Aaf Meijer en Thomas DiebenPrinted & Lay Out by:
Proefschriftmaken.nl || Uitgeverij BOXPressPublished by: Uitgeverij
BOXPress, ’s-HertogenboschISBN: 978-94-6295-116-7
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Imaging of Critical Limb Ischemia
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctoraan de Universiteit van
Amsterdamop gezag van de Rector Magnificus
prof. dr. D.C. van den Boomten overstaan van een door het
college voor promoties
ingestelde commissie, in het openbaar te verdedigen in de
Agnietenkapel
op dinsdag 21 april 2015, te 14:00 uur
door
Sjoerd Jensgeboren te Naarden
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Promotiecommissie
Promotores: Prof. dr. J.A. Reekers Prof. dr. D.A.
LegemateCo-promotores: Dr. M.J.W. Koelemay Dr. S. BipatOverige
leden: Prof. dr. N.C. Schaper Prof. dr. R.J. de Haan Prof. dr. M.M.
Levi Prof. dr. J.A.W. Teijink Prof. dr. O.M. van Delden
Faculteit der Geneeskunde
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5
Table of contents
Chapter 1
Introduction and outline of thesis 7
Chapter 2
Diagnostic Performance of Computed Tomography Angiography and
Contrast-Enhanced Magnetic Resonance Angiography in Patients with
Critical Limb Ischaemia and Intermittent Claudication: Systematic
Review and Meta-analysis. Eur Radiol. 2013 Nov;23(11):3104-14.
17
Chapter 3
Outcomes of Infrainguinal Revascularizations with Endovascular
First Strategy in Critical Limb Ischemia. Cardiovasc Intervent
Radiol. Accepted 2014 Aug 12. 39
Chapter 4
Title: Lowering Iodinated Contrast Concentration in
Infrainguinal Endovascular Interventions: a Three-armed Randomized
Controlled Non-inferiority Trial. Submitted 53
Chapter 5
Three-dimensional rotational angiography of the foot in critical
limb ischemia: a new dimension in revascularization strategy.
Cardiovasc Intervent Radiol. 2013 Jun;36(3):797-802. 69
Chapter 6
Randomized trials for endovascular treatment of infrainguinal
arterial disease: systematic review and meta-analysis (Part 1:
Above the knee). Eur J Vasc Endovasc Surg. 2014 May;47(5):524-35.
81
Chapter 7
Randomized trials for endovascular treatment of infrainguinal
arterial disease: systematic review and meta-analysis (Part 2:
Below the knee). Eur J Vasc Endovasc Surg. 2014 May;47(5):536-44.
103
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6
Chapter 8
Perfusion Angiography of the Foot in Patients with Critical Limb
Ischemia: Description of the Technique. Cardiovasc Intervent
Radiol. 2015 Feb;38(1):201-5. 121
Chapter 9
Assessing the Quality of Available Patient Reported Outcome
Measures for Intermittent Claudication: A Systematic Review Using
the COSMIN Checklist. Eur J Vasc Endovasc Surg. Accepted 2015 Jan
22. 131
Chapter 10
Summary, conclusions and implications 163
Chapter 11
Samenvatting, conclusies en implicaties 171
Chapter 12
Dankwoord, list of publications, portfolio, curriculum vitae
179
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7
Introduction
1
CHAPTER 1
Introduction
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8
Chapter 1
Introduction
Critical limb ischemia
Peripheral arterial disease (PAD) is a comprehensive term for
arterial diseases of the extremities. For the legs, PAD can
clinically result in intermittent claudication (IC) and critical
limb ischemia (CLI). In IC, the patient experiences lower extremity
muscle pain induced by activity, e.g. by walking. When the patient
discontinues the activity, the muscle pain is relieved. In CLI, the
patient has a more severe form of PAD, which presents as lower limb
pain at rest, or as the inability of ulcers or gangrene to heal
spontaneously.
Etiology of ischemic foot ulcers
The major cause of PAD is systemic atherosclerosis.1 The most
common risk factors for developing PAD are age, gender, smoking,
diabetes mellitus, hypertension and dyslipidemia.1 In the
literature on treatment of PAD in patients with CLI, patients with
diabetic foot disease are seen as a separate entity. In patients
with atherosclerosis, arterial occlusive disease is the main cause
of sustained ulcers. However, in diabetic foot disease development
and healing of an ulcer is multifactorial.2 The main contributors
to diabetic foot disease are a combination of neuropathy (autonomic
and sensory), atherosclerosis and microangiopathy.2,3 Autonomic
neuropathy causes loss of sweating of the foot, resulting in dry
skin and callus formation, which increases the pressure on local
pressure points. Sensory neuropathy suppresses the pain sensations,
thereby increasing the risk of developing an ulcer. Moreover, when
an ulcer develops, it may remain unnoticed by the patient due to
the sensory neuropathy. After developing an ulcer, arterial blood
supply should be sufficient to facilitate ulcer healing. However,
due to the atherosclerosis and microangiopathy, which are
associated with diabetes foot disease,3 a sufficient blood supply
to the foot cannot be achieved in many patients, resulting in a
non-healing ulcer. When untreated or inadequately treated, the
ulcer can become infected or gangrenous, eventually leading to a
minor or even major amputation.
Arterial status
The arterial status of patients presenting with rest pain or an
ulcer is evaluated in the vascular laboratory by measuring the
ankle blood pressure, toe blood pressure or transcutaneous oxygen
pressure (tcPO
2). The second Trans-Atlantic Inter-Society
Consensus Document on Management of Peripheral Arterial Disease
(TASC II) defined critical ischemia as an ankle pressure of
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9
Introduction
1pressures can be falsely high due to medial arterial
calcifications.5,6 In these patients a toe pressure of < 30 mmHg
was regarded as indicative of critical ischemia. This cutoff should
not be applied that strict, since it was shown recently that a
toe-brachial index is not sensitive for earlier detection of
ischemia in diabetes.7
Anatomic evaluation
For composing an optimal treatment strategy for the patient, the
full arterial tree of the lower limb should be evaluated. At the
vascular laboratory this can be performed using duplex ultrasound
(DUS), which also gives functional information. For the
above-the-knee arteries, DUS has a median sensitivity for detecting
a stenosis of more than 50% of 88%, and a median specificity of
95%.8 In the below-the-knee arteries this is respectively 84% and
93%.8 Although DUS is considered to be operator dependent,
interobserver agreement seems to be comparable to digital
subtraction angiography (DSA), which is considered to be the gold
standard for popliteal and tibial artery assessment.9,10
Other modalities for anatomic evaluation in PAD are computed
tomography angiography (CTA) and magnetic resonance angiography
(MRA), of which MRA can be subdivided into contrast-enhanced MRA
(CE-MRA) and non-CE-MRA. CTA requires the use of iodinated contrast
agents and for CE-MRA, gadolinium-based contrast agents are
necessary. A drawback of CTA is that intravascular use of iodinated
contrast has an increased risk for contrast-induced nephropathy and
allergic reactions,11 and gadolinium-based contrast agents used for
CE-MRA are associated with the development of nephrogenic systemic
fibrosis in patients with chronic renal failure.12 Therefore,
non-CE-MRA such as time-of-flight MRA would be preferred, but for
this imaging modality the sensitivity and specificity is inferior
to CTA and CE-MRA in detecting arterial stenosis more than 50% or
occlusion in PAD. For detecting significant stenoses or occlusions
in the entire arterial tree, non-CE-MRA has a sensitivity and
specificity ranging between 79-94% and 74-92% respectively.13 For
CTA this is respectively 95% (95%-confidence interval; 95%CI,
92%-97%) and 96% (95%CI, 93-97%).14 For CE-MRA the sensitivity and
specificity is respectively 95% (95%CI, 92-96%) and 96% (95%CI,
94-97%).15
The reported diagnostic accuracy of CTA and CE-MRA is based on
studies of patients with predominantly IC, a less advanced stage of
PAD. Therefore it remains unclear whether the accuracy of these
modalities would be the same in patients with CLI, since their
arterial lesions may differ in number, extent and location from
those of patients with IC.16,17 Also the unpredictable flow pattern
and collateral formation in CLI may influence the accuracy. DSA is
traditionally considered the reference standard in many
studies,14,15 but due to its invasive character and risk for
complications this modality is nowadays not indicated anymore for
initial anatomic evaluation.1,18 Depending on local expertise,
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10
Chapter 1
DUS, CTA and CE-MRA are currently the preferred modalities for
assessment of lower extremity arteries in patients with PAD in whom
an intervention is considered.
Treatment
At our institution, the first line treatment of CLI patients is
endovascular revascularization, especially in those with a poor
condition due to comorbidities, unfavorable anatomy for surgery, no
venous material for bypass, or old age. Other patients are
discussed by a multidisciplinary team to reach consensus on whether
an intervention of any kind, i.e. endovascular or surgical
revascularization, or primary amputation, is indicated, or whether
a conservative approach should be applied. At the Academic Medical
Center, endovascular revascularization is performed by an
interventional radiologist. The current strategy to open an
arterial stenosis or occlusion is to perform a balloon angioplasty.
When several attempts of balloon angioplasty provide inadequate
dilatation, or when a flow-limiting dissection occurs, a bail-out
stent may be placed. Whether one should use a bare stent or a
drug-eluting stent is still under debate. If transluminal
recanalization of an occluded artery cannot be established, a
subintimal angioplasty (SA) may be performed.19 In CLI patients,
the 1 year primary patency rate of SA in patients with CLI is
relatively low, i.e. about 64-74% in femoropopliteal and 46-56% in
tibial artery lesions,20 which is inferior compared to an
infrainguinal bypass.21 However, long-term patency in these
patients seems to be of less importance as ulcer healing mainly
takes place within 6-9 months, and any patency after healing is
therefore not essential.22
For tibiopedal endovascular intervention, three strategies can
be applied. The first strategy is to revascularize as many arteries
as possible, since increasing the number of patent arteries after
angioplasty increases the one year limb salvage rate.23 A second
strategy is to revascularize the artery supplying the ulcer area,
according to the angiosome model.24 According to this model, each
tibial artery supplies a specific region in the foot. A limitation
of this model is that the three tibial arteries have communicating
arteries. Since in patients with CLI additional collaterals are
present, it is difficult to determine which artery should be opened
to promote ulcer healing.25 A third strategy would be to assess by
angiography which tibial artery is most suitable to improve ulcer
perfusion, taking into account the arterial pathology and
inter-arterial connections. Currently this assessment may be done
using DSA, but since this technique is two-dimensional, it is hard
to interpret three-dimensional arterial connections.
Outcome assessment
During endovascular intervention the main criterion for success
is whether the stenosis or occlusion has become fully patent with
adequate outflow.22 Postinterventional parameters such as
ankle-brachial index, toe systolic blood pressure and
transcutaneous oxygen pressure26,27 can be used to predict wound
healing.28 However, there is a need for
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11
Introduction
1techniques that not only assess the state of the
macrocirculation, but also the perfusion status of an ischemic
foot.29 Ideally, an instrument is needed that is able to evaluate
the improvement in foot perfusion during the endovascular
intervention. This would allow the interventional radiologist to
immediately know whether the intervention has led to sufficient
increase of perfusion, or whether additional revascularization is
necessary, if possible. The aim of treating patients with CLI is to
achieve wound healing and prevent amputation, and these outcomes
are frequently used in research. However, since patients with CLI
are generally old and frail, they will not always retain ambulation
and independence despite limb salvage. To be able to attend to the
feelings and opinions of the patient, patient-reported outcome
measures (PROMs) are increasingly considered to be important. Two
patient-reported outcomes (PROs) are quality of life and functional
status. Before a PROM can be used in clinical trials and practice,
several domains, i.e. reliability (the extent to which scores for
patients whose disease status has not changed are the same for
repeated measurements), validity (the degree to which an instrument
measures the outcome it intends to measure) and responsiveness (the
ability to detect change over time in the measured outcome) need to
be evaluated. PROMs are a new area of research for PAD and thus
need further evaluation before they can be used to guide
decisions.
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12
Chapter 1
THESIS OUTLINE
This thesis aims to improve diagnostic evaluation, treatment
selection, endovascular intervention, and outcome assessment in
patients with PAD with a focus on CLI. In Chapter 2 we present a
systematic review, evaluating whether CTA or CE-MRA should be
performed in patients with CLI or IC for optimal diagnostic
work-up. In this review DSA is used as a reference standard, and we
indicate which imaging technique is preferred for the different
stages of disease (i.e. CLI or IC). After optimal diagnostic
work-up, a treatment strategy is selected for patients with CLI.
The study reported in Chapter 3 describes the effectiveness of an
endovascular treatment first strategy in patients with poor
condition due to comorbidities, unfavorable anatomy for surgery, no
venous material for bypass or old age. For the remaining patients,
a multidisciplinary team discussed and proposed the optimal
treatment strategy. We evaluate the clinical outcomes one year
after initial treatment in a cohort of patients with CLI, in
relation to the selected treatment strategy. If the patient is
referred for endovascular intervention, the patient will be exposed
to intravascular iodinated contrast. Since this contrast can affect
renal function, we report in Chapter 4 whether the endovascular
procedure can confidently be performed with the use of two lower
iodinated contrast concentrations, comparing 240 and 140 mg
iodine/ml with the standard concentration of 300 mg iodine/ml.
During endovascular treatment, the interventional radiologist
completely relies on the two-dimensional images provided. In
patients with PAD and an ulcer, this condition complicates the
assessment of which tibial artery is predominantly responsible for
the blood supply to the ulcer. Therefore, we report in Chapter 5
whether availability of real-time three-dimensional angiographic
images of the ankle and foot contribute to anatomical
interpretation and endovascular treatment strategy. For the
treatment of arterial stenosis and occlusion, drug-eluting balloons
and drug-eluting stents have become available over the last decade.
To evaluate whether these ‘new’ devices have additional value over
non-drug-eluting balloons and stents, and whether arterial lesions
should primarily be stented, we systematically review the
literature for femoropopliteal lesions, and for tibial lesions.
These reviews are described in Chapter 6 and Chapter 7,
respectively. To be able to directly assess the change in foot
perfusion before and after percutaneous transluminal angioplasty,
we describe a new two-dimensional imaging technique in Chapter 8.
In this pilot study, we report on our first experience with this
technique, and evaluate the change in perfusion before and after
treatment. In the end, the purpose of treating PAD patients is to
establish an optimal clinical outcome, i.e. prevention of
amputation and relief of ischemic rest pain in CLI, and restoring
walking capacity and improving quality of life in IC. To accurately
assess and evaluate the quality of life and functional status in
patients with IC, and
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13
Introduction
1to monitor their change, a valid, reliable and responsive
measurement instrument is needed. In Chapter 9 we present the
results of a systematic review of literature, and give an overview
of the patient-reported outcome measures that are the most suitable
for evaluating quality of life and functional status. Finally, in
Chapter 10 we summarize the main findings of this thesis and
discuss its implications for clinical practice and scientific
research.
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14
Chapter 1
References
1. Norgren L, Hiatt WR, Dormandy JA et al (2007) Inter-Society
Consensus for the Management of Peripheral Arterial Disease (TASC
II). J Vasc Surg 45 Suppl S: S5-67
2. Boulton AJ (2013) The pathway to foot ulceration in diabetes.
Med Clin North Am 97: 775-790
3. Wiernsperger N, Rapin JR (2012) Microvascular diseases: is a
new era coming? Cardiovasc Hematol Agents Med Chem 10: 167-183
4. Carter SA (1992) Ankle and toe systolic pressures comparison
of value and limitations in arterial occlusive disease. Int Angiol
11: 289-297
5. Resnick HE, Foster GL (2005) Prevalence of elevated
ankle-brachial index in the United States 1999 to 2002. Am J Med
118: 676-679
6. Chistiakov DA, Sobenin IA, Orekhov AN, Bobryshev YV (2014)
Mechanisms of medial arterial calcification in diabetes. Curr Pharm
Des 20: 5870-5883
7. Stoekenbroek RM, Ubbink DT, Reekers JA, Koelemay MJ (2014)
Hide and seek: does the toe-brachial index allow for earlier
recognition of peripheral arterial disease in diabetic patients?
Eur J Vasc Endovasc Surg doi: 10.1016/j.ejvs.2014.10.020
8. Collins R, Burch J, Cranny G et al (2007) Duplex
ultrasonography, magnetic resonance angiography, and computed
tomography angiography for diagnosis and assessment of symptomatic,
lower limb peripheral arterial disease: systematic review. BMJ 16:
1257
9. Koelemay MJ, Legemate DA, van Gurp JA, de Vos H, Balm R,
Jacobs MJ (2001) Interobserver variation of colour duplex scanning
of the popliteal, tibial and pedal arteries. Eur J Vasc Endovasc
Surg 21: 160-164
10. Koelemay MJ, Legemate DA, Reekers JA, Koedam NA, Balm R,
Jacobs MJ (2001) Interobserver variation in interpretation of
arteriography and management of severe lower leg arterial disease.
Eur J Vasc Endovasc Surg 21: 417-422
11. Bottinor W, Polkampally P, Jovin I (2013) Adverse reactions
to iodinated contrast media. Int J Angiol 22: 149-154
12. Daftari Besheli L, Aran S, Shaqdan K, Kay J, Abujudeh H
(2014) Current status of nephrogenic systemic fibrosis. Clin Radiol
69: 661-668
13. Collins R, Cranny G, Burch J et al (2007) A systematic
review of duplex ultrasound, magnetic resonance angiography and
computed tomography angiography for the diagnosis and assessment of
symptomatic, lower limb peripheral arterial disease. Health Technol
Assess 11: 1-184
14. Met R, Bipat S, Legemate DA, Reekers JA, Koelemay MJ (2009)
Diagnostic performance of computed tomography angiography in
peripheral arterial disease: a systematic review and meta-analysis.
JAMA 301: 415-424
15. Menke J, Larsen J (2010) Meta-analysis: Accuracy of
contrast-enhanced magnetic resonance angiography for assessing
steno-occlusions in peripheral arterial disease. Ann Intern Med
153: 325-334
16. Ozkan U, Oguzkurt L, Tercan F (2009) Atherosclerotic risk
factors and segmental distribution in symptomatic peripheral artery
disease. J Vasc Interv Radiol 20: 437-441
17. Graziani L, Silvestro A, Bertone V et al (2007) Vascular
involvement in diabetic subjects with ischemic foot ulcer: a new
morphologic categorization of disease severity. Eur J Vasc Endovasc
Surg 33: 453-60
18. Singh H, Cardella JF, Cole PE et al (2003) Quality
improvement guidelines for diagnostic arteriography. J Vasc Interv
Radiol 14: S283-288
19. Reekers JA, Kromhout JG, Jacobs MJ (1994) Percutaneous
intentional extraluminal recanalisation of the femoropopliteal
artery. Eur J Vasc Surg 8: 723-728
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15
Introduction
120. Met R, Van Lienden KP, Koelemay MJ, Bipat S, Legemate DA,
Reekers JA (2008) Subintimal angioplasty
for peripheral arterial occlusive disease: a systematic review.
Cardiovasc Intervent Radiol 31: 687-697
21. Klinkert P, Post PN, Breslau PJ, van Bockel JH (2004)
Saphenous vein versus PTFE for above-knee femoropopliteal bypass. A
review of the literature. Eur J Vasc Endovasc Surg 27: 357-362
22. Reekers JA, Lammer J (2012) Diabetic foot and PAD: the
endovascular approach. Diabetes Metab Res Rev 28 Suppl 1: 36-39
23. Peregrin JH, Koznar B, Kovác J et al (2010) PTA of
infrapopliteal arteries: long-term clinical follow-up and analysis
of factors influencing clinical outcome. Cardiovasc Intervent
Radiol 33: 720-725
24. Alexandrescu VA, Hubermont G, Philips Y et al (2008)
Selective primary angioplasty following an angiosome model of
reperfusion in the treatment of Wagner 1-4 diabetic foot lesions:
practice in a multidisciplinary diabetic limb service. J Endovasc
Ther 15: 580-593
25. Brownrigg JR, Apelqvist J, Bakker K, Schaper NC, Hinchliffe
RJ (2013) Evidence-based management of PAD & the diabetic foot.
Eur J Vasc Endovasc Surg 45: 673-681
26. Ubbink DT, Spincemaille GH, Reneman RS, Jacobs MJ (1999)
Prediction of imminent amputation in patients with
non-reconstructible leg ischemia by means of microcirculatory
investigations. J Vasc Surg 30: 114-121
27. Ubbink DT, Tulevski II, de Graaff JC, Legemate DA, Jacobs MJ
(2000) Optimisation of the non-invasive assessment of critical limb
ischaemia requiring invasive treatment. Eur J Vasc Endovasc Surg
19: 131-137
28. Schaper NC, Andros G, Apelqvist J et al (2012) Specific
guidelines for the diagnosis and treatment of peripheral arterial
disease in a patient with diabetes and ulceration of the foot 2011.
Diabetes Metab Res Rev 28 Suppl 1: 236-237
29. Apelqvist JA, Lepäntalo MJ (2012) The ulcerated leg: when to
revascularize. Diabetes Metab Res Rev 28 Suppl 1: 30-35
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16
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17
Diagnostic Performance of CTA and CE-MRA in CLI and IC:
Systematic Review
2CHAPTER 2
Diagnostic Performance of Computed Tomography Angiography and
Contrast-Enhanced Magnetic Resonance Angiography
in Patients with Critical Limb Ischaemia and Intermittent
Claudication: Systematic Review and Meta-analysis.
Sjoerd Jens, Mark J.W. Koelemay, Jim A. Reekers, Shandra
Bipat
Eur Radiol. 2013 Nov;23(11):3104-14.
Online Supplementary Figures and Tables can be found at URL:
http://www.boxpress.nl/proefschriften/ebooks/sjoerd_jens/
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18
Chapter 2
Abstract
OBJECTIVE: To evaluate the diagnostic performance of computed
tomography angiography (CTA) and contrast-enhanced magnetic
resonance angiography (CE-MRA) in detecting haemodynamically
significant arterial stenosis or occlusion in patients with
critical limb ischaemia (CLI) or intermittent claudication
(IC).
METHODS: Medline and Embase were searched for studies comparing
CTA or CE-MRA with digital subtraction angiography as a reference
standard, including patients with CLI or IC. Outcome measures were
aortotibial arterial stenosis of more than 50 % or occlusion.
Methodological quality of studies was assessed using QUADAS.
RESULTS: Out of 5,693 articles, 12 CTA and 30 CE-MRA studies
were included, respectively evaluating 673 and 1,404 participants.
Summary estimates of sensitivity and specificity were respectively
96 % (95 % CI, 93-98 %) and 95 % (95 % CI, 92-97 %) for CTA, and 93
% (95 % CI, 91-95 %) and 94 % (95 % CI, 93-96 %) for CE-MRA.
Regression analysis showed that the prevalence of CLI in individual
studies was not an independent predictor of sensitivity and
specificity for either technique. Methodological quality of studies
was moderate to good.
CONCLUSION: CTA and CE-MRA are accurate techniques for
evaluating disease severity of aortotibial arteries in patients
with CLI or IC. No significant differences in the diagnostic
performance of the two techniques between patients with CLI and IC
were found.
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19
Diagnostic Performance of CTA and CE-MRA in CLI and IC:
Systematic Review
2
Introduction
Digital subtraction angiography (DSA) is considered the
reference standard for evaluating arterial stenosis or occlusion in
patients with peripheral arterial disease (PAD).1 In current
practice, however, DSA is not used as a diagnostic tool, because of
the invasive character and risk of complications,1,2 and because
meta-analyses have shown that both computed tomography angiography
(CTA)3 and contrast-enhanced magnetic resonance angiography
(CE-MRA)4 are highly accurate non-invasive imaging techniques. Some
studies even suggest that CE-MRA is superior to DSA in visualising
arteries of the lower leg and foot.5,6
Although CTA and CE-MRA are widely used for diagnostic imaging
of PAD patients,7 it is unclear whether these techniques are
sufficiently accurate in patients with critical limb ischaemia
(CLI). Studies included in the meta-analyses of CTA and MRA mainly
comprised patients with intermittent claudication (IC) or even
asymptomatic patients, and only a small number of CLI patients.3,4
It is important, however, to study both groups separately, as CLI
and IC are two different entities. First of all, patients with IC
have a less severe form of PAD with mostly single-level lesions as
opposed to multilevel disease in patients with CLI.8 Moreover,
arterial lesions in IC are located more proximally, i.e. aortoiliac
and femoropopliteal segments,9 whereas lesions in CLI patients are
mainly located in the femoral and tibial arteries, especially in
patients with diabetes or end-stage renal disease.10 As distal
artery diameters are smaller it is likely that they are more
difficult to assess, especially with concomitant proximal disease.
The objective of our systematic review and meta-analysis was to
compare the diagnostic performance of CTA and CE-MRA to detect
haemodynamically significant arterial stenosis or occlusion, with
DSA as the reference standard, in patients with CLI and IC.
Materials and methods
Inclusion criteria and methods of the analysis were specified in
advance in a formal protocol and were based on the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
guidelines.11 The review protocol was not published or
registered.
Literature search
Studies were identified by searching the electronic Medline and
Embase databases on 3 August 2012. The search was limited to
publication dates from January 1995 to present. The search strategy
was developed in collaboration with a clinical librarian. The
strategy was broad and consisted of three components, with search
terms defined for three components: (1) PAD, (2) CTA or CE-MRA and
(3) DSA. Databases
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20
Chapter 2
were searched by combining the search terms of individual
components using ‘OR’ and subsequently combining the three
components using ‘AND’. The searches were checked for completeness
by verifying whether all potentially relevant articles from three
systematic reviews3,4,12 were identified. See Online Supplementary
Tables 1 and 2 for the detailed search strategies.
Study selection
One author (S.J.) first screened titles and abstracts for
eligibility. Articles were excluded if the article was a review,
case report, comment or letter, if no participants had CLI or IC,
or if no CTA or CE-MRA had been performed. The remaining titles and
abstracts were assessed independently by two authors (S.J. and
M.K.) to identify potentially eligible papers.
Eligibility criteria
A score form was developed, which was first pilot-tested on
multiple included studies. The full text of all potentially
eligible articles was retrieved and assessed for eligibility by
three authors. One observer (S.J.), a PhD student with 4 years of
experience in performing systematic reviews, checked all articles.
Two observers (M.K. and S.B.), a vascular surgeon and
epidemiologist, respectively, both with more than 10 years of
experience with performing systematic reviews, checked a subset of
articles. Discrepancies were resolved by discussion. All studies
comparing CTA or CE-MRA with DSA and including 10 or more patients
older than 18 years with CLI or IC were included. Studies including
patients with conditions other than CLI or IC, including
asymptomatic PAD (Fontaine stage I or Rutherford grade 0), were
excluded when outcome measures could not be extracted for patients
with either CLI or IC. The language used in full-text articles was
restricted to English, Spanish, French, German, Italian and Dutch
if translations of articles in other languages could not be
obtained. All reviewers possessed enough language experience to
understand the studies in these languages. Outcome measures had to
be haemodynamically significant stenosis or occlusion of segments
between the abdominal aorta and foot arteries. For studies to be
included in this review it had to be possible to construct
two-by-two contingency tables, i.e. (1) normal or less than 50 %
stenosis and (2) more than 50 % stenosis or occlusion, or
three-by-three contingency tables, i.e. (1) normal or less than 50
% stenosis, (2) more than 50 % stenosis, and (3) occlusion, to
compare CTA or CE-MRA with DSA as a reference standard.
-
21
Diagnostic Performance of CTA and CE-MRA in CLI and IC:
Systematic Review
2
Data extraction
Three observers extracted data from each article, using the
aforementioned score form. One observer (S.J.) checked all
articles. Two observers (M.K. and S.B.) checked a subset of
articles. Discrepancies were resolved by discussion. Data extracted
were characteristics of study design, study participants, type of
imaging and outcome measures, i.e. data for two-by-two or
three-by-three contingency tables for the main and subgroups.
Methodological quality and risk of bias in individual
studies
Methodological quality and potential bias of included studies
were assessed independently by three authors (S.J. and M.K. or
S.B.). We used the Quality Assessment of Diagnostic Accuracy
Studies (QUADAS) tool.13
The QUADAS items scoring the spectrum of patients, assessment of
target condition by DSA, avoidance of differential verification and
incorporation bias were scored as ‘adequate’ in advance in
accordance with our strict selection criteria. Avoidance of
misclassification bias was defined as ‘adequate’ if the time period
between CTA or CE-MRA and DSA was less than 30 days. All items of
methodological quality were scored as adequate (‘yes’), inadequate
(‘no’) or not reported (‘unclear’). Disagreements were resolved by
discussion.
Group analyses
The main groups analysed were the aortotibial segments evaluated
by CTA and CE-MRA. These groups were analysed for the following:
summary estimates of sensitivity and specificity to identify
arterial stenosis more than 50 % or occlusion; whether prevalence
of CLI in the study population was an independent predictor of
logit-transformed sensitivity and specificity; proportions of
correct diagnosis; understaging and overstaging of arterial
segments; interobserver agreement; and publication bias. The
subgroups analysed were the aortopopliteal and tibial segments
evaluated by CTA and CE-MRA. Additional subgroups for CE-MRA were
tibial segments evaluated with a bolus chase or a separate tibial
imaging technique. Subgroups were analysed for summary estimates of
sensitivity and specificity.
Planned methods of analysis
Two-by-two tables were used to calculate summary estimates of
sensitivity and specificity. Data were analysed using a fixed
effects, mixed effects or random effects bivariate statistical
model depending on the statistical inconsistency assessed with the
I2 statistic.14 A random effects model was used if both I2 values
were higher than 25 %, fixed effects model if both I2 values were
lower than or equal to 25 %, and mixed effects model if one of the
two I2 values was lower than or equal to 25 % and the other higher
than 25 %.
-
22
Chapter 2
Differences between summary estimates of the main or subgroups
were analysed using the z test15 and a p-value less than 0.05 was
considered statistically significant. Prevalence of CLI in the
study population was evaluated as an independent predictor of
logit-transformed sensitivity and specificity by linear regression
analysis incorporated in the same bivariate models.15 A p-value
less than 0.05 was considered statistically significant.
Three-by-three tables were used to calculate summary estimates of
correct diagnosis, understaging and overstaging. These data were
obtained using a multivariate approach previously described by
Bipat et al,16 using either a random effects or fixed effects
multivariate approach, depending on the Akaike Information
Criterion (AIC) values. A lower AIC value indicates a better
fit.17
For the contingency tables, calculations of summary estimates
were based on the averaged outcome if a study compared different
imaging techniques of CTA or CE-MRA in the same study population,
or if data were available for multiple observers. To assess the
possibility of publication bias we constructed funnel plots of the
included studies and performed a modified Egger’s linear regression
test.18 The funnel plot was constructed and a linear regression
test was performed by respectively plotting and analysing the
natural logarithm of the diagnostic odds ratio (DOR) per study
against the sample size of the individual studies. To prevent the
DOR becoming infinite, i.e. no false negative or true negative
results, 0.5 would be used instead of zero to calculate the
DOR.19
Bivariate analyses, z test and linear regression analyses were
performed in SAS (version 9.2; SAS Institute, Cary, NC, USA). I2
statistics were calculated using Excel (Microsoft Office 2003;
Microsoft, Redmond, WA, USA). Multivariate analyses of
three-by-three tables were performed in WinBUGS (version 1.4; MRC
Biostatistics Unit, Cambridge, UK). The modified Egger’s linear
regression test was performed using IBM SPSS statistics (version
19.0; IBM, Chicago, IL, USA).
Results
Study selection
Our initial search yielded 3,135 potentially eligible articles
in Medline and 2,558 articles in Embase. In total 5,693 articles
were identified. Removal of 953 duplicates and screening of title
and abstract led to the exclusion of another 4,516 articles. Of the
remaining 224 articles, 182 did not fulfil the eligibility criteria
and were therefore excluded. In total, 42 articles were included in
this review.5,20–60 See Figure 1 for the flow diagram of the
article selection process.
-
23
Diagnostic Performance of CTA and CE-MRA in CLI and IC:
Systematic Review
2
Study characteristics
Of the 42 studies, 12 studies evaluated CTA20–31 and 30
evaluated CE-MRA 5,32–60 compared with DSA. None of the studies
compared both CTA and CE-MRA with DSA.
CTA
Twelve CTA studies were included; 6 were prospective26–31 and 6
were retrospective20-25 studies. In total 673 participants with CLI
or IC were studied; the median sample size was 35 (range, 18–279).
Of 299 participants (44 %) for whom disease status was available,
51 % had CLI and 49 % had IC. The number of slices of the CT
systems studied ranged between 1 and 64 slices. See Table 1 for
detailed CTA study characteristics.
CE-MRA
Thirty CE-MRA studies were included, of which 28 were performed
prospectively.5,32–40,42–45,47–60 In total 1,404 participants with
CLI or IC were studied;
Figure 1. Flow diagram of the article selection process
Abbreviations: CE-MRA, contrast-enhanced magnetic resonance
angiography; CLI, critical limb ischaemia; CTA, computed tomography
angiography; DSA, digital subtraction angiography; IC, intermittent
claudication
-
24
Chapter 2
Tabl
e 1.
Com
pute
d to
mog
raph
y an
giog
raph
y (C
TA) a
nd c
ontr
ast-
enha
nced
mag
neti
c re
sona
nce
angi
ogra
phy
(CE-
MRA
) stu
dy c
hara
cter
isti
cs
CT
A s
tudi
es
Aut
hor
Des
ign
No.
of
pati
ents
(%
men
)A
ge, m
ean
(SD
or
ran
ge),
YFo
ntai
ne s
tage
II
/III
/IV
(%
)C
T s
lices
Segm
ents
(no
. per
pt
)B
ilate
ral
asse
ssm
ent
Foti
adis
201
1 [2
0]R
etro
spec
tive
41(5
6)66
(12
)27
/22/
5164
Aor
to-p
oplit
eal (
35)
Yes
Kau
201
1 [2
1]R
etro
spec
tive
58(6
0)73
(38
-89)
31/2
2/47
2x32
Aor
to-t
ibia
l (35
)Ye
sLi
GC
200
8 [2
2]R
etro
spec
tive
31(N
A)
NA
(51
-90)
NA
/NA
/23
64Fe
mor
o-ti
bial
(6)
No
Cia
200
7 [2
3]R
etro
spec
tive
279(
NA
)59
(38
-82)
NA
16A
orto
-tib
ial (
17)
Yes
Li X
M 2
007
[24]
Ret
rosp
ecti
ve30
(NA
)N
AN
A64
Aor
to-t
ibia
l (24
)Ye
sB
ui 2
005
[25]
Ret
rosp
ecti
ve25
(96)
63 (
10)
56/2
0/24
4A
orto
-tib
ial (
31)
Yes
Will
man
n 20
05 [
26]
Pros
pect
ive
39(6
9)65
(44
-81)
82/1
8/0
16A
orto
-tib
ial (
35)
Yes
Cat
alan
o 20
04 [
27]
Pros
pect
ive
50(7
8)67
(43
-89)
6/48
/46
4A
orto
-tib
ial (
23)
Yes
Mar
tin
2003
[28
]Pr
ospe
ctiv
e41
(NA
)67
(45
-84)
NA
4A
orto
-tib
ial (
35)
Yes
Ofe
r 20
03 [
29]
Pros
pect
ive
18(8
3)64
(50
-79)
78/1
7/6
NA
Aor
to-t
ibia
l (25
)Ye
sPu
ls 2
001
[30]
Pros
pect
ive
31(5
4)53
(38
-75)
97/3
/04
Aor
to-p
oplit
eal (
7)Ye
sR
ieke
r 19
97 [
31]
Pros
pect
ive
30(N
A)
62 (
42-8
5)87
/10/
31
Fem
oro-
popl
itea
l (7)
Yes
CE
-MR
A s
tudi
es
Aut
hor
Des
ign
No.
of
pati
ents
(%
men
)A
ge, m
ean
(SD
or
ran
ge),
YFo
ntai
ne s
tage
II
/III
/IV
(%
)M
R p
roto
col (
Stre
ngth
, Te
sla)
Segm
ents
(no
. per
pt
)B
ilate
ral
asse
ssm
ent
Anz
idei
201
1 [3
2]Pr
ospe
ctiv
e35
(60
)66
(18
)71
/14/
14St
atio
n by
sta
tion
(1.
5)Fe
mor
o-ti
bial
(16
)Ye
sB
ui 2
010
[33]
Pros
pect
ive
333
(69)
64 (
10)
NA
Bol
us-c
hase
(1.
5)A
orto
-ilia
c (7
)Ye
sG
erre
tsen
201
0 [3
4]Pr
ospe
ctiv
e31
(N
A)
NA
84/1
0/6
Stat
ion
by s
tati
on (
1.5)
Aor
to-t
ibia
l (23
)Ye
sW
ang
2010
[35
]Pr
ospe
ctiv
e31
(67
)72
(46
-87)
0/29
/71
Hyb
rid
(1.5
)A
orto
-tib
ial (
32)
Yes
Posc
henr
iede
r 20
09 [
36]
Pros
pect
ive
20 (
70)
67 (
11)
NA
Bol
us-c
hase
(1.
5)Fe
mor
o-ti
bial
(6)
No
Ow
en 2
009
[37]
Pros
pect
ive
30 (
73)
69 (
37-9
0)0/
40/6
0H
ybri
d (1
.5)
Aor
to-t
ibia
l (13
)N
oB
erg
2008
[38
]Pr
ospe
ctiv
e30
(63
)N
A (
43-8
1)60
/30/
10H
ybri
d (3
.0)
Aor
to-t
ibia
l (30
)Ye
sA
ndre
isek
200
7 [3
9]Pr
ospe
ctiv
e31
(74
)67
(43
-81)
84/3
/13
Bol
us-c
hase
+ h
ybri
d (1
.5)
Fem
oro-
tibi
al (
20)
No
Die
hm 2
007
[40]
Pros
pect
ive
10 (
60)
82 (
8)10
0/0/
0B
olus
-cha
se (
1.5
and
3.0)
Fem
oro-
tibi
al (
8)N
oD
euts
chm
ann
2006
[41
]R
etro
spec
tive
38 (
55)
68 (
49-8
4)N
AB
olus
-cha
se (
1.5)
Aor
to-t
ibia
l (N
A)
NA
Gjo
nnae
ss 2
006
[42]
Pros
pect
ive
58 (
62)
NA
(47
-80)
100/
0/0
Bol
us-c
hase
(1.
5)A
orto
-pop
litea
l (15
)Ye
s
-
25
Diagnostic Performance of CTA and CE-MRA in CLI and IC:
Systematic Review
2
Jank
a 20
05 [
43]
Pros
pect
ive
25 (
NA
)N
AN
AH
ybri
d (1
.0)
Aor
to-t
ibia
l (26
)Ye
sLa
peyr
e 20
05 [
44]
Pros
pect
ive
31 (
70)
65 (
35-8
3)0/
0/10
0H
ybri
d (1
.5)
Fem
oro-
tibi
al (
10)
No
Lein
er 2
005
[45]
Pros
pect
ive
152
(65)
62 (
10)
96/4
/0B
olus
-cha
se (
1.5)
Aor
to-p
oplit
eal (
7)Ye
sSc
hmit
t 200
5 [4
6]R
etro
spec
tive
69 (
73)
67 (
10)
54/1
3/33
Stat
ion
by s
tati
on (
1.5)
Tib
ial (
8)N
ode
Vri
es 2
005
[47]
Pros
pect
ive
38 (
71)
63 (
10)
89/8
/3B
olus
-cha
se (
1.5)
Aor
to-t
ibia
l (29
)Ye
sB
ezoo
ijen
2004
[48
]Pr
ospe
ctiv
e15
(86
)66
(52
-77)
80/1
3/7
Bol
us-c
hase
(1.
5)A
orto
-tib
ial (
29)
Yes
Lein
er 2
004
[5]
Pros
pect
ive
23 (
52)
72 (
56-8
6)0/
100/
0B
olus
-cha
se (
1.5)
Aor
to-i
liac
(21)
No
Cro
nber
g 20
03 [
49]
Pros
pect
ive
35 (
45)
78 (
50-9
8)9/
3/89
Hyb
rid
(1.5
)T
ibia
l (13
)N
oH
uber
200
3 [5
0]Pr
ospe
ctiv
e40
(N
A)
61 (
43-7
8)78
/23/
0St
atio
n by
sta
tion
(1.
5)A
orto
-tib
ial (
19)
Yes
Stef
fens
200
3 [5
1]Pr
ospe
ctiv
e50
(58
)65
(35
-86)
NA
Bol
us-c
hase
(1.
5)A
orto
-tib
ial (
19)
Yes
Wyt
tenb
ach
2003
[52
]Pr
ospe
ctiv
e56
(69
)67
(35
-89)
82/1
8/0
Bol
us-c
hase
(1.
5)A
orto
-tib
ial (
NA
)Ye
sLe
nhar
t 200
0 [5
3]Pr
ospe
ctiv
e20
(N
A)
NA
NA
Stat
ion
by s
tati
on (
1.5)
Aor
to-t
ibia
l (21
)Ye
sLu
ndin
200
0 [5
4]Pr
ospe
ctiv
e39
(53
)67
(51
-87)
87/1
0/3
Bol
us-c
hase
(1.
0)A
orto
-ilia
c (7
)Ye
sSu
eyos
hi 2
000
[55]
Pros
pect
ive
13 (
100)
72 (
61-8
7)10
0/0/
0B
olus
-cha
se (
1.5)
Aor
to-i
liac
(8)
Yes
Lenh
art 1
999
[56]
Pros
pect
ive
17 (
NA
)N
AN
AB
olus
-cha
se (
1.5)
Aor
to-t
ibia
l (20
)Ye
sSu
eyos
hi 1
999
[57]
Pros
pect
ive
23 (
86)
68 (
52-8
5)83
/17/
0St
atio
n by
sta
tion
(1.
5)A
orto
-tib
ial (
19)
Yes
Win
tere
r 19
99 [
58]
Pros
pect
ive
76 (
56)
66 (
36-9
6)87
/13/
0B
olus
-cha
se (
1.5)
Aor
to-t
ibia
l (31
)Ye
sLa
issy
199
8 [5
9]Pr
ospe
ctiv
e20
(85
)53
(42
-62)
100/
0/0
Stat
ion
by s
tati
on (
1.0)
Fem
oro-
tibi
al (
26)
Yes
Rof
sky
1997
[60
]Pr
ospe
ctiv
e15
(60
)66
(49
-89)
0/N
A/N
ASt
atio
n by
sta
tion
(1.
5)A
orto
-tib
ial (
21)
NA
Abb
revi
atio
ns: C
T, c
ompu
ted
tom
ogra
phy;
MR
, mag
neti
c re
sona
nce;
NA
, not
ava
ilabl
e; p
t, pa
tien
t; Y,
yea
r
-
26
Chapter 2
the median sample size was 31 (range, 10–333). Of 901 (64 %)
participants for whom disease status was available, 31 % had CLI
and 69 % had IC. The MR system had a magnetic strength of 1.5 Tesla
(T) in 25 studies, 1.0 T in 3, and 3.0 T in 1. One study compared
1.5 T with 3.0 T.40 The MR protocols consisted of a
single-injection bolus chase in 15,5,33,
36,40–42,45,47,48,51,52,54–56,58 multi-injection station-by-station
imaging in 8,32,34,46,50,53,57,59,60 and of a hybrid protocol with
separate imaging of the tibial arteries in 6
studies.35,37,38,43,44,49 One study compared a bolus chase with a
hybrid protocol.39 See Table 1 for detailed CE-MRA study
characteristics.
Methodological quality and risk of bias in individual
studies
Selection criteria were clearly described in 42 % (5/12) for CTA
and 50 % (15/30) for CE-MRA studies. Risk of misclassification bias
was avoided in 42 % of CTA (5/12) and 80 % of CE-MRA studies
(24/30). Risk of partial verification bias was avoided in 50 %
(6/12) of CTA and 77 % (23/30) of CE-MRA studies. Execution of DSA
was clearly described in 58 % (7/12) of CTA and in 43 % (13/30) of
CE-MRA studies. None of the CTA studies and 3 % of the CE-MRA
studies (1/30) clearly had clinical data available during image
interpretation. See Figure 2 for overall methodological quality of
CTA and CE-MRA studies and Online Supplementary Figures 1 and 2 for
the individual methodological quality of the studies.
Figure 2. Methodological quality of CTA and CE-MRA studies used
for meta-analysis.
Abbreviations: CE-MRA, contrast-enhanced magnetic resonance
angiography; CTA, computed tomography angiography; DSA, digital
subtraction angiography
-
27
Diagnostic Performance of CTA and CE-MRA in CLI and IC:
Systematic Review
2
Syntheses of CTA results
Two-by-two contingency tables
Aortotibial segments
Two of the 12 included studies had an additional segment
analysed outside the aortotibial segments, i.e. renal arteries and
dorsal pedal artery.24,29 The summary estimate of sensitivity was
96 % (95 % CI, 93–98 %; I2 = 92 %) and that of specificity was 95 %
(95 % CI, 92–97 %; I2 = 97 %). Of the arterial segments studied by
CTA 1.0 % were non-diagnostic. Regression analysis was possible in
eight studies reporting the disease status of 292 patients (43 % of
the total study population). The prevalence of CLI in these
patients was not a statistically significant independent predictor
of logit-transformed sensitivity (p = 0.77) and specificity (p =
0.65) in the aortotibial segments.
Aortopopliteal segments
Five studies reported the outcome of the image analysis of
aortopopliteal segments.20,21,26,30,31 The summary estimate of
sensitivity was 97 % (95 % CI, 83–100 %; I2 = 86 %) and specificity
was 95 % (95 % CI, 90–98 %; I2 = 86 %). Of the segments studied by
CTA 1.1 % were non-diagnostic.
Tibial segments
Three studies reported the outcome of image analysis of the
tibial arterial segments.20,21,26 The summary estimate of
sensitivity was 95 % (95 % CI, 91–97 %; I2 = 70 %) and specificity
was 91 % (95 % CI, 60–98 %; I2 = 99 %). Of the segments studied by
CTA 1.6 % were non-diagnostic. See Table 2 for the summary
estimates of the sensitivity and specificity of CTA and Online
Supplementary Tables 3–5 for two-by-two contingency tables of CTA
main and subgroups.
Aortopopliteal versus tibial segments
No statistically significant differences were found between the
summary estimates of the sensitivity (P = 0.58) and specificity (P
= 0.52) of aortopopliteal and tibial segments.
Three-by-three contingency tables
Ten studies allowed reconstruction of three-by-three contingency
tables for outcome measures.20,22–25,27–31 CTA correctly diagnosed
segments as normal or stenosis less than 50 %, stenosis more than
50 % and occlusion in respectively 96 % (95 % CI, 94–97 %), 89 %
(95 % CI, 86–92 %) and 94 % (95 % CI, 92–96 %). Stenoses more than
50 % on DSA were understaged by CTA in 7 % (95 % CI, 4–10 %),
whereas 4 % (95 % CI,
-
28
Chapter 2
Tabl
e 2.
Sum
mar
y es
tim
ates
of C
TA a
nd C
E-M
RA
Sum
mar
y es
tim
ates
fro
m t
wo-
by-t
wo
tabl
esTe
chni
que
Segm
ents
No.
of
stud
ies
Non
-dia
gnos
tic
(%)
Sens
itiv
ity
in %
(95
%C
I)Sp
ecifi
city
in %
(95
%C
I)C
TA
aort
o-ti
bial
121.
096
(93
-98)
95 (
92-9
7)ao
rto-
popl
itea
l5
1.1
97 (
83-1
00)
95 (
90-9
8)ti
bial
31.
695
(91
-97)
91 (
60-9
8)C
E-M
RA
aort
o-ti
bial
301.
293
(91
-95)
94 (
93-9
6)ao
rto-
popl
itea
l22
0.2
93 (
88-9
5)95
(94
-96)
tibi
al19
2.1
94 (
92-9
6)93
(90
-96)
tibi
al b
olus
-cha
se*
107.
393
(88
-96)
92 (
89-9
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-
29
Diagnostic Performance of CTA and CE-MRA in CLI and IC:
Systematic Review
2
3–6 %) were overstaged. See Table 2 for the three-by-three
contingency table summary estimates of CTA studies and Online
Supplementary Table 6 for individual study data.
Interobserver agreement
Interobserver agreement of CTA was assessed using ĸ statistics
in four studies, evaluating stenosis grades ranging from two to
five categories.21,25–27 The median ĸ value was 0.80 (range,
0.66–0.93).
Syntheses of CE-MRA results
Two-by-two contingency tables
Aortotibial segments
In 5 out of 30 studies pedal arterial segments were analysed in
combination with aortotibial segments. The summary estimate of
sensitivity was 93 % (95 % CI, 91–95 %; I2 = 87 %) and that of
specificity was 94 % (95 % CI, 93–96 %; I2 = 91 %). Of the segments
studied by CE-MRA 1.2 % were non-diagnostic. Regression analysis
was possible in 23 studies reporting the disease status of 901
patients (64 % of the total study population). Prevalence of CLI in
these patients was not a statistically significant independent
predictor of logit-transformed sensitivity (p = 0.60) and
specificity (p = 0.16).
Aortopopliteal segments
A total of 22 studies reported the outcome of CE-MRA image
analysis compared with DSA.32,33,35–45,47,48,52–56,58,59 The
summary estimate of sensitivity was 93 % (95 % CI, 88–95 %; I2 = 74
%) and that of specificity was 95 % (95 % CI, 94–96 %; I2 = 67 %).
Of the segments studied by CE-MRA 0.2 % were non-diagnostic.
Tibial segments
Outcome of image analyses was available in 19 studies.
32,35–41,43,44,46–49,52,53,56,58,59 Nine of these studies did not
focus their imaging on tibial arteries,36,41,47,48,52,53,56,58,59
i.e. they used a bolus chase technique that started at the aortic
or femoral level, nine studies imaged the calf
separately,32,35,37,38,40,43,44,46,49 and one study analysed the
tibial arteries using both techniques,39 i.e. bolus chase and
separate imaging of tibial arteries. Summary estimates of
sensitivity and specificity of all tibial segments analysed by
CE-MRA were 94 % (95 % CI, 92–96 %; I2 = 66 %) and 93 % (95 % CI,
90–96 %; I2 = 89 %) respectively. CE-MRA was non-diagnostic in 2.1
% of arterial segments.
-
30
Chapter 2
Bolus chase or separate tibial imaging technique for tibial
segments
Tibial segments imaged using the CE-MRA bolus chase technique
starting from the aortic or femoral level had summary estimates of
sensitivity of 93 % (95 % CI, 88–96 %; I2 = 57 %) and specificity
of 92 % (95 % CI, 89–95 %; I2 = 83 %). About 7.3 % of the tibial
segments were non-diagnostic. Imaging of tibial arteries using a
separate tibial imaging technique had summary estimates of
sensitivity of 95 % (95 % CI, 91–97 %; I2 = 72 %) and specificity
of 94 % (88–97 %; I2 = 92 %). Only 1.3 % of these segments were
non-diagnostic. No statistically significant differences were found
between the summary estimates of sensitivity (p = 0.39) and
specificity (p = 0.56) of the bolus chase and separate imaging of
the calf technique. See Table 2 for the summary estimates of
sensitivity and specificity of CE-MRA and Online Supplementary
Tables 7–9 for the two-by-two contingency tables of the CE-MRA main
and subgroups.
Aortopopliteal versus tibial segments
Summary estimates of the sensitivity (p = 0.43) and specificity
(p = 0.25) between the aortopopliteal and tibial segments showed no
statistically significant differences.
Three-by-three contingency tables
Eleven studies reported outcome measures to construct
three-by-three contingency tables.32,43,44,48,51,53,54,56–59 Of the
segments scored by DSA as normal or stenosis less than 50 %,
stenosis more than 50 %, or occluded, 96 % (95 % CI, 94–97 %), 89 %
(95 % CI, 86–92 %) and 92 % (95 % CI, 89–94 %) respectively were
correctly classified by CE-MRA. Of the segments scored as stenosis
more than 50 %, about 6 % (95 % CI, 4–9 %) were understaged, and 4
% (95 % CI, 3–6 %) were overstaged. See Table 2 for three-by-three
contingency table summary estimates of CE-MRA studies and Online
Supplementary Table 6 for individual study data.
Interobserver agreement
Interobserver agreement of CE-MRA was assessed using ĸ
statistics in 16 studies, reporting on 22 MRA techniques,
evaluating stenosis grades ranging from two to six
categories.5,32,34–40,43–45,50–52,59 The median ĸ value was 0.82
(range, 0.60–1.00).
Comparison of CTA versus CE-MRA
Summary estimates of the sensitivity (P = 0.15) and specificity
(P = 0.61) of CTA and CE-MRA of aortotibial segments did not differ
significantly. No statistically significant differences were found
between CTA and CE-MRA for aortopopliteal (sensitivity, p = 0.34;
specificity, p = 0.22) and tibial (sensitivity, p = 0.74;
specificity, p = 0.73) segments.
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31
Diagnostic Performance of CTA and CE-MRA in CLI and IC:
Systematic Review
2
Publication bias for CTA and CE-MRA
Linear regression analyses showed non-significant regression
coefficients for CTA of 6.5 (95 % CI, −16.7 to 29.7; p = 0.55) and
for CE-MRA of −5.4 (95 % CI, −18.1 to 7.3; p = 0.39). The funnel
plots of natural logarithm DOR plotted against the sample size per
study are presented in Online Supplementary Figures 3 and 4.
Discussion
Summary of evidence
Our meta-analyses show that both CTA and CE-MRA are accurate
tools for detecting haemodynamically significant stenoses and
occlusions in aortotibial arterial segments in patients with either
CLI or IC. CTA had a sensitivity and specificity of 96 % (95 % CI,
93–98 %) and 95 % (95 % CI, 92–97 %) respectively, whereas CE-MRA
had a sensitivity of 93 % (95 % CI, 91–95 %) and specificity of 94
% (95 % CI, 93–96 %). Moreover, CTA and CE-MRA can distinguish
confidently between segments with a stenosis more than 50 % and
occlusion, and both have good to excellent interobserver agreement.
The number of non-diagnostic segments was small, i.e. about 1–2 %,
for both CTA and CE-MRA. Diagnostic accuracy did not change
significantly for both CTA and CE-MRA when prevalence of CLI
increased in the study population, or when only tibial arteries
were evaluated. For tibial arteries the summary estimates of CTA
are inaccurate because of the limited data. Bolus chase or separate
imaging of the calf arteries, used for CE-MRA in lower leg
assessment, had similarly high diagnostic accuracy. However,
separate imaging resulted in fewer non-diagnostic tibial arterial
segments. The methodological quality of both CTA and CE-MRA studies
was moderate to good and there were no indications for the presence
of publication bias.
Limitations
An important aim of our study was to estimate the summary
sensitivity and specificity of CTA or CE-MRA for patients with CLI
or IC separately, but this was not possible. It is striking that
disease status was reported for only 58 % of patients in the
included studies, which significantly limits the external validity
of such studies. For CTA, all 12 study cohorts consisted of a mix
of CLI and IC patients. For CE-MRA, four studies reported the
outcomes of patients with solely IC,40,42,55,59 and five studies
patients with CLI only.5,35,37,44,60 We therefore decided to
perform linear regression analyses to study the association between
prevalence of CLI in the inception cohort, and sensitivity and
specificity. Four CTA and seven CE-MRA studies could not be used
for these analyses, as they did not report the prevalence of CLI.
Linear regression analyses showed no significant associations,
meaning that the prevalence of CLI patients in the study may
-
32
Chapter 2
not affect either sensitivity or specificity. However, the
heterogeneity of studies was great, making these analyses less
reliable. Preferably we would also have performed subgroup analyses
of the aortoiliac, femoropopliteal and tibial segments.
Unfortunately, because of poor reporting, such analyses were not
possible and we combined, therefore, the aortoiliac and
femoropopliteal segments into one subgroup, i.e. ‘aortopopliteal’.
The summary estimates of sensitivity and specificity were based on
the diagnostic arterial segments; non-diagnostic arterial segments
were not included in these analyses. Yet, only 1–2 % of the
arterial segments were non-diagnostic for both CTA and CE-MRA. We
believe, therefore, that exclusion of non-diagnostic segments will
not have a major impact on the diagnostic accuracy of CTA and
CE-MRA. Imaging of tibial arteries using a bolus chase technique
had a 7.3 % rate of non-diagnostic segments, as opposed to 1.3 %
with separate imaging of the tibial arteries. Separate imaging of
the tibial arteries would, therefore, be preferred. Specificity may
be overestimated given that most studies analysed both legs,
resulting in around two thirds (72 %) of arterial segments without
haemodynamically significant lesions. Readers of CTA or CE-MRA
images were, therefore, likely to be biased towards scoring a
negative result, i.e. no occlusion or stenosis more than 50 %. Vice
versa, this may have led to an underestimation of sensitivity.
However, overall data and all subgroups showed high sensitivity
values and therefore the underestimation seems to be limited or
even absent. Because of our restrictive selection criteria, several
studies were not included, resulting in the exclusion of
potentially relevant, but also disruptive data. The language
restriction resulted in the exclusion of 13 potentially eligible
articles. These articles concern the Chinese, Japanese or Russian
languages, making translations by computer programmes
difficult.61–73 Other articles were excluded as outcomes for just
CLI or IC patients were not reported separately, but also for
asymptomatic patients or patients with aneurysms. Furthermore,
authors were not contacted and articles were immediately excluded
if two-by-two contingency tables could not be constructed, because
from previous experience it seems that few authors are able to
provide unpublished data. In summary, both computed tomography
angiography and contrast-enhanced magnetic resonance angiography
are accurate techniques in evaluating disease severity of arterial
segments from the aorta to the tibial arteries in patients with
critical limb ischaemia or intermittent claudication. No
significant difference was demonstrated in the diagnostic
performance of computed tomography angiography and
contrast-enhanced magnetic resonance angiography between patients
with these conditions. For tibial arteries a separate imaging
technique by contrast-enhanced magnetic resonance angiography is
preferred. To perform subgroup meta-analyses in the future, studies
should report outcomes separately for patients with critical limb
ischaemia or intermittent claudication, and for the aortoiliac,
femoropopliteal and tibial segments.
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33
Diagnostic Performance of CTA and CE-MRA in CLI and IC:
Systematic Review
2
Acknowledgements
Joost Daams, MA (clinical librarian at Academic Medical Center
Amsterdam, the Netherlands), provided assistance with the study
search. Mr Daams did not receive compensation for his contribution.
The authors have no conflict of interest.
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34
Chapter 2
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Three-dimensional contrast-enhanced MR angiography in the
classification of peripheral arterial occlusive disease. Chin J
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68. Yuan F, Liu Y-S, Long M-M, Yuan B, Gu X, Gao G-F (2006)
Multiposition dynamic contrast enhanced MR angiography in
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69. Volodiukhin MI, Ibatullin MM, Mikhailov IM, Malinovskii MN,
Ignat’ev IM, Bredikhin RA (2005) Combined bolus magnetic resonance
angiography and two-dimensional time-of-flight magnetic
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Chapter 2
resonance angiography in patients with occlusive diseases of
lower limb arteries. Angiol Sosud Khir 11:29–36
70. Saito Y, Noda H, Itabashi Y et al (2004) Table-moving MRA of
the lower extremities in patients with arterial occlusive disease.
Japan J Clin Radiol 49:547–554
71. Zhang L, Jin Z, Xu Z-R (2004) Diagnostic value of magnetic
resonance angiography for diabetic foot and arterial disease of
lower leg. Chin J Clin Rehabil 8:3626–3627
72. Tomihira A, Hino Y, Sugihara M (2002) Stepping table
gadolinium-enhanced three-dimensional MR angiography in arterial
occlusive disease of the pelvic and lower extremity arteries. Japan
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73. Matsumura K, Sato K, Hashida K, Utsumi N, Ishizawa T (2001)
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Outcomes of Infrainguinal Revascularizations with Endovascular
First Strategy in CLI
3CHAPTER 3
Outcomes of Infrainguinal Revascularizations with Endovascular
First Strategy in Critical Limb Ischemia
Sjoerd Jens, Anne P. Conijn, Franceline A. Frans, Marieke B.B.
Nieuwenhuis, Rosemarie Met, Mark J.W. Koelemay, Dink A. Legemate,
Shandra Bipat,
Jim A. Reekers
Cardiovasc Intervent Radiol. 2014 Aug 12. [Epub ahead of
print]
Online Supplementary Figures and Tables can be found at URL:
http://www.boxpress.nl/proefschriften/ebooks/sjoerd_jens/
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40
Chapter 3
Abstract
PURPOSE: This study was designed to study the outcome of
infrainguinal revascularization in patients with critical limb
ischemia (CLI) in an institution with a preference towards
endovascular intervention first in patients with poor condition,
unfavourable anatomy for surgery, no venous material for bypass,
and old age.METHODS: A prospective, observational cohort study was
conducted between May 2007 and May 2010 in patients presenting with
CLI. At baseline, the optimal treatment was selected, i.e.,
endovascular or surgical treatment. In case of uncertainty about
the preferred treatment, a multidisciplinary team (MDT) was
consulted. Primary endpoints were quality of life and functional
status 6 and 12 months after initial intervention, assessed by the
VascuQol and AMC Linear Disability Score questionnaires,
respectively.RESULTS: In total, 113 patients were included; 86 had
an endovascular intervention and 27 had surgery. During follow-up,
41 % underwent an additional ipsilateral revascularisation
procedure. For the total population, and endovascular and surgery
subgroups, the VascuQol sum scores improved after 6 and 12 months
(p < 0.01 for all outcomes) compared with baseline. The
functional status improved (p = 0.043) after 12 months compared
with baseline for the total population. Functional status of the
surgery subgroup improved significantly after 6 (p = 0.031) and 12
(p = 0.044) months, but not that of the endovascular
subgroup.CONCLUSIONS: Overall, the strategy of performing
endovascular treatment first in patients with poor condition,
unfavourable anatomy for surgery, no venous material for bypass,
and old age has comparable or even slightly better results compared
with the BASIL trial and other cohort studies. All vascular groups
should discuss whether their treatment strategy should be directed
at treating CLI patients preferably endovascular first and consider
implementing an MDT to optimize patient outcomes.
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41
Outcomes of Infrainguinal Revascularizations with Endovascular
First Strategy in CLI
3
Introduction
Patients with critical limb ischemia (CLI) suffer from ischemic
rest pain or nonhealing ulcers,1 severely affecting their quality
of life.2 Treatment in these patients is initially directed at
preventing amputation by achieving ulcer healing and at relieving
ischemic rest pain. When treatment is successful, quality of life
is expected to improve significantly.3
The choice of treatment, i.e., endovascular or surgical
revascularization, primary amputation, or conservative treatment,
differs per patient. The BASIL trial randomized patients with CLI
to primary bypass surgery or endovascular balloon angioplasty and
showed less morbidity and costs for balloon angioplasty within the
first 2 years. However, beyond 2 ye